1. Monocyte/Macrophage Disorders Northeast Regional Medical Center/KCOM

2. Granuloma Annulare Localized Generalized Macular Deep Perforating In HIV In Lymphoma

3. GA - Histology Classic – histiocytes palisading around “necrobiotic” collagen. Granulomas located in the upper dermis with perivascular lymphocytic infiltrate Necrobiosis – “altered” collagen, paler grayer hue, fragmented, haphazardly arranged, more compact. Mucin prominent in older lesions.

4. GA- Histology Interstitial – diffuse dermal infiltrate between collagen bundles consisting of histiocytes, monocytes, neutrophils. “Skip” areas of normal dermis seen. Interstitial mucin often seen. May be adjacent to classic granulomas

5. GA

6. Epithelioid histiocytes

8. Papular GA

15. Localized GA Young adults Acral Annular, scalloped White or pink flat topped papules spread peripherally 75% clear in 2 yrs 25% last 8 yrs

21. Generalized/Diffuse GA MC women past middle age Diabetes reported in 20% cases MC neck, upper trunk, shoulders Sun exposure may trigger MC form of GA seen in HIV. Clears spontaneously in 3-4 years. Difficult to treat.

22. Disseminated GA

26. Subcutaneous GA Aka Deep, Pseudorheumatoid Nodule MC children, boys > girls 2:1 MC ages 5-12. Acral distribution, usually multiple lesions History of trauma preceding lesion Asymptomatic but often an extensive workup is done to rule out JRA.

27. Subcutaneous GA

29. Perforating GA MC dorsum of hands Papules with central keratotic core Core represents transdermal elimination of degenerated or “necrobiotic” material in center of palisaded histiocytes.

30. Perforating GA

32. GA in HIV disease GA may occur at all phases of HIV disease. Typically papular lesions 60% Diffuse, 40% Localized Photodistributed and perforating lesions may occur Identical histology

33. GA and Lymphoma Rare Atypical presentation: Facial or Palmar Painful Any type of lymphoma can occur. Lymphoma may occur before or after the GA.

34. GA- Treatment Biopsy, IL, Cryo, topical Vit. E, Excision GENERALIZED: Problematic Oral steroids, high dose but high relapse rate – diabetes complicates Dapsone, Nicotinomide, SSKI, Cyclosporine, Accutane.

35. Annular Elastolytic Giant Cell Granuloma of Meischer/Actinic Granuloma of O’Brien ? Variants of GA. AEGCG – solitary atrophic thin yellow plaque on the forehead, NLD-like. Chronic and refractory to tx AGOB – Photo- distribution, papules and plaques

36. Annular Elastolytic Giant Cell Granuloma of Meischer/Actinic Granuloma of O’Brien

37. Granuloma Mulitforme of Leiker Similar histology to AEGCG & AGOB Only Central Africa, Adults > 40 yrs old. Upper Trunk and Arms Begin as small papules, expand into round or oval plaques 15cm wide and as much as 4mm in height. Must rule out tuberculoid leprosy.

38. Granuloma Mulitforme of Leiker

39. Sarcoidosis A systemic granulomatous disease of undetermined etiology with a persistant courseinterrupted by remissions and rrelapses Lungs, lymph nodes, skin and eyes MC. 10x more frequent in blacks in US Women under age 40 Irish, African, Afro-Caribbean.

40. NON-CASEATING GRANULOMAS COMPOSED OF EPITHELIOID CELLS AND OCCASIONAL LANGERHAN’S GIANT CELLS

41. “NAKED” GRANULOMAS “NAKED” meanse a sparse rather than a dense infiltrate. Lymphocytes, macrophages & fibroblasts may occur

43. Asteroid Body inside a multinucleated giant cell

44. Sarcoidosis

45. SCHAUMANN OR CONCHOIDAL BODIES ARE COMPOSED OF CALCIUM CARBONATE. THEY ARE EASILY MISSED (LEFT) IF NOT VIEWED UNDER POLARIZED LIGHT (RIGHT)

46. Sarcoidosis AKA…. Besnier-Boeck-Schaumann Disease Boeck’s sarcoid Besnier’s lupus pernio Schaumann’s benign lymphogranulomatosis

47. Sarcoid Skin Involvement Anywhere from 9% to 37% of cases. 2 types: specific and non-specific Specific: granulomas on biopsy Non-Specific: reactive, Erythema Nodosum Skin findings may occur before, during or after systemic findings.

