AMERICAN MERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY
Executives from 2005-2006
Journal of the American Osteopathic
President: Ricardo A.A. Miller, Miller, DO President-Elect: Bill V. Way, DO First Vice President: Jay S. Gottlieb, DO Second Vice President: Donald K. Tillman, DO Third Vice President: Marc I. Epstein, DO DO Secretary-Treasurer: Secretary-Treasurer: Jere J. Mammino, DO Immediate Past President: Ronald C. Miller, DO Trustees: David W. Dorton, DO Bradley P. Glick, DO Daniel S. Hurd, DO Jeffrey N. Martin, OF
Faculty of Dermatology
Managing Director: Rebecca Mansfield, MA
Herausgeber Jay S. Gottlieb, Gottlieb, D.O., D.O., F.O.C.O F.O.C.O.O. .Ö. Stanley E. Skopit, D.O., F.A.O.C.D.
Co-Editor James Q. Del Rosso, D.O., D.O., F.A.O.C.D F.A.O.C.D.
Editorial Board Ronald Miller, D.O. Eugene Count, With You, D.O. Evangelos Poulos, MD Stephen Purcell, DO DO. Darrel Rigel, MD. Robert Black, DO DO Andrew Hanly, MD. Michael Scott, DO DO.. Cindy Hoffman, DO. Charles Hughes, DO IT... Bill Way, DO IT. Daniel Hurd, DO Mark Lebwohl, MD Edward Yob, D.O. Jere Mammino, D.O. DOES. Schild M. Wikas, D.O.
AOCD • 1501 E. Illinois • Kirksville, MO 63501 800-449-2623 • FAX: 660-627-2623 www.aocd.org COPYRIGHT AND PERMISSION: Written permission must be obtained from the Journal of the American Osteopathic College of Dermatology for copying or reprint more than half a page of text, tables or figures. Permissions are normally granted after similar approval by the author(s), inclusion of the original source attribution, and payment of $15 per page, table, or figure of material reproduced. Authors who wish to reproduce their own articles are exempted from the permit fee. Permission requests should be directed to JAOCD c/o AOCD PO Box 7525 Kirksville, MO 63501, Copyright 2003 by Journal of the American Osteopathic College of Dermatology
Impressum von: Stoyles Graphics Services, Mason City, IA 50401 Journal of the American Osteopathic College of Dermatology
BAND 5 NUMBER 1
Jornal do American Osteopathic College of Dermatology
CONTENTS Letter from the editors of JAOCD-Verlag .................................... .... .. ....................................... ... .............. ...... ..... ...................... ... ...................... .. .... ....... ....... ....... ....................... ........ .... .. ..... ................ .................... ... .... ....... ....................................... ..... .. .... ............................................5 ... .. 5. Letter from the President President of the AOC AOCD D .................................... . ................................................... ................... ........ ..... ................. ................... .... .... ...................... ....................... ..... ........ ...... ...... .......................... .................. ... .. . ................. ................................ ....... ......... .................6 ............... .....6 Alternaria skin infection in a patient with Waldenstrom's macroglobulinemia ... ...... ......................... ............... Macroglobulinemia.. ......... ...................... .................................... .... ... ...... .... ................................... ........ ....... ...........9 Benjamin E. Adams D.O., Lloyd J. Cleaver D.O., F.A.O.C.D. What are biologics? A review for the non-dermatologist Dermatologist ...... .................................. .. .................................................. .... ............ ... ... .. .......................... ...... ................................ ... ... ...... .......... .......1 .........12 Ty Hanson, D.O., John Hibler, D.O. Capillary hemangiomas mimicking Kaposi's sarcoma: a new classification system ......... System......................... ............................. ...... .................. .... ..............1 ..........14 Erik Austin, D.O., M.P.M.P.H. .H., Bill Bill V.V. Way, D.O., F.A.A.O.C. .O.C.D. D. Reticulated and confluent papillomatosis - case report and literature review................................. .... ... ......... Literature .................................... .... ...... ...................... ...... .... ........ ... ........1 ...18 Darron D. DiGiulio, D.O., Marvin S. Watsky, D.O. Treatment of Lichen Amyloidosis with Narrowband Ultraviolet-B Phototherapy .................................. .. .......... ........... .................. ........... ........... ............ .. ........2 ................ .....23 Sami Abbasi, D.O., Kimball Silverton, D.O., SL Husain Hamzavi, M.D. P.h.D., and Iltefat Hamzavi, M.D. Epithelioid Angiosarcoma vs. Atypical Epithelioid Hemangioma: A Diagnostic Dilemma ........................................ .. .......................... .. .................... .. .........................two .. .... ....25 Theresa Ng, D.O., Schild Wikas, D.O. Erythromelalgia: case report and literature review ........................................ .... .................................................. ............................. ...... .................. .... ................................... ... ...... .. ................................................... ..... ......... ...... ..... ...31 Shannon M. Campbell, MSIV B.S., Dianne Kreptowski, D.O., Cynthia H. Halcin, M.D. Gianotti-Crosti syndrome: a case presentation ........................ .... ................ ........ ............. ............. ................ .......................................... ... .. .. . ................................. ................ ..........................3 . ..............34 Dimitry Palceski, D.O., Sch Schildd d Wi Wikas, kas, D.O., F.A.A.O.C. .O.C.D D Grover' Morbus Grover unilateral ......... ...................... .... . ....... ....................................... ... ......... .... . ................................... .............. .. .. ...... .......................... ........... ... . .... ............................ ...... .............. ..... ..... .................. ....... .... ............ ............3 ...... ...36 Mary K. McGonagle, D.O., Stephen M. Purcell, D.O., Donald J. Adler, D.O. A cautionary tale about Halo Nevi: Nevi: Case Report and Literature Review .................................... .. ....................... ................... ........ .................................. ........ ........ ............................................ ...... .. .... .........3 ................38 Andrew Racette, D.O., Joseph Machuzak, Machuzak, D.O., Stephen Kessler, D.O. , Alissa Floman, B.S., B.S., Crystal Crystal Kunka, Kunka, B.S. Hyperimmunoglobulin Hyperimmunoglobulin in syndrome E ....................... ........... ....... .. ................................... ............... ... ..... ....................... ....... ............... ... ..... ............ ......... ................. .... . .. ....................... ......... ........... ..40 René Bermudez , Bermudez, D.O., Shield Wikas, D.O., Monte Fox, Fox, D.O Laser : Back to Basics ... ............. Basics ...... .... ......................... . ....................................... ....... .. .. ...................... ................. ........ . ... ...................................... ........ . .................................................. ... ...... ..... ... ................................. .. .. .......... ...................4 .............45 Tony Nakhla, DO. , Navid Nami, D.O., Steven Shapi Shapiro, ro, M.D., Layne Nisenbaum, Nisenba um, D.O., F.A. .A.O.C.D. OCD hypertriglyceridemia in eruptive xanthoma, case report and review of the literature .. ........... Hypertriglyceridemia ......................... .. .......... .. ................................4 ... .. ............. .49 David M. Bracciano, D.O., Kimball Kimball Silverton, D.O. Cutis Leukemia - Case Reports and Discussion ........................................ . ..... ..................................... . ....................................... ....... .. .. ...................... ........ ......... . ...................................51 Suzanne Sirota Rozenberg, DO, David Kessler, DO, Marvin Watsky, DO. In-Office Clinical Study Subantimicrobial Dose of Doxycycline in the Treatment of Acne Vulgaris Garis ........................ ....... ............5 ... .............55 Jason A. Barr, D.O., Don A. Anderson, D.O. Dermatological Applications of Negative Pressure Wound Therapy (NPWT): Overview of Technique, Technique, and Mechanisms ..........56 Daniel J. Hansen, D.O., M.B.A. , Steven K. Grekin, D.O., F.A.O.C.D. Imiquimod in the treatment of extramammary Paget's disease .................. ..................... ... ....... ...................... .......... ........ ... ....... ..................... .. ................. .5 . .........58 David M. Bracciano, D.O. , Kimball Kimball Silverton, D.O. Neutrophilic Palisade Granulomatous Granulomatous Dermatitis A Disease Spectrum: Case Report and Literature Review ........63 Carissa Summa, D.O.*, Risa Gorin, D.O., Cindy Hoffman,, D.O., Damian DiCostanzo, M.D. A case of transformation of pemphigus foliaceus transformation into pemphigus vulgaris ........ ................................. ................. ................................ ........ .... .......... ............................ ........ .............. ... ... .....6 ..........66 Michael R. Hohnade Hohnaell D.O., D.O., Bill V.V. way, way, D.O., F.A. .A.O.C.D., O.C.D., Robert Robert J. Lin, BS Pustular Vasculitis: Vasculitis: Case Report and Review of the Literature ...References...................... .... ....................................... ... ........... ................................... . ... ........... ................................... ...... ................. ............ ......6 ........ ..68 Chava Frankl Lustig D.O., Stanley Skopit D.O., F.A.O.C.D. Pyoderma gangrenosum: A case study and an overview of treatment options ........................................ .. ...................... ... ......... .............. .. .................................................. ......... ................... ..................... . ..... ... ...70 Evangeline Perez, D.O. , Marvin S. Watsky, D.O.
BAND 5 NUMBER 1
Jornal do American Osteopathic College of Dermatology
ONTEN TENTS CONTINUED WITH Scleromyxedema: case report …………………… ……………. .... ....................... ........ ……………………… ……………… …. ......................... ...... ................ ... ............ ...... ....... ................ ......... ....... ..... ............. ..75 Jennifer Bucci, D.O., Schild Wikas, D.O., F.A.O.C.D. Surgical beads ........................................ ........ .. ........................................ . ........................................ ........ ... ...................... ................... ... ...... .......... ......................... ........ ....... ................................... ...... .. ... .... ..................................... .. .... .. ..... ...................7 ..........78 Jay S. Gottlieb Gottlieb, 1999 . , D.O., D.O., F.A .A.O .O.C.D .C.D., ., Am Amy y D. Gottl Gottlieb, ieb, PA-C Tungiasis:: A Case Report and Review Tungiasis Review w ………. ... .......... ......................... ............ ............. ........... .......................... ................................................... .... ...................... . ................ ............ ...................... . ....... ...................... ...7 .......79 Lynora Curtis Bassett, D.O., Brad P . Glick, D.O., Les Rosen, M..D. Allergic contact eczema: dermatitis: historical perspective, clinical review and case report ................................ .. .. .. ......... ................................... ..... ......................... ....... .......81 Mary Mary Evers D.O., Susan Susan T. Nedorost M.D., Mount Mount Fox, D.O., F.A. .A.O.C.D. OCD-Diagnosis tik Diagnosis Pearls Pearls-Photos -Photos with dermatoscopy............................... Dermatoscopy ……. ... ........................................ ..... ...... ................................ . ........................................ ........ ... ...................... ................... ... ...... ..........................88 Jay and S.
Gottlieb, D.O., D.O., F.A.A.O.C. .O.C.D., D., Amy D. Gottlieb, PAA-C C
CARTA DO J A O C D E D I T O R S
JAY S. GOTTLIEB, DO
STANLEY E. SKOPIT, D.O.
JAMES Q. DELROSSO, D.O.
This is the 5th edition of the JAOCD. YES OK. We have great interest in our newspaper from various sectors. Many of these questions came from companies wanting to advertise to our members, while other questions came from companies asking how they could get involved with our newspaper. Daily. All of this is exciting and very, very complementary to what we have worked so hard and for so long to achieve. Any industry and any doctor looking at any issue of JAOCD, JAOCD, quickly realizes that we are not just another dermatology journal. With us, everything revolves around the resident doctor of dermatology, the future of dermatology! Dermatology! I'm currently in talks with several publishers interested in working with us to better and broader distribute our magazine. I also talked about outsourcing much of the verification process. Our members are asked to review each other and help take JAOCD to an even more prestigious level. We will continue to strive to make JAOCD a journal that all dermatologists can look forward to receiving on a regular basis. We are committed to maintaining our position as a community newspaper. We will be widely known as a newspaper “for and by residents”. We value pedagogical education for residents. Resident. I plan to add resident members to our Editorial Review Board in the next six months. Months. These members are the future of dermatology and our faculty. I am still amazed at the unwavering support of our extended family, founding sponsors of JAOCD JA OCD. These six companies continue to support our efforts without hesitation or reservation. efforts. We have built a long and mutually beneficial relationship with each of our sponsors. We hope to form an even closer and stronger bond with each of them. Our deepest gratitude goes to Allergan Skin Care, Connetics Corporation, Corporation, Global Pathology Pathology Laboratory Services, Novartis Novartis Pharmaceuticals Corporation, Medicis-The Dermatology Company, and 3M Pharmaceuticals for their continued financial support to keep our journal thriving - successful. Without your support, JAOCD would have remained a dream and never become a reality. For more information about JAOCD, visit www.aocd.org www.aocd.org or email[email protected]Fraternal Regards in Dermatology, Jay S. Jay S. Gott Gottlie Lieb, b, D.O.O., ., F.O.O.C. .CO OO O. (Ch (Editor-in-Chief)) Stanley E. Skopit, D.O., F.A.O.C.D. (Associate Editor) James James Q. Del Rosso, supra, D.O.O.,., F.A. .TO. O.C.D. C.D. (Ass. (Contributor and Editor))
AO OCD DER A
RICHARD MILLER, DO, FAOCD, PRESIDENT Greetings I would like to thank you for the honor of representing you as President of the AOCD in the coming year. AOCD. As a long-time member of the AOCD Executive Committee, I had the opportunity
could be reached. Although we are a relatively small group, we have unlimited potential. As an organization, the AOCD can have a tremendous impact in the future
to observe and participate in many of our college functions. In doing so, I have endeavored to familiarize myself with the requirements that are necessary for the further and successful growth of our faculty.
our profession. Please do not hesitate to contact me at 727-8418505 or email at[email protected]I look forward to hearing from you with your concerns and ideas.
Our faculty is experiencing remarkable growth. Our membership has doubled in the last ten years and will likely double again in the next ten years. As our numbers and therefore our strength increases, we can also expect an increase in corporate commitment and financial support. With this growing number comes a certain level of power. This is evident to the pharmaceutical companies and subsidiary companies that support our specialty. These additional resources will increase the funds available to educate and research residents. Seek. Therefore, it is important to attract all potential members, retain current members and convince future members why AOCD should play an important role in their career. Attracting all potential members to our faculty will ensure our future place in the field of dermatology. Dermatology. My goal is to reach out to those osteopathic dermatologists who have not joined or left our faculty.
Richard A. Miller, D.O., F.O.D. Präsident des American Osteopathic College of Dermatology
Today, as physicians, we are invited to participate in a variety of organizations. The AOCD The AOCD is an organization by and for osteopathic dermatologists and deals exclusively with the issues and issues unique to our profession. It is currently the only dermatological organization capable of certifying our graduate members. It is the driving force that ensures the quality education needed to develop and educate our residents. The biennial scientific seminars are developed exclusively by osteopathic dermatologists and provide a forum for our residents, members and visiting professors to present lectures on various topics. The faculty has developed pathways to certification in Dermatopathology and Mohs Surgery and will be responsible for recertification required in the future. Iship would expect us to retain AOCD members with great satisfaction only when we are able to practice our specialty. Unfortunately, I know there are members and prospective members who may not feel a connection or appreciation for what they have received thus far. far away. They have no motivation to join the organization or share their knowledge or talent. As President of the AOCD, I would like to bring our members back to the original focus of this organization. I ask that you support this organization by volunteering on one of our committees or adding your unique talents that will help improve and improve AOCD. As a group, we have an enormous wealth of knowledge and experience that we need to share. This is our organization and will continue to improve with your contributions. I urge each of you to get involved and contribute in some way to the appreciation of our school. In the past, AOCD has been instrumental in the development of informational brochures (What is an Osteopathic Dermatologist?), posters and marketing campaigns to promote AOCD and our foundation. These past achievements are just a small part of what
For the temporary treatment of moderate to severe glabellar lines in patients aged 18 to 65 years
Reliable aesthetic art tool
BOTOX® Cosmetic is indicated for the temporary improvement of the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in patients aged 18 to 65 years.
Important Safety Information: BOTOX®Cosmetic is contraindicated in the presence of infection at the proposed injection site(s) and in individuals with known hypersensitivity to any component of the formulation. There have been rare reports of adverse events affecting the cardiovascular system. Serious and/or immediate hypersensitivity reactions have rarely been reported. These reactions include anaphylaxis, urticaria, soft tissue edema and dyspnoea.
The most common side effects after the injection are blepharoptosis and nausea. Less common (<3%) (<3%) adverse reactions are facial pain, injection site erythema, paraesthesia, and muscle weakness. There may be an increased risk of serious adverse events in patients with neuromuscular disorders such as ALS, myasthenia gravis or Lambert-Eaton syndrome.
only on prescription
See the next page for a brief summary of full prescribing information. ©2006 Allergan, Inc., Irvine, CA 92612
Trademarks owned by Allergan, Inc.
BOTOX® COSMETIC (Botulinum Toxin Type A) Purified Neurotoxin Complex INDICATIONS AND USE BOTOX® COSMETIC is indicated for the temporary improvement of the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients < 65 years of age Age. Age . was. CONTRAINDICATIONS BOTOX® COSMETIC is contraindicated in the presence of infection at the proposed injection site(s) and in individuals with known hypersensitivity to any component of the formulation.
viability of the embryo. Breastfeeding mothers: It is not known if this medicine is excreted in breast milk. Because many drugs are excreted in breast milk, care should be taken when administering BOTOX® COSMETIC to breastfeeding women. Pediatric use: The use of BOTOX® COSMETIC in children is not recommended. Use in geriatrics The two clinical trials of BOTOX® COSMETIC did not include a sufficient number of subjects aged 65 and over to determine whether they responded differently to younger subjects. However, response rates appear to be higher in patients younger than 65 than in patients 65 and older. (See: CLINICAL STUDIES) There were too few patients (N=3) older than 75 years to allow meaningful comparisons.
WARNINGS and BOTOX BOTOX® and BOTOX® COSMETIC contain the same active ingredient in the same formulation. Therefore, the side effects observed with the use of BOTOX® can also be associated with the use of BOTOX® COSMETIC COSMETIC. Do not exceed the recommended dosage and frequency of use of BOTOX® COSMETIC. The risks resulting from use in higher doses are not known. Hypersensitivity reactions Reactions Serious and/or immediate hypersensitivity reactions have been reported rarely. These reactions include anaphylaxis, urticaria, soft tissue edema and dyspnoea. A fatal case of anaphylaxis has been reported in which lidocaine was used as a diluent and consequently the causative agent cannot be identified with certainty. If such a reaction occurs, further injection of BOTOX® COSMETIC should be discontinued and appropriate medical treatment instituted immediately. Pre-existing neuromuscular neuromuscular disorders Caution should be exercised when administering BOTOX® COSMETIC to individuals with peripheral motor neuropathic disorders (e.g. amyotrophic lateral sclerosis or motor neuropathy) or neuromuscular junction disorders (e.g. myasthenia gravis or Lambert-Eaton syndrome). Patients with neuromuscular disorders may be at increased risk of clinically significant systemic effects, including severe dysphagia and respiratory impairment, from typical doses of BOTOX® COSMETIC. Conditions in which patients have demonstrated extreme sensitivity to the systemic effects of typical clinical doses. In some of these cases, the dysphagia lasted for several months and required the placement of a nasogastric tube. Dysphagia Dysphagia is a commonly reported adverse reaction after treatment with all botulinum toxins in patients with cervical dystonia. In these patients, there have been reports of rare cases of dysphagia severe enough to warrant nasogastric tube insertion. There is also a case report in which a patient developed aspiration pneumonia and died after being diagnosed with dysphagia. Cardiovascular system There have also been rare reports of adverse events affecting the cardiovascular system, including arrhythmia and myocardial infarction, some of which have been fatal, following the administration of BOTOX®. Some of these patients had risk factors, including pre-existing cardiovascular disease. Human Albumin This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it poses an extremely low risk of transmission of viral diseases. There is also a theoretical risk of transmission of Creutzfeldt-Jakob Disease (CJD).
SIDE EFFECTS REACTIONS General: ® and BOTOX BOTOX and BOTOX® COSMETIC contain the same active ingredient in the same formulation. Therefore, the side effects observed with the use of BOTOX® can also be associated with the use of BOTOX® COSMETIC COSMETIC. , dysphagia, pneumonia,
is considered extremely remote. No cases of transmission of viral diseases or CJD have been identified for albumin.
Blepharoptosis was greater in the BOTOX® COSMETIC-treated arm than in the placebo arm (3% vs. 0). In the open-label repeat injection study, blepharoptosis was reported in 2% (8/373) of patients in the first treatment cycle and 1% (4/343) of patients in the second treatment cycle. Adverse events of any type were reported in a total of 49% (183/373) of study participants. The most commonly reported adverse events in the open-label study included respiratory infections, headache, influenza-like illness, blepharoptosis, pain and nausea. Because clinical trials are conducted under a wide variety of conditions, the rates of adverse reactions observed in clinical trials of one drug cannot be directly compared to rates in clinical trials of another drug and may not predict rates observed in the real world . TABLE 4.
PRECAUTIONS General: The safe and effective use of BOTOX® COSMETIC depends on proper storage of the product, proper dose selection, and proper reconstitution and administration techniques. Physicians administering BOTOX® COSMETIC should understand the relevant neuromuscular and/or orbital anatomy of the affected area, as well as any anatomical changes due to previous surgical procedures, and avoid injections into vulnerable anatomical areas. Caution should be exercised when using BOTOX if treatment with BOTOX® COSMETIC is administered in the presence of inflammation at the planned injection site(s) or in the event of excessive weakness or atrophy of the target muscle(s). Decreased blinking of BOTOX® COSMETIC injection into the orbicularis muscle can lead to corneal exposure, exposure, persistent epithelial defect and corneal ulceration, especially in patients with VII nerve diseases. There was one case of corneal perforation in an aphakic eye when BOTOX® was used to treat blepharospasm, which necessitated a corneal transplant due to this effect. Careful testing of corneal sensation in previously operated eyes, avoidance of injections into the lower eyelid area to avoid ectropion, and vigorous treatment of any epithelial defects should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closing the eye with an eye patch or other means. Inducing paralysis in one or more eye muscles can result in disorientation, double vision, or backwards pointing. Covering the affected eye can relieve these symptoms. Caution should be exercised when treatment with BOTOX® COSMETIC is used in patients with inflammatory skin conditions at the injection site, marked facial asymmetry, ptosis, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin, or the inability to substantially reduce glabellar laxity. Lines that physically separate them, as these patients were excluded from the Phase 3 safety and efficacy studies.Needle-associated pain and/or anxiety may result in vasovagal reactions (including, for
and/or other significant weakness. There have also been rare reports of adverse events affecting the cardiovascular system, including arrhythmia and myocardial infarction, some of which have been fatal. Some of these patients had risk factors, including pre-existing cardiovascular disease. (See: WARNINGS). New attacks or recurrent attacks have also been reported, usually in patients predisposed to these events. The exact association of these events with botulinum toxin injection has not been established. In addition, acute angle-closure glaucoma was reported one day after receiving a botulinum toxin injection for blepharospasm, which recovered four months later after laser iridotomy and trabeculectomy. Focal facial nerve palsy, syncope and exacerbation of myasthenia gravis have also been reported after treatment of blepharospasm. Generally, adverse events occur within the first week after a BOTOX® COSMETIC injection and, while generally transient, may last for several months or more. Local pain, infection, inflammation, tenderness, swelling, erythema and/or bleeding/bruising may be associated with the injection. Glabellar lines In clinical trials with BOTOX® COSMETIC, the most frequently reported side effects after the injection of BOTOX® COSMETIC were headache*, respiratory tract infection*, influenza-like syndrome*, blepharoptosis and nausea. Less common adverse reactions (<3%) were facial pain, injection site erythema*, paraesthesia* and muscle weakness. Although local weakness of the injected muscle(s) is representative of the expected pharmacological effect of botulinum toxin, weakness of adjacent muscles may occur as a result of spread of the toxin. These events are believed to be injection related and occurred within the first week. The events were generally transient but could last for several months or more. (*Incidence not different from placebo) The data described in Table 4 reflect the exposure to BOTOX® COSMETIC in 405 subjects between the ages of 18 and 75 years included in the randomized, placebo-controlled clinical trials evaluating the use of BOTOX® COSMETIC for Improvement in health has been studied the appearance of glabellar lines (see: CLINICAL STUDIES). All-cause adverse events were reported in 44% of patients treated with BOTOX® COSMETIC and 42% of patients treated with placebo. The frequency of
Percentage of patients reporting placebo adverse events (N=130) %
Body as a whole facial pain
Skin and appendages Skin stiffness
Special sense blepharoptosis
Musculoskeletal muscle weakness
digestive system nausea dyspepsia dental disease
The injection intervals of BOTOX COSMETIC should not be more frequent than every three months and should be carried out with the smallest amount (see side effects, immunogenicity). Information for Patients Patients or caregivers should be instructed to seek immediate medical attention if they experience breathing, speech, or swallowing difficulties. Drug interactions Concomitant administration of BOTOX® COSMETIC and aminoglycosides1 or other agents that impair neuromuscular transmission (e.g. curare-type non-depolarizing blockers, lincosamides, polymyxins, quinidine, magnesium sulfate, anticholinesterases, succinylcholine chloride) should be carried out with caution . since the effect of the toxin can be potentiated. The effect of administration of different botulinum neurotoxin serotypes at the same time or several months apart is unknown. Excessive neuromuscular weakness can be made worse by administration of another botulinum toxin before the effects of a previously administered botulinum toxin wear off. Pregnancy: pregnancy category C The use of BOTOX® COSMETIC during pregnancy is not recommended. There are no adequate and well-controlled studies on BOTOX® COSMETIC in pregnant women. When pregnant rats and mice were injected intramuscularly during organogenesis, the developmental NOEL (No Observed Effect Level) of BOTOX® COSMETIC was 4 U/kg. Higher doses (8 or 16 U/kg) have been associated with a decrease in fetal body weight and/or a delay in ossification. In a dose-ranging study in rabbits, daily injection of 0.125 U/kg/day (days 6 to 18 of gestation) and 2 U/kg/day (days 6 to 13 of gestation) resulted in severe maternal toxicity, abortions and/or fetal malformations. Higher doses resulted in the death of the mothers. The rabbit seems to be a very sensitive species to BOTOX® COSMETIC COSMETIC. If the patient becomes pregnant following administration of this medicinal product, she should be apprised of the potential risks, including miscarriage or fetal malformations, observed in rabbits. Carcinogenesis, mutagenesis, impairment of fertility No long-term animal studies have been conducted to evaluate the carcinogenic potential of BOTOX® COSMETIC COSMETIC. The reproductive NOEL after intramuscular injection of 0, 4, 8 and 16 U/kg was 4 U/kg in male rats and 8 U/kg in female rats. Higher doses were associated with a dose-dependent reduction in fertility in male rats (where limb weakness resulted in an inability to mate) and testicular atrophy or an altered oestrous cycle in female rats. There were no side effects
BOTOX® Cosmetics (N=405) %
Events of adverse events by body system
Adverse events reported more frequently (>1%) in the BOTOX® COSMETIC group compared to the placebo group Biological activity of the toxin. The rate of formation of neutralizing antibodies in patients receiving BOTOX® COSMETIC has not been well studied. Critical factors for neutralizing antibody formation have not been well characterized. Results from some studies suggest that botulinum toxin injections at shorter intervals or in higher doses may result in a higher incidence of antibody formation. The potential for antibody formation can be minimized by injecting the lowest effective dose with as long an interval between injections as possible. Rx Only®
Trademarks owned by Allergan, Inc. Based on Package Insert 71711US13S revised January 2005. Manufactured by: Allergan Pharmaceuticals Ireland, a subsidiary of: Allergan, Inc., 2525 Dupont Dr., Dr., Irvine, CA 92612
Reference: 1. Wang YC, Burr DH, Korthals GJ, Sugiyama H. Acute toxicity of aminoglycoside antibiotics as an aid in the detection of botulism. Appl Environ Microbiol 1984; 48:951-955.
Alternaria skin infection in a patient with Waldenstrom Waldenstrom macroglobulinemia Benjamin E Adams D.O.*, Lloyd J. Cleaver D.O., F.A.O.C.D.** *2nd Year Dermatology Resident, Northeast Regional Medical Center, Kirksville, Missouri **Department Program Director de Dermatologia Dermatology, Northeast Regional Medical Center, Kirksville, Missouri SUMMARY The following report is a case of skin lesions in an 82-year-old man with a history of Waldenstrom's macroglobulinemia and hypogammaglobulinemia. hypogammaglobulinemia. Initially, the patient presented with a lump in the left foot, left foot, and then subcutaneous lumps in the thigh. was treated with oral tissue culture in isolation, and organisms of organisms were seen histologically at both sites. The correct patient was Alternaria, later itraconazole and surgical excision for fungi.
An 82-year-old white male presented to the dermatology clinic with a 1-month-old non-healing left foot wound. The patient denied local trauma to the area or unusual exposure. the
basis by your oncologist. He had completed a fludarabine course two years previously and was currently undergoing IVIG treatment. On examination, a reddish lump measuring 1.3 x 1.1 cm at the base of the fifth toe of the left foot was slightly ulcerated (Fig. 1). Due to the rapid growth and clinical appearance of the lesion, an excisional biopsy was performed. The differential diagnosis included: adnexal tumor, basal cell carcinoma, squamous cell carcinoma, dermatofibroma, dermatofibrosarcoma protuberans and foreign body reaction. Histology showed an ulcerated lesion with dense underlying proliferation of multinucleated giant cell histiocytes with mixed acute and chronic inflammation (Fig. 2). Silver and silver methenamine staining revealed fungal elements including broad septate hyphae (Fig. 3). Once a diagnosis of deep fungal infection was made, the patient began oral therapy with terbinafine; However, he was unable to continue treatment because of hives and desquamation of the palms after the start of therapeutic therapy. The lump recurred in the left foot and a core biopsy was performed and sent for culture and histology. large number of fungal elements with branched septate hyphae mixed with an inflammatory infiltrate. infiltrate. The culture isolated one species of Alternariaa. The patient was Alternari and then began pulse dosing of oral itraconazole 200 mg daily seven days a month for four months. Subsequently, one month after the first pre-subsequence for the left foot lump, the patient developed two subcutaneous lumps on the right lower leg. The largest of these nodules measured 1.8 x 1.8 cm. The nodules were insensitive to palpation and had a soft rubbery consistency. The largest of these nodules was excised and cultured positive for an Alternaria species. Histology showed necrotic granulomas with neutrophilic infiltrates. A methenamine silver strain was also uncovered
The patient had a history of Waldenstrom's macroglobulinemia and hypogammaglobulinemia and was monitored regularly
septate The branching hyphae with tuberous ends. the patient had no lymphadenopathy lymphadenopathy or other systemic complaints such as febrile fever, uh,
Summary: A case of skin change is presented in an 82-year-old man with a history of Waldenstrom's macroglobulinemia and hypogammoglobulinemia. inemia. The patient initially presented with a lump on the left foot and then subcutaneous lumps on the right thigh. Leg. Alternaria was isolated from tissue culture and fungal organisms were seen histologically at both sites. The patient was subsequently treated with oral itraconazole and surgical excision.
Alternaria species are pigmented filamentous fungi (also known as dematia or phaeoids) that are known soil saprophytes and plant pathogens that rarely cause infection in humans. They are characterized by the presence of olive-brown or black pigment in the cell wall and macroconidia with muriform septation. The genus Alternaria is distributed worldwide and is commonly isolated from soil, air, and plants. This species of fungus can often be a contaminant and is a rare cause of human disease. The clinical spectrum of diseases caused by Alternaria includes the following: hypersensitivity pneumonitis, granulomatous lung disease, bronchial asthma, sinusitis with and without osteomyelitis, allergic sinusitis and rhinitis, keratitis, peritonitis, and cutaneous and subcutaneous deep tissue infection. Alternaria infections are more common in immunocompromised or transplant recipients and are often secondary to exogenous inoculation of a traumatic event.2
Figure 1 Lesion at the base of the 5th toe of the left foot.
Figure 2 Proliferation of histiocytes with multinucleated giant cells in mixed acute and chronic inflammation. H&E 200X
tiredness or weakness. Due to the patient's immune status and multiple foci of infection, an infectiologist was consulted. The patient was then treated with itraconazole 200 mg orally daily for six months. In addition, the remaining node on the patient's right thigh was excised and was also positive for Alternaria. the patient is
ALTERNA CUTANEOUS INFECTION IN A PATIENT WITH MACROGLOBULINEMIA WALDENSTRÖM
Figure 3 Fungal elements including broad septate hyphae. 400X methenamine silver stain
is currently in her third month of treatment with itraconazole and has shown clinical improvement at the excision sites. In addition, the patient did not develop new nodules.
Discussion: The name Phaeohyphomycois indicates a heterogeneous group of rare fungal diseases caused by Dematiacean fungi. Alternaria is part of a group of closely related genera of fungi in these infections. Infections30 . Although more than 80 Alternaria species are implicated, only 8 have been implicated in human infections. The species most frequently observed in human diseases are A. alternata, A. tenuissima, A. chartarum, A. longipes, A. infectoria, A. chlamydospora, A. stemphyloides and A. dianthicola. Most Alternaria infections are cutaneous in nature and are usually associated with an immunocompromised host. With regard to the pathogenesis of cutaneous alternariasis, two possible routes of infection can be distinguished. In the exogeexogenous variant, the condition arises from traumatic inoculation of fungal elements (e.g., after injury by a plant thorn) or develops after colonization of pathologically altered skin. In the endogenous variant, inhalation of fungal conidia and subsequent systemic dissemination eventually leads to secondary skin involvement. Some authors have also defined "dermatopathic" cutaneous alternation, which consists of secondary colonization of a pre-existing lesion by alternaria, such as B. steroid treated facial eczema. The development of the disease appears to be related to spontaneous or induced host immunodeficiency. Examples of immunocompromised conditions associated with Alternaria infection include: solid organ transplant recipients, Cushing's syndrome, patients receiving chemotherapy for lymphoma, myeloproliferative syndrome,9 bullous diseases and AIDS.
In the reported cases, oral steroids play the most important pathogenic role in the occurrence of cutaneous alternariasis. It has been postulated that corticosteroid-induced skin fragility may increase the risk of percutaneous environmental inoculation. As the population of immunocompromised patients grows, clinicians are likely to encounter more cases of cutaneous alternariasis. Therefore, the recognition of Alternaria as a potential opportunistic pathogen is important for the differential diagnosis of dermatological lesions. the
Skillful is not the primary causative agent. Alternaria shows rapid growth on Sabourand Dextrose Agar and colonies usually appear within 5 days. Forms grey-grey to grey-green colonies that later turn black, usually with a white border. The treatment of cutaneous alternariasis is not well standardized and is currently the subject of controversy. It is recommended to reduce immunosuppression whenever possible and to surgically remove localized lesions.
The clinical manifestations of skin change are very diverse. Lesions may appear as nonhealing flat-based ulcers and develop from nodules, noninflammatory subcutaneous cysts, verrucous lesions, or erythematous, confluent, scaly patches resembling eczema. Lesions usually develop on exposed areas or bony prominences, such as the feet, knees, backs of the hands, and occasionally the face. The most common presentation is a single asymptomatic reddish-brown to purple papule, nodule, or plaque, which may subsequently ulcerate. Histologically, variations in host response and the morphological appearance of hyphae in tissue create the potential for diagnostic confusion. A mixed inflammatory dermal infiltrate (neutrophils, lymphocytes, and plasma cells) is typically seen with or without giant cells and histiocytes. Microabscesses or well-formed granulomas may also be present. A recent article concluded that suppurative granulomas are more common in lesions lasting longer than three months. 2 The epidermis may be unaffected or may show hyperplasia, neutrophilic infiltration with microabscess formation, erosion, or ulceration. Fungal morphology is pleomorphic, ranging from spherical cells to contorted hyphae with variable frequency of septation and branching. The observation of large, round to oval, thick-walled retractable features
gradual reduction in oral corticosteroids, even without interrupting administration of other chemotherapy drugs. 20 Alternaria species are susceptible to oral itraconazole, amphotericin B,15 fluconazole,12 miconazole, terbinafine, and ketoconazole;10 however, the degree of susceptibility varies. Resistance to flucytocin and griseofulvin has been observed. 15 Recent reports have found itraconazole to be as effective as, if not superior to, amphotericin B. Given itraconazole's lower toxicity and ease of administration, some authors consider it the drug of first choice for alternariasis and other pheohyphomycoses. Fomycosis s. Several months of therapy are often required, and it is recommended to treat for several months after clinical resolution. Even after prolonged treatment, relapses are common, so long-term clinical follow-up is advisable.
The presence of structures within histiocytes or neutrophils is a characteristic histopathologic feature of a fungal infection and a morphologic feature that can provide a clue to the diagnosis.2 Due to the ubiquitous nature of Alternaria in the environment, the diagnosis requires the combination of a positive tissue culture, more histological Detection of fungal elements and clinical correlation to distinguish between contamination, colonization and pathogenicity.20 Alternaria is not only easy to isolate from the environment, but is also commonly cultured on the skin surface. Botticcher found that Alternaria spp. comprised 15% of all fungi cultured from over 2,000 specimens in superficial patients, mostly with cases of mycosis. However, would alternate, sp. was not the only isolated fungus and probably
Here we report a case of skin lesions in a patient with Waldenstrom's disease. Waldenstrom's macroglobulinemia is a marked clinicopathological disorder characterized by monoclonal lymphoplasmic neoplasia accompanied by an increase in serum monoclonal immunoglobulin M.M. immunoglobulin and purine nucleoside analogue-induced T-cell dysfunction. Our patient had been treated with the nucleoside analogue fludarabine two years previously and it is not known if this contributed to his Alternaria infection. We hope that prolonged treatment with itraconazole combined with surgical excision will result in resolution of this infection. References 1 Anaissie EJ, Bodey GP, GP, Pinaldi MG. Emerging fungal pathogens, Eur J Clin Microbiol Infect Dis 1989:8:323-30. 2 Gilaberte M, Bartralot R, Torres JM, Reus FS, Rodriguez V, Alomar A, Pujol RM. Cutaneous alternariasis in transplant recipients: clinicopathologic review of 9 cases, J Am Acad Dermatol 2005:52(4):653-9. 3 De Bievre C. Les Alternaria pathogenes purL; homme: mycologie epidemiologique. J Mycol Med 1991:1:50-8. 4 Wiest PM, Wiese K, Jacobs Jacobs MR, et al. Alternaria infection in a patient with acquired immunodeficiency syndrome: a case
Report and Review of Invasive Alternaria Infections, Rev Infect Dis 1987:9:799-803. 5 McGinnis MR, Hilger AE. Black fungus infections. Arch Dermatol 1987:123:1300-2. 6 Lyke KE, Miller NS, Towne L, Merz WG. A case of ulcerative cutaneous alternariasis: Rare association with diabetes mellitus and unusual treatment failure with itraconazole, Treatment, Clin Infec Diseases 2001:32:1178-87. 7 Male O, Pehamberger H. Secondary skin mycoses caused by Alternaria species. Dermatologist 1986:37:94-101. 8 Repiso T, Martin N, Huguet P, et al. Cutaneous alternariasis in a liver transplant patient. Clin Infect Dis 1993:16:7291993:16:729730. 9 Viviani MA, Tortorano AM, Laria G, et al. Two new cases of cutaneous alternariasis with literature review. Mycopathologica 1986:96:3-12. 10 Guerin V, Barbaud A, Duquenne M et al. Cushing's disease and cutaneous alternariasis, Arch Intern Med 1991:151:1865-8.
a patient with acquired immunodeficiency syndrome: case report and review of invasive alternaria infections. Rev. of Infect Dis 1987:4:799-803. 14 Machet L, Jan V, Machet MC, et al. Cutaneous alternariasis: role of corticosteroid-induced skin fragility. Dermatology 1996:193:342-344. 15 Iwatsu T. Cutaneous alternariasis. Arch Dermatol 1988:124:1822-25. 16 Weitzman I. Saprophytic molds as causative agents of cutaneous and subcutaneous infections in immunocompromised hosts. Arch Dermatol 1986:122:1161-1168. 17 Palencarova E, Jesenska Z, Plank L, et al. Phaeohyphomycosis caused by species of Alternaria and Phaeosclera dematioides Sigler, Tsuneda and Carmichael. Clin Exp Dermatol 1995:20:419-22 18 Pec J, Palencarova E, Plank L, et al. Phaeohyphomycosis by Alternaria spp. And Phaeosclera dematioides: a histopathological study. Mycosis 1996:39:217-21. 19 Romano C, Valenti L, Miracco C et al. Two causes of cuts
11 Rovira Martin-Ortega E, et al. Alternaria infection in M, a patient of Martin P receiving chemotherapy for lymphoma. Acta Hematol 1990:84:98-100. 12 Machet MC, Stephanov E, Esthve E, et al. Cutaneous alternaria occurring in the course of treated pemphigus: approximately 2 cases. Ann Pathol 1994:14:186-191. 13 Weist PM, Weis K, Jacobs MR, et al. Alternaria infection
Phaeohyphomycosis neosa caused by Alternaria alternata and Alternaria tenuissima. Mycopathologia 1197:137:65-74. 20 Junkins JM, Beveridge RA, Friedman KJ, et al. Unusual fungal infection in an immunocompromised cancer patient. Arch Dermatol 1988:124:1421-6. 21 Bötticher WW. would alternate as a possible human pathogen. Sabouraudia. 1966:4:256-258.
22 Romero ML, Siddiqui AH. Diagnosis of cutaneous alternariasis. Clinical Infectious Disease 2000:30:174-5. 23 Machet L, Machet MC, Maillot F, F, et al. Cutaneous alternariasis in a patient treated with a corticosteroid enema. Axta Derm Venerol. 1995:75:328-9. 24 Lanigan SW. Alternaria skin infection treated with itraconazole. Br J Dermatol. 1992:127:39-40. 25 De Moragas JM, Prats G, Verger G. Cutaneous alternariasis treated with miconazole. Arch Dermatol. 1981:117:292-294. 26 Altomare GF, Capella GL, Boneschi V, Viviani MA. Efficacy of terbinafine in cutaneous alternariasis. Br J dermatol. 2000:142:840-41. 27 Sharley KP, KP, Graybill JR, Rinaldi MG, et al. Itraconazole in the treatment of pheohyphomycosis. J.Am. Acad. dermatol. 1990:23:577-86. 28 Ghobrial IM, Gertz MA, Fonseca R. Waldenstrom macroglobulinemia. The Lancet Oncology. 2003:4:11.
What are biologics? A Review for the Non-Dermatologist Ty Hanson, D.O.*, John Hibler, D.O.** *Resident, Ohio University College of Osteopathic Medicine, O'Bleness Memorial Hospital Athens, Ohio. **Dermatology **Director of the Dermatology Program at Ohio University University College of Osteopathic Medicine and O'Bleness Memorial Hospital. Clinical Assistant Professor West Virginia School of Osteopathic Medicine.
This is difficult with the increasing number of patients presenting a wider range of new medicines to healthcare providers
founded. In 1983, Bos et al. reported that most inflammation in psoriasis is due to partial activation
as well as most classes of drugs, such as proton pump inhibitors or ACE inhibitors. The rationale is behind it
Kult to associate its maintenance with these side effects, new drugs with drugs and relative and absolute interactions and contraindications. Most doctors are likely to ask the patient what a particular drug is used for, or look up the drug in a physician's reference book or similar book. Fortunately, most of these newer drugs are much more effective and have a higher safety profile with fewer drug interactions. This is certainly true of the largest and most exciting new class of drugs in the field of dermatologic dermatology. This new class of biologics is currently being used in the United States to treat psoriasis and psoriatic arthritis. Traditionally, psoriasis treatments have included products that non-dermatologists would easily recognize. These include topical agents such as corticosteroids, Dovenex, tazorates, and tar products. In addition, oral immunosuppressants such as methotrexate and cyclosporine have been widely used despite a proven history of serious side effects. Against this background, biologics are a welcome alternative for dermatologists and patients alike. The National Psoriasis Foundation reports that psoriasis is a common condition, affecting 2.1% of adults. The prevalence of psoriasis is approaching 4.5 million people. About 1 million Americans have psoriatic arthritis. The incidence of psoriasis is between 150,000 and 260,000
CD4+ and CD45RO express CD8+ cell tone. They also have these cells that indicate they have an effector/memory status7,8. Most of these dermal infiltrating cells also express markers such as interleukin-2 and HLA-DR6. This immunological behavior of psoriasis has been supported by clinical observations by dermatologists. The benefits of anti-T-cell therapies, including cyclosporine, which inhibits interleukin-2 and interferon-gamma through T-lymphocytes, can produce complete remission of psoriasis, which unfortunately returns when the drug is stopped2. T cells are involved in the development of psoriasis in a number of ways. A psoriasis plaque is probably generated by these T cells in three different steps: The first step is the activation of the T cells by an unknown antigenic peptide. The next step is the migration of T cells to the injured skin. Eventually, activated T cells in the skin release cytokines, resulting in the typical psoriasis phenotype5. Because of the side effects of older drugs, new drugs are needed. According to a survey by the National Psoriasis Foundation, only 26% of patient samples were satisfied with their current treatment 9 . And a survey conducted in the UK found that 44% of respondents preferred systemic therapy to topical treatment10. These results help explain why biologists discovered
then oclonal nature of the protein. the name if ends with -zimab is a chimera. monHumanized monoclonal names end in -zumab. Human monoclonal antibodies end in umab. And finally, receptor-antibody fusion proteins end in -cept5. Several biologics are currently in use; However, this article will discuss the three most commonly used drugs. These three are alefacept (Amevive), etanercept (Enbrel), and efalizumab (Raptiva). The first to be admitted was Alefecte. As its name suggests, it is a fully human fusion protein composed of two extracellular domains of type 3 leukocyte function-associated antigen linked to the Fc portion of human IgG111. Alefecept is designed to block the interaction for T-cell activation, which is important for the development of psoriasis. It does this by binding to CD2 and blocking costimulatory signaling12. A side effect of the drug is the selective induction of apoptosis in these T cells by local macrophages and natural killer cells11,12. Alefacept can be given as an IM injection, which is the most common, or as an intravenous injection. 80% of US dermatologists prefer the IM11 route. Injections are 15 mg once a week for 12 weeks. Although the FDA has approved this drug for a single course, it is now becoming common to begin a second 12-week course after an intermittent 12-week period. One of the nice things about Alefecte is his ability to do it
New cases per patient year. Psoriasis affects people regardless of gender, age, ethnicity, or socioeconomic status. It is estimated that 56 million hours of work are lost each year due to psoriasis. Not only does psoriasis cause absenteeism, but the disease costs $3 billion a year to treat1. In his text on immunodermatology in the third edition, Dr. Mark Dahl theorizes that T-cells in particular, along with the immune system, are the causative agents of psoriasis2. Since the publication of this text in 1996, great strides have been made in understanding the pathogenesis of psoriasis, so much so that this is the case now
such a warm welcome to the market.
accepts3,4,5this disease. However, psoriasis is precisely of autoimmune origin, or psoriasis and psoriatic arthritis have neither
cals were defined names by convention. Generic may seem strange at first glance. None of the names seem to end in
produce remissions averaging more than 7 clinical months post-treatment, also 11,12 satisfactory results upon re-treatment. However, the onset of action is slow, with optimal results occurring around 18 weeks after the first injection12. For these reasons, alefacept is the first FDA-approved biologic as a potential first-line treatment for moderate-to-severe psoriasis in patients who are eligible for either systemic therapy or phototherapy. Alefacept's safety profile appears to be excellent. Unlike its traditional predecessors, Organs doesn't seem to have any problems with its internal organs. Amevive reduces CD45RO(+)11 T cells. This raises concerns about immunosuppression and infections. However, in studies there was no difference between Alefecte and placebo.
