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Primary Synovial Sarcomas of the Mediastinum. A Clinicopathologic, Immunohistochemical, and Ultrastructural. Study of 15 Cases. Saul Suster, MD* and Cesar ...
ORIGINAL ARTICLE

Primary Synovial Sarcomas of the Mediastinum A Clinicopathologic, Immunohistochemical, and Ultrastructural Study of 15 Cases Saul Suster, MD* and Cesar A. Moran, MD†

Abstract: A series of 15 cases of primary mediastinal neoplasms displaying histopathologic, immunohistochemical, and ultrastructural features of synovial sarcoma is presented. The patients’ ages ranged from 3 to 83 years, with a male-to-female ratio of 2:1. Nine cases presented as anterior mediastinal masses with chest pain, shortness of breath, and pleural effusion, and 6 cases were in paravertebral location in the posterior mediastinum and presented with neck or back pain and pleural effusion. The tumors measured from 5 to 20 cm in greatest diameter and showed a tan white, soft to rubbery cut surface with areas of hemorrhage and necrosis and foci of gelatinous material. Four cases showed areas of cystic degeneration. In 7 cases, the tumors were well circumscribed; in 6 cases, the tumors grossly invaded the pleura, pericardium, heart, great vessels, chest wall, rib, and vertebra. Histologically, 5 cases displayed a biphasic growth pattern, with well-formed glandular elements admixed with a monotonous spindle cell population. Ten cases were exclusively composed of a monotonous atypical spindle cell proliferation. Immunohistochemical studies showed focal positivity of the tumor cells for cytokeratin and/or epithelial membrane antigen, and strong positivity for vimentin and bcl-2 in the spindle cells in all cases studied (10 of 10). Eight cases also showed focal positivity for CD99. Electron microscopic examination in 5 cases showed oval to spindle tumor cells with closely apposed cell membranes, abundant cytoplasmic intermediate filaments and rough endoplasmic reticulum, and immature desmosome-type cell junctions. Ten patients were treated by complete surgical excision and two by partial excision followed by radiation therapy. In 4 patients, the tumors were inoperable and treated with radiation therapy only. Clinical follow-up was available in 5 patients and showed local recurrence with metastases to lung, lymph nodes, and epidural space from 1 to 3 years in 4 cases and liver metastases and death due to tumor after 6 month in 1 case. Synovial sarcoma should be considered in the differential diagnosis of biphasic and monophasic spindle cell neoplasms of the mediastinum. Key Words: synovial sarcoma, spindle cell tumors, mediastinum (Am J Surg Pathol 2005;29:569–578)

From the *Department of Pathology, Division of Anatomic Pathology, Ohio State University, Columbus, OH; and the †Department of Pathology, M.D. Anderson Cancer Center, Houston, TX. Reprints: Saul Suster, MD, Department of Pathology, Ohio State University, E-411 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210 (e-mail: [email protected]). Copyright Ó 2005 by Lippincott Williams & Wilkins

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ynovial sarcoma is widely recognized as a distinctive soft tissue neoplasm most commonly occurring in the extremities of young adults. Because of its frequent association with joints, tendons, and bursal structures, it was initially postulated that these tumors originated from synovial cells.3,25 A large body of literature has been accrued in recent years, however, indicating that these tumors are not related to normal synovium but rather show features of epithelial differentiation.4,5,8,17,28 These findings, coupled with their documented occurrence at sites where normal synovial, bursal, or tendon sheath structures do nor exist has led to the speculation that these lesions may be derived from pluripotential mesenchymal cells capable of partial or aberrant epithelial differentiation.5,8 An added difficulty for diagnosis associated with these tumors is the frequent occurrence of the monophasic spindle cell variant. Such tumors are distinguished by their propensity to be confused for other types of spindle cell sarcomas, and for their immunoreactivity for epithelial markers that belie their sarcomatoid appearance. When arising at sites unrelated to joints and tendons or where native epithelial structures normally do not exist, these tumors have often gone unrecognized and have been interpreted as examples of carcinosarcoma, sarcomatoid carcinoma, or malignant mesothelioma.7,10 We have studied 15 cases of primary tumors of the mediastinum that showed clinical, histopathological, immunohistochemical, and ultrastructural features identical to those of synovial sarcoma arising at soft tissue sites. It is important to recognize the existence of these tumors in the mediastinum to avoid mistaking them for other conditions with similar histopathologic features but that may follow a different biologic behavior.