48. Sarcoid – like syphillis, mimics many other dz’s Papules, nodules, plaques. Subcutaneous nodules. Scar sarcoid, erythroderma. Ulcerations, verrucous. Ichthyosiform, hypomelanotic

49. Papular Sarcoid MC form AKA Miliary Sarcoid Face, eyelids, neck, shoulders May involute to macules Ddx: syringomas

50. Papular Sarcoid

52. Annular Sarcoidosis Central clearing Hypo- pigment- ation Atrophy Scarring Favor head & neck Assoc. with chronic sarcoidosis

53. Annular Sarcoidosis

54. Hypopigmented Sarcoid May be the earliest sign of sarcoidosis in blacks. MC extremities Visually macular, but often have a palpable dermal or subQ component in center of lesion

55. Hypopigmented Sarcoid

56. Lupus Pernio Violaceous, smooth Nose, cheeks, lips Forehead, ears disfiguring 43% associated with punched out bone lesions. 37% Ocular lesions Nasal perforation

58. Punched-Out Lytic lesions, Bone Cysts

59. Lupus Pernio

61. Ulcerative Sarcoidosis, very rare, young black women, favors lower ext.

62. Darier-Roussy Sarcoid/subcutaneous sarcoidosis 5% or fewer of patients with sarcoidosis have subcutaneous nodules.

63. Darier-Roussy (SubQ)

64. Scar Sarcoid Develop in old scars of various causes Resemble keloids MC seen in chronic disease

65. Scar Sarcoid

66. Erythrodermic Sarcoid Extremely Rare Begins as erythematous patches that become confluent.

67. Ichthyosiform Sarcoid Legs Arms No palpable component Bx confirms dx

68. Ichthyosiform Sarcoid

69. Alopecia Occurs in 2 settings; 1) Existing plaques extend onto scalp. --leads to permanent scarring. 2) Macular lesions appear on scalp resembling Alopecia Areata --may be permanent or reversible

70. Morpheaform Sarcoid Rare Dermal Fibrosis Simulates Morphea Antimalarials may help.

71. Morpheaform Sarcoid

73. Mucosal Sarcoid Pinhead sized papules Grouped or fused together to form a plaque.

74. Erythema Nodosum in Sarcoid MC nonspecific cutaneous finding in sarcoidosis Young females Anterior shins Good prognosis, involution in <6 mo in 80% Lofgren’s Syndrome = fever, arthralgias, hilar adenopathy, fatigue, EN

75. Systemic Sarcoidosis MC – Lungs Ocular 20-30% Bones & Liver 20%, elevated Alk Phos. Renal, Hypercalcemia Heart, CNS, Spleen Elevated ACE levels to follow disease activity only.

76. Heerfort’s Syndrome Parotid gland enlargement Lacrimal gland enlargement Uveitis Fever Sarcoidosis

77. CXR- Hilar Adenopathy

78. Sarcoidosis in Fingers

80. Sarcoid - Treatment Systemic Corticosteroids Antimalarials Methotrexate Thalidomide

81. Non-X Histocytoses Juvenile Xanthogranuloma Benign Cephalic Histiocytosis Solitary/Multicentric Reticulohistiocytosis Generalized Eruptive Histiocytoma Necrobiotic Xanthogranuloma Xanthoma Disseminatum Papular Xanthoma Indeterminate Cell Histiocytosis Progressive Nodular Histiocytoma Hereditary Progressive Mucinous Histiocytosis Rosai-Dorfman Disease Sea-Blue Histiocytosis

