As defined in the World Health Organization (WHO) classification, histiocytic sarcoma is a malignant neoplasm composed of cells with histologic and immunophenotypic features similar to those of mature tissue histiocytes (1).

Reticulum cell sarcoma; reticulosarcoma; true histiocytic lymphoma.

The term histiocytic lymphoma was first introduced by Rappaport as a designation for all large-cell lymphomas because these neoplasms were thought to originate from histiocytes (2). This heterogeneous group had been named earlier as reticulum cell sarcoma or reticulosarcomas (3). Subsequent immunologic and molecular techniques have since proved that almost all large-cell lymphomas originate from transformed lymphocytes of B- or T-cell lineage (1).

Malignant histiocytosis was a term used in the past to refer to a systemic disorder, occurring mainly in children and adolescents, that was associated with pancytopenia, lymphadenopathy, hepatosplenomegaly, and wasting (2,4). Histiocytic medullary reticulosis, histiocytic reticulosis, and malignant reticulosis are additional historical terms that were used as synonyms for malignant histiocytosis by some investigators (1,4,5). These terms were used because these lesions were thought to originate from monocyte/histiocyte precursors. Immunophenotypic and molecular studies have since shown that most of these lesions were pleomorphic T/null-cell lymphomas, mostly anaplastic large-cell lymphoma, with a smaller subset of cases being sinusoidal large B-cell lymphoma, hepatosplenic T-cell lymphoma, and infection-associated hemophagocytic syndromes (1,6,7,8,9).

Current knowledge of lymphocyte and monocyte/histiocyte biology is remarkably greater than it was in the past, although our understanding of monocytes and histiocytes lags behind that of lymphocytes. Monocytes circulate in the peripheral blood, and histiocytes reside in tissues. Monocytes and histiocytes belong to the mononuclear phagocyte and immunoregulatory effector (M-PIRE) system. The cells of this system have two general functions: they may be involved in either antigen presentation or antigen processing. Antigen-presenting cells include interdigitating dendritic cells, Langerhans cells, and follicular dendritic cells in germinal centers, although the latter may arise from fibroblast-type cells of connective tissue and are strictly not a part of the M-PIRE system (10). Antigen-processing cells include phagocytic histiocytes/macrophages. These different cell types have been distinguished using histochemical, ultrastructural, immunophenotypic, and molecular methods. The term histiocytic sarcoma is currently restricted to neoplasms thought to arise from phagocytic histiocytes/macrophages (1). Neoplasms derived from other specialized types of histiocytes are discussed separately (see Chapter 78).

Histiocytic sarcoma, as is currently defined, is truly a rare neoplasm. In a recent study based on data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, only 122 histiocytic neoplasms (including dendritic cell tumors) were recorded among 114,548 hematopoietic neoplasms for a relatively frequency of 0.15% (11). The incidence rate of histiocytic neoplasms was 0.03 per 100,000 person-years in this study.

The low incidence of histiocytic sarcoma has precluded large epidemiologic studies from being published. In five of the larger and/or relatively recent clinicopathologic studies of this entity, a total of 61 patients were reported (59 with age reported) (12,13,14,15,16). The age of these patients ranged from 0.5 to 89 years, with a median of 51 years. The neoplasm also appears to have bimodal distribution, with increased frequency in patients under 30 years of age and over 50 years of age. In these five studies, there were 33 males and 28 females for a gender ratio of 1.2 to 1.

Histiocytic sarcoma may occur in lymph nodes or extranodal sites. Patients can be asymptomatic but commonly present with systemic symptoms including fever and weight loss. The clinical course can be indolent or aggressive. The most common extranodal sites are the gastrointestinal tract, various soft tissue sites, skin, spleen, and liver (1,12,13,14,15,16,17). When the neoplasm presents in lymph nodes, the cervical region is commonly involved (13). Soft tissue masses can be quite large, up to 12 cm in one study (15). Patients with gastrointestinal involvement can develop intestinal obstruction (13). Skin manifestations by histiocytic sarcoma are variable, with a subset of patients presenting with a rash-like clinical picture, and other patients presenting with solitary or multiple skin tumors. The disease may be localized or disseminated at time of initial diagnosis (14). Some patients present with one or more cytopenias (14). Bone marrow involvement has been reported in some patients (13,14), but this finding raises the differential diagnosis of acute monocytic leukemia associated with extranodal monocytic sarcoma (see Differential Diagnosis section) (13,17,18,19,20,21,22).

The clinical course of patients with histiocytic sarcoma is variable. Despite aggressive radiation and combination chemotherapy, many patients go on to die of disease (12,14). Some correlation exists between dissemination and poor prognosis. Some studies also have suggested that large tumor size correlates with poorer prognosis (15,16). Patients with localized disease may have long survival (12,16). Soft tissue masses can recur locally after complete excision (15).

Histiocytic sarcoma can arise as a second malignant neoplasm after therapy for another neoplasm. Cases of histiocytic sarcoma have been described following indolent follicular lymphoma, precursor B- and T-cell lymphoblastic leukemia/lymphoma, myelodysplastic syndromes, chronic idiopathic myelofibrosis, and germ cell tumors, the latter involving either the gonads or the mediastinum (14,23,24,25,26,27).