Japanese Journal of Clinical Oncology Advance Access originally published online on March 13, 2006
Japanese Journal of Clinical Oncology 2006 36(4):249-253; doi:10.1093/jjco/hyl001
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© 2006 Foundation for Promotion of Cancer Research
Case Report |
Follicular Dendritic Cell Tumor of the Liver Associated with Epstein–Barr Virus
1 Division of Hematology and Oncology, Department of Internal Medicine and 2 Department of Pathology, China Medical University Hospital, Taichung, 3 China Medical University, Taichung, 4 Department of Pathology and 5 Division of Medical Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei and 6 National Yang-Ming University, Taipei, Taiwan
For reprints and all correspondence: Li-Yuan Bai, Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung and National Yang-Ming University, Taipei, 2, Yude Road, Taichung 404, Taiwan. E-mail: lybaiii{at}yahoo.com.tw
Received July 4, 2005; accepted December 17, 2005
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Abstract |
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Follicular dendritic cell tumors are an uncommon neoplasm. About half of all cases occur in the lymph nodes, especially in the neck region. Follicular dendritic cell tumors of the liver are even rarer. In this article we report a case of a hepatic follicular dendritic cell tumor. A 30-year-old female was noted to have a hepatic mass 6 cm in size in segment 6. The patient underwent a right lobectomy of the liver. Microscopically, the lesion was an admixture of spindle cells and inflammatory cells, chiefly lymphocytes, plasma cells, histiocytes and a few neutrophils. The spindle cells were arranged in a wavy pattern, with a vague cellular border and eosinophilic cytoplasm. These tumor cells were immunoreactive to CD21 and CD68. The test for Epstein–Barr virus (EBV)-encoded nuclear RNAs using in situ hybridization was also positive. Although hepatic follicular dendritic cell tumors appear similar to conventional inflammatory pseudotumors in terms of histology, they should be regarded as a clonal proliferation of follicular dendritic cells. In contrast to follicular dendritic cell tumors in extrahepatic areas, hepatic follicular dendritic cell tumors have a strong association with EBV and a greater inflammatory component and are more prevalent in females.
Key Words: follicular dendritic cell • liver • Epstein • Barr virus • female
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INTRODUCTION |
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Follicular dendritic cells are non-lymphoid accessory cells of the lymphoid system (1). Their major functions are capture and presentation of antigens and immune complex (2). Follicular dendritic cell tumors have been receiving increasing attention since the first report in 1986 (3). To date fewer than 70 cases of follicular dendritic cell tumors have been reported in the literature in English (2–22). Follicular dendritic cell tumors can be diagnosed by their characteristic histopathology, immunohistochemistry and ultrastructure (2). About half of all cases occur in the lymph nodes, mostly in the neck area. Extranodal follicular dendritic cell tumors have been reported in the tonsil, pharynx, thyroid, liver, spleen, stomach, pancreas, breast, lung and peritoneum (2,5–14,16,18–20). Hepatic follicular dendritic cell tumors, in contrast to follicular dendritic cell tumors outside the liver, have always been shown to be associated with the Epstein–Barr virus (EBV) (6,10–13). In addition, we found that 9 of the 10 previous cases of hepatic follicular dendritic cell tumors occurred in females (6,10–13). This phenomenon of female predominance was not seen in follicular dendritic cell tumors at all sites (2,4). In this article we present a case of a hepatic follicular dendritic cell tumor and review the related literature.
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CASE REPORT |
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A 30-year-old female housekeeper underwent an abdominal sonographic examination during a routine health check-up. A tumor 5.6 x 5.2 cm in diameter was found in the right lobe of the liver. She had no abdominal pain, fever, weight loss or constitutional symptoms. Abdominal computed tomography disclosed a 6 cm mass in segment 6 of the right hepatic lobe. There was a cystic component in the anterior part of the tumor. Hepatic cellular carcinoma or sarcoma was suspected. There was no abnormality in any other area of the abdomen. The chest radiograph looked normal, with a normally sized heart. The patient agreed to a right lobectomy of the liver.
PATHOLOGICAL FINDINGS
A 5.5 x 3.5 cm mass with a well-circumscribed margin, yellowish-white in color and of a firm consistency was noted. This tumor had a cystic compartment containing some debris. Microscopically, the lesion was composed of spindle cells admixed with inflammatory cells, chiefly lymphocytes, plasma cells, histiocytes and a few neutrophils. The spindle cells were arranged in a wavy pattern, with a vague cellular border and eosinophilic cytoplasm (Fig. 1). The nuclei were oval to elongated, with small or inconspicuous nucleoli. The cell boundary was indistinct. Mitoses of the tumor cells were negligible. There were some areas of hemorrhage, with fibrin exudates.
