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Follicular dendritic cell sarcoma

1997; Wiley; Volume: 79; Issue: 2 Linguagem: Inglês

10.1002/(sici)1097-0142(19970115)79

1097-0142

John K. C. Chan, Christopher D.�M. Fletcher, Simon Nayler, Kum Cooper,

Tuberous Sclerosis Complex Research

CancerVolume 79, Issue 2 p. 294-313 Original ArticleFree Access Follicular dendritic cell sarcoma Clinicopathologic analysis of 17 cases suggesting a malignant potential higher than currently recognized John K. C. Chan M.B.B.S., M.R.C.Path, Corresponding Author John K. C. Chan M.B.B.S., M.R.C.Path Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong KongDepartment of Pathology, Queen Elizabeth Hospital, Wylie Road, Kowloon, Hong Kong===Search for more papers by this authorChristopher D. M. Fletcher M.D., M.R.C.Path, Christopher D. M. Fletcher M.D., M.R.C.Path Department of Pathology, Brigham and Women's Hospital, Boston, MassachusettsSearch for more papers by this authorSimon J. Nayler M.B.B.Ch., B.Sc., F.C.Path(SA), Simon J. Nayler M.B.B.Ch., B.Sc., F.C.Path(SA) Department of Anatomical Pathology, University of the Witwatersrand and South African Institute for Medical Research, Parktown, Johannesburg, South AfricaSearch for more papers by this authorKum Cooper M.B.Ch.B., B.Sc., M.R.C.Path, D.Phil, Kum Cooper M.B.Ch.B., B.Sc., M.R.C.Path, D.Phil Department of Anatomical Pathology, University of the Witwatersrand and South African Institute for Medical Research, Parktown, Johannesburg, South AfricaSearch for more papers by this author John K. C. Chan M.B.B.S., M.R.C.Path, Corresponding Author John K. C. Chan M.B.B.S., M.R.C.Path Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong KongDepartment of Pathology, Queen Elizabeth Hospital, Wylie Road, Kowloon, Hong Kong===Search for more papers by this authorChristopher D. M. Fletcher M.D., M.R.C.Path, Christopher D. M. Fletcher M.D., M.R.C.Path Department of Pathology, Brigham and Women's Hospital, Boston, MassachusettsSearch for more papers by this authorSimon J. Nayler M.B.B.Ch., B.Sc., F.C.Path(SA), Simon J. Nayler M.B.B.Ch., B.Sc., F.C.Path(SA) Department of Anatomical Pathology, University of the Witwatersrand and South African Institute for Medical Research, Parktown, Johannesburg, South AfricaSearch for more papers by this authorKum Cooper M.B.Ch.B., B.Sc., M.R.C.Path, D.Phil, Kum Cooper M.B.Ch.B., B.Sc., M.R.C.Path, D.Phil Department of Anatomical Pathology, University of the Witwatersrand and South African Institute for Medical Research, Parktown, Johannesburg, South AfricaSearch for more papers by this author First published: 27 September 2000 https://doi.org/10.1002/(SICI)1097-0142(19970115)79:2 3.0.CO;2-WCitations: 272AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract BACKGROUND The goal of this study was to characterize the clinicopathologic features of follicular dendritic cell sarcoma, a very uncommon neoplasm. METHODS The 17 cases were collected from the consultation and surgical pathology files of the authors, including 8 previously reported cases. The histologic and immunohistochemical features and outcome were analyzed. RESULTS The patients had a median age of 40 years, with a slight female predominance. Seven patients presented with enlarged lymph nodes, and ten presented with tumor in extranodal sites. Two cases were associated with hyaline-vascular Castleman's disease. The tumors had an average greatest dimension of 6.7 cm. The most common histologic feature was a storiform or fascicular array of spindle, ovoid, or polygonal cells with oval nuclei, delicate nuclear membrane, vesicular or granular chromatin, distinct nucleoli, indistinct cell borders, and frequently fibrillary cytoplasm. There were often scattered multinucleated forms. The tumor cells sometimes formed sheets, circular whorls, follicle-like structures, trabeculae, or pseudovascular spaces. There was a sprinkling of small lymphocytes, with or without cuffing around blood vessels. The neoplastic cells were immunoreactive for CD21 (17 of 17 cases), CD35 (17 of 17 cases), desmoplakin (10 of 17 cases), epithelial membrane antigen (14 of 16 cases), S-100 protein (6 of 17 