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Follicular dendritic cell tumor presenting in the lung: A case report
CASE STUDIES
FOLLICULAR DENDRITIC CELL TUMOR PRESENTING IN THE LUNG: A CASE REPORT RAJSHRI N. SHAH, MD, OZER OZDEN, MD, ANJANA YELDANDI, MD, LOANN PETERSON, MD, SAMBASIVA RAO, MD, AND WILLIAM B. LASKIN, MD An example of extranodal follicular dendritic cell sarcoma (FDCS) presenting in the lung, a heretofore unreported site, is described. Macroscopically, a 9.5-cm, tan-white, dominant mass and multiple smaller parenchymal and pleural nodules were identified. Microscopically, the tumor was composed of spindled cells with uniform cytologic features arranged in short, intersecting fascicles and intermixed small lymphocytes and plasma cells. One of 4 peribronchial and hilar lymph nodes evaluated microscopically was focally involved by the process. Immunohistochemically, the neoplastic spindled cells expressed complement receptors CD21 and CD35 and low-affinity nerve growth factor receptor but did not express keratin (AE1/AE3 and CAM5.2), CD45 (leukocyte common antigen), CD20 (L26), S-100 protein, muscle-specific actin, or gp100 protein (HMB45). Ultrastructurally, the tumor cells have complex interdigitating cell surface processes and desmosomes. Epstein-Barr virus (EBV) was not
detected in the tumor cells by in situ hybridization for EBV-encoded RNA or by polymerase chain reaction for viral DNA. FDCS should be considered in the differential diagnosis of any spindled-cell tumor with interspersed chronic inflammatory cells occurring in the lung. An immunohistochemical panel, including anti-CD21 and -CD35, can assist in its diagnosis, especially with small bronchial biopsy specimens. HUM PATHOL 32:745-749. Copyright © 2001 by W.B. Saunders Company Key words: follicular dendritic cell sarcoma/tumor, lung, extranodal, Epstein-Barr virus. Abbreviations: FDC, follicular dendritic reticulum cell; FDCS, follicular dendritic cell sarcoma; CT, computed tomography; NGFR, nerve growth factor receptor; EMA, epithelial membrane antigen; EBV, Epstein-Barr virus; EBER, Epstein-Barr virus– encoded RNA; PCR, polymerase chain reaction.
The follicular dendritic reticulum cell (FDC) is a nonlymphoid immune accessory cell that is confined to the B-cell areas of lymphoid follicles and plays a major role in the induction and maintenance of humoral immune responses.1,2
The cell is characterized immunohistochemically by CD21 (C3d complement receptor) and CD35 (C3b complement receptor) expression. Ultrastructurally, FDC possesses complex interdigitating cytoplasmic processes and numerous desmosomes. Although Lennert3 predicted the existence of a neoplasm with FDC differentiation in 1978, it was not until 1986 that the first description of a nodal-based, FDC tumor/sarcoma (FDCS) appeared in the literature.4 To date, only 56 confirmed examples of FDCS have been reported in the English language literature.5-12 The diagnosis of a FDCS is facilitated by its typical location in a lymph node, characteristic histomorphology, and an immunohistochemical profile and ultrastructural findings
From the Department of Pathology, Northwestern University Medical School, Chicago, IL. Address correspondence and reprint requests to William B. Laskin, MD, 251 East Huron Ave, Northwestern Memorial Hospital, Feinberg Pavilion 7-325, Department of Surgical Pathology, Chicago, IL 60611. Copyright © 2001 by W.B. Saunders Company 0046-8177/01/3207-0012$35.00/0 doi:10.1053/hupa.2001.25595
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HUMAN PATHOLOGY
Volume 32, No. 7 (July 2001)
FIGURE 1. (A) CT scan of the chest showing a large mass in the parenchyma of the left lung (arrow) and a smaller pleural-based mass (arrowhead). (B) Cut surface of the left lung shows a wellcircumscribed, solid, tan parenchymal-based mass.
