Classification and Pathology

Three classes of childhood histiocytosis are recognized, based on histopathologic findings. The most well-known childhood histiocytosis, previously known as histiocytosis X, constitutes class I and includes the clinical entities of eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease. The name Langerhans cell histiocytosis (LCH) has been applied to the class I histiocytoses. The normal Langerhans cell is an antigen-presenting cell of the skin. The hallmark of LCH in all forms is the presence of a clonal proliferation of cells of the monocyte lineage containing the characteristic electron microscopic findings of a Langerhans cell. This is the Birbeck granule, a tennis racket–shaped bilamellar granule that, when seen in the cytoplasm of lesional cells in LCH, is diagnostic of the disease. The Birbeck granule expresses a newly characterized antigen, langerin (CD207), which is involved in antigen presentation to T lymphocytes. CD207 expression has been established to be uniformly present in LCH lesions and thus becomes an additional reliable diagnostic marker. The definitive diagnosis of LCH also can be established by demonstrating CD1a-positivity of lesional cells, which now can be done using fixed tissue. The lesions may contain various proportions of these Langerhans granule-containing cells, lymphocytes, granulocytes, monocytes, and eosinophils.

In contrast to the prominence of an antigen-presenting cell (the Langerhans cell) in the class I histiocytoses, the class II histiocytoses are nonmalignant proliferative disorders that are characterized by accumulation of antigen-processing cells (macrophages). Hemophagocytic lymphohistiocytoses (HLH) are the result of uncontrolled hemophagocytosis and uncontrolled activation (upregulation) of inflammatory cytokines similar to the macrophage activation syndrome (see Table 149-5). Tissue infiltration by activated CD8 T lymphocytes, activated macrophages, and hypercytokinemia are classic features. With the characteristic morphology of normal macrophages by light microscopy, these phagocytic cells are negative for the markers (Birbeck granules, CD1a-positivity, CD207-positivity) characteristic of the cells found in LCH. The 2 major diseases among the class II histiocytoses have indistinguishable pathologic findings. One is familial hemophagocytic lymphohistiocytosis (FHLH), previously called familial erythrophagocytic lymphohistiocytosis (FEL), which is the only inherited form of histiocytosis and is autosomal recessive. Some specific genes involved with FEL include mutations of perforin, Munc 13-4, and Syntaxin-11 and all are related to pathways of granule-mediated cellular cytotoxicity. The other is the infection-associated hemophagocytic syndrome (IAHS), also called secondary hemophagocytic lymphohistiocytosis (Table 501-2). Both diseases are characterized by disseminated lesions that involve many organ systems. The lesions are characterized by infiltration of the involved organ with activated phagocytic macrophages and lymphocytes, in which the lymphocyte (cytolytic pathway) defects are considered to be the primary abnormality. These diseases are grouped together under the term hemophagocytic lymphohistiocytosis (HLH) (Table 501-3).

Table 501-3 DISTINGUISHING CHARACTERISTICS OF THE REACTIVE LYMPHOHISTIOCYTOSES

The mixed cellular lesions of both the class I and class II histiocytoses are increasing believed to point to these as being disorders of immune regulation, resulting from either an unusual and unidentified antigenic stimulation or an abnormal and somehow defective cellular immune response. Mutations in the perforin (PRF1) gene or the Munc 13-4 gene cause defective function of the cytotoxic lymphocytes whose activity is inhibited in FHLH.

The class III histiocytoses, in contrast, are unequivocal malignancies of cells of monocyte-macrophage lineage. By this definition, acute monocytic leukemia and true malignant histiocytosis are included among the class III histiocytoses (Chapter 489). The existence of neoplasms of Langerhans cells is controversial. Some cases of LCH demonstrate clonality.

501.1 Class I Histiocytoses

Stephan Ladisch

Clinical Manifestations

LCH has an extremely variable presentation. The skeleton is involved in 80% of patients and may be the only affected site, especially in children >5 yr of age. Bone lesions may be single or multiple and are seen most commonly in the skull (Fig. 501-1). Other sites include the pelvis, femur, vertebra, maxilla, and mandible. They may be asymptomatic or associated with pain and local swelling. Involvement of the spine may result in collapse of the vertebral body, which can be seen radiographically, and may cause secondary compression of the spinal cord. In flat and long bones, osteolytic lesions with sharp borders occur and no evidence exists of reactive new bone formation until the lesions begin to heal. Lesions that involve weight-bearing long bones may result in pathologic fractures. Chronically draining, infected ears are commonly associated with destruction in the mastoid area. Bone destruction in the mandible and maxilla may result in teeth that, on radiographs, appear to be free floating. With response to therapy, healing may be complete.