82. Juvenile Xanthogranuloma (JXG) MC Non-Langerhans’ histiocytosis 1 st year of life, usu. white males 80% are solitary, well demarcated, firm, rubbery red to pink with yellow tinge Regress in 3-6 years with atrophy. Ocular involvement rare, MC iris Assoc. with NF-1 and JCML

83. Occular involvement occurs in.4% of children with multiple JXG

85. JXG Histopathology Non-encapsulated Infiltrate in the upper and mid reticular dermis Mononuclear cells with abundant amphophilic cytoplasm that is poorly lipidized or vacuolated.

86. MULTINUCLEATED “FOAM” CELLS aka TOUTON GIANT CELLS ALONG WITH EOS, NEUTS, LYMPHS. STAINS: Rarely + CD1 + FACTOR XIIIa - S100

87. JXG histopathology

88. Benign Cephalic Histiocytosis Rare Males 2:1, Onset 6-12 months of age Begins on head, cheeks, spreads to neck and upper trunk Multiple reddish yellow papules 2-3mm, may coalesce into a reticulate pattern. Involute over 2 to 8 years with atrophy

89. BENIGN CEPHALIC HISTIOCYTOSIS DIFFUSE DERMAL INFILTRATION OF NON-LIPIDIZED HISTIOCYTIC CELLS, S-100 NEGATIVE

90. Reticulohistiocytosis Solitary form – aka Reticulohistiocytic Granuloma or Reticulohistiocytoma Solitary form has no systemic involvement Multicentric form – aka Multicentric Reticulohistiocytosis Underlying malignancy in 30%

91. Reticulohistiocytic Granuloma

92. Reticulohistiocytic Granuloma: Multinucleate Giant Cells, Histiocytes, Lymphocytes with some stroma fibrosis

93. Multicentric Reticulohistiocytosis Multisystem disease, 5 th decade, F>M. 90% Face & hands, red-brown papules and nodules Paronychia: “coral bead” appearance Joints symmetrically involved with mutilating arthritis, telescoping shortening of digits, doigts en lorgnette, opera-glass fingers, RF is negative 1/3 have high cholesterol, xanthelasma

95. Reticulohistiocytosis, numerous mononucleated and multinucleated histiocytes extending from the papillary tips into the deep dermis. These histiocytes have abundant eosinophilic, finely granular cytoplasm. (ground glass)

96. “Coral Bead” Paronychia

97. Classic Ground Glass Touton Giant Cells, PAS +

98. 90% Face & Hands

99. Tx: Multicentric Reticulohisticytosis Treatment is problematic because mutilating arthritis requires immunosuppressive therapy. Immunosuppressive therapy can worsen underlying malignancies Prednisone, Antimalarials, MTX, Cytoxan, PUVA, Nitrogen mustard.

100. Generalized Eruptive Histiocytoma Widespread symmetric papules, trunk and proximal extremities, come in crops Progressive development of new lesions over several years with eventual spontaneous involution to hyper- pigmented macules Flesh, brown or violaceous papules

101. Generalized Eruptive Histiocytoma

103. GENERALIZED ERUPTIVE HISTIOCYTOMA: DERMAL INFILTRATE OF NON-LIPIDIZED MONONUCLEAR HISTIOCYTES, S-100 IS NEGATIVE

104. GENERALIZED ERUPTIVE HISTIOCYTOMA: DERMAL INFILTRATE OF NON-LIPIDIZED MONONUCLEAR HISTIOCYTES, S-100 IS NEGATIVE

105. Necrobiotic Xanthogranuloma (NXG) Multisystem disease of older adults Characteristic periorbital yellow plaques that resemble xanthelasmas except that they are deep, firm, indurated and may extend into the orbit. Occur in 80%. Trunk & proximal extremity lesions are orange-red plaques with an active red border and an atrophic border with superficial telangiectiasias.