supporting FDC differentiation. However, FDCS originating outside of the lymph node can present a diagnostic challenge because of its rarity. We report the clinicopathologic, immunohistochemical, and ultrastructural findings of an FDCS presenting within the parenchyma of the lung and discuss its differential diagnosis. CASE HISTORY A 33-year-old man presented to his primary physician with a persistent dry cough. He had been a smoker but relayed no other pertinent medical history. A chest x-ray and a subsequent computed tomography (CT) scan showed a large left lung mass (7.5 cm), several discrete pleural nodules, and hilar lymphadenopathy (Fig 1A). An endobronchial biopsy was performed, and a diagnosis of follicular dendritic cell sarcoma was rendered. The patient underwent additional work-up, which included a whole-body CT scan that failed to identify any other mass lesion. The patient was initially treated with an Adriamycin-based chemotherapeutic regimen. Because of a lack of response, he underwent a left pneumonectomy. Pathologic Findings The left lung weighed 926 g and contained multiple well-circumscribed, variably sized parenchymal and pleural masses, the largest of which was located in the left lower lobe
and measured 9.5 cm in greatest single dimension (Fig 1B). All the masses had a similar tan-white cut surface with focal areas of hemorrhage and necrosis. The bronchial tree was unremarkable. Microscopically, the tumor in the biopsy and the pneumonectomy showed nearly identical features. The neoplasm was highly cellular and composed of elongated, bipolar spindled cells arranged primarily in short, compact, intersecting fascicles and focally in a storiform pattern (Fig 2A). A characteristic feature of the tumor was the presence of small mature lymphocytes and a few plasma cells dispersed rather uniformly throughout the process. The spindled neoplastic cells had lightly eosinophilic, fibrillar cytoplasm and ill-defined cell borders. The tumor cell nuclei were round to oval, with delicate membranes, and typically had a distinct, centrally located nucleolus (Fig 2B). Nuclear pseudoinclusions were occasionally identified. A mitotic rate of 4 mitoses per 20 high-power fields was observed in the biopsy specimen. Whereas the biopsy specimen showed uniform cytologic features, a moderate degree of pleomorphism, including the presence of multinucleation, was focally observed in the resected tumor (Fig 2B, inset). Necrosis was not identified in either specimen. The remaining lung and the bronchial mucosa were unremarkable. One of the 4 peribronchial and hilar lymph nodes submitted for evaluation contained small, focal deposits of FDCS.
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FIGURE 2. Histologic and immunohistochemical features of FDCS. (A) Low-power magnification showing spindle cells arranged in a short fascicular growth pattern. Note the lack of pleomorphism and the interspersed small lymphocytes. (Hematoxylin and eosin; original magnification ⫻100.) (B) Highpower magnification showing spindle cells possessing uniformappearing oval nuclei with conspicuous nucleoli and an intermixed population of small lymphocytes. Inset: Multinucleated tumor cells were present in the resection specimen. (Hematoxylin and eosin; original magnification ⫻400.) (C, D, E) Tumor cells showing strong membranous immunoreactivity with (C) anti-CD21 (immunoperoxidase; original magnification ⫻400), (D) anti-CD35 (immunoperoxidase; original magnification ⫻400), and (E) anti–low-affinity NGFR (immunoperoxidase; original magnification ⫻400).
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Immunohistochemical Findings Immunohistochemical studies were performed on formalin-fixed, paraffin-embedded tissue using the avidin-biotin complex technique and the panel of antibodies listed in Table 1. The tumor cells showed strong cytoplasmic reactivity with antibodies directed against vimentin and strong membranous reactivity for anti-CD21 (Fig 2C), anti-CD35 (Fig 2D), and anti–low-affinity nerve growth factor receptor (NGFR; fig 2E). Epithelial membrane antigen (EMA) expression was also detected in scattered tumor cells. The tumor cells failed to express keratin (AE1/AE3 and CAM5.2), S-100 protein, CD45, CD20, muscle-specific actin, or gp100 protein HMB45. The background small lymphocytes were positive for CD20. Electron Microscopic Findings Ultrastructural examination showed spindled tumor cells with interdigitating cytoplasmic processes (Fig 3). Numerous desmosomes were identified on bordering cell surfaces (Fig 3, inset). The cytoplasm of the cells contained nonbranching, rough endoplasmic reticulum and mitochondria. No Birbeck granules were identified. The nuclei had an even chromatin pattern and irregular contours. In Situ Hybridization Study Findings In situ hybridization for Epstein-Barr virus (EBV)– encoded RNA (EBER) was performed on paraffin-embedded tissue using Epstein-Barr virus probe in situ hybridization kit, NCL-EBV-K (Novocastra Laboratories Ltd, Newcastle upon Tyne, England). EBER was not identified in the tumor cells. Polymerase Chain Reaction Genomic DNA was prepared from fresh-frozen tissue according to standard procedure, and polymerase chain reaction (PCR) was performed. Primer sequence (5⬘ ACG AGG GGC CAG GTA CAG GA 3⬘, 5⬘ CAC CAT CTC TAT GTC TTG GC 3⬘), as previously described by Beham-Schmid et al7 was used to amplify a 200 – base pair (bp) region of EBV. PCR was carried out using 0.5 g of genomic DNA, 20 pmol of each primer, 10 mmol/L Tris-HCL (pH 8.4), 50 mmol/L MgCl2, 10mmol/L deoxynucleoside triphosphate, and 5 U Taq polymerase in a final volume of 50 L. PCR amplification was carried out at 94°C for 1 minute, 55°C for 30 seconds, and
FIGURE 3. Electron microscopy showing tumor cells with irregular nuclei and complex interdigitating cytoplasmic processes. Inset: Numerous desmosomes on apposing cell surfaces.