MATERIALS AND METHODS Fifteen cases showing the features here described were retrieved from the surgical pathology files of the Ohio State University Medical Center, the M.D. Anderson Cancer Center, and from both authors’ personal consultation files over a period between the years 1985 and 2000. From 2 to 9 hematoxylin and eosin-stained tissue sections were available for review in all cases. Representative paraffin blocks from formalin-fixed tissue were available for immunohistochemical studies in 10 cases. In 5 additional cases, a limited number of unstained tissue sections were also available for immunohistochemical assays.

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Deparaffinized tissue sections were incubated with antibodies against broad-spectrum keratin (Dako, Carpinteria, CA; 1:3,000), low-molecular weight cytokeratin CAM 5.2 (BectonDickinson, San Jose, CA), epithelial membrane antigen (EMA; clone E29) (Dako; 1:30), vimentin (Dako), pan-muscle actin (HHF-35) (Enzo, Farmingdale, NY), alpha-smooth muscle actin (clone 1A4) (Dako; 1:100), desmin (clone D33) (Dako), S-100 protein (Dako; 1:5), HMB-45 anti-melanoma antigen (Dako), CD30 (Dako), CD31 (Dako), CD34 (My clone) (Becton-Dickinson; 1:200), bcl-2 (clone 124) (Dako; 1:40), and CD99 (clone O13) (Signet, Dedham, MA; 1:30), by the avidin biotin-complex technique. Sections incubated with antibodies against CAM 5.2, vimentin, and bcl-2 were treated using a microwave epitope retrieval technique with 10 mL of citrate buffer, pH 6.0, at high temperature for 20 minutes. Nonimmune mouse and rabbit serum was substituted for the primary antibodies as negative controls. Appropriate positive controls were run concurrently for all antibodies tested. For electron microscopy, fresh tissue samples from cases nos. 3, 5, 6, 9, and 15 were fixed in glutaraldehyde or Karnovsky’s solution and embedded in EPON. Thin sections were stained with lead citrate and uranyl acetate and examined in a Zeiss EM9 transmission electron microscope. Clinical histories and follow-up information was obtained from the patients’ charts or by contacting the referring physicians.

PATHOLOGIC FINDINGS Clinical Findings The clinical findings in our patients are summarized in Table 1. Five patients were women and 10 were men, ranging in age from 3 to 83 years. The median age was 35 years, and more than 70% of the patients were in the 20- to 50-year age group. All patients presented with symptoms including back or chest pain, shortness of breath, and pleural effusion. Four patients also had constitutional symptoms such as fever, weight loss, and weakness. None of the patients had a previous history of tumor elsewhere, and no other source of malignancy could be identified on thorough clinical or radiographic examination immediately after the initial diagnosis. Six cases were located in the posterior mediastinum, six in the anterior mediastinum, and three occupied the anterior-middle mediastinum with compromise of hilar structures and great vessels. Three of the cases located in the posterior mediastinum showed focal infiltration and destruction of ribs and vertebrae. Radiographic examination showed a well-circumscribed mass with focal calcifications in 7 cases, and an ill-defined, infiltrative tumor mass in 6 (Fig. 1). In 1 case (case no. 7), multiple small pulmonary nodules were also present on the chest radiograph at the time of initial diagnosis. The tumors were treated by complete surgical excision in 10 cases, 2 cases underwent partial excision followed by radiation therapy, and 3 cases were deemed inoperable at the time of diagnosis and were treated by radiation therapy following an open chest biopsy. Clinical follow-up in 5 patients showed local recurrence in 4 cases from 1 to 3 years after diagnosis. Four cases had biopsy-proven metastases to hilar lymph node, lung, liver,

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and epidural space. One patient (case no. 3) died of tumor 6 months after diagnosis with liver metastases.

