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Clinicopathologic Case Studies

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Clinicopathologic Case Studies

  1. 1. Interesting and Unusual Clinicopathologic Case Studies Narayan S. Naik, MD Finan Templeton Dermatopathology Associates
  2. 2. Overview <ul><li>Case History </li></ul><ul><li>Clinical Photos </li></ul><ul><li>Pathology </li></ul><ul><li>Additional Studies </li></ul><ul><li>Diagnosis and Discussion </li></ul><ul><li>Treatment </li></ul>
  3. 3. Overview <ul><li>Importance of adequate biopsy </li></ul><ul><li>Importance of clinicopathologic correlation </li></ul><ul><li>Importance of correlation with laboratory and culture studies </li></ul>
  4. 4. CASE 1
  5. 5. CASE 1 <ul><li>71 y/o Cauc M with a six month hx of “sores” on left dorsal hand and left wrist </li></ul><ul><li>No improvement with two courses of antibiotics </li></ul><ul><li>PMHx: hx renal transplant for chronic ESRD </li></ul><ul><li>SocHx: +fisherman, no hx gardening or pets </li></ul>
  6. 20. PAS
  7. 22. CASE 1 Tissue Culture Results <ul><li>Cultures for bacterial and mycobacterial organisms showed no growth </li></ul><ul><li>Fungal culture grew yeast-like colonies of Prototheca wickerhamii </li></ul>
  8. 23. CASE 1 Diagnosis? Cutaneous Protothecosis
  9. 24. Cutaneous Protothecosis <ul><li>Caused by achlorphyllic algae Prototheca </li></ul><ul><ul><li>Rare cause of infection in humans </li></ul></ul><ul><ul><li>Majority caused by P. wickerhamii species </li></ul></ul><ul><li>Infections mainly seen in immunocompromised individuals </li></ul><ul><ul><li>Localized cutaneous or subcutaneous infection </li></ul></ul><ul><ul><li>Disseminated disease </li></ul></ul><ul><ul><li>Olecranon bursitis secondary to Prototheca may be seen in immunocompetent individuals </li></ul></ul><ul><li>Usually a history of trauma with exposure to contaminated water </li></ul>
  10. 25. Cutaneous Protothecosis <ul><li>Histopathology: </li></ul><ul><ul><li>Spherical to ovoid organisms with thick cell wall </li></ul></ul><ul><ul><li>Divide by internal septation (endosporulation) with characteristic morula forms </li></ul></ul><ul><ul><li>May be difficult to see on H&E but stain well with fungal stains (PAS, GMS) </li></ul></ul><ul><li>Culture: </li></ul><ul><ul><li>White yeast-like colonies on SDA at 30 0 C </li></ul></ul><ul><ul><li>Organisms with sporangia can be identified on lactophenol cotton blue stained wet preps </li></ul></ul><ul><ul><li>Commercially available biochemical assimilation tests to identify specific species </li></ul></ul>
  11. 26. Cutaneous Protothecosis <ul><li>Treatment: </li></ul><ul><ul><li>May be difficult </li></ul></ul><ul><ul><li>No standard regimen </li></ul></ul><ul><ul><li>Surgical excision for localized lesions </li></ul></ul><ul><ul><li>Amphotericin B or ketoconazole +/- tetracycline </li></ul></ul>
  12. 28. CASE 2
  13. 29. CASE 2 <ul><li>78 y/o Cauc M inpatient with a three day hx of worsening “cellulitis” on right forearm associated with fever </li></ul><ul><li>Site of previous intravenous catheter </li></ul><ul><li>PMHx: AML s/p chemo with neutropenia on broad spectrum antibiotics </li></ul><ul><li>Several aerobic and anaerobic blood cultures had been negative </li></ul>
  14. 37. PAS
  15. 38. PAS
  16. 39. PAS
  17. 40. GMS
  18. 42. CASE 2 Tissue Culture Results <ul><li>Cultures for bacterial and mycobacterial organisms showed no growth </li></ul><ul><li>Fungal culture grew Rhizopus sp . </li></ul>
  19. 43. CASE 2 Diagnosis? Cutaneous Zygomycosis
  20. 44. Cutaneous Zygomycosis <ul><li>Opportunistic infection caused by Rhizopus, Mucor, or Absidia species </li></ul><ul><li>Risk factors: diabetes (esp DKA), other metabolic acidosis, burns, organ transplants, hematologic malignancies with neutropenia </li></ul><ul><li>Clinical infections may be subdivided (rhinocerebral, pulmonary, hematogenous, gastrointestinal, and cutaneous) </li></ul>
  21. 45. Cutaneous Zygomycosis <ul><li>Cutaneous infections </li></ul><ul><ul><li>Primary – rare, may be seen in contaminated dressings, burns, IV catheter sites </li></ul></ul><ul><ul><li>Secondary – hematogenous seeding from lesion elsewhere in body </li></ul></ul><ul><li>Typical presentations: </li></ul><ul><ul><li>Indurated tender plaque with dusky purpuric center </li></ul></ul><ul><ul><li>Necrotizing cellulitis </li></ul></ul><ul><ul><li>Echthyma gangrenosum like lesions </li></ul></ul>
  22. 46. Cutaneous Zygomycosis <ul><li>Histopathology: </li></ul><ul><ul><li>Suppuration and necrosis, occasionally only minimal inflammation </li></ul></ul><ul><ul><li>Broad non-septate hyphae with right angle branching </li></ul></ul><ul><ul><li>Angioinvasive with thrombosis and infarction </li></ul></ul><ul><ul><li>Tissue invasion important to demonstrate pathogenicity as Zygomycetes may be frequently cultured from skin surface swabs </li></ul></ul><ul><li>Treatment: </li></ul><ul><ul><li>Surgical debridement </li></ul></ul><ul><ul><li>Treatment of underlying predisposing condition </li></ul></ul><ul><ul><li>Amphotericin B (liposomal more effective) </li></ul></ul>
  24. 49. CASE 3
  25. 50. CASE 3 <ul><li>46 y/o AA M inpatient with one month hx of non-healing right leg ulcers </li></ul><ul><li>? Hx of prior trauma to area </li></ul><ul><li>Unresponsive to broad spectrum antibiotics or local wound care </li></ul><ul><li>PMH: s/p lung transplant on chronic immunosuppressives </li></ul>
  26. 62. GMS
  27. 63. GMS
  28. 64. PAS
  29. 65. PAS
  30. 67. CASE 3 Tissue Culture Results <ul><li>Tissue cultures for bacterial and mycobacterial organisms showed no growth </li></ul><ul><li>Fungal culture: </li></ul>
  31. 73. CASE 3 Diagnosis? Cutaneous Alternariosis (with Candidiasis)