72°C for 1 minute for 35 cycles, and 72°C for 10 minutes. Amplification was performed with a gene AmpPCR System 9700 (Perkin Elmer, Watsonville, CA). PCR products were visualized on 2% agarose gel. EBV-positive Dandi cell lines were used for positive control. PCR did not detect EBV in tumor cells. DISCUSSION Although the FDCS was first described as a nodal-based process,4 reports of extranodal examples of the tumor soon emerged once the neoplasm became more widely recognized as a distinct clinicopathologic entity. To date, 56 cases of FDCS have been reported in the English literature, including 24 examples occurring in extranodal sites. Of the latter, 11 arose within intra-abdominal sites, including the liver, peripancreatic region, and peritoneum5,6; 10 were localized to structures of the neck,5,7,9-11 including the tonsil, thyroid, and palatal and pharyngeal areas; 2 occurred in somatic soft tissues5; and 1 arose in the breast.12 To our knowledge, this is the first case of FDCS presenting within the parenchyma of the lung.
TABLE 1. Immunohistochemical Results Antigen/Antibody
Source
Antibody Dilution
Pretreatment
Results*
CD1A CD3 CD20 (L22) CD21 CD35 CD45 (LCA) CD68 (KP-1) S100 protein gp100 protein (HMB45) NGFR (p75ngfr) EMA BCL-2 Keratin (CAM5.2) Keratin (AE1/3) ␣–Smooth muscle actin Desmin (D33) Vimentin
Immunotech Dako Dako Dako Dako Dako Dako Dako Dako Dako Dako Dako Becton Dickison Dako Sigma Dako Dako
Prediluted 1/100 Prediluted 1/60 1/15 Prediluted 1/400 1/600 1/50 1/400 1/75 1/20 Prediluted 1/50 1/500 1/75 1/10
Target Target Citrate Pepsin Pepsin Citrate Trypsin None None Trypsin None Target Trypsin Trypsin None Target Target
⫺ ⫺ ⫺ ⫹⫹⫹ ⫹⫹⫹ ⫺ ⫺ ⫺ ⫺ ⫹⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
*⫹, weak reactivity; ⫹⫹, moderate reactivity; ⫹⫹⫹, strong reactivity; ⫺, negative reactivity.
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Histologically, the tumor had the characteristic cytologic and architectural features of FDCS. Histologic features that have been associated with a more aggressive course, including presence of coagulative necrosis, a mitotic count of ⬎5 five mitoses per 10 high-power fields, and significant nuclear atypia,5,13 were not evident in the biopsy material or the resection specimen. Histologic examination of the excised peribronchial and hilar lymph nodes showed only focal involvement by FDCS. Furthermore, histologic features of the hyaline-vascular variant of Castleman disease, a disorder considered a potential precursor of FDCS,5,13-15 was not identified in the uninvolved portions of the lymph nodes examined. These last 2 findings garner support for a pulmonary origin of the tumor but do not completely exclude the possibility of a nodal-based lesion with secondary spread to the lungs. Immunohistochemically, the tumor cells expressed CD21 (C3d receptor), CD35 (C3b receptor), EMA, and NGFR. Immunoreactivity with antibodies directed against CD21 and CD35 has been reported in 95% of FDCSs tested, and these 2 complement receptor proteins are considered relatively specific indicators of FDC differentiation.5 On the other hand, expression of NGFR, which has been documented in 90% of examples of FDCS analyzed, is not a specific finding.5 Ultrastructurally, the neoplastic cells have features of FDC differentiation, including the presence of slender intertwining cell processes interconnected by desmosomes. A number of spindle and epithelioid cell tumors primary and metastatic to the lung should be considered in the differential diagnosis of FDCS. The compact fascicular and storiform growth pattern of spindled cells in FDCS is also shared by ectopic meningioma and the spindle-cell or metaplastic variant of carcinoma, whereas the additional finding of an admixed chronic inflammatory cell element creates histologic overlap with the inflammatory myofibroblastic tumor and spindle-cell thymoma. In contrast to FDCS, ectopic meningioma microscopically features tight cellular whorls, intranuclear inclusions, and psammoma body formation. Although meningioma expresses EMA,16 it lacks expression of CD21 and CD35. Unlike FDCS, the cells of carcinoma react with antibodies directed against cytokeratin. The inflammatory myofibroblastic tumor shows less cytologic atypia, a more variable growth pattern, a greater number of intralesional plasma cells, and no immunoexpression of complement receptor proteins, CD21 and CD35. FDCS and spindle-cell thymoma both feature a syncytial arrangement of lesional cells, occasional presence of a lobulated growth pattern, and interspersed lymphocytes. Immunohistochemically, the cells of thymoma show clear-cut cytokeratin immunoreactivity and do not express either CD21 or CD35. With the family of dendritic cell tumors, the fibroblastic reticulum and interdigitating reticulum cell sarcomas constitute neoplasms that may be confused with FDCS. Fibroblastic reticulum cell sarcoma shows the closest histologic resemblance to the spindle-cell variant of FDCS. Moreover, 5 cases of the former have been described in the mediastinum,2,17 although no tumor to date has involved the lung. The fibroblastic reticulum cell sarcoma has myofibroblastic features and can be distinguished from the FDCS by its immunoexpression of desmin, ␣-smooth muscle actin, and keratin. Although the interdigitating reticulum cell sarcoma characteristically features plump, histiocytic-like cells with grooved nuclei, examples of this neoplasm bearing a close histologic resemblance to the FDCS have been reported.1 The former differs immunohistochemically from FDCS by expressing CD45RB, S-100 protein, and CD1a and ultrastructurally by its lack of desmosomes.
