A rare benign disorder of histiocytes characterized histologically by intracellular engulfment of lymphocytes.

Rosai-Dorfman disease; Histiocytose lipidique ganglionnaire pseudotumorale de Destombes; lymphadenitis with massive hemophagocytic sinus histiocytosis of Lennert.

The etiology of sinus histiocytosis with massive lymphadenopathy (SHML) remains unknown. Although the clinical manifestations and histologic appearance are suggestive of an infectious process, no microorganism has yet been identified.

SHML was initially described by Destombes in 1965 (1). Rosai and Dorfman (2,3) subsequently recognized this disease as a clinicopathologic entity and coined the term sinus histiocytosis with massive lymphadenopathy. Initially, Rosai and Dorfman (2,3) described this disorder as massive, bilateral, and mostly cervical lymphadenopathy in young black children. However, a review of 423 cases published or recorded by 1990 in a registry of cases maintained at the Yale University School of Medicine revealed a much broader spectrum of disease (4). The age of patients ranged from newborn to 74 years (mean, 20.6 years). The geographic distribution was worldwide, all races were affected, and males outnumbered females almost three to two (4). In addition to involving lymph nodes, still the principal site, in approximately one-third of patients, SHML, in the form of pseudotumors, can occur in a variety of extranodal sites (4). Virtually any extranodal site can be affected, but the head and neck region (including the sinuses, orbit and ear) is most common (5). Other relatively commonly involved extranodal sites include the soft tissue, skin, upper respiratory tract, gastrointestinal tract, breast, bones, and the central nervous system (6,7,8,9,10,11). In the latter, SHML is usually dural-based but rare intracerebral lesions are also described (12). Some patients experience a short, nonspecific febrile episode, occasionally with pharyngitis and night sweats, before lymph nodes become enlarged. In most cases, however, localized lymphadenopathy is the only manifestation at onset and during the full course of the disease. Most patients remain generally healthy despite large, sometimes deforming, but painless lymph nodes that can persist for several years. In most cases, the disease is self-limited and eventually recedes.

Rare fatal outcomes can occur in two subsets of patients. Rarely, the disease can be locally aggressive and involve vital organs, thereby causing death (13). Also death can occur in patients with SHML who have generalized lymphadenopathy and immune dysfunction, manifested by hematologic autoantibodies, inflammatory joint disease, glomerulonephritis, or Wiskott-Aldrich syndrome (14,15). The cause of death in this subset of patients may be a consequence of the immunologic abnormality (14). In more aggressive forms of disease, combinations of corticosteroids, chemotherapeutic agents, or radiation therapy have been used, but no effective treatment has yet been devised (16).

SHML rarely has been described in identical twins or family members, suggesting a genetic predisposition or common exposure to an etiologic agent (17). A rare genetic syndrome, known as Faisalabad histiocytosis, and characterized by sensorineural deafness, short stature, and joint contractures is associated with lymphadenopathy that closely mimics, or in fact may be, SHML (18). SHML also has been reported to be associated with autoimmune lymphoproliferative syndrome type Ia (19).

SHML is rarely associated with malignant neoplasms. SHML has been described in association with both non-Hodgkin lymphoma and Hodgkin lymphoma (20,21,22). Follicular lymphoma and nodular lymphocyte predominant Hodgkin lymphoma, respectively, are most commonly associated with SHML. In some patients, the same biopsy specimen is involved by lymphoma and SHML. In these cases, the SHML is apparently asymptomatic and detected incidentally (20). SHML also has been rarely reported in patients with solid tumors (23).

Some patients have one or more immune disorders, such as polyarthralgia, asthma, or hemolytic anemia, preceding or associated with the onset of SHML (4,24). Abnormalities in serum protein levels are detected in most patients, who usually show moderate polyclonal hypergammaglobulinemia. In patients tested, a reversal in the ratio of CD4-to-CD8 circulating lymphocytes was recorded (4).

The pathologic features of SHML have been well described in the literature by others (3,25). Involved lymph nodes are large and matted and exhibit fibrosis of the capsule and pericapsular fibrofatty tissues. The architecture is altered by marked dilatation of the sinuses (Fig. 36.1). The sinuses are obstructed by static lymph and contain a mixed population of cells, including lymphocytes, plasma cells, and histiocytes (Fig. 36.2). The most characteristic cells in the sinuses are histiocytes that have that marked phagocytic properties (henceforth referred to as SHML cells). The SHML cells are generally large and irregularly shaped, with abundant, acidophilic, sometimes vacuolated cytoplasm. These cells usually have one nucleus and can have a distinct, central nucleolus (Fig. 36.3).
Mitoses are rare. The intracytoplasmic vacuoles contain engulfed cells, usually lymphocytes, plasma cells, or erythrocytes. The cells engulfed by histiocytes are usually contained in an intracytoplasmic vacuole, protected from cytolytic enzymes. Some cells, particularly lymphocytes in the vacuoles, are viable, reproducing the phenomenon of emperipolesis (“wandering in and around”) (Fig. 36.3); others are degraded, often forming nuclear fragments (25). Some vacuoles include only nuclear debris or lipids that stain with Sudan black, and as many as 20 engulfed cells may be present in one histiocyte. In relatively less involved areas, lymphoid follicles, often hyperplastic, are present. The medullary pulp includes numerous plasma cells, some binucleated; mature lymphocytes; and occasionally large, compact aggregates of lipid-laden histiocytes. Eosinophils are rare. Necrosis is usually not present, but superimposed infarction necrosis can rarely occur (Fig. 36.4). The engulfed lymphocytes are of both T- and B-cell types. Both lymphocytes and plasma cells express different classes of immunoglobulins, in accord with the polyclonal hypergammaglobulinemia.