  32. 74. Cutaneous Alternariosis <ul><li>Alternaria are classified as a phaeohyphomycosis – a subset of dematiaceous (pigmented) fungi found in air, soil, and plants </li></ul><ul><li>Alternaria organisms commonly colonize human skin but are rarely pathogenic in humans </li></ul><ul><li>Alternaria alternata is most frequent pathogenic species </li></ul><ul><li>Mixed infection with Candida albicans has been reported 1,2 </li></ul>1 Bang Peterson et al. Arch Dermatol . 1976; 94: 201-207 2 Higashi et al. Arch Dermatol 1973; 108: 558-560
  33. 75. Cutaneous Alternariosis <ul><li>Majority of cases of cutaneous alternariosis have been in immunocompromised patients </li></ul><ul><ul><li>Mainly solid organ transplant recipients </li></ul></ul><ul><ul><li>Relatively rare in HIV/AIDS patients </li></ul></ul><ul><li>Routes of infection: </li></ul><ul><ul><li>Traumatic inoculation </li></ul></ul><ul><ul><li>Colonization of pre-existing lesions such as eczema </li></ul></ul><ul><ul><li>Rarely by hematologic spread, usually from pulmonary infection </li></ul></ul>
  34. 76. Cutaneous Alternariosis <ul><li>Cutaneous lesions: </li></ul><ul><ul><li>Heterogeneous and nonspecific </li></ul></ul><ul><ul><li>Develop most commonly on exposed sites such as lower extremity, forearms, hands, face </li></ul></ul><ul><ul><li>Often have chronic fluctuating course </li></ul></ul>
  35. 77. Cutaneous Alternariosis Histopathology <ul><li>Dermal suppurative and granulomatous inflammation with abscess formation </li></ul><ul><li>Rarely noncaseating sarcoidal-like or plasma-cell rich granulomas may be present </li></ul><ul><li>Overlying ulceration and pseudoepitheliomatous hyperplasia with microabscesses </li></ul>
  36. 78. Cutaneous Alternariosis Histopathology <ul><li>May be present both as both hyphal and spore forms in tissue: </li></ul><ul><ul><li>Broad, septate hyphal forms </li></ul></ul><ul><ul><li>Round to oval thick walled spores </li></ul></ul><ul><ul><li>Pigmented hyphal elements may also stain with Fontana-Masson </li></ul></ul>
  37. 80. Cutaneous Alternariosis Culture <ul><li>Correlation with clinical presentation and histology is important to distinguish between contamination, colonization, and pathogenicity </li></ul><ul><li>Forms brown-black colonies on SDA agar </li></ul><ul><li>Conidia divide in two directions - often resemble “hand grenades” microscopically </li></ul>
  38. 82. Cutaneous Alternariosis Treatment <ul><li>Surgical excision in localized lesions </li></ul><ul><li>Reduction of immunosuppression </li></ul><ul><li>Antifungal agents (IV, oral and intralesional) variably successful </li></ul><ul><ul><li>Amphotericin B </li></ul></ul><ul><ul><li>Itraconazole </li></ul></ul><ul><ul><li>Dosing and duration regimens not established </li></ul></ul><ul><li>Relapses often occur even after prolonged treatments </li></ul>
  39. 84. CASE 4
  40. 85. CASE 4 <ul><li>30 y/o Asian M presented to emergency department with fever, cough, and widespread skin eruption worsening over last two weeks </li></ul><ul><li>PMHx: none </li></ul><ul><li>SocHx: recent immigrant from Thailand </li></ul>
  41. 96. PAS
  42. 97. GMS
  43. 98. GMS
  44. 100. CASE 4 Additional studies and cultures <ul><li>Patient diagnosed as HIV+ , CD4 count: 55 </li></ul><ul><li>Skin tissue cultures for bacterial and mycobacterial organisms were negative </li></ul><ul><li>Fungal culture: </li></ul>
  45. 101. 37 ˚ C yeast 25 ˚ C mold
  46. 102. 25 ˚ C 37 ˚ C Mold Yeast
  47. 103. 37 0 C YEAST
  48. 104. 25 0 C MOLD
  49. 106. CASE 4 Diagnosis? Cutaneous Penicilliosis
  50. 107. Penicilliosis <ul><li>Disseminated fungal infection secondary to Penicillium marneffei, the only pathogenic and thermally dimorphic Penicillium species </li></ul><ul><li>Predilection for reticuloendothelial system with resultant fungemia and infection of mononuclear phagocytes </li></ul>
  51. 108. Penicilliosis <ul><li>Endemic in SE Asia </li></ul><ul><ul><li>Third most common opportunistic infection in the region </li></ul></ul><ul><ul><li>> 80% patients have underlying HIV/AIDS </li></ul></ul><ul><li>Mode of transmission unclear </li></ul><ul><ul><li>Associated with recent exposure to soil especially during rainy season </li></ul></ul><ul><ul><li>Likely mode is ingestion or inhalation of fungal conidiophores </li></ul></ul><ul><ul><li>Animal reservoir: bamboo rat ( Rhizomys species) but no reports of direct transmission </li></ul></ul>
  52. 109. Penicilliosis <ul><li>Systemic signs and symptoms </li></ul><ul><ul><li>Fever, weight loss, anemia </li></ul></ul><ul><ul><li>Pulmonary symptoms / cough </li></ul></ul><ul><ul><li>Lymphadenopathy, hepatosplenomegaly </li></ul></ul><ul><li>Cutaneous lesions: </li></ul><ul><ul><li>Predilection for upper body </li></ul></ul><ul><ul><li>Discrete flesh-colored “molluscoid” papules </li></ul></ul><ul><ul><li>Infrequent papular or ulcerative lesions on mucosal surfaces </li></ul></ul>
  53. 110. “ Molluscoid” lesions in AIDS <ul><li>Molluscum contagiosum </li></ul><ul><li>Cryptococcus neoformans </li></ul><ul><li>Coccidiodes immitis </li></ul><ul><li>Histoplasma capsulatum </li></ul><ul><li>Penicillium marneffei </li></ul><ul><li>Pneumocystis carinii </li></ul><ul><li>Pityrosporum folliculitis </li></ul>
  54. 111. Penicilliosis Histopathology <ul><li>Most common pattern in immunocompromised patients: </li></ul><ul><ul><li>Zones of focal necrosis and suppuration </li></ul></ul><ul><ul><li>Surrounding diffuse infiltration of histiocytes engorged by proliferating yeast </li></ul></ul><ul><li>Differential diagnosis of “parasitized histiocytes” </li></ul>
  55. 112. Differential Diagnosis of “Parasitized Histiocytes” <ul><li>R hinoscleroma </li></ul><ul><li>Hist oplasmosis </li></ul><ul><li>Gra nuloma inguinale </li></ul><ul><li>P enicilliosis </li></ul><ul><li>L eishmaniasis </li></ul><ul><li>L epromatous L eprosy </li></ul><ul><li>“ R avenous Hist iocytes Gra b P acked L unches” </li></ul>