EBV has been reported in approximately 12% of cases of FDCS,5 in which it is monoclonal and in an episomal form, indicating that infection occurred before neoplastic transformation. The infectivity of follicular dendritic cells by EBV is facilitated by complement receptor CD21, which is found on the surface of the nonneoplastic FDC and acts as the EBV receptor. However, in the present case, we did not detect evidence of the virus by in situ hybridization for EBER-1 gene or PCR for EBV sequences. FDCS is considered an intermediate-grade sarcoma with a reported recurrence rate ⬎43% and a metastatic rate of ⬎24%, with metastatic deposits described primarily in the lymph nodes, lung, and liver.5 Of the 56 cases of FDCS reported in the English literature, 45 have follow-up data with a time interval ranging from 2 months to 5.5 years. Twentyseven of these patients are alive and disease free, whereas 11 are alive with disease, and 7 died of sarcoma.5 The patient we are reporting is presently alive and had a recurrence in the axilla 19 months after surgical excision of the tumor. In summary, we present the first reported case of FDCS in the lung. FDCS can be distinguished from other spindlecell tumors occurring in the lung if attention is focused on the salient histologic characteristics of the neoplasm and if an immunohistochemical panel, including CD21 and CD35, is used. REFERENCES 1. Andriko J-A, Kaldjian E, Tsokos M, et al: Reticulum cell neoplasms of lymph nodes: A clinicopathologic study of 11 cases with recognition of a new subtype derived from fibroblastic reticular cells. Am J Surg Pathol 22:1048-1058, 1998 2. Weiss L: Biology of histiocytic and dendritic cells. Mod Pathol 13:359362, 2000 3. Lennert K: Malignant lymphomas other than Hodgkin’s disease, in Histology, Cytology, Ultrastructure, Immunology. Berlin, Germany, SpringerVerlag, 1978, pp59-65 4. Monda L, Warnke R, Rosai J: A primary lymph node malignancy with features suggestive of dendritic reticulum cell differentiation, a report of 4 cases. Am J Pathol 122:562-572, 1986 5. Chan J: Proliferative lesions of follicular dendritic cells: An overview, including a detailed account of follicular dendritic cell sarcoma, a neoplasm with many faces and uncommon etiologic associations. Adv Anat Pathol 4:387411, 1997 6. Shek T, Liu C, Peh W, et al: Intra-abdominal follicular dendritic cell tumor: A rare tumor in need of recognition. Histopathology 33:465-470, 1998 7. Beham-Schmid C, Beham A, Jaske R, et al: Extranodal follicular dendritic cell tumor of the nasopharynx. Virchows Arch 432:293-298, 1998 8. Fonesca R, Tefferi A, Strickler J: Follicular dendritic cell sarcoma mimicking diffuse large cell lymphoma: a case report. Am J Hematol 55:148-155, 1997 9. Galati L, Barnes E, Myers E: Dendritic cell sarcoma of the thyroid. Head Neck 21:273-275, 1999 10. Araujo V, Martins M, Salmen F, et al: Extranodal follcular dendritic cell sarcoma of the palate. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontics 87:209-214, 1999 11. Desai S, Deshpande R, Jambhekar N: Follicular dendritic cell tumor of the parapharyngeal region. Head Neck 21:164-167, 1999 12. Fisher C, Magnusson B, Hardarson S, et al: Myxoid variant of follicular dendritic cell sarcoma arising in the breast. Ann Diag Pathol 3:92-98, 1999 13. Perez-Oedonez B, Rosai J: Follicular dendritic cell tumor: review of the entity. Semin DiagPathol 15:144-154, 1998 14. Nguyen D, Diamond L, Hansmann M, et al: Castleman’s disease: Differences in follicular dendritic network in the hyaline vascular and plasma cell variants. Histopathology 24:437-443, 1994 15. Ruco L, Gearing A, Pigott R, et al: Expression of ICAM-1, VCAM-1 and ELAM-1 in angiofollicular lymph node hyperplasia (Castleman’s disease): Evidence of dysplasia of follicular dendritic reticulum cells. Histopathology 19: 523-528, 1991 16. Flynn S, Yousem S: Pulmonary menningiomas: a report of two cases. HUM PATHOL 22:469-474, 1991 17. Chan A, Serrano-Olmo J, Erlandson R, et al: Cytokeratin-positive malignant tumors with reticulum cell morphology. Am J Surg Pathol 24:107-116, 2000
