boards’ fodder Histiocytosis Amy Reinstadler, MD (Updated July 2015*) Most common Histiocytosis Age group Other findings Histology mucocutaneous sites Langerhans cell histiocytoses (previously Histiocytosis X) Letterer–Siwe Young infants Scalp, face trunk, but- • Visceral and bone More epidermotropism, (<2 years) tocks (resembles seb- lesions fewer foamy cells orrheic dermatitis) • More fulminant course • Fever, anemia, lymphadenopathy • Hemorrhagic Langerhans component may cells (reniform resemble blueberry nuclei; may be muffin baby foamy or resem- ble Touton histiocytes) Hand– Children May resemble • Diabetes insipidus with epidermo- Less epidermotropism, Schüller–Christian beyond Letterer-Siwe or may • Bone lesions (skull) tropism; mixed more foamy cells, more infancy be papulonodular or • Exophthalmos infiltrate (+mast giant cells granulomatous ulcer- cells) ation in intertriginous areas Birbeck gran- ules on electron Eosinophilic Older children Skin lesions rare. Bone lesions primarily; microscopy Less epidermotropism, granuloma and young Nodulo-ulcerative more benign course fewer foamy cells, more adults lesions in mouth, S100+ diffuse infiltrate with perineal, perivulval, or CD1a+ eosinophils, histiocytes, retroauricular CD68- and giant cells Congenital self-heal- Congenital Widespread, local- Spontaneous resolution +/- Birbeck granules on ing reticulohistiocy- ized, or single lesion in several months; usu- electron microscopy tosis (Hashimoto– ally no systemic disease Pritzker disease) Non-Langerhans cell histiocytoses Cutaneous, self-resolving Juvenile Young infants - Head and neck • Rare eye and visceral • Nodular or diffuse xanthogranuloma (~75% occur > upper trunk > lesions; can lead to infiltrate of histiocytes, in 1st year of extremities blindness lymphocytes, and life) - Small nodular form: • Oral JXG is rare; eosinophils (early) multiple 2–5 mm usually on lateral • Foamy histiocytes papules tongue or midline of and Touton giant - Large nodular form: the hard palate cells (late) one or few 1-2 cm • When associated Dendritic cell • Dermoscopy: orange- nodules with NF1, 20x marker: yellow background increased risk of Factor XIIIa+ with a subtle peripheral developing juvenile erythematous border myelomonocytic Macrophage with linear branched 1 leukemia markers: vessels (“setting 2 CD68+ sun”) Benign cephalic Young infants Face and neck Usually none, spontane- HAM56+/- Diffuse dermal non- histiocytosis ous resolution Mac387 +/- foamy histiocytes with sparse lymphocytes Langerhans cell and eosinophils markers: Reticulohistiocytoma Adults Head (solitary lesion) None CD1a- Circumscribed dermal S100- nodule with oncocytic CD34- mononuclear histio- cytes, multinucleate giant cells with ground glass cytoplasm Generalized eruptive <4 and Widespread (axial); Spontaneous resolution Superficial and mid der- Amy Reinstadler, histiocytosis adults occasional mucosal mis with a uniform infil- MD, is a dermatology involvement in adults trate of histiocytes and resident at University a few lymphocytes of California, Irvine. Indeterminate cell Adults and Widespread > face • Uncommon visceral Immunophenotypic profile–antigenic histiocytosis children and neck and bone lesions markers of both LCH (S100+, CD1a+) • Ocular involvement and non-LCH (CD68+, Factor XIIIa+, has been described HAM56+) • Usually self limited No Birbeck granules irinections D Residency p. 1 • Winter 2011 boards’ fodder Histiocytosis Amy Reinstadler, MD (Updated July 2015*) Most common Histiocytosis Age group Other findings Histology mucocutaneous sites Cutaneous, persistent/progressive Papular xanthoma Any Generalized; None. Affected Foamy macrophages occasionally on individuals are usually and Touton giant cells. mucous membranes normolipidemic