Clinical Summary:
A 70-year-old woman presented with increasing shortness of breath of several weeks duration. Further work-up revealed a large mass located in the thymus, which was surgically resected. The resected mass weighed 144 g, measured 21.0 cm in greatest dimension and on sectioning had a predominantly uniform tan appearance with focal areas of calcifications. The light microscopic appearance of the mass prompted immunohistochemical studies and the pertinent results are as follows: The lesional cells were negative for cytokeratin AE1/AE3, CK19, p63, CD5 and CD117. They showed focal cytoplasmic staining for CD21and strong positivity for CD35 and D2-40.


Criteria for Diagnosis and Comments:
Histologic sections of the tumor show a relatively well-circumscribed mass composed of a proliferation of atypical spindled to polygonal cells in a background of abundant small lymphocytes and plasma cells. The spindled cells show moderate to severe nuclear atypia and pleomorphism and contain prominent eosinophilic nucleoli. Scattered mitoses are identified. Overall the neoplasm is confined by its capsule. Based on the location of the tumor and the histologic features, the differential diagnosis includes a thymic epithelial neoplasm. Immunohistochemical studies showed the atypical spindled and polygonal cells to be negative for cytokeratin AE1/AE3, CK19 and p63, markers associated with thymic epithelium, and negative for CD5 and CD117, markers associated with thymic carcinoma. The lesional cells were also negative for CD45, CD3, CD20, CD15 and CD30, which helps exclude large B cell lymphoma and Hodgkin lymphoma. The background small lymphocytes were positive for CD3 and CD5. The neoplastic cells showed focal cytoplasmic staining for CD21 and strong positivity for CD35 and D2-40, markers associated with dendritic reticulum cells. The overall morphologic features combined with the above immunoprofile best support a diagnosis of follicular dendritic cell sarcoma. 

Follicular dendritic cells (FDCs) are nonlymphoid, nonphagocytic accessory cells of the immune system. They normally reside in the primary and secondary lymphoid follicles and serve as antigen-presenting cells, playing a major role in the induction and maintenance of humoral immune responses and germinal center reaction regulations.  The existence of FDC tumors had been predicted by Lennert in 1978, but it was not until 1986 that the tumor was first characterized by Monda et al. Since then, a number of studies of FDC tumors have been reported, expanding the clinical and morphologic spectrum, including occurrence in extranodal tissues.

Histologically, FDC sarcoma is characterized by syncytial-appearing spindled cells arranged in a storiform to whorled pattern. The spindled cells possess oval nuclei with vesicular chromatin and distinct nucleoli. Lymphocytes are characteristically sprinkled throughout the tumor, but they also commonly form perivascular cuffs. The recognized morphologic spectrum of FDC sarcomas has broadened over the years to include endocrine tumor-like vasculature, polygonal cells, hyaline cytoplasm, and myxoid stroma. FDC sarcoma cells generally share the immunophenotype of non-neoplastic FDCs, with CD21, CD35 and/or CD23 being the most specific diagnostic markers. Other positive markers include vimentin, fascin, HLA-DR and EMA. Some tumors are also positive for S-100 protein, CD68, CD45 and CD20, whereas others are not.

Some FDC sarcomas appear to be associated with hyaline-vascular type Castleman disease. This finding is not surprising given that Castleman disease affects extranodal sites as well. Several reports have suggested that the FDC proliferation and dysplastic changes occurring in Castleman disease can form the background from which an FDC sarcoma develops. As such, the relationship of Castleman disease and FDC sarcomas has been suggested to parallel the hyperplasia–dysplasia–neoplasia sequence that is seen in other tumor types.

A number of spindled and epithelioid cell tumors arising in the thymus and the mediastinum should be considered in the differential diagnosis of FDC sarcoma. They include spindle cell thymoma, spindle cell variant of thymic carcinoma, nodular sclerosis and mixed cellularity subtypes of classical Hodgkin lymphoma, and primary mediastinal large B-cell lymphoma. Spindle cell thymomas show cytologically bland epithelial cells and non-neoplastic lymphocytes; they rarely can have a marked plasma cell infiltrate. Unlike FDC sarcoma, the spindled cells in thymoma are immunoreactive for vimentin and cytokeratin, while negative for CD21 and CD35. The spindle cell variant of thymic carcinoma will show overt histologic features of malignancy and complete loss of organotypic features of thymic differentiation with rare intermixed lymphocytes and a similar immunohistochemical profile as thymomas. Nodular sclerosis classical Hodgkin lymphoma shows nodules composed of an inflammatory cell infiltrate with scattered lacunar cell variants of Reed-Sternberg cells, separated by thick collagenous bands, whereas mixed cellularity Hodgkin lymphoma shows a mixed inflammatory cell infiltrate consisting of lymphocytes, eosinophils, plasma cells, epithelioid histiocytes and neutrophils with occasional intermixed classic Reed-Sternberg cells. The neoplastic cells in Hodgkin lymphoma are immunoreactive with CD15 and CD30. Primary mediastinal large B-cell lymphoma shows pleomorphic large cells including centroblasts and immunoblasts with abundant clear cytoplasm and distinct cellular borders, intermixed with small lymphocytes and histiocytes. A characteristic feature is the presence of delicate interstitial fibrosis in the background. The neoplastic cells typically express pan B-cell markers such as CD19, CD20 and CD79a. In addition, CD30 is positive in more than 80% of the cases.

The biological behavior of FDC sarcoma is generally indolent and low-grade but late local recurrence rate is seen in 50% of cases, while distant metastases can occur in 25% of patients. Larger lesions with significant cytologic atypia and necrosis may have a more fulminant course.

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