cases), and CD68 (2 of 17 cases), but not cytokeratin. Ultrastructural studies showed villous processes connected by desmosomes. Only one harbored the Epstein-Barr virus. Among 13 patients with a median follow-up of 3 years, local recurrence occurred in 6, metastasis in 6, and 3 died of disease. CONCLUSIONS Follicular dendritic cell sarcoma exhibits distinctive histologic features that permit its presumptive recognition, but a firm diagnosis requires confirmation with special studies. Because it has a significant recurrent and metastatic potential (the latter risk having been previously underestimated), it should be viewed as an intermediate grade malignancy. An intraabdominal location is associated with a particularly aggressive clinical course. Cancer 1997; 79:294-313. © 1997 American Cancer Society. Follicular dendritic cells (FDC), also known as dendritic reticulum cells, constitute an essential component of B-cell follicles, serving the functions of antigen presentation, and generation and regulation of the germinal center reaction.1-3 They form a tight meshwork in the primary and secondary lymphoid follicles, and can be recognized on morphologic grounds by their indistinct cellular borders, oval nuclei, delicate nuclear membrane, clear nucleoplasm, and small but distinct nucleoli.4 These cells, with their profuse interconnecting cell borders, are best visualized by immunostaining with various FDC markers, such as CD21, CD35, R4/23, KiM4, KiM4p, and Ki-FDC1p.4-8 Proliferation of FDC occurs in a number of reactive and neoplastic conditions, such as reactive follicular hyperplasia, follicular lymphoma, mantle cell lymphoma, nodular lymphocyte predominant Hodgkin's disease, and angioimmunoblastic T-cell lymphoma.9 The existence of FDC tumors had already been predicted by Lennert in 1978,10 but it was not until 1986 that the tumor was first characterized by Monda et al.11 Since then, a number of studies have been reported, expanding the clinical and morphologic spectrum, including occurrence in extranodal tissues.12-23 However, with the exception of the recent series of Perez-Ordonez et al.,24 most studies include only a single or a few cases. The follow-up information is limited in most series. To the authors' knowledge, the current study of 17 cases is the largest series to date, and discusses the clinical behavior of this tumor based on a reasonable length of follow-up, the morphologic spectrum of the tumor (including some previously undescribed features), therapy-related changes, immunophenotypic profile, and the possible etiologic role of hyaline-vascular Castleman's disease. MATERIALS AND METHODS The cases were retrieved from the consultation files of JKCC and CDMF, and the surgical pathology files of the Departments of Pathology at Queen Elizabeth Hospital (Hong Kong), and the South African Institute for Medical Research (Johannesburg, South Africa). Among the 17 cases, the first 8 had previously been reported,12, 15, 22 but additional studies have now been performed and follow-up information updated. All available histologic materials were reviewed, and clinical information obtained from the hospital records and contributing pathologists and clinicians. Four-micrometer thick sections cut from the paraffin blocks were stained with hematoxylin and eosin. Immunohistochemical studies were performed on paraffin sections using standard avidin-biotin peroxidase complex technique (Table 1). The antigen retrieval procedure adopted for all the antibodies was pressure cooking in citrate buffer or microwaving in citrate buffer,25 with the exception of CD21 and CD35, for which trypsinization (0.1 g trypsin and 0.1 g calcium chloride in 100 mL Tris buffer saline at pH 7.6) at 37 °C for 1 hour was used. Paraffin sections were also studied for the presence of Epstein-Barr virus (EBV) using a nonisotopic in situ hybridization detection technique for EBV-encoded early nuclear RNAs (EBERs), as previously described.26 Ultrastructural studies were performed on 12 cases (all cases except Cases 1, 6, 10, 13, and 15). Table 1. Panel of Antibodies Used Antibody Source Major reactivities 1F8 (CD21) Dakopatts, Copenhagen, Denmark