Factor XIIIa+ No chronic inflamma- CD68+ tory cells Progressive nodular Any Nodules on trunk and Normolipidemic HAM56+ Histiocytes, foam cells, histiocytoma papules widespread spindled cells (including genitals) Cutaneous with frequent systemic involvement Necrobiotic Teens to Periorbital > trunk, Paraproteinemia (IgG • Broad zones of hyaline necrobiosis xanthogranuloma adults exremities kappa), hepa- tospleno- and granulomatous foci composed of megaly, lympho-prolifer- histiocytes, foam cells, and multinucleate ative disease giant cells (Touton and foreign body type) • Cholesterol clefts may be present Multicentric Adults Head, hands, fingers • Arthritis (often • Nodular infiltrate of histiocytes with reticulohistiocytosis (usually >30) (‘coral bead’ appear- destructive) ground glass cytoplasm ance periungually), • Up to 30% with internal • Bizarre multinucleated giant cells ears, and articular malignancy • Mixed infiltrate regions of the limbs; • Assoc with • CD68+, S100- mucosa (oral, naso- hyperlipidemia, pharyngeal) + PPD, systemic vasculitis, and autoimmune disease Rosai–Dorfman Kids and Eyelids and malar Massive • Affected lymph nodes with dilated Disease (Sinus young adults area Lymphadenopathy (most sinuses containing neutrophils, Histiocytosis often cervical) lymphocytes, plasma cells, and with Massive in a subset of patients, histiocytes with large vesicular nuclei Lymphadenopathy fever, hyper-gamma- and abundant cytoplasm (SHML) globulinemia • Cutaneous lesions with dense dermal infiltrate of histiocytes with scattered lymphocytes, plasma cells and H Syndrome3 Mean age Hyperpigmentation LAD, HSM, hearing loss, neutrophils ~20 and hypertrichosis heart anomalies, hypo- • Emperipolesis (inner thighs and gonadism, low height, • S100+, CD68+, CD1a- shins) hyperglycemia, hallux valgus Xanthoma Young adults, Flexural areas to Diabetes insipidus, • Histiocytes, foam cells, spindle cells, disseminatum children widespread > osteolytic bone lesions; Touton cells, and a moderate number of mucosa (oral, normolipemic chronic inflammatory cells nasopharyngeal) • CD68+, factor XIIIa +, S100-, CD1a- Systemic, with rare cutaneous involvement Erdheim–Chester Usually adults Dermal and subQ • Primarily a disease of • Lipidized histiocytes involve the dermis, disease but can be nodules, xanthelas- long bones of lower often with extension into the subcutis any age mas/ xanthomas, limbs producing • CD68+, factor XIIIa+, CD1a−, and intertrigo-like lesions, patchy medullary S100− pretibial dermopathy, sclerosis with sparing +/- Touton giant cells pigmented patches on of epiphyses the lips and mucosa • BRAF V600E mutation in 54% Hemophagocytic Usually in Jaundice and non- Fever, splenomegaly, • Non-specific spongiosis and a mild lymphohistiocytosis infancy/ early specific morbilliform liver dysfunction, cytope- perivascular infiltrate of lymphocytes and childhood but rash nia, hypofibrinogenemia, histiocytes can be any and tissue hemophago- • S100-, CD68+ age cytosis References: 1. Mallory M, Bryer BM, Wilson BB. JAAD Grand Rounds quiz. Café-au-lait macules and enlarging papules on the face. J Am Acad Dermatol. 2013 Feb;68(2):348-50. 2. Pretel M, Irarrazaval I, Lera M, Aguado L, Idoate MA. Dermoscopic “setting sun” pattern of juvenile xanthogranuloma. J Am Acad Dermatol. 2015 Jan;72(1 Suppl):S73-5. 3. Molho-Pessach V, et al. H syndrome: The first 79 patients. J Am Acad Dermatol 2014;70(1):80-87. 4. Kornik RI, Naik HB, Lee CC, Estrada-Veras J, Gahl WA, Cowen EW. Diabetes insipidus, bone lesions, and new-onset red-brown papules in a 42-year-old man. J Am Acad Dermatol. 2013 Jun;68(6):1034-8. *Reviewed and updated July 2015 by: Alina Goldenberg, MD, Elise Herro, MD, and Sharon Jacob, MD. irinections Winter 2011 • p. 2 D Residency.