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Primary Intraprostatic Synovial Sarcoma.

Synovial sarcoma is a well-defined entity that constitutes approximately 10% of all soft tissue sarcomas. (1,2) It has been identified in a multitude of anatomic sites, including the heart, kidney, cerebellum, retroperitoneum, parapharyngeal region, lungs, and abdominal wall, yet has a strong predilection for the para-articular areas of the lower extremities. It predominantly occurs in young adults with a median age of 35 years and an overall age range of 5 to 85 years. (2)

One prominent and unifying factor is the t(X;18)(p11;q11) chromosomal translocation, which is unique to synovial sarcoma and is identified in more than 95% of all cases. This translocation results in an in-frame fusion of the SSX1 or SSX2 gene and the SS18 gene. This produces a chimeric gene that encodes for a transcription-activating protein. (3) A translocation involving SSX4 has been documented in rare cases. (2)

Despite its name, the definitive origin of synovial sarcoma remains unclear. However, studies have suggested that a multipotent mesenchymal stem cell is the most likely candidate. (4) Histologically, synovial sarcoma is organized into 4 broad categories by the proportion of epithelial to spindle cells: (1) biphasic type with varying degrees of epithelial and spindle cell components; (2) monophasic fibrous type, consisting solely of spindle cells; (3) monophasic epithelial type, consisting of predominantly epithelial cells with only scant spindle cell populations present; and (4) poorly differentiated type, which can resemble a small round cell tumor, a large-cell/epithelioid tumor, or a spindle cell tumor with high-grade nuclear features, high mitotic activity, and areas of necrosis. (5) Interestingly, a strong correlation has been identified between the SYT-SSX fusion transcript and the histologic pattern; the SYT-SSX2 fusion is associated with monophasic histology, whereas the SYT-SSX1 fusion is related to the biphasic form. (6) Within the category of monophasic synovial sarcoma, the monophasic fibrous type is the most common. On the contrary, monophasic epithelial type is very rare and is diagnosed with the help of cytogenetic and molecular studies and/or the identification of small areas of spindle cells. Lastly, the poorly differentiated form may represent progression of monophasic or biphasic tumors. (5)

CLINICAL FEATURES

To date, only 10 cases of intraprostatic synovial sarcoma have been reported in the literature. (7-13) Of these, the mean age at time of diagnosis is 42 years old, with an overall age range of 28 to 63 years. It typically presents with nonspecific lower urinary tract symptoms, including dysuria, increased urinary frequency, and nocturia. Less prevalent presenting symptoms include hematuria, micturition, constipation, and pelvic, perineal, or rectal pain. In all reported cases, prostate-specific antigen was within normal range (0.33-5.04 ng/mL, with a mean of 1.35 ng/mL; reference <4 ng/mL).Four of the 10 published cases of intraprostatic synovial sarcoma comment on initial diagnostic workup. Of these, a diagnosis of synovial sarcoma was made before prostatic resection through the use of a core needle biopsy in 1 case and transurethral resection of the prostate in a second. A preliminary diagnosis of sarcoma was made by using core needle biopsies in the remaining 2 cases. Given its insidious onset, it is no surprise that most cases are fairly advanced with metastases and/or invasion of surrounding soft tissue at the time of diagnosis.

MACROSCOPIC FINDINGS

Gross examination of excised tumors reveals a gray-white, solid, and rubbery mass. Areas of necrosis and hemorrhage may be present. Tumors ranged in size from 4 to 15 cm, with a mean size of 9.9 cm in greatest dimension. (7-13)

HISTOPATHOLOGY

Not surprisingly, intraprostatic synovial sarcoma histologically mirrors those found elsewhere in the body. However, to the best of our knowledge only the biphasic and monophasic fibrous types have been described in the English literature to date. In the biphasic type, the epithelial cells may be cuboidal or columnar, can be arranged in nests, cords, or glandular structures, whereas their nuclei are large, round to oval, and demonstrate a vesicular pattern. The spindle cell component typically consists of solid sheets of monomorphic, plump spindle cells with oval nuclei. Mitotic figures can be seen in both components. Alternating areas of cellular and hypocellular areas are common; the latter may exhibit myxoid change, hyalinization, and/or calcifications, which can be seen in approximately 20% of cases. Lastly, the monophasic fibrous type, as the name implies, is predominantly composed of sheets of spindle cells, which are monomorphic, plump with oval nuclei, and are arranged in solid sheets (Figure, A through F). Myxoid change, hyalinization, and calcification can also be seen. (5)