Follicular dendritic cells; some B cells Ber-MAC-DRC (CD35) Dakopatts Follicular dendritic cells; some B cells S-100 protein (antiserum) Dakopatts Interdigitating reticulum, melanocytic, Schwann, and myoepithelial cells KP1 or PGM1 (CD68) Dakopatts Histiocytes; KP1 also reacts with myeloid cells E29 (EMA) Dakopatts Epithelial membrane antigen (epithelial, meningeal, and perineurial cells) CAM 5.2 or MNF-116 (cytokeratin) CAM 5.2: Becton-Dickinson (Mountainview, CA); MNF-116: Dakopatts Epithelial cells CD3ε(polyclonal) Dakopatts T cells L26 (CD20) Dakopatts B cells DP2.17 (desmoplakin) Progen, Heidelberg, Germany Desmoplakin 1 (Mr 250,000 polypeptide of desmosomal plaques), found on epithelial, mesothelial, meningeal, and follicular dendritic cells EMA: epithelial membrane antigen. RESULTS Clinical Features The patients, 7 men and 10 women, ranged in age from 17 to 63 years, with a mean age of 37.6 and a median age of 40 (Table 2). Fourteen were younger than age 45. Fifteen patients presented with a mass lesion, which prompted biopsy or excision for diagnosis, and two, both with intraabdominal tumors, presented with abdominal pain. Table 2. Clinical Features Case no. Gender Age Presentation Site/size of tumor Initial treatment Outcome 112 a F 49 Subcutaneous nodule in left supraclavicular fossa Left supraclavicular lymph node, 1.5 cm; no other sites of disease Excision At 2 yrs, developed local recurrence, which was further excised. Alive and disease free 9 years after diagnosis. 212 a F 35 6-mo history of enlarging mass in right axilla Right axillary lymph node, 7 cm × 5 cm × 3 cm; no other sites of disease Marginal excision and radiotherapy (30 Gy) to axilla Alive and disease free at 5.5 yrs 315 a F 63 2-mo history of painless swelling over palate Hard and soft palate, left tonsillar fossa and retromolar trigone area, 3 cm × 3 cm × 2 cm; no other sites of disease (including negative radical neck dissection) Biopsy, followed by radiotherapy to oral cavity and upper anterior lymphatic chain (57.5 Gy), with only partial response. Residual tumor was widely excised together with left radical neck dissection. Alive and disease free at 4.5 years 415 a M 44 3-week history of tonsillar polyp Tonsil, 1.5 cm; no other sites of disease Removal of polyp in fragments, followed by tonsillectomy Alive and disease free at 3 yrs 516 a M 42 2-week history of low back pain and generalized abdominal pain with accentuation in left lower quadrant. Mesenteric mass discovered by computed tomography and ultrasound Mesocolon and mesenteric lymph nodes 8 cm × 5 cm × 4 cm; also small peritoneal deposits (Histologic examination showed evidence of residual hyaline vascular Castleman's disease) Debulking excision of main tumor mass, followed by chemotherapy (protocol as used for aggressive lymphomas) Developed recurrence at 18 mos in the abdomen, in the form of a large intraabdominal mass and liver metastasis, and then died shortly after 617 a F 23 Abdominal pain during final 2 mos of pregnancy; pain persisted for 1 mo after normal delivery Wall of small intestine, 6.5 cm; no other sites of disease Resection of small bowel Recurred at 6 mos with multiple intraperitoneal deposits, necessitating hysterectomy, bilateral salpingo-oophorectomy and further small bowel resection. Also given chemotherapy (six courses of CHOP, followed by six courses of cisplatin and etoposide). Two yrs after diagnosis, developed second recurrence (multiple intraabdominal masses, up to 15 cm), which was recently palliatively resected. At last follow-up, was receiving chemotherapy, and alive with disease at 2 yrs 717 a M 63 Short history of epigastric mass, nausea, and weight loss Head of pancreas (adjacent to duodenum), 15 cm; no other sites of disease Subtotal excision Extensive intraabdominal recurrence (11-cm tumor mass) 8 mo after presentation, and was given chemotherapy (epirubicin and cisplatin). After an initial minor response, disease relapsed within 1 mo, with peritoneal deposits, ascites, cachexia, and hypercalcemia. Died of disease at 11 mos 822 a F 18 Bilateral enlarged tonsils Tonsil, 2 cm Tonsillectomy, followed by chemotherapy (CHOP) Lost to follow-up after initiation of chemotherapy 9 F 41 Mass in the neck Left cervical lymph node, 2 cm (probable pancreatic mass and paraaortic lymph node, but without histologic proof) Excision and chemotherapy (protocol as used for aggressive lymphoma) Treatment complicated by severe infection, and died of disease at 2 mos 10 M 40 Presented with night sweats, malaise, and weight loss. Found to have splenomegaly; splenectomy revealed splenic hamartoma. Mass then developed in right axilla Axillary lymph node, 12 cm × 11 cm × 9 cm Excision and chemotherapy (six courses of EORTC lymphoma protocol), followed by radical radiotherapy to axillary region Alive and disease free at 5.5 yrs 11 M 31 Noted by a friend to have a mass in left side of neck (clinically lymph node) Cervical lymph node 5 cm × 3 cm × 3 cm Excision, followed by radiotherapy to left neck (50 Gy) and then incision site (10 Gy) Alive and disease free at 3 yrs 12 M 17 2-yr history of enlarging mass in right side of neck Soft tissue of neck, 11 cm × 8.5 cm × 3.5 cm Biopsy, followed by 8 weeks of chemotherapy (4 courses of CHOP, followed by ifosfamide, carboplatin, and epiadriamycin, and then excision of residual tumor Recent case, with > 95% response to chemotherapy (excision specimen showing only small islands of tumor among a prominent histiocytic reaction) 13 F 40 Slowly growing parapharyngeal mass Pharynx, 7 cm × 3 cm × 2 cm Excision Local recurrence (with lymphatic permeation) at 1 yr 14 M 32 Enlarged right tonsil Tonsil, weighing 8 g Tonsillectomy, followed by postoperative radiotherapy Local recurrence and cervical lymph node metastasis (2 of 12 supraomohyoid lymph nodes positive) at 4.5 yrs. Further treated by surgical excision 15 F 44 Cough for 1 yr, with occasional hemoptysis. Anterior mediastinal mass discovered on chest roentgenogram Multiple lymph nodes (approximately 3 cm in dimension for the largest one) tightly wrapping around the trachea and carina Mediastinoscopic biopsy, followed by chemotherapy (CHOP, to be followed by ifosfamide, carboplatin, and epirubicin) Recent case (subjective improvement of symptoms obtained after first course of chemotherapy) 16 F 25 Large left neck mass Soft tissue of neck, anterior to sternomastoid muscle, 7 cm × 6 cm × 3 cm Diagnosed as that time as "poorly differentiated sarcoma/malignant tumor of neural origin," and treated by left radical neck dissection and postoperative radiotherapy Developed shortness of breath at 20 mos after diagnosis. Chest roentgenogram showed complete opacification of left lung field, and multiple large nodules in right lung. Treated by chemotherapy (CY-VA-DIC, as used for sarcomas), with relief of respiratory symptoms, 50% reduction in the right lung nodules, and clearing of the left pleural opacification after the first course of treatment. Lost to follow-up after second course of chemotherapy 17 F 33 Swelling of left neck for 5 months Lymph node of upper neck and parotid region, 15.4 cm × 11.5 cm × 6.4 cm, with involvement of the facial nerve. (Patient had a mass located at the same site 5.5 years earlier, and excision showed hyaline-vascular Castleman's disease with focal overgrowth of follicular dendritic cells) Radical neck dissection Recent case M: male; F: female; Gy: Gray; CHOP: cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone; EORTC: European Organization for Research and Treatment of Cancer; CY-VA-DIC: Cyclophosphamide, vincristine, doxorubicin, and dacarbazine. The predominant site of tumor involvement was lymph node in 7 cases (cervical, 3; axillary, 2; supraclavicular, 1; and mediastinal, 1), and extranodal sites in the others, including the tonsil (3), palate (1), pharynx (1), soft tissues of the neck (2), small intestine (1), pancreas (1), and mesocolon (1). The mesocolonic tumor was accompanied by mesenteric lymph node and peritoneal involvement (Case 5). One patient presenting with cervical lymphadenopathy also had clinical and radiologic evidence of intraabdominal disease, but there was no histologic proof (Case 9); the exact primary site was unclear. Treatment and Outcome Most patients were treated by surgical excision, which was often