106. NXG: Periorbital yellow plaques that resemble xanthelasmas except that they are deep, firm, indurated, may involve the orbit

107. NXG: Trunk & proximal extremity lesions are orange-red plaques w/ active red border & an atrophic border with superficial telangiectasias

108. NXG: conjunctivitis, keratitis, scleritis, uveitis, iritis, ectropion or proptosis

109. NXG: Process extends into the fat, obliterating fat lobules. Extensive zones of degenerated collagen or “necrobiosis” surrounded by palisaded macrophages.

110. NXG: Foam Cells with abundant infiltrate of lymphocytes, plasma cells

111. NXG: Cholesterol Clefts

112. NXG and Malignancy 80% IgG monoclonal paraproteinemia (Kappa) Bone marrow may show plasmacytosis, anemia, leukopenia, myeloma, myelodysplastic syndromes. Cause unknown, course progressive Treat aimed at paraproteinemia: Melaphan, Chlorambucil, Corticosteroids, Plasmapheresis, Alpha Interferon-2b

113. Xanthoma Disseminatum Serum lipids are normal, MC young males Mucocutaneous, discreet, disseminated Intertriginous distribution Diabetes Insipidus 40% due to xanthomatous infiltration of the pituitary gland. Chronic and Benign, may persist, may involute spontaneously after some years

115. XD - Periorbital

116. XD - Axillary

117. XD - Pathology Xanthoma Cells Eosinophilic Histiocytes Numerous Touton giant cells Inflammatory cell infiltrate usually present.

118. Papular Xanthoma Small yellowish papules Localized or generalized No tendency to merge into plaques Aggregates of foam cells in the dermis without a cellular or histiocytic phase Absence of inflammatory cells.

119. Indeterminate Cell Histiocytosis Dermal precursors of Langerhan’s cells S-100 positive CD1 positive NO BIRBECK GRANULES! Chronic without spontaneous involution No systemic involvement

120. Progressive Nodular Histiocytosis Superficial papules & deeper nodules Diffuse, symmetrical, non-flexural. Larger lesions may ulcerate, become painful Face lesions may coalesce into leonine facies General health is good

121. Progressive Nodular Histiocytosis Histo: DF-like, few Toutons, lacks the PAS+ ground glass giant cells of MRH. Stains positive for Vimentin, CD68, Factor XIIIa Stains negative for S-100 and CD34

122. Hereditary Progressive Mucinous Histiocytosis in Women AD or X-linked Few to numerous flesh to red-brown papules up to 5mm in diameter Face, arms, forearms, hands, legs Onset 2 nd decade Slow progression, no tendency to spontaneous involution, no systemic involvement

123. Hereditary Progressive Mucinous Histiocytosis in Women May histologically differentiate from other non-X histiocytoses as follows: Familial pattern Abundant mucin + Alcian blue staining Lack of lipidized and multinucleated cells

124. Rosai-Dorfman Disease Aka Sinus Histiocytosis with Massive Lymphadenopathy Onset 1 st or 2 nd decade of life Fever, massive cervical LAD, polyclonal hyperglobulinemia, leukocytosis, anemia, elevated SED rate. Males and blacks MC. Skin involvement in 43% of cases Most patients with skin lesions are > age 40

125. Rosai-Dorfman Disease Isolated or disseminated yellow-brown papules or nodules, or macular erythema. Large annular lesions resembling GA may occur. HHV-6 identified in numerous reports. May clear spontaneously Skin biopsy non-specific unless emperipolesis is present but lymph node pathology is characteristic…..

126. RDD

127. Large histiocytes are located inside a dermal lymphatic. Surrounding the lymphatic are numerous histiocytes and groups of lymphocytes. The inset shows a histiocyte which has engulfed severl lymphocytes (emperipolesis).