ULTRASTRUCTURAL FINDINGS

In biphasic tumors, the epithelial component contains groups of cells joined by terminal bar complexes that are enclosed by a thin layer of external lamina. Microvilli or villous filopodia extend into the glandular lumens or intercellular spaces created by these groupings. In monophasic fibrous tumors, rare intercellular gaps between neighboring cells can be seen. These gaps are bound by thickened cell membranes from which short and long processes extend into the intercellular space. (14) The spindle cell components of biphasic and monophasic fibrous tumors are indistinguishable. (5) Nuclei are elongated with indentations, peripheral margination of chromatin, and scattered heterochromatin. (15) The epithelial and fibrous components of biphasic tumors remain discrete with no discernible transitional zone with features of each. (16)

IMMUNOHISTOCHEMISTRY

Most synovial sarcoma tumors stain positively for the epithelial markers cytokeratin (CK) and epithelial membrane antigen (EMA). Immunoreactivity is more pronounced in the epithelial component of biphasic tumors. In monophasic fibrous-type tumors, only rare spindle cells express these antigens, thereby mandating the need to use caution when evaluating core needle biopsies and to sample resected tumors generously. Unlike other spindle cell tumors, synovial sarcoma is almost always negative for CD34 yet consistently positive for CK7, CK19, and CK8/18 (Table). B-cell lymphoma 2 (Bcl-2) shows diffuse positivity in almost all synovial sarcomas; however, its expression in multiple tumor types limits its diagnostic utility. Calponin and CD99 immunoreactivity is common. (5) Transducer-like enhancer of split 1 (TLE1) is present in more than 90% of cases, making it a highly sensitive marker for synovial sarcoma. However, it lacks specificity as it is expressed in other soft tissue tumors that are commonly included in the differential diagnosis, such as malignant peripheral nerve sheath tumors, solitary fibrous tumors, and neurofibromas. (16) Reduced INI-1 expression secondary to the interaction of SS18-SSX with the SWI/SNFchromatin-remodeling complex (see below) has been reported, although this is barely of diagnostic utility. (17) Of the 5 published cases of intraprostatic synovial sarcoma with documented immunohistochemical staining patterns, positive immunoreactivity was noted for CK, EMA, Bcl-2, CD99, and E-cadherin. All cases were negative for S100, smooth muscle actin, desmin, and CD34. (7-11)

MOLECULAR FEATURES

The signature molecular abnormality of synovial sarcoma consists of a balanced chromosomal translocation t(X;18)(p11;q11) that results in an in-frame fusion of SS18 to SSX1, SSX2, or in rare instances, SSX4. This translocation is identified in virtually all synovial sarcomas and is not seen in any other malignancy. This provides an ideal means of establishing a diagnosis of intraprostatic synovial sarcoma despite its unusual location. Only 2 of the 10 documented cases of intraprostatic synovial sarcoma have reported the tumor's specific SYT-SSX fusion gene, one exhibiting the SYT-SSX1 fusion and the other the SYT-SSX2 fusion. (10,11) The correlation between fusion transcript and histologic pattern discussed above was not observed, as both tumors were of the monophasic fibrous type. Beyond the t(X;18) translocation, synovial sarcomas demonstrate a diverse array of genetic mutations. For example, using Sanger sequencing, Vlenterie et al (3) were able to identify 8 novel somatic mutations in the following genes: KRAS, CCND1, SEPT09, RNF213, KDR (VEGFR2), CSMD3, MLH1, and ERBB4 (HER4). A maximum of 1 mutation per tumor was identified with no similar mutations being shared. Chromosomal aberrations, including partial loss of chromosome 3 or gain of chromosome 8, were identified in approximately half of synovial sarcomas included in the study. (3) Similarly, single-nucleotide polymorphism analysis of synovial sarcomas by Qi et al (1) revealed 23 significantly mutated genes not previously identified. Of these, 65% (15 of 23) were specific for the spindle cell component and 35% (8 of 23) were specific for the epithelial component of biphasic tumors.

