Primary Synovial Sarcoma of the Kidney

Duck-Hwan Kim, M.D., Jin H. Sohn, M.D., Min C. Lee, M.D., Gilho Lee, M.D., Ghil-Suk Yoon, M.D., Hiroshi Hashimoto, M.D., Hiroshi Sonobe, M.D., and Jae Y. Ro, M.D.

The authors present two cases of primary synovial sarcoma cytoma, hemangiopericytoma, osteosarcoma, rhabdo- of the kidney. Both patients had a mass in the upper part of myosarcoma, angiosarcoma, and malignant peripheral the right kidney without any primary extrarenal neoplastic le- nerve sheath tumor have been reported in this site. Fre- sions. Grossly, the tumors were soft to rubbery masses measuring 5.5 cm and 5 cm in diameter, respectively. Histologi- quently, the diagnosis of primary sarcoma of the kidney cally, both tumors were poorly differentiated synovial sarcoma. is difficult because sarcomatoid renal cell carcinomas The lesions exhibited a hypercellular solid or lobular growth of and primary retroperitoneal soft-tissue sarcomas with round, oval, or short spindle cells in variably solid sheets, in secondary renal invasion may mimic the primary renal intersecting fascicles, or in a haphazard fashion. Areas of solid sarcoma. To make a diagnosis of primary renal sarcoma, aggregation or fascicles of the tumor cells alternating with hypocellular myxoid tissues, together with areas displaying a the possibility of sarcomatoid renal cell carcinoma and prominent hemangiopericytoma-like pattern, were found. Im- primary retroperitoneal sarcoma as well as metastatic munohistochemically, vimentin was diffusely positive and a sarcoma to the kidney should be excluded. few tumor cells were positive for cytokeratin, epithelial mem- Synovial sarcoma is the fourth most common type of brane antigen, and neurofilament. The tumor cells were nega- soft-tissue sarcoma, and it occurs primarily in the ex- tive for S-100 protein, CD34, smooth muscle actin, and desmin, 10 whereas CD56 and CD99 were positive. In both cases, reverse tremities in young adults. Synovial sarcoma has been transcription–polymerase chain reaction using ribonucleic acid reported in a variety of unusual locations in which there extracted from formalin-fixed, paraffin-embedded tissues de- is no synovial structure, such as the head and neck,10 tected SYT-SSX2 fusion gene transcripts, which are character- third ventricle of the brain,25 peripheral nerve,35 heart,32 istic molecular findings of synovial sarcoma. One patient died pericardium,1 pleura,16,31 lung,20,22,44 intravascular 10 months after diagnosis. These tumors are unique cases of 29,36 43 12 primary synovial sarcoma of the kidney confirmed by molecu- space, mediastinum, abdominal wall, peritoneal 23 37 33 21 lar study. cavity, retroperitoneum, vulva, and prostate. Re- Key Words: Synovial sarcoma—Kidney—SYT-SSX— cently, three cases of primary synovial sarcoma of the RT-PCR. kidney, among seven cases of which previous diagnosis was embryonal renal sarcoma, were described in abstract Am J Surg Pathol 24(8): 1097–1104, 2000. form, and they were confirmed by the presence of SYT-SSX fusion transcripts or cytogenetic study.11 A reciprocal translocation, t(X;18)(p11.2;q11.2), has Primary sarcoma of the kidney is a rare neoplasm. The been shown to be specific for synovial sarcoma.6 Five most common renal sarcomas are leiomyosarcoma, lipo- variants of the SSX gene (SSX1, SSX2, SSX3, SSX4, sarcoma, and fibrosarcoma.30 Malignant fibrous histio- and SSX5) have been identified,18 but only SSX1 and SSX2 have been shown to fuse with the SYT gene in the 6,8 From the Department of Pathology (D.H.K., J.H.S.), Hallym translocation t(X;18) in synovial sarcoma. University College of Medicine, Seoul, Korea; the Departments of We describe two cases of primary renal synovial sar- Pathology (M.C.L.) and Urology (G.L.), Dankook University Hospital, coma, for which diagnosis was facilitated by detection of Cheonan, Korea; the Department of Pathology (G.S.Y., J.Y.R.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, SYT-SSX fusion transcripts using reverse transcription– Korea; the Department of Pathology and Oncology (H.H.), School of polymerase chain reaction (RT-PCR) analysis. Medicine, University of Occupational and Environmental Health, Kitakushu, Japan; and the Department of Pathology (H.S.), Kochi CLINICAL HISTORY Medical School, Japan. Address correspondence and reprint requests to Duck-Hwan Kim, Patient No. 1 MD, Department of Pathology, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 445 Gil-dong, Kangdong-gu, A 53-year-old man presented with a 10-day history of Seoul 134-701, Korea; e-mail: [email protected] right flank pain in February 1999. Physical examination

