Inpatient dermatopathology. Inpatient dermatopathology. Inpatient dermatopathology: Histologic patterns that matter most

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1 Inpatient dermatopathology: Histologic patterns that matter most Beth S. Ruben, M.D. Associate Clinical Professor University of California, San Francisco Departments of Dermatology and Pathology Dermatopathology Section Inpatient dermatopathology Impatient dermatopathology Results needed quickly Diagnosis often affects further workup and treatment decisions Diagnosis may significantly affect the outcome of hospitalization Several clinical and histologic themes are most frequent Clinicopathologic correlation crucial Inpatient dermatopathology Case-based approach Illustrate recurrent themes in this area vasculopathy, drug reaction, infection Discuss the differential diagnosis of various histologic patterns Describe additional ways to resolve histologic differential diagnoses 1

2 Case 1 79 y.o.. Caucasian woman presented to an outside hospital with blood in her urine and intermittent nosebleeds 8 days later developed painful 5 cm ecchymoses on her abdomen and right elbow PMH: HTN, mild renal insufficiency, PVD Six weeks prior to presentation, she began Coumadin (warfarin)) for treatment of bilateral deep vein thromboses Courtesy of Drs. Lindy Fox, Jackie Dolev 2

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4 Diagnosis: Thrombotic vasculopathy Warfarin-induced cutaneous necrosis Late onset Thrombotic vasculopathy: Small vessel pseudovasculitis pseudovasculitis Hypercoagulable states Warfarin, heparin, enoxaparin induced necrosis Protein C, protein S, antithrombin III deficiency Lupus anticoagulant (anti-cardiolipin antibody syndrome) Disseminated intravascular coagulation, purpura fulminans Calciphylaxis Infection (septic vasculitis) Embolic phenomenon (cholesterol, infectious) Livedo vasculopathy (atrophie blanche) Carlson JA, Chen KR. Cutaneous pseudovasculitis. Am J Dermatopathol Feb;29(1):

5 Calciphylaxis 5

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8 von Kossa (calcium) 8

9 Thrombotic vasculopathy: Infectious Septic vasculitis Histologic findings can range from pauci-inflammatory thrombotic to a pattern which overlaps with LCV In general, it is difficult to find the causative organism histologically: Meningococcemia: organisms difficult to identify in tissue (blood culture better) Gonococcemia: organisms rarely identifiable (better to culture mucosal source of infection, smear from pustule) Rickettsial: not identifiable in tissue except by immunofluorescence or immunoperoxidase BCG immunostain, PCR may help but slow 9

10 Leukocytoclastic vasculitis Differential diagnosis: Leukocytoclastic vasculitis (LCV), small vessel Palpable purpura Inflammatory, versus relatively noninflammatory for thrombotic vasculopathy Neutrophils, and also nuclear dust, eosinophils Earliest changes may mimic urticaria When vessel damage is severe, thrombi may result Underlying causes may overlap with thrombotic vasculopathy (i.e., connective tissue disease) DIF and ANCA are some adjunctive studies 10

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12 Case 2 55 yo man with disseminated anaplastic large T-cell lymphoma, in CR after 4 cycles of ICE (ifosphamide, carboplatin, etoposide) Day 10 s/p autologous stem cell transplant after BEAM conditioning (BCNU, etoposide, cytarabine, melphalan) Neutropenia day 8 Several week history of reddening of lesions on scalp, some present for 2 years One week of pruritic lesions on forearms 12

13 Courtesy of Dr. Linda Chang 13

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15 Starburst cell Diagnosis: Drug reaction, due to chemotherapy Ultraviolet enhancement/recall Chemotherapy reactions (dysmaturation) Clinically, variable (including acral erythema) Histologically, keratinocyte dysmaturation, nuclear pleomorphism, loss of polarity, vacuolar interface change, starburst mitoses in etoposide Very difficult to distinguish from early graft versus host disease (GVHD) Time course critical Evolution, and assessment of other target organs Lymphocytic infiltrate more common in GVHD May need progressive biopsies Common agents: cyclophosphamide, etoposide, busulfan, thiotepa, cytarabine, docitaxel, CyA Castano E et al. J Cutan Pathol Nov;29(10): Henry LB, Horn TD. J Cutan Pathol Nov;29(10):

