Inflammatory Dermatopathology: Financial Relationships

3/27/2017

Disclosure of Relevant Inflammatory Dermatopathology: Financial Relationships

A Case‐based Update USCAP requires that all planners (Education Committee) in a position to Claudia I. Vidal, M.D., Ph.D. influence or control the content of CME disclose any relevant financial Associate Professor of relationship WITH COMMERCIAL INTERESTS which they or their Dermatology and Pathology spouse/partner have, or have had, within the past 12 months, which relates to Department of Dermatology Saint Louis University School of Medicine the content of this educational activity and creates a conflict of interest.

Case 1 DISCLOSURE OF RELEVANT RELATIONSHIPS WITH INDUSTRY

No relevant disclosures

53 year old male with metastatic melanoma Nivolumab currently being treated with Nivolumab

• Human IgG4 anti–programed cell death 1 (PD‐1) antibody • Approved for the treatment of advanced melanoma, advanced non‐small cell lung cancer, advanced renal cell carcinoma and classical Hodgkin lymphoma • Works by activating the immune response against cancer cells • Member of the novel class of drugs known as immune checkpoint inhibitors (ICIs) – Other similar agents include • Anti–cytotoxic T‐lymphocyte–associated antigen 4 (CTLA‐4) • Anti–programmed death ligand 1 (PD‐L1) inhibitors

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Dermatologic Toxicity From Anti‐PD‐1 Therapy • • Occurs in 14‐40% of patients Histologically appears as a lichenoid – Less than that seen in patents treated with anti‐CTLA‐4 (47‐68%) dermatitis • Classically manifests as a faintly erythematous and maculopapular rash, involving the trunk and extremities (head, palms, and soles are often spared), and may be pruritic – Parakeratosis – Appears weeks to months following therapy and are not does dependent • Vitiligo is also common – Perivascular/ periadnexal inflammation – Incidence between 8‐25% – Has delayed appearance after several months of treatment – Eosinophils – Seen exclusively in patients being treated for melanoma • Other dermatologic adverse events include xerosis (5.3%), alopecia (2%), stomatitis (1.5%), • Unsure if lichenoid eruption is secondary to urticaria (1.4%), photosensitivity (1.4%), hyperhidrosis (0.9%), skin exfoliation (0.7%) antigen unmasking, neoantigen created by • Case reports of exacerbation and new onset psoriasis, bullous pemphigoid, lupus, etc. • Early studies suggest an association with cutaneous toxicity and positive outcome antibody, or generalized immune upregulation

Dermatologic complications of anti‐PD‐1/PD‐L1 immune checkpoint antibodies. Curr Opin Oncol. 2016 Jul;28(4):254‐63. Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Lichenoid Dermatologic Toxicity From Immune Checkpoint Blockade Therapy: A Detailed Examination of the Clinicopathologic Features. Am J Dermatopathol. 2017 Therapy. Front Pharmacol. 2017 Feb;8:49. Feb;39(2):121‐129.

Take home points Case 2 • ICIs can be added to the ever growing list of medications that induce a lichenoid drug reaction • Mnemonic “HANG PIC” HCTZ Antimalarials / Allopurinol / Anti –TNF / Anti‐CD20 Naproxen/NSAIDS Gold Penicillamine / Phenothiazine ICIs (immune checkpoint inhibitors) Captopril / ACEI / Ca Channel blockers

4 month old infant; r/o viral, mast cell, LCH

Courtesy of Dr. Elaine C. Siegfried Courtesy of Dr. Cirilo Sotelo‐Avila, MD

2 3/27/2017

Dx: Superficial and deep perivascular dermatitis

Additional photos

T. pallidum IHC

• Acquired Syphilis 1. Primary –painless chancre, 21 days after sexual exposure • Caused by spirochete T. 2. Secondary – mucocutaneous, condyloma lata lesions 4‐8 weeks pallidum after • T. Pallidum IHC (sensitivity of 71% versus 41% Warthin‐Starry stain) • Histopathology – *Interstitial inflammation – *Vascular changes – endothelial cell swelling – Elongated rete ridges – Plasma cells variable – Epidermal changes (spongiosis, psoriasiform, lichenoid reaction) – Exocytosis of neutrophils 3. Latent –no signs or symptoms 4. Tertiary – cardiovascular, CNS, skeleton, less likely skin (nodular or chronic gummatous ulcer)

https://en.wikipedia.org/wiki/History_of_syphilis Histologic features of secondary syphilis: A multicenter retrospective review. J Am Acad Dermatol. 2015 Dec;73(6):1025‐30.