Biologics: background information Biologics are engineered proteins that modify immune responses. Some examples are: antibodies, fusion proteins, and recombinant cytokines. "Biological response modifiers" are said to act on pathways involved in the psoriasis process, such as B. T cell activation, antigen presenting cell interaction and cytokine production5. Biologics are classified into three groups: monoclonal antibodies, fusion proteins, and cytokines. The nomenclature of biology
in terms of infections. Recommended monitoring includes CD4 count. Alefacept should not be administered at CD4 counts below 250/ul. If CD4 cell counts are below this level for 4 consecutive weeks, Amevive should be discontinued. Although it is a very safe and effective drug, it should be used with caution in patients with systemic cancer or chronic infections11,12. The next biologic isn't just used for psoriasis, it's the only drug approved to treat psoriatic arthritis. Etanercept is a fully human fusion protein of the p75 receptor for the tumor necrosis moiety and the Fc of human factor IgG 13α. This specific drug binds and inactivates TNF in tissues, helping to hinder its work in the pathogenesis of psoriasis and psoriatic arthritis. The interesting thing about etanercept is its apparent disease-modifying properties. It appears to prevent the progressive bone degeneration seen in psoriatic arthritis11. Etanercept is given as a single subcutaneous injection of 25 mg twice a week. However, a more practical dose of 50 mg twice a week with 50 mg once a week for maintenance is now used. It is FDA approved for the treatment of juvenile rheumatoid arthritis but is used outside of psoriasis in a package insert at a dose of 0.8 mg/kg in pediatric patients every other week. With over 250,000 patients treated with etanercept, safety is well documented. As with alefacept, there does not appear to be any internal organ toxicity. Additionally, there is no recommended laboratory monitoring. However, most dermatologists will obtain a PPD prior to treatment because of concerns about TNF blocking and tuberculosis reactivation. Some dermatologists also request complete and quarterly blood counts, metabolic profiles, and antinuclear antibodies when using any of the biologics 13. There are some very rare effects that have been observed with etanercept, not all of which are understood in terms of causality. These are demyelinating disease progression, worsening congestive heart failure, susceptibility to infection, and drug-associated lupus erythematosus11. From now on there are no restrictions on the duration of therapy or the total dosage of drugs. Efalizumab is a humanized monoclonal antibody directed against CD11a, a subunit of the type 1 function-associated leukocyte antigen (LFA (LFA-1)-1)14. This is the major ligand for intercellular adhesion molecule-1 (ICAM-1)11. The interaction of efalizumab helps block activation and migration of T cells to the skin. After administration, efalizumab saturates available CD11a binding sites on T cells15,16. However, this effect is reversible if CD11a binding sites return to pre-treatment levels within 10%
Circulation days of 17.Efalizumab Dosing is 1 to 2 mg/kg per week, administered subcutaneously. As with the
other biologics discussed do not seem to have problems with systemic toxicity 18,19. Eight patients (0.3%) in controlled studies evaluating efalizumbab developed thrombocytopenia (platelets less than 52,000) during therapy. A causal relationship is not possible due to the small number. Therefore, the package insert recommends monitoring platelets monthly for the first three months and then quarterly14,20. The most commonly reported side effects are flu-like symptoms after the first 14 doses. As with etanercept, most dermatologists
5. De Rie MA, Goedkoop AY, Bos JD, Overview of psoriasis, Dermatologic Therapy 2004, 17: 341-349 6. Bos JD, Hulsebosch HJ, Krieg SR, Bakker PM, Cormane RH. Immunocompetent cells in psoriasis. In situ immunophenotyping by monoclonal antibodies. Arch Dermatology 1983:275:181-189 7. Bos JD, Hagenaars C, Das PK, Krieg SR, Voorn WJ, Kapsenberg ML. Predominance of AgmemoryÅh T cells (CD4+, CDw29+) over AgniveÅh T cells (CD4+, CD45R+) in normal and diseased human skin. Arch Dermatol 1989:281:24-30 8. Morganroth GS, Chan LS, Weinstein GD, Voorhees JJ, Cooper KD. Proliferating cells in the psoriatic dermis consist mainly of T cells, endothelial cells and Factor XIIIa+ perivascular dendritic cells. J Invest Dermatol 1991:96:333-340 9. Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. The impact of psoriasis on quality of life. 1998 Results Natl Psoriasis Foundation Patient Membership Sur-
Get a PPD before psoriasis usually gets bigger after treatment. efalizumab suspension. Due to its safety, however, it should be used as a long-term therapy. Although all three of these drugs are unique, they all have a few things in common. First is the price. The monthly cost for alefacept is $3,300, for etanercept $720, and for efalizumab $1,100. Certainly these prices are quite prohibitive for most. However, when you factor in the cost of multiple doctor visits, minimal monthly lab monitoring, liver biopsies, and the likelihood of serious side effects from traditional treatments, the cost seems right. Pregnancy and lactation safety are other issues that have quite a lot in common. Alefacept is Category B in pregnancy and safety in breast-feeding is unknown or disputed. Etanercept is category B in pregnancy and considered unsafe during breastfeeding. Efalizumab is Category C in pregnancy because the offspring in mice can elicit an antibody response several months after birth. Safety in lactation is unknown or disputed 14 . Finally, it is recommended not to vaccinate patients receiving these drugs with acellular, live and attenuated drugs14.
vey. Arch Der matol 2001:137:280-284 vey 10. Richards HL, Fortune DG, OÅfSullivan TM, Main CJ, Griffiths CEM. Patients with psoriasis and their adherence to therapy. J Am Acad Dermatol 1999: 41: 581-583 11. Camisa C, Handbook of Psoriasis 2nd ed. Malden MA, Blackwell, 2004: 328-336 12. Hodak E, David M. Alefacept: a literature review and practical guidelines for management . Dermatol Ther, Vol. 17, 2004, 383-392 13. Gottlieb AB. Etanercept used to treat psoriasis and psoriatic arthritis. The Matol Ther, Volume 17, 2004, 401-408 14. Leonardi CL. Efalizumab in the treatment of psoriasis. Dermatol Ther, Vol. 17, 2004, 393-400 15. Bauer RJ, Dedrick RL, White ML, Murray MJ, Garovoy MR. Population pharmacokinetics and pharmacodynamics of the anti-CD11a antibody hu1124 in people with psoriasis. J Pharmacokinet Biopharm 1999:27(4):397420 16. Gottlieb AB, Krueger JG, Bright R, et al. Effects of administration of a single dose of a humanized monoclonal antibody against CD11a on the immunobiology and clinical activity of psoriasis. J Am Acad Dermatol 2000:42(3):428-435 17. Papp K, Bissonnette R, Krueger JG, et al. Treatment of moderate to severe psoriasis with a novel anti-CD11a monoclonal antibody. J Am Acad Dermatol 2001:45(5):665674 18. Gottlieb AB, Gordon KB, Koo J, et al. Long-term treatment with efalizumab maintains clinical benefit in patients with moderate-to-severe plaque psoriasis: updated results from an open-label study. Poster presented at: Summer Academy 2003 by Am Assoc by Dermtol Acad; July 25-29, 2003; Chicago, IL. 19. Lebwohl M, Papp KA, Tyring S, et al. Continued treatment with subcutaneous efalizumab is safe: pooled results from two phase III studies. Poster presented at the Am Acad of Dermatol Annual Meeting July 31-August 4, 2002. New York, NY. 20. Raptiva (efalizumab) package insert. South San Francisco, CA: Genentech, Inc., October 2003.
Conclusions In summary, this new line of therapies represents a welcome addition to the effective treatment of psoriasis. Not only are they, but their security is excellent. The future will probably bring more and more of these drugs not only into the field of dermatology, but into all disciplines. A primary care physician may feel uncomfortable treating his patients with systemic methotrexate or cyclosporine, but can safely use these drugs with relative confidence. References: 1. National Psoriasis Foundation, Psoriasis Treatment Options and Patient Management, Psoriasis Consensus Meeting, 2002; 1 2. Dahl, MV: Clinical immunodermatology. 3rd ed. St. Louis, MO: Mosby, 1996: 301-315 3. Bos JD, De Rie MA, The pathogenesis of psoriasis: immunological facts and speculation. Immunology Today 1999:20:40-46 4. Kupper TS. Immune targets in psoriasis. N Engl J Med 2003: 349: 1987-1990
WHAT ARE ORGANIC PRODUCTS? A REVIEW FOR THE NON-DERMATOLOGIST
Capillary Hemangiomas Mimicking Kaposi's Sarcoma Kaposi's Sarcoma: Sarcoma: A New Classification System Department of Dermatology – Texas Division, Duncanville, Texas **Program Director and Associate Professor, Northeast Regional Medical Center, Kirksville College of Osteopathic Medicine, Department of Dermatology – Texas Division, Duncanville, Texas SUMMARY Due to the spread of AIDS and its associated manifestations of skin diseases, vascular lesions have been studied in more detail and more intensively than before. until now. This article discusses the most common vascular lesions that should be considered in the differential diagnosis of Kaposi's sarcoma, with a particular focus on capillary hemangiomas, which can mimic Kaposi's sarcoma both histologically and clinically. singularly mentioned in the differential diagnosis of Kaposi's sarcoma; However, capillary hemangiomas have not been grouped into a classification system to show their histopathologic logical similarities and differences and to contrast each entity with Kaposi's sarcoma. This article attempts to provide a new conceptual integration of the four capillary hemangiomas that should be useful in the differential diagnosis of Kaposi's sarcoma.
Introduction The primary objective of this article is to discuss vascular lesions, particularly capillary hemangiomas, which can mimic Kaposi's sarcoma. Since vascular vascular entities "masquerading" as Kaposi's sarcoma have not yet been incorporated into a classification system in the available literature; an additional purpose is to fill a gap in the existing literature. This article begins with an overview of Kaposi's sarcoma and then a discussion of the entities to consider in the differential diagnosis.
I. Kaposi Kaposi's sarcoma This vascular neoplasm was first described by Kaposi in 1872 under the name "idiopathic multiple pigmented sarcoma of the skin". 1 The skin is the most common site, but other organ systems can also be affected.
A. Clinical setting The classic European form of Kaposi's sarcoma (KS) is a rare condition that usually affects individuals over the age of 50 of Jewish, Italian, Mediterranean or African descent.2,3 The process is usually confined to the lower extremities in these individuals Patients, although the lesions increase in number over time and may occur proximally. Kaposi sarcoma lesions develop in stages such as patches, plaques, and nodules; Multistage clinical lesions are often present in a single patient. The lesions may gradually coalesce and the nodules may eventually ulcerate. It is important to note that the clinical course of the classic form is relatively sluggish.1 Epidemic or AIDS-related Kaposi's sarcoma occurs predominantly in homosexual men; make up 95% of all
Cases.1 In this variant, KS lesions appear clinically as red, purplish, or purple spots, papules, plaques, and nodules. The disease can manifest on any surface of the skin or affect the lungs or gastrointestinal tract. Extensive lymphatic and visceral involvement may occur in this group.
Siderin and eosinophilic hyaline globules are often present. The most characteristic feature of this stage is the presence of a significant component of spindle cells. Among the fusiform cells, the formation of irregular, fissured, or slit-like spaces is notable, giving rise to new angular vascular vessels.
in addition. All very good buttitters have serological antibodies, in cases of AIDS they have type 1 virus. It is important to emphasize that the KS associated with AIDS is a more aggressive variant of the disease.1
Channels small amounts of hemosiderin from erythrocytes to the tes. As previously mentioned, deposits and hyaline globules are more prominent within the proliferating spindle cells than in the patch stage of Kaposi's sarcoma. These cytoplasmic inclusions stain positive for PAS; because of their relative specificity, they are particularly useful in detecting Kaposi's sarcoma.6 The nodular lesions of Kaposi's sarcoma show additional proliferation of spindle cells in crossing fascicles and laminae. The spindle cells show some degree of cytologic atypia (mild to moderate). moderate). Irregular spaces appear between all bundles, representing attempts at vascularization. Nuclear pleomorphism, atypia, and atypical mitotic figures are evident at this stage. Spindle cells from nodular lesions of Kaposi's sarcoma show patchy reactivity to factor VIII-related antigen and have reduced reactivity to ulex europaeus lectin 1. 8 can be detected by immunoperoxidase staining and may be useful in the diagnosis of Kaposi's sarcoma. Clinical entities to be distinguished in the differential diagnosis of Kaposi's sarcoma are discussed in the following sections (i.e. Sections II and III).
B. Histopathology Histopathological features Histopathologically, lesions associated with Kaposi's sarcoma are usually described according to their stage at presentation. In the patch stage, patch stage, KS presents as a proliferation of irregularly shaped small angular vascular spaces lined by a single layer of flattened or fatty endothelial cells.4 A variable, predominantly lymphocytic perivascular infiltrate is present and contains a number of plasma cell- variables . There are subtle vascular changes, the earliest of which is a proliferation of irregular or small blood vessels around normal or ectatic dermal blood vessels and across adnexal structures.4 Newly formed vessels may protrude into a vascular lumen or surround and partially isolate the normal dermal structures (this is referred to as referred to as “Promontory Signal”). There are other useful diagnostic criteria at this stage, which have been extensively addressed by several investigators.1-6 Plaque-stage lesions of Kaposi's sarcoma show further progression of the neoplastic process, filling the entire dermis and affecting the superficial subcutaneous tissue. The neoplastic process is more cellular and there is a denser inflammatory infiltrate. 5 erythrocytes inside and outside the vascular spaces are numerous and breakdown products of erythrocytes are phagocytosed, including hemoAUSTIN, WA WAY Y
II. Capillary hemangiomas mimicking Kaposi's sarcoma: a new classification system in incidence and therefore specific vascular tumors are important to include in the differential diagnosis and Kaposi's sarcoma. Hunt Santa Cruz7 discusses vascular entities in general and uses the following categorization: (1) benign vascular lesions, for example: ectasia/telangiectasia and capillary hemangiomas, (2) lesions with borderline or indeterminate status, for example: Kaposi's sarcoma, and (3 ) Malignant vascular lesions, such as angiosarcoma. This work is primarily concerned with benign vascular lesions, particularly capillary hemangiomas, mimicking Kaposi's sarcoma. Although several researchers have pointed out unique clinical entities that mimic Kaposi's sarcoma, such as B. hemosiderotic hemangioma 8,9 10,11 12 , microvenular hemangioma, pyogenic granuloma 16 17,18 or acquired tufted angioma, this study attempted to integrate all these entities conceptually. A new categorization scheme is proposed below, in which the four capillary hemangiomas are categorized according to the presence or absence of lobular structures. It is expected that this conceptual hypothesis presented below will stimulate further research into the similarities and differences between these lesions: A. Non-lobular capillary hemangiomas 1. Target-like hemosiderotic hemangioma (also known as hobnail hemangioma) 2. Microvenular hemangioma
Lobular capillary hemangiomas 1. Pyogenic granuloma 2. Progressive capillary hemangioma (also known as acquired tufts angioma). A detailed description of each of the capillary hemangiomas follows below using the proposed new classification system.
A. Non-lobular capillary hemangiomas mimicking Kaposi's sarcoma
In the differential diagnosis of Kaposi's sarcoma, the unusual vascular tumors, both nonlobular and lobular, called capillary hemangiomas are of great concern. lobular. Of the nonlobular capillary hemangiomas, Santa Cruz and Aronberg, 8 described in 1988 8 cases of
Target hemosiderotic hemangioma as a new and distinct vascular disease. In 1990, Rapini and Golitz9 presented a single case of a targeted hemosiderotic hemangioma. Since then, the literature has been replete with examples of this entity, also known as "hobnail hemangioma." Hemangioma.” Targetoid hemosiderotic hemangioma is one of the histological simulations of Kaposi's sarcoma, and knowledge of its clinical and pathological features is essential to avoid diagnostic errors. Hemosiderotic hemangioma typically presents as a single purple papule, 2 to 3 mm in diameter, with a pale border and a more peripheral ecchymotic ring, giving it a target-like appearance.9 The histology of hemosiderotic hemangioma varies with the patient's age or duration of the lesion. The earliest finding is a proliferative proliferation of thin-walled, widely dilated, irregular vascular lumens in the superficial dermis. endothelial cells are flattened to epitheloid; there is a "nail-to-nail" appearance, with epitheloid cells often protruding into the vessel lumen. Later, the lesions show a collapsed lumen and spindle cells appear. Endothelial cells stain positive for CD31, weak for Factor VIII-related antigen, and strong for Ulex europaeus lectin 1. 2. Microvenular Microvenular Hemangioma
Another nonlobular capillary hemangioma, microvenular hemangioma, was described by Hunt, Santa Cruz, and Barr. 10 Five more cases were added to the literature by Aloi and colleagues. 11 Microvenular hemangiomas present clinically as relatively small (approximately 1 cm) purplish to red lesions, typically on the extremities of young adults. Adult. Histologically, there is a pattern of irregular and branching vessels with discrete lumens and the absence of cellular atypia. Microvenular hemangioma has a very distinctive histological appearance, although there is some resemblance to early Kaposi's sarcoma.1 In addition, the venular differentiation resembles that sometimes seen in later stages of tufted angioma and targeted hemosiderotic hemangioma. Early Kaposi's sarcoma can be ruled out by the clinical picture, along with the absence of tortuous and irregular vascular spaces with pre-existing dermal blood vessels; plasma cells; hyaline (eosinophilic) blood cells; and each population of spindle cells.1 B. Lobular capillary hemangiomas mimicking Kaposi's sarcoma 1. Pyogenic granuloma
Lobular capillary hemangioma (also known as pyogenic granuloma) is a common vascular lesion that was once thought to be secondary
pyogenic infection or as granular tissue in response to trauma. Currently, it is better understood as a lobular capillary hemangioma due to its lobular architecture at low magnification. 12-16 Typically presents as a single, rapidly growing, dark red, exophytic, raised, or polypoid vascular lesion with frequent superficial ulceration.1 Many lobular capillary hemangiomas arise without a cause, others are associated with trauma, pregnancy, or retinoid use. Therapy; common places are fingers, face, face and oral cavity. Cavity. Histopathologically, lobular calluses develop through three distinct phases of capillary hemangioma. Develop the levels first. a compact vascular proliferation of solid, largely closed vascular structures occurs. Later these structures develop into a multilobular arrangement with regular looking lumens. In the final phase, there is progressive development of pericyte cells. Immunohistochemically, vimentin stains all endothelial cells; and any proliferation of spindle cells will be stained for muscle-specific actin type IV collagen and will likely be pericytic.1 Lobular capillary hemangioma has features that link it to the tufted hemangioma. 2. Progressive Capillary Hemangioma (aka Acquired Tufted Angioma) 17
Wilson-Jones and Orkin described acquired swollen angioma, also known as progressive capillary hemangioma or angioblastoma. In the past, these entities were considered to be similar or identical, with the differences being considered purely semantic. However, Padilla Padilla et al.18 advocated that this lesion should be considered as a distinct clinicopathologic entity. Acquired tufted angiomas are certainly related to pyogenic granulomas (lobular capillary hemangioma), and peripheral satellite nodules resembling pyogenic granulomas have been observed. in the deep neck and upper trunk of children and young adults. Histopathologically, the hallmark of this hemangioma is the presence of small tufts of cells and capillaries that are spread like “cannonballs” across the dermis. Clumps tend to be larger in the mid to lower dermis. Immunoreactivity for CD31, CD34, Factor VIII-related antigen and Ulex europaeus lectin is best observed in endothelial cells of larger, well-formed vascular channels. The lectin from Ulex europaeus also surrounds the capillaries of the vascular tufts, but apart from the occasional dilated lumen within these tufts, there is little or no staining for factor VIII-related antigen. The progressive nature of acquired tufted angioma may require consideration of a low-grade tumor
CAPILLARY HEMANGIOMAS MIMICKING KAPOSI SARCOMA: A NEW CLASSIFICATION SYSTEM
angiosarcoma or Kaposi's sarcoma. The most likely differential diagnosis of angiosarcoma is a pyogenic granuloma; Although the vascular lobules are very similar, the diffuse nature of acquired tufted angioma is quite distinctive.
III. Other vascular vascular lesions in the differential diagnosis of Kaposi's A. Benign sarcoma 1. Acro-angiodermatitis. Also known as random dermatitis, angiodermatitis, or pseudo-Kaposi's sarcoma, acroangiodermatitis is a reactive vasoproliferative disorder. 1 9 -2 2 The vessels of acroangiodermatitis are arranged in a lobular manner; have a round and regular outline; are centered in the papillary dermis; and show no tendency to localize around pre-existing skin structures. In contrast, Kaposi's sarcoma shows a random arrangement of slit-like vascular spaces around dermal structures. The inflammatory infiltrate of Kaposi's sarcoma is more pronounced than that of acroangiodermatitis and contains more plasma cells. 2. Bacillary Angiomatosis Angiomatosis: This disorder, also known as epitheloid angiomatosis, typically occurs in patients with AIDS and in this context the clinical presentation may be confused with Kaposi's sarcoma, particularly because of the highly vascularized features of bacillary angiomatosis. 23-25 The most useful features in the differential diagnosis and detection of bacillary angiomatosis are the presence of neutrophils and fine-grained interstitial aggregates. The bacilli can be detected and the diagnosis confirmed by means of silver staining, staining and, if necessary, electron microscopy. Diagnosis. Bacterial angiomatosis may exhibit lobular collections of blood vessels but lacks the well-organized lobular architecture characteristic of pyogenic granulomas. 3. It is a benign lymphangioendothelioma. Lymphangioendothelioma. This is a rare entity that can be diagnostically difficult to distinguish from low-grade angiosarcoma and the lymphangioma-like form of Kaposi's sarcoma.26,27 It mimics patch-stage Kaposi's sarcoma. The caveat is that the clinical setting is important and that the diagnosis of benign lymphangioendothelioma should not be made from a small biopsy without a clinical history.1 4. Spindle cell hemangioma. However, there is another category of benign vascular lesions that mimic Kaposi's sarcoma, known as spindle cell hemangioma. First discovered in 1986, Weiss and Enzinger28 described this lesion with unique vascular characteristics as a low-grade gliosarcoma with cavernous hemangioma and Kaposi's sarcoma. Additionally
Cases of spindle cell hemangioma were reported by Scott and Rosai29 in 1988 and their results indicated that there was insufficient evidence to consider spindle cell hemangioma a low-grade angiosarcoma; rather, it appears that spindle cell hemangioma is a non-neoplastic reactive vascular proliferation associated with malformed blood vessels and repeated cycles of recanalization following thrombosis.30,31 Kaposi's sarcoma.
B. Borderline 1. Kaposiform hemangioendothelioma. Also known as a hemangioma, this lesion, with features similar to Kaposi's sarcoma, is an extremely rare vascular tumor that occurs almost exclusively in childhood and affects the soft tissues and skin. 32 The differential diagnosis includes Kaposi's sarcoma, capillary hemangioma, spindle cell hemangioma, and acquired tufts angioma.
C. Malignant 1. Angiosarcoma. Also known as malignant hemangioma or lymphangiosarcoma, this lesion is a rare malignant endothelial tumor that can occur in the skin, soft tissues,
mimic Kaposi's sarcoma both histologically and clinically. This article attempted to provide a new conceptual integration of relevant clinical entities. Although several researchers have pointed out unique entities mimicking Kaposi's sarcoma, that is, although there have been discussions of each unique type of capillary hemangioma, such as angioma acquired,17,18 this article attempted to put all of these entities into one article and to integrate them conceptually, noting the presence or absence of a lobular architecture in the structural histopathology of these clinical entities. A new categorization scheme has been introduced; this integration should be useful in the differential diagnosis of Kaposi's sarcoma. Furthermore, the conceptual hypothesis presented here is expected to stimulate further research into the similarities and differences of capillary hemangiomas and related vascular neoplasms. V. References
Breast, liver, exhibits and other entrails. of Kaposi's bones, the sarcoma breaks down skin collagen through newly formed vascular channels similar to those found in angiomatous and lymphangiomatous areas of angiosarcoma. 1 Angiosarcoma (AS) has a predominant pattern of spindle cells and can mimic Kaposi's sarcoma plaques and nodules. Distinguishing features include the identification of more angiomatous areas in angiosarcoma and a greater degree of cytologic atypia than even in florescent nodules in Kaposi's sarcoma.1 Alongside several important features, clinical context also aids in differential diagnosis, as AS is common on the The head and neck of the elderly or unilaterally confined to a lymphedematous upper extremity, while KS does not generally affect these anatomical sites in the elderly.1
Due to the spread of AIDS and its associated cutaneous manifestations, vascular lesions have been studied in more detail and with greater intensity than before. Through this investigation, Kaposi's sarcoma has been increasingly characterized; however, more time needs to be invested in the differential diagnosis of a broad spectrum of related dermatopathologic entities. This article discusses the most common vascular injuries that must be
1. Barnhill Barnhill RL, editor. gate. Dermatopathology extbook book Dermatopathology ology, 1st ed. New York: McGraw-Hill, 1998: 539-591. 2. Cox FH, Helwig EB. Kaposi's sarcoma. Cancer 1959;12:289-298. 3. Centers for Disease Control Task Force on Kaposi's Sarcoma and Kaposi's Opportunistic Infections: Special Report, Epidemiological Aspects of the Current Outbreak of Kaposi's Sarcoma and Opportunistic Infections. infections. N Engl J Med 1982; 306: 248-252. 4. Malon Maloney ey ME, ME, Torres Torres A, Hoffman Hoffman TJ, TJ, Helm KF KF, eds. Surgery Surgical Dermatopathology. Malden, MA: Blackwell Science, Inc., 1999: 379-381. 5. Cock Cockerell erell CJ. Histopathol characteristic pathologic features of Kaposi's sarcoma in HIV-infected individuals. Cancer Surg 1991; 10:73-89. 6. Murphy Murphy,, GF. GF. Dermatopath Dermatopathology: ology: A Practical Guide to Common Disorders. Philadelphia: W.B. WB Saunders Co., 1995; 284-288. 7. Hunt SJ, Santa Cruz DJ. DJ. Acquired Acquired and borderline benign vascular lesions. Dermatol Clinic 1992; 10:97-112. 8. Santa Cruz DJ, Aronberg J. Targetoid hemosiderotic otic hemangioma. J.Am. Acad. dermatol. 1988; 19:550-558. 1988;19:550-558. 9. Rapini RP RP, Golitz LE. Target hemosiderotic hemangioma. J Cutan Pathol Pathol 1990;17:233-235. 10. Hunt SJ, SJ, Santa Cruz DJ, Barr RJ. R.J. Microvenular hemangioma. J Cutan Pathol 1991; 18:235-240. 11. Aloi F, Tomasini F, Tomasini C, Pippione M. Microvenular hemangioma. At the. J Dermatopathol 1993; 15:534-538. 1993; 15:534-538. 12. Mills SE, Cooper PH, Fechner Fechner RE. Lobular capillary hemangioma: the underlying lesion of pyogenic granuloma: study of 73 cases of oral and nasal mucosa. At the. J.Surg. pathol. 1980; 4:471-479. 1980;4:471-479. 13. Cooper PH, McAllister HA, Helwig EB. Intravenous pyogenic granuloma: study of 18 cases. Am J Surg Pathol 179;3:221-228. 14. Cooper PH, PH, Mills SE. SE. Subcutaneous granuloma Subcutaneous pyopogenic granuloma: lobular capillary hemangioma. Arch Dermatol 1982; 118:30-33. 15. Braunstein Wilson B, B, Greer KE, Cooper PH. Eruptive disseminated lobular capillary hemangioma (pyogenic granuloma). J.Am. Acad. dermatol. 1989; 21:391-394. 1989;21:391-394. 16. Strohal R, Gillitzer R, Zonzits E, Stingl G. Localized versus generalized pyogenic granuloma: a clinicopathologic study. Arch Dermatol 1991; 127:856-861. 1991;127:856-861. 17. Wilson-Jones E, Orkin M. Tufted angioma (angioblastoma): A benign progressive angioma not to be confused with Kaposi's sarcoma or low-grade angiosarcoma. angiosarcoma. J.Am. Acad. dermatol. 1989; 20:214-225. 18. Padilla RS, Orkin M, Rosai J. Acquired tufted angioma (progressive capillary hemangioma): a clinic in its own right
considers the differential diagnosis of Kaposi in sarcoma, with particular emphasis on capillary hemangiomas, which can
pathologic entity associated with lobular capillary hemangioma. At the. J Dermatopathol 1987; 9: 292-300. 19. Strutton GF GF, Weedon D. Acroangiodermatitis. A Kaposi's sarcoma stimulant. Am J Dermatopathol 1987;9:85-
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89. 20. Kolde G, Worheide 20 Worheide J, Baumgartner R, Brocker EB. EB. Kaposi-like acroangiodermatitis in a transfemoral amputation stump. Br J Dermatol 1989; 120: 575-580. 1989; 120: 575-580. 21. LeBoit PE. Lobular capillary proliferation. Proliferation. The underlying underlying process in many benign cutaneous vascular neoplasms and reactive conditions. Semin Dermatol 1989; 8:298-310. 1989;8:298-310. 22. Marshall ME, ME, Hatfield ST ST, Hatfield DR. Arteriovenous malformation mimicking Kaposi's sarcoma (Kaposi's pseudo-sarcoma). Arch Dermatol 1985; 121: 99-100. 1985; 121: 99-100. 23. Cockerell CJ, LeBoit LeBoit PE. PHYSICAL EDUCATION. Bacillary angiomatosis: Angiomatosis: A newly characterized infectious pseudoneoplastic cutaneous vascular disease. Disturbance. J.Am. Acad. dermatol. 1990; 22:501-512. 1990;22:501-512. 24. Koehle Koehlerr JE, Quinn FD, Berger Berger TG, et al. Isolation of Rochalimaea species from skin and bone lesions of bacterial angiomatosis. N Engl J Med 1992; 327: 1625-1631. 25. Koehler JE, Glaser CA, Tappero Tappero JW. JW. Rochalimaea heshnenselae infection: A new zoonosis with the domestic cat as a reservoir. JAMA 1994;271:531-535. 1994;271:531-535. 26. E Wilson-Jones, Winkelmann RK, RK, Zachary CB, Reda AM. Benign lymphangioendothelioma: report of 2 cases. J.Am. Acad. dermatol. 1990; 23:229-235.
27. Mehregan DR, Mehregan, Mehregan AH, Mehregan DA. Benign Lymphangioendothelioma: Phangioendothelioma: report of 2 cases. J Cutan Pathol 1992; 19:502-505. 28. Weiss SW, Enzinger FM. Spindle cell hemangioendothelioma: a low-grade angiosarcoma resembling cavernous hemangioma and Kaposi's sarcoma. At the. J.Surg. pathol. 1986; 10:521-530. 29. Scott GA, Rosai J. Spindle cell hemangioendothelioma: report of seven additional cases of a newly described vascular neoplasm. At the. J Dermatopath 1988; 10:281-288. 30. Fletche Fletcherr CD, CD, Beham A, A, Schmid CC Spindle C. Le Cell hemanhemangioendothelioma: A clinicopathologic and immunohistochemical study indicative of a non-neoplastic lesion. Histopathology 1991;18:291-30. 31.. Pell 31 Pellegrini egrini AE, AE, Drake RD, RD, Qualman SJ. SJ Spindl spindle cell hemangioendothelioma: neoplasm associated with Maffuci syndrome. J Cutan Pathol 1995; 22:173-176. 1995;22:173-176. 32. Zukerberg LR, Nickoloff Nickoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of childhood: an aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. Am J Surg Pathol 1993;17(4):321-328. 33. Holden CA, CA, Saliva MF MF, Jones EW. angiosarcoma the
35. 36. 37.. 37
Face and scalp, prognosis and treatment. Cancer 1987;59:1046-1057. Offori TW, TW, Platt CC, Stephens M, Hopkinson GB. Angiosarcoma in congenital hereditary lymphedema (Milroy's disease) - diagnostic landmarks and literature review. Clin Exp Dermatol 1993; 18:174-177. 1993;18:174-177. Mark RJ, Tran LM, Sercarz J, et al. Head and neck angiosarcoma: UCLA experience from 1955 to 1990. Arch Otolaryngol Head Neck Surg 1993;119:973-978. Girard C, C, Johnson WC, Graham Graham JH. Cutaneous angiosarcoma. Cancer 1970;26:868-883. Fletcher CD, Beham A, Bekir S, et al. Epithelioid angiosarcoma of deep soft tissue: A distinctive tumor easily confused with an epithelial neoplasm. neoplasm. At the. J.Surg. pathol. 1991; 15:915-924. Rosai J, Sumner HW, Kostianovsky Kostianovsky M, Perez-Mesa Perez-Mesa C. Angiosarcoma of the skin: A subtle clinicopathologic and structural study. Hum Pathol 1976;7:83-109. 1976;7:83-109. McWilliam McWillia m LJ, Harris Harris M. Granular air cell angiosarcoma cutaneous angiosarcoma: histology Histology, electron microscopy and immunohistochemistry of a newly recognized tumor. Histopathology 1985;9:1205-1216.
CAPILLARY HEMANGIOMAS MIMICKING KAPOSI SARCOMA: A NEW CLASSIFICATION SYSTEM
Confluent and Reticulated Papillomatosis A Case Report and Literature Review Darron D. DiGiulio, D.O.*, Marvin S. Watsky, D.O.** *St. John's Episcopal Hospital - South Shore Far Rockaway, Rockaway, NY ** Dermatology Residency Program Director St. John's Episcopal Hospital ** Dermatolog Hospita l- South Shore Far Rockaway Rockaway, NY 11691 SUMMARY Papillomatosis Reticular and confluent papillomatosis (PCR) was first described in 1927 by Gougerot and Carteaud Carteaud described central coalescence and peripheral fading into a normal reticular network. treatment network. Its etiology is unknown with theories implying an ionic keratinizing response to the keratinization of the disorder. and an abnormal skin host formation response to Pityrosporum. Modalities include oral antibiotics and retinoids with variable We present a patient who was initially treated for pityriasis (tinea) versicolor but was diagnosed with CRP due to lack of response to systemic antifungal therapy and subsequent biopsy, biopsy. This article will review the clinical presentation, pathophysiology, pathophysiology, biopsy findings, and treatment of this entity through a literature review.
A 20-year-old Hispanic woman presented with a mildly itchy brown rash for approximately 1.5 years. The patient first noticed the lesions in the center of the chest, then noticed the subsequent spread to the neck, back, abdomen, arms and legs. She had received several treatments from her GP, including oral ketoconazole, topical ciclopirox cream containing ciclopirox, and 12% lactic acid lotion, with no improvement. There was no family history of similar injuries. History was relevant only for salbutamol-treated asthma. The patient reported no drug allergy and the system check was unremarkable.
Physical examination revealed 0.5 to 1.5 cm brown scaly papules and plaques mainly on the chest, back, and abdomen, with lesser involvement of the neck, arms, and legs. The lesions were confluent in the intermammary region and faded peripherally in the abdomen, lumbar region and extremities, forming a reticular pattern (Figures 1, 2, 3). Intertriginous areas were spared and no oral lesions were observed.
Rating rating and course
After Wood's lamp and KOH examinations showed no fluorescence or evidence of hyphae or spores, respectively, a 4 mm core biopsy was obtained. The differential diagnosis included CRP, CRP, pityriasis versicolor, Darier's disease and typed dermatosis. Findings showed hyperkeratosis, papillomatosis, and acanthosis with sparse superficial perivascular lymphocytic infiltrate. Periodic acid-Schiff and acid-Schiff staining revealed no evidence of fungus. With the diagnosis of CRP, the patient was treated with 100 mg minocycline twice daily. This was followed by the addition of 0.005% calcipotriene cream and then 0.025% tretinoin cream with slight improvement at 4 months. Isotretinoin was considered, but the 18th
The patient did not want to use this treatment method.
Symptoms CRP was first described by Gougerot and Carteaud in 19271 as one of the primary papillomatosis and is usually an asymptomatic dermatosis of unknown etiology. 2 Most cases are sporadic, although familial cases have been reported in the literature.3,4 Onset typically occurs in adolescence or early adulthood,5 with a mean age of 21 years. 6 It has a gender and race preference and is 2.5 times and 2 times more common in females and blacks, respectively.7 The primary lesion described by Gougerot and Carteaud is a red papule 1-2 mm in size, which turns gray and then brown and reaches a 4-5 mm in size.8 Initial locations of involvement include the intermammary,11 interscapular,12 and epigastric regions.8 The papules then increase in number and fuse, becoming centrally confluent2,8 and forming a rhomboid pattern with the long axis running cranially caudally.13 There are also peripheral lesions with centrifugal spread9
12,13,17,18,19,20,21 This was first suggested by Meischer when he observed the response to vitamin A.22 Further support comes from electron microscopic studies showing an increase in transitional cells between the stratum corneum and show granulosum.15,4 This finding suggests premature keratinization and has been associated with ichthyotic diseases4, which are also responsive to retinoids. There is also a change in keratinized cell structures and
However, the etiology of CRP is unknown
increased number of Odland bodies, also23 compatible with a keratinization defect. Enhanced expression of keratin 16 (K16), which is observed in squamous epithelium with hyperproliferation or abnormal differentiation4, has also been observed in CRP lesions. Pityrosporum yeasts, classified under a recent taxonomy in the genus Malassezia, are part of the normal skin microflora and can cause superficial skin infection under certain conditions.24 Whether CRP is due to an abnormal host response to P. orbiculare is unclear. and it is controversial.10,15 Reasons supporting this theory include the occasional presence of yeast in CRP lesions2,25,13,1,11,26 and its close clinical resemblance to fungal pityriasis versicolor4 ,27. Additional support comes from CRP's responsiveness to topical and systemic antifungal agents,15,13,28, although this may vary.11 Factors arguing against the role of Malassezia (old term pityrosporum) as a cause of CRP include the fact That organism is a common non-pathogenic part of the normal skin microflora in the form of yeast. 29 Its presence in CRP lesions does not prove a causal relationship 30 since most lesions are devoid of the organism.2 Furthermore, antifungal drugs are not effective in most cases 30 and the effectiveness of one of these agents, selenium sulfide, may be due to its keratolytic properties instead of antifungal properties.11
There are several related to its pathogenesis. Since CRPtheorien is sensitive and calcipotria was a keratinization disorder
Other suggested causes and associations 31 are endocrine disorders, including bacterial infections22, UV light induction35 and a
Fading of the lesions to normal form, producing a reticulated pattern, hence the name PCR skin.10 Areas of this peripheral extension may include the face and neck,10 axillae,7 abdomen and extremities, albeit to a lesser extent.15 Emphasis on skin folds on the neck and axillary have been observed,6 and oral oral lesions have not been observed.2 The lesions are generally asymptomatic, with occasional pruritus.10 In summary, CRP classically presents with multiple papules and scaly brown plaques in a primarily seborrheic distribution16 with central confluency and meshing peripherally.
DIGIULIO, WA WATSKY TSKY
A clinical variant of cutaneous amyloid as amyloid has been observed in skin lesions.33,34 Perhaps due to its clinical and histological similarity to acanthosis nigricans, endocrine abnormalities associated with CRP include insulin resistance, thyroid dysfunction, menstrual irregularities, and obesity.2 It however, not a single hormonal abnormality is detected, and the assessment is usually negative in most patients free of the disease.11,36 Since antibiotics have also been used successfully in treatment, it has been postulated that CRP is triggered by a bacterial infection .32 Staphylococci can be isolated from lesions of keratinization disorders,32 and staphylotoxin can affect keratinization through the induction of inflammatory cytokines such as TNFa.37 In people with a genetic predisposition, bacterial infection can result in CRP be triggered by an abnormal response to Staph toxins or Malassezia colonization.
The main histological findings include hyperkeratosis, papillomatosis,2 granular layer thinning,10 and acanthosis (Figures 4 and 5). Acanthosis tends to be mild and focal, limited to the "valleys" between the elongated papillae.29 Papillomatosis is minor or may be absent.25 Other findings that may be present include a sparse superficial perivascular lymphocytic infiltrate,2 basal layer hyperpigmentation5 and atrophy of the malignant layer.14,5 The histological differential diagnosis includes some epidermal nevi along with acanthosis nigricans, although the latter does not show the slight dilatation of the superficial dermal blood vessels and pearlescence of elastic fibers seen in CRP lesions.14
The diagnostic criteria originally described by Gougerot and Carteaud are based on the morphology, configuration, location of initial manifestation, distribution, and presence of concomitant manifestations of the lesion.1,8 the midline of the chest and/or upper back, converging centrally and peripherally disappear peripherally. Biopsy findings of hyperkeratosis, papillomatosis, and acanthosis are supportive, not diagnostic, as similar findings are seen in acanthosis nigricans and epidermal nevi.25
The main differences in the diagnosis of CRP are pityriasis versicolor and acanthosis nigricans. Pityriasis versicolor versicolor presents similarly with brown scaly lesions at a similar age of onset and distribution as CRP,
however, there is no reticulation2 and typically no acral involvement.21 Diagnosis is confirmed by fluorescence in the Wood lamp and KOH examination showing hyphae and spores characteristic of Malassezia in the so-called spaghetti and meatball pattern.24 Biopsy shows none papillomatosis . The site of onset and the presence of a reticulated pattern are probably the most important clinical criteria for distinguishing acanthosis nigricans from CRP.6 Acanthosis nigricans is characterized by hyperpigmented velvety plaques, usually beginning in the axilla and neck and affecting the intertriginous areas .21 It is often associated with endocrinopathy, 2 and mucosal involvement. CRP usually begins in the midline of the chest or back, spares the intertriginous areas, and does not involve the oral mucosa. Pseudoacanthosis Pseudoacanthosis hosis nigricans presents similarly to acanthosis nigricans with velvety hyperpigmented plaques in intertriginous areas. It is a direct result of obesity leading to papillomatosis through sweating, maceration and friction. By definition, there are no associated endocrinopathies and the condition improves with weight loss.2,8,6 Other differential diagnoses in CRP include8 nummular and confluent papillomatosis, Darier disease, pseudoatrophoderma colli,8,11 epidermodysplasia verruciformis,8 congenital dyskeratosis,7 Dowling-Degos -Disease and non-inflammatory epidermal nevi.5
In terms of treatment, it is difficult to assess effectiveness as the disease is relatively rare and its natural history is not fully understood. Understood. CRP can be resistant to therapy without a single agent being consistently successful in providing long-term relief. Agents reported to be successful include antibiotics, retinoids, vitamin D3 analogs, and antifungals. The CRP response to antibiotics was first observed in 1965.38 One of the antibiotics most commonly reported to be effective is minocycline, a synthetic lipophilic derivative of tetracycline. In a study by Montemarano et al. at 50 mg twice daily for 6 weeks, all 9 patients responded, including 4 who resolved and 3 who had only residual pigment changes. The recurrence rate was 33% with a median follow-up of 11 months, with all patients responding to retreatment.39 Although unknown, possible mechanisms of action in the pathogenesis of CRP include minocycline antibiotic or immunomodulatory effects, including anti-inflammatory and anti-inflammatory effects. inflammatory actions. proliferative property
IL1a and TNF cultured keratinocytes are inhibited. 42 It also suppresses leukocyte chemotaxis43 and blocks protein/DNA synthesis, resulting in decreased epidermal proliferation.44 According to Poskitt and Wilkinson, it is these latter properties that may account for its usefulness in CRP.40 Other antibiotics , which are considered effective include azithromycin,32,45 clarithromycin,32 an eerthromycin.32,46 The observation that various antibiotics result in clearance when little inflammation is seen clinically or histologically raises another possibility that CRP is triggered by an infectious bacterium responsible for epidermal proliferation.32 Retinoids are vitamin A analogues and differentiate and proliferate cells through intracellular nuclear receptors that regulate gene expression.47 They are active in many dermatological disorders, including cornification disorders.48 Topical and systemic retinoids have been used in the PCR, and ih re responsiveness suggests keratinization disordered. 9 Topical tazarotene, an acetylenic retinoid with b/g RAR9 specificity that normalizes epidermal differentiation49, was as successful as tretinoin cream50 and gel. 13,36 Systemic retinoids are also said to be effective, although they should be considered as second-line therapy after antibiotics to increase the side effect profile. Specific opportunistic agents included de 6 17 vitamin A, etretinate, and isotretinoin.20,21 In one study, isotretinoin in combination with lactinol lotion at a dose of 1 mg/kg for 14-18 weeks resulted in a complete response with no recurrence of Lesion at 18 weeks-months follow-up.20 Calcipotriol, a vitamin D3 analogue, may be useful in epidermal hyperproliferative disorders12 as it is a potent regulator of cell differentiation and an inhibitor of cell proliferation in keratinocytes. 51 It reduces markers of abnormal keratinization52,53 such as suprabasilar expression of suprabasilar expression of K16.12 Its beneficial effect on CRP was first observed by Kurkenoglu et al.18 and supported by other case reports.12,19 Finally, antifungal drugs were effective in some cases patients. These include selenium sulfide,11,13 propylene glycol,28 and ketoconazole.54 Selenium sulfide is worth mentioning in the context of the controversial role of pityrosporum in CRP. It has antifungal and keratolytic properties and the latter effect might explain its effectiveness as most patients with CRP do not have pityrosporum13,11 as previously discussed.
course and prognosis
The course of CRA is unpredictable and subject to exacerbations and remissions11, although spontaneous resolution can occasionally occur.13 Transient or partial resolution
ties. Minocycline may decrease or inhibit the conversion of lymphocytes, collagenase, lipase, and sebum free fatty acids. In the
The course, followed by disease progression by recurrence after termination and treatment, is frequently reported.27
CONFLUENT CONFLUENT AND RETICULATE APILOMATOSIS OF PAPILLOMATA-A OSIS CASE REPORT AND LITERATURE REVIEW LITERATURE
CRP should be considered in the differential diagnosis of hyperpigmented squamous lesions with seborrheic distributions. Commonly used agents that are effective in treating acne include antibiotics and retinoids. The therapeutic response to multiple drugs suggests that this entity is a response pattern to a variety of endogenous and/or exogenous drugs that have not yet been clearly defined. References 1. Gougerot H. and Carteaud A. Papillomatosis pigmentee inominee, Bull Soc Franc Derm Syph 1927;34:719-21. 2. Pierson D, Bandel C, Ehrig T and Cockerell. Benign epidermal tumors and proliferations. In: Bologna JL, Jorizzo JL, Rapni RP, RP, et al, editors. The Matology Matology.. Philadelphia: Elsevier 2003. P.1717-1718. 3. Henning JP, JP, DeWit RFE. Familial occurrence of CRP. Arch Dermatol. 981;117:809-10. 4. Inaloz HS, Uzeri KY and Patel GK. familial PCR. CRP. Arch Dermatol. 2002;138:276-7. 5. Berger CM. Clinicopathological challenge. Challenge. CRP by Gougerot and Carteaud. Am J Dermatopathol. 2003 Apr;25(2)179-80. 6. Hamilton D, Tavafoghi V, et al. CRP by Gougerot and Carteaud. JAAD 1980 May;2(5):401-10. 7. El-Tonsy MH, El-Benhawi MO, et al. CARP. JAAD 1987 Apr;16(4):893-4. 8. Palomeque FE, Hairston MA. CRP by Gougerot and Carteaud. Arch Dermatol 1965 Jul;92(1):49-51. 9. Bowman PH, Davis LS. CARP: Response to Tazarotene. Tazarotes. JAAD 2003;48:580-1. 10. Barnette DJ, Yeager Yeager JK and others. A progressive asymptomatic hyperpigmented papular eruption. CARP by Gougerot and Carteaud. Archives Archives of Derm 1993 Dec;129(12):1608-12. 11. Nordby CA, Mitchell AJ. CRP Responsive Responds to selenium sulfide. Int J Dermatol 1986 abr:25(3):194-9. 12. Gulec AT, Seckin D. CRP: Treatment with topical calcipotriol. British Jour Dermatol 1999 Dec;141(6):1150-1. 13. Schwartzberg JB, Schwartzberg HA. Gougerot and Carteaud CRP response to topical tretinoin. Cutis 2000 Oct;66(4):291-3. 14. Weedon D. Skin pathology. NY: Pearson Professional Limited; 1997. pp. 575–576. 15. Lee SH, Choi EH, et al. PCR: A clinical, histopathological, histopathological,
and study in the electron microscope. J Dermatol 1991 Dec;18(12):725-30. 16. Fuller JC, Hay RJ. R.J. Gougerot and Carteaud PCR Carteaud compensation with minocycline. Clinical and Experimental Dermatology. 1994 Jul;19(4):343-5. topology 17. Bruyhzeel-Koome Bruyhzeel-Koomenn CAFM, DeWit RFE. PCR successfully treats aromatic acid treatment with etretinate. Arch of Derm 1984;120:1236-7. 18. Kurkcuoglu N, Celebi Celebi CR. CRP: Response to topical calcipotriol. Dermatology 1995;191:341-2. 19. Carrozzo AM, Gatti S, Ferranti Ferranti G, et al. Calciprotriol treatment of CRP (Gougerot-Carteaud Syndrome). J Eur Acad Dermatol Venereal 2000 Mar;14(2):131-3. 20. Solomon BA, Laude TA. AT. Two patients with CA: Response to oral isotretinoin and 10% lactic acid lotion. JAAD 1996;35(4):pp.645-6. 21. Lee MP, MP, Stiller MJ, et al. CRP: Response to high-dose oral therapy with isotretinoin and reassessment of epidemiological data. JAAD 1994;31:327-31. 22. Miescher G. Erythrokeratodermia papillaris et reticularis. Dermatologica 1954; 108:303-14. 23. Jimbow M, Talpash Talpash O, Jimbow K. CRP: Clinical, Light, and Electron on mic micros Roscop Copee Studies. international J Dermatol 1992; 31:480-3. 24. Gupta AK, Batra R, et al. Skin diseases Diseases related to Malassezia species. JAAD 2004;51:785-98. 25. Mutasim DF. DF. PCR without papillomatosis. JAAD 2003;49:1182-4. 26. Yesudian P, P, Kamalam S, Razack A. CRP (Gougerot Carteaud). An abnormal host response to Malassezia furfur. Acta Derm Venereal 1973;53(5):381-4. 27. Sau P, Lupton GP. Reticular stem pigmentation. Archives of Derm 1988 Aug;124(8):1272-5. 28. Broberg A, Faergemann. Färgemann. A case of CRP (Gougerot(GougerotCarteaud) with unusual localization. Acta Derm Venereal Venereal 1988;68(2):158-60. 29. Maize J, Metcalf J. Metabolic Diseases of the Skin. In: Elder D, Elenitsas R , Jaworsky C Johnson B Editors Lever's Histopathology of the Skin Phil adelphia: Lippincott-Raven 1997: p395 30 Chang SN Kim SC et al Minocycline treatment for for for CRP CRP Cutis 1996 June 57 (6):454-7 31. Watkins D, Lockwood J. CRP CRP. Arch Dermatol 1957;76:648 32. Jang HS, Oh CK, et al. Six cases of CRP alleviated by different antibiotics JAAD JAAD 2001; 44: 652-5 33 Groh V, V, Schnyder UW UW Nosologie der Papillomatosis papeluse confluente et reticulee (Gougerot-Carteaud) 34 Groh V, Schnyder V, UW Carteaud: another form of cutaneous amyloidosis Dermatologica 1981; 162:118-23 35 Vassile Vassilevava S, Pramatarov K et al., Ultra Violet P CR induced by ultraviolet light JAAD 1989;21:413-4 36 Nagy R Fairfield JC CRP CRP Cutis 19 82 Jan;29(1):48-50. 37. Katayama I, Yokozeki Yokozeki H, et al. oral minocycline improved
DIGIULIO, WA WATSKY TSKY
39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53.