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FOLLICULAR DENDRITIC CELL TUMOR PRESENTING IN THE LUNG: A CASE REPORT RAJSHRI N. SHAH, MD, OZER OZDEN, MD, ANJANA YELDANDI, MD, LOANN PETERSON, MD, SAMBASIVA RAO, MD, AND WILLIAM B. LASKIN, MD An example of extranodal follicular dendritic cell sarcoma (FDCS) presenting in the lung, a heretofore unreported site, is described. Macroscopically, a 9.5-cm, tan-white, dominant mass and multiple smaller parenchymal and pleural nodules were identified. Microscopically, the tumor was composed of spindled cells with uniform cytologic features arranged in short, intersecting fascicles and intermixed small lymphocytes and plasma cells. One of 4 peribronchial and hilar lymph nodes evaluated microscopically was focally involved by the process. Immunohistochemically, the neoplastic spindled cells expressed complement receptors CD21 and CD35 and low-affinity nerve growth factor receptor but did not express keratin (AE1/AE3 and CAM5.2), CD45 (leukocyte common antigen), CD20 (L26), S-100 protein, muscle-specific actin, or gp100 protein (HMB45). Ultrastructurally, the tumor cells have complex interdigitating cell surface processes and desmosomes. Epstein-Barr virus (EBV) was not
detected in the tumor cells by in situ hybridization for EBV-encoded RNA or by polymerase chain reaction for viral DNA. FDCS should be considered in the differential diagnosis of any spindled-cell tumor with interspersed chronic inflammatory cells occurring in the lung. An immunohistochemical panel, including anti-CD21 and -CD35, can assist in its diagnosis, especially with small bronchial biopsy specimens. HUM PATHOL 32:745-749. Copyright © 2001 by W.B. Saunders Company Key words: follicular dendritic cell sarcoma/tumor, lung, extranodal, Epstein-Barr virus. Abbreviations: FDC, follicular dendritic reticulum cell; FDCS, follicular dendritic cell sarcoma; CT, computed tomography; NGFR, nerve growth factor receptor; EMA, epithelial membrane antigen; EBV, Epstein-Barr virus; EBER, Epstein-Barr virus– encoded RNA; PCR, polymerase chain reaction.
The follicular dendritic reticulum cell (FDC) is a nonlymphoid immune accessory cell that is confined to the B-cell areas of lymphoid follicles and plays a major role in the induction and maintenance of humoral immune responses.1,2
The cell is characterized immunohistochemically by CD21 (C3d complement receptor) and CD35 (C3b complement receptor) expression. Ultrastructurally, FDC possesses complex interdigitating cytoplasmic processes and numerous desmosomes. Although Lennert3 predicted the existence of a neoplasm with FDC differentiation in 1978, it was not until 1986 that the first description of a nodal-based, FDC tumor/sarcoma (FDCS) appeared in the literature.4 To date, only 56 confirmed examples of FDCS have been reported in the English language literature.5-12 The diagnosis of a FDCS is facilitated by its typical location in a lymph node, characteristic histomorphology, and an immunohistochemical profile and ultrastructural findings
From the Department of Pathology, Northwestern University Medical School, Chicago, IL. Address correspondence and reprint requests to William B. Laskin, MD, 251 East Huron Ave, Northwestern Memorial Hospital, Feinberg Pavilion 7-325, Department of Surgical Pathology, Chicago, IL 60611. Copyright © 2001 by W.B. Saunders Company 0046-8177/01/3207-0012$35.00/0 doi:10.1053/hupa.2001.25595
745
HUMAN PATHOLOGY
Volume 32, No. 7 (July 2001)
FIGURE 1. (A) CT scan of the chest showing a large mass in the parenchyma of the left lung (arrow) and a smaller pleural-based mass (arrowhead). (B) Cut surface of the left lung shows a wellcircumscribed, solid, tan parenchymal-based mass.