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Congenital syphilis • Transplacental infection • Diagnosis: immunoblotting for T. palladium‐specific IgM • Early or late • Early – Prematurity – Low birth weight – Rhinorrhea – Mucocutaneous lesions • Macular rash, vesiculobullous or scaling lesions predominantly on palms and soles • Condyloma lata Incidence in the US has more than doubled since its lowest recoded rate in 2000

Why are the rates of syphilis climbing again? • Increase of infection in medically hard to reach groups, with partners difficult to locate • Growing role of technology in people’s sex lives –apps that facilitate casual sex • Most Americans don’t think of it as a threat since the worst epidemics happened centuries ago, when the infection had no known cause or cure • Syphilis can be difficult to recognize or can go unnoticed, especially if the chancre (the primary lesion of syphilis) presents on a non‐ genital location and because the chancre is painless

Take home points • Syphillis is not new but rising • Remember to consider syphilis in your differential diagnosis as many of the histologic features are subtle • T. Pallidum IHC (71% versus 41% Warthin‐Starry stain) • As a result of this case we changed our comment for cases signed out as “Superficial and deep perivascular dermatitis” – COMMENT: The histological differential diagnosis is extensive and includes a viral / rickettsial infection an infectious related exanthem, a drug eruption, gyrate erythemas, connective tissue disorder, and less likely lymphoma/leukemia cutis. Clinical correlation is recommended. https://www.cdc.gov/hiv/risk/oralsex.html http://www.johnyfit.com/can‐i‐get‐hiv‐from‐oral‐sex/

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A 65 year old male; clinical history r/o med vessel Case 3 vasculitis, thromboembolic, infectious

Courtesy of Dr. M. Yadira Hurley

Courtesy of Dr. M. Yadira Hurley

Ecthyma Gangrenosum

• Generally accepted definition = Severe variant of ecthyma present in 5% of immunosuppressed individual and is 2/2 septicemia with Pseudomonas aeruginosa • Erythematous macule or patch that becomes vesicular and develops into a gangrenous ulcer with an erythematous halo • Histopathology – Necrosis of epidermis and dermis with hemorrhage into the dermis – Mixed inflammatory infiltrate surrounds infarcted region

Tissue culture: Fusarium spp. – Vascular thrombosis present at the margins

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Ecthyma‐like Take home points • Disease not limited to infection by Pseudomonas or • There are cases in the literature that have immunocompromised as once thought been reported in immunocompetent patients, • Skin infection of various etiologies can lead to not associated with septicemia and other vasculitis and local skin necrosis bacterial or fungal microorganisms • Thus, the disease should be defined by clinical and • EG is not new but there is a call for acceptance histologic features not determined by the etiologic of a broader definition of the disease agent

Ecthyma gangrenosum and ecthyma‐like lesions: review article. Eur J Clin Microbiol Infect Dis. 2015 Apr;34(4):633‐9. The Concept of Ecthyma Gangrenosum Illustrated by a Fusarium oxysporum Infection in an Immunocompetent Individual. Mycopathologia. 2016 Oct;181(9‐10):759‐63.

38 year old female with painful Case 4 “bumps” at right abdomen

Courtesy of Dr. Sofia Chaudhry

6 3/27/2017

The rest of the story… • Using insulin pump • Four weeks ago started on exenatide injections

Exenatide Panniculitis Take home points • Exenatide is a glucagon‐like peptide‐1 receptor agonist that is administered once‐weekly subcutaneously in a long‐acting, formulation • Don’t be afraid to use all the resources – Utilizes a PLG [poly(D,L‐lactide‐co‐glycolide)] microsphere available to you technology • Panniculitis with new foreign body with • Causes a lobular or mixed lobular and septal panniculitis consisting of lymphocytes, histiocytes, and eosinophils rather characteristic morphology and possibly • Injected material, that appears as slightly retractile, rounded staining pattern structures corresponding to the injected microspheres of PLG – Only occasionally found depending on the timeframe of biopsy as microspheres degrade

Exenatide‐Induced Eosinophil‐Rich Granulomatous Panniculitis: A Novel Case Showing Injected Microspheres. Am J Dermatopathol. 2015 Oct;37(10):801‐2.

60 year old female; r/o calciphylaxis, nephrogenic Case 5 system fibrosis, focal anasarca, other

Courtesy of Dr. Eddy Prodanovic

7 3/27/2017

Calciphylaxis • Also known as calcific uremic arteriolopathy, calcifying • Pathogenesis: panniculitis, uremic gangrene syndrome – Activation of the NF‐KB pathway • Lethal variant of metastatic calcification – Treatment: inhibitors of the RANKL‐RANK‐NF‐KB pathway • Incidence is 4.5 per 1 million / Prevalence in patients on (bisphosphonates, recombinant osteoprotegerin) hemodialysis is 4.1% – Diagnosis based on wedge biopsy – Net‐like pattern on plain radiographs (90% specific) • Usually seen after the onset of end stage renal disease • Mortality rate 60‐80% related to wound infection, sepsis with secondary hyperparathyroidism and organ failure – Hypercoagulable state • Surgical debridement is associated with improved survival – Obesity – Systemic steroids Calciphylaxis: Controversies in Pathogenesis, Diagnosis and Treatment. Am J Med Sci. 2016 Feb;351(2):217‐27.