Follicular keratosis, icular squamous keratosis (Dohi), and reticular diseases: Bacterial factors may be involved in aberrant keratinization. J Dermatol 1994;21:604-8. Carteaud A. A case of Gougerot and Carteaud's reticulated and confluent papular papillomatosis completely eliminated by antibiotics. Bull Soc Franc Dermatol Syphiligr. 1965;72:396-7 Montemarano A. Hengge M. et al. PCR: Response to Minocycline. JADE 1996;34:253-6. Poskitt L, Wilkinson JD. PCR clearance by Gougerot and Carteaud with minocycline. Brit J Dermatol 1993 Sep;129(3):351-3. Puig L, DeMoragas J. CRP de Gougerot and Carteaud: Minocycline deserves a try before etretinate. Arch of Dermatol 1995; Drain B, celeriac P, P, et al. In vivo modulation of epidermal inflammatory cytokines (IL-1a, IL-6 and TNF-a) by minocycline. J Invest Dermatol 1993; 101:407. Humber t P, Treffel P, Treffel P, et al. Tetracyclines in dermatology. JAAD 1991;25:691-7. Roberts S, Lachapelle J. CRP (Gougerot and Carteaud) and Pityrosporum orbiculare. Br J Dermatol 1969; 81:8415. Grurer E, Zamolo G, et al. Treatment Treatment of CRP with azithromycin. Clin Exp Dermatol 1998;23:191. Baalbaki SA, Natarajan S, S, et al. PCR: treatment with antibiotics. J Dermatol Treat 1995; 6:13-15. [ PubMed ] Künzli S, Saurat Saurat JH. retinoids. In: Bolognia ognia JL, Jorizzo JL, Rapni RP, et al, editors. Dermatology. Philadelphia. Elsevier;2003. pp. 1991-3. Peck G, DiGiovanna DiGiovanna J. Retinoids. In: Freedberg Freedberg IM, Eisen AZ, Wolff K, et al., editors. Fitzpatrick's dermatology in general practice. NY: McGraw-Hill; 1995. p2810-3. Esgleyes-Ribot T, T, Chandraratna et al. Psoriasis response to a new Asian topical retinoid, AGN JAAD 1994;30:581-90. Kagi MK, Trueb, Trueb, et al. CRP related to atopy. atopy Successful treatment with topical urea and tretinoin. Br J Dermatol 1996 Feb;134(2):381-2. Kragballe K. Non-calciotropic The non-calciotropic vitamin D3 analogue stimulates differentiation and inhibits proliferation of cultured human keratinocytes. J Invest Dermatol 1988; 91:383. Gerritsen MJP, MJP, Rulo HFC, et al. Topical treatment of psoriatic plaques with 1,25-dihydroxyvitamin D3; a cell biological study. Br J Dermatol 1993; 128:666-73. Gerritsen MJP, MJP, Boezman JBM, et al. The effect of tacalcitol (1,24(OH)2D3) (1,24(OH)2D3) on dermal inflammation, epidermal proliferation and keratinization in psoriasis: a double-blind, placebo-controlled study. Br J Dermatol 1994; 131:5763. Kellet JK, Macdonald RH. CRP CRP. Archive of Dermatol 1985;121:587-8.
Class 1 strength
P R E S E R F R V E T THE I V E
Safety information Most commonly reported side effects
An FDAFDA approved, ved, superpotent r-potent
were headache, headache, application site burning, nasopharyngitis and nasal congestion. Due to possible HPA axis suppression, treatment should not exceed two weeks or 60 grams per week.
• Class I1 Proven Strength
In potential glucocorticoid insufficiency, reversible suppression of the HPA-HPA axis may occur after treatment discontinuation. Twice-daily treatment for two weeks demonstrated HPA axis suppression
• QD or BID* dosing options
in two out of 18 adult adults. ts. VANOS should not be used on the face, groin, groin or underarms; in patients
• An elegant cream alternative
Under 18 years old; less than years; or for the treatment of rosacea rosacea or perioral perioral dermatitis. Dermatitis.
for ointments, gels, lotions and foams Reference 1. VANOS (Fluocinonide) Prescribing Information. Medicis Pharmaceutical Corporation
Available in 60g and 30g tubes. * Twice-daily application has proven to be the most effective in achieving treatment success. © 2006 Medicis Pharmaceutical Corporation. VAN05048 R2
The blue man is a symbolic representation - not intended to represent actual results. Results.
VANOS™ cream should not be used to treat rosacea or perioral dermatitis and should not be used on the face, groin or underarms.
Patient Information: Patient Patient: Patients using VANOS™ Creme should receive the following information and instructions. This information is intended to assist in the safe and effective use of this medication. It is not a disclosure of all potential adverse or unintended effects:
(Fluocinonid) Creme, 0,1 % Rx Only
FOR DERMATOLOGICAL USE ONLY, NOT FOR OPHTHALMIC, ORAL OR INTRAVAGINAL USE
1) VANOS™ Cream should be used as directed by your doctor. For external use only. just. Avoid contact with eyes.
3) The treated skin area must not be bandaged or otherwise covered or wrapped occlusively without the doctor's instruction.
2) VANOS™ cream should not be used for conditions other than those for which it was prescribed. required.
VANOS™ (Fluocinonide) Cream, 0.1% contains fluocinonide, a synthetic corticosteroid for topical dermatological use. Corticosteroids form a class of mostly synthetic steroids used topically as anti-inflammatory and antipruritic agents. Fluocinonide has the chemical name 6 alpha, 9 alpha-difluoro-11 beta, 21-dihydroxy-16 alpha, 17 alpha-isopropylidenedioxypregna-1, 4-diene-3,20-dione 21-acetate. Its chemical formula is C 26 H 32 F2 O7 and it has a molecular weight of 494.58. It has the following chemical structure:
O CH2OCCH3 C CH3
5) Other products containing corticosteroids should not be used with VANOS™ Cream without first consulting your doctor. 6) If there is no improvement within 2 weeks, the patient should be instructed to see a doctor. Physician. The safety of using VANOS™ Creme for more than 2 weeks has not been proven.
• • •
• • • • • •
PRO • • • •
Laboratory Tests The cosyntropin stimulation test (ACTH 1-24) may be useful in evaluating patients for HPA axis suppression.
CH3 • • •
Carcinogenesis, Mutagenesis and Impairment of Fertility: No long-term animal studies have been performed
4) Patients should report any signs of local side effects to their doctor. reactions.
• • •
Fluocinonide is an almost odorless to off-white crystalline powder. It is practically insoluble in water and slightly soluble in ethanol.
To evaluate the carcinogenic potential or the effect of fluocinonide on fertility. Fluocinonide did not indicate any mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames test and an in vitro chromosome aberration test in human lymphocytes). However, fluocinonide was positive for clastogenic potential when tested in the in vivo mouse micronucleus assay.
Each gram of VANOS™ Cream contains 1 mg of micronized fluocinonide in a cream base of Propylene Glycol USP, Dimethyl Isosorbide, Glyceryl Stearate (and) PEG-100 Stearate, Glyceryl Monostearate NF, Purified Water USP, Carbopol 980 NF, Diisopropanolamine and Citric Acid USP.
Pregnancy Category C: Teratogenic Effects: Effects of Corticosteroids: Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low doses. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.
There are no adequate and well-controlled studies in pregnant women. Therefore, VANOS™ cream should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus.
The exact mechanism of action of topical corticosteroids such as fluocinonide in the treatment of psoriasis is not known. However, topical corticosteroids are thought to be effective primarily because of their anti-inflammatory, antipruritic, and vasoconstrictor effects. The mechanism of the anti-inflammatory effects of topical corticosteroids is generally unclear. However, it is believed that corticosteroids work by inducing phospholipase A2-inhibiting proteins, collectively known as lipocortins. It is postulated that these proteins control the biosynthesis of potent inflammatory mediators such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A. 2. Pharmacokinetics The extent of percutaneous absorption of topical corticosteroids is determined by many pharmacokinetic factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressings containing hydrocortisone for up to 24 hours have not been shown to improve penetration; however, hydrocortisone occlusion for 96 hours significantly improves penetration. Topical corticosteroids can be absorbed through normal intact skin. Inflammation and/or other pathological processes in the skin can increase percutaneous absorption.
Breastfeeding mothers: Systemic mothers: Systemically administered corticosteroids are found in breast milk and may suppress growth, impair endogenous corticosteroid production, or cause other undesirable effects. It is not known whether topical administration of corticosteroids can result in sufficient systemic absorption to produce detectable amounts in breast milk. However, a decision must be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Use in children: Use Use: Use in patients under 18 years of age is not recommended. Safety and efficacy in pediatric patients have not been established. Due to a greater skin surface area to body mass ratio, pediatric patients are at greater risk of HPA axis suppression and Cushing's syndrome than adults when treated with topical corticosteroids. They are therefore also at an increased risk of adrenal insufficiency during or after stopping treatment. Adverse effects, including stretch marks, have been reported with inappropriate use of topical corticosteroids in infants and children.
Vasoconstrictive studies performed with VANOS™ Cream, 0.1% in healthy subjects indicate that it is in the super-high potency range compared to other topical corticosteroids; however, similar whitening scores do not necessarily imply therapeutic equivalence.
HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations Manifestations of adrenal suppression in children include low plasma cortisol levels and lack of response to cosyntropin (ACTH1-24) stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headache, and bilateral papilledema.
Application of VA NOS™ Cream, 0.1% twice daily for 14 days to 18 adult patients with plaque-type psoriasis (10-50% BSA, mean 19.6% BSA) demonstrated demonstrable HPA axis suppression 2 patients (at 12% and 25% BSA respectively) where the criterion for HPA axis suppression is a serum cortisol level of less than or equal to 18 micrograms per deciliter 30 minutes after stimulation with cosyntropin (ACTH1-24).
Use in geriatrics: Clinical use: Clinical studies with VANOS™ Creme did not include a sufficient number of subjects aged 65 years and older to determine whether they responded differently than younger subjects. In general, dose selection for an elderly patient should be cautious.
Treating patients with VANOS™ cream for more than 2 weeks at a time is not recommended and only small areas should be treated at a time due to the increased risk of HPA axis suppression (see PRECAUTIONS).
In clinical studies, a total of 443 patients with atopic dermatitis or plaque psoriasis were treated with VANOS™ cream once a day or twice a day for 2 weeks. The most frequently observed side effects in these clinical studies were the following:
HPA axis suppression has not been studied in psoriasis patients younger than 18 years of age. CLINICAL STUDIES A double-blind, vehicle-controlled, randomized study of VA NOS™ Cream was conducted in patients with plaque psoriasis. Patients with 2% to 10% body surface area involvement at baseline applied VANOS™ cream or vehicle cream once daily (qd) or twice daily (bid bid) to all affected areas for 14 consecutive days. The primary measure of effectiveness was the proportion of patients whose psoriatic lesions had disappeared or almost disappeared by the end of treatment. The results are presented in the table below as patients recovering or almost recovering at week 2 after once or twice daily application of VANOS™ cream.
once a day
once a day
twice a day
twice a day
Patients with treatment success*
*Released or nearly eliminated No efficacy studies have been conducted to compare VANOS™ (Fluocinonide) Cream 0.1% to other topical corticosteroid products, including Fluocinonide Fluocinonide Cream 0.05%. INDICATIONS AND USE
VANOS™ cream, once a day (n=216)
twice daily (n=227)
Vehicle cream, once or twice daily (n=211)
Burning the application page
Undetermined app website response
No other adverse reactions were reported by more than 1 subject on active treatment. The incidence of all adverse events was similar between the active treatment groups and the vehicle control groups. The following additional local adverse reactions have been reported with topical corticosteroids and may be more common with the use of occlusive dressings and high potency corticosteroids. These reactions are listed in approximate descending order of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneic eruptions, hypopigmentation, hypopigmentation, perioral dermatitis, allergic contact dermatitis, skin maceration, secondary infection, skin atrophy, striae, and miliaria. Systemic absorption of topical corticosteroids has resulted in manifestations of hypothalamic-pituitary-adrenal (HPA) axis suppression of Cushing's syndrome, hyperglycemia, and glycosuria in some patients.
VANOS™ (Fluocinonide) Cream 0.1% is a corticosteroid indicated for the treatment of plaque psoriasis affecting up to 10% of body surface area (BSA). Use in patients under the age of 18 is not recommended as safety has not been established (See PRECAUTIONS - Use in children. Use.)
Treatment for more than 2 consecutive weeks is not recommended and the total dose should not exceed 60g/week as the safety of VANOS™ cream for more than 2 weeks has not been established and the drug has the potential to suppress the hypothalamic pituitary axis -Adrenal glands (HPA). Therapy should be discontinued when psoriasis control is achieved. If there is no improvement within 2 weeks, a reassessment of the diagnosis may be necessary.
DOSAGE AND DIRECTIONS Apply a thin layer of VANO S™ Cream to affected skin once or twice daily as directed by a healthcare professional. Twice daily dosing has been shown to be most effective after 2 weeks of treatment to achieve treatment success (see CLINICAL STUDIES).
Treatment with VANOS™ cream should be limited to 2 consecutive weeks and no more than 60 g/week should be used.
VANOS™ cream is contraindicated for patients with known hypersensitivity to any component of the preparation. PRECAUTIONS Hypothalamic-pituitary-adrenal (HPA) General: Systemic absorption of topical corticosteroids may result in reversible hypothalamic-pituitary-adrenal (HPA). Manifestations of Cushing's syndrome, hyperglycemia, and glycosuria may also be produced in some patients by systemic absorption of topical corticosteroids during treatment. Concomitant use of more than one corticosteroid medicinal product may increase the total systemic exposure to glucocorticoids. Patients applying a topical steroid to a large surface area or to areas under occlusion should be regularly evaluated for signs of HPA axis suppression. This can be done with the cosyntropin stimulation test (ACTH 1-24). Patients should not be treated with VANOS™ cream for more than 2 weeks at a time and only small areas should be treated at a time due to the increased risk of HPA axis suppression. Oppression.
Topically applied VANOS™ cream can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS).
Therapy should be discontinued when control is achieved. If there is no improvement within 2 weeks, a reassessment of the diagnosis may be necessary. necessary. SCOPE OF DELIVERY VANOS™ (fluocinonide) cream, 0.1% is supplied in aluminum tubes as follows: 30 g (NDC 99207-525-30) 60 g (NDC 99207-525-60) Store at controlled room temperature: 15 to 30 oC (59 oto 86 oF). Manufactured for: MEDICIS, The Dermatology Company® Scottsdale, AZ 85258
If suppression of the HPA axis is observed, attempts should be made to discontinue the drug, reduce the frequency of dosing, or substitute a less potent corticosteroid. Recovery of HPA axis function usually occurs immediately after topical corticosteroids are stopped. Rarely, there may be signs and symptoms of glucocorticosteroid insufficiency that require systemic corticosteroid supplementation. For information on systemic supplementation, see the prescribing information for these products.
Manufactured by: Patheon, Inc. Mississauga, Ontario Canada L5N 7K9
Application of VA NOS™ cream, 0.1% twice daily for 14 days to 18 adult patients with plaque psoriasis (10-50% BSA, mean 19.6% BSA) demonstrated demonstrable HPA axis suppression in 2 patients (11%).
Made in Canada
HPA axis suppression has not been studied in psoriasis patients younger than 18 years of age. Pediatric patients may be more susceptible to systemic toxicity at equivalent doses due to their increased skin surface area to body mass. (See PRECAUTIONS - Use on Children. Use.)
Prescribing information as of February 2005.
If irritation occurs, VANOS™ Cream should be discontinued and appropriate therapy initiated. Allergic contact dermatitis to corticosteroids is usually diagnosed by observing a failure to heal, rather than observing a clinical exacerbation, as with most topical products that do not contain corticosteroids. Such an observation should be confirmed by appropriate diagnostic patch testing. If skin infections are present or developing at the same time, an appropriate antifungal or antibacterial agent should be used. If a positive reaction does not occur immediately, use of VANOS™ Creme should be discontinued until the infection is adequately controlled.
Treatment of Lichen Amyloidosis with Narrow Band Ultraviolet-B Phototherapy Regional Medical Center, Grand Blanc, MI **Silverton **Silvert on Skin Institute, Grand Blanc, MI ***Hamzavi Dermatology, Port Huron Medical Center ****Faculty Department of Dermatology, Wayne State University, Detroit, MI Department of Dermatology, Henry Ford Hospital, Detroit, MI SUMMARY This manuscript describes two cases of lichen amyloidosis, a persistent, itchy condition that usually affects the front legs. Narrow-band ultraviolet-B phototherapy has been used to treat many skin diseases, but reports of its use to treat lichen amyloidosis are lacking, and no reports have shown histological cure of the disease. We describe two cases of lichen amyloidosis successfully treated with narrow-band ultraviolet B phototherapy and provide evidence for histological clearance.
CASE 1 A 74-year-old white male presented with a history of an pruritic rash on the lower extremities within the past 7 months. Examination revealed multiple pretibial and bilateral erythematous papules. Subsequent biopsy showed eosinophilic deposits in the papillary dermis and a light blue acid-Orcein-Giemsa stain, confirming that the rash was AL (Fig. 1). Attempts to control pruritus with topical fluocinolone acetonide 0.01% have failed.
Irradiation at 4.45 mW) followed by a reduction in itching and subsequent resolution of visible lesions. injuries. Another biopsy of
Figure 2. Legs of the same patient and repeat biopsy histology after treatment with NBUVB.
Rash on legs and back. Examination of her legs revealed multiple erythematous papules in a pretibial distribution bilaterally. A hyperpigmented erythematous patch was found in the interscapular region of her back. Biopsy of a pretibial lesion showed pale eosinophilic deposits in the papillary dermis that stained light blue with acid-orcein-Giemsa, consistent with amyloid. The overlying epidermis showed focal hydropic degeneration of the basal layer, confirming the diagnosis of AL. A biopsy of the spinal patch also showed eosinophilic deposits stained light blue with acid-orcein-giemsa, consistent with the diagnosis of macular amyloidosis. Treatment with NBUVB phototherapy (20 treatments, cumulative dose 28.5 J/cm 2 , irradiance 4.45 mW) first improved the pruritus and then the lesions. However, about a month later, the itching returned. Attempts to control the itching with 0.1% triamcinolone acetonide cream, 5% doxepin hydrochloride, 0.1% tazarotene cream, and 0.05% halobetasol ointment failed. Phototherapy with NBUVB was restarted (26 treatments, 24.8 second
Figure 1. Erythematous papules on legs of patient with multiple and corresponding pretibial histology before treatment.
cumulative dose J/cm, irradiance 4.45 mW) and again proved successful in controlling her symptoms and preventing her lesions from returning. The patient's condition is maintained with 0.1% tazarotene cream and NB-UVB as needed. severely affected skin showed no features of AL and acid-Orcein-Giemsa staining was negative (Fig. 2). The patient remained asymptomatic without further treatment for the following year.
CASE 2 NBUVB was then initiated (18 treatments, 15.0 J/cm2 cumulative dose,
A 41-year-old healthy Asian woman complained of a 2-year itch
DISCUSSION Finding an effective and durable treatment for AL is difficult. We present two cases of resistant LA that responded well to NBUVB phototherapy. One patient experienced histological elimination of amyloid deposits after treatment, a previously unreported result. additional exams
of NBUVB phototherapy for this condition are needed to establish their effectiveness and to develop reproducible protocols. Given the resistance of this disease to most treatment options and the success of NB-UVB in these patients, phototherapy can also be used to elucidate the pathophysiology of the disease. References IY Yashar ashar S, Gielczyk R, Scherschun L, et al. Narrow band ultraviolet B treatment for vitiligo, pruritus and inflammatory dermatoses. Photodermatol Photoimmunol Photomed. 2003 Aug;19(4):164-8 Aug;19(4):164-8. II Hudson LD. Macular amyloidosis: treatment with UV light and B. cutis. 1986 Jul;38(1):61-2. III Jin AG, Por A, Wee LK et al. Comparative study of phototherapy (UVB) vs. photochemotherapy (PUVA) vs. topical steroids in the treatment of primary cutaneous lichen amyloidosis. Photodermatol Photoimmunol mmunol Photomed. Photomed. 2001 Feb;17(1):42-3. IV Parsi K and Kossard Kossard S. Lichen thermosensitive amyloidosis. Int J Dermatol. 2004 Dec;43(12):925-8. Dec;43(12):925-8. V Hughes A, Chan H, Aronson P, P, et al. Lichen amyloidosis treated with NB-UVB. Case presented at the 2003 Michigan Dermatological Society meeting at Wayne State University, Detroit, Michigan. Available at http://www.med.wayne.edu/dermatology/MichDerm03/case16.htm.
ABBASI, SILVERTON, HAMZAVI, HAMZAVI
Epithelioid angiosarcoma vs. atypical epitheloid hemangioma: a diagnostic dilemma Theresa Ng, D.O.*, Schield Wikas, D.O.** Summa Healthcare System: Cuyahoga Falls General Hospital, Cuyahoga Falls, OH
SUMMARY Epithelioid angiosarcoma is a rare variant of high-grade cutaneous angiosarcoma. It is clinically indistinguishable from conventional cutaneous angiosarcomas. angiosarcoma. Histologically, epithelioid angiosarcomas may have similar features compared to other epithelioid tumors and may exhibit variable expression of cellular markers such as cytokeratin. cytokeratin. Because of this, it often poses some diagnostic difficulties for both the clinician and the dermatopathologist. dermatopathologist. We report the case of a 39-year-old man who presented with undefined papules on the penile shaft and subsequent biopsy led to conflicting opinions. One expert favored the diagnosis of an epitheloid angiosarcoma, the other an atypical or exuberant epitheloid hemangioma. hemangioma. We report this case because of its unusual clinical presentation and diagnostic dilemma. We also reviewed the literature on epitheloid angiosarcoma and summarized the information in a concise table.
Case Report: A 39-year-old man presented with a 2-month history of 2 asymptomatic penile nodules. The patient thought that this might be due to an injury. j. The patient reports that he was exiting a "personal protection device" to free himself from a parachute when he experienced an intense friction event, with the equipment rubbing against his genital and groin area. The patient reports that there were no abrasions or cuts on the genitals after this event. However, in the following weeks, the patient noticed the development of lesions on the penis. Physical examination reveals two well-circumscribed, purple, motile subdermal papules, approximately 2-2.5 mm in diameter, on the dorsal penile shaft, posterior to the coronet. These penile lesions were biopsied. Histopathology shows two intradermal nodular accumulations of large pleomorphic epithelioid endothelial cells arranged singly and in whorled aggregates. There were scattered lymphocytes and erythrocytes, eosinophils. (Figure 1-3) Immunohistochemical studies show strong positivity for CD31 (Figure 4) and were negative for CD34, CEA, S100 and EMA. Histological features supported the diagnosis of epitheloid angiosarcoma. Due to the rarity of this tumor, out-of-hospital consultations have been conducted with conflicting results. One of the specialists confirms and favors the diagnosis of epitheloid angiosarcoma; while the other favors the diagnosis of exuberant epitheloid hemangioma over epitheloid angiosarcoma. Despite opposing opinions, both experts recommended the patient to have definitive infestation. Total surgical excision of the patient was subsequently referred to a
Urologist for the final complete surgical removal of the affected area down to the bodies. Final pathology showed a microfocus of angiosarcoma with clear margins. This case was reviewed by a tumor panel composed of urologists and oncologists, and the consensus was that the area should undergo radiotherapy. It was also agreed that no further extirpative surgery was required. necessary. A blood count panel consisting of a complete blood count with differential, blood urea nitrogen, creatinine, electrolytes, glucose and liver profiles, and imaging studies consisting of a chest X-ray and a CT scan of the abdomen and basin, was also created. All were normal. At the 12-month follow-up status of the patient after surgical excision and radiotherapy, the patient had no therapy for tumor recurrence.
Figure 1 Low magnification: Intradermal nodular accumulations of basophil cells with extravasated red blood cells
Discussion Epithelioid angiosarcoma is a rare variant of high-grade cutaneous angiosarcoma. Clinically, it resembles conventional angiosarcomas. it often presents as a red or bluish spot, plaque, plaque, or nodule. nodules. These lesions are prone to ulceration. It occurs most commonly on the lower extremities and less commonly on the face and scalp. It is common in the middle-aged and elderly population, with a male to female ratio of 2:1. (1,2,3) The underlying pathophysiology remains unclear. Suggested implied causes are radiation exposure and foreign body reaction. (4,5) Histologically, epithelioid angiosarcomas consist of rounded epitheloid cell layers with abundant eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Irregular vascular channels lined with atypical endothelial cells can occasionally be seen dissecting the collagen bundles. Some intracytoplasmic vacuoles can be seen. This is usually an expression of
Figure 2 Higher magnification: Magnification: Irregular vascular channels can be seen
differentiated primitive luminal differentiation. in. Immunohistochemical studies that may help demonstrate vascular differentiation include Factor VIII-related antigen showing a beneficial effect on neoplastic cells in angiosarcoma; CD31, which is an antibody against the adhesion molecule found on endothelial cells and is a highly sensitive and specific marker for endothelial differentiation; CD34, the discriminating antibody proposed to distinguish between benign and malignant skin proliferation and Europaeus, is only positive in benign vascular lesions; and the Ulex I lectin, which is more delicate but less sensitive
EPITELOID ANGIOSARCOM ANGIOSARC OMA VS. ATYIC EPITELOID HEMANGIOMA: A DIAGNOSTIC DIAGNOSTIC DILEMMA
Perez Atayde and others (16)
- Recurrent tumor and
Metastases in cervical lymph nodes and right humerus at 20 months of follow-up - Pt died 6 months later from meningitis due to direct tumor extension to the meninges.
Marrogi et al. (8)
- Observed axillary metastases
Lymph nodes at 30 months and cervical lymph nodes at 59 months. - 67 months after treatment, the patient is in good condition with no new metastases or recurrences
- tumor recurrence and
Metastases in lymph nodes and right posterior rib. - 53 months after the initial excision, the patient remained healthy with no clinical signs of tumor
On the side
- 10 months after presentation, the patient is alive with disseminated tumor
Fletcher and others (11)
- Rapidly growing tumor and metastases in the inguinal lymph nodes and right lung within 3 weeks - Pt died 2 months after initial presentation
-after a few weeks, metastases
on right maxillary gingiva - 1 year later, metastases in femoral artery and abdominal aorta resected and transplanted - 2 1/2 years after presentation, the patient is alive and disease free
- at the 1-year follow-up
treatment, pt lives and
Lung lobectomy and rib resection 36/M
considered a tumor
- in 1 year follow-up is pt
terminally ill with extensive
Next Next Table 1
- pt was diagnosed with multiple lung and pleural metastases on presentation - pt died 4 months after the first metastasis
-Local recurrence occurred in 4 months of follow-up -Lost to follow-up
Prescott and others (12)
- after 2 months follow-up, no
Evidence of observed Mets
-pt died 6 months later
-pt died 5 years after the first
secondary lung recurrence
several surgical su
-pt died 4 years later
Metastases in the lungs, adrenal glands,
and kidneys, as observed in
Autopsy McCluggage and others (6)
- 3 months after the first excision, metastases were observed in the removed right fibula. -no more follow-up data available
Hallel-Halevy and others (15)
Above the knee
-rare complication of
Elephantiasis - follow-up data not available
specifically as a factor VIII-related antigen in the identification of angiosarcoma. (1) There have been some reports of angiosar-
Figure 3 Higher magnification: Magnification: Large, pleomorphic endothelial cells arranged solitary and in whorled aggregates, with lymphocytic infiltrate containing some scattered eosinophils and extravasated red blood cells
Figure 4 Immunohistochemical studies showed strong CD31 positivity
Comas expressing positivity for cytokeratin. (6) Because of its variable cytokeratin expression, it poses diagnostic difficulties in distinguishing between angiosarcoma and epithelioid melanoma and other carcinomas. (7) Ultrastructural studies often reveal abundant cytoplasmic intermediate filaments, numerous pinocytic vesicles, intracytoplasmic vacuoles, and few or no Weibel-Palade bodies in neoplastic endothelial cells. (1,6,8) Differential diagnoses of epitheloid angiosarcoma include epitheloid hemangioma, epitheloid hemangioendothelioma, epitheloid sarcoma, and malignant epitheloid melanoma. The epitheloid hemangioma is a rare benign vascular tumor. Typical and atypical or exuberant examples of epithelioid hemangiomas have been reported. Exuberant epithelioid hemangiomas can often be confused with epithelioid angiosarcomas. Histologically, they may be similar; however epithelial
Angiosarcomas show a more pronounced destructive growth pattern, a high mitotic rate with atypical mitoses, and significant nuclear variability. (9) Epithelioid hemangioendothelioma is a low-grade angiosarcoma first described in 1982 by Weiss and Enzinger. Histologically, this tumor is characterized by a proliferation of strands and nests of fleshy epitheloid eosinophilic cells embedded in a fibromyxoid or sclerotic stroma. Cytoplasmic vacuoles and slight pleomorphism and occasionally mitotic figures are present. Except in the periphery, large vascular canals are rarely seen. These features confer an intermediate histopathologic appearance between epitheloid hemangioma and epitheloid angiosarcoma. The latter differs from epitheloid hemangioendothelioma in increased cellularity, characterized by tighter layers of neoplastic cells with pronounced atypia and pleomorphism and abundant mitotic figures. In addition, mass necrosis is when necrosis occurs both in individual cells and in large areas of the neoplasm. (10) In addition, epithelioid angiosarcoma has been misinterpreted due to the fact that epithelioid carcinoma and melanoma have been misinterpreted
Table 1. Of the 18 cases, 13 were males and 5 were females. Women. The age of the patients ranged from 32 to 32 to 83 years. Sites of involvement, in descending order of frequency, were: lower extremities (26%), upper extremities (16%), face (16%), buttocks (16%), scalp (11%), trunk (11%), and groin (1 case). ). The treatment regimens these patients received ranged from varying degrees of surgical excision, chemotherapy, chemotherapy, and radiotherapy. One of 18 patients succumbed to the disease 2 months after presentation before data treatment could begin. In 2 of the 18 cases no treatment was available; and follow-up data were not available in 3 of the 18 cases. Cases. Local recurrences were observed in 4 of 15 cases (27%). Metastases were observed in 11 of 15 cases (73%).
that these immunohistochemical tumors express cytokeratin. (6, 11, 12) Studies including S100, CD31, CD34, Factor VIII-related antigen, Ulex europaeus I-lectin, and EMA are invaluable in delineating these differential diagnoses. (7, 13) Epithelioid angiosarcomas usually follow an aggressive behavior with high local recurrence and the possibility of metastasis in about one third of the cases. (14) However, a few cases of slow and persistent-onset epitheloid angiosarcoma representing a lesser grade of malignancy have been reported. Malignancy. (8) It is still unclear whether this tumor has a better prognosis compared to other variants of angiosarcomas. Treatments for epitheloid angiosarcoma include surgical excision with wide margins with or without chemotherapy and radiation therapy. Therapy.
and gluteal epitheloid regions. Angiosarcoma We report a case of a skin tumor on the dorsal shaft of the penis. Due to its histological and morphological basis, this tumor often presents diagnostic difficulties for both clinicians and pathologists. There was conflicting information about the prognosis. Despite aggressive therapy, local recurrences and metastases often occur due to its multifocal nature and unremarkable subclinical spread. (fifteen)
Literature review Angiosarcoma was first systematically described in 1945 by Caro and Stubenrauch. Its association with lymphedema after mastectomy was later described by Stewart & Treves 1948. Angiosar Angiosarcomas occurring on the face and scalp of the elderly were described by Wilson-Jones in 1964. (14) Cutaneous epithelioid angiosarcomas have only recently been described. To our knowledge, a total of 18 cases of cutaneous epitheloid angiosarcoma have been reported in English. language.reported These cases are summarized and presented in
Conclusion: In summary, cutaneous epitheloid angiosarcoma is a rare histological variant of cutaneous angiosarcoma with a predilection for the lower extremities. Extremities. However, there have been some reports of it on the scalp, face, upper extremities,
References 11. Requena L., Sanqueza, OP. OP. Cutaneous vascular proliferations. Part III: Malignant neoplasms, other cutaneous neoplasms with a significant vascular component, and diseases mistaken for vascular neoplasms. J.Am. Acad. Dermatol 1998; 38:143-175. 2. Odom R, et al. Andrews Diseases of Andrews Skin. 9th ed. Philadelphia, PA: PA:WB Saunders Co. 2000; pages 760-762. 3. Bolognia J. et al. Dermatology. 1st Ed. New York: Elsevier Ltd. 2003; pp. 1833-1835. 4. Jennings TA, Peterson L, Axiotis CA, Freidlander GE, Cooke RA, Rosai J. Angiosarcoma associated with foreign body material: report of three cases. Cancer 1988;62:24362444. 5. Rao J, DeKoven JG, Beatty JD, Jones G. Cutaneous angiosarcoma as a late complication of radiotherapy in breast cancer. J.Am. Acad. Dermatol 2003; 49:532-538. 6. McCluggage WG, Clarke R., Tonerner PG. Cutaneous epitheloid angiosarcoma with cytokeratin positivity. Histopathology 1995; 27:291-294. 7. Pastor D, van den Oord (President). Symposium 8: Pathology and Pathophysiology of Melanocytic Disorder. Histopathology 2002; 41 (Supplement 2): 120-146. 8. Marrogi AJ, Hunt SJ, Santa Cruz DJ. Cutaneous epitheloid angiosarcoma. Am J Dermatopath 1990; 12(4): 350-356. 9. Fetsch JF, Sesterhenn IA, Miettinen M, Davis CJ. Epithelioid hemangioma of the penis: Clinicopathologic and immunohistochemical analysis of 19 cases with special reference to exuberant examples commonly confused with epitheloid hemangioendothelioma and epitheloid angiosarcoma. Am J Surg Pathol 2004; 28:523-533. 10. Forschner A, Harms D, Metzler G, Sonnichsen K, Ulmer A, Rassner G, Fierlneck G. Ulcerated epitheloid hemangioendothelioma of the foot in childhood. J.Am. Acad. Dermatol 2003; 49:113-116. 113-116. 11. Fletcher CDM, Beham A, Bekir S, Clarke AMT, Marley NJE. Deep epitheloid angiosarcoma of the soft tissues: a disease
EPITELOID ANGIOSARCOM ANGIOSARC OMA VS. ATYIC EPITELOID HEMANGIOMA: A DIAGNOSTIC DIAGNOSTIC DILEMMA
Tinctive tumor easily mistaken for an epithelioid neoplasm. Am J Surg Pathol 1991; 15(10): 915-924. 12. Prescott RJ, Banerjee SS, Eyden BP, Haboubi NY. Cutaneous epitheloid angiosarcoma: A clinicopathologic study of four cases. Histopathology 1994; 25:421-429. 13. Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D. Angiosarcomas express mixed endothelial phenotypes of blood and lymph capillaries: Podoplanin as a specific marker for lymphatic endothelium. Am J Surg Pathol 1999; 154:385-394. 14. Perez-Atayde, AR, Achenbach J, Lack EE. High grade epitheloid angiosarcoma of the scalp. Am J Dermatopath 1986; 8(5): 411-418. 15. Hallel-Halevy D, Yerushalmi J, Grunwald MH, Avinoach I, Halevy S. Stewart-Treves syndrome in a patient with elephantiasis. J.Am. Acad. Dermatol 1999; 41:349-350.
Erythromelalgia: Case Report and Literature Review Shannon M. Campbell, MSIV BS*, Dianne Kreptowski, D.O.**, Cynthia H. Halcin, M.D.*** *4. year medical student at the Ohio University College of Osteopathic Medicine. Medicine. **Family **GP in North Canton, Canton, Ohio. *** Board-Certified Dermatologist from the Dermatology Institute of Brevard in Rockledge, Florida. SUMMARY Erythromelalgia is a rare condition characterized by severe pain, erythema, and increased skin temperature, primarily affecting the hands and feet. Although the pathophysiology is not fully understood, it has been hypothesized that erythromelalgia is the result of a combination of neuropathy and a disruption in vascular dynamics. Treatment Treatment of erythromelalgia is empirical with mixed results. Recent clinical studies have suggested promising results using calcium channel blockers and magnesium therapy. Below is a case report and a literature review.
Case Report A 66-year-old Caucasian female patient was referred for dermatological evaluation after one year of presenting with an intensely painful erythematous rash extending bilaterally from the dorsal surface of the feet to the medial region of the tibia in a circumferential pattern (Figures 1 and 2 ). There was thickening and yellowing of the nail plate on all ten toenails. The patient first noticed paresthesia in her left foot a year before presentation. Presentation. Gradually, the erythema and pain in the left foot progressed cranially. A similar pattern emerged a week later in the right limb. His history was significant for surgery on his left ankle four years prior to presentation. Dog. First she was diagnosed with cellulitis by her GP and was treated with Cephalexin for 14 days. When her symptoms did not improve, the patient was placed on vancomycin for a period of ten days. Vancomycin was discontinued when the patient's symptoms did not improve. In addition, nail scrapes taken for fungal culture in the family doctor's office were negative. On presentation to the dermatology clinic, macroscopic examination revealed edema, extensive desquamation of the lower extremities, and erythema (Figure 3). The plantar surface of the feet was spared on both sides. The skin on the foot and shin was warm and blanched slightly when light pressure was applied. All ten toenails showed thickening and yellow discoloration of the nail plate (Figure 3). Foot pustules were present and normal on both sides. KOH preparations of toenails were repeated and found negative for fungal elements. The laboratory evaluation was positive for antinuclear antibodies (ANA) and an ESR value was positive at 95. The lupus panel, without ANA, was negative. CBC, EKG results, normal limits. and Repeated punching of a chest X-ray in which the internal biopsies were normal and showed no histological findings consistent with cellulitis,
systemic lupus erythematosus, discoid lupus, sarcoidosis, or scleroderma. Reflex sympathetic dystrophy (RSD) was suspected due to the patient's previous traumatic event of ankle surgery and her symptoms of abnormal heat, erythema, and burning pain. However, based on the medical history, this was ruled out. Story. The patient's symptoms were spontaneous and unrelenting. In RSD, symptoms can usually reverse and the affected limb may become cold and contract, a feature not seen in this patient. Patiently. In addition, the patient's disease course was bilateral. Although RSD can occur bilaterally, it usually follows a unilateral distribution. Based on the medical history, medical history, description of symptoms, and laboratory findings, a diagnosis of erythromelalgia was made. Treatment was started with aspirin but was unsuccessful in relieving pain or other symptoms. Trials of calcium channel blockers, gabapentin, and the fentanyl patch were also tried but failed to bring relief to the patient. The patient is still suffering from erythromalagia without significant pain relief and is currently experimenting with magnesium therapy.
Literature review Erythromelalgia (EM) is a rare condition consisting of erythema (erythro), burning pain (algia), and increased skin temperature, usually affecting the lower limbs (melos). Erythromelalgia has also been termed erythermalgia to reflect the rise in skin temperature (thermos) so characteristic of the condition1-3. There are currently no definitive diagnostic studies confirming the presence of the disease2-5. However, general criteria are used to make a diagnosis. In the Davis et al. The study used three inclusion criteria: red, hot and burning extremities4. Thompson et al established five criteria for making a diagnosis of MS: 1) burning pain in the extremities, 2) pain aggravated by heating, 3) pain relieved by cooling, 4) erythema of the affected skin, and 5) increased temperature of the affected skin skin2-
Figure 1 Front view of the patient's lower extremities. Note erythema and symmetrical involvement
Figure 2 Posterior aspect of the patient's lower limbs. Note the perimeter distribution
ERYTHROMELALGIA: CASE REPORT AND LITERATURE REVIEW
Figure 3 Patient's left foot. Note the involvement of the toenails and the swelling and peeling of the skin
. Although these inclusion criteria are helpful in making a diagnosis of MS, the incidence and prevalence of erythromelalgia in the United States is unknown5. Researchers classified erythromelalgia as primary or secondary5,6. Primary erythromelalgia occurs spontaneously and affects patients of all ages, while secondary erythromelalgia is associated with a variety of disorders ranging from blood dyscrasias to autoimmune disorders. Mork's additional classification of MS divides erythromelalgia into two broad categories, 'syndrome' and 'phenomenon'. Adolescence, while "phenomenon" is reserved for all other cases. In this classification, the “phenomenon” is divided into primary and secondary EM as described above. 2 The exact pathophysiology of EM is unknown. The underlying pathophysiology appears to be an ambiguous interaction between disruption of vascular dynamics and small fiber neuropathy1,7. The vascular component of the pathophysiology of MS lies in a fundamental imbalance of blood perfusion 2,5,6. The precapillary sphincters responsible for oxygen supply are contracted. restricted. in the 3rd
In response, the body's blood flows to the affected area. At the same time, the arteriovenous anastomoses, which are responsible for heat and temperature regulation, are left open. The combination of these two events results in increased total blood flow with poor nutrient flow. Consequently, there is "the coexistence of hypoxia and hyperemia in the affected skin" 8 (p. 191). In addition, Davis et al. observed that most patients with MS have small fiber neuropathy7. Interestingly, the neuropathy is speculated to affect vascular tone, resulting in the pathologic environment previously described. until now. However, there is no conclusive evidence as to how the two findings interact or what the primary abnormality is7. There is some speculation about the role of genetics in erythromelalgia. A study published in the American Journal of Human Genetics 32
suggests that there is a primary erythromelalgia susceptibility gene located on chromosome 2q31-329. The natural history of erythromelalgia differs from patient to patient and based on a study by Davis et al. compiled with 168 patients with MS4. Onset can be gradual over years or sudden over weeks. Some cases remain mild and only manifest during acute exacerbations. Patients with mild erythromelalgia have "accidents" that usually occur later in the day. Patients are usually asymptomatic between attacks. Other people with MS have a steady course, mild or severe in quality, that can progressively worsen over time. Typically, erythromelalgia romelalgiaa occurs on the feet and hands with bilateral distribution. However, erythromelalgia can be unilateral and occur in areas where arteriovenous anastomoses predominate, such as the nose and ears 3-5. Erythromelalgia sufferers are incredibly intolerant of heat, a reality that greatly affects their lifestyle. Lifestyle. Heat serves as a trigger for attacks and aggravates current episodes, increasing their severity and the patient's need for relief. Relief. Some patients are more sensitive to heat changes than others.
The treatment of erythromelalgia remains a trial and error process5. For many patients, lifestyle changes have proven to be very beneficial, ranging from simple adjustments like wearing open-toe shoes year-round to more drastic measures like moving to cooler environments1,5. Initial research has shown relief with capsaicin cream, but later studies have disputed this 4. A wide range of medications have been used with mixed success. One of the most common options is aspirin, which has been shown to be therapeutic for patients with MS secondary to blood dyscrasias5. According to Cohen, calcium channel blockers, specifically diltiazem and amlodipine besylate (Norvasc™), are the first-line treatments for MS11. Similarly, Ly, magnesium that also acts as a calcium antagonist, provides relief for MS patients1,10,11. Chelated or liquid magnesium usually produces the most beneficial results. Selective serotonin reuptake inhibitors such as venlafaxine12 (Effe (Effexor™), xor™), tricyclic antidepressants, and anticonvulsants such as gabapentin reduce pain associated with the condition. It is common to use gabapentin in combination with an SSRI or a tricyclic antidepressant5,11. Other treatment options include
he. To combat the patient's room temperature increase in water immersion, a practice discouraged due to the increased risk of causing skin lesions, irritant contact dermatitis, ulcers and possible amputations3,5. Some erythromelalgia victims find relief by elevating the affected areas, avoiding tight clothing or shoes, or taking portable respirators with them wherever they go. walk. Other triggers for the disease include exercise, certain foods or drinks such as alcohol, and psychological elements such as stress or depression5. In addition to being physically demanding, erythromelalgia has psychological and social costs for patients. Pronounced erythema, swelling and nail changes are a cosmetic problem for many. The pain associated with erythromelalgia interferes with daily functioning, including activities of daily living and work performance. acting. In addition, many patients avoid triggers such as heat, exercise, or excessive exercise, which includes going to the store or leaving the home. Heat, in particular, has forced many MS patients to avoid hot weather, change clothes, or avoid hot baths. As a result, many patients are homebound, a risk factor for developing loneliness and depression1. In addition, suicide remains a problem that is often overlooked by physicians and their patients. Patients, particularly those with severe MS, are frustrated by this
enteralhas addresses this inasome nitroprusside that has been useful in children and adolescents and is considered the drug of choice for these age groups 5,11. Lidocaine and prostaglandin infusions are also used with mixed results. Invasive procedures available to patients with MS include sympathetic and epidural blocks, sympathectomies, and use of a spinal cord stimulator5. In addition, there was also a documented case of treatment with hyperbaric oxygen11. In this patient, hyperbaric therapy did not improve symptoms, but actually aggravated them. Overall, treatment is a complicated process and should be approached in stages. Erythromelalgia remains a rare condition that poses challenges for both patients and clinicians. MS has a complicated profile, from its pathophysiology to its natural history, and continues to have a profound impact on patients' physical, social and psychological lives.
their illness, its disabling nature, treatment and lack of lastingly effective options.