  56. 113. Penicillium marneffei Histoplasma capsulatum
  57. 114. Penicillium marneffei Histoplasma capsulatum
  58. 115. Differentiation between Histoplasmosis and Penicilliosis <ul><li>Clinical features </li></ul><ul><li>Histopathologic features </li></ul><ul><li>Culture characteristics </li></ul>
  59. 116. Histoplasmosis vs. Penicilliosis Clinical Features <ul><li>Histoplasmosis </li></ul><ul><ul><li>Skin involvement INFREQUENT </li></ul></ul><ul><ul><li>Involves lung and reticuloendothelial system </li></ul></ul><ul><ul><li>Predisposition for adrenals and mucosal surfaces </li></ul></ul><ul><li>Penicilliosis </li></ul><ul><ul><li>Skin involvement COMMON </li></ul></ul><ul><ul><li>Involves lung and reticuloendothelial system </li></ul></ul><ul><ul><li>Spares adrenals and infrequently affects mucosal surfaces </li></ul></ul>
  60. 117. Histoplasmosis vs. Penicilliosis Histopathologic Features <ul><li>Histoplasmosis </li></ul><ul><ul><li>2-5 microns </li></ul></ul><ul><ul><li>Uniform round to oval yeast </li></ul></ul><ul><ul><li>Reproduction by budding (narrow neck spore) </li></ul></ul><ul><li>Penicilliosis </li></ul><ul><ul><li>1-8 microns </li></ul></ul><ul><ul><li>Pleomorphic round to sausage shaped yeast </li></ul></ul><ul><ul><li>Reproduction by fission (prominent central wall) </li></ul></ul>
  61. 118. Penicilliosis - Septation Histoplasmosis - Budding
  62. 119. Culture Characteristics Histoplasma Penicillium 25 ˚ C mold 25 ˚ C mold
  63. 120. Culture Characteristics Histoplasma Penicillium
  64. 121. Penicilliosis Treatment <ul><li>High response rate with systemic antifungals </li></ul><ul><ul><li>Amphotericin B followed by oral itraconzaole </li></ul></ul><ul><ul><li>Long term prophylaxis with itraconazole to reduce high relapse rate </li></ul></ul><ul><li>HAART for underlying HIV infection </li></ul><ul><ul><li>May obviate need for long-term antifungal prophylaxis. </li></ul></ul>
  65. 123. CASE 5
  66. 124. CASE 5 <ul><li>69 y/o AA F presents with one year hx of pruritic lesions on arms and upper back, previously diagnosed and treated as prurigo nodules </li></ul><ul><li>Skin lesions have persisted despite treatment with high potency topical and intralesional corticosteroids </li></ul><ul><li>ROS: Patient was seeing a hematologist for evaluation of episodes of bleeding and anemia </li></ul>
  67. 136. PAS
  68. 137. KAPPA
  69. 138. DIF - IgM
  70. 140. CASE 5 Additional Laboratory Studies <ul><li>Hb / Hct: 8.8 / 26.4 </li></ul><ul><li>Serum IgM level: 13.3 g/L (NL 0.45-2.25) </li></ul><ul><li>Serum protein electrophoresis: IgM Kappa monoclonal peak </li></ul><ul><li>Bone marrow bx: diffusely infiltrated by lymphoplasmacytoid cells </li></ul>
  71. 141. CASE 5 Diagnosis? Cutaneous Macroglobulinosis (IgM Storage Papule)
  72. 142. Cutaneous Macroglobulinosis <ul><li>Waldenstrom’s macroglobulinemia – lymphoproliferative d/o with IgM producing lymphoplasmacytoid cells </li></ul><ul><li>Cutaneous manifestations usually non-specific -urticaria, purpura, ulcers </li></ul><ul><li>Two types of specific skin lesions (both relatively rare) </li></ul><ul><ul><li>Infiltrative violaceous plaques </li></ul></ul><ul><ul><li>IgM storage papule </li></ul></ul><ul><li>Usually develop late in course of disease, but may be presenting feature </li></ul>
  73. 143. Cutaneous Macroglobulinosis <ul><li>Infiltrative violaceous plaque </li></ul><ul><ul><li>More common </li></ul></ul><ul><ul><li>Usually on extremities, ears, or face </li></ul></ul><ul><ul><li>Dermal infiltrate of monomorphous lymphoplasmacytoid cells </li></ul></ul><ul><li>IgM storage papule </li></ul><ul><ul><li>Rare </li></ul></ul><ul><ul><li>Extensor surfaces of elbows, knees, buttocks usual locations </li></ul></ul><ul><ul><li>Dermal deposits of monoclonal IgM </li></ul></ul><ul><ul><li>May fluctuate with course of disease </li></ul></ul>
  74. 144. Cutaneous Macroglobulinosis Histopathology <ul><li>Nodular dermal collections of eosinophilic, homogenous material resembling amyloid </li></ul><ul><li>Material is strongly PAS (+) but amyloid stains (-) </li></ul><ul><li>May have associated cellular infiltrate of lymphocytes and lymphoplasmacytoid cells </li></ul><ul><li>Diff Dx: Amyloidosis,colloid milium, erythropoietic protoporphyria, lipoid proteinosis </li></ul>
  75. 145. Cutaneous Macroglobulinosis Additional Studies <ul><li>Immunohistochemistry </li></ul><ul><ul><li>Can demonstrate monoclonal light chain restriction with kappa and lambda stains </li></ul></ul><ul><li>Immunofluorescence </li></ul><ul><ul><li>Deposits of monoclonal IgM strongly positive </li></ul></ul><ul><li>Electron microscopic studies </li></ul><ul><ul><li>Amorphous electron dense granular material </li></ul></ul><ul><ul><li>Non-branching fibrillar material with cross striations </li></ul></ul><ul><ul><li>Distinct from amyloid </li></ul></ul>
  76. 146. Cutaneous Macroglobulinosis Treatment <ul><li>Cutaneous lesions usually respond to treatment of underlying disease and declining serum IgM levels </li></ul><ul><ul><li>Plasmapheresis </li></ul></ul><ul><ul><li>Chemotherapy </li></ul></ul><ul><ul><ul><li>Chlorambucil </li></ul></ul></ul><ul><ul><ul><li>Glucocorticoids, cladribine, cyclophosphamide </li></ul></ul></ul><ul><ul><ul><li>Rituximab </li></ul></ul></ul><ul><ul><li>XRT for localized disease </li></ul></ul><ul><ul><li>Transplantation </li></ul></ul><ul><li>Long term follow-up not available </li></ul>
  77. 148. CASE 6
  78. 149. CASE 6 <ul><li>53 y/o Hisp F presents with four year hx of progressively darkening patches over cheeks </li></ul><ul><li>Patient had used many creams on face without resolution of eruption, unsure of their names </li></ul><ul><li>PMHx: HTN controlled with amlodipine and atenolol </li></ul>