1097 1098 D.-H. KIM ET AL. was remarkable for right costovertebral angle tenderness. routine histopathologic processing and immunohisto- Abdominal computed tomography (CT) revealed a large, chemical study. Histologic sections 5 ␮m in thickness heterogeneous mass that arose in the anterosuperior side were prepared and stained with hematoxylin and eosin. of the right kidney, measured 5.5 cm in greatest dimen- Immunohistochemical stains were performed according sion, and was surrounded by subcapsular hematoma (Fig. to the labeled streptavidin–biotin complex method with 1). Radiologically, the mass was considered consistent primary antisera against pancytokeratin (CK; monoclo- with renal cell carcinoma. No local invasion or lymph- nal, 1:50; Dako, Glostrup, Denmark), high-molecular adenopathy was identified. The patient underwent a right weight cytokeratin (monoclonal, 1:50; Dako), low- radical nephrectomy without complication. He refused molecular weight cytokeratin (LMWCK; monoclonal, systemic chemotherapy and had an uneventful recovery 1:50; Dako), vimentin (monoclonal, 1:200, Dako), epi- during 6 months of follow up, after which he was lost to thelial membrane antigen (EMA; monoclonal, 1:200; follow up. Dako), CD34 (monoclonal, 1:50; Immunotech, Marseille, France), CD56 (monoclonal, 1:50; Zymed, Patient No. 2 San Francisco, CA, USA), CD99 (monoclonal, 1:50; A 47-year-old man presented with a 3-week history of Dako), neurofilament (NF; monoclonal, 1:50; Dako), gross hematuria and right flank pain in June 1997. On S-100 protein (monoclonal, 1:100; Dako), desmin physical examination, tenderness of the right costoverte- (mono-clonal, 1:50; Dako), smooth muscle actin (mono- bral angle was detected. Abdominal CT revealed a large, clonal,1:200; Dako), chromogranin (monoclonal, 1:200; heterogeneous mass that arose from the superolateral Dako), and synaptophysin (monoclonal, 1:80; Dako). side of the right kidney, measured 5 cm in greatest di- Diaminobenzidine was used as a chromogen. mension, and exhibited subcapsular hematoma and vena For the molecular analysis, to detect the SYT-SSX cava thrombosis. A right radical nephrectomy was per- fusion gene transcript characteristic of synovial sarcoma, formed with vena cava thrombectomy under the impres- RT-PCR analysis using ribonucleic acid (RNA) ex- sion of renal cell carcinoma. The hospital course of this tracted from the formalin-fixed, paraffin-embedded tis- patient was uneventful. He visited the urologic depart- sue of each patient was performed as described previ- 39 For positive control, two cases of conventional ment because of respiratory difficulty and hemoptysis 5 ously. soft-tissue synovial sarcoma, in which the existence of months after the nephrectomy. He showed multiple me- SYT-SSX1 and SYT-SSX2 were already confirmed, tastases to both lungs and received systemic chemo- were examined. For negative control, two cases of ma- therapy. The systemic disease progressed and the patient lignant peripheral nerve sheath tumor were examined.39 died 10 months after nephrectomy. Briefly, five 5-␮m-thick sections sliced from paraffin blocks were prepared from each representative tumor MATERIALS AND METHODS sample. To avoid cross-contamination of samples, the The material obtained at surgery from the two patients area of microtome around the blade was cleaned with was fixed in 10% formalin and embedded in paraffin for 70% ethanol before cutting each paraffin block. An ali- quot of the extracted RNA was reverse transcribed into complementary deoxyribonucleic acid (cDNA) using 1 ␮L of random primers and 200 U of reverse transcriptase (SuperScript II, Gibco BRL, Gaithersburg, MD, USA). PCR was performed using the primer set, which was designed to amplify both the junctional regions of the SYT-SSX1 and SYT-SSX2 gene transcripts reported previously.39 The primer sets used were as follows. The SYT-SSX consensus primer set, which amplifies a 98-base pair (bp) fragment of SYT-SSX messenger RNA (mRNA), is forward primer (FP) (SYT) 5Ј- CCAGCAGAGGCCTTATGGATA-3Ј and reverse primer (RP) (SSX) 5Ј-TTTGTGGGCCAGATGCTTC- 3Ј. The SYT-SSX1 primer set is FP (SYT) 5Ј- CCAGC- AGAGGCCTTATGGATA-3Ј and RP (SSX) 5Ј-GTGC- AGTTGTTTCCCATCG-3Ј, and the SYT-SSX2 primer set is FP (SYT) 5Ј-CCAGCAGAGGCCTTATGGATA- FIG. 1. An abdominal computed tomographic scan of pa- Ј Ј Ј tient no. 1 reveals a heterogeneous mass (arrows) in the 3 and RP (SSX) 5 -GCACAGCTCTTTCCCATCA-3 . anterior portion of the kidney with bulging into the anterior These primer sets similarly amplify a 118-bp fragment of perirenal space. Subcapsular hematoma is also noted. each fusion gene mRNA. PCR for ubiquitously ex-