Presentation and outcome in 168 patients. Archives of Dermatology 2000;136:330-336.
CAMPBELL, KREPTOWSKI, HALCIN H ALCIN
Davis, MDP MDP. Rooke, Rooke, T. erythromelalgia. Current treatment options in cardiovascular medicine 2002; 4(3):207-222.
Mork, C. Erythromelalgia: A Mysterious Condition? Archives of Dermatology 2000 Mar;136:406-409.
Thompson GH Hahn, G. Rang M. Eritromelalgia. erythromelalgia. Clinical Orthopedics 1979;114:249-254.
Davis, M.D.P. M.D.P.. O'Fallon W.M. R. Rogers, R. S. III, Rooke T. W. História Natural da Eritromelalgia: T.W.
Cohen J.S.J.S. Erythromelalgia: Erythromelalgia: New theories and new therapies. Journal of the American Academy of
Dermatology 2000; 43(5 point 1):841-7. 6.
Mork, C. Kvernebo, K. Asker, Asker, C.L. and Salerud, Salerud, E.G. Reduced cutaneous capillary density during attacks of erythromelalgia implicates arteriovenous shunt as a pathogenic mechanism. Journal of Investigative Dermatology 2002;119:949-953. Davis, MDP MDP Sandroni, P. Rooke, T.W. TW Bass, Bass, PA Erythromelalgia: vasculopathy, neuropathy, or both? Dermatological Archive 2003; 139:1337-1343. Kalgaard O.M., Seem E. Seem, Kvernebo K. Erythromelalgia: Erythromelalgia: A clinical study of 87 cases. Journal of Internal Medicine 1997;242:191-197.
Heutink, P. P. The primary gene for susceptibility to erythermal pain is located on chromosome 2q31-32. American Journal of Human Genetics 2001; May 68(5): 1277-82. 10. Cohen, J.S. Oral magnesium in high doses Magnesium treatment Treatment of chronic and intractable erythromelalgia. The Annals of Pharmacotherapy 2002; 36: 255-259. 11. Cohen, J.S. Current treatment information Treatment of erythromelalgia (leaflet). (flyers). Association for Erythromelalgia. June 2002. 12.
DiCaudo, D.J. DJ Relief of Erythromealgia with Venlafaxine. Archives of Dermatology 2004;140:621-623.
Drenth, J.P.J.P. Gut, W.H. Breedveld, G.J. Testers, L. Michiels, J.J. Guillet G. Taib Taib, A. Kirby R.L.
ERYTHROMELALGIA: CASE REPORT AND LITERATURE REVIEW
Gianotti-Crosti syndrome: case presentation Dimitry Palceski, DO*, Schield Wikas, DO, F.A.O.C.D** *3. Year Resident Dermatology **Program Director Cuyahoga Falls General Hospital Dermatology Resident, Ohio University College of Osteopathic Medicine Gianotti-Crosti (GSC) syndrome is a self-limiting disorder of acute onset and characterized by lymphadenopathy, monomorphic erythematous papules symmetrically affecting the face, extremities and Buttocks are distributed. Buttocks. We present a case and a review of the literature.
A 1-year-old Caucasian patient presented with her parents with reddish papules on her arms, legs, and feet that had been visible for at least 5 days (Figs. 1 and 2). This rash was minimally itchy and not progressive. Her parents noted that she was irritable and somewhat lethargic for a few days before the performance, but had no fever, nausea, vomiting, or diarrhea. The child was in good health with no history of recent illness. A week before her presentation at the clinic, she had received a vaccine against Haemophilus influenzae type B and hepatitis B. No other family members were affected and there were none
chronic liver disease).3 When it was not associated with hepatitis, he called it acrolocalized papulovesicular syndrome. 2 Since that first description, studies have shown that GCS is actually more commonly associated with Epstein-Barr virus than with HBV infection in Western countries. 4 Other viral infections associated with GCS include cytomegalovirus, coxsackievirus, enterovirus, human immunodeficiency virus,
travel history. Story. and the child was not taking any medication, had no known drug allergy. Past medical history was essentially normal with a history of uncomplicated delivery. There was a positive family history of asthma. At the time of the examination, the child appeared to be doing well. His development seemed appropriate for his age. Discrete flattened erythematous papules and papulovesicles were observed bilaterally on the arms, legs, and dorsum of the feet. Foot. Face, cheeks, torso, palms of hands, soles of feet and mucous membranes were spared. No lymphadenopathy or hepatosplenomegaly was observed. Blood cell counts showed increases in white blood cells (12.78 [3510.0]), platelets (408 [133-364]) and lymphocytes (71 [16-41]). The liver function panel showed an increased alkaline phosphatase of 1208 [50-136]. Serology was negative for HCV antibody (AB), HAV-AB (IgM), HB surface antigen and HB core antigen (IgM). The dermatopathological evaluation of a skin biopsy showed a dense superficial and middermal lymphohistiocytic infiltrate with reactive lymphoid atypia and focal lymphocytic exocytosis (Fig. 3 and 4). Based on dermatopathology, medical history, physical findings and diagnosis of Gianotti Crosti Syndrome (papular acro-
19 influenza virus, varicella virus, human-human parvovirus, herpesvirus B6 and poxvirus.5-9 GCS has also been reported following immunization with diphtheria-tetanus-acellular pertussis, oral polio, measles, mumps and rubella, hepatitis B and Encephalitis B vaccines reported Japanese. 10-16 An interesting case of GCS after milking knots was also reported by de la Torre17
childhood dermatitis) has been identified. Gianotti's papular matitis of childhood (CAP) was first described in 1955 and later by Crosti in 1956. , symmetrical, flat papules (25 mm in diameter), pink to reddish brown, on face, extensor surfaces of limbs and buttocks. These papules usually last 3 to 5 weeks, do not itch, do not recur, and may Koebnerize. Mucous membranes are not affected. Gianotti originally described three features of the syndrome: non-recurrent erythematopapular dermatitis of the face and extremities (lasting about 3 weeks); paracortical hyperplasia of lymph nodes; and acute anicteric hepatitis lasting at least 2 months (with the possibility of progression PALCESKI, WIKAS
Because GCS is an enigmatic response to many different drugs and less than half of patients are diagnosed etiologically,18 Ricci et al. the tendency to atopy in patients with this syndrome.19 In this study of 29 patients, atopic dermatitis was observed in 24.1% of children with GCS; a statistically significant percentage. Considering that the atopic disease does not fully manifest in the subjects studied in this study (mean 31 months) and that family history is a strong risk factor for the future development of atopy (73%), 20 this is suggested the association between atopics and GCS may be even greater.19 This suggests an interesting correlation that atopy may play a conditioning role in the development of GCS in children exposed to various microbiological agents. There is a history of differences in previous descriptions of the GCS entity. The diagnostic criteria were established by Chuh (Table 1). 21 All positive criteria were shown to be 100% sensitive for diagnosis. The most specific and predictive
Table 1. Diagnostic criteria for Gianotti-Crosti syndrome Diagnostic criteria for Gianotti-Crosti syndrome
Proposed Diagnosis Eastern Criterion Proposed Criterion Patient Patient exposure shows at least once all possible clinical and clinical features or
clinical clinical encounter, and the patient patient does not show any negative negative features on any occasion or related clinical clinical encounter of the rash, h, e criteria, and when a biopsy of the lesion is performed, the final findings are consistent with h GCS
Positivo Pos itive ve Clínico Al Featur tures es Monomorpho Monom orphous, us, flat-top -top, ed, pinkpink-braun braun
Papule without papule or papule papulovesculae vesicles 1-1 1-10 0 mm diameter Any 3 or all 4 sites affected: cheeks, s, buttocks, buttocks, ks, extensor extension, or superficial surfaces es of forearms, ms, extens ens sensor, or surfaces es de leges es de expectas gs symmetry duration duration 10 days or more re
Negative Negative ve Clinical features Extensive Extensive shortened lesions Squamous lesions Squamous lesions
The definitive criterion is a rash lasting at least 10 days (61.3% and 47.8%, respectively). Interestingly, the interesting symmetry was (19.4% as less specific and predictive and 30.6%, respectively). The absence of extensive trunk lesions was reported to be 35.5% specific for GCS. It is important to emphasize that the presence of trunk lesions does not preclude the diagnosis of GCS; Trunk lesions may be present but are usually much less prominent and of shorter duration than acral distributed lesions.22 Differential diagnosis requires that lichenoid eruptions be contrasted for onset, distribution, color, pruritus, and Koebnerization. Rashes to consider include lichen planus, lichen nitidus, lichen striatum, purpura pigmentosa, and lichenoid drug eruptions.23 Other pathologic conditions to consider in the differential diagnosis include acrodermatitis enteropathica, erythema
Infection theme, hand-foot-mouth disease, Henoch-Schonlein purpura, Kawasaki disease, scabies, papular urticaria, viral rashes, erythema multiforme, molluscum contagiosum, and childhood asymmetric periflexural rash. The presence of another co-occurring dermatological condition does not preclude the diagnosis of GCS, and conversely, failure to identify a causative agent (usually viral) does not preclude a case of GCS.6
1979;100:49-59. 4. Chuh A, Lee A, Zawar V. The diagnostic criteria for GianottiCrosti syndrome: are they applicable to children in India? Pediatric Deramtol; 21:542-47. 5. Chuh A, Chan H, Seng S, et al. A Prospective Case-Control Study of the Association of Gianotti-Crosti Syndrome with Human Herpesvirus 6 and Human Herpesvirus 7 Infections Pediatr Dermatol 2002;19(6):492-97. 6. Carrascosa J, Just M, Ribera M et al. Papular acrodermatitis in infancy associated with smallpoxvirus and parvovirus B19 infection. Cutis 1998;61:265-7. 7. Yoshida M, Tsuda N, Morihata T et al. Five patients with localized facial rashes associated with Gianotti Crosti syndrome caused by primary Epstein-Barr virus infection. J Pediatrics 2004;145(6):843-4. 8. Baldari U, Cattonar P, Nobile C et. Al. Gianotti-Crosti infantile acrodermatitis and Lyme disease. Acta derm Venereol Venereol 1996:76:242-3. 9. Metry D, Katta R. New and emerging pediatric infections. Dermatol Clin 2003;21(2):269-76 2003;21(2):269-76. Crosti syndrome. Dermatol 2002;204:75-6. 11. Velangi SS, Tidman MJ. Gianotti Crosti syndrome after measles, mumps and rubella vaccination. Br J Dermatol 1998; 139:1122-3. 12. Tay Y. Gianotti-Crosti syndrome after immunization. Pediatr Dermatol 2001;18(3):262. 13. Mruphy LA, Buckley C. Gianotti-Crosti syndrome in a child after immunization. Pediatr Dermatol 2000;17:225-6. 14. Erkek E. Gianotti-Crosti syndrome preceded by oral polio vaccination and followed by chickenpox infection. Pediatr Dermatol 2001;18(6):516-18. 15. Haug S. [Gianotti-Crosti syndrome after immunization]. Dermatologist 2002;53(10):683-5. 16. Kang NG, oh CW. Gianotti-Crosti syndrome after vaccination against Japanese encephalitis. J Korean Med Sci 2003;18:459-61. 17. de la Torre C. Gianotti-Crosti syndrome after milk nodules. Cutis 2004;74:316-8. 18. Taieb A, Plantin P, Pasquier PD, Guillet G, Maleville J. Gianotti-Crosti syndrome: a study of 26 cases. Br J Dermatol 1985; 115:49-59. 19. Ricci G., Patrizi A., Neri I. et. Al. Gianotti Crosti syndrome and allergic background. Acta Derm Venereol 2003;83:20205. 20. Bolognia, Joseph Jorizzo, Fonald Rapini, eds. Dermatology. New York: Mosby, 2003. 21. Chuh A. Diagnostic Criteria for Gianotti-Crosti Syndrome: A Prospective Case Control Study for Validity Assessment. Cutis 2001;68(3):207-13. 22. Chuh A, Trunk lesions do not preclude the diagnosis of Gianotti-Crosti syndrome. Aust J Dermatol 2003;44:21516. 23. Tilly J, Drolet B, Esterly N. Lichenoid eruptions in children. J.Am. Acad. the Matol. 2004;51(4):606-24. 24. Stefanato C, Goldberg L, Andersen W, Bhawan J. GianottiCrosti syndrome presenting as lichenoid dermatitis. Am J Dermatopathol 2000;22(2):162-5.
The histology of GCS is nonspecific. Dermatopathologic features usually include perivascular and interstitial lymphohistiocytic infiltrate in the upper dermis, dermal papillary edema, diffuse lichenoid infiltrate, mild basal vacuolar change, focal parakeratosis, psoriasiform epidermal hyperplasia, and occasionally extravasated red blood cells. Stefanatoet. Al. speculated that the different histopathologic patterns of GCS reflect the different etiological agents that cause it.24 This syndrome usually resolves within 3-4 weeks with a good prognosis. Treatment should be determined symptomatically. Oral antihistamines are sometimes helpful, while corticosteroids are usually ineffective. ineffective. References 1. Crosti A, Gianotti F. Dermatosis eruptive acrosituee d origineprobably virosique. Acta Derm Venereol 1957;2:14649. 2. Gianotti F. [Infantile papular acrodermatitis. papulosa and the acrolocalized syndrome of infantile papulovesicular acrodermatitis.] Hautarzt 1976;27:467-72. 3. Gianotti f. Papular acrodermatitis in childhood and other acrolocalized papular-vesicular syndromes. Br J Dermatol
GIANOTTI CROSTI SYNDROME: A CASE PRESENTATION
Unilateral Grover's Disease Mary K. McGonagle, D.O.*, Stephen M. Purcell, D.O.**, Donald J. Adler, D.O.*** , Lehigh Valley Hospital Dermatology Residency Program, Allentown, PA *** Lehigh Valley Hospital Dermatology Residency Clinical Educator, Doylestown, PA SUMMARY Grover's disease is a transient acantholytic dermatosis that typically affects men over forty. 1 Lesions are most commonly found in a generalized pattern on the trunk.2 Pattern.2 Unilateral eruptions are rare.3 Rare.3 A case of Grover's disease is reported that was unilateral. The clinical and histopathologic features of Grover's disease are generally described. The etiology, etiology, associated diseases, and treatment options are discussed.
Case Report: Our patient is a 65-year-old white male who presented with an pruritic abdominal and flank rash that was mainly confined to the right side. The rash seemed to get worse during the winter months. Physical examination revealed erythematous and keratotic papules in a linear array on the right abdomen, extending to the right flank. The eruption appeared to follow Blaschko's lines (Figures 1A, B, C). Histopathological examination of two core biopsy specimens revealed acantholysis (Fig.
2A) 2B focal cells, known bodies and circles, and dyskeratotic granules (Figures 2C). When
Discussion Transient acantholytic dermatosis was first described in 1970 by Ralph Grover, M.D.4. It mainly affects males over 40 years of age.1 Clinical Small erythematous papules or small, discrete papulovesicles are observed clinically. The lesions are mainly distributed on the trunk and often occur around the collarbones, anterior chest, lower chest, upper back and lumbar region.2 The rash may spread to involve the deltoids, lateral neck and thighs.5 There have been reports of localized cases affecting only the face, lateral neck, or lower lower extremities. Extremities. The rash usually spares the palms and soles.6 The scalp is usually unaffected, and lesions of the mucous membranes are rarely seen in the larynx and nostrils.5 When the oral cavity is affected, the lesions resemble cancerous growths. The presence of itching is variable. The condition is self-limiting but can last months to years.2
Histopathology The main histopathological feature of Grover's disease is acantholysis. This typically follows four patterns:5,7 a. Pattern of Darier-White disease: There are clearly circumscribed areas of focal acantholysis with formation of suprabasilar fissured cells. The presence of dyskeratotics in the form of round bodies and body granules 36
the epidermis is present with numerous acantholytic cells and scattered dyskeratotic cells. The epidermis is less hyperplastic and the acantholysis more localized than in classic Hailey-Hailey disease. c. Pemphigus vulgaris variant: There are narrow slit-like suprabasilar clefts with some acantholytic acantholytic cells. Typically, dyskeratosis is not observed. i.e. Spongiotic variant: Well-circumscribed and tense intraepidermal spongiotic vesicles with some acantholytic cells are present. The presence of spongiosis and acantholysis distinguishes it from spongiotic dermatitis. A variable number of eosinophils may be present. The intensity of the eosinophilic infiltrate may correlate with the intensity of the pruritus.2 Eosinophils may indicate some type of hypersensitivity reaction. 6 In general, the immunofluorescence test is usually negative.3 When positive results were obtained, the results were inconsistent.2,8
Etiology Figure 1B
Figure 1C Figures 1A, B, C: Erythematous papules distributed mainly unilaterally on the right abdomen and extending to the right flank and right back and distributed along the Blaschko lines
are also characteristic. B. Hailey-Hailey disease pattern: the classic crumbling mural of McGONAGLE, PURCELL, ADLER
The etiology of Grover's disease is largely unknown; However, several causes have been speculated. Grover' Grover's disease may be a reaction to excessive heat as it commonly 2,10,11 affects the backs of bedridden and febrile patients. The rash has also been reported in patients who frequently use steam rooms, hot tubs, or heating pads. Initial flares coinciding with recent intense sun exposure have also been observed.2,6 There are several reports of the development of transient acantholytic dermatosis in cancer patients following radiation therapy.2,11 Only two drugs have been associated with the development of Grover's disease brought. Sulfadoxine-pyrimethamine is believed to be an antimalarial agent that causes Grover's disease by lowering the patient's erythema threshold to UVB radiation.2,12 Recombinant IL-4 is believed to cause Grover's disease by activating the Plasminogen / plasmin system induced. Plasminogen has been detected in basal buds and acantholytic cells in Grover's disease.
Figure 2A [Right Abdomen, Specimen 1] There is a suprabasilar cleft and early acantholysis. Hematoxylin and Eosin stain, 10X
Figure 2B [Right abdomen, part 2] Parakeratotic stratum corneum, hypergranulosis and focal dyskeratosis in the granular layer and irregular acanthosis of the epidermis. A sparse lymphocytic infiltrate is present in the upper dermis. Hematoxylin and Eosin stain, 10X
Figure 2C At higher magnification, the focal accumulation of dyskeratotic cells in the stratum corneum can be seen. These dyskeratotic cells are more commonly known as round bodies and body granules. Hematoxylin and Eosin stain, 40X
Plasminogen is known to degrade desmosomes. 13 The infection is speculated to cause Grover's disease; So far, however, there is no evidence of a bacterial or viral infection
Cause.2 Grover's disease may have been caused by the organism responsible for tinea versicolor, Malassezia furfur.14 It has been speculated that the Demodex mite may produce an enzyme-like substance that induces acantholytic changes in the epidermis.15 Nonspecific irritation It Inflammation has been suggested to lead to the development of Grover's disease.2,6 A large retrospective study showed a statistically significant association between transient acantholytic dermatosis and asteatotic eczema, atopic dermatitis, and allergic contact dermatitis. Other dermatological disorders loosely associated with Grover's disease include bullous pemphigoid, lichen planus, and seborrheic dermatitis.2,16 Grover's disease has been associated with internal malignancies, particularly those of the genitourinary tract, as well as some hematological malignancies, such as acute myeloid leukemia.10,11 Many other malignancies have also been found in patients with Grover's disease. Some believe this is a coincidence since Grover's disease usually affects the same age group where most malignancies occur. Still others believe there may be a connection. Other disorders found associated with Grover's disease include thymoma, benign monoclonal gammopathy, chronic gastritis, glomerulonephritis, rheumatoid arthritis, pregnancy, HIV virus infection, and poliomyelitis. The meaning of these associations has yet to be determined.2
Treatment The treatment of Grover's disease varies in success. Treatment is primarily aimed at reducing aggravating factors. factors. Patients are advised to avoid strenuous exercise and excessive sun exposure to reduce heat-induced sweating. 1, 9 Patients are also advised to avoid drying16 soaps, topical drugs, and cleansers. include oatmeal Some potency baths, lactic acid and mint lotions, topical urea products, high potency corticosteroids, topical retinoids, topical vitamin D analogs, and zinc oxide ointment.1,2 Systemic therapies included vitamin A, isotretinoin, etretinate, systemic corticosteroids, methotrexate, and antihistamines.1 ,2,17 Ironically, PUVA has been shown to be effective in treating Grover's disease; however, short-term deterioration in his condition should be expected.2,18 The mechanism for the beneficial effects of PUVA in Grover's disease is largely unknown.18 Finally, two or three borderline radiation treatments have been shown to be effective in chronic, recalcitrant Grover's disease to other treatment modalities .2
UNILATERAL GROVER'S DISEASE
Conclusion Recognizing the different clinical presentations of Grover's disease and understanding the histopathology are essential for making the correct diagnosis in a timely manner. Grover's disease Grover's disease was first described over thirty years ago, but its etiology is still unknown. Unknown. Although typical Grover's disease is well characterized, unusual manifestations of Grover's disease may go undetected. forgotten. The cause of Grover's disease and the significance of its association with other diseases remains speculative. Therapy is generally empirical and outcomes vary. Further elucidation of the cause of this confusing condition may lead to more effective targeted therapy. References: 1. Heenan PJ, Quirk CJ. Tr Transient acantholytic dermatosis (Grover's disease). Illness). In: Freedberg IM, Eisen AZ, Wolff Wolff K, et al., editors. Fitzpatrick's dermatology in general practice. New York: York: McGraw-Hill, 2003; 529-31. 2. Parsons Parsons JM. Transient acantholytic dermatosis (Grover's disease): a global perspective. Journal of the American Academy of Dermatology. 1996; 35(5 point 1): 653-66. 3. Fantini F, Kovacs E, Scarabello A. Unilateral transient acantholytic dermatosis (Grover's disease) according to Blaschko. Journal of the American Academy of Dermatology. 2002; 47(2):319-20. 4. Grover RW. RW. Transient acantholytic dermatosis. Archive of Dermatology. 1970; 101(4):426-34. 5. Chalet M, Grover R, Ackerman AB. Transient acantholytic dermatosis: a reassessment. Dog. Archives of Dermatology Dermatology.. 1977; 113(4):431-5. 6. Davis MD, Dinneen AM, Landa N, Gibson LE. Grover's disease: clinicopathologic review of 72 cases. Annals of the Mayo Clinic. 1999; 74(3):229-34. 7. Cohen LM, Skopicki Skopicki DK, Harrist TJ, Clark WH. Non-infectious vesiculobullous and vesicopustular diseases. In: Elder D, Elenitsas R, Jaworsky C, Johnson B, editors. Histopathology of the hepatic skin. Philadelphia: Lippincott Williams & Wilkins, 1997; 244. 8. Bystryn JC. Immunofluorescence studies in transient acantholytic dermatosis (Grover's disease). American Journal of Dermatopathology matopathology.. 1979;1(4):325-7. 9. HuCH, Michel B, Farber EM. Transient acantholytic dermatosis (Grover's disease). Skin disease related to heat and sweating. Archive of Dermatology. 1985;121(11):1439-41. 10. Manteaux AM. Rapini PR. Transient acantholytic dermatosis in cancer patients. Cutis. nineteen hundred ninety; 46(6):488-90. 46(6):488-90. 11. Guana AL. Cohen PR. Tr Transient acantholytic dermatosis in cancer patients. Journal of Clinical Oncology. 1994; 12(8):1703-9. 12. Ott A. Persistent acantholytic dermatosis in a patient with increased photosensitivity. Z skin cr. 1987; 62:369-78. 62:369-78. 13. Mahler SJ, DeVillez RL, Pulitzer DR. Transient acantholytic dermatosis induced by recombinant interleukin 4. Journal of the American Academy of Dermatology. 1993;29:206-9. 14. Segal R, Alteras I, Sandbank M. Rapid response of transient acantholytic dermatosis to selenium sulfide treatment in pityriasis versicolor. Dermatologica 1987;175:205-7. 15. Lindmaier A, Jurecka W, Lindemayr H. Demodicosis mimics granulomatous rosacea and transient acantholytic dermatosis (Grover's disease). Dermatologica 1987;175:200-4. 16. Grover RW. Rosenbaum R. The association of transient acantholytic dermatosis with other skin diseases. Journal of the American Academy of Dermatology. 1984; 11(2 point 1):253-6. 17. Helman R.J. Grover's disease treated with isotretinoin. Report of four cases. Journal of the American Academy of Dermatology. Dermatology. 1985; 12(6):981-4. 981-4. 18. Paul BS, Amdt Amdt KA. Response of transient acantholytic dermatosis to photochemotherapy. photochemotherapy. Archive of Dermatology. Dermatology. 1984; 120:121-2.
A Cautionary Tale on Halo Nevi: Case Report and Literature Review Andrew Racette, D.O.*, Joseph Machuzak, D.O.**, Stephen Kessler, D.O.***, Alissa Floman, B.S.****, Crystal Kunka, B.S.* ** * * Resident Freshman, Western University Health Sciences, Mesa, AZ ** Researcher, Western University Health Sciences, Mesa, AZ *** Program Director, Western University Health Sciences, Mesa, AZ **** Research Assistant, Western University Health Sciences, Mesa, AZ SUMMARY Halo nevus is characterized by a central melanocytic nevus surrounded by a hypopigmented macular halo and has been considered a benign nevus. We report the case of a 15-year-old boy who presented to our clinic with a typical halo nevus that was biopsied at the insistence of his parents. The pathology report showed that he had severe cytologic atypia with features consistent with early-stage melanoma. We report this case to revisit the topic of halo nevi and to remind clinicians that although most halo nevi are benign, we still need to remember the conditions under which they are considered suspicious lesions and the need for biopsy should be considered.
Introduction Halo nevus, a lesion characterized by a central melanocytic nevus surrounded by a hypo- or depigmented macular halo, is generally considered a benign nevus. nevus. It occurs most commonly in the upper back of people under the age of twenty, with no difference in frequency between men and women. The halo of hypopigmentation develops over weeks to months, with probable regression of the central nevus over the following months to years.1 Nevus regression is thought to be an example of immune surveillance in humans because it is due to a combination of immunological factors not involved known with absolute certainty.2,3 Sensitivity.2,3 It is believed to be due to an immune response to antigenically altered dysplastic nevus cells or a cell-mediated and/or humoral response against non-specifically altered nevo-melanocytes.1 First, in principle, all Halonevi must be atypical being. For the second principle to be true, there must be some physical or chemical insult to alter nevomelanocytes in a non-specific way and trigger an immune response. an abundance of activated CD8+ T cells in the halo nevus.5,6 In addition, T cells from a patient with a halo nevus have been shown to be able to lyse the melanocytes of a normal nevus7, producing cytotoxic T cells play the dominant role. in the regression.8
Case Report: A 13-year-old boy came to our clinic because his parents were concerned about a changing mole on his right upper back. A full body scan was performed and several normal nevi were seen along with the worrying lesion on her upper back. When we asked the parents, they informed us that this nevus had been present for 38 years
unknown number of years but not present at birth. It changed color and by the previous week had begun to develop a rim of hypopigmentation and erythema. The injury was asymptomatic for the patient and he had never received treatment for this injury before. He denied recent trauma or manipulation of the nevus. When her parents were questioned, they stated that there was a family history of
A 2001 Journal of Pediatrics article stated that "we have never seen a case of" malignant halo nevus. Nevus.”9 ”9 In this study, 78 pediatric dermatologists completed questionnaires and stated that they had never seen a typical halo nevus as a malignant lesion. Although the same dermatologists had never seen a malignant halo nevus, 68% of them replied that they still biopsy it.
Melanoma in the first relative. conThe lesion in question was gradual 7 mm relative. Macula consisting of a symmetrical rim of hypopigmentation and mild erythema surrounding a nevus. The central nevus was symmetrical, had regular margins, was uniformly brown, and was 4 mm in diameter. It resembled a typical benign halo nevus and we thought the best thing would be to observe the lesion lesion. However, at the parents' insistence, the lesion was biopsied and sent to a dermatopathologist. Histologically, the lesion showed a compound dysplastic nevus with severe atypia. MART-1 staining showed no significant lateral growth but highlighted several areas of early confluency along the dermis/epi-
Halo nevi with "if 4% central lesion of the reaction seemed unusual" that they biopsied all halo nevi "often". "Common."9 "9 This information seemed to support the theory that the typical halo nevus in children does not undergo malignant transformation.9 This would then lead to the conclusion that without the need for biopsy, the halo nevus is not a major clinical one would pose a problem. However, recently there was a case report of a possible malignant melanoma in which the clinician believed the lesion to be a typical halo nevus.10 Nevus.10 In this report, the physicians were reluctant to biopsy the lesion but did so on the patient .of the patient at his insistence. When the pathology report came back, they were very surprised.
dermal atypy logical connection connection. in. The melanocytes were heavy with severe cytosis with an extensive bridge of rete ridges which was worrisome for the development of melanoma (Figs. 1 and 2). The specimen was then sent for a second opinion with a similar diagnosis of a compound dysplastic nevus with moderate to severe atypia and lymphohistiocytic infiltrate (compatible with the halo phenomenon). Some cells had severe atypia and Spitz features, hence it could be considered as a melanocytic nevus overlaid with features of severely dysplastic nevus and Spitz tumor. The lesion was then re-excised conservatively to ensure complete complete removal.
to see our case the result. result where . Unfortunately we had to report that the very similar lesion was a typical benign halo nevus but we biopsied the lesion due to the family's great concern. When speaking to the dermatopathologist in our case, she felt that the lesion we biopsied was an early stage melanoma and could have developed into that entity in a few years. The question then arises as to whether these lesions, which we call "typical halo nevi", represent really severe dysplastic nevi or early stage melanomas that our immune system can recognize, attack and destroy. to destroy. There has long been a theoretical association between circulating antibodies to Halo nevi11 due to the ability of patients with Halo nevi to produce antibodies against the cytoplasm of melanoma cells.
Discussion The typical long Visa nevus halo has been considered a benign childhood lesion that does not require treatment.
RACETTE, HIGH, KESSLER, FLOWMAN, HALS
ssion of the central nevus. Rather, circulating antibodies appear to be the result of destruction of nevus cells with subsequent release of nevocellular antigen, which is then processed and presented by antigen-presenting cells. This then leads to antibody production, but only after the nevus nevus cells have been lysed.12 Further evidence against this antibody model comes from immunohistochemical studies, which have shown that lymphocytes infiltrating the halo consist of CD4+ T helper cells (25% ). 13, the remainder are CD8+ T cells.13,14 A significant number of B cells are absent from the infiltrate, suggesting that they do not play an important role in the regression process.13 Furthermore, it is not yet entirely clear whether or not whether this lymphocytic infiltrate is directly responsible for the regression of the nevi or whether there are other factors that are not yet understood.
It is clear that much work has gone into understanding halo nevi at the cellular level. However, it is also clear that there are many parts of the process that we still do not understand. Being able to elucidate the cellular interactions that cause these lesions could help us answer some of the questions that also surround them clinically. Should we reconsider our position on Halo nevi as completely benign lesions, or are these few reports of severely dysplastic Halo nevi exceptional? References: 1. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. Mosby 2003. 2. Cui Z, Willingham MC. Halo nevus: a visible case of immune surveillance in humans? Lancet Oncol. 2004 Jul;5(7):397-8. 3. Wayte DM, Helwig EB. Halo nevus. Cancer 1968 22:69. 4. Akusu R, De L, Kahn H. Characterization of the mononuclear infiltrate involved in regression of Halo nevi. J Cutan Pathol 1994; 21:302. 5. Fernandez-Herrera J, Fernandez-Ruis E, Lopez-Cabrera M, et. Al. Expression of CD69 and tumor necrosis factor-alpha
Immune reactivity in the inflammatory cell infiltrate of Halo nevi. Br J Dermatol 1996; 134:388. 6. Musette P, Bachelez H, Flageul B, Delarbre C, et al. The immune-mediated destruction of melanocytes in halo nevi is associated with local expansion of a limited number of T cell clones, J. Immunol 1999;162:1789-1794. 7. Mitchell MS, Nordlund JJ, Lerner A. Comparison of cell-mediated immunity against melanoma cells in patients with vitiligo, halo nevi or melanoma. J Invest Dermatol 1980; 75: 144. 8. Bayer-Garner IB, Ivan D, Schwartz M, Tschen J. The immunopathology of regression in benign lichenoid keratosis, keratoacanthoma and halo nevus. Clin Med Res. May 2004; 2(2):89-97. 9. Lai CH, Lockhart S, Mallory SB. Typical halo nevi in childhood: is a biopsy necessary? J Pediatr 2001;138:283-4. 10. Mandalia MR, Skillman JM, Koch MG, Powell BW. Halo nevus or malignant melanoma? A case report. Br J Plast Surg 2002;55:512-513. 11. Copeman PWM, Lewis MG, Phillips TM, Elliott PG. Immune associations of halo nevus with cutaneous malignant melanoma. Br J Dermatol. 1973;88:127137. 12. Zeff RA, Friday A, Grin CM, Grant-Keis Grant-Keis JM. The immune response in Halo nevi. J.Am. Acad. Derm 1997; 37:62-624. 13. Akasu R, DeL, Kahn HJ. Characterization of the mononuclear infiltrate involved in regression of Halo nevi. J Cutan Pathol 1994; 21:302-311. 14. W. Bergman, R. Willemze, C. DeGraaff-Reitsma, et al. Analysis of key histocompatibility antigens and mononuclear cell infiltrate in Halo nevi. J Invest Dermatol 1985; 85:25-29.
A STORY OF CARE ABOUT HALO NEVI: CASE REPORT AND LITERATURE REVIEW
Hyperimmunoglobulin Syndrome E Rene Bermudez, DO*, Shield Wikas, DO**, Monte Fox, DO*** *3. Year Resident-Summa Health Systems-Cuyahoga Falls General Hospital, Cuyahoga Falls, Ohio **Program Director- Summa Health Systems- Cuyahoga Falls General Hospital, Cuyahoga Falls, Ohio ***Assistant Clinical Professor-Summa Health Systems-Cuyahoga Falls General Hospital, Cuyahoga Falls, Ohio
Health. Past medical history was normal. Previous surgical history included
HyperIgE syndrome, also known as Job syndrome, was first described by Davis
HyperIgE, also called Job syndrome, is a rare multisystem syndrome that often occurs in the first few months of life. It was first described as a primary immunodeficiency disorder characterized by staphylococcal skin abscesses, recurrent pneumonias with formation of pneumatoceles, eczema, peripheral eosinophilia, and elevated serum IgE levels.1 Since its initial description by Davis et al. in 1966 further studies and case reports were expanded this initial description includes recurrent skin infections of staphylococci and streptococci species, recurrent systemic infections particularly of the joints and lungs, chronic eczematous dermatitis frequently affecting the flexor regions and face, and elevated serum IgE Mirror. 2 Recurrent staphylococcal and streptococcal pneumonias can result in persistent pneumatocele formation, bronchopleural fistulae, cyst formation, and restrictive pulmonary disease. Mucocutaneous candidiasis, characteristic facies, and involvement of the teeth, bones, and immune system have been reported. 3-4 We report the case of a 6-year-old boy who presented to our clinic with clinical manifestations and a history suggestive of HyperIgE syndrome. We reviewed the literature to expand our knowledge of this rare disease. Disturbance. The longer patients with HyperIgE syndrome live, the more phenotypic expressions of this syndrome become visible, which will help clarify options. Etiology, pathogenesis and treatment
bilateral ridges after birth. There is no family history of hernia repairs, only atopy or immunodeficiency diseases. Development milestones were reached in a timely manner. Physical examination at her first visit revealed a single erythematous papule over the fourth metacarpal of the left hand. However, at follow-up examinations, a few more excised erythematous papules were noted on the back and lower extremities. See Figure 1 and Figure 2. There was no evidence of secondary infection. The facial features showed deep-set eyes, a prominent forehead and widely spaced nostrils. Oral examination revealed poor dentition. a bone story
et in 1966. The term Job was derived from what the Bible believes to be plagued by painful boils from the soles of the feet to the top of the head. (Job 2:7) This term refers to a subgroup of patients with HyperIgE syndrome, who are usually women of Italian descent who have red hair, hyperextensive joints, blue eyes, freckles, atrophic or dystrophic nails, and have a tendency to develop severe chronic diseases and recurrent cold staphylococcal abscesses that deform and distort the contour of the body. 2 Approximately 200 cases have been reported in 2001 since it was first described in 1966. 5 HyperIgE syndrome affects men and women equally. A familial trend was observed. It can be observed in people of different ethnic backgrounds.
Case Report: This 6-year-old white male presented to our clinic with a history of recurrent skin infections, childhood recurrent otitis media, chronic eczema, poor dentition with multiple dental caries, elevated serum IgE levels, and peripheral eosinophilia. eosinophilia. He was born in the 29th week of pregnancy with a birth weight of 720 grams. He was born to a 28-year-old White woman, 3 to 1 pregnant, 1 stillborn, female negative. The pregnancy was complicated by pregnancy-induced hypertension, oligohydramnios, first trimester bleeding and decreased fetal movement. After 9 weeks of hospitalization in the neonatal intensive care unit, she was discharged well
Fractures were not denied, evidence of hyperextensible joints on examination, or scoliosis. Although eczematous rashes were described in her medical records, at our initial examination there was no evidence of an eczematous process other than mild xerosis. No capillary, mucosal or nail changes were observed on examination. Serum IgE levels varied between 5233 and 9000 U/ml. Serum IgG and IgA were slightly lower than normal. Serum IgM levels were within the normal reference range. Serum complement levels were within the normal range. The bone density measurement was negative. Histopathological examination of the lesion on the left hand revealed nonspecific spongiotic dermatitis. In reviewing her medical records and previous admissions, Staphylococcus aureus was the most common pathogen isolated from anterior skin abscesses and boils. This patient has received multiple courses of oral and intravenous anti-staph antibiotics since he was 2 years old. His current prophylactic regimen consists of a first-generation cephalosporin twice daily for the past 2 months. Twice-daily application of mupirocin-mupirocin cream (Bactroban) to all new lesions was also recommended. Since the prophylaxis he has not had any recurrent boils or abscesses.
BERMUDEZ, WIKAS, FUCHS
Clinical manifestations The clinical manifestations of HyperIgE syndrome usually appear in the first years of life. Life. HyperIgE syndrome can result in a fusion of immunologic, skin, dental, skeletal, and head and neck abnormalities. These patients suffer from recurrent skin infections, including impetigo, cellulitis, furunculosis, paronychia, and cold abscess of the scalp, neck, axillae, and intertriginous region infected with S. aureus, C. albicans, or Group A. 6-7 Dahl Streptococcus are et al. state that patients with recurrent furunculosis and severe absence of infections of the skin and other organs do not have this syndrome, although patients with the syndrome often have furuncles. He also believes patients have recurring serious and recurrent infections in other organs, particularly the lungs and upper respiratory tract. 8 Sinopulmonary infections present as otitis media, external otitis, sinusitis, recurrent bronchitis, or pneumonia secondary to S. aureus and H. influenza, lung abscesses, pneumatoceles with bacterial or fungal superinfections, and empyema. 7 Grimbacher et al. studied 30 patients with HyperIgE syndrome and found that 77% of patients with pneumonia developed pneumatocele. Acute pneumonia was most commonly caused by S. aureus or H. influenza; in contrast, superinfections have been associated with pneumatoceles
with Pseudomonas aeruginosa and Aspergillus fumigatus. Fifteen patients required a thoracotomy to drain infected pneumatoceles. Other infections observed in his cohort were recurrent bacterial arthritis, staphylococcal osteomyelitis, chronic mucocutaneous candidiasis and candida onychomycosis, moderate rhomboid-like glossitis, and Carinii pneumocystic pneumonia. 4
The teeth of patients with HyperIgE syndrome can be affected. affected. Grimbacher et al. described the previously unrecognized feature of impacted deciduous teeth. In their cohort, 72% of patients older than eight years reported preserving milk teeth. This observation was attributed to the lack of root resorption rather than defective eruption in these patients. 4 Although our patient's history is consistent with multiple caries in his deciduous teeth, it remains to be seen if this patient will show impacted deciduous teeth. Patiently. Caries occurred even though the patient's mother, who is a dental hygienist by profession, performed diligent dental hygiene. Skeletal abnormalities in HyperIgE syndrome have been reported previously. Osteoporosis and a tendency to fracture were recognized characteristics. Feature. This has been termed delayed osteogenesis imperfecta. 10 However, the incidence of fractures was not known until Grimbacher et al. reported that 57% of their patients had at least 3 fractures. Fractures were often due to unrecognized or minor trauma. These fractures occurred in long bones, ribs and pelvic bones. Bone. Other common skeletal findings in your patients
Cutaneous manifestations of HyperIgE syndrome are often described as eczematous or atopic. The eczematous rash is seen in a flexural distribution along the hairline and posterior pinna region. It can even mimic the lichen formation seen in atopic dermatitis. 7 Chamlin et al. however, performed a retrospective review of 8 patients diagnosed with HyperIgE syndrome. They describe a pronounced papulopustular rash as the initial manifestation of the disease, which later develops into eczematous dermatitis. All 8 patients developed a papulopustular rash within the first year of life, with 6 patients developing the rash within the first month of life. Crusting in these lesions was a prominent feature. 9 In contrast, Dahl believes that rash can be divided into three types. He describes the first type as mild inflammatory papules suggestive of folliculitis but usually without many pustules. The second type is clinically indistinguishable
were hyperextensible in 68% and scoliosis in 76% of joints aged 16 years or older. 4 Distinctive facial features in patients with HyperIgE syndrome were reported by Davis et al. and by Buckley et al. described. 11 In 1998, Borges et al. the facial features of 9 patients from 7 families with Job syndrome. The most noticeable findings in his patients were a prominent eyebrow and orbital ridge with the appearance of sunken eyes, enlarged nose width, full lower lip, and thickening of the nose and ears. ears. You feel that there is a characteristic face to be seen in these patients. They report that these patients tend to resemble each other more than other members of their family. 11 These results were further supported by Grimbacher et al. who found that similar facial features are universal at age 16. They had facial asymmetry with evidence of hemihypertrophy; a prominent forehead; deep eyes; a wide bridge of the nose; a broad, fleshy tip of the nose; and mild prognathism. The skin of the face was rough and had protruding pores. The distance between the wings has been increased. Head circumference tended to be larger than normal. The previously reported craniosynostosis was not found in their cohort. Anomalies in mean facial development were also noted. These abnormalities consisted of a high palate in 71% of patients, a cleft lip and palate in one patient, and sagittal midline clefts in the middle third of the mouth.
a similar chronic eczema. the third type is severe for the rash that occurs with incontinentia pigmenti.
tongue at two sisters. We believe that our patient's facial features are characteristic of those described above and will continue to appear
for the development of additional functions with increasing age. See Figure 3.
Associated diseases Associated diseases In addition to the immunological and non-immunological findings already described, several diseases have been reported, such as systemic mastocytosis, systemic lupus erythematosus and 4 reports of malignancy. Reported malignancies were Hodgkin's lymphoma, histiocystic lymphoma of the brain and 2 cases of Burkitt's lymphoma. 5 The finding of non-infectious vascular events of the central retinal artery, leaky Berry aneurysm, bilateral aneurysms at the bifurcation of the internal carotid artery, cerebral embolism and thrombotic stroke have also been reported. 4
Etiology and pathogenesis Although the primary cause remains unknown, most authors assume that hyperIgE is an autosomal dominant disease with variable expression. Expression. It has been localized to a region on chromosome 4 in several families. 1,9 Most cases appear to be sporadic. Like the etiology, the pathogenesis is unknown. Most authors believe that the primary defect is caused by an intermittent chemotactic defect in neutrophils. 2 Others have suggested an abnormality in T lymphocyte function, specifically an imbalance of Th1 and Th2 cells, which secondarily affects neutrophil mobility. 12-13 Although not all patients share a common immunodeficiency, Grimbacher et al note that the presence of peripheral eosinophilia, the presence of eosinophils in sputum and abscesses, defective granulocyte chemotaxis, T-cell abnormalities, defective antibody production and decreased and / or responsiveness of cytokines such as interleukin 4 and interferon gamma play a role.4
Histopathology Histopathological findings in HyperIgE syndrome are nonspecific. In one study, the most consistent finding from skin biopsy was eosinophilic spongiotic dermatitis. Other histopathological findings
were and deep eosinophilic perivascular folliculitis, superficial dermatitis with abundant eosinophils and abundant eosinophils
HYPERIMMUNOGLOBULIN AND HYPERIMMUNOGLOBULIN SYNDROME
extends into the subcutaneous fat. Demodex folliculitis was reported in one patient. 9
Laboratory findings Laboratory findings in HyperIgE syndrome consist of elevated serum IgE levels, which can range from 10 to 100 times normal, elevated sputum and peripheral serum eosinophilia, elevated serum levels of anti-S.aureus IgE, low or no serum and saliva anti-S. aureus IgA. 2-3 Although the name "hyper" IgE implies chronically elevated serum IgE levels, in approximately 20% of affected adults, serum IgE levels may decline to normal levels over time. 3 However, these patients have normal levels of IgG, IgA, IgM and elevated IgD levels.