  79. 157. CASE 6 Diagnosis? Exogenous Ochronosis
  80. 158. Exogenous Ochronosis <ul><li>Acquired disorder characterized by deposition of yellow-brown/ocher pigment ( homogentisic acid ) on collagen fibers </li></ul><ul><li>Majority of cases felt to be secondary to extended use of hydroquinone -containing compounds </li></ul><ul><li>Other implicated compounds include phenol, picric acid, mercury, resorcinol, and oral and intramuscular administration of antimalarial drugs </li></ul>
  81. 159. Exogenous Ochronosis <ul><li>Mechanism: local inhibition of homogentisic acid oxidase with subsequent accumulation and polymerization of homogentisic acid on dermal collagen fibers </li></ul><ul><li>No systemic features such as arthropathy or darkening of urine or sweat as in hereditary alkaptonuria (endogenous ochronosis) </li></ul>
  82. 160. Exogenous Ochronosis <ul><li>Clinical presentation: </li></ul><ul><ul><li>Blue-black macules at sites of application </li></ul></ul><ul><ul><li>Malar areas most common but temples, neck, ears may also be affected </li></ul></ul><ul><ul><li>Fine “caviar-like” papules or pigmented colloid milia may develop in some patients </li></ul></ul><ul><li>Epidemiology: </li></ul><ul><ul><li>Vast majority of cases in South African black population </li></ul></ul><ul><ul><li>Relatively uncommon among blacks in America </li></ul></ul><ul><ul><li>Occasionally rare reports in Caucasians and Hispanics </li></ul></ul>
  83. 161. Exogenous Ochronosis Histopathology <ul><li>Similar findings in endogenous and exogenous forms </li></ul><ul><li>Earliest lesions – basophilia of collagen in upper dermis </li></ul><ul><li>Well-developed lesions – Sharply defined irregular, crescentic, or banana-shaped homogenous ocher-colored deposits </li></ul><ul><li>Occasional findings include transepidermal elimination of deposits and associated granulomatous inflammation </li></ul>
  84. 162. Exogenous Ochronosis Treatment <ul><li>Successful treatment is usually difficult </li></ul><ul><li>Most topical preparations, liquid nitrogen, and chemical peels often ineffective </li></ul><ul><li>Dermabrasion, CO 2 laser, and Q-switched ruby and alexandrite lasers have shown success in small numbers of patients </li></ul>
  85. 164. CASE 7
  86. 165. CASE 7 <ul><li>70 y/o Cauc F presents with six month hx of non-pruritic eruption in groin and extremities </li></ul><ul><li>Eruption has been treated as nummular eczema with superimposed impetigo and candidiasis </li></ul><ul><li>Patient has received multiple courses of oral and IM steroids as well as oral antibiotics and antifungals </li></ul><ul><li>ROS: One year hx of weight loss with episodes of diarrhea </li></ul>
  87. 184. CASE 7 Additional Laboratory Studies <ul><li>Glucose: 156 </li></ul><ul><li>AST /ALT: 348 / 171 </li></ul><ul><li>Alkaline Phosphatase: 415 </li></ul><ul><li>Amylase / Lipase: WNL </li></ul><ul><li>Hb / Hct: 9.9 / 29.7 </li></ul><ul><li>Albumin: 2.8 (NL 3.5-5.8) </li></ul><ul><li>Zinc: 75 mg/dl (NL 65-256) </li></ul><ul><li>Glucagon: 3800 pg/ml (NL 50-200) </li></ul>
  88. 185. CASE 7 Additional Laboratory Studies <ul><li>CT scan abdomen – revealed mass in pancreatic neck </li></ul><ul><li>Patient underwent a resection of the mass: </li></ul><ul><li>Pathology: </li></ul>
  89. 189. GLUCAGON
  90. 191. CASE 7 Diagnosis? Necrolytic Migratory Erythema (Glucagonoma Syndrome)
  91. 192. Necrolytic Migratory Erythema <ul><li>Distinctive skin eruption usually associated with glucagon secreting alpha islet cell tumor of pancreas </li></ul><ul><li>Associated features: </li></ul><ul><ul><li>Glossitis/stomatitis/angular cheilitis </li></ul></ul><ul><ul><li>Anemia, weight loss, fatigue, diarrhea </li></ul></ul><ul><ul><li>Hyperglycemia/ diabetes, hypoaminoacidemia </li></ul></ul><ul><li>Liver disease/ cirrhosis often present in cases without a glucagonoma </li></ul><ul><li>>50% cases have metastatic disease at time of diagnosis </li></ul>
  92. 193. Necrolytic Migratory Erythema <ul><li>Clinical lesions: </li></ul><ul><ul><li>Recurrent waves of annular and circinate erythema with superficial necrosis </li></ul></ul><ul><ul><li>Exfoliation of skin with vesicles and flaccid bullae which rupture to form erosions and crusted plaques </li></ul></ul><ul><ul><li>Hyperpigmentation and scaling with healing </li></ul></ul><ul><ul><li>Lesions often in various stages of development </li></ul></ul><ul><li>Clinical distribution: </li></ul><ul><ul><li>Groin and perioral skin almost always involved </li></ul></ul><ul><ul><li>Lower abdomen, thighs, distal extremities also frequent sites </li></ul></ul>
  93. 194. Necrolytic Migratory Erythema Histopathology <ul><li>Several patterns depending on stage of lesion </li></ul><ul><ul><li>Psoriasiform epidermal hyperplasia with pallor and presence of vacuolated keratinocytes in upper epidermis </li></ul></ul><ul><ul><li>May have areas of focal and confluent necrosis </li></ul></ul><ul><ul><li>Subcorneal pustulation and neutrophilic spongiosis may be present </li></ul></ul><ul><ul><li>Confluent parakeratosis with scale-crust </li></ul></ul><ul><ul><li>Vascular dilatation and intraepidermal and superficial dermal edema </li></ul></ul>
  94. 195. Necrolytic Migratory Erythema Treatment <ul><li>Resection of underlying tumor </li></ul><ul><li>Chemotherapy for metastatic dz </li></ul><ul><ul><li>Streptozotocin </li></ul></ul><ul><ul><li>Octreotide </li></ul></ul><ul><li>Supplementation of amino acids, zinc, and essential fatty acids can also result in resolution of eruption </li></ul>
  95. 197. CASE 8
  96. 198. CASE 8 <ul><li>53 y/o AA M presents with ten year hx of generalized pruritic eruption </li></ul><ul><li>Eruption began on neck and chest and spread to involve face, lower trunk, extremities </li></ul><ul><li>ROS: difficulty swallowing, hoarseness, extremity muscle weakness </li></ul><ul><li>PMHx: HTN, carpal tunnel syndrome </li></ul>
