A 30-year-old white man presented to his primary care physician with a 2-week history of “swelling” in his left groin. The patient had no other complaints and denied any systemic or organ-specific symptoms. He had no history of malignancy. He was moderately obese. Physical examination revealed a 3.0-cm, solitary, painless, freely movable, firm subcutaneous lesion located in the middle inguinal region, which was believed clinically to represent an enlarged lymph node. No palpable adenopathy was identified in other lymph node chains. The patient was treated with oral antibiotic therapy without diminution of the mass. Subsequently, a surgical consultation was obtained. The general surgeon's findings at physical examination were identical to those reported herein. The surgeon performed a fine needle aspiration biopsy of the mass using a 22-gauge, 1-in needle. The smears were immediately alcohol fixed and subsequently Papanicolaou stained.

Cytomorphologic assessment of the smears revealed a polymorphic population of hematolymphoid cells at low-power magnification, including numerous small, mature-appearing lymphocytes, a few admixed activated lymphoid cells and plasmacytoid lymphocytes, occasional true plasma cells, and rare eosinophils dispersed in a clean background containing moderate numbers of erythrocytes (Figure 1). Scattered “tingible body” macrophages were detected at high power (Figure 2). A diagnosis consistent with reactive lymph node was rendered based on the cytomorphologic impression and correlation with the clinical setting of young chronologic age, absence of systemic symptoms, and unifocal presentation.

When the lymph node had not diminished in size after a 6-week interval, the lesion was excised. The excised specimen was grossly described as a 3.5 × 3.0 × 2.0-cm lymph node with minimal attached fatty tissue. The capsule of the node was grossly intact. Cut sections were described as having a firm-to-rubbery consistency. Histologic sections of the lymph node revealed a diffuse infiltrate of mostly small lymphocytes and occasional plasma cells. Focal small residual germinal centers were noted at the periphery. The central portion of the lymph node displayed mild fibrosis, and the sinuses were noted to be obliterated and markedly distended by a cellular infiltrate consisting of large histiocytic cells with ample pale-staining cytoplasm (Figure 3). Readily discernible emperipolesis (lymphophagocytosis) was noted in these histiocytic cells. No immature or cytologically aberrant hematolymphoid cells were present, and Hodgkin cells or variants were not identified. Flow cytometric analysis of fresh tissue from the lymph node demonstrated a polyclonal population of B lymphocytes and admixed T cells. Special stains for microorganisms (Ziehl-Neelsen and Gomori methenamine silver) were negative. An ancillary immunohistochemical study for S100 protein demonstrated diffuse, strong cytoplasmic immunoreactivity (positivity) in the histiocytic cells (Figure 4).

What is your diagnosis?

Cases of sinus histiocytosis with massive lymphadenopathy are at times also labeled with the eponymic brand of Rosai-Dorfman disease. This surname tag line is given to the condition because it was first described in the medical literature by Rosai and Dorfman in 2 publications from the late 1960s and early 1970s.1,2 These early publications reported cases of a “newly recognized benign disease” that was clinically characterized by massive lymphadenopathy, especially of the cervical region, with associated fever and leukocytosis. The disease process was pathologically described as a prominent enlargement of lymph nodes due to dilation of the subcapsular and medullary sinuses with progression to total effacement of nodal architecture by an infiltrate of nonneoplastic histiocytes, often containing phagocytosed lymphocytes. The original reports indicated that the disease most often progressed with a benign, albeit prolonged, clinical course and that the origin and pathogenesis were unknown. The then unanswered questions of cause and course are open-ended still today. Since the original reports of sinus histiocytosis with massive lymphadenopathy were issued, the medical literature has been peppered with reports of numerous extranodal body sites that may also be involved in Rosai-Dorfman disease. Some of these nonlymphoid sites include bone, kidney, breast, lacrimal gland, brain, pituitary, skin, and mucous membranes.3–6 

