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CHAPTER 71 CLASSIFICATION OF THE

HISTIOCYTOSES
INFLAMMATORY AND The general description of cells in the monocyte-macrophage system
MALIGNANT HISTIOCYTOSIS (mononuclear phagocyte system) has been largely clarified (Chaps. 67
to 69), although some ambiguity remains. Nomenclature committees
remain loyal to the term “histiocyte,” a designation assigned in the 19th
century to tissue macrophages, although the “histiocytosis” umbrella
Kenneth L. McClain and Carl E. Allen includes functional and neoplastic disorders of a broad range of cells in
the monocyte, macrophage, and dendritic cell (DC) lineages. The dis-
tinctions among diseases in this category are determined by (1) clinical
SUMMARY findings, (2) histopathology, (3) immunocytology to define the antigens
on the surface of the pathologic cells, and (4) cytogenetic or genetic
Diseases of the histiocyte (i.e., macrophage or dendritic cell) lineage can be features (Table 71–1).
divided into four groups based upon the final maturation steps from their The histiocytic disorders have been classified based upon whether
myeloid progenitor cells: (1) Langerhans cell histiocytosis (LCH), (2) malig- they are (1) DC related, (2) monocyte-macrophage related, or (3) malig-
nancies of macrophages or DCs (Table 71–2). Evolving understanding
1,2
nant histiocytoses or dendritic cell sarcomas, (3) juvenile xanthogranuloma/ of myelomonocytic differentiation, as well as cellular origins of histio-
Erdheim-Chester disease, Rosai-Dorfman disease, and (4) hemophagocytic cytic disorders, will likely necessitate revision of these classifications in
lymphohistiocytosis syndromes. Storage diseases of macrophages are dis- the near future.
cussed in Chap. 72. The distinction among these diseases is based upon clinical The pathologic cells in Langerhans cell histiocytosis (LCH) lesions
characteristics and histopathologic staining for unique surface markers. LCH have phenotypic similarity to epidermal Langerhans cells (LCs), which
may present at birth or in adulthood with skin rash, bone pain, draining ears, has led to the hypothesis that LCH is derived from aberrant activation
oral ulcers, gingivitis, pulmonary dysfunction, chronic diarrhea, diabetes insip- and/or neoplastic transformation of the epidermal LCs. LCH originates
3
idus, and marrow or liver failure. Therapy for LCH in children has been studied from aberrant proliferation and differentiation of myelomonocytic pre-
4,5
in clinical trials by the Histiocyte Society. Treatment for adults is based primar- cursors. Regardless of ontogeny, LCH lesions are characterized by
ily on case series. Although relapses are not typically rapidly fatal, they are pathologic DCs with phenotypic similarity to epidermal LCs, includ-
associated with a higher risk of endocrine and central nervous system com- ing positive staining with anti-CD207 (antilangerin) and the presence
of Birbeck granules identified by electron microscopy. Birbeck gran-
6,7
plications. The diagnostic criteria for the malignant histiocytosis have been ules are racket-shaped inclusions that are thought to be involved in
clarified by cell-surface marker studies. Treatment options and prognosis vary antigen processing. Cells staining with anti-CD207 and/or anti-CD1a
widely. Erdheim-Chester disease and juvenile xanthogranuloma are pheno- are required for the diagnosis of LCH. Other antigens, such as S100 or
typically similar, but are treated differently. Erdheim-Chester disease is found HLA-DR (human leukocyte antigen-D related) are not specific for LCH.
almost exclusively in adults and juvenile xanthogranuloma occurs primarily in The histiocytes in Erdheim-Chester disease (ECD) and juvenile xantho-
children. Rosai-Dorfman disease presents with massive cervical lymphade- granuloma (JXG) have phenotypic similarity to the dermal–interstitial
nopathy in most patients, but may also involve other parts of the body. There dendrocyte that stains with antibodies to CD68, fascin, and factor XIIIa.
are several treatment options for Rosai-Dorfman disease, Erdheim-Chester However, the DCs in these disorders also express surface CD163 that is
disease, and juvenile xanthogranuloma, but no clinical trials of specific drugs characteristic of macrophages.
have been published. Hemophagocytic lymphohistiocytosis (HLH) is charac- Malignant histiocytosis (or “histiocytic sarcoma”) has evolved as a
terized by pathologic inflammation and may present with infections, hepatitis, diagnosis of exclusion involving malignant histiocytes that lack markers
for anaplastic large cell lymphoma or other hematologic malignancies.
meningitis, or autoimmune diseases. Without therapy, HLH is almost univer- Malignant histiocytosis represents a spectrum of malignancies that pre-
sally fatal. Most patients who receive prompt diagnosis and treatment with sumably derive from DCs of different lineages at different stages of dif-
immune suppression therapy survive. ferentiation. Human DCs are defined as hematopoietic cells expressing
high levels of major histocompatibility complex II (MCHII) and CD11c
while lacking other specific lineage markers. Under normal conditions,
these cells reside in tissue or circulate in the blood. Once stimulated
by antigen, they migrate to lymphoid tissue and interact with effector
or suppressor T cells. Malignant histiocytoses are variable and share
Acronyms and Abbreviations: AHSCT, allogeneic hematopoietic stem cell surface markers with DC subsets: follicular DC “sarcoma” (CD21+,
transplantation; ALL, acute lymphoblastic leukemia; ATG, antithymocyte CD35+), interdigitating DC “sarcoma” (CD14+), and Langerhans cell
globulin; CD, cluster designation; CT, computed tomography; DC, dendritic “sarcoma” (CD1a+).
cell; DI, diabetes insipidus; DLCO, diffusing capacity in lung for carbon dioxide; The monocyte-macrophage disorders include Rosai-Dorfman dis-
ECD, Erdheim-Chester disease; FEV , forced expiratory volume in 1 second; ease (RDD) and hemophagocytic lymphohistiocytosis (HLH). RDD,
also known as sinus histiocytosis with massive lymphadenopathy, has
1
HLA-DR, human leukocyte antigen-D related; HLH, hemophagocytic lympho- the telltale histopathologic finding of intact lymphocytes in the cyto-
histiocytosis; IFN, interferon; IL, interleukin; JXG, juvenile xanthogranuloma; plasm of macrophages (emperipolesis), a feature that must be present
LC, Langerhans cell; LCH, Langerhans cell histiocytosis; M-CSF, macrophage to diagnose this disorder. HLH is distinct among the diseases discussed
colony-stimulating factor; MRI, magnetic resonance imaging; NK, natural in this chapter in that the macrophages are nonneoplastic, otherwise
killer; PET, positron emission tomography; RDD, Rosai-Dorfman disease. normal histiocytes, characterized by a pathologic reaction to aberrant
stimuli.

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