DIAGNOSIS: LEPTOMENINGEAL ROSAI-DORFMAN DISEASE
Rosai and Dorfman first described sinus histiocytosis with massive lymphadenopathy in 1969 as a benign lymphohistiocytic proliferative condition involving lymph nodes (1). The classic clinical presentation of Rosai-Dorfman disease is massive painless cervical lymphadenopathy, but can also include nasal obstruction, tonsillar enlargement, or hearing abnormalities. The disease occurs most often in the third and fourth decades and may be accompanied by leukocytosis, elevated erythrocyte sedimentation rate (ESR), weight loss, and hypergammaglobulinemia. While lymph node involvement often dominates the clinical presentation, other anatomic sites are involved in 30-40% of cases, most commonly the skin, upper respiratory tract, orbit and testes (2).
Less commonly (<5%) the central nervous system (CNS) can be involved by Rosai-Dorfman disease (3-5). In 2/3 of CNS cases, the presentation is limited to the brain or spinal cord and is not accompanied by lymphadenopathy. CNS Rosai-Dorfman can present at any age, but most commonly involves patients between 20- and 40-years-old, with a slight male predominance. Symptoms vary depending on the location of the primary lesion. Approximately 75% of cases are intracranial, whereas 20% involve the spine (6). Symptoms of intracranial disease include seizures, headache, weakness, and cranial nerve palsy. Over 90% of CNS Rosai-Dorfman cases involve the leptomeninges and are seen by neuroimaging as a dural-based, contrast-enhancing masses that often elicit vasogenic edema in the underlying cerebral cortex and white matter. Thus, clinically and radiologically, the disease is thought to represent meningioma (7). Definitive diagnosis of Rosai-Dorfman disease involving the leptomeninges is established by biopsy and pathologic examination.
Histopathologically, Rosai-Dorfman disease involving the leptomeninges has features similar to that of lymph node disease. Generally the dura is thickened, fibrotic and contains a variable density of chronic inflammatory cells dominated by lymphocytes and plasma cells. Occasionally, neutrophils and eosinophils are noted. Either interspersed or in sheets are large, pale histiocytes with abundant vacuolated cytoplasm. The finding of emperipolesis is characteristic of Rosai-Dorfman disease of the leptomeninges, but in 30% of cases, this feature will not be identified. Large pale histiocytes of Rosai-Dorfman disease are immunoreactive for S-100 protein and KP1, but negative for CD1a.
The differential diagnosis of a chronic inflammatory infiltrate containing numerous, large histiocytes includes granulomatous diseases such as Wegener's graulomatosis and sarcoid, Hodgkin's disease, and Langerhans histiocytosis. The pathologic work-up should begin with close inspection of H&E slides since the morphologic features of large pale histiocytes in combination with lymphophagocytosis are strongly suggestive of Rosai-Dorfman disease. Nonetheless, special stains for organisms should be performed to rule out infection. A lack of sheet-like necrobiotic type necrosis and necrotizing capillaritis should essentially exclude Wegener's granulomatosis; the absence of small, well formed granulomas makes sarcoid less likely. The morphologic features histiocytes in Langerhans histiocytosis are relatively distinct, with xanthomatous cytoplasm and longitudinal nuclear grooves, neither of which are typical of the large pale histiocytes of Rosai-Dorfman disease. In addition, Langerhans histiocytes are CD1a-positive, whereas those of Rosai-Dorfman disease are CD1a-negative. Hodgkin's disease can have a mixed inflammatory infiltrate and fibrosis, but lacks the histiocytes and emperipolesis of Rosai-Dorfman disease. Morphologic confusion may arise from similarities of Reed-Sternberg cell variants and the histiocytes of Rosai-Dorfman disease. The distinction can be aided by immunohistochemistry. RS variants are S-100 negative and positive for CD15 and CD30, whereas Rosai-Dorfman histiocytes are S-100 positive and negative for CD15 and CD30.
Leptomeningeal Rosai-Dorfman disease is considered a benign condition and in most cases surgical resection is the treatment of choice. Although the number of cases in the literature is small, disease progression following surgical resection is uncommon. Disease progression and poor outcome appear to occur most often when the patient has bulky, multi-organ disease. In cases of persistent or progressive disease, a number of adjuvant therapies have been administered with variable success, including corticosteroids, vincristine, cytoxan, and radiation.
Little is known regarding the pathogenesis of Rosai-Dorfman disease. Most have suggested that it represents either an autoimmune disease or a reaction to an infectious agent that has yet to be discovered. Currently it is best considered a benign, idiopathic histiocytosis.
Contributed by Amilcar A Castellano-Sanchez, MD and Daniel J Brat, MD, PhD