Gross Features The tumors ranged in size from 5 to 20 cm in greatest diameter. Seven tumors were well circumscribed and described as partially surrounded by a thin fibrous capsule. Six cases were described as poorly circumscribed, infiltrative masses that invaded surrounding structures including pleura, lung, heart, great vessels, chest wall, rib, and vertebrae. One tumor (case no. 3) was described as a bilobed mass, with a large dominant component extending from the apex of the heart to the diaphragm, and a second smaller component extending into the right hemithorax. Case no. 4 showed invasion by tumor of the right subclavian artery, innominate vein, superior vena cava, and the aorta, with extension of the tumor in a polypoid fashion into the right atrium. One patient (case no. 11) had a diagnosis of infiltrating ductal carcinoma of the breast and underwent radiographic evaluation of the chest for symptoms of chest pain and shortness of breath. A well-circumscribed anterior mediastinal mass was identified showing infiltration of the superior segment of the lingula and multiple small left pleural implants. On cut section, the tumors were composed of gray-white to tan homogeneous soft tissue with focal areas of gelatinous consistency, as well as areas of hemorrhage and necrosis. Four cases showed focal cystic changes; the cysts ranged from 0.3 to 3 cm in greatest diameter and were lined by a thin fibrous wall and filled with clear fluid. One case (case no. 7) presented with a rapidly enlarging cystic mass filled with hemorrhagic fluid grossly reminiscent of a cavernous hemangioma.

Histopathologic Findings Two distinct growth patterns could be identified in these tumors: 5 cases displayed a biphasic pattern of growth, and 10 showed a monophasic growth pattern.

Biphasic Tumors Well-formed glandular structures admixed with a monotonous atypical spindle cell proliferation in the stroma characterized these tumors (case nos. 4, 6, 8, 11, and 14) (Fig. 2). The epithelial glandular component was focal in 2 cases, present in about equal proportion to the spindle cell elements in 2, and predominated in 1. In 2 cases, the glandular structures adopted a pseudopapillary configuration (Fig. 3). The glandular and pseudopapillary structures were lined by round, cuboidal, or columnar cells containing round to oval nuclei with abundant eosinophilic or amphophilic cytoplasm. Some of the glandular lumens were filled with homogeneous eosinophilic material. The intervening stromal spindle cell population was comprised of cells containing elongated, vesicular nuclei with tapered ends that were surrounded by scant, lightly eosinophilic cytoplasm. Occasional mast cells could be seen scattered among the spindle cells. Mitoses ranged from 2 to 5 per 10 high power fields (HPF). In 2 cases, the glandular component displayed prominent cytoplasmic clearing of the cells resulting in a very distinctive biphasic morphologic appearance (Fig. 4). None of the biphasic tumors displayed areas of hemorrhage or necrosis. q 2005 Lippincott Williams & Wilkins

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Monophasic Tumors In 10 cases, the tumors displayed the features of monophasic synovial sarcoma of spindle cell type. These tumors were characterized by a monotonous proliferation of tumor cells with oval to spindle, vesicular nuclei surrounded by an indistinct rim of amphophilic to lightly eosinophilic

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cytoplasm (Fig. 5). The tumor cells grew as sheets or forming fascicles that often adopted a prominent ‘‘herringbone’’ or storiform pattern (Fig. 6). Two cases contained foci of round, epithelioid cells that resembled the ‘‘poorly differentiated’’ variant of synovial sarcoma (Fig. 7). All tumors displayed prominent vascularity. Areas showing a prominent

TABLE 1. Clinicopathlogic Features in 15 Patients With Primary Synovial Sarcomas of the Mediastinum Case No.

Sex/Age (yr)

1

F/3

2

F/4

3

M/13

4

F/23

5

M/23

6

M/24

7

M/25

8

M/27

9

M/36

10

M/42

11

F/46

12

M/48

13

M/50

14

F/54

15

M/83

Case No.