Differential Diagnosis The most important disorder to differentiate from HyperIg-E syndrome is atopic dermatitis. In contrast to HyperIg-E syndrome, atopic dermatitis is a relatively common skin disease. Despite this, their clinical similarity sometimes cannot be denied. Other cutaneous skin conditions that mimic HyperIg-E syndrome include seborrheic dermatitis, Wiscott-Aldrich syndrome, DiGeorge syndrome, and Omenn syndrome. In one study, the most common diagnoses prior to the diagnosis of HyperIgE syndrome were infantile acne, acne rosacea, demodex folliculitis, bacterial folliculitis, candida folliculitis, eosinophilic pustular folliculitis, scabies, impetigo, seborrheic dermatitis, and atopic dermatitis. 9
Treatment Treatment with long-acting antistaphylococcal antibiotics, incision and drainage of appropriate abscesses, appropriate antibiotics and antifungals for specific infections, thoracotomy for superinfection or persistence greater than six months, with treatment of the eczematous component with topical corticosteroids and antihistamines. Oral pruritus medications are are the mainstays of therapy for HyperIgE syndrome.13 In cases that do not respond to the above treatment modalities, several studies suggest treatment with systemic therapy such as cimetidine, ascorbic acid, isotretinoin, cyclosporine A, IVIG, and methotrexate. According to Fitzpatrick et al. Ascorbic acid and cimetidine reduced the number of infections and chemotactic defect in some patients. Isotretinoin has been reported to eliminate recurrent staphylococcal abscesses in an isolated patient without altering the immunological status.6 Etzioni et al. reported the beneficial effects of ciclosporin A in a 3-year-old boy with HyperIgE syndrome in whom multiple therapeutic modalities were ineffective. This 3 year old boy
was treated with ciclosporin A at 3 mg/kg/day for a total of 6 months. He has not experienced any side effects. They believe that the positive response observed in this patient was due to Cyclosporin A's ability to shift the immune response from Th2 to Th1 dominance. 14 The results of several studies analyzing the effectiveness of IVIG in the treatment of HyperIgE syndrome are conflicting. An open label study evaluating one patient with HyperIgE syndrome and nine with atopic dermatitis showed no clinical benefit in these patients. These patients received 10% IVIG solution at a dose of 2 g/kg every 30 days for a total of seven infusions. It was well tolerated and there were minimal side effects. The most common side effects were headache, fatigue and myalgia, as shown in other studies. The primary endpoints in this study were improvement in skin lesions, reduction in steroid medication, improvement in pulmonary function tests, or reduction in IgE IgE production. Although the primary endpoints improved, they did not reach statistical significance. 15 However, Rutter and Luger cited an improvement in the eczematous component in 2 patients with HyperIg-E syndrome and Kawasaki IVIG monotherapy disease with a regimen treated at 0.4 g/kg daily for 5 days. In addition, a decrease in the IgE serum level was observed. 16 Finally, in a study of the Indian literature, 2 patients with HyperIg-E syndrome were treated with methotrexate and reported efficacy in controlling skin symptoms. Long-term effects were not reported as one patient died from complications of Burkitt's lymphoma and the other from complications related to a lobectomy for a lung abscess. 5 Fortunately, our patient remains lesion-free since being placed on prophylactic antibiotics. References: 1. Grimbacher B, Holland SM, Shaffer AA, Gallin JI, Davis J, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am. J. Hmm. genetics 1999; 65:735-744. 2. Hurwitz S. Eczematous eruptions in childhood. IN: HurwitzS, Ed. Clinical Pediatric Dermatology. A textbook of skin diseases of children and adolescents. Philadelphia, Pennsylvania, W.B. Saunders, second edition. 1993: 6061. 3. Braunwald E, Fauci Fauci AS, Kasper DL, et al. Diseases of granulocytes and monocytes. IN: Braunwald E, Fauci AS, Kasper DL, et al., eds. Harrison's Principles of Internal Medicine, San Francisco, California, McGraw-Hill, 15th edition. 2001: 371. 4. Grimbacher B, Holland SM, Gallin JI, Greenberg F, et al. Hyper-IgE syndrome with recurrent infections - an autosomal dominant multisystem disease. N. Engl. J. Med. 1999; 340: 692-702. 5. Pherwani AV, Madnani NA. Hyperimmunoglobulin E Syndrome Indian Pediatrics. 2001; 38:1029-1034 6. Fitzpatrick TB, Freedberg IM, Eisen AZ, Wolff K, et al. Genetic immunodeficiency diseases. IN: Fitzpatrick TB, Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick's Dermatology in General Medicine, San Francisco, California, McGraw-Hill, 5th edition. 1999:1404. 7. Spitz JL. Hyper IgE Syndrome. IN: Kiefer JW, Ed. Genodermatoses-A Full-Color Clinical Guide to Genetic Skin Disorders, Baltimore, Maryland, Lippincott Williams and Wilkins, 1st edition. 1996: 218-219.
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8. Dahl MV. Hyper-IgE relaunched. International Society of Dermatology. 2002; 41:612-621. 9. Chamlin SL, McCalmont TH, Cunningham BB, et al. Cutaneous manifestations of hyper-IgE syndrome in infants and children. Journal of Pediatrics. 2002; 141:572-5. 10. Brestel EP, Klingberg WG, Veltri RW, Dorn JS. Late osteogenesis imperfecta in a child with hyper-IgE syndrome. I am. J.Dis. Son. 1982; 136:774-776. 11. Borges WG, Hensley T, T, Carey JC, et al. Job's face; Clinical and laboratory observations. Journal of Pediatrics. 1998; 133:303-5. 12. Gorbach SL, Bartlett JG, Blacklow NR. Abnormalities in the formation and content of neutrophil granules. IN: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious Diseases, Philadelphia, Pennsylvania, WB Saunders, 2nd edition. 1998: 53. 13. Behrman RE, Kliegman Kliegman RM, Arvin Ann M. Combined B and T cell Diseases. IN: Nelson WE, Ed. Nelson's Textbook Pediatrics, Philadelphia, ids, 15th edition. 1996: 576-7. Pennsylvania, W.B. Saun14. Etzioni A, Shehadeh N, et al. Cyclosporin A in hyperimmunoglobulin E syndrome Ana. Allergy Asthma Immunol. 1997; 78:413-4. 15. Wakim M, Alazard M, Yajima A, et al. High-dose intravenous immunoglobulin for neurodermatitis and hyper-IgE syndrome. A-N-A. Allergy Asthma Immunol. 1998; 81:1538. Rutter A, Luger TA. High-dose intravenous immunoglobulins: an approach to the treatment of severe immune-mediated and autoimmune skin diseases. Jelly. academic Dermatol. 2001:44:1010-24.
LASER: BACK TO BASICS Tony Nakhla, D.O.*, Navid Nami, D.O.**, Steven Shapiro, M.D.***, Layne Nisenbaum, D.O., FAOCD**** * Medical Intern, Saint Vincent's Midtown Hospital / New York ** 3 year Resident Chief of Dermatology, Columbia Hospital West Palm Beach *** Gardens Dermatology/Palm Beach Gardens, Volunteer Associate Professor, Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine **** Program Director, Columbia Hospital/Nova Southeastern University / West Palm Beach, FL ABSTRACT The ruby continuous wave laser was the first laser to be developed nearly 40 years ago and marked the birth of laser medicine. Medicine. Significant technological advances have been made in this area across the many disciplines of medicine. These advances have enabled the development of lasers with greater efficiency and fewer adverse and undesirable effects. We will review the physics, mechanics, types and clinical indications of the laser systems currently available. today.
LASER BASICS The term laser is an eponym for Light Amplification by Stimulated Emission of Radiation. Physics and atom should help to better understand lasers. An electron circling in an atom can be excited to a higher orbit by absorbing energy (stimulated absorption) and vice versa by releasing energy to a lower orbit (spontaneous emission). This energy is represented as a light photon. Lasers deal with the concept of stimulated emission. Stimulated emission occurs when a photon is directed at an atom that contains a metastable electron in its orbit. This interaction causes the electron to fall from orbit to a lower orbit and in turn emit a new photon of light. Thus, an original photon directed at that atom produced two resultant photons. The term light amplification refers to a chain reaction that occurs when those two emitted photons are directed towards other atoms, creating even more photons. This light amplification process takes place in a device called an optical resonator. The optical resonator not only amplifies but also directs the light. A cylindrical chamber filled with laser coating and mirrors in the center, each absorbing endan responsible for producing collimated laser light. The photons are reflected between the mirrors. Any light that does not travel in a parallel direction is absorbed by the coating. At one end of this optical cavity with a partially reflecting mirror (which allows 5% of the energy to escape) is an instrument to periodically emit light from the chamber. c chamber. How does laser light differ from other light sources? Laser light is monochromatic, coherent and collimated. Monochromatic light has a single wavelength, or "color". Coherent light has all wavelengths of light in the same phase with "equal peaks and valleys". Valleys". Collimated light is parallel and travels great distances without divergence, allowing for precise target destruction. In contrast, a flashlight produces white light that is incoherent and
different1. Each laser system is unique due to its medium and the emitted wavelength. Laser media consist of solids, gases or liquids. Liquids. Examples of solid media are ruby crystals, alexandrite crystals, Nd:YAG (neodymium:yttrium aluminum garnet) crystals (neodymium:yttrium aluminum garnet) or Er:YAG Er:YAG (erbium:yttrium) crystals -A ( erbium:ytrium-aluminum-luinum-garnet) Examples of a gaseous medium are carbon dioxide, argon, krypton, or copper vapor Vapor Rhodamine is a fluorescent liquid dye used in some laser systems.
Laser-Skin Interactions Approximately 5-7% of laser light directed at the skin is reflected due to the high index of refraction between the atmosphere and the skin. There is also some degree of reflection at the dermal-epidermal junction. The rest of the light energy is absorbed by the epidermis or scattered by the dermis. The final destination of the photon is a specific chromophore. chromophore. Chromophores are molecules in the skin that absorb photon energy when delivered in an appropriate range of wavelengths. wavelengths. ideally all
around 1000 nm, where lasers such as Nd:YAG (1064 nm) are used to treat deeper vascular lesions, albeit with less efficacy than the aforementioned PDL. Melanin has a broad absorption spectrum, gradually increasing from the infrared range and peaking in the ultraviolet range. Range. Due to this broad absorption spectrum and the presence of melanin in the basal layer of the epidermis, almost all laser systems have the potential for unintended absorption and unwanted skin damage2. This can lead to depigmentation and increases the risk in patients with darker skin. The competitive uptake of light energy by the epidermal melanin can also reduce the energy transferred to the target chromophore and in turn reduce the desired clinical effect. Using a longer wavelength laser such as Nd:YAG (1064nm) allows for deeper penetration beyond the basal layer with less melanin absorption.
Parameters Important parameters of light and lasers are wavelength, energy, power, fluence,
The energy of the photon is canceled and transferred to the chromophore. Examples of chromophores are water, oxyhemoglobin, melanin and tattoo pigments. It is important to become familiar with the range of maximum wavelengths of light at which a given chromophore absorbs energy. Energy. This is demonstrated in the chromophore absorption curve. Water The absorption spectrum of water begins to broaden in the mid to high infrared range. wavelengths. Lasers targeting the superficial layers of skin with high water content take advantage of this property. Property. Examples are CO2 (10,600 nm) or Er:YAG (2,940 nm) for ablative surface renewal processes. Oxyhemoglobin has a peak absorption spectrum around 400-600 nm where pulsed dye lasers (585 nm/595 nm) are most effective. Oxyhemoglobin also has a second broad but smaller absorption peak in
pulse width and spot size. The electromagnetic spectrum is represented by wavelengths measured in nanometers. From the lower wavelengths of gamma rays to the higher wavelengths of microwaves. Microwave. Between these extremes are ultraviolet (200-400 nm), visible (400-760 nm), and infrared (760-10,000 nm) (760-10,000 nm) light. lights. As a rule, longer light waves can penetrate deeper into the skin because they are less scattered by the dermal skin collagen. Mid to high infrared wavelengths are an exception as water becomes the major chromophore. As a result, due to the high water content, light penetrates the skin only superficially. Ablative resurfacing lasers take advantage of this phenomenon. Energy, which is inversely proportional to wavelength, is measured in joules. joules. Pow Power er is the rate of energy delivered that is measured
LASER: BACK TO BASICS BASICS
in joules/second. Flowability is the amount of energy dissipated per area and is measured in joules/cm 2 . This amount of energy should be enough to heat the target past its damage threshold. Fluidity is increased to deliver more energy to deeper lesions and should be used at more conservative levels on darker skin types to reduce the risk of depigmentation. Wave mode is just as important as fluency. Lasers can be continuous or pulsed. Because continuous laser light has no interruptions in the delivered energy, non-selective tissue damage and an increased risk of damage and scarring can occur. happen. With pulsed lasers, on the other hand, the energy is generated in bursts, giving the target chromophore ample time to dissipate the energy before receiving a subsequent pulse and limiting any unwanted energy transfer to the surrounding tissue. This ability to deliver enough energy to affect only the target tissue while sparing the surrounding tissue is defined by the term “selective photothermolysis”. Lasers can have long pulse widths, measured in milliseconds, or short pulse widths, measured in microseconds. The pulses must be short enough to deliver enough energy to the target before it cools. This results in appropriately localized, pulsed heating. The exposure or duration/width must be less than the thermal relaxation time (TRT)3 of the specific chromophore. TRT is the time required for 50% of the peak heat to diffuse out of a chromophore. If the TRT TRT is exceeded, the heat diffuses to the surrounding tissues, causing collateral damage and undesirable outcomes. Chromophores like melanin and tattoo pigment have TRT in the micro- and nanosecond range, nanoseconds respectively. To stay within the limits of this very short pulse width, the lasers can be Q-switched. In such systems, electro-optical shutters are used to release stored energy and obtain ultra-short and powerful pulses. The TRT for hair follicles and vessels is 100 ms and 1-10 ms, respectively.
Cooling Most laser systems must be used with additional cooling. The benefits of cooling are less epidermal damage, allowing for greater fluences and an anesthetic effect on the patient. Cooling can be by contact, dynamic spray, or air blast. fans. Contact cooling and dynamic spray are usually included and part of the laser device. Contact cooling uses a cooled probe tip in direct contact with the epidermis. The dynamic cooling creates a cryogenic spray before each laser pulse. Air-cooled fans can also be used. In addition, cold gels or ice cubes can be applied to the skin before the therapy.
LASER TYPES The following section covers ablative resurfacing lasers (CO2 and Er:YAG), vascular lasers (pulsed dyes), and systems for removing hair and pigmented lesions (Nd:YAG (Nd:YAG and Alexandrite) .
with preservation of the epidermal integrity. These systems also target and improve pigmentation and vascular changes. For non-ablative therapy, these lasers use low energy. Energy. Other long-wavelength non-ablative systems used to treat photoaging, acne, and scarring include Nd:YAG (1320 nm), Diode (1450 nm), Erbium:Glass (1540 nm), and various pulsed lights.
CO2 (10,600 nm) and Er:YAG (2,940 nm) with their longer wavelengths use the targeting of water molecules in the superficial layers of the skin to cause tissue evaporation and collagen contraction4. This leads to re-epithelial re-epithelialization and formation of new skin. Formation. Because of its longer wavelength, the CO2 laser is more destructive than the Er:YAG laser. CO2 laser light can be focused or defocused. Focused laser light is used in precise surgical incisions, also known as “the light scalpel”, and is currently used by gynecologists (colposcopy), general surgeons (laparoscopy), and neurosurgeons 5. Defocused CO2 lasers are used in ablative resurfacing and in the treatment of certain lesions such as common wart, trichoepithelioma, xanthelasma and rhinophyma. Depending on the number
pulse cutting laser
goes, the penetration depth can only be controlled. Further passes may not result in epidermal ablation but may result in dermal remodeling due to collagen shrinkage. The disadvantages and side effects of ablative resurfacing are post-treatment erythema and the risk of depigmentation, scarring and infection6. Post-treatment Enteric erythema after treatment, which can last about 2–4 weeks with erbium:YAG and 1–3 months with CO2 laser, is due to re-epithelialization of the skin and is uncomfortable for patients. Prolonged erythema and itching after treatment can be caused by yeast or fungal infections7. This postoperative period is sometimes referred to as "down time." The Er:YAG Laser Er:YAG is less able to penetrate the dermis and cause collagen contraction and eventual remodeling. However, for darker skin types, where there is a risk of pigmentation and scarring, it is easier to use and also results in less "down time". Er:YAG Er:YAG can be used with longer pulse widths to increase tissue damage and achieve the same levels as CO2 lasers. These two are the best systems available today for ablative skin resurfacing at the skin's surface and can regenerate collagen and elastin from within. It is recommended that patients stop Accutane for 6 to 12 months prior to these procedures. Other lasers such as PDL, Nd:YAG, KTP and Alexandrite as well as non-laser sources such as pulsed light and light emitting diode (LED) can be
Superficial purpura from vascular rupture This may be due to minimized flu reduction. or increasing the pulse width. However, this maneuver reduces effectiveness. Lower concentrations should also be used on more sensitive skin, e.g. As in children, are used. PDLs are better suited to treat superficial vascular lesions. injuries. Increasing the spot size on the laser probe allows the light to better penetrate the skin and reach the deeper vessels, losing the full energy delivered. The Nd:YA Nd:YAG G laser (1064nm) is also a good option for treating deeper vessels due to its longer wavelength. It uses a second, even smaller, oxyhemoglobin peak in the near infrared. Nd:Y Nd:YAG AG for vascular lesions is less effective than PDL, but does not cause postoperative purpura and does not cause as many pigment changes in black patients. Dual frequency Nd:YAG (532 nm) and KTP (532 nm) can also be used to treat very superficial telangiectasia without postoperative purpura. A second type of PDL (510nm) (510nm) is also worth noting as it can target superficial pigmented lesions and orange/red tattoos, but has fallen out of favor due to pigment and scar side effects9.
Used as a non-ablative agent to rejuvenate photoaged skin by causing collagen/elastin growth and remodeling
treats pigmented lesions such as leg veins. This and the vascular laser can also be Q-switched to treat melanin lesions.
NAKHLA, NAMI, SHAPIRO, NISENBAUM
Oxyhemoglobin has a multipeak absorption spectrum at wavelengths of 410nm-429nm, 541nm and 577nm. The argon laser (410nm-420nm/540nm/580nm) was the first system to target this chromophore. Argon lasers have fallen out of favor due to the increased incidence of depigmentation and scarring in children. Pulse-D pulse-dye lasers (585nm/595nm) are now being implemented to treat vascular lesions such as rosacea, port wine stains and angiomas. They are also used to disrupt vessels supplying lesions such as warts, erythematous striae, and hypertrophic scars. PDL uses a flash lamp to generate energy and contains a fluorescent dye (rhodamine) as a medium. A major disadvantage of using PDL is the 7 to 10 postoperative days 8
Alexandrite laser Alexandrite (755 nm) is the most widely used hair removal laser. That too
Laser types and application lasers
Argonium Ruby Nd:YAG
Vascular Pigment / Depilation Depilation / Deep Vascular Pigment Superficial vascular and
Q-Switched Pulsed Coring COs/Erbium:YAG
Pigment hair removal / pigment deep vascular hair removal / pigment deep vascular tattoo Ablative resurfacing
10.600 / 2.940
Thermal relaxation time (TRT) and pulse widths for specific chromophores
width of the laser pulse
Tattoo ink particle melanosome PWS vessel hair follicle leg vein
as well as tattoo tattoo pigment. It is the most effective laser used for photoepilation because its wavelength is able to reach the deepest melanin pigment contained in the hair shaft and matrix. Its main disadvantage is depigmentation when used on darker skin types10. As previously mentioned, this is due to undesired absorption by melanin in the basal layer of the epidermis.
and non-ablative remodeling. With a potassium titanyl phosphate (KTP) crystal, the frequency can be doubled from Nd:YAG 1064nm to 532nm (halving the wavelength), allowing for better targeting of superficial vessels, melanin and tattoo pigments at a lower wavelength.
The Nd:YAG laser (1064 nm) is probably the most versatile laser system available. It can be used for hair removal, vascular lesions and non-ablative remodeling. This laser can also be Q-switched to treat pigmented lesions and tattoos containing melanin. It is less effective than PDL for vascular lesions and less effective than alexandrite for hair removal, but should be used in a subset of patients with darker skin types who are more prone to post-treatment pigment changes. deeper with less disruption of the basal cell layer pigment. Nd:YA Nd:YAG G (1320n (1320nm)m) with
The best option for laser treatment of vascular lesions is PDL. Because of its shorter wavelength, this laser is more effective in treating more superficial vessels. The goal is to cause the vessel to coagulate and collapse. PDL is used to treat port wine stains, hemangiomas, telangiectasia, psoriasis, poikiloderma, and superficial leg veins. KTP (532 nm) is also very effective in treating superficial vessels. Ships. Because of their deeper penetration, Nd:YAG lasers (1064 nm) and diodes (810 nm) can be used to treat deeper and thicker leg veins11. As mentioned above, the Nd:YAG Nd:YAG laser saves the patient from reoperation
Its even longer wavelength reaches the best water in the surface layers of the skin and is now used to treat acne and scars
purple and dudes. depigmentation. It's better for darker skin.
LASER: BACK TO BASICS BASICS
Laser hair removal is probably the most widespread laser application today. Also known as photoepilation, it is used for cosmetic indications as well as conditions such as hirsutism12 and pseudofolliculitis barbae13. The patient should refrain from waxing, waxing, plucking or electrolysis for about a month before better results can be seen. Photoepilation is best performed with a longer wavelength laser because the target chromophore is deeper. The target of photoepilation is the follicular melanin in the anagen hair bulb 14 . Alexandrite (755 nm) is the best modality for this indication, followed by Nd:YAG which is less effective in destroying the hair follicle. The benefit of Nd:YAG is less epidermal melanin interaction and unwanted postoperative pigment changes observed in darker skin types. The lasers used for hair removal are also long-pulse lasers. This happens because follicular melanin has a higher TRT than epidermal melanin. This difference in TRT occurs because follicular melanin has a higher volume to surface area ratio and is less able to radiate absorbed energy across its relatively small surface area. The longer pulse duration also allows us to exceed the TRT to dissipate melanin, allowing energy and pigment to destroy the surrounding unpigmented hair follicles and the hair bulge where the stem cells reside. Other hair removal options include diode (810 nm) and ruby (694 nm) lasers. The expected response after therapy includes erythema and perifollicular edema in the first few days and follicular ejection in approximately two weeks15. Gray hair without pigment and red/blonde hair with pheomelanin are more resistant to these treatments and may require shorter pulse widths. This is due to the lack of eumelanin, which is the best target for photodepilation. photoepilation. Several other modalities for removing lighter hair are currently being investigated. These include the use of high frequency electrical synergy, photodynamic therapy, and pre-coating the hair with squid melanin or carbon solution. Photoepilation may also be enhanced with the supplemental topical drug eflornithine (Vaniqa), which inhibits orthinine decarboxylase.
Pigmented Lesions Because of its broad absorption spectrum, melanin can be targeted by many laser systems. As mentioned above, some of this alignment is undesirable. Ruby laser (694 nm), one of the first lasers developed for pigments with a high affinity for melanin, is currently in limited use due to the amount of epidermal damage. After the next (755 nm) the best laser for melanin is the ruby, alexandrite, followed by the diode (810 nm) and the Nd:YAG (1064 nm).
Due to the very short TRT of the melanin pigment, most of these lasers must be Q-switched for best results. Lower wavelength lasers are better able to target melanin because the absorption spectrum of melanin increases towards the ultraviolet region. Range. Shorter wavelength lasers cannot penetrate the skin as well as higher wavelength systems and are only better suited for superficial pigmented lesions16. Superficial pigmented lesions such as lentigines, freckles and latte are best treated with Q-Nd:YAG (532nm) (532nm). QNd:YAG (1064nm) and Q-Alexandrite (755nm) are also very effective on these superficial lesions but can be used to treat deeper lesions such as blue nevi, Ito or Ota nevi, Becker nevi and post-inflammatory pigment changes. Many pigmented lesions are difficult to treat with unpredictable results. Postinflammatory pigmentary changes and melasma respond most differently to therapeutic therapy. In addition, clinically suspicious lesions should be biopsied prior to laser therapy to rule out malignancy. IPL devices, devices although not lasers, are also effective in treating superficial pigmentation.
Tattoo lasers are also used to treat tattoo pigments
must be Q-switched17. When light energy is applied to this exogenous chromophore, the pigment is dispersed into small clumps and then removed by macrophages. This process is less effective in the lower extremities due to decreased lymph flow. Flow. Pigment breakage is not only due to the expansion of particles due to heat, but also to a mechanical “shock wave” effect called the photoacoustic effect. There are five types of tattoos: amateur, medical, medical, traumatic, cosmetic, and professional. Professi Professional oral and cosmetic tattoos are more resilient due to their deeper location and high pigment concentration. B. Traumatic tattoos or asphalt powder guns can be treated more easily and with fewer treatments. For darker or retouched tattoos, lower fluences should be used to avoid hyperpigmentation and scarring. Tattoo removal options are Q-Ruby (694nm), Q-Nd:YAG, Q-Nd:Y AG (1064nm), Dual Frequency Nd:YAG (532nm), and Q-Alexandrite (755nm) lasers18. All are more effective at controlling black pigment and not as effective at controlling yellow or white pigment. In fact, treating white pigment (titanium dioxide) via an oxidation reaction can result in an immediate paradoxical darkening reaction. Reaction. If this occurs, further treatment is required to target the newly formed black black pigment. Some tattoo artists may also use white pigments to create pink, gray, light green/blue color.
higher affinity for blue and green pigments, while Q-Nd:YAG (532 nm) is better suited for red and orange pigment removal. Because many wavelengths are needed to treat multicolored tattoos, more than one system should be used for best results. Results.
Conclusion Laser technology is a valuable tool and has contributed significantly to improving medical care and cosmetic outcomes for many years. Year old. As this technology is refined, newer lasers and applications can be expected with even more impressive results and reduced side effect profiles. The laser will continue to be an integral part of dermatology and other areas of medicine. References: 1. Elizabeth L. Tanzi, et al. Lasers in dermatology: four decades of progress. JAAD 2003;49(1):1-31 2. Jackson BA. Ethnic skin lasers: a review. JAAD 2003;48(6):13-138 3. Altshuler GB et al. Extended theory of selective photothermolysis. Lasersurgery Med. 2001;29(5):416-32 4. Fitzpatrick RE et al. Carbon dioxide laser-induced collagen correction compared to Erbium:Yag laser. Lasers Surg Med 2000;27(5):395-403 5. Absten GT: Physics of light and lasers. Obstet Gynecol Clin North Am 1991;18(3):407-27 6. Ratner D et al. Laser Skin Rejuvenation. JAAD 1999 Sep;41(3):365-92 7. Alam M et al. A prospective study of fungal colonization after facial laser resurfacing: correlation between culture positivity and pruritus symptoms. Dermatol Surg 2003;29(3):255-60 8. Cantatore J et al. Laser surgery: an approach for the pediatric patient. JAAD2004;50(2):16 JAAD2004;50(2):165-84 5-84 9. Dover J et al. Care guideline for laser surgery. JAAD 1999;41(3):484-95 10. Weisberg NK et al. Pigment Changes After Alexandrite Laser Hair Removal Alexandrite. Dermatol Surg 2003;29(4):415-9 11. Nayomi E et al. Treatment of reticular leg veins with 1064 nm long-pulse Nd:YAG laser. JAAD 2003;48(1):7681 12. Wendelin DS et al. hypertrichosis. JAAD 2003;48(2):16179 13. Ross EV et al. Treatment of pseudophiliculitis barbae in skin types IV, V and VI with a long-pulse neodymium:yttrium aluminum garnet laser. Laser. JAAD 2002;47(2):263-70 2002;47(2):263-70 14. Oslen EA. depilation methods. JAAD 1999;40(2):14358 15. Nanni CA et al. Laser-assisted hair removal: Removal: side effects of Q-switched Nd:YAG, long-pulse, and alexandrite lasers. JAAD 1999;41(2):165-71 16. Hamilton MM. In-office laser treatment of pigmented and vascular lesions. Facial Plast Surg 2004 Feb;20(1):63Feb;20(1):639 17. Kuperman-Beade Kuperman-Beade M et al. Laser tattoo removal. Am J Clin Dermatol 2001;2(1):21-5 18. Prince BM et al. Efficacy of laser treatment of tattoos with lasers emitting wavelengths of 532 nm, 755 nm and 1064 nm. dr J Dermatol 2004;150(2):245-5 2004;150(2):245-511
Q-Alexandrite from Q-Ruby (694nm) Tem 48
NAKHLA, NAMI, SHAPIRO, NISENBAUM
Hypertriglyceridemia in Eruptive Xanthoma, Hypertriglyceridemia A Case Report and Review of the Literature Resident in Dermatology, Genesys Regional Medical Center, Grand Blanc, Michigan ABSTRACT Lipid disorders are becoming increasingly common in the United States. Dyslipidemia can often occur with easily recognizable dermatological manifestations. It is up to all physicians to familiarize themselves with these presentations in order to initiate appropriate patient management. patients. Although most xanthomas represent benign conditions, certain lesions can be associated with significant clinical disruption. We present a case of eruptive xanthoma associated with massive hypertriglyceridemia and hypercholesterolemia with elevated serum lipid levels exceeding those found in a search of the relevant literature. Lipid disorders have become increasingly common in the United States. Dyslipidemia can often occur with easily recognizable dermatological manifestations. It is up to all physicians to familiarize themselves with these presentations in order to initiate appropriate patient management. patients. Although most xanthomas represent benign conditions, certain lesions can be associated with significant clinical disruption. We present a case of eruptive xanthoma associated with massive hypertriglyceridemia and hypercholesterolemia with elevated serum lipid levels exceeding those found in a search of the relevant literature.
AT Case Report A 33-year-old white male presented to the Department of Dermatology with a chief complaint of rash. He described a history of an itchy rash that began on the extensor side of the arms and spread to the back, chest, abdomen, and lower extremities in the month prior to presentation to our clinic. He denied any history of similar injuries. He denied any systemic complaints. Medical history included hypertension, depression, and sleep apnea. Medications include Atenolol and Zyprexa (olanzapine). However, the itchy rash began before starting olanzapine therapy. Therapy. Previous surgical history included splenectomy. He was a non-smoker with no known allergies. allergies. He admits to drinking two cans of beer a day and eating fast-food burgers and fried chicken regularly. Physical examination revealed a moderately obese male with no acute medical condition. He presented with multiple 2-3 mm yellow papules with mild erythema around the chest, back, upper and lower extremities. There were a few scattered lesions on the face; Palms and soles were spared. A core biopsy of a lesion was performed. The histology was consistent with the eruptive xanthoma. This revealed nodular clusters of foam cells in the upper and middle dermis. The nuclei were placed centrally in a foamy cytoplasm. There was no atypia. There was a background of lymphocytic infiltration of the perivascular zones. Screening labs were noted for a triglyceride level of 15,125 mg/dL, with a normal lab value of less than 150 mg/dL. Total serum cholesterol was 1331 mg/dl with a laboratory normal of less than 200 mg/dl cells.
Multiple yellow papules 2-3 mm in size.
Papules with an inflammatory halo.
Nodular aggregates of foam cells can be seen
Medium strength shows foam cells with a center
at low power to wrap around the top and middle part
placed core and frothy character
dermis. There are antecedents and perivascular perivascular ular
HYPERTRIGLYCERIDAEMIA IN ERUPTIC XANTHOMA, CASE REPORT AND LITERATURE REVIEW
middle dermis. There is background perivascular inflammation. Medium magnification shows foamy cells with a central nucleus and characteristic foamy cytoplasm. The patient was informed of the diagnosis of an eruptive xanthoma with underlying hypercholesterolemia and hypertriglyceridemia. Olanzapine was discontinued and a change in diet was discussed. The patient was started on simvastatin (Zocor) and fenofibrate (T (Tricor) Ricor). After about two months of therapy, the patients' lesions had completely disappeared. Her lipid levels remain normal seven months later on treatment with simvastatin alone. Therapy.
Discussion Xanthomas result from lipid infiltration into the dermis and tendons. The major types include eruptive xanthomas, tuberous xanthomas, sinewy xanthomas, and flat xanthomas. In the United States, it is estimated that more than 100 million people have serum cholesterol levels greater than 200 mg/dL.11 Eruptive xanthomas are usually associated with elevated triglyceride levels. 1 They usually appear as small, 1-4 mm, yellow to orange papules in clusters. 2 Buttocks, extremities, and trunk are the most common locations. A generalized form can be seen in severe severe cases. The lesions are tender and may be itchy with a surrounding inflammatory halo. In eruptive xanthoma hypertriglycemia
Eridemia can be the result of a primary genetic defect in lipid metabolism (primary hyperlipoproteinemia) or secondary. 3 Abnormal transport of lipoproteins may be due to increased endogenous production, defective clearance, or decreased catabolism. Secondary causes of hyperlipoproteinemia include; Diabetes mellitus, obesity, pancreatitis, chronic renal failure, hypothyroidism, cholestatic liver disease, paraproteinemia and medications. Drugs known to induce or aggravate hyperlipoproteinemia include estrogens, corticosteroids, and retinoids.4,5 Retinoid therapy can induce hypertriglyceridemia by inducing hepatic VLDL secretion.11 Eruptive xanthomas have recently been associated with its use of olanzapine (Zyprexa).6 All of these cases showed evidence of hypertriglyceridemia, but even the most severe cases had significantly lower values than our patient. 5 Our patient was initiated on olanzapine therapy by his GP two weeks prior to his first visit to the dermatology clinic because he was experiencing "depression" from his "rash". It is quite possible that olanzapine contributed to the patient's pre-existing hypertriglyceridemia to cause these previously unobserved elevations in serum lipids. The literature review reveals no cases of eruptive xanthoma with a greater increase in cholesterol or triglyceride levels than in our patient.3, 7, 6, 8, 9, 10, 11
BRACCIANO, SIL SILVERTON VERTON
Summary In this article we present a case of eruptive xanthoma with serum levels of triglycerides and cholesterol at previously unreported levels. This patient illustrates a possible additive effect of drug-induced lipoproteinemia combined with underlying hyperlipidemia to cause massive dyslipidemia. Dermatologists must be vigilant in searching for drug dressings when patients have an eruptive xanthoma. Untreated, this patient is certainly at increased risk for atheromatous disease, including myocardial infarction and stroke.11 References: 1. Love JR. Dubin HV, Xanthomas and lipoproteins., Cutis. 1978 June:21(6):801-5. 2. Gotto AM Jr., Clinical Diagnosis of Hyperlipoproteinemia. Am J Med. 1983 May 23;74(5A):5-9. 3. Bickley L., Yellow papules in a middle-aged woman, Eruptive Xanthoma, Arch Dermatol. 1989 Feb:125(2):288-9, 291. 4. Parker F, Xanthomas and hyperlipidemias, J Am Acad Dermatol, 1985 July Vol. 13(1):1-34. 5. Dicken CH, Connolly SM, Isotretinoin-associated eruptive xanthomas., Arch Dermatol. 1980 Aug:115(8):951-2. 6. Chang HY, eruptive xanthomas associated with olanzapine use. Arch Dermatol. 2003:139:1045-1048 2003:139:1045-1048. 7. Sanchez RL, Papular xanthoma. A clinical, histological, and ultrastructural study., Arch Dermatol. 1985 May: 121(5): 626-31. 8. Barker DJ, The Koebner phenomenon in eruptive xanthoma. Arch Dermatol. 1979 January: 115 (1): 112. 9. Miwa N, The Koebner phenomenon in eruptive xanthoma. J for Dermatol. Vol. 19 Vol. 19:48-50, 1992. :48-50, 1992. 10. Miller DM, Brodell RT, Eruptive xanthomatosis with linear Köbnerization. J.Am. Acad. dermatol. 1995 Nov:33(5Pt 1):834-5. 11. Massengale WT, Xanthomas in Bolognia J, Jorizzo JL, Rapini RP, Dermatology, Mosby, 2003, 1447-1454.
Cutis Leukemia - Case Reports and Discussion Suzanne Sirota Rozenberg, DO*, David Kessler, DO**, Marvin Watsky, DO*** *3. Johns Hospital Far Rockaway, New York **Assistant Clinical Professor of Dermatology at Touro College of Osteopathic Medicine ***Program Director of Dermatology, St. Johns Hospital, Far Rockaway, New York ABSTRACT Cutaneous leukemia is an unusual disease process in which neoplastic leukocytes infiltrate the skin locally or diffusely. a disseminated systemic disease or a relapse of an existing leukemia. Patients are usually over 50 years old, but can occur in younger patients depending on the type of leukemia. 25-30% of children with congenital leukemia, particularly of the myeloid type, have cutaneous leukemia. Cutaneous leukemia is most commonly seen in patients with M5 acute monocytic leukemia and M4 acute myelomonocytic leukemia. Leukemia cutis leukemia is often the disease that precedes bone marrow infiltration and systemic symptoms. In addition to skin biopsy, these patients require hematologic hematology studies with complete analysis of bone marrow aspirate and peripheral blood smear. stain. Cutaneous Histopathology Histopathology and immunophenotyping are essential. significant. The treatment and prognosis of cutaneous leukemia are directly related to the underlying disease. Joint treatment of these patients with the haematologist, oncologist and radiotherapist is essential.
Cutaneous Leukemia Case #1 A 61-year-old white male presented to the office with a 4-week history of a rash on his face and body. The patient claims to have taken esomeprazole for acid reflux for 4 weeks. The rash started around that time, so the GP switched him to lansoprazole. Physician. The patient was started on prednisone by his doctor the day before his presentation. He also stated that he had felt weak and had muscle pain since starting the medication. Upon further questioning, the patient stated that the rash began in the abdomen and spread to the face and extremities. Her system check was positive for a 6 pound weight loss in the previous month and fatigue. He denied fever, chills and night sweats. He had no shortness of breath or chest pain. A previous examination for chest pain was negative. His medical history was significant for GERD for GERD, and his previous surgical history was positive for hemorrhoidectomy. hemorrhoidectomy. He had no known allergies. His last medications were rabeprazole, aprazolam, loratidine and acetaminophen. paracetamol. His father had diabetes and two brothers have diabetes and coronary artery disease. Her social history has been negative for tobacco, alcohol, and drugs. He was a school teacher.
Figure 2 Figure 5 higher performance
Figure 6 Lysozyme staining
On physical examination, multiple indurated, erythematous to purple nodules were observed on the face, chest, and back. The rest of the physical was essentially negative. It is particularly important to note that no lymphadenopathy was present. (see Figure 14) Her CBC lab results were 3.1, 10.9/31.8, 241 Figure 4 h and e, low magnification
RDW-16.9%. Skin biopsy revealed infiltrated mononuclear cells between collagen bundles
CASE REPORTS OF LEUKEMIA CUTIS AND DISCUSSION
Figure 7 CD45Ro
Figure 13 higher magnification Figure 9
Figure 14 CD68 Figure 10 Figure 8 Leader staining
in the superficial and middle dermis. Mononuclear cells have a high nucleus to cytoplasm ratio, irregular nuclear borders, prominent nucleoli, and sparse basophilic cytoplasm. The epidermis appears normal. The cells are positive by Leder stain and are highlighted by immunohistochemical stains for lipozyme and CD45. Myelopero Immunohistochemical stains for myeloperoxidase, xidase, CD-3, CDCD20 and CD34 are negative. (See Figures 5-8) Final Diagnosis - Cutis Leukemia
Case 2 old white male complained aged 79
Rash on both arms, arms, scalp and face for the last month and a half. Guy. The patient reported no symptoms or pain. 6 months earlier, the patient had multiple skin nodules that resolved on their own. Had had no prior medical treatment. Symptom review was positive for bilateral testicular masses unrelated to current condition. He denied nausea, vomiting, diarrhea, constipation, fever, chills, bleeding, bleeding or weight loss. He had no medical or surgical history. He also denied allergies. On physical examination, multiple 1-3 cm erythematous nodules and
the remainder of the physical examination was negative except for +1 edema in the lower extremities. There was no lymphadenopathy. (See Figures 9-11) Skin biopsy revealed cutaneous leukemia with a dense diffuse infiltrate of
Numerous mitotic figures are present. CD68, CD43 and lysozyme are positive, myeloperoxidase, myeloperoxidase, CD3, CD20, CD30, CD79A are all negative. (See Figures 1215) Her lab results were CBC- 5.1/ 9.5/ 27.6/ 165 RDWRDW- 19.6 RBCRBC- 3.22 Peripheral blood smear showed normocytic anemia, mild neutropenia. Bone marrow biopsy and aspiration revealed
Face, back and legs were recorded arms, in addition to the thorax, right testicle mass of 10 cm and left of 7 cm, the
mononuclear cells characterized by vesicular shape and irregular nucleus by relatively abundant pale stained cytoplasm.
hypercellular bone marrow, medulla, and megakarylinear hematopoiesis with ocytic myeloid hyperplasia, irregular irregular, mild to moderate
Figure 15 CD43, Lisozima
Figure 12 h and e, low power
ROZENBERG, KESSLER, WATSKY
ate reticular fibrosis and increased iron storage. Evaluation and plan - leukemia section diagnosis based on a biopsy. The patient was referred for hematological and oncological evaluation and initiation of treatment for acute leukemia. Unfortunately, this patient died within a year of diagnosis.
Cutaneous Leukemia Cutaneous leukemia is a disease of the skin, either a sign of a systemic disease process or a relapse of an existing leukemia. The skin is locally or diffusely infiltrated with leukemia cells. Leukemia cells are neoplastic neoplastic leukocytes. Cutaneous leukemia is most commonly seen in patients with M5 acute monocytic leukemia and M4 acute myelomonocytic leukemia. These patients are usually over 50 years old but can be of any age depending on the type of leukemia. Leukemia. The incidence of leukemia cutaneous leukemia is high, 25-30% in children with congenital leukemia. Leukemia. Most of these cases are of the myelogenous type. (1,5,7) Cutaneous leukemia is observed with or without a diagnosis of hematological malignancy. Can be seen before systemic leukemia occurs. to 50%. In up to 7% of patients with cutaneous leukemia, local disease precedes bone marrow infiltration and systemic symptoms. Cutaneous leukemia occurs in both males and females, with a slightly higher prevalence in males.(6,1) The primary skin lesions seen in cutaneous leukemia are small papules, 2 to 5 mm in size, nodules, or plaques. The color tends to be pink, purple, or darker than normal skin. The lesions are palpable, palpable, indurated, and firm. Patients may have single or multiple nodules. They appear as psoriasiform guttata or similar lymphomatoid papulosis. tends to be painless, localized or disseminated skin leukemia. Lesions can be found on the trunk, extremities, and face. Guy. There is significant overlap with other inflammatory eruptions. Secondary lesions can be seen in cutaneous leukemia. If thrombocytopenic thrombocytopenia is present, bleeding is possible. Ulceration may be present, as may generalized erythroderma. Leukemic gingival infiltration may occur in acute monocytic leukemia. (1) Inflammatory diseases in leukemia patients occur with unusual presentations due to the involvement of leukemia cells in the infiltrates. infiltrate. Associated reaction patterns that can be seen are Sweets syndrome, bullous gangrenous urticaria, pyoderma and palpable purpura.(1,6) lesions resulting in all types of leukemia
abnormal development of leukocytes in the bone marrow. Maturation stops and a proliferative clone population of cells develops. Cutaneous leukemia may result from local proliferation of leukemia cells in the skin. But how does that happen? Why do leukemia cells migrate into the skin? The answer is not clear. Several theories are afoot. One theory is that in HTLV-1-induced HTLV-1 leukemia there is abundant expression of the cc chemokine receptor 4 (CCR4) on the cell surface of leukemia cells. In adult T-cell leukemia affecting the skin, thymus- and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine ligands (MDC/CCL22) are observed in the skin. Another theory suggests that the presence of T-cell-related antigens on the cell surface of acute monocytic leukemia (AML-M5) leukemia cells may promote selective skin targeting in patients with cutaneous leukemia.(1) Cutaneous leukemia is relatively rare . . . The highest incidence is observed in adult T-cell leukemia/lymphoma (ATLL), followed by acute myeloid leukemia (AML), followed by subtypes M4 and M5. Cutaneous leukemia is also observed in children, particularly children with congenital leukemia.(7,1) Medical history is very important in evaluating a patient with cutaneous leukemia. Signs and symptoms to consider are extramedullary involvement, meningeal signs, anemia, secondary neutropenia, and other constitutional signs and symptoms. Bacterial, viral, or fungal infections may be present. CNS involvement may be observed, as may bone and joint pain due to leukemic infiltration.(1,9) On physical examination, pallor, organomegaly, purpura, petechiae, drug reactions, LCV, infections, candidiasis, and disseminated zoster may be present. Inflammatory skin reactions can occur due to drugs, infections, and the leukemia itself. per se. Examples of this are graft-versus-host disease, acute fever
For me. Metastatic skin carcinoma, anaplastic large cell CD30+ lymphoma, and non-Hodgkin's lymphoma are malignancies that must be considered in the differential diagnosis.(3,1,10) Laboratory tests should be performed when a patient has cutaneous leukemia. A complete blood count helps evaluate anemia, thrombocytopenia, neutropenia, or leukocytosis. Peripheral blood smear shows circulating leukemia cells. Chemistry profiles will assess BUN and creatinine
neutrophilic dermatosis, persistent arthropod bite-like reaction. and more unusual lesions vary depending on the underlying leukemia. AML-M4 and AML-M5 show characteristic gingival hypertrophy due to leukemic infiltration. Erythema nodosum, annular centrifugal erythema, pyoderma gangrenosum, urticaria, urticaria pigmentosa, guttate psoriasis, lion's facies, and macular erythema may be observed. Cutaneous leukemia can occur in established scars and in areas of recent trauma.(1) The differential diagnosis of cutaneous leukemia is broad and varied. Disseminated infections occurring in an immunocompromised neutropenic host should be considered.
In AML, the nuclei are large and have cytooval vesicular basophilic plasma. All different degrees of maturation are observed in CML, as well as eosinophils. ALL has medium to large sized blasts with a high nucleus to cytoplasm ratio. Reason. CLL is more uniform, uniform, mature lymphocytes. Monocytic leukemia is similar to large cell lymphoma but affects the entire dermis and the superficial panniculus. ATLL cells retreated into lobed lobed nuclei. Epidermotropism is present. Hairy cell leukemia Leukemia has monomorphic mononuclear cells. (1) The prognosis of patients with cutaneous leukemia is directly related to the underlying disease. Most patients die months after diagnosis. Patients should be treated systematically
The aforementioned inflammatory; The candy differential includes the syndrome, such as B. Adverse drug reactions, transfusion reactions, GVHD, vasculitis and multi-
caly form, the time of diagnosis is the poor prognosis. The treatment offered depends on the type of leukemia found. found. Combination therapy is best; systemic chemotherapy
apy LDH mirror, apy. especially uric acid and important are tendentially increased chemotherapy in leukemic leukemia patients. If a patient has a fever or signs of infection, cultures should be taken. Imaging studies should be performed when cancer/leukemia is suspected and to assess the extent of the disease.(1,8) A skin biopsy is essential. An appropriate core or excisional biopsy should be performed. Immunohistochemical staining is key to diagnosis. Help determine cell lineage. CD45(LCA) and CD45RO CD45RO are T cell positive, CD20 is normally B cell positive and CD43 is negative. Lysozyme and chloroacetate esterase are positive for granulocytes, while CD68 is negative. Lysozyme and CD68 are positive for monocytes, while chloroacetate esterase is negative.(4,1) Bone marrow aspiration and biopsy are definitive for the diagnosis of systemic leukemia. Special stains must be performed to determine cell lineage and degree of maturation. Histological findings vary by subtype of leukemia. A leukemic leukemic infiltrate is present in the dermis. It is perivascular and periperiadnexal. Bundles of collagen bundles are separated by leukemia cells. cells. Leukemia cells can infiltrate the lumen of blood vessels, their walls, and the fibrous septa of subcutaneous fat. fat. The epidermis remains relatively normal and a border zone is present.(1)
CASE REPORTS OF LEUKEMIA CUTIS AND DISCUSSION
Apia and local radiation. PUVA A can also be radiation. PUV considered. Treatment should be considered together with the hematologist and oncologist.(1,8) References: 1.
Rencic, Adrienne and others. Leukemia Cutis emedicine.com/derm/topic 924.h+m 2004 2. McCollum, Amy BS; Bigelow, Bigelow, Carolyn L. MD et al. Unusual skin lesions in chronic myelomonocytic leukemia, Southern Medical Journal 2003; 96:681-684 3. Wong, Raymond; Raimundo; Couriel, Daniel and others. The Effect of Graft versus Leukemia in Cutaneous Leukemia Tr Transplantation ansplantation 2003; 76:619-620 4. Miller, Michael K. MD et al. Concomitant chronic lymphocytic cutaneous leukemia and acute myeloid cutaneous leukemia in a patient with untreated CLL American Journal of Dermatopathology 2001: 23(4) 334-340 5. Chang, Howard Y.Y. MD et al. Stasis dermatitis-like myeloid skin leukemia JAAD 2003; 49:128-129 6. Sakalosky, Pamela Pamela E. MD et al. A case of acantholytic dermatosis and leukemia Leukemia cutis: Cutis: cause or effect? It is done? The American Journal of Dermatopathology 2002; 24(3) 24(3) 257259 7. Isaacs, Hart Jr. Jr. MD. Fetal and neonatal leukemia. Leukemia. Journal of Pediatric Hematology/Oncology 2003; 25(5) 348-361 8. Zweegman, Sonja et al. Cutaneous leukemia: characteristic clinical features and treatment strategies. it. Haematologica 2002; 2002; 87(04) ECR13 9. Bolognia, Jean MD, et al. Dermatology Dermatology, Philadelphia, Pennsylvania, Leukemia Cutis; 2003 pp. 1946-1950 10. Odom, Richard B, et al. Al. Andrew's Diseases of the Skin, Philadelphia, Pennsylvania Leukemia cutis of Pennsylvania; 2000. p. 937940
ROZENBERG, KESSLER, WATSKY
Office Clinical Study Subantimicrobial Dose of Doxycycline in the Treatment of Acne Vulgaris Jason A. Barr, D.O.*, Don A. Anderson, D.O.** *3rd year resident, AZ Desert Dermatology/Midwestern Dermatology/Midwestern University/Kingman Regional Medical Center* * Program Director; AZ Desert Dermatology/Midwestern Dermatology/Midwestern University/Kingman Regional Medical Center SUMMARY In the treatment of acne, submicrobial dosing of doxycycline offers the proven benefit of reducing inflammation without the side effects associated with traditional dosing. Pa patients receiving 25 mg twice daily achieved a modest reduction in lesion count without any side effects. Submicrobial dose doxycycline should be considered as add-on or maintenance therapy in the treatment of acne.