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The gross specimen from patient no. 2 consisted of kidney with a tumor on the superolateral portion. The tumor was an ill-defined, yellow-tan, soft-to-rubbery mass measuring 5 × 4 × 4 cm (Fig. 2). The tumor exhibited infiltrative growth with invasion into calices and peripelvic adipose tissue. Focal necrosis and hemorrhage were present in the tumor. A subcapsular hematoma around the tumor was demonstrated. There was tumor thrombus in the wall of the inferior vena cava and renal vein. Both tumors had a solid growth pattern with no obvi- ous epithelial components, despite extensive sampling. Histologically, the lesions were poorly differentiated. Microscopic examination of the tumor in patient no. 1 revealed an unencapsulated cellular tumor with a rela- tively well-defined, encroaching borders (Fig. 3). At higher magnification, the tumor was characterized by solid sheets, haphazard patterns, or short fascicles consisting of round-to-oval, or spindle cells. The cells had oval or elongated vesicular nuclei with indistinct cytoplasm. They often formed more densely packed solid cellular sheets, in which the tumor cells were round to oval with less cytoplasm (Fig. 4). The average mitotic rate was 18 mitoses/10 high-power fields (hpf). In some FIG. 2. Gross photograph of the kidney in patient no. 2 areas, hypercellular areas alternated with hypocellular shows an ill-defined, soft-to-rubbery mass (arrows) with subcapsular hematoma. areas, in which the tumor cells were interspersed within

pressed porphobilinogen deaminase (PBGD) gene transcripts was performed with the primers of PBGD-S (5Ј- TGTCTGGTAACGGCAATGCGGCTGCAAC-3Ј) and PBGD-A (5Ј-TCAATGTTGCCACCACACTGTCCG- TCT-3Ј), amplifying a 127-bp fragment of PBGD mRNA. In each PCR procedure, a control without RT to exclude cDNA contamination, and another control con- taining all reagents except cDNA template, were included. To confirm the type of the fusion gene, the PCR product was cloned into a pCR2.1 vector (Invitrogen, San Diego, CA, USA) by thymine-adenine (TA) ligation, and sequenced using an automated sequencing system (ALFexpress DNA sequencer; Pharmacia Biotech, Uppsala, Sweden).

PATHOLOGIC FINDINGS

The specimen obtained from patient no. 1 was from the right kidney, a 5.5 × 4.7 × 4-cm solid mass on the anterosuperior side of the kidney. The mass was a rela- tively well circumscribed, yellow–tan solid tumor, and was surrounded by a subcapsular hematoma. The tumor originated from the kidney parenchyma and bulged into the subcapsular area. The tumor did not involve the FIG. 3. The tumor is composed of solid sheets with a pelvic–calyceal system or the renal vessels. well-defined border.

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FIG. 4. Areas of solid aggregations of round-to-oval cells FIG. 5. An alternative pattern of a hypercellular and a with less cytoplasm were found. hypocellular myxoid area is noted. loose myxoid stroma (Fig. 5). In patient no. 2, the tumor was ill defined with infiltrating borders, and revealed a highly cellular and solid growth pattern that was composed of large, round-to-oval cells with substantial nuclear pleomorphism (Fig. 6). In contrast to the cells in patient no. 1, the nuclei of the cells were more round and vesicular, and showed irregular nuclear contours (Fig. 7). The average mitotic rate was 27 mitoses/10 hpf. The tumor cells often demonstrated a coarse chromatin pattern with prominent nucleoli. The tumor also revealed a nesting pattern with a few intervening spindle cells. In both cases, there were foci of hemorrhage and necrosis, which were more prominent in patient no. 2. In both cases, a hemangiopericytic growth pattern was present, and thick collagen deposition was also seen (Fig. 8). Calcifications were not observed. Both tumors had similar immunohistochemical features (Fig. 9). The tumor cells were diffusely and strongly positive for vimentin. A few scattered cells were positive focally for CK, high-molecular weight cytokeratin (HMWCK), LMWCK, EMA, and NF. Immunore- activity for CD99 and CD56 in patient no. 1 was found in approximately half of the tumor. In patient no. 2, CD99 and CD56 were more strongly and diffusely stained in approximately 80% of the tumor. No immu- noreactivity was found for S-100 protein, CD34, desmin, FIG. 6. Solid sheets of the tumor show irregular infiltration smooth muscle actin, chromogranin, and synaptophysin. of the renal parenchyma.