Size/Location 5 3 4 3 4 cm Left Posterior mediastinum 16 3 13 3 8 cm Anterior mediastinum ‘‘Large’’ Anterior mediastinum 13 3 7 3 5 cm Anterior mediastinum 7 3 5 3 5 cm Anterior mediastinum 9 3 6 3 4 cm Posterior mediastinum 7 3 3 3 2 cm Anterior mediastinum 20 3 20 3 10 cm Posterior mediastinum ‘‘Large mass’’ Anterior mediastinum 8 3 8 3 3 cm Posterior mediastinum 6 3 5 3 5 cm Anterior mediastinum 12 3 10 3 9 cm Posterior mediastinum 7 3 5 3 3 cm Posterior mediastinum 8 3 7 3 7 cm Anterior mediastinum 8 3 7 3 6 cm Anterior mediastinum

Histology fascicular epithelioid myxoid

Clinical Presentation Cough, chest pain, neck pain Weight loss, weakness, fever, bloody pleural effusion Weakness, shortness of breath, right pleural effusion Weakness, chest pain, nodule within right atrium of heart on echocardiogram Chest pain Back pain, mediastinal mass on x-ray Chest pain and left pleural effusion Fever, anemia Not applicable Not applicable Chest pain, shortness of breath, history of breast carcinoma Chest pain Three-year history of recurrent chest pain and pericardial effusion Pain on left shoulder Shortness of breath and pleural effusion

Treatment

Follow-up

Surgical excision Surgical excision Biopsy + radiation therapy Partial excision + radiation therapy Surgical excision Surgical excision Surgical excision Surgical excision Surgical excision Surgical excision Surgical excision + pneumonectomy Open biopsy followed by radiation therapy Surgical excision

— — Died 6 months later with metastases to liver — Local recurrence at 1 year Local recurrence and bilateral lung metastases at 3 years Recurrence at 1 year — — — — — Hilar lymph node metastases at the time of diagnosis, then lost to follow-up Local recurrence and epidural metastases at 1 year; died of tumor and complication of chemo-radiation therapy —

1 2 3 4 5 6 7 8 9 10 11 12 13

Monophasic, Monophasic, Monophasic, Biphasic Monophasic, Biphasic Monophasic, Biphasic Monophasic, Monophasic, Biphasic Monophasic, Monophasic,

14

Biphasic

Partial excision + radiation therapy

15

Monophasic

Open biopsy followed by radiation therapy

fascicular fascicular epithelioid fascicular fascicular fascicular

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FIGURE 1. Chest CT scan shows a right pleural effusion with a well-circumscribed right anterior mediastinal mass (*) showing low attenuation (case no. 2).

hemangiopericytic growth pattern, with numerous small branching blood vessels with open lumens that occasionally adopted a ‘‘staghorn’’ appearance characterized 3 cases (Fig. 8). All tumors showed prominent stromal changes including focal

FIGURE 3. Focal pseudopapillary structures are seen (case no. 4) containing atypical spindle cells within the stroma.

deposition of thick intercellular collagen, areas of myxoid degeneration, and foci of hemorrhage and necrosis. Scattered microcalcifications were identified in 2 cases. Mast cells were also present in varying proportions in all tumors. Mitotic activity ranged from 2 to 12 per 10 HPF. All the grossly cystic cases were of the monophasic spindle cell type (Fig. 9). The cyst walls contained a dense spindle cell proliferation and were devoid of an epithelial lining. The lumens of the cysts were occasionally filled with hemorrhagic or clear proteinaceous material.

Immunohistochemical Findings

FIGURE 2. Biphasic synovial sarcoma of the mediastinum (case no. 4) showing a glandular proliferation surrounded by a dense spindle cell stroma.