  97. 215. COLL. IRON
  98. 216. COLL. IRON
  99. 217. COLL. IRON
  100. 218. COLL. IRON
  101. 219. CASE 8 Additional Laboratory Studies <ul><li>CBC, LFT’s, TFT’s, electrolytes WNL </li></ul><ul><li>Total serum protein: 8.8 (NL 6.1-8.5) </li></ul><ul><li>Albumin: 4.3 (NL 2.6-5.2) </li></ul><ul><li>Serum IgG level: 18.0 g/L (NL 7.0-13.0) </li></ul><ul><li>Serum protein electrophoresis: diffuse band in slow gamma region, reacting on immunofixation as IgG lambda </li></ul>
  102. 220. CASE 8 Diagnosis? Scleromyxedema
  103. 221. Scleromyxedema <ul><li>Rare chronic and progressive cutaneous mucinosis in which generalized lichenoid papules and plaques are present with skin thickening </li></ul><ul><li>Paraproteinemia, usually of IgG lambda type almost always present </li></ul><ul><li>Generally middle-aged to elderly adults </li></ul><ul><li>Patients may have associated hepatitis C </li></ul>
  104. 222. Scleromyxedema <ul><li>Cutaneous disease features: </li></ul><ul><ul><li>Multiple waxy papules coalescing into plaques </li></ul></ul><ul><ul><li>May have linear array </li></ul></ul><ul><ul><li>Skin often diffusely indurated limiting ROM </li></ul></ul><ul><li>Distribution: </li></ul><ul><ul><li>Dorsal hands, face, elbows, extensor extremities most commonly affected </li></ul></ul><ul><ul><li>“ Leonine facies” may develop </li></ul></ul><ul><ul><li>“ Doughnut sign” around PIP joint </li></ul></ul>
  105. 223. Scleromyxedema <ul><li>Visceral disease features: </li></ul><ul><ul><li>Gastrointestinal involvement most frequent </li></ul></ul><ul><ul><ul><li>Dysphagia from esophageal involvement </li></ul></ul></ul><ul><ul><li>Pulmonary disease </li></ul></ul><ul><ul><ul><li>SOB from obstructive or restrictive lung disease </li></ul></ul></ul><ul><ul><li>Musculoskeletal </li></ul></ul><ul><ul><ul><li>Proximal muscle weakness / inflammatory myopathy </li></ul></ul></ul><ul><ul><ul><li>Arthralgia / inflammatory arthritis </li></ul></ul></ul><ul><ul><li>Neurologic </li></ul></ul><ul><ul><ul><li>Peripheral neuropathies </li></ul></ul></ul><ul><ul><ul><li>CNS disturbances (confusion, dizziness, dysarthria, seizures, paralysis, syncope, coma </li></ul></ul></ul><ul><ul><ul><li>Carpal tunnel syndrome </li></ul></ul></ul>
  106. 224. Scleromyxedema Histopathology <ul><li>Dermal deposits of mucin in association with proliferation of fibroblasts and collagen in upper and mid-dermis </li></ul><ul><li>Areas of fibroblasts and collagen may have irregular or whorled arrangement </li></ul><ul><li>Inflammation usually sparse </li></ul>
  107. 225. Scleromyxedema Treatment <ul><li>Difficult, prognosis poor </li></ul><ul><li>Physical therapy </li></ul><ul><li>High dose corticosteroids </li></ul><ul><li>Plasma exchange +/- melphalan , cyclophosphamide </li></ul><ul><li>Retinoids, IVIG, Electron beam, PUVA, IFN, cyclosporin, thalidomide have helped selected patients </li></ul>
  108. 227. CASE 9
  109. 228. CASE 9 <ul><li>51 y/o Cauc F presents with one and a half year hx of eruption on legs and lower abdomen </li></ul><ul><li>Lesions were increasing in size and number over this period </li></ul><ul><li>ROS: Patient was being evaluated by hematologist for leukopenia and splenomegaly </li></ul><ul><li>PMHx: Long history of arthritis in hands, no history of diabetes or increased lipids </li></ul>
  110. 245. CASE 9 Additional Laboratory Studies <ul><li>WBC 2.3, Hb/ Hct: 14/42, Plt: 119 </li></ul><ul><li>Blood glucose: 83 </li></ul><ul><li>Lipid profile: WNL </li></ul><ul><li>Skeletal surveys and bone scan WNL </li></ul><ul><li>Serum IgG level: 20.8 g/L (NL 7.0-13.0) </li></ul><ul><li>Serum protein electrophoresis: spike in mid- gamma region, reacting on immunofixation as IgG kappa </li></ul><ul><li>Bone marrow bx: mildly elevated % plasma cells </li></ul>
  111. 246. CASE 9 Diagnosis? Necrobiotic Xanthogranuloma
  112. 247. Necrobiotic Xanthogranuloma <ul><li>Rare chronic and progressive disorder characterized by multiple painless violaceous xanthomatous nodules and indurated plaques </li></ul><ul><li>Atrophy, ulceration, and telangiectasia may be present </li></ul><ul><li>Predominantly involves periorbital area but trunk and limbs often involved </li></ul><ul><li>IgG paraproteinemia, usually kappa, is usually present as an isolated finding in approximately 80% patients </li></ul><ul><li>Usually in middle aged to elderly men and women </li></ul>
  113. 248. Necrobiotic Xanthogranuloma <ul><li>Ophthalmologic involvement usually most common and account for most severe complications: </li></ul><ul><ul><li>Episcleritis, keratitis, ulceration of palpebral fissure, blindness </li></ul></ul><ul><li>Associated systemic findings: </li></ul><ul><ul><li>Frequent: leukopenia, splenomegaly </li></ul></ul><ul><ul><li>Infrequent: hypocomplementemia, hyperlipidemia, cryoglobulinemia </li></ul></ul>
  114. 249. Necrobiotic Xanthogranuloma Histopathology <ul><li>Extensive necrobiosis of collagen with surrounding granulomatous inflammation involving the dermis and subcutaneous tissue </li></ul><ul><li>Granulomatous inflammation usually includes histiocytes, foam cells, and multinucleate giant cells (both Touton type and bizarre foreign body type) </li></ul><ul><li>Cholesterol clefts, lymphoid nodules, and plasma cell collections may be present </li></ul><ul><li>Usually more cellular and has more atypical giant cells than necrobiosis lipoidica </li></ul>
  115. 250. Necrobiotic Xanthogranuloma Treatment <ul><li>Cytotoxic agents </li></ul><ul><ul><li>Chlorambucil </li></ul></ul><ul><ul><li>Melphalan </li></ul></ul><ul><ul><li>Nitrogen mustard </li></ul></ul><ul><ul><li>Cyclophosphamide </li></ul></ul><ul><ul><li>Methotrexate </li></ul></ul><ul><li>Systemic corticosteroids </li></ul><ul><li>Plasmapheresis </li></ul><ul><li>Localized XRT </li></ul>