supplemented by adjuvant radiotherapy or chemotherapy (protocol as used for aggressive lymphomas), especially for those likely to have residual disease (Table 2). Among the five cases treated by excision alone, recurrence developed in four (Cases 1, 6, 7, and 13). Four patients treated by combination therapy were event free on a mean follow-up of 4.6 years (Cases 2, 3, 10, and 11), although use of adjuvant therapy did not invariably prevent recurrence or metastasis. One patient (Case 15) was primarily treated by chemotherapy only because the close adherence of multiple involved lymph nodes to the trachea and carina rendered excision difficult and dangerous. Two patients were treated by radiotherapy (Case 3) or chemotherapy (Case 12) followed by excision. Follow-up information was available in 13 patients, with a follow-up duration of 2 months to 9 years (mean, 3.3 years; median, 3 years). Local recurrence occurred in 6 patients at a median of 15 months. Six patients had metastatic disease, including four who also had local recurrence (Cases 5, 6, 7, and 14). The sites of metastases were the liver, peritoneum, pancreas, lymph nodes, and lung. Three patients died of disease, at 2 months, 11 months, and 18 months, respectively; all had an intraabdominal tumor at presentation. Association with Castleman's Disease In Case 5, the main tumor mass showed small foci of residual hyaline-vascular Castleman's disease, comprising follicles with concentric arrangement of small lymphocytes, small germinal centers depleted of lymphoid cells, and penetration by hyalinized venules, as well as interfollicular venules intermingled with small lymphocytes. In addition, there was 5 mm × 1 mm focus of benign vascular neoplasm at one pole of the tumor. In Case 17, hyaline-vascular Castleman's disease preceded the development of FDC sarcoma at the same anatomic site by 5.5 years. It showed typical hyaline-vascular follicles (some of which apparently had multiple germinal centers) and rich interfollicular vascularity. However, there were areas in which the FDCs proliferated beyond the boundaries of the original follicles, forming multiple irregular, small, pale-staining islands in the interfollicular zones (Fig. 1). The FDCs had indistinct cell borders, lightly eosinophilic cytoplasm, and round vesicular nuclei, with occasional binucleated forms, without mitotic figures or formation of discrete expansile mass lesions. They were highlighted by immunostaining for CD21, CD35, and epithelial membrane antigen (EMA). This lesion was interpreted as Castleman's disease with FDC overgrowth/dysplasia. Figure 1Open in figure viewerPowerPoint Castleman's disease with follicular dendritic cell overgrowth. (Case 17) (A) The lymph node excision shows hyaline-vascular follicles separated by richly vascularized lymphoid tissue (upper field). In the interfollicular regions, there are irregular lightly eosinophilic patches representing overgrowth of follicular dendritic cells (lower field). (B) The interfollicular follicular dendritic cells have ovoid vesicular nuclei, with occasional binucleated forms. There is no significant cellular atypia, and these cellular clusters do not exhibit destructive growth. This lesion subsequently recurred as a frank follicular dendritic cell sarcoma (see Fig. 6). Pathologic Findings Regardless of the site of involvement, FDC sarcoma formed a solitary well circumscribed or invasive tumor that invariably exhibited pushing rather than permeative margins (Fig. 2). Figure 2Open in figure viewerPowerPoint The tumor typically shows pushing borders. (A) The tumor in the lymph node shows sharp demarcation from the residual parenchyma (Case 5). (B) The tumor in the tonsil appears discrete (Case 14). The tumor was traversed by sclerotic bands or delicate fibrovascular septa in eight cases. The tumor cells were spindly, ovoid, or polygonal, and exhibited a storiform (17 of 17), fascicular (10 of 17), whorled (9 of 17), diffuse (7 of 17), follicle-like (2 of 17), or trabecular (2 of 17) pattern (Figs. 3 and 4). Usually more than one growth pattern was observed in an individual tumor. The cellular whorls were circular, and were