The histological and immunohistochemical features support Sinus Histiocytosis with Massive Lymphadenopathy, also known as Rosai-Dorfman Disease. This biopsy may represent either an intra-mammary lymph node involved by the disease or extranodal mammary Rosai-Dorfman Disease.
Sinus Histiocytosis with Massive Lymphadenopathy (SHML) is a rare, idiopathic, histiocytic proliferative disorder that was first described by Rosai and Dorfman in 1969 in a report of four cases that were each originally diagnosed as "malignant reticuloendotheliosis" (1). It may occur either in lymph nodes alone, extra-nodal locations alone, or both simultaneously. Technically the name Rosai-Dorfman Disease (RDD) applies to cases with extra-nodal disease without concurrent lymph node involvement; however, it is often used in cases that have extra-nodal involvement regardless of the lymph node status. In a registry of 423 patients, 43% of cases had at least one site of extra-nodal involvement as well as lymph node involvement, while 23% of cases had extra-nodal involvement only. The most frequent extranodal sites in decreasing order are skin, nasal cavity and paranasal sinuses, soft tissue, eyelid and orbit, and bone (2).
The classic patient presents with lymphadenopathy, which is cervical in 90% of cases. Patients may be either asymptomatic or have pain, fever, and constitutional symptoms. There may be associated hematologic or immunologic abnormalities such as anemia (usually mild normochromic microcytic or hypochromic microcytic), positivity for red blood cell autoantibodies, an elevated erythrocyte sedimentation rate (in 90% of cases), or a polyclonal hypergammaglobulinemia (in 90% of cases). Rarely patients are positive for rheumatoid factor, anti-nuclear autoantibodies, or systemic lupus erythematosus. One study demonstrated a reversal of the CD4: CD8 ratio of circulating lymphocytes (2).
In nodal cases, the sinuses are distended with histiocytes with abundant eosinophilic cytoplasm, round to oval vesicular nuclei, and (usually) one small nucleolus. One of the characteristic features is emperipolesis, or lymphocytes within the cytoplasm of the histiocytes. Mitoses are rare, as is cellular atypia. The lymph node capsule may be fibrotic, with an infiltration of lymphocytes and plasma cells. The immunohistochemical staining profile of the SHML cells is also characteristic: they are always S-100 positive, and usually CD1a negative. In extranodal cases, the emperipolesis is less evident. Both cytology and electron microscopy highlight the emperipolesis; electron microscopy also demonstrates filopodia extending from the histiocyte membranes enveloping lymphocytes (2-4).
The exact nature of the SHML cells and the disorder is unknown. While macrophages are CD68(+), S-100(-), and CD1a(-), and many types of dendritic cells are CD68(-), S-100(+), and CD1a(+), the SHML cells are CD68(+), S-100(+), and usually CD1a(-). They also lack reactivity for R4/23, a monoclonal antibody specific for follicular dendritic cells. They express antigens associated with phagocytosis (such as the Fc receptor of IgG) and lysosymal activity (such as lysosome alpha-1-antitrypsin), antigens associated with early inflammation (Mac-387), and antigens found on monocytes but not tissue macrophages (OKM5 and CD15). They also express "activation" antigens, and receptors for transferrin and interleukin (4-6). These cells have been demonstrated to be polymorphic (7). The SHML cells have been called "true, functionally activated macrophages that may derive from circulating monocytes"(3). Two studies have demonstrated an association with human herpesvirus-6 (8-9). One case report suggested a relationship with or histologic continuum between SHML and an inflammatory pseudotumor (10).
The differential diagnosis consists mainly of histiocytic proliferative disorders that present with distention of the sinuses. On one end of the spectrum is Langerhans Histiocytosis X (LCH). However, these cells tend to have a nucleus that is smaller than that of the SHML cells and has a characteristic groove. Ultrastructurally the nucleus contains Birbeck granules. LCH usually shows fewer plasma cells and eosinophils than SHML. Immunohistochemically, it is always S-100(+) and CD1a(+). On the other end of the spectrum is reactive sinus hyperplasia. The sinuses in these cases are usually less distended, and the cells are S-100(-). Finally, metastatic melanoma may be confused with SHML; however, melanoma stains positively for HMB45 and MelanA in addition to S-100 (4).
The majority of SHML patients have a complete and spontaneous remission, while some may experience recurrent or persistent but stable lymphadenopathy. In very few cases, the disease follows an aggressive course and may be fatal. A poor prognosis correlates with widespread dissemination, involvement of the kidneys, lower respiratory tract, or liver, and immunologic abnormalities or anemia (2).
Treatment is usually unnecessary due to the benign nature of SHML; however, the mass may be surgically removed for comfort or cosmetic reasons. If there is systemic or extensive lymph node involvement, the patient may require chemotherapy or radiation. There are no established regimens, although a combination of vinca alkaloid, an alkylating agent, and corticosteroids appears most beneficial (7).
The breast is an extremely infrequent site of occurrence; there are currently 14 documented cases (10, 12-18). The age of these patients ranged from 15 to 84 with a mean of 54. Ten of these 14 cases had unilateral involvement, while three were unilateral. Ten had no other sites of involvement, two had systemic and extensive lymph node involvement, one had involvement of an ipsilateral lymph node, and one had a concurrent small mass of the soft tissue of the flank. At last follow up, seven of these patients were alive and well, and one was dead of disease (this was one of the patients with systemic and extensive lymph node involvement).
Rosai-Dorfman Disease of the breast presents both clinically and radiologically as a malignancy, and therefore requires tissue diagnosis. Because of its rarity, the diagnosis is often not initially considered in the differential. Proper diagnosis of this generally benign entity spares the patient the need for any further treatment.
Contributed by Melina Flanagan, MD, MSPH and Swaminathan Rajendiran, MD