ONCOGENESIS

The SS18-SSX fusion product has been established as the primary genetic driver mutation in synovial sarcoma. Recent studies have identified high-affinity binding of the SS18 subunit of SS18-SSX to the core subunits of the SWI/SNF chromatin remodeling complex. (2) This well-studied complex allows transcription factors to bind to their target sequences, thereby promoting cell proliferation. (18) Conversely, the SSX component of the SS18-SSX fusion possesses an opposing function to that of SS18 by binding to the Polycomb repressor complex, which results in the suppression of transcription through chromatin remodeling. (2) Of note, exon sequencing studies have identified mutations in the subunits of the SWI/SNF complex in more than 19% of human tumors. (18) Binding of the SS18-SSX fusion protein to the SWI/SNF complex has been associated with a reduction in the binding of the tumor suppressor SMARCB1 to the complex and overall depletion of SMARCB1 in synovial sarcoma cell lines. Other studies designed to identify potential SS18-SSX binding partners revealed that SS18-SSX acts as a bridge between the transcription corepressors ATF2 and TLE1, thereby down-regulating ATF3, EGR1, and CDKN2A. (2)

DIFFERENTIAL DIAGNOSIS

Primary sarcomas of the prostate are exceedingly rare and constitute less than 0.1% of all primary prostate malignancies in adults. A handful of case series investigating the occurrence of prostate sarcomas have implicated a surprising number of histologic subtypes. Of these, the predominant subtypes are leiomyosarcoma followed by rhabdomyosarcoma. The remaining sarcomas described include prostatic stromal sarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, osteosarcoma, Ewing sarcoma/primitive neuroectodermal tumor, angiosarcoma, undifferentiated sarcoma, and mixed sarcomas. (13,19-21)

CURRENT TREATMENT

The rare incidence of intraprostatic synovial sarcoma presents a challenge to the establishment of best practices. Each case presented in the literature thus far has been treated with a combination of surgical resection, chemotherapy, and/or radiation therapy. The extent of surgical intervention required is largely influenced by tumor size and the involvement of surrounding soft tissues. Surgical procedures have ranged from radical prostatectomy to pelvic exenteration with en bloc penectomy and pubectomy. (7-11)

PROGNOSIS

For patients with localized disease at the time of diagnosis, high mitotic count ([greater than or equal to]10 mitoses/10 high-power fields), size greater than 7 cm, tumor necrosis, and areas of poorly differentiated morphology are negative prognostic factors for disease-specific survival and metastasis-free survival. (21) The pronosis associated with intraprostatic synovial sarcoma is poor, and death is often the result of metastases. The most common sites of metastases are the lungs and liver. Only 7 of the 10 cases reported in the literature have documented information on overall survival. Of these, the median length of survival following diagnosis is 18.3 months. (7-13)

CONCLUSIONS

Intraprostatic synovial sarcoma is a rare disease with an insidious onset and poor prognosis. Its histologic and genetic features mirror those seen elsewhere in the body. It possesses a well-characterized and consistent t(X;18) translocation that facilitates its diagnosis despite its unusual location. Immunohistologic staining allows for the elimination of other sarcomas that may arise in the prostate. Treatment options are limited to nontargeted chemotherapy, radiation, and surgical resection. As the genetic pathways implicated in the oncogenesis are better understood, the ability to formulate improved, targeted treatment strategies may become a viable option.

References

(1.) Qi Y, Wang N, Pang LJ, et al. Identification of potential mutations and genomic alterations in the epithelial and spindle cell components of biphasic synovial sarcomas using a human exome SNP chip. BMC Med Cenomics. 2015; (8):69. doi:10.1186/s12920-015-0144-7.

(2.) Nielsen TO, Poulin NM, Ladanyi M. Synovial sarcoma: recent discoveries as a roadmap to new avenues for therapy. Cancer Discov. 2015;5(2):124-134.

(3.) Vlenterie M, Hillebrandt-Roeffen MH, Flucke UE, et al. Next generation sequencing in synovial sarcoma reveals novel gene mutations. Oncotarget. 2015; 6(33):34680-34690.

(4.) Naka N, Takenaka S, Araki N, et al. Synovial sarcoma is a stem cell malignancy. Stem Cells. 2010;28(7):1119-1131.

(5.) Weiss SW, Goldblum JR, Folpe AL. Malignant soft tissue tumors of uncertain type. In: Soft Tissue Tumors. 6th ed. Philadelphia, PA: Elsevier Saunders; 2014:1028-1112.

(6.) Kawai A, Woodruff J, Healey JH, Brennan MF, Antonescu CR, Ladanyi M. SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med. 1998;338(3):153-160.

(7.) Jun L, Ke S, Zhaoming W, Linjie X, Xinru Y. Primarysynovial sarcoma of the prostate: report of 2 cases and literature review. Int J Surg Pathol. 2008;16(3):329-334.

(8.) Iwasaki H, Ishiguro M, Ohjimi Y, et al. Synovial sarcoma of the prostate with t(X;18)(p11.2;q11.2). Am J Surg Pathol. 1999;23(2):220-226.