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synovial sarcomas.10 The poorly differentiated synovial sarcoma (PDSS) shows three histologic variants, including a large cell epithelioid variant, a small cell variant, and a high-grade spindle cell variant.28,42 The specimens from our patients demonstrated a poorly differentiated histologic pattern. Histologically, the lesion from patient no. 2 was compatible with the large cell type of PDSS, whereas the lesion from patient no. 1 did not match any subtypes of PDSS. The lesion from patient no. 1 showed mixed patterns of short fascicles or a haphazard arrangement of oval-to-short spindle cells, and solid sheets of poorly differentiated small cells. PDSS can pose particu- lar difficulties in diagnosis and differential diagnosis. We had diagnostic problems with these cases on histologic analysis. Because of an alternative pattern of cellular and less cellular area in patient no. 1, and a solid hypercellular growth pattern in patient no. 2, our differential diagnoses included malignant peripheral nerve sheath tumor, primitive neuroectodermal tumor, solitary fibrous tumor, hemangiopericytoma, and sarcomatoid renal cell carcinoma. Hemangiopericytoma is a rare lesion in the kidney, often in the perirenal tissue or in the renal capsule.30 PDSS differs from hemangiopericytoma by having a fas- cicular arrangement, spindle cells, various growth patterns, cellular pleomorphism, and frequent mitoses. To FIG. 7. The tumor demonstrates marked hypercellularity and large pleomorphic cells with frequent mitotic figures.

RT-PCR ANALYSIS

The molecular assay using RT-PCR showed SYT-SSX fusion gene transcripts, and the fusion type was SYT-SSX2 in both cases (Fig. 10). Nucleotide se- quences of these products were confirmed by sequence analysis (data not shown). The internal control of PBGD (127 bp) for RNA extraction identification was detectable.

DISCUSSION

Although synovial sarcoma is an uncommon tumor of unknown histogenesis, this neoplasm is a clinically and pathologically well-defined entity that occurs predomi- nantly in the para-articular, deep soft tissues of the ex- tremities in adolescents and young adults.10 Histologi- cally, it is subclassified into biphasic and monophasic types, and poorly differentiated variants. Although the biphasic type is easily recognized by both epithelial cell and spindle cell components, the monophasic spindle cell type can be difficult to distinguish from other spindle cell sarcomas. The poorly differentiated type of synovial sarcoma is composed of sheets of undifferentiated round FIG. 8. A portion of the tumor shows a heman- cells with hyperchromatic, high-grade nuclei and scant giopericytoma-like area consisting of dilated, thin-walled cytoplasm. It may be present in as many as 20% of vessels.

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FIG. 9. Immunohistochemical findings of synovial sarcoma. (A) A few cytokeratin-positive cells are scattered. (B and C) The tumor cells are strongly positive for CD99 (B) and CD56 (C). (D) There is no immunoreaction of the tumor cells for CD34. Note the positive immunostaining of the vascular endothelial cells. our knowledge, only three cases of solitary fibrous tumor sheath tumors are positive for S-100 protein, which is of the kidney have been reported.15,17 Three cases of observed more frequently in epithelioid malignant pe- solitary fibrous tumor occurred in the peripelvis or renal ripheral nerve sheath tumors.10 However, PDSSs are capsule. Immunohistochemical findings of synovial sar- rarely reactive for S-100 protein.14 Although immuno- coma are different from hemangiopericytoma and soli- staining against EMA, CD56, and NF was also positive tary fibrous tumor, which show positive immunoreactiv- in both synovial sarcoma and malignant peripheral nerve ity for CD34 and are negative for epithelial markers. sheath tumor, cytokeratin and CD99 immunostainings Because focal positive immunostaining against cytoker- are always negative or rarely positive in malignant pe- atin was described in malignant solitary fibrous tumors, ripheral nerve sheath tumor in contrast to frequent ex- the morphologic differentiation between synovial sar- pression in synovial sarcoma.14 The primitive neuroec- coma and malignant solitary fibrous tumor is difficult in todermal tumors are always negative for HMWCK and the CD34-negative solitary fibrous tumor cases.2 Ap- show rare expression with antibody to CD56.14 Our proximately 50% to 90% of malignant peripheral nerve cases were positive for CK, HMWCK, LMWCK, EMA,