Introduction Acne vulgaris is a common disease with significant psychosocial morbidity associated with its curative potential. In the United States, acne affects most people between the ages of 11 and 30. (1) The therapy goals include the inhibition of microcomedo formation and the reduction of inflammation. For the latter, tetracyclines have traditionally been used in antimicrobial (standard) doses. Excellent clinical outcomes seem to correlate with reduced numbers of Propionibacteria acnes (P.. acnes). (2) In addition, tetracyclines have additional benefits independent of their antimicrobial properties. Using adult periodontitis as a model, researchers have demonstrated inhibition of cytokines, decreased matrix metalloproteinase (MMP) activity, and subsequent collagenolysis.(3,4) Acne, like chronic periodontitis, involves an exaggerated host response to the overgrowth of resident bacteria. Doxycycline is a member of the tetracycline class of antibiotics that bind to and inhibit the 30S ribosome, thereby inhibiting protein production. Doxycycline has a more favorable side effect profile than minocycline or tetracycline and appears to be a more effective MMP inhibitor. (5) Side effects of the antimicrobial gastrointestinal dose of doxycycline include photosensitivity, irritation, vaginitis, and gram-negative folliculitis. (6) Increased resistance to P. acnes has been reported due to frequent and prolonged use of tetracyclines and should be considered when using doxycycline. (7) Recently, a submicrobial dose of doxycycline has recently been shown to be effective and well-tolerated in the treatment of acne without inducing bacterial resistance. (8) Our aim was to study the efficacy and tolerability of a submicrobial dose of doxycycline in a rural dermatology practice. METHODS: Six patients with acne hyclate vulgaris were treated with mild doxycycline 100 mg orally as a tablet twice daily.
This formulation was chosen due to its lower cost compared to doxycycline hyclate 20mg. tablets. tablets. No other systemic or topical medications were allowed, including oral contraceptives. permitted. None of the patients had previously used isotretinoin. Lesion counts included open comedones, closed comedones, and cysts. Patients were asked if they experienced any side effects, including gastrointestinal irritation, photosensitivity, or vaginitis. Baseline lesion scores were compared to lesion counts at six weeks and three months. Results: All patients tolerated the therapy well. No side effects have been reported. All patients reported excellent adherence. Conformity. All injury numbers have been reduced. The number of open comedones was reduced from 3% to 44%. The number of closed comedones was reduced from 25% to 78%. Cysts reduced by 100%.
Discussion The multifactorial action of doxycycline makes it an excellent choice in the treatment of acne vulgaris. It is beneficial in conventional doses but has the potential to cause gastrointestinal irritation, vaginitis, photosensitivity, gram-negative folliculitis, and resistance to P. acnes. Doxycycline's anti-inflammatory effects include decreased polymorphonuclear leukocyte (PMN) chemotaxis and MMP activity, cytokine inhibition, and decreased collagenolysis. These effects are independent of the antimicrobial activity of doxycycline. In our small series of patients, we observed a modest reduction in the number of total lesions and inflammatory lesions with no undesirable side effects. Effects. we believe believe
Submicrobial dose doxycycline is an excellent choice for adjunctive therapy in combination with topical retinoids. retinoids. This regimen may also be useful as maintenance therapy once clinical improvement has been achieved with the standard dose of doxycycline alone or in combination with another therapy. References: 1) Leiden JJ. Treatment of acne Acne vulgaris. N Engl J Med 1997; 336:1156-1162. 2) Bikowski JB. Doxycycline sub-antimicrobial dose doxycycline for acne and rosacea. skinned. 2003:2(4):234-45. 2003:2(4):234-45. 3) Golub LM, Lee HM, Ryan ME, Giannobile WV, WV, Payne J, Sorsa TT. Tetracyclines inhibit connective tissue degradation through multiple non-antimicrobial mechanisms. Adv Dent Res;12(2):12-26. 4) Choi DH, Moon IS, Choi BK, Paik Paik JW, Kim YS, YS, Choi SH, Kim CK. Effects of subantimicrobial doxycycline Crobial dose of doxycycline therapy on gingival fluid MMP-8 and MMP-9, TIMP-1 and IL-6 levels in gingival tissue in chronic periodontitis. periodontitis. J
Resolution periodontal. 2004;39(1):20-6. 5) Burns FR, Stack S, Gray RD. RD. Inhibition of purified collagenases from rabbit corneas burned with alkali. Invest Ophthalmol Vis Sciences. 1989; 30:1569-1575 1989; 30:1569-1575. 6) Vibramycin [insert] New York, York, NY: Pfizer Inc; 1993. 7) Del Rosso JQ A status report on the use of doxycycline at a subantimicrobial dose: a review of the biological and antimicrobial effects of tetracyclines. Cutis. 2004;74(2):118-22. 8) Skidmore R, Kovach R, Walker C, Thomas C, Bradshaw J, Bradshaw M, Leyden J, Powala C Powala, Ashley Ashley R. Effects of submicrobial dose doxycycline in the treatment of moderate acne. Arch Dermatol. 2003;139(4):459-64 2003;139(4):459-64..
CONSULTATION CLINICAL STUDY SUBANTIMICROBIAL DOXYCYCLINE IN THE TREATMENT OF ACNE VULGARIS
Dermatological Applications of Negative Pressure Wound Therapy (NPWT): Review of Technique and Mechanisms Director of the Dermatology Residency Program, Oakwood Southshore Medical Center, Trenton, Michigan SUMMARY Increase. Its effectiveness continues to be demonstrated in the hospital setting. Most dermatologists have not yet incorporated this modality into the treatment of wounds found in the outpatient setting. The technical technique is described and the mechanisms are discussed. discussed. The benefits and costs of negative pressure wound therapy are explained.
Introduction The negative pressure bandage is a relatively new concept in the management of acute and chronic wounds. Wounds that were previously treated in an open environment can now be treated in a closed negative pressure environment that creates ideal conditions for healing. The use of negative pressure dressings has become more common since Morykwas et al. 1997 have demonstrated their effectiveness in pig models. Level of nutrient flux as measured by random pattern lobe survival. Each of these parameters has been shown to improve with the use of a negative pressure dressing.1 In recent years, the use of negative pressure wound therapy has become more widespread, particularly in hospitals and long-term care facilities, but has not yet become mainstream in outpatient care conquered place. The names by which negative pressure dressing is known are topical negative pressure therapy or NPT, vacuum blanket technique pressure device or VST, SPD, subatmospheric sealed surface with suction SSS, and the more commonly used and proprietary term pressure assisted closure, vacuum or VAC.
NPWT Engineering The vacuum assisted closure (VAC) device is supplied by Kinetic Concepts Incorporated (KCI, San Antonio, Texas), the exclusive manufacturer in the United States. This device uses an FDA-approved, medical-grade, open-cell polyurethane foam as a dressing to fill the wound cavity. The foam is trimmed to fit the wound, filling the base, walls and undercuts of the wound. The built-in evacuation with side ports is then inserted into the foam tube and covered with a self-adhesive plastic cover
the area bounded by 3 to 5 cm of intact skin. The opposite end of the tube is then connected to the aspirator with a container for collecting the wound fluid. Sewage. The vacuum can be set for continuous vacuum or intermittent cycles. Depending on the wound and the doctor's preferences, the device can be set to different negative pressures. The original study by Morykwas et al. showed that peak blood flows, measured by Doppler ultrasound, were recorded with the phy vacuum setting.
these processes can lead to the formation of a chronic wound. Research is still ongoing to determine the exact mechanisms by which negative pressure bandages accelerate wound healing. Since the first publication by Morykwas et al. in 1997, the number of studies on the effects of negative pressure wound therapy increased sharply. The studies are based on proposed mechanisms of edema reduction, increased blood flow, increased granulation formation, direct mechanical stress, etc
of 125 mmHg flows. With more negative pressure, the negative blood began to decrease. It was also noted that blood flow decreased after five to seven minutes of negative pressure and eventually returned to baseline. After the negative pressure is briefly removed, blood flow increases and then settles.1 Based on this information, many clinicians have chosen a five-minute on and two-minute off regimen. Many of the recommendations are based on anecdotal experience rather than scientifically proven protocols for any type of situation. It is believed that lower pressures are better suited for chronic ulcers, skin grafts and certain painful wounds. Higher pressures are recommended for larger cavities and acute traumatic wounds.2 Banwell et al.3 recommend changing the negative pressure dressing every four to five days. However, if the wound is infected, the recommended time interval for changing the negative pressure dressing is every 48 hours. Nonetheless, these recommendations are based on anecdotal evidence.
Reduction of bacterial colonization. Edema Reduction: It is postulated that applying negative pressure to the wound can remove excess edema. This edema can compress blood and lymphatic vessels and restrict their flow. The fluid removed by NPT was analyzed and found to contain high levels of proteolytic enzymes.3 If left in the wound, these enzymes slow down the formation of the collagen matrix. Formation. The removal of discharge from the wound stimulates the diffusion of nutrients through the tissue. Increased Blood Flow: Negative pressure stimulates blood flow to the area. Using laser Doppler flowmetry with a needle probe, Morykwas et al.1
Mechanisms of action In order for a wound to heal, keratinocytes must migrate from side to side and re-epithelialize the skin defect. Before this can happen, deposits must be removed, infections controlled, inflammatory processes weakened and granulation tissue formed. Format. Proliferation Proliferation, On, angiogenesis, chemotaxis, cell migration, Sion, and protein production are important steps involved in wound healing. Any interruption in
a four-fold increase in mmHg blood flow at -125 subatmospheric pressure in porcine models. Chen et al.4 recently used a rabbit model to show that increased blood flow is associated with increased capillary caliber, increased capillary density, and with angiogenesis. Application of NPWT to human burns has also shown a similar increase in blood flow.3 These direct effects on the vasculature are thought to increase vasomotor tone and cause the release of vasoactive mediators. Mechanical Stress: Stress: Mechanical stress on the intracellular cytoskeleton, which is normally balanced by the extracellular matrix, has been shown to cause increased protein transcription leading to the synthesis of matrix molecules5, angiogenesis6 and re-epithelialization7. This process is then gradually controlled via the intermittent vacuum adjustment.
This explains the faster healing times observed by Morykwas.1 Granulation tissue: Morykwas et al. 1 showed increased granulation tissue formation in pig models taking daily alginate impressions of wounds treated with NPWT. These molds showed a NPWT increase in granulation tissue formation over the control of 63% with continuous suction and 103.4% with intermittent suction. The observation of increased granulation tissue formation was reported by Fabian et al.
Leg ulcers that require careful nursing and repeated dressings as the healing process is slow. place, place. The negative negative pressure dressing increases the rate of granulation tissue formation by increasing blood flow, removing metalloproteinase-laden edema, and reducing bacterial colonization, allowing the chronic ulcer to heal. A group in France studied the technique of negative pressure wound therapy for chronic leg ulcers. Fifteen patients who
8.9 al. Joseph et al., using rabbit ear models and bacterial colonization: The use of negative pressure wound therapy correlates with a decrease in wound infection rates.1,10,11 This improvement is believed to be due to either the closed nature of the dressing, removal of edema, and fewer dressing changes. Edema slows wound healing by impeding capillary blood flow to the wound bed and serving as a reservoir for infection. Negative pressure removes excess edema by allowing an increase in blood flow to the area, which in turn brings in neutrophils and macrophages along with increased oxygen delivery for the oxidative destruction of bacteria. In addition, polyurethane foam placed on the wound bed has been found to attract immune cells, possibly due to a foreign body reaction.12
had been treated unsuccessfully with other methods of negative pressure therapy. After six days, four patients had a greater than 50% reduction in wound size and six patients had a greater than 25% reduction.13 Flaps and Grafts: NPWT is indicated for use with flaps and grafts. Assists in preparing a bed of granulation tissue suitable for graft placement. Once the graft or flap is in place, the dressing acts as a reinforcement, providing firm fixation and avoiding shear forces.14 The vacuum dressing is useful because it easily conforms to convex and concave surfaces. Negative pressure helps evacuate seromas and hematomas that could compromise the viability of tissue grafts.15 As previously mentioned, there is also increased oxygen tension and angiogenesis and decreased infection rates with the use of negative pressure dressings.
Indications/Contraindications The use of negative pressure wound therapy is indicated for chronic open wounds, diabetic ulcers, wound dehiscence, second degree burns, bedsores, flaps and grafts, acute and traumatic wounds. Contraindications include malignancy in the wound, untreated osteomyelitis, the presence of necrotic tissue and open pus. The physician should also use good judgment when treating an actively bleeding wound and when treating a patient with anticoagulants.
Dermatological Applications To date, most clinical trials of negative pressure wound therapy have been conducted by surgeons and surgical sub-specialists with patients housed in hospitals or nursing homes. This is largely due to the static nature of the Vacuum Assisted Closure Device (V.A.C.TM) supplied by Kinetic Concepts Incorporated (KCI, San Antonio, Texas), the exclusive manufacturer in the United States. r, However, KCI has recently introduced a more compact and portable model that is more suitable for ambulatory patients, which dermatologists most often encounter. Chronic Ulcers: Dermatologists frequently encountered patients with
Cost One of the first objections to the use of NPWT was its unnecessary cost. Costs. There is a cost associated with purchasing or renting a VAC machine and special dressings (foam, adhesive pad, and tubing). The reported analysis shows that this high cost is offset by the shorter treatment time compared to more traditional treatment16
traditional regime. Since the dressing is medically necessary, the device will be sourced from KCI, currently the only supplier of negative pressure wound therapy devices in the United States. Medicare or other third-party reimbursements are sent directly to KCI. Reimbursement criteria for the use of NPWT vary from state to state and should be reviewed before use is prescribed.
Conclusion Negative pressure wound therapy is a relatively new concept in wound care. It has been shown to be a useful and effective modality for treating wounds. So far, the focus of the application has been on patients who are unable to walk. Since wounds are as varied as patients, negative pressure wound therapy is not indicated
all situations. As knowledge of its effectiveness increases, more suppliers of the equipment will enter the market, reducing costs. It could soon be added to the dermatologist's arsenal to treat chronic non-healing ulcers and as an adjuvant therapy in the management of surgical wounds. References: 1. Morykwas MJ, Argenta LC, Shelton-Brown EI, et al. Vacuum-assisted closure: a new method of wound management and management: animal studies and fundamental principles. Ann Plast Surg 1997;38:553-562. 2. Morykwas MJ, Argenta LC. Vacuum-assisted closure: a new method for wound control and management: clinical experience. Ann Plast Surg 1997;38:563-576. 3. Banwell PE, Teot L, Topical negative pressure (NPP): the development of a new wound therapy. J Wound Care 2003;12:28-30. 4. Chen SZ, Li J, Li XY, et al. Effects of assisted vacuum closure on wound microcirculation: an experimental study. Asian Jour of Surg 2005;28:211-7 5. Ilizarov GA, The effect of tension stress on tissue formation and growth. Part I. The impact of fixation stability and soft tissue preservation. Clin Orthop Relat Res 1989;238:249-281. 6. Ichioka S, Shibata M, Kosaki K, et al. Effects of shear stress on wound healing angiogenesis in the rabbit ear chamber. J Surg Res 1997;72:29-35 7. Morena DM, Mechanical stretching increases the number of epithelial cells synthesizing DNA in culture. J Cell Sci 1984;69:35-45 8. Fabian TS, Kaufman HJ, Lett ED, et al. Evaluation of subatmospheric pressure and hyperbaric oxygen in the healing of full-thickness ischemic wounds. Am Surg 2000;66:1136-43 9. Joseph E, Hamori CA, Bergman S, et al. A prospective randomized study of Vaccurm-assisted wound closure compared to standard therapy in chronic non-healing wounds. Wounds 2000;3:60-7 10. Gustaffson R, Johnsson P, Algotsson L, et al. Vacuum-assisted closure therapy controlled by C-reactive protein levels in the treatment of deep sternal wound infections. J Thorac Cardiovasc Surg 2002;123:895-900. 11. Buttenschoen K., Fleischmann W., Haupt U. et al., The influence of vacuum-assisted closure on inflammatory tissue reactions in the postoperative course of ankle fractures, Foot Ankle Surg 2001;7:165–173. 12. Gouttefangeas C, Eberle M, Ruck P, et al. Functional T lymphocytes infiltrate polyvinyl alcohol foams implanted during surgical wound closure therapy, Clin Exp Immunol 2001;24:398-405. 13. Loree S, Dompmartin A, Penven K, et al., Is vacuum-assisted closure a valid technique for chronic leg ulcer debridement? J Wound Care 2004;13:249-252 14. Blackburn JH 2nd, Boemi L, Hall WW, et al. Negative pressure bandages as reinforcement for skin grafts. Ann Plast Surg. 1998;40:453-7 15. Schneider AM, Morykwas MJ, Argenta LC. A new and reliable method for securing skin grafts in the difficult recipient bed. Plast Reconstr Surg 1998;102:1195-8 16. Philbeck TE Jr., Whittington KT, KT, Millsap MH, et al. The clinical and economic efficacy of externally applied negative pressure wound therapy in wound care in the home care patient. Management of ostomy wounds 1999;45:41-50
DERMATOLOGICAL APPLICATIONS OF NPWT
Imiquimod in the Treatment of Extramammary Paget's Disease David M. Bracciano, D.O.*, Kimball Silverton, D.O.** *Resident in 3rd year, Michigan State University, Genesys Regional Medical Center, Grand Blanc, Michigan **Program Director, Dermatology residency, Genesys Regional Medical Center, Grand Blanc, Michigan SUMMARY The diagnosis and treatment of extramammary Paget's disease can be challenging for even the most accomplished dermatologist. Surgery remains the "gold standard" of treatment, but morbidity associated with excision in elderly patients is high. In this article, we present a novel approach to the treatment of Paget' Paget's disease Extramammary Extramammary disease with topically applied immiquimod. currently. A history of extramammary Paget's disease and other treatment options are also discussed.
Introduction Extramammary Paget's disease (EMPD) is a relatively rare and often difficult to treat intraepithelial neoplasia. Several treatment modalities have been tried in the past with mixed results. These include broad local surgical excision, radiotherapy, chemotherapy, photodynamic therapy, and microscopic surgery of MOHS.4,5,6,7 Despite these efforts, high rates of local recurrence continue to frustrate patients and their physicians. Doctors. The introduction of biological response modifiers offers many theoretical advantages when applied to the treatment of viral and neoplastic skin diseases. Illness. In this article, a case of primary extramammary cutaneous Paget's disease of the scrotum is treated with imiquimod monotherapy. We will also review the current literature to provide physicians with a rationale for treating this intriguing entity.
ductal epithelium. These cells are mucicarmine (Fig. 2) and Alcian blue/PAS (+), pancytokeratin (AE1/3) (+), EMA (+), HMB45 (-) and S100 protein (-).
Figure 1 H&E staining
The patient and her family were informed of the diagnosis of primary extramammary Paget's disease and treatment options were discussed
Figure 4 Pre-treatment
Case Report A 93-year-old white male was referred to the Department of Dermatology for a left groin 'rash'. The patient stated that he first noticed itching and redness in the groin and scrotum about six months before his appointment. He self-treated this area with topical antibiotics with no improvement. Her GP prescribed topical antifungal medication and there was no improvement. He denied any pain or discomfort in the area. She denied any change in urinary or bowel habits. Habits. Physical examination revealed diffuse erythema with some excoriations in the left groin and scrotal area. The penis, rectum, right scrotum, and right inguinal region were unremarkable. KOH prep and fungal cultures from the site were negative. Punch biopsy of the left inguinal region showed large polygonal cells with pale, focally vacuolated cytoplasm, large nuclei, and prominent nucleoli (Fig. 1). Similar tumor cells extend along the apocrine lineage
Figure 5 Post-treatment with imiquimod
Mucicarmine staining The patient underwent abdominal computed tomography, which revealed no masses or adenopathies. Urological and gastroenterological examinations, including cystoscopy and colonoscopy, were normal.
Detail. The extent of affected skin in the left scrotum and inguinal area (11 cm x 9.5 cm) meant that surgical treatment would require substantial flaps or grafts to close the defect (Fig. 3). The patient and his family were concerned about the patient's ability to tolerate such a prolongation.
BRACCIANO, SIL SILVERTON VERTON
surgery in old age. At the time of the patient's diagnosis, a literature review identified some early case reports showing promising results in the treatment of EMPD with imiquimod.13,12 The patient was advised that a trial of imiquimod therapy could be attempted, with rescue surgery reserved for treatment failure . Treatment was initiated with imiquimod applied once daily, five days per week (six total) to all areas of erythema
Cancer.8 The most common locations of associated cancers are rectal, urogenital, uterine, breast, liver, pancreatic, and adnexal (porocarcinoma) carcinomas. The apocrine derivation of EMPD is supported by its histological picture and immunohistochemical studies. Paget' Paget cells are large round cells with abundant pale stained cytoplasm and a large central reticular nucleus. Paget's cells can be seen singly or in groups scattered across the epidermis. Epidermis. there are epi
weeks. The cream patient should apply the entire affected area and include a 2 cm area of normal looking skin around it. Initially, the patient felt a slight burning sensation at the application site, which subsided after a five-day break in treatment. After three weeks of treatment, a faint scream was heard in the center of the treatment area. After completion of the 6-week treatment with imiquimod, a central resolution of the erythema was noted and the patient denied itching or discomfort. After one month, another six-week course of imiquimod was initiated. After four weeks, a third six-week course was completed. The second and third treatment cycles were well tolerated. The lesion had improved clinically (Fig. 4). However, a repeat biopsy revealed a small area (2.4 cm) of residual disease. Again, surgery versus add-on imiquimod has been discussed, and the patient is currently on his fourth cycle of topical imiquimod therapy.
Sir James Paget first described a lesion of the nipple in 18741. This case was associated with an underlying breast carcinoma. In the same article, he also described a similar lesion with "roughness" of the glans. The "gross" erosive lesions he described were
dermal acanthosis Definitive diagnosis or hyperkeratosis. EMPD requires immunohistochemical staining.10 Because of its epithelial origin, cytokeratin is found in pagetoid cells. Therefore, staining with cytokeratin 7 (CK7) and cytokeratin 8 (CK8) is positive. positive. The apocrine association of tumors is reflected by the presence of mucin in Paget cells. Subsequent mucin staining is positive with Musicarmen, Alcian blue, fuschsinaldehyde, and colloidal iron.6 Slides are PAS-positive, AS-positive, clear, and diastasis-resistant. Further immunohistochemical studies with antibodies against low molecular weight keratins will lead to positive results (GCDF-15, EMA, Cam 5.2). CEA levels can also be elevated in cases associated with an underlying malignancy. EMPD is more common in women than men, with an incidence rate of 1.4/1.0 and a median age of onset of over 50 years. In most cases, EMPD eludes diagnosis for a period of years. lesions on the vulva vulva in 60%, perianal area in 33%, the rest elsewhere; axillae, eyelids, navel, external auditory canals, mucocutaneous junctions, and more recently the face.14 The symptom that presents is usually itching at the site. Examination of the skin reveals an undefined area of erythema. Weeping and discharge with excoriations may occur. Chronic
known as Crocker reported "Paget's Paget's Disease". First case of inscrotal EMPD 18892. As of 2001, fewer than 100 cases of scrotal EMPD have been reported in the literature3. The exact etiology of extramammary Paget's disease (EMPD) remains a matter of debate. Most The Authors believe that it arises from malignant degeneration and aberrant proliferation of epithelial stem cells, often apocrine in origin, presenting as a solitary primary epithelial neoplasm called primary cutaneous extramammary Paget's disease, the incidence of this association with underlying malignancy and related
Findings include a localized area of eczematous skin with plaque formation, averaging 6 to 12 cm in diameter. Diameter. Crusts, scales, and ulcerations can eventually signal the malignant nature of the disease. The unspecific clinical picture often leads to misdiagnoses. Generally, patients for entities such as tina cruris, vulvar pruritus, lichen sclerosis et atrophicus, or candidiasis are treated for an average of two years before a biopsy confirms the true diagnosis of EMPD. Recent treatment protocols for EMPD have emphasized the need for a vigorous search for underlying malignancy once a skin condition has been identified. By the time an underlying malignancy is found, up to 50% of patients already have metastases and have a poor prognosis, with a median survival of less than three years. Treatment options include:
wide local excision with 2 cm margins, Mohs operation, radiotherapy, chemotherapy, photodynamic therapy and chemotherapy, most recently topical therapy with imiquimod.7,11 Surgical therapy is currently the “gold standard” for the treatment of EMPD. Mohs in particular showed improvement the EMPD high recurrence rate. The multicentric nature of EMPD is a major cause of treatment failure. Mohs surgery with intraoperative cytokeratin-7 immunostaining can help map the peripheral edges of the tumor. tumor.99
Conclusion Due to the localization, surgical access to the primary EMPD of the scrotum is fraught with difficulties. Difficulty. These patients are often elderly, and wide excision with flaps and/or grafts to close the defect can expose these patients to significant perioperative morbidity and mortality rates. Therefore, the promise of imiquimod as a topical monotherapy is quite attractive. Imiquimod is an attractive biological response modifier that stimulates both innate and adaptive immunity. The stimulation of cytokine production by dendritic macrophage cells activates the innate immune system and increases natural killer cell activity. The acquired arm of immunity is stimulated indirectly through increased cytokine production. Interleukin 2 production is increased causing production of interferon gamma by T lymphocytes. Activation of B cell activation has also been shown to stimulate increased production of immunoglobulin. Phase 1 clinical trial of oral imiquimod shows possible systemic effects similar to injected interferon. In vitro studies have shown that imiquimod inhibits tumor-associated angiogenesis. melanoma, angiogenesis, renal cell carcinoma, . In patients with hairy cell leukemia, this holds promise of delivering the benefits of interferon therapy without the associated immunogenicity and tolerance seen with current injectable interferon treatments. Topical imiquimod has low (less than 1%) systemic absorption. However, side effects include local irritation, fever, malaise, fatigue, nausea, arthralgia, and diarrhea.12 Local irritation is more common in the treatment of skin cancer and can be exacerbated by increased absorption through actinically damaged skin. Case reports of imiquimod in the treatment of warts, basal cell, squamous cell carcinoma, melanoma, colon cancer, bladder sarcoma cancer and EMPD prompt further investigation of both as topical oral therapy in the future.
IMIQUIMOD IN THE TREATMENT OF EXTRAMAMMARY PAGET'S DISEASE
In conclusion, extramammary Paget's disease of the scrotum is a somewhat rare and difficult entity to treat. legal entity. EMPD often occurs in elderly patients in whom conventional surgical treatment or radiotherapy is precluded due to patient comorbid factors. With further study, topical imiquimod treatment protocols may play a significant role in the dermatologist's arsenal. References:
Acad Dermatol Vol 51:5 Nov-Nov 2004:767-773. 6. O'Connor, WJ: Comparison of Mohs micrographic surgery and wide excision in extramammary Paget's disease. Dermatol Surg 2003 July 29:7, 723-727. 7. Berman, B: Novel Dermatologic Uses of the Immune Response Modifier Imiquimod 5% Cream, Skin Therapy Letter, Vol. 7:9 Nov. 2002, 1-6. 8. Braverman, IM: Cutaneous Manifestations of Internal Malignancy. Malignancy. Clinics in Geriatric Medicine, Vol. 18:1, February 2002, 119. 9. Naohito H: Sentinel lymph node biopsy in patients with extramammary Paget's disease. Dermatol Surg 30:10: October 20041329-1334 10. Yang, Yang, C-C: Depigmented extramammary Paget's disease. British Journal of Dermatology 2004, 151:1049-1053. 11. Shieh S: Photodynamic therapy for the treatment of extramammary Paget's disease. British Journal of Dermatology 2002; 146:100-1005.
1. Paget in disease of the areola before cer ofJ: the mammary gland. St Bartholomew's Hospital Rep 10:87-89,1874. 2. Crocker HR: Paget's disease affecting the scrotum and penis. Transcr Pathol Soc Lond 40: 187-191, 1889. 3. Ng LG: Extramammary Paget's disease of the scrotum. Urology 58(1), 105ix-105xi, 2001. 4. Guerrieri M: Extramammary Paget's Paget's Disease: Role of radioradiation therapy. Australasian Radiology 46, 204-208, 2002. 5. Hendi, A., Zittelli, JA: Extramammary Paget's disease: Surgical treatment with Mohs micrographic surgery. jelly
12. Wang LC: Recurrent Mary Paget's disease with successful treatment of the vulva with topical 5% extra mamimiquimod cream. J Am Acad Dermatol, Vol. Volume 49, Number 4, October 2003, 769-770. 13. Zampogna JC: Treatment of limited primary cutaneous extramammary Paget's disease with topical imiquimod monotherapy: reports of two cases. J Am Acad Dermatol, Vol. 47, Number 4, October 2002, S229-S235. 14. Cohen MA: Extramammary Paget's disease of the face. Dermatol Surg, 30:10: October 2004, 13611363.
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AOCD members can advertise "position available". This is a free service for all active AOCD members. A 3 inch black and white advertisement will be provided in the newspaper as a free service. If members want to use a larger space, they can do so. The cost of this ad is: Black & White - 1/4 page - $125, 1/2 page - $200, full page - $350 Full 4 color ad - 1/4 page - $275, 1/2 page - 350 $, full page - $500 Resident members may place a black ad and 3 inch white columns to advertise their desired job position. These ads must be sent as an email attachment and sent to[email protected]All photos to be included in an active member's listing must be in .pdf format.
Position available soon!! MIRAMAR, Fla. New practice. Great
Informe-se: Jay S. Gottlieb, DO, FAOCD www.miramarDermatology.com E-Mail:[email protected]Phone: 954-963-5875
demographics! die (including two prestigious Memorial Mirooms), Ramar Hospital Campus, 6 exam rooms, Miramar Surgery Office, Frozen Surgery Department, Aesthetic Room, Full-time Beautician, Full-time PA, Paperless Electronic Medical Records (no charts, no Rx pads and no Pads), exclusive line of skin care products, state-of-the-art website enabling patient registration and skin care product sales, Lumenis IPL, LightSheer hair removal laser, Iridex laser Diolite, laser, office marketing and patient education with flat panel displays in every exam room, reception and surgical waiting room in the Practice. XFM music throughout the office, office, employee biometric biometric time clock. Watch. I'm looking for a dermatologist who wants to build a great practice in a great location. It can be part time. Willi Ready to talk to dermatology residents over the next 18 months. Medical appointments only, no job placement
Palisade Neutrophilic Granulomatous Dermatitis A Spectrum of Disease: Case Report and Literature Review Lutheran Medical Center, Brooklyn, New York **Assistant Dermatology Physician, MD, New Jersey ***Program Director, Lutheran Medical Center, Brooklyn, New York ****Dermatopathologist, Ameripath Inc. , Port Chester, New York SUMMARY Palisade neutrophilic granulomatous dermatitis (PNGD) is an entity that has not been clearly defined clinically or histopathologically. It typically presents in patients with histopathologic findings. in rheumatoid arthritis and other connective tissue diseases. The diverse clinical and histological presentations of PNGD have led to several different names. A case of a 61-year-old woman with rheumatoid arthritis who develops PNGD is presented. In addition, the clinical and histological features of PNGD are reviewed. It is proposed to view PNGD as a spectrum of diseases with many clinical and histological presentations coinciding with disease progression.
Case Report A 61-year-old Hispanic woman attended the dermatology outpatient clinic for evaluation of multiple lesions. The lesions started a few years earlier on the elbows and later developed on the hips and distal fingers. Topical Topical antibiotics and oral steroids have been used twice daily without relief. The patient had a known history of diabetes mellitus, hypertension, congestive heart failure, peripheral vascular disease and rheumatoid arthritis. The surgical history was significant for bilateral below-the-knee amputations, which left her in a wheelchair. He denied any drug allergy. She was taking azathioprine, etanercept, furosemide, nitroglycerin, colchicine, calcium, and oral steroids. A comprehensive skin examination revealed well-defined erythematous to purple annular plaques on bilateral elbows (Figure 1). Multiple clustered tense vesicles on left hip and crusted erosions
Crusted erosions on the left hip
Erythematous spots on right finger
A few weeks before presentation, erythematous and purple plaques were observed on the right elbow and right hip (Figure 2). vi
a few days earlier, non-squeezable lacy spots were observed on the right first and fourth digits and the left fourth and fifth digits (Figure 3). Mucous membranes were spared. Positive laboratory studies included rheumatoid factor from one to forty-six antinuclear antibodies in a stippled pattern. The clinical differential diagnosis
Elbow lesions included psoriasis, erythema diutinum elevatum, urticarial vasculitis, Sweet's syndrome, Sweet's neutrophilic rheumatoid dermatitis, neutrophilic granulomatous palisade dermatitis, gut-associated dermatosis-arthritis syndrome, pyoderma gangrenosum, and Behcet's disease. Hip and finger injuries were considered separate disease processes at the time. The differential diagnosis of the hip. including herpes simplex virus, pressure or friction blisters from wheelchair use, and autoimmune bullous disease. Vasculitis, trauma, and infection have been considered for digital lesions. Two 3mm core biopsies were taken from the right elbow and left hip. The patient refused a digital biopsy. Histologically, the elbow biopsy showed palisade granulomas with suppuration and neutrophilic dust. There was a dense perivascular and interstitial neutrophilic infiltrate, fibrin chains on the vessel walls, and diffuse fibrosis (Figures 4 and 5). These findings were consistent with the diagnosis of PNGD. Hip biopsy found focal subepidermal neutrophils with necrosis and bullae. These findings are representative of the spectrum of histological findings associated with PNGD. Therapy with fluocinonide 0.5% ointment and mupirocin cream was started twice daily. The patient continued to be treated with biologics and immunosuppressants by the rheumatologist. The lesions improved over several weeks. Since then, the patient has been lost to follow-up.
Comments Palisade neutrophilic granulomatous dermatitis (PND) is still considered a rare entity and is not fully defined clinically or histologically.1 This process has gone by several names over the course of its evolution.
GRANULOMA NEUTROPHIL PALISADATO GRANULOMATOSUS DERMATITIS ALL DISEASES SPECTRUM OF DISEASES
ule resources. 1 In 1989, Smith et al. papular lesions in patients with rheumatoid arthritis with features of leukocytoclastic vasculitis and palisade granulomas.6 In 1990, Sanchez and Cruz described three patients with rheumatoid arthritis with nodules and papules on the extremities. Histological examination revealed a dense neutrophilic infiltrate resembling Sweet's syndrome.7 Noteworthy is a review of PNGD and rheumatoid arthritis by Sangueza et al
Lars separated from vessels by fibrin. In mature lesions, neutrophil counts were reduced. Palisade granulomas surrounded fibrin and thick collagen bundles. In old lesions, palisade granulomas contained degenerated collagen and only scattered neutrophils. No fibrin was found in the vessel walls, but the dermis was fibrotic.8 The exact cause of this disease process is speculative at best. These lesions appear to begin as vessels.
Figure 4 H&E staining of a 3mm core biopsy of the right elbow at x100 magnification showing palisade granulomatous and neutrophilic dermatitis with suppuration and neutrophilic dust. There is a dense perivascular and interstitial neutrophilic infiltrate, fibrin collars in the blood vessel walls, and diffuse fibrosis.
H&E stain of an elbow biopsy at 400x magnification showing dense, diffuse neutrophilic dust. These include Churg-Strauss granuloma, extravascular cutaneous necrotizing granuloma, rheumatoid papules, superficial ulcerative rheumatoid necrobiosis, linear subcutaneous bands, and interstitial granulomatous dermatitis with skin cords and arthritis.2,3,4,5 This process has been associated with rheumatoid arthritis, systemic lupus erythematosus, other connective tissue diseases, inflammatory bowel disease, and systemic vasculitis.1 The numerous terms reflect the spectrum of clinical presentations associated with PNGD. Dykman et al. first reported patients with PNGD and severe rheumatoid arthritis in 1965.4 These patients had linear subcutaneous bands on the lateral trunk that histologically resembled rheumatoid nodules. In 1995, Gottlieb and Ackerman reported ten patients with similar linear ligament lesions with rheumatoid nodules.
2002. Clinically, patients presented with purple erythematous plaques, papules and nodules, and subcutaneous linear bands. The lesions ranged from painful to asymptomatic and occurred on different areas of the body including fingers, buttocks, shoulders, wrists, thighs, chest and sacrum. Most of these patients suffered from rheumatoid arthritis or other associated connective tissue diseases. The above references demonstrate the range of clinical presentations of PNGD. There are several differential diagnoses to consider when a patient has skin lesions and a history of rheumatoid arthritis or other connective tissue diseases. These diagnostic options should be summarized as neutrophilic dermatoses associated with connective tissue diseases. The most notable are PNGD, rheumatoid neutrophilic dermatitis, erythema elevatum diutinum and Sweet's syndrome. Ackerman originally described rheumatoid neutrophilic dermatitis in 1978. 1 These lesions usually appear on the trunk, shoulders, neck, and extremities and are more likely to be associated with elevated rheumatoid factors in middle-aged women. Erythema elevatum diutinum most commonly presents as symmetrical papules or plaques on the extensors that wax and wane over several years. Sweet's disease presents as erythematous plaques with a "mountain" appearance.
Secondary Kullitis probably due to deposition of immune complexes and associated connective tissue diseases. Vasculitic injury causes ischemia, alters collagen, and induces a granulomatous response. These immune complexes can also trigger a granulomatous reaction. A histological differential diagnosis should also be checked for completeness. Since the initial lesions of PNGD are marked small-vessel vasculitis, it must be differentiated from conventional leukocytoclastic vasculitis. LCV has profuse extravasation of red blood cells and PNGD has collagen degeneration that occurs with vasculitis. Rheumatoid neutrophilic dermatitis (RND) should also be considered in early lesions. RND has a dense neutrophilic infiltrate without LCV. RND does not develop a granulomatous reaction. Features of PNGD may overlap with rheumatoid nodules, but PNGD is primarily dermal and rheumatoid nodules extend to the subcutaneous tissue. Fully developed lesions can resemble granuloma annulare, but only PNGD has altered and thickened collagen bundles. Erythema elevatum diutinum is a form of localized vasculitis that resolves with fibrosis but without the development of palisade granulomas.8 PNGD should be viewed as the clinical and histological spectrum of a pathologic process. PNGD has multiple clinical and histological presentations consistent with disease progression. Evolution. early injuries
Maintains appearance on multiple body areas. Lesions can sometimes be painful. All of these diseases have similar clinical presentations and may present with connective tissue disorders. Histologically, they all show prominent neutrophilic infiltration. In addition to the clinical spectrum of PNGD, a histological spectrum corresponding to the course of the disease was described. In 1994, Chu et al. several patients diagnosed with PNGD and reviewed the histopathologic trend.8 Multiple biopsies revealed early lesions typically showing small vessel vasculitis. Leukocytoclastic vasculitis was evident throughout
appear clinically and histologically as vasculitis. As the disease progresses, the lesions appear clinically and histologically as a granulomatous dermal process and may present with vesicles. It should be emphasized that PNGD is a neutrophilic dermatosis and occurs as part of a connective tissue disease, primarily rheumatoid arthritis. The pathophysiological role of immune complexes requires further investigation. This patient appeared to have lesions at various stages of PNGD. The fingers presented clinically as early-onset vasculitis. Hip injuries resemble the progression of granuloma formation and elbows are the old injuries with fibrosis and collagen
the entire trophically infiltrated dermis. and pandermal collagen degeneration have been observed. The vasculitic foci had a palisade appearance where they were large
Degeneration. rheumatoid arthritis She also had severe rheumatoid factor positive. In summary, PNGD and other neutrophilic dermatoses should
SUMMA, GORIN, HOFFMAN, DICOSTANZO
should be considered in any patient with rheumatoid arthritis or other connective tissue diseases and skin conditions. Treatment is symptomatic and if there is no improvement, immunosuppressants and/or dapsone can be used. Let's not forget that the cutaneous manifestations of internal disease are usually the first presentation. As dermatologists, it is imperative that we work closely with general practitioners and/or rheumatologists when treating these patients.
References: 1. Sangueza OP, Caudell MD, Mengesha YM. Palisade neutrophilic granulomatous dermatitis in rheumatoid arthritis. J.Am. Acad. Dermatol 2002;251-7. 2. Finan MC, Winkelmann RK. Cutaneous extravascular necrotizing granuloma and systemic disease: a review of 27 cases.Medicine 1983;62:142-58. 3. Magro CM, Crowson AN, Schapiro BL. Interstitial granulomatous drug reaction: a distinct clinical and pathologic entity. J Cutan Pathol 1998; 25:72-8. 4. Dykman CJ, Galens GJ, good AE. Linear subcutaneous ligaments in rheumatoid arthritis: a rare form of rheumatoid granuloma. Ann Intern Med 1965;63:134-40. 5. Gottlieb GJ, Duve RS, Ackerman AB. Interstitial granulomatous dermatitis with skin strands and arthritis: linear subcutaneous ligaments in rheumatoid arthritis revisited. Dermatopathology: Practical and conceptual 1995;1:3-6.
6. Smith ML, Jorizzo JL, Semble E, Arrington JH, White WL. Rheumatoid papules: lesions that show features of vasculitis and palisade granulomas. J.Am. Acad. dermatol. 1989; 20:348-52. 7. Sanchez JL, Cruz A. Rheumatoid neutrophilic dermatitis. J.Am. Acad. dermatol. 1990; 22:922-5. 8. Chu P, Connolly MK, LeBoit PE. The histopathologic spectrum of palisaded neutrophilic granulomatous dermatitis in patients with collagenosis. Arch Dermatol 1994; 130:1278-83.
GRANULOMA NEUTROPHIL PALISADATO GRANULOMATOSUS DERMATITIS ALL DISEASES SPECTRUM OF DISEASES
A case of transformation from pemphigus foliaceus to pemphigus vulgaris Michael R. Hoh Nadel D.O.*, Bill V. Way, D.O., F.A.O.C.D.**, Robert J. Lin, B.S.*** *3. Year Resident, K.C.O.M. Department of Dermatology, Texas Division. Duncanville, Texas. **President, KCOM Department of Dermatology, TX Division, Duncanville, TX. *** Graduate College of Electrical Engineering, University of California, San Diego
SUMMARY A male patient initially presented with biopsy-proven pemphigus foliaceus. After six months, the patient developed with a clinical and histopathological picture of pemphigus vulgaris. Methotrexate therapy, which originally controlled the patient's symptoms, became ineffective and eventually high doses of oral prednisone and mycophenolate mofetil were required. A literature review discussing similar cases and the immunological basis for the change is presented.
Initial presentation A 31-year-old Hispanic male presented with a 1-month history of erosive, erythematous, nonhealing papules bilaterally distributed over the facial area of the cheekbones, central chest, back, scalp, and thighs. The lesions presented a scale collar and a perilesional Nikolsky sign (Figures 1 and 2). No oral lesions or nail changes were observed. At the time of presentation, two arm punch biopsies were taken for H&E and immunofluorescence studies. H&E biopsy revealed superficial acantholysis with suppuration between the stratum corneum and the superficial nuclear layer and a mixed infiltrate of inflammatory cells in the dermis, consistent with a superficial vesicular disorder (Figure 3). Direct immunofluorescence (IFD) studies on perilesional skin revealed IgG and complement deposition in the epidermis. Indirect immunofluorescence (IFA) was positive with a titer of 1:80 for antibodies to intracellular substance (Ab) and negative for antibodies to the basement membrane zone. Based on the clinical picture and the laboratory findings, the diagnosis of pemphigus foliaceus (PF) was considered. Initially, topical and oral corticosteroids were used. Methotrexate (MTX), 15 mg/week, was then introduced for several months. The patient's symptoms remained well controlled for six months with some new localized skin lesions developing. There were no oral lesions.
Bleeding and discoloration along the proximal nail folds and lunula of all fingernails and most toenails (Figure 4). Because of his mouth condition, the patient had difficulty eating and lost weight. Several etiologies for the patient's new presentation were considered. Oral lesions and nail changes suggested a diagnosis of pemphigus vulgaris. Paraneoplastic pemphigus, development of an idiopathic aphthae, side effects to the drug MTX, infectious infection were also part of the differential diagnosis. Repeat biopsy with H&E and immunofluorescence studies were performed. H&E staining revealed a slightly inflammatory suprabasilar acantholytic vesicle characteristic of PV (Figure 5). Direct immunofluorescence studies revealed IgG deposition on the surfaces of keratinocyte cells homogeneously distributed along the surface
New presentation Six months after his first presentation, the patient developed new painful oral erosions. Examination revealed aphthous ulcers, mainly spreading through the gingival mucosa (Figure 4). Skin lesions increased significantly, with an increase in both size and the number of new lesions. Number The distribution of was similar to the original presentation. The patient developed erythematous to purple subungual hemorrhage
HOHNADEL, WA WAY Y, LIN
(Figure 6). Indirect immunofluorescence studies revealed circulating anti-epithelial cell surface IgG antibodies with a titre of 1:1280. No evidence of mouse bladder-directed IgA antibodies or anti-epithelial antibodies denied paraneoplastic pemphigus. The patient was diagnosed with pemphigus vulgaris. Prednisone 100 mg/day was initiated. MTX was discontinued and mycophenolate mofetil (MMF) was started at 3000 mg/day and prednisone was slowly tapered. The patient responded well and the oral and skin lesions began to improve. He tolerated this therapeutic therapy without difficulty.