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All cases showed at least focal membrane or cytoplasmic positivity for one or more epithelial markers in the spindle cells, including broad-spectrum and low-molecular weight cytokeratin and EMA (Fig. 10A). The glandular elements strongly stained with all three epithelial markers in the biphasic cases. The spindle cell component in all cases also stained strongly with vimentin. Ten cases were stained with antibodies against bcl-2 and CD99. The majority of the spindle cells (.80%) in all these cases were strongly positive for bcl-2 and showed focal to diffuse positivity for CD99 in 8 of 10 q 2005 Lippincott Williams & Wilkins

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FIGURE 4. Biphasic synovial sarcoma of the mediastinum (case no. 11) showing unusual clearing of the cytoplasm in the glandular component.

cases (Fig. 10B). Stains for muscle actin (HHF-35), smooth muscle actin, desmin, S-100 protein, HMB45, CD30, CD31, and CD34 were uniformly negative in the tumor cells in all the cases tested.

Ultrastructural Features Five cases were studied by electron microscopy (case nos. 3, 5, 6, 9, and 15). Ultrastructural examination of the spindle cell component in these tumors revealed a fairly cohesive population of oval to spindle cells with focally scant intercellular stroma (Fig. 11). The cells showed elongated nuclei with occasional nuclear indentations, peripheral margination of chromatin, and scattered heterochromatin. The cell membranes were closely apposed with little to no intervening intercellular stroma. The cytoplasm showed strands or rough endoplasmic reticulum and abundant intermediate filaments. The cell membranes showed short cytoplasmic interdigitations partially covered by a thin layer of external lamina. Scattered immature, desmosome-type cell junctions could be observed along cell processes and in the cell membranes of adjoining cells (Fig. 12). No tonofilaments, granules, microvilli, dense bodies, or other specific organelles could be identified. q 2005 Lippincott Williams & Wilkins

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FIGURE 5. Monophasic spindle synovial sarcoma (case no. 1) showing monotonous proliferation of atypical spindle cells with scant cytoplasm and occasional mitoses (center).

DISCUSSION Synovial sarcoma is a rare but distinctive soft tissue neoplasm that was first described nearly a century ago19 yet still remains a controversial entity. Although initially thought to arise from synovium, it has slowly become apparent that this tumor is not related to normal synovium but rather demonstrates evidence of epithelial differentiation. Because of this, it has been proposed by some that this tumor be renamed carcinosarcoma or spindle cell carcinoma of soft tissue.11,18,21 Although the most common location for this tumor includes the soft tissues of the extremities and the head and neck region, examples of this entity have now been recognized in previously undescribed locations, including the chest wall,9 lung,39 heart,14,26 pleura,10 esophagus,1 mesentery,13 retroperitoneum,22,29 vulva,27 and in intracranial location within the third ventricle.16 An additional unusual site where this tumor has also been described is the mediastinum. In 1989, Witkin et al37 reported 4 cases of biphasic tumors of the mediastinum with features of synovial sarcoma. The patients were all adult men who presented with solitary mediastinal masses in the region of the aortic arch or in the perihilar region. All tumors histologically

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FIGURE 6. Monophasic spindle synovial sarcoma of the mediastinum showing (A) prominent storiform pattern and (B) areas displaying herringbone pattern (case no. 5).

FIGURE 7. Monophasic synovial sarcoma composed of sheets of round to oval tumor cells with abundant eosinophilic cytoplasm imparting the cells with a more rounded, epithelioid appearance (case no. 9).

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FIGURE 8. Hemangiopericytic growth pattern in monophasic synovial sarcoma showing numerous branching small vessels with patent lumens (case no. 10). q 2005 Lippincott Williams & Wilkins

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FIGURE 9. Monophasic synovial sarcoma showing prominent cystic changes (case no. 7).

displayed a biphasic growth pattern with an admixture of glandular structures and spindle cell elements. Based on the morphologic appearances and the results of immunohistochemical stains, the authors concluded that their cases corresponded to rare examples of biphasic synovial sarcomas originating in the mediastinum. One additional case was subsequently reported20 that showed the characteristic X;18 chromosomal translocation by cytogenetic analysis, further supporting the occurrence of these tumors as primary mediastinal neoplasms. A more recent study by Trupiano et al36 reported 2 cases of biphasic synovial sarcomas occupying the anterior and middle mediastinum that also demonstrated the t(X:18) cytogenetic abnormality characteristic of these tumors. We have described here the clinicopathologic features in 15 cases of primary synovial sarcomas of the mediastinum. Our study confirms previous observations on these tumors and, more importantly, documents the existence of a monophasic spindle cell variant in the mediastinum. Five of the cases in our study occurred in paravertebral location within the posterior mediastinum, a previously undescribed form of presentation for this lesion. In our series, the tumors were distributed throughout all mediastinal compartments, with a 2:1 q 2005 Lippincott Williams & Wilkins

