Hepatic Follicular Dendritic Cell Sarcoma Without Epstein-Barr Virus Expression

Primary sarcomas of the liver are extremely rare, accounting for less than 0.1% of all primary hepatic malignancies. The most common histologic types of liver sarcoma are angiosarcoma, leiomyosarcoma, epithelioid hemangioendothelioma, and embryonal sarcoma. Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm that originates from or differentiates toward follicular dendritic cells. Follicular dendritic cells are located primarily in the germinal centers of secondary lymphoid organs and function primarily to present antigen to B cells.1 Follicular dendritic cell sarcoma is a neoplastic proliferation of spindle cells, showing morphologic and phenotypic features of follicular dendritic cells. Follicular dendritic cell sarcoma occurs in young to middle-age patients (mean, 46 years), with a peak incidence between the ages of 30 and 65 years. However, FDCS has been reported in patients ranging in age from 14 to 80 years. The disease is more common in females than males (1.4:1). Follicular dendritic cell sarcoma exhibits distinct immunohistochemical features, including reactivity for the follicular dendritic cell markers CD21, CD35, CD23, Ki-M4, Ki-FDC1p, vimentin, and S100.2 The biological behavior of FDCS is thought to resemble that of sarcoma more than lymphoma.3 

Most FDCSs are located in peripheral lymph nodes. Most FDCSs occur in the lymph nodes of the neck or, less commonly, the axilla, mediastinum, small bowel mesentery, or retroperitoneum. Follicular dendritic cell sarcoma arises in extranodal sites approximately 40% to 50% of the time.2,4 Such sites include the palate, pharynx and nasopharynx, soft tissue of the neck, gastrointestinal tract, liver, skin, and peripancreatic region.4 Involvement of the tonsil or spleen is rare. Only 5 patients with primary hepatic FDCS have been previously described. In each case, the tumor has had histologic features of inflammatory pseudotumor and expression of Epstein-Barr virus (EBV). Herein, we describe another patient with primary FDCS of the liver and compare the pathologic characteristics, immunohistochemical features, and surgical management with those of the published cases.

We evaluated an 82-year-old white man who was found to have an incidental 10-cm liver mass on an abdominal computed tomographic (CT) scan performed to evaluate renal calculi. A fine-needle aspiration biopsy sample revealed lymphocytic and spindle cell proliferation. No therapy was administered. Another CT scan performed 5 months later showed an increase in tumor size to 13 cm. In addition, there was also a question of mild thickening of the gastric wall. A search was initiated for a primary tumor. Serum carcinoembryonic antigen and α-fetoprotein levels and upper endoscopy and colonoscopy results were normal. A core liver biopsy was performed. The tumor was thought to be a malignant fibrous histiocytoma based on morphologic appearance and staining for vimentin. At that point, 7 months from the initial CT scan, the patient developed weakness, intermittent fever, anorexia, a 9-kg weight loss, and 1 episode of syncope.

The patient was then referred to our institution. On physical examination, the patient had hepatomegaly. Initial laboratory data were notable for a hemoglobin level of 8 g/dL and significant hypoalbuminemia (albumin, 2.8 g/dL). A subsequent CT scan (Figure 1) showed a 15 × 10-cm mass that occupied segments VI, VII, and VIII of the liver. The clinical differential diagnosis included metastasis from either a gastrointestinal stromal tumor or leiomyosarcoma of the stomach, given the possible gastric wall thickening on CT, or a primary liver sarcoma. A CT-guided core biopsy specimen again showed spindle cell proliferation with immunoreactivity for vimentin, and there was focal staining for S100 protein. All other markers tested, including cytokeratin, Kit, CD34, HMB-45, and desmin, were negative. Therefore, a definitive pathologic diagnosis could not be rendered, and a differential diagnosis of sarcoma versus sarcomatoid carcinoma was suggested.