(9.) Zhang Q, Wang H, Ren L, Qi X, Liu F, Zhang D. Primary synovial sarcoma ofthe prostate metastatic to the liver and lung: a case report. World J Surg Oncol. 2014;12:194. doi:10.1186/1477-7819-12-194.

(10.) Pan CC, Chang YH. Primary synovial sarcoma of the prostate. Histopathology. 2006;48(3):321-323.

(11.) Williams DH, Hua VN, Chowdhry AA, et al. Synovial sarcoma of the prostate. J Urol. 2004;171(6, pt 1):2376.

(12.) Sohn M, Kwon T, Jeong IG, et al. Histologic variability and diverse oncologic outcomes of prostate sarcomas. Korean J Urol. 2014;55(12):797-801.

(13.) Wang X, Liu L, Tang H, et al. Twenty-five cases of adult prostate sarcoma treated at a high-volume institution from 1989 to 2009. Urology. 2013;82(1):160-165.

(14.) Fisher C. Synovial sarcoma. Ann Diagn Pathol. 1998;2(6):401-421.

(15.) Suster S, Moran CA. Primary synovial sarcomas of the mediastinum: a clinicopathologic, immunohistochemical, and ultrastructural study of 15 cases. Am J Surg Pathol. 2005;29(5):569-578.

(16.) Kosemehmetoglu K, Vrana JA, Folpe AL. TLE1 expression is not specific for synovial sarcoma: a whole section study of 163 soft tissue and bone neoplasms. Mod Pathol. 2009;22(7):872-878.

(17.) Kohashi K, Oda Y, Yamamoto H, et al. Reduced expression of SMARCB1/INI1 protein in synovial sarcoma. Mod Pathol. 2010;23(7):981-990.

(18.) Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell. 2013; 153(1):71-85.

(19.) Sexton WJ, Lance RE, Reyes AO, Pisters PW, Tu SM, Pisters LL. Adult prostate sarcoma: the M. D. Anderson cancer center experience. J Urol. 2001; 166(2):521-525.

(20.) Musser JE, Assel M, Mashni JW, Sjoberg DD, Russo P. Adult prostate sarcoma: the Memorial Sloan Kettering experience. Urology. 2014;84(3):624-628.

(21.) Guillou L, Benhattar J, Bonichon F, et al. Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a multicenter, retrospective analysis. J Clin Oncol. 2004;22(20):4040-4050.

Andrea M. Olofson, MD; Konstantinos Linos, MD

Accepted for publication May 3, 2016.

From the Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Konstantinos Linos, MD, Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, One Medical Center Dr, Lebanon, NH 03756 (email: Konstantinos.linos@hitchcock.org). Please Note: Illustration(s) are not available due to copyright restrictions.

Caption: In this case of primary intraprostatic monophasic synovial sarcoma, reverse transcription-polymerase chain reaction confirmed the diagnosis with the presence of an SYT-SSX2 fusion product. Immunohistochemical markers showed positivity for calretinin and epithelial membrane antigen, and negativity for CD34, CD117, smooth muscle actin, desmin, and S100. A, At low-power magnification a proliferation of monomorphic spindle cells diffusely infiltrating native prostatic tissue is seen. B, Higher magnification highlights plump, fibroblast-like spindle cells with vesicular nuclei and indistinct cytoplasm. C, The tumor cells tightly surround prostatic nerve bundles. D, Spindle cells are organized in irregular fascicles to form compact sheets. E, Higher magnification reveals densely packed monomorphic spindle cells. Extravasated red blood cells and hemosiderin are present in this case, secondary to chemoradiation treatment. F, High magnification shows dense collagen, which can form broad bands (hematoxylin-eosin, original magnifications 340 [A, D], 3200 [B, E], 3100 [C], and 3400 [F]).
Molecular and Immunohistochemical Features

Diagnosis          Genetic Alteration   CD34   CK7   TLE1   CK19

Synovial            t(X;18)(p11;q11)     -      +     +      +
sarcoma

Diagnosis          CK8/18   Bcl-2   CD99   Calponin   EMA

Synovial             +        +      +        +        +
sarcoma

Abbreviations: Bcl-2, B-cell lymphoma 2; CK,
cytokeratin; EMA, epithelial membrane antigen; TLE1,
transducer-like enhancer of split 1; +, positive staining;
-, negative staining.
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Author:Olofson, Andrea M.; Linos, Konstantinos
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Date:Feb 1, 2017
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