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IMMUNOHISTOCHEMICAL STUDIES
For immunohistochemical studies, antigen retrieval by microwaving in sodium citrate buffer was performed. The following monoclonal antibodies were used for the avidin–biotin–peroxidase complex method: CD3 (Novocastra), CD20 (Dako), CD21 (Dako), CD35 (Dako), CD45 (leukocyte common antigen; Dako), CD68 (Dako) and anti-cytokeratin (Dako). The spindle cells were immunoreactive to CD21 (Fig. 2), CD35 and CD68 in the cell membrane. Other immunostaining tests, including CD3, CD20, CD45 and anti-cytokeratin, were all negative. The background lymphocytes were mostly CD3-positive. There were a few CD20-positive cells.
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IN SITU HYBRIDIZATION
EBV-encoded nuclear RNA in situ hybridization was performed using a digoxigenin-labeled 30-base oligonucleotide antisense probe, as described previously (23). EBV-encoded nuclear RNA signals were positive on the spindle cells (Fig. 3), but not on the lymphocytes.
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Based on these findings, a follicular dendritic cell tumor of the liver was diagnosed. The post-operation period was uneventful and the patient received regular follow-up after discharge.
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DISCUSSION |
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The dendritic cell compartment is composed of follicular dendritic cells at the germinal center of the lymph nodes, and the Langerhans cells of the skin, epidermis, cervix, vagina, stomach and esophagus. The interstitial dendritic cell represents the counterpart of the Langerhans cell in parenchymal organs. The indeterminate cell is derived from the Langerhans cell or the interstitial dendritic cell migrating to local lymphoid tissue following antigen capture. After taking up residence in the T-zone of lymph nodes, the indeterminate cell becomes interdigitating dendritic cell (1). The major function of these non-lymphoid accessory cells of the lymphoid system is the capture and presentation of antigens and immune complexes (2). Follicular dendritic cells also participate in the regulation of the germinal center reaction (14). The site of origin of follicular dendritic cells remains controversial; both hematopoietic origin and fibroblastic reticulum origin have been proposed (4).
Monda et al. reported the first case of a tumor with follicular dendritic cell differentiation in 1986 (3). Since then, such tumors have received increasing attention. There are some isolated case and two relatively large series reports (2–22). To date, fewer than 70 cases of follicular dendritic cell tumors have been reported in the literature in English. The majority of these follicular dendritic cell tumors have occurred in the lymph nodes, especially in the neck region. Extranodal sites of follicular dendritic cell tumors include tonsil, thyroid, palate, pharynx, liver, pancreas, peritoneum, breast and lung (2,5–14,16,18–20).
The mean age of patients at presentation is 43 years, with a range of 17–75 years (2). Males and females are affected with equal frequency. About half of the patients have lesions as a solitary, painless cervical or axillary lymphadenopathy. Constitutional symptoms are uncommon (4). Recognized symptoms include abdominal pain, weight loss, cough and hemoptysis secondary to invasion of the tracheobronchial wall.
The diagnosis of follicular dendritic cell tumors depends on morphology in histopathology, immunohistochemistry and electron microscopic examination. Follicular dendritic cell tumors have usually been described as well-circumscribed nodular masses of a white, pink or tan-gray color, with a solid consistency (2). Microscopically, the tumors are composed of oval to spindle cells arranged in sheets and interlacing fascicles (2). A storiform or whorled growth pattern is frequently encountered. Typically, there is an admixture of small lymphocytes with tumor cells and perivascular cuffs of lymphocytes (1). On electron microscopic examination, the tumor cells are shown to possess long, thin cytoplasmic processes connected to each other by desmosomes. There is no tonofilament, myofilament, basement membrane, complex junction, cytoplasmic interdigitation or Birbeck granule. The latter exists in Langerhans dendritic cells.
Immunohistochemistry is undoubtedly an important tool for the diagnosis of follicular dendritic cell tumors and their differentiation from other, similar tumors. Pileri et al., Perez-Ordonez and Rosai, and Fonseca et al. have described the immunostaining of follicular dendritic cell tumors in detail (1,2,4). The characteristic follicular dendritic cell markers include CD21 (93%), CD35 (89%), R4/23 (63%), Ki-FDC1p (88%) and Ki-M4 (94%). Most cases (92%) express two or more follicular dendritic cell markers (1). In addition, follicular dendritic cell tumors may express HLA-DR (57%), S-100 protein (31%), CD45 (21%), CD68, vimentin (61%), EMA (41%) and Ki-67 (5–50%) (1,4,8). Follicular dendritic cell tumors are negative for CD1a, which is the marker for Langerhans dendritic and interstitial dendritic cells.