FIG. 10. SYT-SSX fusion transcripts in patient no. 1 and patient no. 2. Both lesions showed positive products on reverse transcription– polymerase chain reaction analysis using SYT-SSX consensus and SYT-SSX2 primers, whereas the lesions are negative when ana- lyzed with the SYT-SSX1 primer. M, molecular size marker; 1, patient no. 1; 2, patient no. 2; P, positive control; N, negative control (distilled water); PBGD, porphobilinogen deaminase (127 base pair [bp]); S-S con., SYT-SSX consensus primer (98 bp); S-S1, SYT-SSX1 primer (118 bp); S-S2, SYT-SSX2 primer (118 bp).

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CD99, CD56, and NF, which were helpful findings in were reinterpreted as synovial sarcoma, and the excluding the possibility of malignant peripheral nerve SYT-SSX fusion transcripts are not seen in spindle cell sheath tumor and primitive neuroectodermal tumor. Sar- sarcomas other than synovial sarcoma. The diagnosis of comatoid renal cell carcinoma is characterized by inter- synovial sarcoma is often difficult, particularly for the lacing or whorled bundles of spindle cells, and often poorly differentiated variants. In our patients, the iden- shows malignant fibrous histiocytoma and a heman- tification of the SYT-SSX fusion transcript was ex- giopericytoma-like pattern. The sarcomatoid area of sar- tremely useful in excluding other sarcomatous lesions. It comatoid renal cell carcinoma could be positive for ep- is likely that the detection of these hybrid transcripts in ithelial markers, vimentin, and S-100 protein.9 Our cases formalin-fixed, paraffin-embedded tissue by RT-PCR failed to show a carcinomatous component despite ex- may represent a useful diagnostic method, and that this tensive sampling. Even if an epithelial component is not assay allows reclassification of some spindle cell or identified, the diagnosis of sarcomatoid renal cell carci- poorly differentiated sarcomas as synovial sarcoma in noma cannot be completely excluded. archival tissues. As the development of cytogenetic and molecular Recent studies of SYT-SSX fusion products in syno- analysis, numerous chromosomal changes have been vial sarcoma have suggested that the type of SYT-SSX demonstrated in the vast majority of malignant tumors as fusion transcript, SSX1 or SSX2 involvement, correlates well as some benign tumors. Chromosomal study, cyto- with the histologic subtype and the clinical behavior of genetics, and molecular analysis may become increas- the tumor,24,34 but the association of SSX type with his- ingly useful in the diagnosis of tumor, especially hema- tologic type or prognosis was not confirmed in other topoietic or soft-tissue tumors, and may aid in our un- studies.6,13,26,39 Both tumors in the current study re- derstanding of differentiation pathways of tumor.7 Since vealed SSX2 involvement. The lesion from patient no. 2 a characteristic translocation, t(X;18), was discovered showed multiple pulmonary metastases, and the patient cytogenetically in 1987,40 this type of translocation has died of disease. The association between the SSX type been shown to be specific for synovial sarcoma and is and prognosis remains to be elucidated in a larger study. found in approximately 90% of synovial sarco- In conclusion, we report two cases of synovial sar- mas.6,13,26,38,39 Cloning of the translocation breakpoints coma, presenting as an intrarenal mass, that were con- identified two novel genes, which are then rearranged, firmed by RT-PCR analysis of the SYT-SSX fusion tran- SYT at 18q11 and a duplicated SSX at Xp11.5 Crew et scripts, which are extremely useful in diagnosing syno- al.6 demonstrated that t(X;18)(p11.2;q11.2) found in hu- vial sarcoma, particularly the poorly differentiated man synovial sarcoma results in the fusion of the chro- tumor. ᮀ mosome 18 SYT gene to either of two highly homolo- gous genes, SSX1 or SSX2. The SSX1 and SSX2 genes encode closely related proteins of 188 amino acids that REFERENCES are rich in charged amino acids. This translocation has 1. 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