The original classification or description of Rosai-Dorfman disease as a discreet clinicopathologic entity was given in a preimmunohistochemical era and was essentially based on routine light microscopic evaluation of hematoxylin-eosin–stained sections. Since that time, numerous investigators have probed the origin, differentiation, and nosologic classification of the disease's originally described lesional “histiocytic” cell type. These endeavors have shown the large cells with abundant cytoplasm that distend the medullary sinuses in the lymph nodes of individuals affected by this condition to display strong S100 immunoreactivity, suggesting a possible relationship with the dendritic cell family. This known pattern of reactivity has become useful as a diagnostic adjunct and is well recognized. In addition to S100 positivity, these large cells are generally positive for concanavalin agglutinin and peanut agglutinin lectins and the monocyte-macrophage–associated antigens CD11c, CD14, CD33, CD68, and LN5.7 Labeling with other macrophage markers (MAC 387 and lysozyme) has been found to be variable.7 The lesional cells have also been reported to be immunohistochemically nonreactive for CD1a.8 Negativity for CD1a can prove useful in a diagnostic sense in separating this lesion from one of its chief morphologic differential diagnoses, namely Langerhans cell histiocytosis, a histiocytic proliferation that is classically reported to be CD1a positive and in which numerous eosinophils are frequently admixed.

The literature pertaining to the cytopathology of sinus histiocytosis with massive lymphadenopathy is less abundant and chronologically younger. One of the earliest cytologic illustrations of Rosai-Dorfman disease is from an Italian group of authors who described large histiocytes with abundant pale, eosinophilic cytoplasm containing well-preserved lymphocytes.9 These cells were depicted as being admixed with occasional plasma cells and granulocytes. The Italian authors also pointed out that S100 reactivity was demonstrable by immunocytochemical techniques. Although Touton-type giant cells may be seen in sinus histiocytosis with massive lymphadenopathy, epithelioid histiocytes and well-formed granulomata are generally not part of the cytologic picture. Relatively large nuclear size, nucleolar prominence, cytoplasmic abundance, lymphophagocytosis, and strong S100 immunoreactivity are features that favor Rosai-Dorfman disease over ordinary sinus histiocytosis, another important differential diagnostic entity. The diagnostic sequence of events in our case highlights a potential pitfall that may be encountered in needle aspiration biopsies of sinus histiocytosis with massive lymphadenopathy, namely, failure to recognize prominent lymphophagocytosis and/or misinterpretation of the lesional histiocytic cells as tingible body macrophages. Recognition of emperipolesis or lymphophagocytosis is important in suggesting or firmly establishing an accurate cytodiagnosis of Rosai-Dorfman disease. The high-power photomicrograph on the previous page depicts this cellular process and is actually not a tingible body cell (Figure 2). Emperipolesis, the phenomenon of mature phagocytic cells ingesting intact viable leukocytes (most often macrophages ingesting lymphocytes), is not, however, a morphologic finding with perfect specificity for Rosai-Dorfman disease. Emperipolesis has also been reported in patients with postinfectious and familial hemophagocytic syndromes, neuro-Behçet disease, acquired immunodeficiency syndrome, regressive germinal centers associated with organ transplantation, idiopathic thrombocytopenic purpura, chronic myeloproliferative disorders, gray platelet syndrome, cytophagic histiocytic panniculitis, and natural killer cell lymphomas. An accurate cytodiagnosis of sinus histiocytosis with massive lymphadenopathy, like an accurate cytodiagnosis of any other lymphoid proliferation, must be made in the context of all available cytomorphologic clues and would most likely require immunocytochemical support. Cytodiagnosticians should also remember the possibility of partial nodal involvement by both this entity and other lymphoproliferative disorders.8 

Numerous treatments for Rosai-Dorfman disease have been proposed and investigated.10 Because the condition generally follows a prolonged clinical course with exacerbations and remission phases, multiple therapeutic strategies may be instituted in any given patient. The options include but are not limited to surgical excision or debulking, chemotherapy, radiotherapy, and interferon alfa administration. In most instances, clinical observation without treatment is advised, with aggressive therapies held in reserve for refractory or exceptionally bulky disease that may compromise organ function.

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Author notes

Reprints: Charles D. Sturgis, MD, Evanston Hospital, 2650 Ridge Ave, Evanston, IL 60201 ([email protected])