Some patients with follicular dendritic cell tumors show a prolonged and indolent clinical behavior, and some patients die when the disease progresses. Surgical removal of the tumor is the primary treatment in most patients. However, local recurrence after surgical resection (36%) is not uncommon (2). In such cases, another operation is performed if possible. Metastasis is also a problem. Follicular dendritic cell tumors usually metastasize to sites such as the lung, liver and lymph nodes. In their study Perez-Ordonez et al. reported that 13 out of 47 patients (28%) had metastatic disease (2). Owing to the limited number of patients with follicular dendritic cell tumors, it is difficult to define the role of radiation therapy and chemotherapy.
Histologically, follicular dendritic cell tumors of the liver are similar to conventional inflammatory pseudotumors. In inflammatory pseudotumors, lesions are characterized by a proliferation of spindle-shaped cells and plasma cells, although occasional histiocytes and lymphocytes are also present. Ultrastructurally, these spindle cells show features of fibroblastic differentiation (24,25). The lesions arise in a variety of tissues, including lung, intestine, stomach and liver. They are believed to be lesions caused by an inflammatory response. Immunohistochemical studies indicate that an inflammatory pseudotumor is a polyclonal non-neoplastic lesion. (25,26). Inflammatory pseudotumors of the liver have been reported in patients over a wide age range (10 months to 83 years; mean 37 years) and with a male-to-female ratio of 2.9 (25). Pathologically, it may be difficult to distinguish hepatic follicular dendritic cell tumors from inflammatory pseudotumors of the liver. Therefore, the diagnosis of hepatic follicular dendritic cell tumor requires the identification of follicular dendritic cells using immunohistochemical studies (12).
Hepatic follicular dendritic cell tumors have interesting features when compared with follicular dendritic cell tumors outside the liver. Eleven cases of hepatic follicular dendritic cell tumors have been reported in the English-language literature (Table 1) (6,10–13, plus ours). First, as mentioned above, follicular dendritic cell tumors of the liver have marked inflammatory infiltrates, which makes it difficult to distinguish them from conventional inflammatory pseudotumors. In contrast, the vast majority of follicular dendritic cell tumors do not contain numerous inflammatory cells (27). Second, all hepatic follicular dendritic cell tumors reported to date have been shown to be EBV-positive. In contrast, EBV is rare in follicular dendritic cell tumors outside the liver. Of 17 patients reported by Chan et al. (9), only one case was shown to be positive for EBV-encoded early nuclear RNAs. Perez-Ordonez et al. (8) also showed that all six cases they studied were negative for EBV-encoded nuclear RNAs. The strong association of hepatic follicular dendritic cell tumors and EBV, in contrast to follicular dendritic cell tumors in extrahepatic areas, needs further investigation (28,29). There is another distinct feature of hepatic follicular dendritic cell tumors. Although follicular dendritic cell tumors are not more prevalent in one sex than in the other (2,4), it is worth noting that 10 of the 11 reported cases of hepatic follicular dendritic cell tumors were in females. The inflammatory feature, consistent expression of EBV and prevalence in females of hepatic follicular dendritic cell tumors may suggest that they are different from follicular dendritic cell tumors of other sites. These differential features have also been noted in splenic follicular dendritic cell tumors (10,19).
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Most reported hepatic follicular dendritic cell tumors have been found in Asian patients. In Asia, EBV tends to infect children at an early age. In general, primary infection occurs in almost all children before 10 years of age in developing countries, at an earlier age than in developed countries. Nasal type NK/T cell lymphoma has a similar presentation. The lesion is almost consistently associated with EBV, and it is also more prevalent in Asian patients. Although the underlying cause is still unknown, we suspect that the age at which infection occurs (earlier in Asians) may contribute to it.
In conclusion, follicular dendritic cell tumors are receiving increasing attention and the diagnosis is becoming more common by virtue of advances in immunohistochemistry. The incidence of follicular dendritic cell tumors may have been underestimated in the past. Follicular dendritic cell tumors of various sites, in particular those of the liver, probably have different natures and causes.
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References |
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