supporting FDC differentiation. However, FDCS originating outside of the lymph node can present a diagnostic challenge because of its rarity. We report the clinicopathologic, immunohistochemical, and ultrastructural findings of an FDCS presenting within the parenchyma of the lung and discuss its differential diagnosis. CASE HISTORY A 33-year-old man presented to his primary physician with a persistent dry cough. He had been a smoker but relayed no other pertinent medical history. A chest x-ray and a subsequent computed tomography (CT) scan showed a large left lung mass (7.5 cm), several discrete pleural nodules, and hilar lymphadenopathy (Fig 1A). An endobronchial biopsy was performed, and a diagnosis of follicular dendritic cell sarcoma was rendered. The patient underwent additional work-up, which included a whole-body CT scan that failed to identify any other mass lesion. The patient was initially treated with an Adriamycin-based chemotherapeutic regimen. Because of a lack of response, he underwent a left pneumonectomy. Pathologic Findings The left lung weighed 926 g and contained multiple well-circumscribed, variably sized parenchymal and pleural masses, the largest of which was located in the left lower lobe
and measured 9.5 cm in greatest single dimension (Fig 1B). All the masses had a similar tan-white cut surface with focal areas of hemorrhage and necrosis. The bronchial tree was unremarkable. Microscopically, the tumor in the biopsy and the pneumonectomy showed nearly identical features. The neoplasm was highly cellular and composed of elongated, bipolar spindled cells arranged primarily in short, compact, intersecting fascicles and focally in a storiform pattern (Fig 2A). A characteristic feature of the tumor was the presence of small mature lymphocytes and a few plasma cells dispersed rather uniformly throughout the process. The spindled neoplastic cells had lightly eosinophilic, fibrillar cytoplasm and ill-defined cell borders. The tumor cell nuclei were round to oval, with delicate membranes, and typically had a distinct, centrally located nucleolus (Fig 2B). Nuclear pseudoinclusions were occasionally identified. A mitotic rate of 4 mitoses per 20 high-power fields was observed in the biopsy specimen. Whereas the biopsy specimen showed uniform cytologic features, a moderate degree of pleomorphism, including the presence of multinucleation, was focally observed in the resected tumor (Fig 2B, inset). Necrosis was not identified in either specimen. The remaining lung and the bronchial mucosa were unremarkable. One of the 4 peribronchial and hilar lymph nodes submitted for evaluation contained small, focal deposits of FDCS.
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FIGURE 2. Histologic and immunohistochemical features of FDCS. (A) Low-power magnification showing spindle cells arranged in a short fascicular growth pattern. Note the lack of pleomorphism and the interspersed small lymphocytes. (Hematoxylin and eosin; original magnification ⫻100.) (B) Highpower magnification showing spindle cells possessing uniformappearing oval nuclei with conspicuous nucleoli and an intermixed population of small lymphocytes. Inset: Multinucleated tumor cells were present in the resection specimen. (Hematoxylin and eosin; original magnification ⫻400.) (C, D, E) Tumor cells showing strong membranous immunoreactivity with (C) anti-CD21 (immunoperoxidase; original magnification ⫻400), (D) anti-CD35 (immunoperoxidase; original magnification ⫻400), and (E) anti–low-affinity NGFR (immunoperoxidase; original magnification ⫻400).
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Immunohistochemical Findings Immunohistochemical studies were performed on formalin-fixed, paraffin-embedded tissue using the avidin-biotin complex technique and the panel of antibodies listed in Table 1. The tumor cells showed strong cytoplasmic reactivity with antibodies directed against vimentin and strong membranous reactivity for anti-CD21 (Fig 2C), anti-CD35 (Fig 2D), and anti–low-affinity nerve growth factor receptor (NGFR; fig 2E). Epithelial membrane antigen (EMA) expression was also detected in scattered tumor cells. The tumor cells failed to express keratin (AE1/AE3 and CAM5.2), S-100 protein, CD45, CD20, muscle-specific actin, or gp100 protein HMB45. The background small lymphocytes were positive for CD20. Electron Microscopic Findings Ultrastructural examination showed spindled tumor cells with interdigitating cytoplasmic processes (Fig 3). Numerous desmosomes were identified on bordering cell surfaces (Fig 3, inset). The cytoplasm of the cells contained nonbranching, rough endoplasmic reticulum and mitochondria. No Birbeck granules were identified. The nuclei had an even chromatin pattern and irregular contours. In Situ Hybridization Study Findings In situ hybridization for Epstein-Barr virus (EBV)– encoded RNA (EBER) was performed on paraffin-embedded tissue using Epstein-Barr virus probe in situ hybridization kit, NCL-EBV-K (Novocastra Laboratories Ltd, Newcastle upon Tyne, England). EBER was not identified in the tumor cells. Polymerase Chain Reaction Genomic DNA was prepared from fresh-frozen tissue according to standard procedure, and polymerase chain reaction (PCR) was performed. Primer sequence (5⬘ ACG AGG GGC CAG GTA CAG GA 3⬘, 5⬘ CAC CAT CTC TAT GTC TTG GC 3⬘), as previously described by Beham-Schmid et al7 was used to amplify a 200 – base pair (bp) region of EBV. PCR was carried out using 0.5 g of genomic DNA, 20 pmol of each primer, 10 mmol/L Tris-HCL (pH 8.4), 50 mmol/L MgCl2, 10mmol/L deoxynucleoside triphosphate, and 5 U Taq polymerase in a final volume of 50 L. PCR amplification was carried out at 94°C for 1 minute, 55°C for 30 seconds, and
FIGURE 3. Electron microscopy showing tumor cells with irregular nuclei and complex interdigitating cytoplasmic processes. Inset: Numerous desmosomes on apposing cell surfaces.