Discussion The etiology of epidermal blisters in PF and PV is explained by the desmoglein compensation theory. This suggests that the deposition of IgG antibodies directed against desmoglein-1 (DSG-1) and desmoglein-3 (DSG-3) leads to these bullous dermatoses. Desmogleins are critical for proper cell-to-cell adhesion across desmosomal structures. In the epidermis, DSG-1 is more strongly expressed in the superficial regions near the nuclear layer and its dissolution explains the formation of superficial PF vesicles. This is in contrast to PV where IgG antibodies may be directed against DSG-3 alone or against both DSG-1 and DSG-3. Antibodies directed only to
DSG-3 primarily disrupts the oral mucosa as this is the predominant adhesion molecule present in this mucosa. This leads to the well-known oral erosions that herald PV. Antibodies directed against desmoglein types 1 and 3 result in full-thickness epidermal dissolution and the mucosal lesions seen in PV PV. 1, 2 Evolution from FP to VP is a rare occurrence. Although acquisition of DSG-1 antibodies is commonly seen in PV, development of DSG-3 antibodies rarely occurs.
op. MTX is a competitive inhibitor of dihydrofolate reductase (DHFR) that inhibits cell division and acts as a broad immunosuppressant. In addition, it has powerful anti-inflammatory properties on the epidermis. Unfortunately, high doses of MTX can be necessary for the level of B-cell suppression needed to cause severe blistering disorders like PV, which can lead to other dangerous side effects like pancytopenia. 6, 8 This is why the MMF was created.
were reported to the PF. PF Komai al reported on several cases of. Transformations from PF to PVet. Using ELISA (Enzyme Linked Immunosorbent Assay), Komai was able to show that initially only anti-DSG-1 antibodies were present in PF patients and that anti-DSG-3 antibodies developed in these patients over time . Elevated anti-DSG-3 antibodies correlated with the clinical onset of PV. 3 Another possible explanation for our patient's transformation was that this patient had a rare 'skin only' PV. have VP. PV. In these cases, DSG-1 antibodies were found to be co-expressed with DSG-3 antibodies, but DSG-3 antibodies were expressed at lower levels than DSG-1 antibodies. In addition, it has been theorized that DSG-3 antibodies have less pathogenic potential than those typically found in PV. The authors speculated that DSG-1 antibodies combined with the less potent DSG-3 antibodies might induce skin blisters typical of PV, but not oral erosions or oral lesions over time. In addition, these patients showed signs of PV-like histopathology. Since the initial histopathology of our patient
MMF inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH), which blocks the de novo synthesis of guanine nucleotides and their subsequent incorporation into DNA. MMF preferentially inhibits DNA synthesis in B and T lymphocytes since these cells lack the purine rescue pathway and are dependent on de novo purine synthesis. Therefore, MMF is a potent inhibitor of B cell activity, limiting the production of pathogenic antibodies. The main side effects of MMF are nausea, vomiting and abdominal cramps. Other less rare but potentially serious side effects including pancytopenia and liver toxicity have been reported. Ultimately, a limiting factor for MMF can be cost. 6,8,9
The presentation showed only a clear picture of PF, ruling out a "cutaneous form of PV as a possible etiology". Etiology. The conversion from PF to PV has several implications. s. PV is generally a more serious entity than PF, particularly the mucocutaneous form. Lesions are often more painful and prevent adequate nutrition. Morbidity and mortality are also higher in these patients.5,6 PV requires significantly more aggressive therapy than PF PF. Adherence in PV and presumably in PF PF.. Immunosuppressants Immunosuppressive therapy is the cornerstone of treatment. A higher rejection of 7 compared to PF may be required for PV. In our case presentation, MTX became ineffective when PV symptoms developed.
Conclusion This case represents an interesting study of immune bullous disease and its manifestations. Our experience shows that autoimmune bullous disease is not always a static condition and that progression to various autoimmune diseases can have a major impact on patient care and prognosis. References: 1.) Amagi M. Desmoglein as a target in autoimmunity and infection. JAAD 2003; 48-2: 244-52. 2.) Anhalt G, Diaz, L. Pemphigus vulgaris-A cutaneous autoimmunity model. JAAD 2004; 51:S20-1. 3.) Komai A. The clinical transition between pemphigus foliaceus and pemphigus vulgaris correlates well with changes in the autoantibody profile assessed by ELISA. Br J Dermatol 01/2001. 144(6):1177-82. 4.) Yoshida K. et al. Cutaneous-type pemphigus vulgaris: a rare clinical phenotype of pemphigus. JAAD 52:839-845. 5.) Sami N, Yeh SW, Ahmed AR. Bullous diseases in the elderly: diagnosis and treatment. Dermatology Clinics 2004; 22(1): 73-86 6. Bolognia J. Der Matology matology. Mosby 2003. 7 Nousari HC Pemphigus and pemphigoid. Lancet 1999; 354(9179): 667-72 8.) Wolverton S. Comprehensive Dermatological Drug Therapy. Saunders 2001. 9.) Korman N. New immunomodulatory drugs in autoimmune bullous diseases. Derm Clinics 2001; 19(4): 637-48.
A CASE OF TRANSFORMATION OF PEMPHIGUS FOLIACEUS INTO PEMPHIGO VULGARIS
Pustular Vasculitis: Vasculitis: Case Presentation Review of Literature Chava Frankl Lustig D.O.*, Stanley Skopit D.O., FAOCD** *3. Year Resident Nova Southeastern University/BGMC University/BGMC ** Program Director Nova Southeastern University/BGMC University/ BGMC ABSTRACT Pustular vasculitis is a reported rare condition occurring on the dorsum of the hand and clinically resembling atypical Sweet's syndrome and pyoderma pyoderma gangrenosum. gangrenous. These three conditions represent different spectra in the classification of neutrophilic neutrophilic dermatosis. We report a case of pustular vasculitis in a woman who developed shortly after receiving a glycolic peel on the dorsum of the hand for lentigines. After proper work to exclude an underlying malignant or inflammatory disease, we believe that these lesions developed as a result of the glycol peel due to a pathergy or hypersensitivity reaction. The patient improved with a graduated dose of prednisone over 3 months.
Case Summary The patient is a 50-year-old Caucasian female with a 2-week history of slowly growing painful sores on her hands after receiving a glycolic peel on the back of her hand at a local salon. Her symptoms didn't change after her GP prescribed her on Keflex and Tequin. She denies trauma to the area and complains of minimal pain. Your history is relevant to arthritis and fibromyalgia. Family history is negative for connective tissue disease or malignancy. Her medications include Paxil, Xanax, Darvocet. The review of systems of systems shows widespread problems that remain unchanged over several years. She denies hematochezia, SOB, or weight loss.
there is exudate in the center of the lesion on the right hand and two ulcerated nodules on the left hand measuring 1.3 and 0.9 cm (Figures 1 and 2). There is also minimal erythematous lymphatic spread in the right arm. No lymphadenopathy is estimated in trochlear and axillary lymph nodes.
Laboratories and CBC histopathology, sedimentation rate and peripheral swab were normal. Bacterial hepatitis and HIV wound plaques were negative. ture, PAS and AFB were negative for microorganisms. Dermatopathologic examination of a representative biopsy of the ulcer reveals an intense neutrophilic infiltrate with leukocytoclastic vasculitis and edema (Figures 3 and 4). These findings suggest pustular vasculitis.
Figure 3: Heavy neutrophilic neutrophilic infiltrate
Figure 1 Right hand
Figure 2 Left hand
On physical examination she is well fed and slightly anxious. There is a 4 cm necrotic ulcer with an erythematous and edematous border. yellow pendant
Pustular vasculitis is a rare manifestation of neutrophilic dermatosis that is clinically indistinguishable from hand involvement in atypical Sweet's syndrome
Figure 4: Leukocytoclastic vasculitis and fibrinoid alteration
and also bullous bullous pyoderma gangrenosum. renosum. The histological picture and the response to treatment between these three dermatological conditions have been shown to overlap significantly (1). Galaria et al. described three patients with clinical lesions resembling pustular vasculitis and histological changes of Sweet's syndrome. He therefore referred to this group as neutrophilic dermatosis of the hands (2). For the purposes of this paper, these diseases will be discussed separately. Sweet's syndrome is described as an acute febrile neutrophilic dermatosis that occurs mainly in women in a 4:1 ratio. These injuries usually affect the head, upper trunk, and proximal extremities. The atypical term refers to lesions that occur in unusual locations. Patients usually present initially with symptoms of URTI
grooved plates. sensitive A painful erythematous third showed an increase in patient-associated systemic symptoms such as fever, arthralgia, and myalgia (3). Five types of subfever in Sweet's syndrome have been described. These include classic, malignancy-associated (10–20%), inflammatory and autoimmune-associated, pregnancy-associated, and drug-induced (such as granulocyte colony-stimulating factor and oral contraceptives). Biopsy of these lesions shows an intense skin infiltrate consisting of many neutrophils and papillary skin edema. Fibrin deposits and leukocytoclastic vasculitis are not features of Sweet's syndrome (4). There have been reports of an association of preleukemia and leukemia with atypical Sweet's syndrome and bullous pyoderma gangrenosum, a superficial variant of pyoderma gangrenosum (5-10).
and then clearly marked
atypical Sweet's syndrome, pyoderma gangrenosum, neutrophilic dermatosis, and pustular vasculitis when hands are involved. In addition, there was some evidence that these lesions represent different spectra of the same condition. Regardless of the terminology, if these lesions develop, it is important to rule out any underlying malignancy or inflammatory disease. References:
Figure 5: Right hand after 3 months of treatment
Chan et al. reported that in their review of patients with Sweet's syndrome, 40% were associated with a hematologic malignancy and 7% with solid tumors. Other reports show different percentage associations between Sweet's syndrome and malignancy, but these differences may be due to biased baseline referral by the associated medical center (1, 11, 12). Report Reports by DiCaudo involving seven patients showed no association with malignancy, arthritis, or inflammatory bowel disease (13). The picture of pustular vasculitis described in the literature is consistent with lesions clinically resembling Sweet's syndrome but reveals leukocyclastic vasculitis on biopsy. These patients are often initially misdiagnosed as having bacterial, mycobacterial infection, Sweet's syndrome, pustular drug reaction, erythema elevatum diutinum, and pyoderma gangrenosum (14). These lesions, as in Sweet's disease and pyoderma gangrenosum,
Figure 6: Left hand after 3 months of treatment
are unresponsive to oral antibiotics and respond quickly to oral prednisone. In a previous report, a patient exposed to chemical fertilizers containing ammonium nitrate and calcium salts developed lesions called pustular vasculitis. They concluded in this case report that exposure to this chemical compound may have caused the lesions described as pustular vasculitis (14). In our patient, exposure to glycolic acid on the hands could have been the etiological factor due to pathergy or hypersensitivity reaction. After her negative examination, the patient's lesions healed quickly with a graduated dose of oral prednisone supplemented with calcium, vitamin D, and Fosamax. The lesions were treated locally and complete resolution occurred after 12 weeks (Figures 5 and 6). In summary, there are inconsistencies in the literature regarding terminology
11. Weenig Weenig RH, Bruce AJ, McEvoy MT, MT, Gibson LE, Davis MDP Neutrophilic dermatosis of the hands: Four new cases of MDP and review of the literature. International Journal of Derm 2004; 43: 95-102. 2. Galaria NA, Junkins-Hopkins JM, Kligman D, James WD. Neurophilic dermatosis of the dorsum of the hand: recurrent pustular vasculitis. J.Am. Acad. Dermatol 2000; 43:870-874. 3. Bolognia JL et al. Dermatology. Mosby. Mosby. 2003 page 412 4. Barnhill RL. Textbook RL. Textbook of Dermatopathology. dermatopathology. McGraw-Hill Companies, Inc. 1998. Pages 108-110 5. Vance E, Granter S, Skarin A. Sweet's syndrome. J.Clin. oncol. 1997; 15:860-861. 6. Cramers M. Bullous pyoderma gangrenosum associated with myeloid leukemia. Acta Derm Venereol Venereol 1976; 56: 311-312 7. Sheps M, Sharpero H, Ransay C. Bullous pyoderma gangrenosum and acute leukemia. Leukemia. ArchDermatol 1978; 114: 1842-1843. 8. Hay CR, Messenger AG, Cotton DW, DW, et al. Atypical bullous pyoderma gangresnosus associated with myeloid malignancies. J Clin Pathol 1987; 40:387-392. 387-392. 9. Dompmartin A, Trussard Trussard X, Lorier E, et al. Sweet's syndrome associated with acute myeloid leukemia. Leukemia. Atypical shape simulating facial erysipelas. international J Dermatol 1991; 30: 644-647. 10. Koester G, Toarnower Toarnower A, Levisohn D, Burgdorf WW. Bullous pyoderma gangrenosum. gangrenous. J.Am. Acad. Dermatol 1993; 29:875-878. 11. Fett DL, Gibson LE, Su WP. Sweet's syndrome: systemic signs and symptoms and associated disorders. Mayo Clin Proc 1995; 70: 234-240. 12. von den Driesch P. Sweet's syndrome (acute febrile neutrophilic dermatosis). J.Am. Acad. Dermatol 1994; 31: 535556. 13. Dicaudo DJ, Connolly Connolly SM. Neutophilic dermatosis (pustular vasculitis) of the dorsum of the hand: report of 7 cases and review of the literature. ArchDermatol 2002; 138:138:361-365. 14. Aydin F, F, Senturk N, Yild is L, Canturk MT, Turanli AY. YES. Neutrophilic dermatosis on the back of a farmer's hand. Farmer. European Acad Derm and Venereology reology 2004; 18:716-717.
PUSTULAR VASCULITIS: A CASE PRESENTATION PRESENTATION AND LITERATURE REVIEW
Pyoderma Gangrenosum: Case Study and Overview of Treatment Options Evangeline Perez, D.O. *, Marvin S. Watsky, D.O. ** *2nd Year Resident, St. John's Episcopal Hospital, Far Rockaway, New York ** Program Director, St. John's Episcopal Hospital, Far Rockaway, New York SUMMARY Pyoderma gangrenosum (PG) is a rare, destructive, neutrophilic skin disease whose etiology remains unclear. This is why success with specific treatment options has been so mixed. We report a case of PG associated with ulcerative colitis (UC) that was successfully treated with systemic corticosteroids. In addition, we review the anecdotal literature on treatment options to consider when systemic steroids fail or when side effects of therapy become unbearable.
Pyoderma gangrenosum Pyoderma gangrenosum was first described by Brunsting, Goekerman, and O'Leary in 1930,1 and is a rare and destructive inflammatory dermatosis most commonly associated with inflammatory bowel disease.2 When associated with ulcerative colitis (UC). disease activity is not always associated with intestinal disease.3 The PG lesion usually begins as a painful papule or pustule that decomposes into a rapidly growing ulcer. Ulcers may exhibit pathergy, which is an exaggerated response to trivial trauma that can cause the ulcer to expand. Several possible mechanisms have been proposed for the etiology of PG, including abnormalities in neutrophil function and disorders in immune regulation and immune effector functions, but none of these have consistently been shown to be the primary cause.3 Histological findings are nonspecific and are mainly used to rule out other possible entities, such as infections and Malignancy. Malignancy. The diagnosis is based on clinical findings and is primarily a diagnosis of exclusion. Other possible infections, collagen vascular diseases and various vasculitides must be ruled out before definitive diagnosis can be made 4 . Systemic corticosteroids remain the mainstay of therapy and remain the most effective therapeutic option for PG.3
Case Study A 52-year-old African American female with a history of ulcerative colitis was hospitalized with a recurrent painful rash affecting the abdomen, groin, and thighs for two weeks. weeks. The eruption began as a papulovesicle that ruptured and formed a widespread area of ulceration. She had previously been hospitalized twice in the past two years for similar episodes, which were diagnosed and treated as infectious processes.
Figure 1 Confluent and well-defined ulceration
On physical examination, there was a painful, well-demarcated, symmetrical area of confluent ulceration, involving the umbilicus, groin, and upper inner thighs, which was extremely tender on palpation 1). The margins were sclerosed and (Fig. undermined) and the base of the fracture was covered with necrotic material (Fig. 2). Histological examination revealed skin edema, massive neutrophilic inflammation, vascular congestion and thrombosis (Fig. 3). Bacterial examinations and stains were fungal infections negative.The diagnosis of PG was made based on the history of UC, the recurrent nature and history of the onset, and histological findings demonstrating no infectious or malignant process.The patient was treated with oral prednisone (40 mg/day) for one month This resulted in a dramatic and rapid improvement in the patient's rash. The patient continued to be treated with oral prednisone (20 mg/day), which was gradually tapered off. She continued this until she eventually experienced remission of the disease (Fig. 4 ).
Figure 2 Degraded purple edges
Figure 3 Massive neutrophilic inflammation, edema and necrosis
had two recurrences that were successfully treated with short courses of oral prednisone.
PEREZ, WA WATSY NO
Treatment options Systemic corticosteroids Systemic corticosteroids are the mainstay of therapy as they dramatically halt progression and prevent new lesion development.5 Pulse dosing with suprapharmacological doses of methylprednisolone (1 g/d x 5d) can be used for severe cases6 and is the first choice of Treatment in many settings.3 Unfortunately, chronic administration of systemic steroids is associated with many potential side effects, necessitating research into other classes of drugs.
Cells in the epidermis.15 Epidermis.15 It also reduces the chemotactic capacity of neutrophils.16 neutrophils.16 Its main disadvantages include nephrotoxicity, hypertension, and the potential for many drug interactions. While it is widely regarded as an alternative form of therapy, one report suggests that it is being seriously considered as a primary form of therapy for PG.17
Tacrolimus (FK 506) has a similar mechanism
leukocytapheresis, the extra
Bioavailability Action anismus, similar to sidecyclosporine. Effects and Majors The specific mechanism of action by which it acts to improve PG is unclear, but it is thought to inhibit neutrophil accumulation and activation by inhibiting granulocyte-macrophage colony factor (GMCSF). rapid clearance of refractory PG with systemic tacrolimus.2,18 One anecdotal report claims clearance of a prednisone-resistant PG lesion with topical tacrolimus.19 The proposed mechanism of action was decreased expression of interleukin-8, resulting in chemotaxis of impaired neutrophils . 19
Removal of leukocytes from the body was successful in colitis in a patient with ulcerative and refractory PG.26 Rapid healing was achieved without recurrence or major complications.
Figure 3 Massive neutrophilic inflammation, edema and necrosis
Mycophenolat de Mofetil Mycophenolat de Mofetil
Immunomodulatory drug that suppresses lymphocyte proliferation by inhibiting de novo purine synthesis, resulting in reduced antibody production.12 Its major disadvantages include a possible increased risk of carcinogenicity9 and infection.9,12 Several reports of refractory PG have been unsuccessful treated with prednisone, dapsone, some of the other commonly used cytotoxic agents, and the immunomodulatory biological immunomodulator infliximab showed dramatic improvement and long-term remission when treated with mycophenolate mofetil.1 mofetil.13,14 3,14
Cyclosporine Cyclosporine is an immunosuppressive drug that significantly inhibits cellular immunity by inhibiting interleukin-2 production, resulting in a decrease in activated CD4 and CD8
Intravenous immunoglobulin (IVIG) has been shown to be successful in refractory PG, inducing complete healing within months.25 Although the mechanism of action is unknown, it is thought to alter levels of cytokines and cytokine antagonists.25
Thalidomide is an immunomodulatory and anti-inflammatory agent that inhibits tumor necrosis factor alpha (TNF-α), suppresses interleukin-2 production and decreases neutrophil chemotaxis and phagocytosis. The main disadvantages include teratogenicity, peripheral neuropathy and sedation. It has been shown to improve long-term refractory PG and prevent recurrence in a patient with extensive disease.20
Nicotine ulcerative colitis is largely a disease of non-smokers. It has been observed that non-smokers. Patients who smoke intermittently often experience improvement in their symptoms during periods without smoking.21 Pyoderma gangrenosum, often associated with UC, appears to respond to similar treatment modalities. Based on this premise, topical nicotine has been applied to refractory PG lesions in several studies. This resulted in improvement and elimination of lesions.21,22
Colchicine Colchicine is an anti-inflammatory and antimitotic immunomodulator that is well-targeted to white blood cells.23 white blood cells.23 It also decreases polymorphonuclear motility, adhesion, and chemotaxis, making it very successful in treating neutrophilic dermatoses.24 A recent The report demonstrated the resolution of refractory PGlow lesions treated with one dose of colchicine in two patients.23
Infliximab Infliximab has been shown to be successful in multiple patients in three separate studies.27,28,29 These patients had refractory PG that did not improve with conventional therapies and demonstrated rapid resolution with infliximab. infliximab. Infliximab, a chimeric anti-TNF-alpha monoclonal antibody that specifically binds to and decreases TNF-alpha levels, inflammatory cell infiltration, interleukin-6 levels, and C-reactive protein levels. The main disadvantages include the potential for immediate hypersensitivity reactions and the possible increased long-term risk of developing lymphoma.
Etanercept Etanercept is a bivalent recombinant fusion protein that targets and neutralizes TNF-alpha. A study based on the successful use of infliximab demonstrated a rapid and complete cure using etanercept as a steroid-sparing agent in intractable disease and suggested the possible role of TNF-alpha in the pathogenesis of PG.30
Conclusion Pyoderma gangrenosum, a disease of unknown etiology, remains with an unpredictable course and highly variable response to multiple therapies. Systemic corticosteroids remain the most effective treatment and should still be considered first-line therapy. Therapy. However, for severe, refractory severe cases, or cases where the side effects of systemic corticosteroids may not be tolerable, there are many other options available that have shown some success. References: 1. Brunsting LA, Goekerman WH, O'Leary PA. SHOVEL. Pyoderma gangrenosum: clinical and experimental observations in five adult cases. Adult. ArchDermatol 1930; 22:65580. 2. Weichert G, Sauder DN resistant to treatment. Sauder's efficacy of tacrolimus (FK506) in J (FK506) treatment-resistant idiopathic pyoderma gangrenosum. gangrenous. Am Acad Dermatol 1998; 39:648-50. 3. Wolff K, K, Stingl G. Pyoderma gangrenosum. gangrenous. In: Freedberg Freedberg IM, Eisen AZ, Wolff Wolff K, et al, eds. Fitzpatrick's Dermatol-
Pyoderma gangrenosum: a case study and review of treatment options
ogy in general medicine. 6th ed. New York, York, NY: McGrawHill; 2003: 969-76. 4. Trent JT, JT, Kirsner RS. Diagnosis of pyoderma gangrenosum. gangrenous. Adv Skin Wound Care 2001; 14:1. 5. Hickman JG, Lazarus GS. Pyoderma gangrenosum: New concepts in etiology and treatment, in Dermatology Update: Review for Physicians, edited by SL Moschella. New York, Elsevier, 1979; 325. 6. Chow RK, Ho VC. YOU. Treatment of pyoderma gangrenosum. gangrenous. J.Am. Acad. Dermatol 1996; 34:1047. 7. PR room. dapsone In: Wolverton Wolverton SE, ed. Comprehensive dermatological drug therapy. Philadelphia, PA: PA: W.B.W.B. Saunders Company; 2001:230-250. 8. Arbeiser JL, Moschella SL. Clofazimine: A review of its medicinal uses and mechanisms of action. J.Am. Acad. Dermatol 1995; 32:241. 9. Pan TD, TD, McDonald CJ. Cytotoxic Agents. In: Wolverton SE, ed. Comprehensive dermatological drug therapy. Therapy. Philadelphia, PA: W.B. Saunders Company; 2001:180-204. 10. Badalamenti S, Kerdel FA. azathioprine. In: Wolverton SE, ed. Comprehensive dermatological drug therapy. Therapy. Philadelphia, PA: W.B. Saunders Company; 2001:165-179. 11. Callen JP, JP, Kulp-Shorten CL, Wolverton SE. methotrexate. In: Wolverton SE, ed. Comprehensive dermatological drug therapy. Philadelphia, PA: PA: W.B.W.B. Saunders Company; 2001:147-164. 12. Mutasin DE. Management of autoimmune bullous diseases: pharmacology and therapeutics. J.Am. Acad. dermatol. 2004; 51:859-877. 13. Nousari HC, Lynch W, Anhalt GJ. The effectiveness of
Mycophenolate mofetil in refractory pyoderma gangrenosum. Arch Dermatol. 1998; 134:1509-11. 14. Daniels NH, Callen JP. JP Mycophenolate mofetil is an effective treatment for peristomal pyoderma gangrenosum. Arch Dermatol. 2004;140:1427-9. 15. Baker BS, Griffiths CEM, Lambert S, et al. The effects of cyclosporin A on subpopulations of T lymphocytes and dendritic cells in psoriasis. Br J Dermatol 1987; 116:503-10. 16. Demidem A, Taylor Taylor JR, Grammer SF, et al. T-lymphocyte activation properties of epidermal antigen-presenting cells from normal and psoriatic skin: evidence that psoriatic epidermal antigen-presenting cells resemble cultured normal Langerhans cells. J Invest Dermatol 1991; 97:454-60. 17. Matis WL, Ellis CN, Griffiths CE, et al. Treat pyoderma gangrenosum treatment with ciclosporin. Arch Dermatol. 1992; 128:1060-4. 18. Baumgart DC, Wiedenmann B, Dignass AU. AU. Successful therapy of refractory pyoderma gangrenosum and periorbital cellulitis with tacrolimus (FK506) in ulcerative colitis. Inflamm Intestine Intestinal Dys. 2004; 10:421-4. 10:421-4. 19. Richter-Hintz D, Schuppe HC, Homey B, B, et al. Topical tacrolimus (FK506) is effective in treating pyoderma gangrenosum. J.Am. Acad. dermatol. 2000; 42:304. 20. Hecker MS, MS, Lebwohl MG. Pyoderma recalcitrant pyoderma gangrenosum: treatment with thalidomide. J.Am. Acad. Acad. dermatol. 1998; 38:490-1. 38:490-1. 21. Wolf R, Ruocco V.V. Nicotine for pyoderma pyoderma gangrenosum. Arch Dermatol. 1998; 134:1071-2. 134:1071-2. 22. Patel GK, Rhodes JR, Evans B, et al. successful treatment
Treatment of pyoderma gangrenosum with topical nicotine cream 0.5%. J Treat dermatologist. To treat. 2004; 15:122-5. 23. Kontochristopoulos GJ, Stavropoulos PG, Gregoriou S, et al. Treatment of pyoderma gangrenosum with low-dose colchicine. Dermatology. 2004; 209:233-6. 24. Davis LS. LS. Recent uses of older drugs - an update. In: Wolverton SE, ed. Comprehensive dermatological drug therapy. Philadelphia, PA: PA: W.B.W.B. Saunders Company; 2001:426-444. 25. Dirschka T, T, Kastner U, Behrens S, S, et al. Successful treatment of pyoderma gangrenosum with intravenous human immunoglobulin. J.Am. Acad. dermatol. 1998; 39:789-90. 26. Fujimoto E, Fujimoto N, Kuroda Kuroda K, et al. Treatment of leukocytapheresis in pyoderma pyoderma gangrenosum. Br J Dermatol. 2004; 15:1090-2. 27. Tan Tan MH, Gordon M, Lebwohl O, et al. Improvement of pyoderma gangrenosum and psoriasis associated with Crohn's disease with anti-tumor necrosis factor-alpha monoclonal antibody. Arch Dermatol. 2001; 137:930-3. 28. Andersen TH, Moerk NJ. Therapeutic therapy with infliximab in patients with severe refractory active pyoderma gangrenosum. J.Am. Acad. dermatol. 2004; 50. 29. Lopez AS, Bermejo F, F, Aldanondo I, et al. Pyoderma gangrenosum associated with ulcerative colitis: response to infliximab. Rev. Esp Enferm Dig. 2004; 96:420-4. 96:420-4. 30. McGowan JW, Johnson CA, Lynn A. Treatment of gangrenous pyopyoderma gangrenosum with etanercept. J Drugs Dermatol. 2004; 3:441-4.
PEREZ, WA WATSY NO
Where there is acne, there is EVOCLIN. Finally, an acne formulation that can be easily applied to multiple areas of the body.1 EVOCLIN is supplied in a patient-preferred foam vehicle with minimal residue.1,2 It effectively reduces both inflammatory and non-inflammatory lesions. Plus, it's safe and well tolerated.3 Are you looking for a treatment that works wherever acne breaks out? EVOCLIN is here. EVOCLIN is a daily topical clindamycin foam for the treatment of acne vulgaris. The most common adverse reactions were headache (3%) and application site reactions, including burning (6%), itching (1%) and dryness (1%). EVOCLIN is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin, or a history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis. Diarrhoea, bloody diarrhea and pseudomembranous colitis have been reported with systemic use of clindamycin and rarely with topical use of clindamycin. Discontinuation is recommended if diarrhea occurs. See the following page for full prescribing information. Visit www.evocalin.com for more information.
(Clindamycin Phosphate) Foam, 1% Rx FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL OR INTRAVAGINAL USE. DESCRIPTION Evoclin (clindamycin phosphate) phosphate, 1%, a topical antibiotic in an effervescent vehicle, contains clindamycin phosphate, USP, at a concentration equivalent to 10 mg clindamycin per gram, in a vehicle consisting of cetyl alcohol, dehydrated alcohol (58% ethanol), Polysorbate 60, potassium hydroxide, propylene glycol, purified water and stearyl alcohol pressurized with a hydrocarbon propellant (propane/butane). Chemically, clindamycin phosphate is a water-soluble ester of the semi-synthetic antibiotic produced by a 7(S)-chloro substitution of the 7(R)-hydroxyl group of the parent antibiotic lincomycin and has the structural formula shown below: Figure 1: Structural formula CH3
The genotoxicity tests performed included a mouse micronucleus test and an Ames Salmonella reverse test. Both tests were negative. Reproduction studies in rats with oral doses of clindamycin hydrochloride and clindamycin palmitate hydrochloride revealed no evidence of impaired fertility. Pregnancy: Teratogenic Effects - Pregnancy Category B Reproductive studies were performed in rats and mice with subcutaneous and oral doses of clindamycin phosphate, clindamycin hydrochloride phosphate and clindamycin palmitate hydrochloride. hydrochloride. These studies revealed no evidence of harm to the fetus. The highest dose used in teratogenicity studies in rats and mice corresponded to a clindamycin phosphate dose of 432 mg/kg. In a rat, this dose is 84 times higher and in a mouse 42 times higher than the predicted human dose of Evoclin's clindamycin phosphate based on a mg/m2 comparison. However, there are no adequate and well-controlled studies in pregnant women. Because animal reproductive studies do not always predict human response, this medicinal product should not be used during pregnancy unless clearly necessary. Breast-feeding mothers: It is not known whether clindamycin is excreted in breast milk after use of Evoclin. However, oral and parenteral clindamycin has been reported to be excreted in breast milk. Because of the potential for serious adverse reactions in breastfed infants, a decision must be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. Use in children: The safety and effectiveness of Evoclin in children under 12 years of age have not been studied. he studied. Geriatric use: The Evoclin clinical study did not include a sufficient number of patients aged 65 years and older to determine whether they responded differently than younger patients. ADVERSE REACTIONS The incidence of adverse reactions occurring in ≥ 1% of patients in clinical trials comparing Evoclin and its vehicle are presented below: Selected adverse reactions occurring in ≥ 1% of patients
References: 1. Feldman SR, Sangha N, Setaluri V. Thread
Corticosteroid in foam vehicle provides coverage comparable to traditional vehicles. J.Am. Acad. dermatol. 2000;42:1017-1020. 2. Data in file , Connetics Corporation.3. EVOCLIN™ prescribing information. Evoclin, the "Wisp" logo and the foam ball are trademarks and VersaFoam and Connetics are registered trademarks of Connetics Corporation. © 2005 Connetics Connetics Corporation PRM-CLF-030 2/05 Printed in USA
The chemical name of clindamycin phosphate is methyl 7-chloro-6,7,8-trideoxy-6-(1methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-4-propyl-L - 2 -pyrrolidinecarboxamido)-1-thio-L-threo--D-galactooctopyranoside octopyranoside-2-(dihydrogen phosphate). CLINICAL PHARMACOLOGY Pharmacokinetics: In an open label, parallel group study in 24 patients with acne vulgaris, 12 patients (3 men and 9 women) applied 4 grams of Evoclin Foam once daily for five days and 12 patients (7 men and 5 women) applied 4 grams of Clindagel® ( clindamycin phosphate) topical gel, 1%, once daily for five days. At day 5, the mean Cmax and AUC(0-12) of Evoclin Foam were 23% and 9% lower than Clindagel®, respectively. After multiple doses of Evoclin Foam, less than 0.024% of the total dose was excreted unchanged in the urine over 12 hours on Day 5. Microbiology: The clindamycin component has been shown to be active in vitro against Propio Propionibacterium nibacterium ium acnes, an organism associated with vulgar acne; However, the clinical relevance of this activity against P. acnes has not been evaluated in clinical trials with this product. Cross-resistance between clindamycin and erythromycin has been demonstrated. CLINICAL STUDIES In a multicenter, randomized, double-blind, vehicle-controlled clinical study, patients with mild to moderate acne vulgaris used 1% Evoclin (clindamycin phosphate phosphate) or the vehicle foam once daily for twelve weeks. Treatment Response to treatment, response defined as proportion of patients healed or nearly healed based on the Investigator Static Global Assessment (ISGA), and the mean percent reduction in lesion count at the end of treatment in this study are presented in the following table: :
Evoclin Fo-Schaum N = 386
Vehicle Fo foam N=127
Efficacy Parameters Treatment Response (ISGA) Percent reduction in lesion count
INDICATIONS AND ADMINISTRATION Evoclin is indicated for topical use in the treatment of acne vulgaris. Given the possibility of diarrhea, bloody diarrhea, and pseudomembranous colitis, the clinician should consider whether other agents are more appropriate. (See CONTRAINDICATIONS, WARNINGS and ADVERSE REACTIONS.) CONTRAINDICATIONS Evoclin is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin, a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated antibiotic-clindamycin-associated colitis . WARNINGS WARNINGS Oral and parenteral clindamycin has been associated with severe colitis, which can result in patient death. Application of the topical formulation of clindamycin results in absorption of the antibiotic through the skin's surface. Diarrhoea, bloody diarrhea and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin. Studies indicate that a toxin produced by Clostridial is a major cause of antibiotic-associated colitis. Colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps, and may be accompanied by discharge of blood and mucus. Endoscopic examination may show pseudomembranous pseudomembranous colitis. Stool culture for Clostridium difcile and stool analysis for C. diphyceletoxin toxin can aid in diagnosis. diagnostic. If significant diarrhea occurs, the drug should be discontinued. If diarrhea is severe, colon endoscopy should be considered for definitive diagnosis. Antiperistaltic agents such as opiates and diphenoxylate with atropine can prolong and/or worsen the condition. Diarrhoea, colitis and pseudomembranous colitis were observed several weeks after the cessation of oral and parenteral clindamycin therapy. Mild cases of pseudomembranous colitis usually respond only to drug discontinuation. In moderate to severe cases, fluid and electrolyte management, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difcile colitis should be considered. Avoid contact of Evoclin with the eyes. In case of contact, flush eyes with plenty of water. PRECAUTIONS General: Evoclin should be prescribed with caution to individuals with atopy. Drug Interactions: Clindamycin has been shown to have neuromuscular blocking properties that may potentiate the effects of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such funds. Therefore Carcinogenesis, Carcinogenesis, Mutagenesis, Reduced Fertility The carcinogenicity of a 1% clindamycin phosphate gel similar to Evoclin was evaluated by daily dosing in mice for two years. The daily doses used in this study were approximately 3- to 15-fold higher than the 5 mL dose of Evoclin for human clindamycin phosphate, assuming complete absorption and based on body surface area comparison. Comparison n. No significant increase in tumors was observed in the treated animals. A 1% clindamycin phosphate gel similar to Evoclin caused a statistically significant reduction in the median time to tumor onset in a study in hairless mice that developed tumors
Headache Application site burning Application site itching Application site dryness Application site reactions, not otherwise stated
Number (%) of persons Evoclin Foam Vehicle Foam N = 439 N = 154 12 (3%) 1 (1%) 27 (6%) 14 (9%) 5 (1%) 5 (3%) 4 (1% ) 5 (3%) 3 (1%) 4 (3%)
In a contact sensitization study, none of 203 subjects developed signs of allergic contact sensitization to Evoclin. Oral and parenteral clindamycin has been associated with severe, potentially fatal colitis. Cases of diarrhoea, bloody diarrhea and colitis (including pseudomembranous colitis) have been reported as adverse reactions in patients treated with oral and parenteral formulations of clindamycin and rarely topical clindamycin (see PRECAUTIONS). Abdominal pain and gastrointestinal upset and gram-negative folliculitis have also been reported with the use of topical clindamycin formulations. OVERDOSE Topically applied Evoclin can be absorbed in amounts sufficient to produce systemic effects (see WARNINGS). DOSAGE AND DIRECTIONS Apply Evoclin to the affected areas once a day, after washing the skin with mild soap and drying it completely. Use enough to cover the entire affected area.
How to use Evoclin 1. Do not put Evoclin directly on your hands or face as the foam will start to melt on direct contact with warm skin. 2. Remove the clear cover. Align the black mark with the actuator nozzle. 3. Hold the can at a vertical angle and press down firmly to eject. Pour a quantity directly onto the lid or onto a cool surface. Dispense an amount of Evoclin to cover the affected area(s). (s). If the can feels hot or the foam seems to run, place the can in cold water. 4. Take small amounts of Evoclin with your fingertips and massage gently into the affected areas until the foam disappears.
Discard any unused medication that you dispensed from the can. Avoid contact of Evoclin with the eyes. In case of contact, flush eyes with plenty of water.
SUPPLY CONTENTS Evoclin contains clindamycin phosphate equivalent to 10 mg clindamycin per gram and is available in the following sizes: 100 gram jar - NDC 63032-061-00 and 50 gram jar - NDC 63032-061-50 STORAGE AND HANDLING Store at controlled room temperature environment 20°- 25°C (68°- 77°F). FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING AND IMMEDIATELY AFTER APPLICATION. print content. Do not pierce or burn. Do not expose to heat or store in temperatures above 120°F (49°C). Keep away from children. Manufactured for printing in the USA Connetics Corporation October 2004 Palo Alto, CA 94304 USA For more information: 1-888-500-DERM or visit www.evoclin.com Patent pending
Evoclin is a trademark of VersaFoam, VersaFoam, Corporation. the V logo, the interlocking C logo, and Connetics are registered trademarks of Connetics © 2004 Connetics Corporation
were induced by exposure to simulated sunlight.
Scleromyxedema: Scleromyxedema a: Case Report Jennifer Bucci, DO*, Schield Wikas, DO, FAOCD** *2nd Year Resident, SUMMA Cuyahoga Falls General Hospital **Program Director, Dermatology Residency, Clinical Professor, College of Osteopathic Medicine, Ohio University, Athens , Ohio SUMMARY Scleromyxedema is a chronic disability with little tendency to spontaneous remission. Systemic involvement Involvement of scleromyxedema can be fatal. Extracutaneous and extracutaneous manifestations can be associated with significant disabilities. Inability. Due to the rarity of this disease, studies on therapeutic options for these patients have not been conducted. There are only case reports describing the success or failure of patients undergoing therapy. Therapy. A 39-year-old Caucasian female met specific criteria for the diagnosis of scleromyxedema, including a generalized papular and sclerodermoid rash, histological evidence of mucin deposition, fibroblast proliferation, fibrosis, and monoclonal gammopathy. 1. Gamma path
Case Report: This is the case of a 39-year-old Caucasian female who presented with a rash on the upper extremities and face lasting several months. She later developed many extracutaneous manifestations, including xerostomia, dysphagia, fatigue, anorexia with subsequent weight loss, and bilateral lower extremity paresthesias. Extremities. Most troubling to her, however, was an accelerated loss of motor function; She had difficulty getting out of a chair and climbing stairs. His history was significant for an episode of expressive aphasia and visual disturbance, which, upon completion of a negative examination, was diagnosed as a possible transient ischemic attack. The patient was a Caucasian female, approximately 67 inches tall and weighed 160 pounds. The dorsal hands and wrists presented 2-3 mm firm, waxy papules symmetrically present in no particular arrangement. (See figures 1 and 2). The range of motion in the wrist and wrist joints was not restricted and there was no associated or associated stiffness. firm waxy papules were symmetrically present in the preauricular area of the face and along the lateral nasal wall. Side wall. There was a speckled pigmentary lesion of the skin, particularly seen on the bilateral lower extremities, consistent with livedo reticularis. Pulses were easily palpable in the distal arteries in the lower extremities. Extremities. Neurological examination was normal except for slightly decreased ankle reflexes. Over the next few months, the patient developed a general tightening of the skin over the front and back shoulders. The patient presented with sclerodactyly with reduced movement of the bilateral metacarpophalangeal, proximal, and distal interphalangeal joints. However, a microstomy was not evident on physical examination.
Figure 1: Right hand and wrist with 2-3mm thick, firm, waxy papules
Figure 2: Left hand with similar firm, waxy papules of 2 to 3 millimeters
Test. The left parietal scalp showed diffuse capillary rarification with no evidence of cicatricial alopecia. The hair had no major brittleness. Fragility. She had progressive weight loss, which was recorded in pre-therapy examinations. A skin biopsy taken from the right hand before the start of therapy was a perforated preparation. The changes were consistent with myxedema lichen. The epidermis of the epidermis was intact with dermal proliferation of fibroblasts and increased interstitial mucin, confirmed by colloidal iron staining. (See Figures 3 and 4). Antibody screening was negative for
antinuclear antibody (ANA), anti-double-stranded DNA (anti (anti-ds-DNA), rheumatoid factor (RF), SSA and SSB antibodies, and scl-70. Serum protein electrophoresis (SPEP) confirmed monoclonal IgG gammopathy kappa quantitative immunoglobulins were within normal limits Thyroid studies revealed hypothyroidism Thyroid stimulating hormone (TSH) was increased by 10.956 and triiodothyronine (T3) was decreased by 248 Muscle muscle enzymes were increased Creatinine phosphokinase (CPK) was 585, lactate dehydrogenase (LDH) was 230 and aldolase was 17.2. an acute generalized myositis of moderate to severe type affecting both the proximal and distal muscles.Computed tomography (CT) of the abdomen and pelvis showed no acute pathology.Medulum aspiration and bone marrow biopsy were essentially nondiagnostic.Plasma cells accounted for fewer than five percent thyroid scintigraphy showed a slight increase in uptake. Absorption. The ultrasound of the thyroid showed a non-enlarged gland with many small colloid cysts and foci of calcification. A diagnosis of scleromyxedema was made. This patient was referred to multiple subspecialties including neurology, hematology/oncology, rheumatology, and physical therapy. Therapy. After collaboration between the subspecialists, combination therapy with an alkylating agent, melphalan (L-phenylalanine mustard) and intravenous immunoglobulin (IVIG) was initiated. Recognizing the possible side effects of this drug regimen, the deterioration in the patient's physical condition justified its introduction. Melphalan was administered at 2 milligrams (mg) every other day for one month until
SCLEROMYXEDEMA: CASE REPORT
reduced to every five weeks. The main side effects of IVIG administration in the patient were nausea and mild flare-ups of stomatitis. At the end of therapy, the patient reported that he "didn't feel well" despite being pretreated with 1000 mg of oral paracetamol. The patient experienced remission with single drug therapy. The patient remained under the care of the Department of Hematology and Oncology. Oncology. The patient was successfully continued on melphalan
stimulatory effects when eluted and isolated 8. Subsequently, the same results of a causal relationship between serum from patients with scleromyxedema and fibroblast proliferation could not be duplicated by another research group. Instead, Yaron Yaron et al. showed that serum can induce a 2-fold increase in hyaluronic acid synthesis and a 13-fold increase in prostaglandin E 9 synthesis. These findings may suggest a causal relationship between prostaglandin
over the last year. based on the year. We define therapy success as patient-reported quality of life. Life. Her lower extremity weakness improved with increasing ability to perform activities of daily living (ADLs) that previously required assistance. The patient is now working full-time. Serum protein electrophoresis continued to show an elevated M peak over the course of therapy. Muscle enzymes, including CPK, which were previously elevated, returned to normal over the course of systemic chemotherapy.
Scleromyxedema is a generalized variant of cutaneous mucin deposition with systemic, even fatal, manifestations. The exact pathogenesis of scleromyxedema is unknown and there are several etiological hypotheses. exist. Several immunomodulatory mechanisms have been proposed to try to link monoclonal gammopathy to fibroblast proliferation. The exact relationship between skin changes and paraproteinemia remains unclear. It has been suggested that paraprotein acts as an autoantibody and directly stimulates fibroblast proliferation and mucin deposition in the skin 6. Harper and Rispler 7 provided evidence against this hypothesis by showing that the serum of
It is a synthesis of a hyaluronic mediator, which then stimulates acid synthesis. Scleromyxedema is a rare condition in middle-aged people with no gender preference. The disease typically presents with a two-component rash. The papular component presents as firm, waxy, symmetrical papules approximately 2 to 3 millimeters in diameter. These papules are most commonly found on the bilateral hands, arms, face, neck, upper trunk, and proximal lower extremities. Papules are typically arranged in a linear pattern. standardize. A generalized, woody hardening of the skin is the second component and presents in a manner similar to scleroderma. In the case of skin involvement, both the mucous membranes and the scalp are usually spared. Telangiectasia and calcinosis are always absent. Patients with scleromyxedema can have significant cutaneous and extracutaneous involvement, resulting in significant comorbidity associated with this disease. Patients with scleromyxedema may have paraproteinemia with rare progression to multiple myeloma. Central and peripheral nervous system involvement may include post-influenza-like illness coma and paraesthesia. Patients may present with varying degrees of proximal muscle weakness. Interestingly, autopsy of patients with known scleromyxedema showed no mucin deposition in the brain. Mucin deposition in muscles was observed in only 2 patients10. The pulmonary manifestation can present as obstructive or restrictive pulmonary disease. Patients may present with progressive dysphagia. Although many patients with scleromyxedema report a wide range of systemic symptoms, correlation with mucin deposition rarely occurs at postmortem autopsy. 11. Myopathy is a common finding in patients with scleromyxedema, but muscle biopsy does not usually find mucin deposition.12,13. Thus, something other than mucin may contribute to the extracutaneous systems involved in this pathologic process. Histologically, the skin at biopsy shows diffuse mucin deposition on the upper and lower surfaces
3 patients with serum containing paraprotein without paraprotein stimulating fibroblast DNA synthesis and proliferation in vitro. in vitro The paraprotein doesn't
reticular and middle dermis, increased collagen deposition and marked proliferation of irregularly arranged fibroblasts. fibroblasts. The epidermis can be normal or thinned through
Discussion: This case underlines the importance of scleromyxedema as a generalized papular and sclerodermoid form of lichen myxedematosus with systemic, even lethal manifestations. It differs from a localized form that does not carry out a course of disability. The original description of cutaneous mucinosis was given by Dubreuilh 2 in 1906 and by Reitmann 3 in 1908. In 1953, Montgomery and UnderUnderwood 4 proposed a clinical classification distinguishing four types of lichen myxedematosus: a generalized lichenoid eruption, a discrete papular form, a generalized or localized lichenoid plaque form, and an urticarial form. The term scleromyxedema scleromyxedema was first proposed by Gottron in 1954 to refer to the generalized lichenoid papular rash with sclerodermoid features 5. Figure 4
she developed leukopenia and therapy was then discontinued for a period of nine days. She then continued melphalan at 2 mg every other day for a total of 8 cycles. The patient's dose was then reduced to 2 mg administered only on Mondays and Thursdays for 4 cycles. Finally, due to bone marrow suppression demonstrated in repeated laboratory reports, melphalan was only given once a week. Darbepoetin alfa alfa support was used due to the onset of anemia. At the same time, the patient began IVIG therapy consisting of 5-day infusions administered every three weeks. weeks. IVIG was dosed at 30 grams per day for 5 consecutive days. After 12 consecutive cycles was the frequency of drug administration by the patient
the pressure of the underlying mucin and fibrosis. The hair follicles may be atrophic and a mild perivascular superficial lymphocytic and plasmacytic infiltrate is often present. Elastic fibers are usually fragmented and reduced in number14. Due to the rarity of this disease, no prospective controlled therapy studies have been described in the literature. Literature. This disease presents on the skin with systemic involvement and the etiology of this systemic disease is not clearly understood.
Melphalan and other chemotherapy drugs. Due to significant hematological malignancies and the possibility of life-threatening infections, these therapies are limited to patients severely affected by comorbidities associated with the disease. High-dose immunoglobulin has also been used following reports of success in the treatment of neurological disorders associated with a paraprotein15. Granulocyte colony stimulating factor, factor, cyclosporine, thalidomide and interferon alfa have been used to a limited extent
6 Lister R, Jolles S, et al. Scleromyxedema: Response to high doses of intravenous immunoglobulin. Amer Academy Dermatology Magazine 08/2000 Part 2; Vol. 43 7, 8 Harper, RA, Rispler J. Serum from lichen myxedema stimulates human dermal fibroblast proliferation. Proliferation. Science 1978; 199: 545-547. 9 Yaron M, Yaron I, Yust I, Brenner S. Myxedema lichen serum stimulates hyaluronic acid and prostaglandin E production by human fibroblasts. J Rheumatol 1985; 12:171-5.