  116. 252. CASE 10
  117. 253. CASE 10 <ul><li>60 y/o male presented with 2 month hx ulcerations bilateral dorsal hands occurring after minor trauma </li></ul><ul><li>Lesions initially began as small papules that expand to plaques and ulcerate </li></ul><ul><li>No response to two courses of antibiotics </li></ul><ul><li>ROS: denies fever, no hx of malignancy or gastrointestinal disorder </li></ul><ul><li>PMH: HTN </li></ul>
  118. 264. CASE 10 Additional Laboratory Studies <ul><li>CBC WNL </li></ul><ul><li>Radiologic studies: no underlying osteomyelitis </li></ul><ul><li>Two sets of tissue cultures: No growth of bacteria, fungi, or mycobacteria </li></ul>
  119. 265. CASE 10 Diagnosis? Neutrophilic Dermatosis of the Dorsal Hands
  120. 266. Neutrophilic Dermatosis of the Dorsal Hands (NDDH) <ul><li>First described in 1995 as “pustular vasculitis of the hands” 1 </li></ul><ul><li>Term “neutrophilic dermatosis of the dorsal hands” proposed in 2000 for cases with a similar presentation but no histologic evidence of vasculitis </li></ul><ul><li>Violaceous papulonodules evolving into spreading ulcerating plaques usually on radial aspect of dorsal hands </li></ul><ul><li>Total of 52 cases have been reported in literature </li></ul>1 Strutton et al. J Am Acad Dermatol . 1995; 32: 192-198 2 Galaria et al. J Am Acad Dermatol . 2000;43: 870-874
  121. 267. NDDH <ul><li>Most likely represents a localized variant of Sweet’s syndrome </li></ul><ul><li>Vesiculobullous (atypical) pyoderma gangrenosum may also be the same disease </li></ul>
  122. 268. NDDH vs. Sweet’s Syndrome <ul><li>F:M ratio: 2.2 </li></ul><ul><li>Mean age onset: 60 </li></ul><ul><li>% w/malignancy: 27% </li></ul><ul><li>% w/ IBD: 15% </li></ul><ul><li>% w/ vasculitis: 25% </li></ul><ul><li>% steroid response: 71% </li></ul><ul><li>F:M ratio: 3.7 </li></ul><ul><li>Mean age onset: 53 </li></ul><ul><li>% w/malignancy: 21% </li></ul><ul><li>% w/ IBD: 16% </li></ul><ul><li>% w/ vasculitis: 18% </li></ul><ul><li>% steroid response: 97% </li></ul>Walling et al. Arch Dermatol . 2006; 142: 57-63
  123. 269. NDDH and atypical pyoderma gangrenosum (PG) <ul><li>Atypical PG usually presents as hemorrhagic bullous lesions which superficially ulcerate </li></ul><ul><li>Usual presentation is on upper extremities, especially dorsal hands </li></ul><ul><li>More often associated with malignancy and underlying systemic disease </li></ul><ul><li>Prompter remission </li></ul><ul><li>Clinically and histopathologically very similar presentation to NDDH </li></ul>
  124. 270. NDDH Histopathology <ul><li>Diffuse neutrophilic infiltrate </li></ul><ul><li>Papillary dermal edema </li></ul><ul><li>+/- small vessel leukocytoclastic vasculitis </li></ul><ul><li>+/- overlying ulceration and pseudoepitheliomatous hyperplasia </li></ul>
  125. 271. NDDH and vasculitis <ul><li>Evidence of leukocytoclastic vasculitis present in 27% patients with NDDH 1 </li></ul><ul><li>Comparable percentage in 2 series of patients with classical Sweet’s syndrome (18-30%) 2,3 </li></ul><ul><li>Vasculitis probably represents a secondary process as a result of the brisk neutrophilic infiltrate and accompanying cytokine and enzymatic cascade </li></ul>1 Walling et al. Arch Dermatol . 2006; 142: 57-63 2 Malone et al. Arch Dermatol. 2002: 138: 345-349 3 Jordaan HF. Am J Dermatopathol. 1989; 11: 99-111
  126. 272. NDDH Treatment <ul><li>Systemic corticosteroids </li></ul><ul><li>Steroid sparing immunosuppressants </li></ul><ul><li>Dapsone </li></ul><ul><li>Minocycline </li></ul><ul><li>Recurrences are common </li></ul>
  127. 274. CASE 11
  128. 275. CASE 11 <ul><li>77 y/o AA male presents with 1 year hx of a lesion on upper back </li></ul><ul><li>Area had initially began as localized oval area of painful erythema which then became ulcerated and indurated </li></ul><ul><li>ROS: Did not recall any trauma to area, denied any new medications </li></ul><ul><li>PMH: Prostate AdenoCA, HTN, CAD, and hyperlipidemia </li></ul>
  129. 292. CASE 11 Additional Clinical History <ul><li>Upon further directed questioning, patient remembered he had undergone four hour coronary stenting procedure prior to onset of lesion </li></ul><ul><li>He had a repeat procedure one day later </li></ul>
  130. 293. CASE 11 Diagnosis? Fluoroscopy-induced Radiation dermatitis
  131. 294. Fluoroscopy-induced Radiation Dermatitis <ul><li>Increased incidence with use of fluoroscopic guided interventional procedures, especially coronary artery stenting and angioplasty </li></ul><ul><li>Majority of patients have been middle-aged to elderly men </li></ul><ul><li>Typical clinical presentation: </li></ul><ul><ul><li>Pruritic to painful oval to square shaped lesions on scapular region of the back corresponding to location of beam </li></ul></ul><ul><ul><li>Often began as erythematous or vesicular patches progressing to indurated poikilodermatous plaques with secondary necrotic ulceration </li></ul></ul>
  132. 295. Stone MS et al. J Am Acad Dermatol. 1998; 38: 333-6 EARLY LATE
  133. 296. Radiation Dermatitis Histopathology <ul><li>Findings depend on stage of lesion biopsied </li></ul><ul><li>Previously classified into acute and chronic stages </li></ul><ul><li>A subacute stage with clinical features intermediate between acute and chronic stages and distinctive histologic features has been recognized 1 </li></ul>1 Leboit PE. J Am Acad Dermatol . 1989: 20: 236-41