FIGURE 10. A, Immunohistochemical stains for cytokeratin AE1/AE3 in monophasic synovial sarcoma (case no. 1) showing focal cytoplasmic positivity in the tumor cells. B, Immunohistochemical stain for bcl-2 in the same case showing strong cytoplasmic positivity in the majority of the tumor cells.

male/female distribution and a median age of 35 years. Two cases were described as partly cystic tumors on radiographic examination, and in 2 cases spotty calcifications were noted on chest radiographs. One case was accompanied by gross invasion of the superior vena cava, and the tumor extended in a polypoid fashion into the right and left ventricles of the heart.

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FIGURE 11. Ultrastructural appearance of tumor cells in monophasic synovial sarcoma of the mediastinum showing cohesive tumor cells with closely apposed cell membranes and elongated nuclei with margination of chromatin (case no. 3).

The original pathologic diagnoses rendered on these cases ranged from malignant schwannoma (in 5), to angiosarcoma (in 1), to spindle cell thymoma (in 1), to malignant mesothelioma (in 2) and spindle cell sarcoma, not otherwise specified (in 3). Five cases showed a biphasic growth pattern and 10 cases were characterized by a monophasic spindle cell growth. Immunohistochemical stains in these tumors showed at least focal positivity for epithelial markers and strong positivity for vimentin, bcl-2, and CD99 in the spindle cells, a combination of markers that that been found to be characteristically expressed in synovial sarcoma but not in any of the other conditions that may enter in the differential diagnosis of similar tumors at this location.32,34 Electron microscopy in 5 cases showed features of synovial sarcoma, including oval to spindle cells with closely apposed cell membranes, poorly formed

FIGURE 12. Higher magnification from the preceding case showing desmosome-type junctions between the tumor cells (center) (case no. 3).

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desmosome-type cell junctions, and abundant cytoplasmic intermediate filaments admixed with strands of rough endoplasmic reticulum. Clinical follow-up in 5 of our patients demonstrated a biologic behavior similar to that of synovial sarcoma at other locations, with local recurrence and distant metastases within 1 to 3 months after diagnosis in 4 patients and death due to tumor within 6 months in 1 case. The differential diagnosis for these tumors in the mediastinum can be quite complex. The biphasic lesions can be easily confused for metastatic carcinoma, pulmonary blastoma, thymic carcinosarcoma, and biphasic malignant mesothelioma. Metastatic carcinoma can generally be ruled out by identifying the atypical spindle cell component surrounding the glands. Additionally, the nuclei in the glandular elements of synovial sarcoma are more uniform and less pleomorphic than those generally encountered in metastatic adenocarcinoma. Pulmonary blastoma may rarely infiltrate the mediastinum but will generally present with a bulky intraparenchymal lung mass. The cells lining the glands in pulmonary blastoma display a characteristic clearing of the cytoplasm reminiscent of the fetal lung at 16 weeks of gestation and are often accompanied by focal accumulations of round, basaloid stromal cells at the base of the glands (so-called ‘‘morules’’). Thymic carcinosarcoma is a rare variant of primary thymic carcinoma characterized by the admixture of atypical glandular epithelial elements with poorly differentiated, sarcomatous spindle cell elements.30,35 Unlike synovial sarcoma, the spindle cell component in these tumors should be negative for epithelial markers, and the glandular component will display more overtly atypical cytologic features. Finally, biphasic malignant mesothelioma involving the mediastinum can also pose difficulties for diagnosis owing to the presence of glandular and spindle cell structures that are positive for keratin.24,34 The gross morphologic findings can be quite helpful in such cases; synovial sarcoma will usually present as a discrete mass as opposed to mesothelioma, which has a tendency to grow as a diffuse, plaque-like tumor mass extending along the pleural or pericardial surface. The spindle cell population in biphasic mesothelioma also will show a tendency to display more pronounced nuclear pleomorphism, unlike the spindle cells in synovial sarcoma, which are usually characterized by their strikingly uniform and monotonous appearance. The most difficult challenge for differential diagnosis in these tumors when arising in the mediastinum lies in distinguishing the monophasic spindle cell variant of synovial sarcoma from other spindle cell neoplasms more commonly encountered at this location. A wide range of spindle cell neoplasms can present as a primary tumor in the mediastinum. Sarcomatoid carcinoma, spindle cell thymoma, spindle cell thymic carcinoma, and a variety of primary and metastatic spindle cell mesenchymal neoplasms, including solitary fibrous tumor, leiomyosarcoma, malignant peripheral nerve sheath tumor (MPNST), and malignant fibrous histiocytoma, have been described in this location.32 Metastatic sarcomatoid carcinoma can present with extensive involvement of mediastinal lymph nodes, particularly from primary tumors of the lung. Histologically, sarcomatoid carcinoma tends to be more pleomorphic and shows a higher degree of cytologic atypia and pleomorphism than synovial sarcoma. The two may be q 2005 Lippincott Williams & Wilkins

