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1102 Part VIII: Monocytes and Macrophages Chapter 71: Inflammatory and Malignant Histiocytosis 1103

TABLE 71–1. Differentiating Characteristics of Histiocytes*
Histologic Features LCH Malignant Histiocytosis ECD/JXG HLH RDD
HLH-DR ++ + − + +
CD1a ++ +/− − − −
CD14 − +/− ++ ++ ++
CD68 +/− +/− ++ ++ ++
CD163 − − + ++ ++
CD207 (Langerin) +++ +/− − − −
Factor XIIIa − − ++ − −
Fascin − +/− ++ +/− +
Birbeck granules + +/− − − −
Hemophagocytosis +/− − − +/− −
Emperipolesis − − − − +

CD, cluster of differentiation; ECD, Erdheim-Chester disease; HLH, hemophagocytic lymphohistiocytosis; JXG, Juvenile Xanthogranuloma; LCH,
Langerhans cell histiocytosis; RDD, Rosai-Dorfman disease.
Data from Jaffe R: The diagnostic histopathology of Langerhans cell histiocytosis, in Histiocytic Disorders of Children and Adults. Basic Science
Clinical Features, and Therapy, edited by Weitzman S, Egeler RM, pp 14–39. Cambridge University Press, Cambridge, UK, 2005; Chikwava K,
Jaffe R: Langerin (CD207) staining in normal pediatric tissues, reactive lymph nodes, and childhood histiocytic disorders. Pediatr Dev Pathol
7:607–614, 2004; and Lau SK, Chu PG, Weiss LM: Immunohistochemical expression of Langerin in Langerhans cell histiocytosis and non-Langer-
hans cell histiocytic disorders. Am J Surg Pathol 32:615–619, 2008.

TABLE 71–2. Classification of Histiocytic Disorders LANGERHANS CELL HISTIOCYTOSIS
1. Disorders of varying biologic behavior, lacking cytologic atypia HISTORY
a. Dendritic-cell-related
Langerhans cell histiocytosis LCH has a complicated history that underlies the current clinicopatho-
logic approach to the disease. What has come to be identified as LCH
Juvenile xanthogranuloma was first described in case reports and series in the early 1900s. By
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Erdheim-Chester disease the 1950s, patterns of clinical presentations had been categorized as
b. Monocyte-macrophage related Hand-Schüller-Christian (multifocal eosinophilic granulomas) and
Hemophagocytic lymphohistiocytosis Letterer-Siwe (disseminated disease including marrow, spleen and
Familial and/or with identified dysfunctional gene mutation liver). However, these apparently disparate entities were found to share
the same histopathology: histiocytes with abundant cytoplasm and
Secondary hemophagocytic syndromes reniform nuclei among an inflammatory infiltrate that could include
Infection-associated lymphocytes, eosinophils and macrophages. Lichtenstein hypothesized
Malignancy-associated that these clinical disorders must be linked by a common etiology,
Autoimmune-associated and proposed the designation “Histiocytosis X,” with “X” indicating
Other incomplete knowledge of pathogenesis and cell of origin. Two decades
Sinus histiocytosis with massive lymphadenopathy later, Birbeck granules, which had previously been identified only in
epidermal LCs, were identified in DCs of LCH lesions by electron
(Rosai-Dorfman disease) microscopy. Nezelof and colleagues therefore extended Lichtenstein’s
Solitary histiocytoma of macrophage phenotype hypothesis that this spectrum of disorders arises from the epidermal
2. Malignant disorders Langerhans cell. Histiocytosis X has since been regarded as “Langer-
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Dendritic cell related hans cell histiocytosis.”
Histiocytic sarcoma
Monocyte-macrophage related EPIDEMIOLOGY AND INHERITANCE
Leukemias: monocytic M5A and M5B, myelomonocytic M4,
chronic myelomonocytic leukemia The incidence of LCH is 2 to 10 cases per 1 million children younger
than age 15 years. 9–11 A survey of LCH patients in France revealed an
Data from Jaffe R: The diagnostic histopathology of Langerhans cell incidence of 4 to 6 per 1 million in children younger than age 15 years.
histiocytosis, in Histiocytic Disorders of Children and Adults. Basic Sci- The male-to-female ratio is close to 1 and the median age of presentation
ence Clinical Features, and Therapy, edited by Weitzman S, Egeler RM, is 30 months, although patients may present with the disease from birth
pp 14–39. Cambridge University Press, Cambridge, UK, 2005 and
Favara BE, Feller AC, Pauli M et al: Contemporary classification of his- through the ninth decade. Identical and fraternal twins with early onset
tiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell of LCH have been described. There are occasional reports of affected
Proliferations. Reclassification Working Group of the Histiocyte Society. nontwin siblings and multiple cases in one family, although it is not
Med Pediatr Oncol 29:157–166, 1997. clear if this is significantly greater than one would expect by chance.
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