  134. 297. Radiation Dermatitis Histopathology <ul><li>Acute Stage (Uncommonly biopsied) </li></ul><ul><ul><li>2 to 7 days after exposure </li></ul></ul><ul><ul><li>Intracellular edema, pyknotic nuclei, fibrin thrombi in small vessels with hemorrhage and dermal edema </li></ul></ul><ul><li>Chronic Stage (Most commonly biopsied) </li></ul><ul><ul><li>Months to years after exposure </li></ul></ul><ul><ul><li>Epidermal atrophy and /or acanthosis </li></ul></ul><ul><ul><li>Dermal sclerosis with telangiectases and loss of adnexal structures and presence of atypical “radiation fibroblasts” </li></ul></ul>
  135. 298. Radiation Dermatitis Histopathology <ul><li>Subacute Stage </li></ul><ul><ul><li>Weeks to months after exposure </li></ul></ul><ul><ul><li>Lichenoid interface dermatitis with features mimicking acute graft versus host disease or a fixed drug eruption </li></ul></ul><ul><ul><li>Immunohistochemical studies suggest a cytotoxic T-cell and natural killer cell process </li></ul></ul>
  136. 299. Fluoroscopy-induced Radiation Dermatitis - Treatment <ul><li>Can be difficult as areas usually show poor or very delayed wound healing </li></ul><ul><li>Superficial injures – local wound care </li></ul><ul><li>More necrotic lesions may require surgical excision with split or full thickness skin grafts </li></ul>
  137. 300. Fluoroscopy-induced Radiation Dermatitis - Prevention <ul><li>Screening for pre-existing conditions </li></ul><ul><li>Establishment of FDA protocols </li></ul><ul><ul><li>Continuous monitoring of cumulative radiation doses during interventional fluoroscopic procedures </li></ul></ul><ul><ul><li>Recording absorbed doses that approach or exceed threshold for skin injury </li></ul></ul><ul><li>Limiting exposure of specific site: </li></ul><ul><ul><li>Reducing size of exposed area </li></ul></ul><ul><ul><li>Using different projections </li></ul></ul>
  138. 302. CASE 12
  139. 303. CASE 12 <ul><li>69 y/o female presents with three week hx of an intermittently painful left leg ulcer, developing after minor trauma. </li></ul><ul><li>Progressively more painful with conservative management (leg elevation, local wound care) </li></ul><ul><li>Ulcer had not respond to 2 week course of cephalexin </li></ul><ul><li>ROS: prior hx of ulcer on other leg which healed spontaneously </li></ul><ul><li>PMH: HTN, hx of colon rupture and colostomy </li></ul>
  140. 315. CD31
  141. 316. CD31
  142. 317. CD31
  143. 319. CASE 12 Additional Laboratory Studies <ul><li>Tissue cultures: showed no growth </li></ul><ul><li>Non-invasive vascular studies showed severe bilateral ischemic disease in legs (L>R) </li></ul>
  144. 320. CASE 12 Diagnosis? Diffuse Dermal Angiomatosis
  145. 321. Diffuse Dermal Angiomatosis <ul><li>First reported in 1994 as a variant of reactive angioendotheliomatosis (RAE). 1 </li></ul><ul><li>Painful violaceous plaques with ulceration usually on lower extremities </li></ul><ul><li>Majority of patients have evidence of severe peripheral atherosclerotic disease </li></ul><ul><li>Lesions often develop rapidly but disappear quickly after surgical revascularization </li></ul>1 Krell JM, Sanche RL, Solomon AR. J Cutan Pathol . 1994; 21: 363
  146. 322. Draper BK, Boyd AS. J Cutan Pathol . 2006: 33: 646-648
  147. 323. Diffuse Dermal Angiomatosis Pathogenesis <ul><li>Not fully elucidated </li></ul><ul><li>Possible explanations: </li></ul><ul><ul><li>Tissue ischemia induces local increase in vascular endothelial growth factor (VEGF) which induces endothelial cell proliferation </li></ul></ul><ul><ul><li>Irregular intimal surface of partially occluded large vessels may provide a source of emboli that are carried distally to small dermal vessels where they can induce endothelial cell hyperplasia (similar to Masson’s tumor) </li></ul></ul>
  148. 324. Diffuse Dermal Angiomatosis Histopathology <ul><li>Diffuse dermal interstitial proliferation of endothelial cells (CD31+) </li></ul><ul><li>Proliferating cells may show a spindled appearance with vacuolated cytoplasm and formation of vascular lumina </li></ul><ul><li>Absence of atypical endothelial cells or mitoses </li></ul><ul><li>Hemosiderin deposition and extravasated erythrocytes may be present </li></ul>
  149. 325. Draper BK, Boyd AS. J Cutan Pathol . 2006: 33: 646-648
  150. 326. Diffuse Dermal Angiomatosis Treatment <ul><li>Surgical revascularization has resulted in resolution of lesions in most cases </li></ul><ul><li>Isotretinoin successfully used in 1 case described from breast 1 </li></ul>1 McLaughlin ER et al. J Am Acad Dermatol . 2001; 45: 462
  151. 328. CASE 13
  152. 329. CASE 13 <ul><li>21 y/o Asian F presents with long hx episodic and recurrent erythematous scaly patches involving trunk and extremities </li></ul><ul><li>Eruption has been present since birth and has been noted to migrate over her body before fading over weeks to months </li></ul><ul><li>Since age five, patient has had a fixed palmoplantar keratoderma </li></ul><ul><li>By adolescence, persistent linear, corrugated verrucous plaques had developed over flexural and extensor surfaces of several joints </li></ul>
  153. 330. CASE 13 <ul><li>ROS: No hx blisters, No abnormalities with hair, nails, teeth, or mucous membranes </li></ul><ul><li>FMHx: Mother and multiple maternal relatives with PPK and verrucous plaques; one male cousin with similar migratory patches </li></ul><ul><li>PMHx: None </li></ul><ul><li>Meds: Oral contraceptives </li></ul>
  154. 345. CASE 13 Additional Laboratory Studies <ul><li>CBC WNL </li></ul><ul><li>Chemistry panel WNL </li></ul><ul><li>Hepatic panel WNL </li></ul><ul><li>Genetic studies: </li></ul><ul><ul><li>detected a keratin 1 mutation in the patient and her mother but not in the father or an unaffected sister </li></ul></ul>
  155. 346. CASE 13 Diagnosis? Annular Epidermolytic Ichthyosis