Therefore, treatment for intralesional skin involvement includes topical and systemic corticosteroids, topical and intralesional hyaluronidase, topical dimethyl sulfoxide, corticotropin, and PUVA, which can reduce skin thickness. Long-term use of PUVA increases the risk of squamous cell carcinoma. Boundary rays, radiation, electron beam therapy, retinoids potentially reducing fibroblast proliferation can be used. Plasmapheresis, dermabrasion, and extracorporeal photochemotherapy also play a role in treating this disease. The underlying disease process; However, it can be attacked by drugs used to treat other hematological conditions, such as:
reported disappointing literary literature. and. Treatment is usual and the overall prognosis is poor.
Int J Dermatology 1989; 28:657-60 11 Godby A, Bergstresser P, et al. Fatal scleromyxedema: case report and literature review. Journal A,er Academy Dermatology 02/1998, part 2; Volume 38 12 Verity MA, Toop J, McAdam LP, Pearson CM. Scleromyxedema Myopathy. American Journal Clinical Pathology 1978; 69:446-52. 13 Espinosa A, De Miguel E, Morales C, Fonseca E, GihonBanos J. Scleromyxedema associated with arthritis and myopathy: case report. Clin Exp. Rheum 1993; 11:545-547. 15 Van Doorn PA, PA, Vermeulen M, Brand A, Mulder PGH, Busch HFM. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: clinical and laboratory features associated with improvement. ArchNeurol 1991; 48:217-20.
Montgomery H, Underwood LJ. Myxedematous lichen (distinction from cutaneous myxedema or mucous conditions). J Investdermatol 1953; 20:213-36. 2 Dubreuilh W. Follicular miliary myomas: consecutive scleroderma. Ann Dematol Syph 1906; 37:569-72. 3 Reitmann K. About a peculiar affection close to scleroderma. Arch Dermatol Syph 1908; 92:417-424. 5, 14 Rongioletti F, F, Rebora A. Updated classification of papular mucinosis, lichen myxedema, and scleromyxedema. Amer Journal Amer Academy Dermatology 02/2001, Part 1; volume 44
References 10 Rothe MJ, Rivas R, Gould E, Kerdel FA. scleromyxedema and severe myositis.
SCLEROMYXEDEMA: CASE REPORT
Surgical Beads Jay S. Gottlieb, DO, FAOCD, Amy D. Gottlieb, PA-C
Here's how I did it... The diamond-shaped transposition flap is a workhorse in the temple area for us. With a precise and filigree technique, an impressive
When using a diamond rag, it is important to ensure all lengths and angles are accurate. Plan the position of the donor flap in a way
a noticeable surgical scar can be preserved in most patients.
to ensure the resulting scar is optimal
All incisions are the same length
The two tabs are swapped
placed. In a diamond lobe, all cut lengths are equal. Acute angles are 60 degrees and obtuse angles are 120 degrees. In a rhomboid, rhomboid, there are two keys that are created, overlapped and transposed. Subcutaneous sutures are required. 5-0 Single interrupted black nylon sutures are used. Fashion. The depth of the detachment is just below the reticular dermis at the subcutaneous level. In the area of the temples, care must be taken not to injure the temporal ramus of the facial nerve.
Tungiasis: A Case Report and Review Lynora Curtis Bassett, D.O.* Brad P.P. Glick, D.O.** Les Rosen, M.D.*** *Second-year resident, Wellington Regional Medical Center/Lake Erie College of Osteopathic Medicine, Dermatology Residency Program, Wellington, FL **Residency Director, Director, Wellington Regional Medical Center/Lake Erie College of Osteopathic MedicineDermatology Residency Program Wellington, FL ***Dermatopathologist, Dermpath Diagnostics Division of AmeriP AmeriPath at Laboratories, Pompano Beach, FL ABSTRACT Tungiasis is an ectoparasitosis caused by the pregnant sand flea, Tunga penetrans. Tunga penetrans is endemic to Central and South America, the Caribbean, Africa, India and Pakistan. Pakistan. Prevalence in endemic areas ranges from 15 to 40%.1 It has become a major public health problem in areas where incidence of severe infestations is increasing. Although rare and sporadic in the United States and many other countries, it has been reported in people who have traveled to endemic areas. This is a case report of tungiasis in a 45-year-old man who traveled to Brazil. Following this case report is a discussion of tungiasis, tungiasis, possible complications, treatment alternatives, preventive alternatives, and preventative measures. measurements.
Introduction Tungiasis is an infestation of the female sea flea, Tunga penetrans. When the female sand flea becomes pregnant, it needs a host's blood supply to mature and release its eggs. It burrows into the epidermis and dermis, maintaining an opening to release its eggs outside the skin. and dies after the eggs are shed from the shed skin. Isolated flea lesions tend to be self-limiting. It is brought to the United States by travelers to endemic regions.
Case report Male, 45 years old, healthy, Caucasian, with a lesion on the right plantar foot. The lesion was present for a week. The patient denied itching or tenderness. He also denied any systemic symptoms, including fever, chills, nausea, vomiting, diarrhea and headache. The lesion was solitary and there was no evidence of a widespread rash. He recently traveled to Brazil where he spent some time walking on the beach in sandals and barefoot. Her dermatological history was significant for Mycosis fungoides in the inactive plaque stage. He denied any drug allergy. Additional medical and social history did not contribute. Physical examination revealed a 4-5mm pink papule on the sole of the right foot. Foot. Biopsy of the lesion was delayed due to upcoming knee surgery. Surgery. At subsequent follow-up, the patient reported that the lesion was slowly increasing in size and itching. There was no pain or tenderness. The second physical examination revealed a 1 cm yellow-purple spongy nodule with a spongy appearance and a deep subcutaneous component. was taken. (Figure A1) The 3 mm core biopsy was The initial histopathologic diagnosis was arthropod bite reaction, but a second one
the opinion of the slides established the diagnosis of tungiasis. Hematoxylin-eosin staining revealed an insect body cavity inserted into the epidermis and dermis and lined by an eosinophilic cuticle. Inside the cavity were eggs, hollow annular components of the tracheal system and digestive tract. (Figures 2-3)
Discussion sand flea infestation ingTungiasisTunga Tan non penetrans. It is part of the Phylum Arthropoda, the class Insects and the order Siphonaptera (fleas). Command. endemic
Territories Tunga penetrans is also known as sand flea, chigoe, jigger, pige, nigua, pico, and bicho de pie.2 It is the only member of the Tungidae family known to attack humans. 2 It is the smallest known sand flea (1 mm). Tungiasis originated in Central and South America and was first reported in the crew of Columbus in 1492.3 It is endemic to Central and South America, the Caribbean, Africa, India and Pakistan. In endemic areas, the prevalence ranges from 1,540%.2 In the United States and Europe, it is introduced by travelers. Traveler. He was also in the West Indies. The main reported habitat for the flea is hot, dry soil and sand on beaches, stables, and livestock farms. Unfertilized male and female fleas feed intermittently on warm-blooded hosts including cattle, sheep, horses, mules, rats, mice, dogs, pigs and other wild animals.2 After copulation, the male flea dies.3 It is the pregnant flea sand flea, a bad jumper, most commonly digging into human skin on the feet (solar, interdigital, interdigital, subungual). subungual). Other parts of the body can also be affected. affected. How the flea burrows into the skin is not known, but it is believed to be due to a keratolytic enzyme within the flea since the process is painless.2 Initial physical examination reveals a small inflammatory papule with a central black one Point. The papule slowly enlarges (4-10 mm) to a pea-sized nodule
TUNGIASIS: CASE REPORT AND REVIEW
some weeks. There may be pusborders over some tular or ulcerative. ulcerative. The site or wound through which it breathes and excretes has the potential for secondary infection. The lesion can range from asymptomatic to itchy and/or extremely painful. Multiple or severe infestations may present as clusters of nodules with a honeycombed appearance.2 Physiologically, the female sand flea requires a blood supply for the eggs to mature. With his head in the upper dermis,
In villages, ground-level flyscreen to collect jumping fleas, avoid contaminated areas, avoid stray animals, treat infected reservoir hosts (livestock and pets), and improve poor or non-existent sanitation and waste disposal.3 Also, the use of an effective skin repellent may reduce morbidity associated with heavy infestation.5
a feeds on blood from the tip of its host flea, while the caudal fin forms the punctum from the vessels of the abdomen on the skin surface. Over the next 1-2 weeks, eggs will be released from the opening. Opening. After all of the eggs are released without complications, the flea dies and sheds itself from the host's skin. Eggs that fell on the ground hatch in 3-4 days, pupate in 10-14 days, and then become adults in 1-2 weeks. The complete life cycle is one month.4 The clinical differential diagnosis of tungiasis includes: fire ant bite, tick bite, scabies, cercarial dermatitis, early insidious eruption, myiasis, folliculitis, dracunculiasis, and neoplasm. In addition, nodular cutaneous T-cell lymphoma was considered
Tunga penetrans is a serious health threat in endemic and underdeveloped areas with poor socioeconomic conditions. These resource-poor communities struggle with massive infestations and serious complications. Effective chemotherapy is urgently needed in these areas. Standard therapy is sufficient in most cases outside of the endemic areas. Isolated, uncomplicated injuries tend to be self-limiting. Although tungiasis is rare in the United States, as more people travel to endemic areas, physicians should have high clinical suspicion.
this patient with complications due to his history. Severe involvement can include severe inflammation, ulceration, and fibrosis. There is also the possibility of gangrene, sepsis, lymphangitis, lymphadenitis, bone necrosis, finger amputation, secondary infection (tetanus), cellulitis, erysipelas, superinfection (staph aureus or gram-negative bacteria), and death.1 Treatment involves many physician and surgical options. Standard therapy involves removal with a needle or forceps within the first 48 hours, followed by disinfecting the site. The occlusive petrolatum suffocates the flea. Electrodissection is good for the intermediate stages of development. If the flea is swollen, surgical options include curettage or surgical excision to remove the cavity from the cavity. Other treatments with unknown success include: formaldehyde, chloroform, turpentine, and dichlorodiphenyltrichloroethane (DDT). Topical or systemic antibiotics can prevent secondary infections. infections. Tetanus prophylaxis may also be indicated. In endemic areas where higher infestations are more common, there is a need for an effective systemic agent. Orally administered ivermectin has been studied but has not demonstrated clinically significant efficacy.5 Our patient was successfully treated with surgical excision and secondary healing. Prevention of tungiasis in endemic areas
1.Tungiasis Gibbs N.Tungiasis. www.eMedicine www.eMedicine.com .com 2003 August 2001 13. 2. Biology and Treatment. Treatment. www.stanford.edu. 3. Samlaska CP. Arthropod infestation and disease vectors. Military Dermatology.. 192-193. 4. Wolf R, Orion E, Matz H. Winged stowaways: reports of two cases of flying insects. DOJ 2003; 9(3):10 5. Heukelbach J, Franck S, Feldmeier H. Treatment of tungiasis: Tungiasis: a double-blind randomized controlled trial with oral ivermectin. December 2004. Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 99(8): 873-876. 6. Janvier-Fevrier. tungiasis. European Journal of Dermatology 1999; 9(1):57-59 7. Feldmeier H, Eisele M, Sabonia-Moura RC, Heukelbach J. Severe tungiasis in poor communities: case series from Brazil. Emerging Infectious Diseases [Serial online] 2003 August; 9(8). www.cdc.gov 8. Golouh R, Spiler M. A paraungual tumor? No, only tungiasis. Radiol Oncol 2000:34(1):35-39 9. Bertrand R. Parasitic nail infections. Abstracts of the fifth meeting of the European Nail Society: DOJ 9(1):17C
Various cleaning measures can be performed: wearing shoes, personal disinfection of clothes, bedding, furniture, insecticide used on floors in infested areas
BASSET, GLICK, ROSEN
Allergic Contact Dermatitis: Historical Perspective, Clinical Overview, and Case Report Assistant Professor, Department of Dermatology, Case Western Reserve University ***Program Director, UHHS Richmond Heights Program, Cleveland, Ohio ABSTRACT Allergic contact dermatitis (ACD) is a condition observed in clinical trials of dermatology . First described by Jadassohn1 in 1895, we now have a much better understanding of the immunological complexity of this delayed and delayed-type hypersensitivity. well-defined edges showing the contact area. However, the clinical presentations of ACD can vary, making diagnosis difficult. Challenger. Patch testing remains the gold standard for diagnosing ACD. The Thin Layer Thin Layer Patch Test (T.R.U.E.) (T.R.U.E.) test is the only US approved patch test. Food Food and Drug Administration10. This test, which contains only 23 of over 3,700 known allergens, allergens, is an accurate but insensitive method of detecting ACD10. We present the case of a 22-year-old woman who presented to our contact dermatitis clinic with a 15-month history of an itchy and sometimes painful rash. Patch testing for a modified North American screening series (Chemotechnique Diagnostics AB, Malmö, Sweden) showed current relevant positive reactions to both Kathon CG and cocamidopropyl betaine.
Historical perspective Contact dermatitis was first described in 1895 by Jadassohn. 1 He is considered the “father” of contact dermatitis and reported a case of contact allergy to mercury. Mercury. It wasn't until the 20th century that we began to understand the immunological complexity of this disease. In 1927 Landsteiner published his early work on antigens containing "simple chemical compounds."1 His work with Jacobs in 1935 established that epicutaneous application of allergens could induce contact sensitivity. 2, 3 We now know that most contact allergens are small haptens, less than 500 daltons in size, that are able to penetrate the skin barrier. A disruption of this barrier, e.g. B. dermatitis or ulceration, puts the skin at a higher risk for contact sensitivity. But where on the skin does sensitization to an allergen occur? Marion Sulzberger published a series of articles in the 1930s describing the skin as the origin and site of hypersensitivity.4 He coined the term special status to denote a specific site on the skin involved in sensitization. In his attempt to localize this site, he showed that intracutaneous injection of a sensitizing material resulted in peripheral sensitization. His research also showed that a hypersensitivity reaction cannot be elicited when the antigen is administered by non-cutaneous routes (intravenous, intramuscular, intraperitoneal, intramuscular, intraperitoneal, intrapulmonary, intratesticular, monal, intratesticular and intracardiac). Although a special status was never established, Sulzberger was able to demonstrate that the skin is both a sensitizing and a sensitizing organ. It is now known that allergens are mainly taken up by antigen-presenting cells
Langerhans cells (LCs), in the epidermis. As a medical student, Paul Langerhans was the first to identify these cells in 1868.4 Initially thought to be of neural origin, CLs are now thought to be of bone marrow origin. 4, 5 Like macrophages, epidermal CLs are dendritic cells that carry a variety of antigenic determinants on their cell surface.4 Pehamberger et al. showed in 1983 that CLs are necessary for the generation of contact sensitivity. 6 Exposure to ultraviolet (UV) radiation is known to result in a reduction in the density of LCs and inhibition of contact sensitization.1,7,8 After allergen absorption, the LC migrates to the lymph node where it is presented to T-T lymphocytes occurs. A subset of antigen-specific T lymphocytes are then produced and migrate to the site of skin exposure. In 1942, Landsteiner first described Landsteiner and Chase's relationship
Contact Allergy and Delayed Sensitivity.1 Their work demonstrated that both contact allergic hypersensitivity to low molecular weight antigens and delayed-type hypersensitivity to microbial antigens can be transmitted passively with lymphocytes in guinea pigs. Upon renewed exposure to the allergen, an inflammatory response is observed, which is recognized as eczematous dermatitis. This reaction is a delayed-type acquired hypersensitivity. Prior sensitization is required and can occur after exposure or even years of contact with an allergen. This fact is important for the clinician to consider, as patients may not cite products they have been using for many years as a potential source for theirs
Contact dermatitis (irritant and allergic) is a common condition, accounting for 6% to 10% of all dermatology consultations. 9 The diagnosis of allergic contact dermatitis (ACD) can be difficult to make on clinical grounds alone. Classic Classically, ACD appears as an itchy, well-demarcated, erythematous, vesicular, and/or scaly patch or plaque with well-defined borders indicating the area of contact. Atypical manifestations can be patchy or diffuse dermatitis, depending on the type of causative allergen. Other less common clinical presentations of ACD are urticaria and photosensitivity reactions. A biopsy can help diagnose ACD while ruling out other diagnoses such as psoriasis, tinea, and cutaneous T-cell lymphoma. and chronic lesions may produce less diagnostically confounding histologic patterns for ACD. ACD. Patch testing remains the gold standard for diagnosing ACD. The only patch test approved by the U.S. Food and Drug Administration approved is the Thin-Patch Rapid Use Patch Test (T.R.U.E.). 10 The T.R.U.E. The test contains 23 allergens and a negative control. Although this test contains only about 1.4% of the more than 3,700 known allergens, it is an accurate but insensitive method of detecting ACD.10 Detection rates of 23% to 62% have been reported in patients tested for ACD . test.10 for
Dermatitis. Mental Knowledge Despite its complexity, this X immune complex is a fundamental process that is essential in the treatment of patients with contact dermatitis.
demonstrated the reproducibility of a positive Maibach reaction in the patch test, Ale, and performed a simultaneous right-left study.11 Their data suggest that the patch test
ALLERGIC CONTACT DERMATITIS: HISTORICAL PERSPECTIVE, CLINICAL REVIEW AND CASE REPORT
ing is a reasonably reproducible test if methodological errors are kept to a minimum. Patch testing is performed by applying a series of patches to a completely dermatitis-free area, most commonly the back. The patches are left in place for 48 hours and then removed. Readings are taken 48 to 72 hours and again between 72 and 168 hours after placement. Patients are instructed not to wet their backs, shower, or sweat profusely during this time.
Predominant allergens identified by the T.R.U.E. Test are nickel, thimerosal, cobalt, fragrance blend and balsam of Peru.9 In comparison, the 2001-2002 NACDG patch test results show that the 5 most common allergens in the tested patients were nickel (16.7%), neomycin (11.6%) , Peru Balsam (11.6%), Fragrance Blend (10.4%) and Thimerosal (10.2%). 13 In conclusion, when performed and interpreted correctly, patch testing is a reliable method for identifying ACD. ACD. It might look like
evaluated for contact dermatitis and/or patch testing.15
Patch test scale responses are evaluated quantitatively as recommended by the International Contact Dermatitis Research Group1 (Table (Table 1). Absence of a positive response may be due to test error. Wet or loose patches or removal prior to 48 hours may result in a lead to false negative reaction reactions. Inadvertent washing of the back can remove grid patterns, making it impossible to read positive reactions accurately. Application of strong topical steroids to the test site for several days before or during the test can suppress the immune response. This is also true for systemic ones Corticosteroid doses in excess of 20 mg per day.1 Finally, a delay can be missed by not reading too late
easy to apply and read, identification, but it's actually a complicated process. of a relevant positive allergen requires experience with contact dermatitis on the part of the clinician. Contact dermatitis education, including patch testing, should be an integral part of all dermatology residency programs. Recent research from High and Cruz shows that only 27% of shows had dedicated rotations.
reported that her legs were intermittently affected and only her feet were never affected. She had no significant past medical history and denied any personal history of atopy. Family history was negative for atopy, psoriasis, autoimmune disease, or other skin conditions. Her only drug allergy was to ampicillin, which caused hives. Before the rash appeared, she was a
Case Report A 22-year-old woman presented to our contact dermatitis clinic with a 15-month history of an itchy and sometimes painful rash. The rash began bilaterally and symmetrically on the back of the hands and spread to the palms, scalp, neck, and chest (Figure 1-4). Is it over there
positive reaction. Table Table 1. Patch Test Interpretation -
weak macular erythema
Erythema, possibly papules
Erythema, papules, blisters
A negative patch test does not prove the absence of an allergy. Allergy. It is often due to a "missing" allergen. The results of a meta-analysis by Krob et al. suggest that T.R.U.E. The test is, at best, a screening test.9 The North American Contact Dermatitis Group (NACDG) recognizes that important allergens are identified by the T.R.U.E. Test.12,13 Targeted and detailed surveys of the patient's hobbies, personal care products and work environment are essential and can identify possible untested allergens. A study by Soni and Sherertz found that 27 of 43 patients had additional relevant allergens when additional patch testing was performed.14 Identifying a positive reaction is only the first step in determining the clinical relevance of an allergen. The relevance is classified as possible, probable, certain or past depending on the clinical rules for the underlying clinical situation. There is no absolute relevance. It depends on the knowledge and experience of the doctor. The most
Figure 1.4 Scaly, erythematous plaques on the face, neck, back, and palms.
EVERS, NEDOROST NED OROST, FUCHS
Table 2. University Hospitals of Cleveland screening series *additional allergens added to North American screening series (Chemotechnique, Malmö, Sweden)
Thiomersal (Merthiolat) Propylenglykol 2-Hydroxy-4-methoxybenzophenon (Benzophenon-3) 4-Chloro-3, 5-xylenol (PCMX) Ethylenharnstoff Melaminmischung Formaldehyd 2-tert-Butyl-4-methoxyphenol (BHA) Thiosulfat goldenes Natrium
Neomycin Sulfate Thiuram Mix Formaldehyde Ethylenediamine Dihydrochloride Quaternium 15 Epoxy Resin 4-tert-butylphenol Formaldehyde Resin Mercapto-Mix N-Isopropyl-N-phenyl-4-phenylenediamine Potassium Dichromate Turkey Balm Nickel Sulfate Hexahydrate 2,5-Diazolidinyl Urea DMDM Hydantoin Bacitracin Mixed Dialkylthiureas 5-Chlorine-2 -methyl-4-isothiazolinone (Kathon CG, 100ppm) Paraben Blend Euxyl K400 (Methyldiromoglutaronitrile and Phenoxyethanol) Fragrance Blend Glutaraldehyde 2-Bromo-2-nitropropane-1,3-diol (Bronopol) Sesquiterpene Lactone Blend
Ethylacrylat Glycerylmonothioglycolat (Glycerylthioglycolat) Toluolsulfonamid Paraluolsulfonamid Formaldehydharz Methylmethacrylat Kobalt(II)-chlorid-Hexahydrat Thixocortal-21-pivalat Budesonid Stearylalkohol* 2-Phenoxyethanol* Sorbitansesquioleat* Benzylalkohol* Clioquinol (5-Chlor-7-Iodochinolinol) * Wollalkohole (Lanolin)* 2-Chloracetamide* Triethanolamine* Abitol (Hydroabietyl Alcohol)* Dimethylol Dihydroxyethyleneurea (Fix. CPN)* Dimethylol Dihydroxyethyleneurea, modifiziert (Fix. ECO)* Cocamidopropyl Betaine* Triclosan* Lidocaine* Tea Tree Oil*
College student but has since withdrawn from school and social activities due to this condition. She had previously been examined for this condition by several doctors, including internists, dermatologists, rheumatologists and infectious disease specialists. Experts. The differential diagnosis included lupus erythematosus (possibly subacute type),
fluorescence were negative. Negative. These histological features are nonspecific but are more consistent with eczematous dermatitis with secondary inflammation or impetigination. After consultation with our contact dermatitis clinic, the patient was scheduled for a patch test. It was tested on its hair gel 'as is' and on the North American screen.
Dermatomyositis, eczema, tarda. Extensive laboratory tests for psoriasis and guttate cutaneous prophyria including ANA, anti-SM, anti-RNP, anti-SSA, anti-SSB, anti-Scl-70, anti-DNA and HIV were negative. Negative. Serum aldolase, ESR, IgE, latex IgE, CBC with differential, BMP (except glucose 120), LFT, lipid profile, plasma prophyrins, SPEP, C3, C4, serum fungal titers, and ASO titers were all within normal limits . AI, UPEP UPEP and RXT also normal. Previous treatments have included topical and oral steroids, topical immunomodulators, oral antihistamines, and oral cyclosporine without complete elimination. A skin punch biopsy of the neck was performed (Figure 5,6).
ing AB, Series Malmö, (Chemotechnique Sweden) modified diagnostics to include 15 additional allergens (Table (Table 2). Positive results are shown in Table 3. A 1+ response to cocamidopropyl betaine and Kathon CG on days 4 and 7 are we
It showed spongiotic keratinocyte epidermis with occasional apoptosis and focal areas of neutrophils in the stratum corneum. immunoimmuno
recorded. After three weeks of strictly avoiding these allergens, she was sparkling clean apart from a patch test spot on her upper left back. Other responses included a 2+ response to neomycin and bacitracin (considered previously relevant), a 1+ response to a mixture of carba and mixed dialkylthioureas, and a questionable response to nickel. Nickel. The patient was instructed to avoid antibiotic neomycin and bacitracin ointments. Nickel and rubber accelerators were relevant to the application of the eyelash curler.
Figure 6 Figure 5.6 Low and high magnifications showing a spongiotic epidermis with focal areas of neutrophils in the stratum corneum. Within the superficial dermis there is a mild lymphocytic perivascular inflammatory infiltrate.
Table 3. Positive patch test results in the case presented by ALLERGEN
Bacitracin Dialkylthioureas Mixed
ALLERGIC CONTACT DERMATITIS: HISTORICAL PERSPECTIVE, CLINICAL REVIEW AND CASE REPORT
Discussion Kathon CG was first marketed in 1980.1 It is a potent preservative with excellent antimicrobial activity against gram-negative and gram-positive bacteria, yeast and fungi. 16 The active chemical ingredients are 5-chloro-2-methyl-4-isothiazolin-3-one (chloromethylisothiazolinone) and 2-methyl-4-isothiazolin-3-one (methylisothiazolinone) in an approximate 3:1 ratio. 1, 16, 17 Other isothiazolinones are names. Currently available and marketed under many commercial biocides. Currently, patch testing for Kathon CG allergy is performed at 0.01% aq or 100 ppm. 1 Kathon CG is found in many rinse-off and leave-on hygiene products such as body washes, shampoos, hair gels, cosmetics and body lotions.16 The prevalence of a positive patch test reaction is reported to be up to 8% 8.5%. 1, 16 However, other studies report much lower positive reactions (0.8% to 3.5%)16, 18, 19 (approximately 4% in our University of Cleveland Hospitals Contact Dermatitis Clinic). NACDG data from 1998-2000 reported a 1.4% positive response to Kathon CG in over 5,000 patients tested.12 This allergen has also been reported in women, with the most common cosmetics being the main source of sensitization.16 Cocamidopropyl betaine ( CABP) is a nonionic surfactant found primarily in personal care products.1, 20 It is available from many suppliers under more than 50 brand names. CAPB is made by reacting coconut fatty acids (found in coconut oil) with dimethylaminopropylamine (DMAPA) (DMAPA) to produce cocamidopropyldimethylamine, which then reacts with sodium monochloroacetate to form the final CAPB product.20,21 Test contact is performed at 1% aqueous CAPB. CAPB allergy was first reported in 1983.21 It is commonly found in over 600 personal care products including shampoos, shower gels, body washes, dishwashing detergents, pet shampoos, skin lotions, makeup removers and contact lens cleaners.1,20,21,22 A CAPB- Allergy can present as dermatitis on the scalp, face, eyelids, neck and/or hands. The prevalence of ACD secondary to CAPB ranges from 3.0 to 7.2%21,23 (approx
approximately 4% at our University Hospitals of Cleveland Contact Dermatitis Clinic). This allergen has been responsible for occupational allergic contact dermatitis in hairdressers and healthcare professionals.21,23 The true allergen in patients with a positive patch test for CAPB has been debated in the literature.21,22,23 Amidoamine (AA) and DMAPA , products used in used in the synthesis/production of CAPB may be the true contact allergen. Fowle Fowlerr reports that European patients are rarely allergic to AA but test positive for both DMPA22. On the other hand, CAPB patients in North America are allergic to CAPB or AA or both, but rarely allergic to DMAP.24 Our patient was only tested for CAPB. The difference in North American studies can be explained by differences in manufacturing and supply in North America compared to other countries. Countries.
Conclusion ADC is a common dermatological disease with significant economic and morbidity implications. A detailed medical history, including an occupational history of morbidity, can provide clues to possible allergens. Patch testing is often required to make an ACD diagnosis. Relevance needs to be determined and additional patch testing may be required. Studies have shown that up to 10% of tested patients are allergic to cosmetic products or their ingredients.25 Head and neck dermatitis should raise clinical suspicion of CAPB allergy. We recommend patch testing CAPB as part of a standard series. REFERENCES
1. Rietschel RL and Fowler JF. JF Fisher contact dermatitis Philadelphia: Lippincott Williams & Wilkins; 2001. 2. Landsteiner K, Jacob J. Studies on Animal Sensitization to Simple Chemical Compounds J Exp Med 1935; 61:643-656. 3. Tamaki K. et al. The role of epidermal cells in the induction and suppression of contact sensitivity J Invest Derm 1981;76(4):275-278. 4. KatzSI.1985;13(3):530-536. The skin as an immunological organ J Am Acad Dermatol 5. Volc-Platzer B et al. Cytogenetic identification of allogeneic epidermal Langerhans cells in a bone marrow transplant recipient NEJM 1984;310(17):1123-1 1984;310(17):1123-1124. 124. 6. Pehamberger H. et al. Epidermal cell-induced generation of cytotoxic T-lymphocyte responses against alloantigens or TNP-modified syngeneic cells: requirement for Ia-positive Langerhans cells J Invest Derm 1983;81(3):208-21 1983;81(3):208-211. 1. 7. Freedberg IM et al., editors. Fitzpatrick's Dermatology in General Medicine New York: McGraw-Hill; 1999
8. Kripke ML et al. Role of DNA damage in local suppression of contact hypersensitivity in mice by UV radiation Exp Dermatol 1996;5(3):173-80. 9. Krob HA et al. Prevalence and relevance of contact dermatitis allergens: a 15-year meta-analysis by T.R.U.E. Test data J Am Acad Dermatol 2004;51(3):349353. 10. Belsito DV. dv Patch testing with a standard allergen tray (“screening”): opportunities and risks Dermatologic Therapy 2004;17:231-239. 11. Ale SI, Maibach HI. Reproducibility of patch test results: a simultaneous right-left study using the TRUE test Contact Dermatitis 2004;50(5):304-12. 12. Marks JG et al. North American Contact Dermatitis Group patch test results, 1998 to 2000 Am J Contact Dermat 2003;14(2):59-62. 13. Pratt MD et al. North American Contact Dermatitis Group patch test results, study period 2001-2002 Dermatitis 2004;15(4)176-83. 14. Soni BP and Sherertz EF. Evaluation of patients who previously had patch testing referred to a contact dermatitis clinic Am J Contact Dermat 1997;8(1):10-14. 15. High WA and Cruz PD Jr. Contact dermatitis education in dermatology residency programs: Can the American Contact Dermatitis Society be (become) a force for improvement? Am J Contact Dermat 2004;14(4):195-9. 16. Hasson A. et al. Sensitivity of the Kathon CG patch test for preservatives in Spain Contact Dermatitis 1990;22(5):25761. 17. Bjorkner B. et al. Contact allergy to preservatives Kathon CG Contact Dermatitis 1986;14(2):85-90. 18. Hjorth N. and Roed-Petersen J. Patch test sensitivity to Kathon CG Contact Dermatitis 1986;14(3):155-7. 19. Shuster S and Spiro J. Sensitization risk measurement and its application to Kathon Contact Dermatitis 1987;17(5):299-302. 20. Mowad CM. Cocamidopropyl Betaine Allergy Am J Contact Dermat 2001;12(4):223-224 2001;12(4):223-224. 21. De Groot AC et al. Contact allergy to cocamidopropyl betaine Contact Dermatitis 1995;33:419-22. 22. Fowler JF Jr. Cocamidopropyl Betaine Dermatitis 2004;15(1):3-4. 23. Brey NL and Fowler JF Jr. Relevance of positive patch test reactions to cocamidopropyl betaine and amidoamine dermatitis 2004;15(1):7-9. 24. Fowler JF Jr et al. Cocamidopropyl Betaine and Amidoamine Allergy in North America Dermatitis 2004;15(1):5-6. 25. Orton DI and Wilkinson JD. Cosmetic allergy: incidence, diagnosis and treatment Am J Clin Dermatol 2004;5(5):327-37.
EVERS, NEDOROST NED OROST, FUCHS
At the first sign...
In patients with recurrent genital herpes or herpes zoster
Famvir ® (Famciclovir) Pills Rx only BRIEF SUMMARY: See package insert for full prescribing information. INDICATIONS AND USE Herpes Zoster: Famvir® (famciclovir) is indicated for the treatment of acute Herpes Zoster (shingles). Herpes simplex infections: Famvir is indicated for: • the treatment or suppression of recurrent genital herpes in immunocompetent patients. • Treatment of recurrent mucocutaneous herpes simplex infections in HIV-infected patients. CONTRAINDICATIONS Famvir ® (famciclovir) is contraindicated in patients with known hypersensitivity to the product, its components and Denavir ® (penciclovir cream). PRECAUTIONS General The efficacy of Famvir® (famciclovir) has not been established for initial episodes of infection with genital herpes, ophthalmic zoster, disseminated zoster or in immunocompromised patients with herpes zoster. Dose adjustment is recommended when administering Famvir to patients with creatinine clearance < 60 mL/min. (See DOSAGE AND DIRECTIONS in full leaflet). Education). Acute renal failure has been reported in patients with underlying renal disease receiving doses of Famvir inappropriate for their renal function.
Information for patients Patients should be informed that Famvir is not a cure for genital herpes. There is no data on whether Famvir will prevent transmission of the infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with the lesions or sexual intercourse if lesions and/or symptoms are present to avoid infecting a partner. Genital herpes can also be transmitted without symptoms through asymptomatic viral shedding. If medical treatment of recurrent episodes is indicated, patients should be instructed to initiate therapy at the first sign or symptom. Drug interactions Co-administration with probenecid or other drugs significantly eliminated by active renal tubular secretion may result in increased plasma concentrations of penciclovir. The conversion of 6-deoxy-penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme may occur.
Carcinogenesis, mutagenesis, decreased fertility Famciclovir was administered orally unless otherwise stated. Carcinogenesis: Two-year dietary carcinogenicity studies were conducted with famciclovir in rats and mice. Carcinogenesis: A 2-year increase in the incidence of mammary adenocarcinoma (a common tumor in animals of this lineage) observed oral doses of 500 mg three times daily, 250 mg twice daily, or 125 mg twice daily based on comparisons of area under the plasma concentration curve [24 hour AUC] for penciclovir). In male mice treated at doses up to 240 mg/kg/day (0.9 to 5.4 times human AUC) or in male and female mice dosed at up to 600 mg/kg/day ( 0.4 to 2.4 times the human AUC). Mutagenesis: Famciclovir and penciclovir (the active metabolite of famciclovir) were tested for genotoxic potential in a variety of in vitro, vitro and in vivo assays. Mutagenesis: famciclovir. live trials. Famciclovir and penciclovir were negative in vitro tests for genetic mutations in bacteria (S. typhimurium and E. coli and coli) and unscheduled DNA synthesis in mammalian HeLa-83 cells (at doses up to 10,000 and 5,000, respectively µg/plate). Famciclovir was also negative in the L5178Y mouse lymphoma assay (5000 mcg/mL), in the in vivo micronucleus test in live mice (4800 mg/kg) and in the dominant lethal study in rats (5000 mg/kg). . Famciclovir-induced increase in polyploidy in human lymphocytes in vitro in vitro in the absence of chromosomal damage (1200 mcg/ml). Penciclovir was positive for gene mutation/chromosomal aberrations in the L5178Y mouse lymphoma assay, with and without metabolic activation (1000 mcg/mL). In human lymphocytes, penciclovir induced chromosomal aberrations without metabolic activation (250 µg/ml). Penciclovir caused an increase in the incidence of bone marrow micronuclei in mice in vivo when administered intravenously at highly bone marrow toxic doses (500 mg/kg), but not when administered orally.
Geriatric use Of 816 patients with herpes zoster treated with Famvir in clinical trials, 248 (30.4%) were 65 years old and 103 (13%) were 75 years old. Overall, no differences in the incidence or type of adverse events were observed between younger and older patients. ADVERSE REACTIONS Immunocompetent patients The safety of Famvir ® (famciclovir) was established in clinical trials involving 816 patients with herpes zoster treated with Famvir (Famvir, 250 mg three times a day to 750 mg three times a day); 528 Famvir-treated patients with recurrent genital herpes (Famvir, 125 mg twice daily to 500 mg three times daily); and 1197 patients with recurrent genital herpes treated with Famvir as suppressive therapy (125 mg q.d. to 250 mg 3d.), of whom 570 patients received Famvir (open-label and/or double-blind) for at least 10 months. Table 5 lists selected adverse reactions. Table 5 Selected adverse events reported by 2% of patients in placebo-controlled trials of Famvir® (famciclovir)*
Herpes Zoster Famvir® Placebo (n=273) (n=146) % %
Genital herpes Famvir® Placebo (n=640) (n=225) % %
Famvir® placebo suppression (n=458) (n=63) % %
Headaches in the nervous system 22.7 17.8 23.6 16.4 39.3 42.9 Paraesthesia 2.6 0.0 1st 3 0.0 0.0 0.0 Migraine 0.7 0.7 1 .3 0.4 3.1 0.0 Gastrointestinal nausea 12.5 11.6 10.0 8.0 7.2 9.5 Diarrhea 7.7 4.6 4.6 7.6 9.6 9.6. 4 1.3 0.9 3.1 1.6 flatulence 1.5 0.7 1.9 2.2 4.8 1.6 abdominal pain 1.1 3.4 3.9 5.8 7.9 7, 9 Body as a whole Fatigue 4.4 3.4 6.3 4.4 4.8 3.2 Itching skin 3.3 1.6 Female reproductive dysmenorrhea 0.0 0.7 2.2 1.3 7.6 6 ,3 *Patients may have participated in more than one clinical study. The following adverse events have been reported during post-marketing use of Famvir: urticaria, hallucinations and confusion (including delirium, disorientation, confusion occurring predominantly in the elderly). Because these adverse events were reported voluntarily from a population of unknown size, it is not possible to make frequency estimates. Table 6 lists selected laboratory abnormalities in genital herpes suppression assays. Table 6 Selected Laboratory Abnormalities in Genital Herpes Suppression Studies* Parameters
Anemia (<0.8 x NRL) Leukopenia (<0.75 x NRL) Neutropenia (<0.8 x NRL) AST (SGOT) (>2 x NRH) ALT (SGPT) (>2 x NRH) Total bilirubin >1 .5 x NRH) Fat Creatinine (>1.5 x NRH) Amylase (>1.5 x NRH) Lipase (>1.5 x NRH)
Famvir® (n=660)† %
Placebo (n=210)† %
0,1 1,3 3,2 2,3 3,2 1,9 0,2 1,5 4,9
0,0 0,9 1,5 1,2 1,5 1,2 0,3 1,9 4,7
Impairment of Fertility: Testicular Fertility: Testicular toxicity has been observed in rats, mice and dogs after repeated administration of famciclovir or penciclovir. Testicular changes included seminiferous tubule atrophy, decreased sperm count, and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of male reproductive toxicity depended on dose and duration of exposure. Reduced fertility was observed in male rats
*Percentage of patients with laboratory abnormalities that increased or decreased from baseline and were outside of the specified ranges. †N-values represent the minimum number of patients evaluated for each laboratory parameter. NRH = High normal range. NRL = Low Normal Range.
After 10 weeks, the toxicity of a dose of 500 mg/kg/day in the following weeks was (1.9 to 11.4 times the (26 human AUC, no observable sperm and testis levels in weeks of chronic dosing in rats) of 50 mg/kg/day (0.2- to 1.2-fold effect at human systemic exposure based on AUC comparisons) Testicular toxicity was dosed after chronic dosing in mice (104 weeks) and dogs (26 weeks). of 600 mg/kg/day (0.4 to 2.4 times the human AUC) and 150 mg/kg/day (1.7. to 10.2.) observed x the human AUC).
HIV-infected patients In HIV-infected patients, the most frequently reported adverse reactions for famciclovir (500 mg twice daily; n=150) and aciclovir (400 mg, 5 times daily; n=143) were headache (16.7% vs .4%), nausea (10.7% vs. 12.6%), diarrhea (6.7% vs. 10.5%), vomiting (4.7% vs. 3.5%), fatigue (4th .0% vs. 2.1%) and abdominal pain (3.3% vs. 5.6%).
Famciclovir had no effect on general reproductive performance or fertility in rats at doses up to 1000 mg/kg/day (3.6 to 21.6 times the human AUC). Two placebo-controlled studies enrolling a total of 130 healthy men with a normal sperm profile for an 8-week baseline and recurrent genital herpes who received oral therapy with famvir (250 mg b.i.d.) (n=66) or placebo (n=64) for 18 weeks showed no evidence for significant effects on sperm count, motility, or morphology during treatment or during an 8-week follow-up.
Pregnancy Teratogenic Effects - Pregnancy Category B: Famciclovir B: Famciclovir has been evaluated for effects on embryofoetal development in rats and rabbits at oral doses up to 1000 mg/kg/day (approximately 3.6- to 21.6-fold and 1.8- to 10.8-fold the human systemic dose of penciclovir) tested exposure based on AUC comparisons for rats and rabbits, respectively) and intravenous doses of 360 mg/kg/day in rats (2 to 12 times the human dose based on body surface area [BSA] area comparisons) or 120 mg/kg/day in rabbits (1.5 to 9.0 times the human dose [BSA]). No adverse effects on embryo-foetal development were observed. Likewise, after intravenous administration of penciclovir in rats (80 mg/kg/day, 0.4 to 2.6 times the human dose [BSA]) or rabbits (60 mg/kg/day, 0.7 to 4, 2 times the human dose [BSA]) no side effects observed human dose [BSA]). However, there are no adequate and well-controlled studies in pregnant women. Because animal reproductive studies do not always predict a response in humans, famciclovir should be used during pregnancy only if the benefit to the patient clearly outweighs the potential risk to the foetus. Pregnancy Exposure Registry: Registry: The Novartis Pharmaceuticals Corporation maintains a Famvir Pregnancy Registry to monitor maternal-fetal outcomes in pregnant women exposed to TotoFamvir. Physicians are encouraged to schedule their patients by calling (888) 669-6682.
Breast-feeding mothers Following oral administration of famciclovir to lactating rats, penciclovir was excreted in breast milk at levels higher than those observed in plasma. It is not known if it is excreted in breast milk. No data available
Store at 25°C (77°F); allowable deviations at 15-30°C (59-86°F) [see USP Controlled Room Temperature].
REV: MÄRZ 2004 Hergestellt von: Novartis Farmacéutica S.A. 08210 Barberà del Vallès Barcelona, Spanien Vertrieb durch:
on the safety of Famvir in infants.
Use in children Safety and effectiveness in children under 18 years of age have not been established.
Novartis Pharmaceuticals Corp. East Hanover Hannover, NJ 07936 ©Novartis
For recurrent genital herpes, FAMVIR stops pain and burning in a median of 2 days or less with episodic episodic therapy* 1 ®
<0.006; burning sensation: 1.7 vs. 2.1, P<0.001) <0.001) • Median time (days) to cessation vs. placebo (pain: 2.0 vs. 2.4, P<0.006;
FAMVIR keeps patients on suppression therapy relapse-free for almost a year2,3 <0.001)2 • Median time to first relapse was 336 days with FAMVIR versus 47 days with placebo (p<0.001) • The safety and efficacy of FAMVIR on suppression therapy has been established established no longer than 1 year
In herpes zoster‡§4.5 4.5 FA only FAMVIR MVIR was shown to reduce the median duration of PHN by 100 days compared to placebo‡§
• For patients ≥ 50 years of age FAMVIR (famciclovir) tablets are indicated for the treatment or suppression of recurrent genital herpes in immunocompetent, immunocompetent patients; patients; the treatment of recurrent recurrent herpes simplex skin infections in HIV-infected HIV-infected patients; and the treatment of acute herpes zoster (shingles). In clinical trials, the most commonly reported adverse event compared to placebo was headache (zoster: 22.7% vs. 17.8%; episodic: 23.6% vs. 16.4%; suppression: 39.3% vs. 42.9 %); nausea (zoster: 12.5% vs. 11.6%; episodic: 10.0% vs. 8.0%; suppression: 7.2% vs. 9.5%); and diarrhea (zoster: 7.7% vs. 4.8%; episodic: 4.5% vs. 7.6%; suppression: 9.0% vs. 9.5%). The efficacy of FAMVIR has not been established for initial episodes of infection with genital herpes, ophthalmic zoster, disseminated zoster or in immunocompromised patients with herpes zoster. Genital herpes is not curable. There is no evidence that FAMVIR can prevent transmission of herpes to other people. FAMVIR, Pregnancy Category B, is contraindicated in patients with known hypersensitivity to the product, its components or DENAVIR® (penciclovir cream). See Summary of Prescribing Information on previous page. *In patients with moderate to severe genital herpes. †
In clinical trials administering drugs up to 6 hours after onset of symptoms or injury. No significant difference in overall incidence of PHN for famciclovir versus placebo. No statistically significant difference in the duration of PHN was observed in patients < 50 years. § Therapy should be started as soon as herpes zoster is diagnosed. The effectiveness of treatment started more than 72 hours after the onset of the rash has not been established. ‡
References: 1. Data on file, Novartis Pharmaceuticals Corp. 2. Diaz-Mitoma F, Sibbald RG, Shafran SD, et al, for the Collaborative Famciclovir Genital Herpes Research Group. Oral famciclovir for suppression of recurrent genital herpes: a randomized controlled trial. JAMA JAMA.. 1998;280:887-892. 3. Tyring SK, Diaz-Mitoma F, Shafran SD, et al. Oral famiciclovir for suppressing recurrent genital herpes:
the combined data from two randomized controlled trials. J. Cutan Med Surg. 2003;7:449-454. 4. Tyring S, Barbarash RA, Nahlik JE, et al, and the Collabo Collaborative Rative Famciclovir Herpes Zoster Study Group. Famciclovir for the treatment of acute herpes zoster: effects on acute illness and postherpetic neuralgia: a randomized, double-blind, placebo-controlled study. Ann Intern Med. 1995;123:89-96. .1995;123:89-96. 5. Dworkin RH, Boon RJ, Griffin DRG, Phung D. Postherpetic neuralgia: effects of famciclovir, age, rash severity, and acute pain in patients with herpes zoster. J Infection Dis. 1998; 178 (Supplement 1): S76-S80.
FAMVIR is a registered trademark of Novartis. ©2005 Novartis
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Diagnostic Gems - Photos with Dermoscopy Jay S. Gottlieb, DO, FAOCD, Amy D. Gottlieb, PA-C
When we discuss with our patients the need for a biopsy of a pigmented lesion, we often take a digital photo of the lesion and show the photo to the patient. We enlarge the photo and show the variation that was abnormal at the time, which is a cause for concern. This is a great way to educate our patient about the change in pigmented lesions and reassure them that there is a real reason to have the procedure done. We use a 5.0 megapixel Canon Power Shot 500 Digital Elph camera in our office. If we enlarge the photo, the image quality decreases, but the anomaly becomes more obvious. In April 2005 we bought and used a 3rd generation Dermlite 00 ProHR. Dermoscopy has become a real asset in our practice. We now feel much more comfortable when making the decision to biopsy a pigmented lesion. lesion We have chosen not to spend the money it takes to buy a quality dermatoscopy camera. Today we decided to try something new. We took a digital photo of a pigmented lesion through our Dermlite without using any special equipment. Attachments. We were amazed at what we found and what we can now show our patients. We will use this procedure regularly in our practice from this point on. We hope some readers find it as fascinating as we do!
Figure 1 Macro Digital macro photography in normal mode and then 4x digital magnification as seen on the digital camera screen.
Figure 2 Digital photo of the same lesion in Figure 1 taken by holding our camera against the Dermlite 00 ProHR ProHR and then a 4x digital magnification of the same lesion as seen on the digital camera screen.