128. Rosai-Dorfman Disease – LN Biopsy Expansion of the sinuses by large foamy histiocytes admixed with plasma cells CD4, Factor XIIIa and S-100 positive No Birbeck granules

129. RDD - Emperipolesis – Histiocytes engulf plasma cells and lymphocytes

130. RDD - Emperipolesis

131. RDD - Treatment Radiation Chemotherapy Systemic corticosteroids Thalidomide

132. Sea-Blue Histiocytosis Familial or Acquired Characteristic and diagnostic cell is a histiocyte containing cytoplasmic granules that stain as follows: Blue-green with Geimsa Blue with May-Gruenwald

133. Sea-Blue Histiocytosis Lesions include papules, eyelid swelling and patchy gray pigmentation of the face and upper trunk. Infiltrates marrow, spleen, liver, lymph nodes, lungs and skin in some cases. Similar findings seen in patients with Myelogenous leukemia and Neimann-Pick Disease, and following prolonged use of IV fat supplementation

134. Sea-Blue Histiocytosis – Bone Marrow

135. X-type Histiocytoses Hashimoto-Pritzker aka Congenital Self-Healing Reticulohistiocytois Histiocytosis X Aka Letterer-Siwe Aka Hand-Schuller Christian Aka Eosinophilic Granuloma

136. Hashimoto-Pritzker Onset: birth or very soon thereafter Solitary or multinodular Red, brown, pink or dusky Lesions > 1 cm characteristically ulcerate as they resolve Asymptomatic, resolves in 8 to 24 weeks

137. Hashimoto-Pritzker

138. Hashimoto-Pritzker Before and After

139. Hashimoto-Pritzker

141. EM: 10-25% of cells have Langerhans’ cell granules, but this does not distinguish Hashimoto-Pritzker from Histiocytosis X.

142. H&E: large mononuclear cells & multinucleated giant cells with ground glass or foamy cytoplasm

143. S-100 stainCD1a stain HASHIMOTO-PRITZKER

144. H-P MANAGEMENT Must rule out Histiocytosis-X as both present similarly Rule out systemic involvement with physical exam, CBC, LFT, Bone survey. If any of the above are abnormal, consider liver-spleen scan and bone marrow biopsy.

145. Histiocytosis X Proliferation of Langerhans’ cells MC-Bone, Skin, Lymph, Lungs, Liver and Spleen, Endocrine glands, CNS. Children age 1-4 years old Lymphs are clonal, but not as atypical appearing as lymphoma cells – debate as to whether this is neoplastic v. reactive

146. Histiocytosis X RESTRICTED TYPES: A) Biopsy proven skin rash without other involvement B) Monostotic lesions, with or without diabetes insipidus, LAD or rash C) Polyostotic lesions with or without diabetes insipidus, LAD or rash.

147. Histiocytosis X EXTENSIVE TYPE: A) Visceral involvement with or without bone lesions, diabetes insipidus, LAD or rash but WITHOUTsigns of organ dysfunction of lung, liver or hematopoetic system B) Visceral involvement with or without bone lesions, diabetes insipidus, LAD or rash but WITH signs of organ dysfunction.

148. Histiocytosis X Distribution MC is Letterer-Siwe: Tiny red, red- brown or yellow papules that are widespread but favor the intertriginous areas, behind ears and scalp. Lesions may erode or weep. In children, LS distribution is assoc. with multisystem disease, but in adults 25% have disease limited to skin only.

149. Letterer-Siwe

151. Langerhans cell disease

155. Langerhans cell disease mistaken for refractory diaper dermatitis

156. Histicytosis X - scalp

157. Often mistaken for SD, but focal hemorrhage is present

161. Histiocytosis X - TX Skin only: topical steroids, nitrogen mustard, PUVA, Interferon Alpha. extensive disease but without organ dysfunction: oral corticosteroids Extensive disease with orgain dysfunction: Vinblastine, Cyclosporine, Radiation. Refractory: 2-chlorodeoxyadenosine

162. Guess what the ACS recommends annually for men over the age of 40

163. SLICK RICK SAYS: “I know” THE END