Because the patient was otherwise in good health, we decided to resect the solitary liver tumor responsible for his symptoms. At operation, there was no evidence of extrahepatic disease and, by inspection and intraoperative ultrasound, there were no other intrahepatic tumors. A right hepatic lobectomy was performed with extrahepatic control of the right hepatic vein and intrahepatic division of the right anterior and posterior pedicles individually. The estimated intraoperative blood loss was 200 mL. Postoperatively, the patient developed a sustained fever, and a search for the source revealed a small subdiaphragmatic fluid collection, which turned out to be a sterile seroma on CT-guided needle aspiration. The fever abated and the patient was discharged home on postoperative day 11 in stable condition and tolerating a regular diet. The patient's hemoglobin and albumin levels returned to normal. A surveillance CT scan performed 18 months after surgery did not demonstrate any evidence of recurrent disease.

The surgical specimen measured 20 × 17 × 12 cm and weighed 1670 g. It contained a 15 × 12 × 9-cm right liver mass, which grossly had a tan-gray, glistening, and lobulated cut surface with central areas of necrosis and hemorrhage. The tumor was 1.5 cm away from the closest hepatic resection margin, and the remaining liver parenchyma was unremarkable. Microscopically, the lesion had a uniform ovoid to spindle cell proliferation, which was arranged in compact whorls and short storiform patterns and associated with a brisk lymphoplasmacytic infiltrate. The individual neoplastic cells had indistinct cell borders and vesicular nuclei, with small nucleoli. There was no significant cytologic atypia, and mitotic figures were rarely identified. Despite the easily identifiable inflammatory cells, the tumor cells were arranged in cohesive clusters, more in keeping with a conventional type of FDCS rather than the inflammatory pseudotumor variant (Figure 2, A).

The submitted tissue was fixed in formalin, embedded in paraffin, and stained with hematoxylin-eosin using routine methods. Immunohistochemical analysis was performed in a standard fashion with the following antibodies (all from Ventana Medical Systems Inc, Tucson, Ariz, except where noted): CD21 (1:500; DakoCytomation, Carpinteria, Calif), CD35, vimentin, S100 protein (1:500; Dako), anaplastic lymphoma kinase protein, CAM 5.2, AE1/AE3, HHF-35, smooth muscle actin, and HMB-45. There was strong and diffuse reactivity for CD21 (Figure 2, B), CD35, and vimentin and no staining for S100 protein, anaplastic lymphoma kinase protein, CAM 5.2, AE1/ AE3, HHF-35, smooth muscle actin, or HMB-45. This immunoprofile supported the diagnosis of FDCS. Epstein-Barr virus expression was absent by EBV-encoded nuclear RNA in situ hybridization (PNA probe, Dako). The positive control used was a posttransplantation EBV-associated diffuse large cell lymphoma.

Electron microscopy revealed plump spindle cells admixed with numerous inflammatory cells that were mainly lymphocytes. The distinctive features of the lesional cells included (1) markedly irregular and indented nuclear contours; (2) well-developed and dilated rough endoplasmic reticulum complexes (Figure 3, A); (3) numerous, well-formed desmosomes, present in small junctional complexes (Figure 3, B); (4) scattered lysosomes; and (5) well-developed Golgi. In addition, vague condensations of fine filaments were noted in some cells. The ultrastructural findings also were consistent with the diagnosis of FDCS.

Shek et al5 reported the first primary liver FDCS in 1996, and only 4 additional cases have since been published (Table 1).3,6,7 Four of the patients were women, and all were middle-aged except our elderly patient. The clinical presentation is nonspecific and includes malaise, anorexia, weight loss, hepatomegaly, intermittent abdominal pain, and mild fever. Laboratory tests may reveal anemia or an elevated alkaline phosphatase level. The average tumor size was 14 cm (Table 2).

Follicular dendritic cell sarcoma is diagnosed by the pathologic findings. Macroscopically, the tumor is well circumscribed but lacks a capsule. It is soft to slightly firm and may contain areas of necrosis and hemorrhage. Microscopically, there are spindle cells with lymphocytes, plasma cells, histiocytes, and some neutrophils. The nuclei may be bilobed, duplicated, or even multinucleated with prominent nucleoli, although in some cases, the nuclei are inconspicuous with fine chromatin.8 In some extranodal FDCSs, other typical characteristics may be observed. The spindle cells may be arranged in sheets and fascicles and concentric whorls, resembling those seen in meningioma. Two critical features are the intimate admixture of tumor cells and small lymphocytes and the presence of perivascular cuffs of mature lymphocytes. Certain pathologic characteristics have been associated with a more aggressive course, including coagulative necrosis, large tumor size (>6 cm), increased mitotic rate (>5 mitoses per 10 high-power fields), and significant atypia.9,10 