72°C for 1 minute for 35 cycles, and 72°C for 10 minutes. Amplification was performed with a gene AmpPCR System 9700 (Perkin Elmer, Watsonville, CA). PCR products were visualized on 2% agarose gel. EBV-positive Dandi cell lines were used for positive control. PCR did not detect EBV in tumor cells. DISCUSSION Although the FDCS was first described as a nodal-based process,4 reports of extranodal examples of the tumor soon emerged once the neoplasm became more widely recognized as a distinct clinicopathologic entity. To date, 56 cases of FDCS have been reported in the English literature, including 24 examples occurring in extranodal sites. Of the latter, 11 arose within intra-abdominal sites, including the liver, peripancreatic region, and peritoneum5,6; 10 were localized to structures of the neck,5,7,9-11 including the tonsil, thyroid, and palatal and pharyngeal areas; 2 occurred in somatic soft tissues5; and 1 arose in the breast.12 To our knowledge, this is the first case of FDCS presenting within the parenchyma of the lung.
TABLE 1. Immunohistochemical Results Antigen/Antibody
Source
Antibody Dilution
Pretreatment
Results*
CD1A CD3 CD20 (L22) CD21 CD35 CD45 (LCA) CD68 (KP-1) S100 protein gp100 protein (HMB45) NGFR (p75ngfr) EMA BCL-2 Keratin (CAM5.2) Keratin (AE1/3) ␣–Smooth muscle actin Desmin (D33) Vimentin
Immunotech Dako Dako Dako Dako Dako Dako Dako Dako Dako Dako Dako Becton Dickison Dako Sigma Dako Dako
Prediluted 1/100 Prediluted 1/60 1/15 Prediluted 1/400 1/600 1/50 1/400 1/75 1/20 Prediluted 1/50 1/500 1/75 1/10
Target Target Citrate Pepsin Pepsin Citrate Trypsin None None Trypsin None Target Trypsin Trypsin None Target Target
⫺ ⫺ ⫺ ⫹⫹⫹ ⫹⫹⫹ ⫺ ⫺ ⫺ ⫺ ⫹⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
*⫹, weak reactivity; ⫹⫹, moderate reactivity; ⫹⫹⫹, strong reactivity; ⫺, negative reactivity.
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Histologically, the tumor had the characteristic cytologic and architectural features of FDCS. Histologic features that have been associated with a more aggressive course, including presence of coagulative necrosis, a mitotic count of ⬎5 five mitoses per 10 high-power fields, and significant nuclear atypia,5,13 were not evident in the biopsy material or the resection specimen. Histologic examination of the excised peribronchial and hilar lymph nodes showed only focal involvement by FDCS. Furthermore, histologic features of the hyaline-vascular variant of Castleman disease, a disorder considered a potential precursor of FDCS,5,13-15 was not identified in the uninvolved portions of the lymph nodes examined. These last 2 findings garner support for a pulmonary origin of the tumor but do not completely exclude the possibility of a nodal-based lesion with secondary spread to the lungs. Immunohistochemically, the tumor cells expressed CD21 (C3d receptor), CD35 (C3b receptor), EMA, and NGFR. Immunoreactivity with antibodies directed against CD21 and CD35 has been reported in 95% of FDCSs tested, and these 2 complement receptor proteins are considered relatively specific indicators of FDC differentiation.5 On the other hand, expression of NGFR, which has been documented in 90% of examples of FDCS analyzed, is not a specific finding.5 Ultrastructurally, the neoplastic cells have features of FDC differentiation, including the presence of slender intertwining cell processes interconnected by desmosomes. A number of spindle and epithelioid cell tumors primary and metastatic to the lung should be considered in the differential diagnosis of FDCS. The compact fascicular and storiform growth pattern of spindled cells in FDCS is also shared by ectopic meningioma and the spindle-cell or metaplastic variant of carcinoma, whereas the additional finding of an admixed chronic inflammatory cell element creates histologic overlap with the inflammatory myofibroblastic tumor and spindle-cell thymoma. In contrast to FDCS, ectopic meningioma microscopically features tight cellular whorls, intranuclear inclusions, and psammoma body formation. Although meningioma expresses EMA,16 it lacks expression of CD21 and CD35. Unlike FDCS, the cells of carcinoma react with antibodies directed against cytokeratin. The inflammatory myofibroblastic tumor shows less cytologic atypia, a more variable growth pattern, a greater number of intralesional plasma cells, and no immunoexpression of complement receptor proteins, CD21 and CD35. FDCS and spindle-cell thymoma both feature a syncytial arrangement of lesional cells, occasional presence of a lobulated growth pattern, and interspersed lymphocytes. Immunohistochemically, the cells of thymoma show clear-cut cytokeratin immunoreactivity and do not express either CD21 or CD35. With the family of dendritic cell tumors, the fibroblastic reticulum and interdigitating reticulum cell sarcomas constitute neoplasms that may be confused with FDCS. Fibroblastic reticulum cell sarcoma shows the closest histologic resemblance to the spindle-cell variant of FDCS. Moreover, 5 cases of the former have been described in the mediastinum,2,17 although no tumor to date has involved the lung. The fibroblastic reticulum cell sarcoma has myofibroblastic features and can be distinguished from the FDCS by its immunoexpression of desmin, ␣-smooth muscle actin, and keratin. Although the interdigitating reticulum cell sarcoma characteristically features plump, histiocytic-like cells with grooved nuclei, examples of this neoplasm bearing a close histologic resemblance to the FDCS have been reported.1 The former differs immunohistochemically from FDCS by expressing CD45RB, S-100 protein, and CD1a and ultrastructurally by its lack of desmosomes.