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Histopathology

• Epidermal ulceration, focal dermal necrosis and vascular calcification • Calcification involves small to medium vessels particularly in the subcutis • Intimal fibroblastic proliferation • Microthrombi / Fibrin thrombi in smaller vessels • Extracellular soft tissue calcification / Calcifying panniculitis • *Perieccrine calcification • * Von Kossa or Alizarin red for subtle calcification • Rule out Mönckeberg's sclerosis • Elderly patients • Small amount of calcification in small vessels w/o thrombosis

Cutaneous calciphylaxis: a retrospective histopathologic evaluation. Am J Dermatopathol. 2013 Jul;35(5):582‐6.

Take home points Cases 6 and 7 • Perieccrine calcification is rare but highly specific • Special stain Von Kossa or Alizarin red for subtle calcification • Excisional biopsy (wedge) at a site where the edge of the necrotic eschar, the livedoid area, and the indurated skin can all be simultaneously captured to include subcutaneous tissue

25 year old female with progressive hyperpigmented nodular plaques

Courtesy of Dr. Patricia Missall

9 3/27/2017

40 year old female with discoloration/nodules on buttocks/hips A) Left low back B) Left lateral thigh C) Left anterior thigh following buttock augmentation with sesame oil

A C

B

Courtesy of Dr. Hala Adil

10 3/27/2017

GMS negative Fite negative

Amateur Silicone Injection Reported Adverse Events • Adverse reactions • Immediate (seconds to hours) – related to the filler product itself – Bleeding, Vessel Occlusion, Necrosis, Embolization, Sudden Death, Multiorgan System Failure, Acute pneumonitis, Alveolar Hemorrhage, Respiratory Failure • most injectable fillers are particulate or break down into particulates upon injection • Early (days to weeks) • size, shape, mechanical properties and surface chemistry of the particulates – Inflammatory nodules, Infection (bacterial, AFB), Migration, Angioedema, Lymphadenitis are known to influence their in vivo performance • Late (months to years) – Migration: smaller – Amount of inflammatory cytokines (TNF): phagocytosis – Granulomas – Surface chemistry: inflammatory response – Recurrent Cellulitis – Shape: angular forms lead to more foreign body response – Morphea‐like changes – procedural techniques – Reactive Amyloidosis (28 years latent) – concentration of the product – Auto‐Inflammatory Syndrome Induced by Adjuvants – presence of impurities – End organ Toxicity – Autoimmune Dz, Hypercalcemia due to granuloma

Adverse cutaneous reactions to soft tissue fillers‐‐a review of the histological features. J Cutan Pathol. 2008 Jun;35(6):536‐48.

What is the cause of the late Lipogranuoloma appearing reticular cutaneous pattern? • Incidence is likely higher with improper technique and materials • Described in the literature in the gluteal region, limbs, male and • Rare report of sesame oil injections causing female breast, orbital region, abdomen and male genitalia vasculitis for which the authors postulated was • Hotel/House parties (aka “pumping parties”) secondary to an allergic reaction – Patient 5 injected Silicone and Hydrogel – Patient 6 injected Sesame oil • Migration of filler along septae in the SQ • Muscle augmentation as an alternative or additive to intramuscular injections of steroids where it can cause muscle necrosis, fibrosis and atrophy • Mass effect – Diminished blood flow secondary to amount of substance injected or exuberant inflammatory response Bodybuilder oleoma. Br J Dermatol. 2003 Dec;149(6):1289‐90. Irreversible muscle damage in bodybuilding due to long‐term intramuscular oil injection. Int J Sports Med. 2012 Oct;33(10):829‐34. Subcutaneous oleomas induced by self‐injection of sesame seed oil for muscle augmentation. J Am Acad Dermatol. 2000 Feb;42(2 Pt 1):292‐4. Bodybuilding, sesame oil and vasculitis. Rheumatology (Oxford). 2005 Sep;44(9):1135.

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Take home points Important Information Regarding CME/SAMs • Popularized dangerous trends can be sources for inflammatory dermatoses • Pumping parties are a dangerous way to obtain curves The Online CME/Evaluations/SAMs claim process will only be available on the USCAP website until September 30, 2017. • Cutaneous reactions may occur at sites distant from injected sites as a result of migration of the filler No claims can be processed after that date! substance • There may also be a lapse of months to years prior to After September 30, 2017 you will NOT be able to obtain any the development of acutaneous reaction CME or SAMs credits for attending this meeting. • Reticular pattern can be a late manifestation

Thank you

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