  156. 347. Annular Epidermolytic Ichthyosis <ul><li>Annular epidermolytic ichthyosis (AEI) </li></ul><ul><ul><li>Rare phenotypic variant of bullous congenital ichthyosiform erythroderma (BCIE) first reported in 1992 1 </li></ul></ul><ul><ul><ul><li>+/- widespread erythroderma and blisters at birth </li></ul></ul></ul><ul><ul><ul><li>Episodic migratory annular and polycyclic erythematous plaques on trunk and proximal extremities </li></ul></ul></ul><ul><ul><ul><li>Fixed corrugated ridged hyperkeratotic plaques develop over the body folds and joints similar to classic BCIE </li></ul></ul></ul><ul><ul><ul><li>Variable presence of fixed palmoplantar keratoderma </li></ul></ul></ul><ul><ul><ul><li>Hair, nails, and mucous membranes unaffected </li></ul></ul></ul><ul><ul><li>Clinical presentation varies markedly between family members and over the lifetime of each individual </li></ul></ul>1 Sahn et al. J Am Acad Dermatol. 1992;27:348-35
  157. 348. Annular Epidermolytic Ichthyosis <ul><li>Seven previous kindreds reported in the literature </li></ul><ul><li>Mutations often found in 2b segment of of Keratin 1 and 10 genes (similar to BCIE) </li></ul><ul><ul><li>Keratin 10 mutations – no associated PPK </li></ul></ul><ul><ul><li>Keratin 1 mutations - associated PPK </li></ul></ul>
  158. 349. Annular Epidermolytic Ichthyosis Histopathology <ul><li>Epidermolytic hyperkeratosis (EHK) </li></ul><ul><ul><li>Hyperkeratosis of the stratum corneum </li></ul></ul><ul><ul><li>Vacuolization with irregular keratohyalin granules within the spinous and granular layers </li></ul></ul><ul><li>Similar histology seen in both migratory patches or in fixed verrucous plaques </li></ul><ul><li>Pattern identical to that seen in classic EHK-BCIE, hereditary epidermolytic PPK and sporadic epidermolytic acanthomas. </li></ul><ul><li>Epidermal nevi with EHK on histology thought to represent a mosaic form of the disorder in carriers </li></ul>
  159. 350. Annular Epidermolytic Ichthyosis Treatment <ul><li>Annular plaques </li></ul><ul><ul><li>Topical and oral retinoids </li></ul></ul><ul><ul><li>Present patient showed good response to topical tazarotene </li></ul></ul><ul><ul><li>Natural or artificial UV light treatments </li></ul></ul><ul><li>Palmoplantar keratoderma </li></ul><ul><ul><li>Propylene glycol </li></ul></ul><ul><ul><li>Urea </li></ul></ul>
  160. 352. CASE 14
  161. 353. CASE 14 <ul><li>45 y/o Cauc F presents with hx pruritic lesions involving right side of body since age 18 involving trunk and extremities </li></ul><ul><li>Has had little response to topical steroids, topical and oral retinoids </li></ul><ul><li>ROS: Denies any nail or oral abnormalities, no neurologic disorders </li></ul><ul><li>PMHx: none </li></ul><ul><li>FMHx: no hx similar disorder in other family members </li></ul>
  162. 366. CASE 14 Diagnosis? Unilateral Darier’s Disease (Keratosis Follicularis)
  163. 367. Unilateral Darier’s Disease <ul><li>Represents segmental manifestation of classic Darier’s disease </li></ul><ul><li>Genetic defect localized to chromosone 12q23-24.1 coding for SERCA2 (sarcoplasmic reticulum calcium ATPase) </li></ul><ul><li>Majority of cases autosomal dominant; however, sporadic cases occur </li></ul><ul><li>Segmental disease often lacks other associated features such as oral and nail findings </li></ul>
  164. 368. Unilateral Darier’s Disease <ul><li>Two clinical phenotypes: </li></ul><ul><ul><li>Isolated segmental or linear disease (Type 1) </li></ul></ul><ul><ul><ul><li>Segmental areas show same degree of severity as that seen in non-mosaic trait </li></ul></ul></ul><ul><ul><ul><li>Skin outside segmentally affected areas normal </li></ul></ul></ul><ul><ul><ul><li>Postzygotic mutation with somatic mosaicisim </li></ul></ul></ul><ul><ul><ul><li>More common (>50 patients reported) </li></ul></ul></ul><ul><ul><li>Segmental disease in combination with diffuse distribution (Type 2) </li></ul></ul><ul><ul><ul><li>Segmental areas more severe and superimposed on a milder diffuse form of same disease </li></ul></ul></ul><ul><ul><ul><li>Germline mutation present, but postzygotic mutation needed resulting in loss of heterozygosity </li></ul></ul></ul><ul><ul><ul><li>Rare (only 4 patients reported) </li></ul></ul></ul>
  165. 369. Unilateral Darier’s Disease Histopathology <ul><li>Acantholytic dyskeratosis: </li></ul><ul><ul><li>Multifocal suprabasilar acantholysis </li></ul></ul><ul><ul><li>Dyskeratotic keratinocytes with formation of corps ronds and grains </li></ul></ul><ul><ul><li>Parakeratosis </li></ul></ul>
  166. 370. Unilateral Darier’s Disease Histopathology <ul><li>Acantholytic dyskeratosis: </li></ul><ul><ul><li>Multifocal suprabasilar acantholysis </li></ul></ul><ul><ul><li>Dyskeratotic keratinocytes with formation of corps ronds and grains </li></ul></ul><ul><ul><li>Parakeratosis </li></ul></ul>
  167. 371. Unilateral Darier’s Disease Treatment <ul><li>Localized disease: </li></ul><ul><ul><li>Topical retinoids </li></ul></ul><ul><li>Severe generalized disease: </li></ul><ul><ul><li>Oral retinoids </li></ul></ul><ul><li>Hypertrophic lesions: </li></ul><ul><ul><li>Excision </li></ul></ul><ul><ul><li>Dermabrasion </li></ul></ul><ul><ul><li>Laser ablation (Erbium:YAG) </li></ul></ul><ul><li>Prevention of secondary bacterial or herpetic infection </li></ul>
  168. 373. CASE 15
  169. 374. CASE 15 <ul><li>32 y/o Cauc M presents with two month hx of diffuse non-pruritic eruption </li></ul><ul><li>Patient had been previously treated for “hives” by his PMD and was also given methylprednisolone and an oral in an emergency department subsequently </li></ul><ul><li>ROS: denied fever </li></ul><ul><li>PMHx: none per patient </li></ul>
  170. 392. WARTHIN STARRY
  171. 394. CASE 15 Additional Laboratory Studies <ul><li>CBC wnl </li></ul><ul><li>Initial RPR negative, Repeat one week later positive </li></ul><ul><li>HIV test positive </li></ul>
  172. 395. CASE 15 Diagnosis? Secondary Syphilis
  173. 396. Hoang et al. J Cutan Pathol . 31 (9): 595-9