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impossible to distinguish based on immunohistochemistry due to their shared antigenic profile for cytokeratins. The finding of strong bcl-2 and CD99 positivity, however, would favor a diagnosis of synovial sarcoma over metastatic sarcomatoid carcinoma.31 A detailed clinical history and thorough clinical and radiographic examination are always indicated before rendering a diagnosis of synovial sarcoma in the mediastinum. Spindle cell thymoma can also share similar features with monophasic synovial sarcoma, including a monotonous population of relatively bland-appearing spindle cells that react with cytokeratin antibodies. Histologic features helpful in separating the two include lobular architecture, perivascular spaces, presence of small T lymphocytes admixed with the spindle cells, and lack of mitotic activity in the epithelial cell population in spindle cell thymoma. Moreover, although the tumor cells in both entities share keratin positivity, the spindle cells in thymoma do not express vimentin intermediate filaments and are negative for CD99 and EMA antibodies. Also, they do not share the same extent and consistency of staining for cytokeratin and bcl-2 antibodies2; for instance, cytokeratin positivity is usually strong and diffuse in thymoma, whereas it is generally only focal in synovial sarcoma. A more difficult morphologic differential may be posed by the spindle cell variant of thymic carcinoma,33 a tumor characterized by more pronounced nuclear atypia and mitotic activity than spindle cell thymoma. Absence of reactivity for bcl-2 and CD99 can be helpful features to distinguish spindle cell thymic carcinoma from monophasic synovial sarcoma. Also, the identification of areas of transition with elements displaying more conventional features of spindle cell thymoma may be of aid in establishing the correct diagnosis in such cases.33 Although rarely, a wide variety of spindle cell sarcomas can also be encountered in the mediastinum, either as primary lesions or as the result of metastatic spread from a soft tissue primary. The two entities that can most closely resemble monophasic synovial sarcoma in this location are solitary fibrous tumor and MPNSTs. Solitary fibrous tumors have now been well documented in the mediastinum38 and can show areas that are morphologically indistinguishable from monophasic synovial sarcoma.23 Unlike synovial sarcoma, solitary fibrous tumor will stain positively for CD34 in up to 80% of cases and will not express keratin or EMA. MPNST represents one of the most common malignant spindle cell neoplasms of the posterior mediastinum. Histologically, MPNST may closely resemble monophasic synovial sarcoma, with fascicles of monotonous spindle cells that often adopt a ‘‘herringbone’’ pattern and display brisk mitotic activity. Although approximately 50% of these tumors react with antibodies to S-100 protein, this marker may not reliably discriminate between these two neoplasms since synovial sarcoma has also been found to express S-100 protein in up to 30% of cases.12 Demonstration of keratin or EMA positivity, or strong and diffuse positivity for bcl-2 and CD99 may be of aid in the immunohistochemical differential diagnosis. In equivocal cases, ultrastructural examination coupled with demonstration of the characteristic (X;18) chromosomal translocation in synovial sarcoma may be the only means for establishing a definitive diagnosis. q 2005 Lippincott Williams & Wilkins