sometimes centered on a blood vessel (Fig. 3C). The ovoid and polygonal cells usually displayed a diffuse or occasionally trabecular pattern (Figs. 3D and 4B). Focal intercellular edema could sometimes be observed. Figure 3Open in figure viewerPowerPoint Growth patterns of follicular dendritic cell sarcoma. Note also the characteristic sprinkling of small lymphocytes. (A) Storiform pattern (Case 2). (B) Interlacing fascicles (Case 10). This case also exhibits rich vascularity and perivascular sclerosis. (C) Circular whorls (Case 15). This whorl is centered on a blood vessel. (D) Diffuse sheets (Case 14); note the perivascular cuffing of small lymphocytes. Figure 4Open in figure viewerPowerPoint Rarely, the tumor may assume a coalescent nodular pattern, reminiscent of the architectural features of follicular lymphoma (A) (Case 5), or trabecular pattern (B) (Case 9). The tumor cells had a moderate amount of lightly eosinophilic cytoplasm and indistinct cell borders, giving rise to a syncytial appearance (Fig. 5). The nuclei were oval to round, and usually had smooth contours, with the exception of Case 13, in which some nuclei were irregularly folded or showed pseudoinclusions. The nucleoplasm was predominantly clear in 11 cases, and granular in 6. However, the variations could be due to differences in fixation or processing, because nuclei with both appearances could be observed in different regions of the same case. The distinct, usually single nucleoli, which ranged from small (nine cases) to medium sized or large (nine cases), were located centrally or apposed to the nuclear membrane (Fig. 5). Nuclear atypia was usually mild, although more pleomorphic foci could be found in some tumors or in recurrences (Fig. 6). In Case 14, the polygonal tumor cells were particularly large, and possessed eosinophilic hyaline cytoplasm and large nucleoli (Fig. 7). The mitotic count was highly variable from case to case, ranging from 1 to 20 per 10 high-power fields (HPF) (Nikon microscope, field size 0.159 mm2, using ×40 objective and ×10 eyepieces) (Table 3); the counting was performed according to the method of Kempson and Hendrickson.27 Occasional scattered multinucleated tumor cells, which sometimes resembled Warthin-Finkeldey giant cells, were identified in 15 cases, although they were abundant in only 2 cases (Cases 3 and 10) (Fig. 8). Coagulative necrosis was observed in three cases (Fig. 6B). In nine cases, there were irregular pseudovascular, cystic, or perivascular spaces, with the last type highly reminiscent of those seen in thymomas (Fig. 9). These spaces sometimes contained eosinophilic proteinaceous material or blood. Figure 5Open in figure viewerPowerPoint Cytologic spectrum of follicular dendritic cell sarcoma. Note the sprinkling of small lymphocytes throughout the tumor. (A) The prototype is spindly cells with oval nuclei, empty nucleoplasm, and distinct small nucleoli (Case 4). (B) The chromatin pattern can be more coarsely granular. (C) Some cases are formed by syncytial-appearing ovoid cells with fine chromatin. Lymphocytes are often decreased in the ovoid and polygonal cell areas (Case 13). Note the fibrillary quality of the cytoplasm. (D) Some cases show large nucleoli. This feature, together with the syncytial growth pattern and lymphocytic infiltrate, may lead to an erroneous diagnosis of lymphoepithelioma-like carcinoma (Case 9). However, the tumor cells are negative for cytokeratin. Figure 6Open in figure viewerPowerPoint Variations in histology within the tumor (Case 17). (A) Some areas of the tumor show typical features of follicular dendritic cell sarcoma. (B) In other areas, there is significant nuclear pleomorphism and hyperchromasia, as well as geographic coagulative necrosis. Figure 7Open in figure viewerPowerPoint Spindly tumor cells merging into polygonal tumor cells (Case 14). In this example, the large polygonal cells possess prominent nucleoli and voluminous eosinophilic hyaline cytoplasm, mimicking malignant melanoma or undifferentiated carcinoma. Figure 8Open in figure viewerPowerPoint Multinucleated cells. (A) The intermingling of spindly cells with multinucleated cells can