EBV has been reported in approximately 12% of cases of FDCS,5 in which it is monoclonal and in an episomal form, indicating that infection occurred before neoplastic transformation. The infectivity of follicular dendritic cells by EBV is facilitated by complement receptor CD21, which is found on the surface of the nonneoplastic FDC and acts as the EBV receptor. However, in the present case, we did not detect evidence of the virus by in situ hybridization for EBER-1 gene or PCR for EBV sequences. FDCS is considered an intermediate-grade sarcoma with a reported recurrence rate ⬎43% and a metastatic rate of ⬎24%, with metastatic deposits described primarily in the lymph nodes, lung, and liver.5 Of the 56 cases of FDCS reported in the English literature, 45 have follow-up data with a time interval ranging from 2 months to 5.5 years. Twentyseven of these patients are alive and disease free, whereas 11 are alive with disease, and 7 died of sarcoma.5 The patient we are reporting is presently alive and had a recurrence in the axilla 19 months after surgical excision of the tumor. In summary, we present the first reported case of FDCS in the lung. FDCS can be distinguished from other spindlecell tumors occurring in the lung if attention is focused on the salient histologic characteristics of the neoplasm and if an immunohistochemical panel, including CD21 and CD35, is used. REFERENCES 1. Andriko J-A, Kaldjian E, Tsokos M, et al: Reticulum cell neoplasms of lymph nodes: A clinicopathologic study of 11 cases with recognition of a new subtype derived from fibroblastic reticular cells. Am J Surg Pathol 22:1048-1058, 1998 2. Weiss L: Biology of histiocytic and dendritic cells. Mod Pathol 13:359362, 2000 3. Lennert K: Malignant lymphomas other than Hodgkin’s disease, in Histology, Cytology, Ultrastructure, Immunology. Berlin, Germany, SpringerVerlag, 1978, pp59-65 4. Monda L, Warnke R, Rosai J: A primary lymph node malignancy with features suggestive of dendritic reticulum cell differentiation, a report of 4 cases. Am J Pathol 122:562-572, 1986 5. Chan J: Proliferative lesions of follicular dendritic cells: An overview, including a detailed account of follicular dendritic cell sarcoma, a neoplasm with many faces and uncommon etiologic associations. Adv Anat Pathol 4:387411, 1997 6. Shek T, Liu C, Peh W, et al: Intra-abdominal follicular dendritic cell tumor: A rare tumor in need of recognition. Histopathology 33:465-470, 1998 7. Beham-Schmid C, Beham A, Jaske R, et al: Extranodal follicular dendritic cell tumor of the nasopharynx. Virchows Arch 432:293-298, 1998 8. Fonesca R, Tefferi A, Strickler J: Follicular dendritic cell sarcoma mimicking diffuse large cell lymphoma: a case report. Am J Hematol 55:148-155, 1997 9. Galati L, Barnes E, Myers E: Dendritic cell sarcoma of the thyroid. Head Neck 21:273-275, 1999 10. Araujo V, Martins M, Salmen F, et al: Extranodal follcular dendritic cell sarcoma of the palate. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontics 87:209-214, 1999 11. Desai S, Deshpande R, Jambhekar N: Follicular dendritic cell tumor of the parapharyngeal region. Head Neck 21:164-167, 1999 12. Fisher C, Magnusson B, Hardarson S, et al: Myxoid variant of follicular dendritic cell sarcoma arising in the breast. Ann Diag Pathol 3:92-98, 1999 13. Perez-Oedonez B, Rosai J: Follicular dendritic cell tumor: review of the entity. Semin DiagPathol 15:144-154, 1998 14. Nguyen D, Diamond L, Hansmann M, et al: Castleman’s disease: Differences in follicular dendritic network in the hyaline vascular and plasma cell variants. Histopathology 24:437-443, 1994 15. Ruco L, Gearing A, Pigott R, et al: Expression of ICAM-1, VCAM-1 and ELAM-1 in angiofollicular lymph node hyperplasia (Castleman’s disease): Evidence of dysplasia of follicular dendritic reticulum cells. Histopathology 19: 523-528, 1991 16. Flynn S, Yousem S: Pulmonary menningiomas: a report of two cases. HUM PATHOL 22:469-474, 1991 17. Chan A, Serrano-Olmo J, Erlandson R, et al: Cytokeratin-positive malignant tumors with reticulum cell morphology. Am J Surg Pathol 24:107-116, 2000
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