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Finally, the possibility of a metastasis to the mediastinum from a synovial sarcoma of soft tissue should always be ruled out first before making a diagnosis of primary synovial sarcoma at this site. Although rare, a few instances of such an occurrence have been described in the literature.6,15 In the present series, none of the patients had a history or evidence on clinical or radiographic examination of tumor elsewhere, supporting their primary origin at this site. Because of their unusual location, these tumors were initially misdiagnosed for other conditions. Synovial sarcoma must therefore be entertained in the differential diagnosis of biphasic and monophasic spindle cell tumors arising in the mediastinum.

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22. Miyashita T, Imamura T, Ishikawa Y, et al. Primary retroperitoneal synovial sarcoma. Intern Med. 1994;33:692–696. 23. Moran CA, Suster S, Koss MN. The spectrum of histologic growth patterns in benign and malignant fibrous tumors of the pleura. Semin Diagn Pathol. 1992;9:169–180. 24. Moran CA, Wick MR, Suster S. The role of immunohistochemistry in the diagnosis of malignant mesothelioma. Semin Diagn Pathol. 2000;17:178– 183. 25. Murray MT, Stout AP, Pogogeff IA. Synovial sarcoma and normal synovial tissue cultivated in-vitro. Ann Surg. 1949;31A:619. 26. Nicholson A, Rigby M, Lincoln C, et al. Synovial sarcoma of the heart. Histopathology. 1997;30:340–352. 27. Nielsen GP, Shaw PA, Rosenberg AE, et al. Synovial sarcoma of the vulva: a report of 2 cases. Mod Pathol. 1996;9:970–974. 28. Salisbury JR, Isaacson PG. Synovial sarcoma: an immunohistochemical study. J Pathol. 1985;147:49–57. 29. Shmookler BM. Retroperitoneal synovial sarcoma: a report of four cases. Am J Clin Pathol. 1982;77:686–691. 30. Snover DC, Levine GD, Rosai J. Thymic carcinoma: five distinctive histological variants. Am J Surg Pathol. 1982;6:451–470. 31. Suster S, Fisher C, Moran CA. Expression of bcl-2 oncoprotein in benign and malignant spindle cell tumors of soft tissue, skin, serosal surfaces, and gastrointestinal tract. Am J Surg Pathol. 1998;22:863–872.

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32. Suster S, Moran CA. The mediastinum. In: Weidner N, Cote R, Suster S, et al, eds. Modern Surgical Pathology. Philadelphia: Saunders, 2003:439– 504. 33. Suster S, Moran CA. Spindle cell thymic carcinoma: clinicopathologic and immunohistochemical study of a distinctive variant of primary thymic epithelial neoplasm. Am J Surg Pathol. 1999;23:691–700. 34. Suster S. Recent advances in the application of immunohistochemical markers for the diagnosis of soft tissue tumors. Semin Diagn Pathol. 2000; 17:225–235. 35. Suster S, Rosai J. Thymic carcinoma: a clinicopathologic study of 60 cases. Cancer. 1991;67:1025–1032. 36. Trupiano JK, Rice TW, Herzog K, et al. Mediastinal synovial sarcoma: report of two cases with molecular genetic analysis. Ann Thorac Surg. 2002;73:628–630. 37. Witkin GB, Miettinen M, Rosai J. A biphasic tumor of the mediastinum with features of synovial sarcoma: a report of four cases. Am J Surg Pathol. 1989;13:490–499. 38. Witkin GB, Rosai J. Solitary fibrous tumor of the mediastinum: a report of 14 cases. Am J Surg Pathol. 1989;13:547–557. 39. Zeren H, Moran CA, Suster S, et al. Primary pulmonary sarcomas with features of monophasic synovial sarcoma: a clinicopathological, immunohistochemical, and ultrastructural study of 25 cases. Hum Pathol. 1995; 26:474–486.

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