impart a striking resemblance to malignant fibrous histiocytoma (Case 10). (Inset) A multinucleated cell. This apparent multinucleation results from marked nuclear lobation. (B) In this example, the multinucleated cells have multiple nuclei clustered together in a grape-like pattern, resembling Warthin-Finkeldey polykaryocytes (Case 3). Figure 9Open in figure viewerPowerPoint Pseudovascular spaces are common within the tumor. (A) Some appear as large fluid-filled spaces (Case 2). (B) Some appear as irregular shaped clefts and pseudopapillae (Case 3). (C) Some resemble the perivascular spaces seen in thymomas (Case 5). Some spaces contain blood. Table 3. Histologic Features Case Cell shape Cellular atypia Mitotic count (per 10 HPF) Coagulative necrosis 1 Spindly Mild (moderate in recurrence) 20 Absent 2 Spindly Mild 14 Absent 3 Spindly and ovid Mild 1 Absent 4 Spindly Mild 4 Absent 5 Spindly and ovoid Mild; moderate in a small focus 12 Absent 6 Ovoid; focal spindly Moderate 6 Present (focal) 7 Spindly Mild 5 Present 8 Spindly Mild 10 Absent 9 Ovoid Moderate 6 Absent 10 Spindly Mild 1 Absent 11 Spindly Mild 3 Absent 12 Ovoid Mild 1 Absent 13 Ovoid Moderate 1 Absent 14 Spindly and ovoid Mild 2 Absent 15 Spindly Moderate 1 Absent 16 Spindly and ovoid Mild 9 Absent 17 Spindly Moderate (marked focally) 14 Present; extensive in areas with greater nuclear atypia HPF: high-power fields. In eight cases, the tumor was notable for the presence of a rich network of small blood vessels, which could show perivascular sclerosis (Figs. 3B and 10). A constant and highly characteristic feature was the sprinkling throughout the entire tumor of small lymphocytes (mild in 13 cases and moderate in 4 cases) (Fig. 5). In addition, plasma cells were seen in two cases (Cases 3 and 17) and neutrophils in one (Case 16). The lymphocytes sometimes also showed cuffing around the blood vessels (seven cases) (Fig. 3D). In Case 13, lymphatic invasion was identified in the recurrence. Figure 10Open in figure viewerPowerPoint Some tumors show a prominent vascularity. In this example, the prominent fibrovascular septa impart an endocrine appearance to this tumor (Case 6). Therapy-Related Histologic Changes In Case 3, comparison of the postradiotherapy specimen with the pretreatment biopsy showed that the tumor cells were larger, although the nuclear-cytoplasmic ratio was maintained. The nuclear contours had become highly irregular, with frequent nuclear grooves, indentations, and pseudoinclusions (Figs. 8B and 11). Necrosis was not evident. Figure 11Open in figure viewerPowerPoint Histologic changes attributed to radiotherapy (Case 3). The appearance of the original tumor is depicted in Figure 8B. After radiotherapy, the excision specimen shows larger, plumper, polygonal tumor cells with remarkable nuclear irregular foldings and frequent nuclear pseudoinclusions (arrow). The cytoplasm exhibits a fibrillary quality. In Case 12, the postchemotherapy specimen showed sheets of foamy histiocytes with fine, brownish, cytoplasmic granular debris, interspersed among fibrous bands (Fig. 12). Only on careful scrutiny were irregular small islands of residual tumor identified among the "sea" of histiocytes (CD68 positive and S-100 protein negative). The tumor cells appeared remarkably squamoid, with the polygonal cells showing many spiky cell processes and intercellular bridges. Nuclear pleomorphism was much more striking compared with the pretreatment biopsy, with large, irregular, and hyperchromatic nuclei. However, mitotic figures were not seen. The tumor islands were best visualized in preparations immunostained for CD21 or CD35 (Figs. 12C and 12D). Figure 12Open in figure viewerPowerPoint Histologic changes attributed to chemotherapy (Case 12). (A) The postchemotherapy excision specimen shows extensive sheets of foamy histiocytes and sclerotic bands, with only interspersed small islands of residual tumor that stain a more deeply eosinophilic color. (Compare with Part C). (B) The tumor clusters have a squamoid appearance. There appear to be intercellular bridges attributable to the individual cells breaking away from one another due to damage by t