Immunohistochemistry is the cornerstone of distinguishing FDCS from other liver tumors, such as inflammatory pseudotumor. Staining for CD21, CD35, and Ki-M4P is found consistently. There may be reactivity to R4/ 23, HHF-35, CD23, vimentin, and CNA-42 (Table 2). Extranodal tumors may stain for factor XIIIa, CD68, epithelial membrane antigen, and S100 protein.2,11 Ki-FDC1 staining was found in 6 of 7 nodal and extranodal cases.2 Follicular dendritic cell sarcoma has weak immunoreactivity to HLA-DR, desmoplakin (desmosome-associated protein), and occasionally actin.

The differential diagnosis of liver FDCS is broad and includes primary (malignant fibrous histiocytoma) or metastatic (gastrointestinal stromal tumor and leiomyosarcoma) sarcoma to the liver, ectopic thymoma, carcinoma, meningioma, melanoma, inflammatory pseudotumor, and Hodgkin disease. In hepatic FDCS, the surrounding liver tissue is usually unremarkable.5,7 Follicular dendritic cell sarcoma may contain some Reed-Sternberg–like cells and may be confused with Hodgkin disease, particularly on needle biopsy specimens. It may be difficult to distinguish FDCS from inflammatory pseudotumor, which does not have well-formed fascicles, concentric whorls, or cellular atypia. An important difference is that FDCS has a relatively sparse background population of plasma cells. Follicular dendritic cell sarcoma can be distinguished from inflammatory pseudotumor by the presence of nuclear atypia and the immunohistochemical profile. The current case possessed more conventional morphologic features of FDCS, with strong and diffuse expression for both CD21 and CD35, which are usually weak in liver FDCS.

The pathogenesis of FDCS is multifactorial. Epstein-Barr virus has been associated with FDCS in approximately 12% of the reported cases.5–7 Although EBV is usually absent in nodal and most extranodal FDCS, it is common in FDCS of the liver and spleen. The presence of EBV proteins is certainly not pathognomonic, since they may be present in Hodgkin disease and inflammatory pseudotumor. The present case is the first reported liver FDCS that lacks EBV expression.3–7,9,12,13 Interestingly, CD21 is the EBV receptor that is commonly expressed in FDCS. Furthermore, freshly isolated follicular dendritic cells infected by EBV became cell lines that possess the phenotype and function of freshly isolated follicular dendritic cells.14 The pathogenesis of FDCS in EBV-negative cases is unknown.14 Lastly, Castleman disease may be linked to FDCS. Rare cases of Castleman disease have nodular hyperplasia or dysplasia of follicular dendritic cells outside the follicles.15 Chan et al4 found that 2 of 17 FDCSs were associated with Castleman disease.

Surgery is the mainstay of treatment for primary FDCS. The efficacy of chemotherapy and radiotherapy is unclear.5 Five of the patients with liver FDCS have undergone partial hepatectomy (Table 2). The remaining patient developed bilateral lower limb purpura secondary to a polyclonal increase of γ-globulin and was treated with steroids.6 

Several reports have suggested that patients with FDCS have a significant risk of both local recurrence and metastatic disease.4,13 In their review of both nodal and extranodal FDCS, Perez-Ordonez et al2 found that 8 of 12 patients were alive without disease, 2 were alive with recurrent disease, and 2 had died of disease. In a separate study of 13 patients with a median follow-up of 3 years, 2 had isolated local recurrence, 2 had metastasis only, and 4 had both local recurrence and metastasis.4 Overall, 5 were free of disease, 5 were alive with disease, and 3 had died of disease. The most common sites of distant failure include distant lymph nodes, lung, and liver.4,13 The most appropriate treatment for locally recurrent FDCS of the liver is unknown. Shek et al5 described 1 patient with a perihepatic recurrence 30 months following a right hemihepatectomy who was successfully palliated with surgical resection.