16 UV enhancement or recall reaction Similar to radiation recall Enhancement: drug administered soon after UV exposure (days); sunburn-like Recall: drug administered weeks to months later; pruritus, macules, papules Histology identical to other chemotherapy reactions (distribution is the clue) Goldfeder KL et al. Ultraviolet recall reaction after total body irradiation, etoposide, and methotrexate therapy. J Am Acad Dermatol Mar;56(3): Graft versus host disease (GVHD) Occur with allografts, autografts, organ transplantation Several stages (Lerner grades I-IV): Lerner I: basal vacuolar change Lerner II: dyskeratotic cells in epidermis, follicle, dermal lymphocytic infiltrate Lerner III: fusion of basilar vacuoles to forms clefts Lerner IV: separation of epidermis from dermis (TEN-like) Horn TD. J Cutan Pathol. 1994; 21: Kohler S et al. Am J Surg Pathol Sep;21(9): Courtesy, Dr. Janet Maldonado 16

17 GVHD versus drug eruption Both may have a subtle interface reaction May be impossible to distinguish reliably Time course, internal involvement Histologic clues favoring GVHD Lymphocytic infiltrate more pronounced Involvement of the adnexa Eosinophils not a helpful feature Horn TD. J Cutan Pathol. 1994; 21: Kohler S et al. Am J Surg Pathol Sep;21(9):

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22 Drug reactions (continued): Morbilliform drug eruption (ddx: viral exanthem) Stevens-Johnson (SJS), toxic epidermal necrolysis (TEN) Acute generalized exanthematous pustulosis (AGEP) Drug hypersensitivity syndrome (DHS/ DRESS ) Pseudolymphoma syndrome Other chemotherapy reactions: Acneiform/pustular eruptions (epidermal growth factor inhibitors, erlotinib) Neutrophilic eccrine hidradenitis Nigen S, Knowles SR, Shear NH. Drug eruptions: approaching the diagnosis of drug-induced skin diseases. J Drugs Dermatol Jun;2(3): Acute generalized exanthematous pustulosis (AGEP) Acute generalized exanthematous pustulosis (AGEP) Very similar and often indistinguishable from pustular psoriasis Some patients have a predisposition to psoriasis Clinical scenario essential (drug history) Antibiotics, esp. PCN, cephalosporins, macrolides Tends to have a rapid onset (days) and is self-limited (weeks) Key histologic features Subcorneal neutrophilic pustules Subepidermal edema Eosinophils usually present Rare vasculitis DDX: pustular psoriasis, impetigo, dermatophyte, Candida 22

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25 Case 3 13 year old boy admitted for his 3rd bone marrow relapse of acute lymphocytic leukemia Multiple bacterial and fungal infections in past Had re-induction chemotherapy and fludarabine for 5 days with no response, with pancytopenia Pt was febrile despite broad spectrum antibiotics and antifungals On hospital day 18, he developed skin lesions Courtesy of Drs. Sarah Arron, Erin Mathes Differential Diagnosis Septic emboli Fungal Bacterial Atypical mycobacteria Leukemia cutis Vasculitis Neutrophilic dermatoses 25

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27 PAS-D stain 27

28 Diagnosis: Disseminated fungal infection in an immunosuppressed patient Disseminated Trichosporon asahii (culture-proven) 28

29 Histologic patterns of infection Subcorneal acantholysis (SSSS) Pustular (impetigo, dermatophyte, Candida, etc.) Psoriasiform lichenoid (syphilis) Suppurative Suppurative and granulomatous Granulomatous Panniculitis Vasculitic/thrombotic Staphyloccal scalded skin syndrome 29

30 Subcorneal acantholysis DDX: Superficial pemphigus 30

31 missing stratum corneum sign Toxic epidermal necrolysis 31

32 Full thickness epidermal necrosis Erythema multiforme/ Stevens-Johnson syndrome 32

33 Disseminated coccidioidomycosis 33

34 Suppurative/granulomatous, Pseudocarcinomatous hyperplasia 34

35 PAS stain 35

36 Other techniques to find microorganisms BCG immunoperoxidase stain polyclonal anti-mycobacterium bovis (BCG) Detects a wide variety of micro-organisms, including mycobacteria, fungi, and bacteria Not virus, spirochetes, protozoa, Leishmania Treponema pallidum immunostain Spirochetes, bacteria Rickettsia immunostain, and immunofluorescence PCR analysis (slow) Most microorganisms; Leishmania available Secondary syphilis (lues) Psoriasiform lichenoid 36

37 Treponema pallidum immunostain Hoang MP, High WA, Molberg KH. Secondary syphilis: a histologic and immunohistochemical evaluation. J Cutan Pathol Oct;31(9):

38 African Tick Bite Fever: Rickettsia africae Owen CE et al. African tick bite fever: a not-souncommon illness in international travelers. Arch Dermatol Oct;142(10): Courtesy of Dr. Lindy Fox 38

39 Rickettsia immunostain Courtesy, Dr. David Walker Dumler JS et al. Rapid immunoperoxidase demonstration of Rickettsia rickettsii in fixed cutaneous specimens from patients with Rocky Mountain spotted fever. Am J Clin Pathol Mar;93(3):

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