Synovial sarcoma (SS) is a highly aggressive malignant neoplasm usually arising in the deep soft tissue of the lower and upper extremities. It most commonly occurs in adolescents and young adults but can occur at any age and is equally distributed between the sexes 1. Microscopically, SS is classified as monophasic, biphasic, and poorly differentiated. The biphasic SS harbors both spindle and epithelial cell components in varying proportions, and SS sometimes poses a diagnostic challenge especially if it arises in a rare location. Although its origin is still uncertain, it has been reported to occur in a variety of body sites including intra-abdomenal and pelvis 2–6. Because of the limited number of cases reported the prognosis of SS in the pelvis is still poorly understood.
PAX8 is a member of the paired-box (PAX) family of transcription factors which plays a fundamental role during organogenesis and is expressed in normal and neoplastic cells of the same lineage. It is a nephric-lineage transcription factor that is crucial in embryonic development and organogenesis of the thyroid gland, Müllerian tract, 7 and kidney 8,9. Tacha et al. 9 did a comprehensive immunohistochemical study and found PAX8 positive in 90% of renal cell carcinoma, 79% of ovarian cancers, and 90% of thyroid carcinoma. Expression of PAX8 in soft tissue tumors has been reported. Chinchilla-Tábora et al. 10 studied 15 cases of Ewing sarcoma and found that 12 cases (80%) showed a mild to moderate nuclear staining of PAX8. Fan 11 studied 123 cases of poorly differentiated small round cell tumors of childhood and found PAX8 immunoexpression in 5 cases of alveolar rhabdomyosarcoma, 3 cases of embryonal rhabdomyosarcomas, and about one-third of malignant rhabdoid tumors. Expression of PAX-8 in SS is rare and only reported in single case reports and small case series in the literature 12–14.
Estrogen is a steroid hormone that has critical roles in reproductive development, bone homeostasis, cardiovascular remodeling, and brain functions. However, it also promotes mammary, ovarian, and endometrial tumorigenesis and estrogen receptor (ER) is widely expressed in different tumor types including breast carcinoma, ovarian and endometrial carcinoma, colorectal cancer, prostate and brain tumors 15. Expression of ER in soft tissue sarcoma is rare 16,17. Furthermore, the co-expression of PAX8 and ER with positive cytokeratin is highly suspicious for tumors from the Müllerian tract, and it can pose significant diagnostic challenges. Herein, we report 2 cases of biphasic SS with co-expression of PAX8 and ER.
A 42-year-old G3P3 woman had a 1-year history of increased pain with her periods. She subsequently noticed an abnormality in her right groin when performing exercises on her stomach. Computed tomography of the pelvis showed a nonspecific 1.5 cm centrally enhancing coarsely calcified mass in the right inguinal canal with a differential diagnosis of nonspecific lymphadenopathy, granulomatous disease, and sarcoma. Right inguinal core biopsy was performed.
Microscopically, the cores showed spindle cell infiltration in the background of stromal fibrosis with focal calcifications, and small areas of tumor cells showed epithelioid morphology with vague glandular formation. Tumor cells were positive for pancytokeratin, Cam 5.2, PAX8, CK7, and ER, and essentially negative for CK20, WT-1, p40, GATA3, and p16 (Fig. 1). Taken together the morphology and immunohistochemical findings favored a diagnosis of metastatic carcinoma, most consistent with Müllerian tract origin. A positron emission tomography was performed and showed mild FDG uptake in the inguinal mass with SUV of 2.2 and a small focus of mild FDG avidity in the posterior fundus of the uterus (Fig. 2).
In view of the presumed gynecological origin, surgical management was performed. Patient underwent robotic hysterectomy with bilateral salpingo-oophorectomy, right pelvic and right inguinal lymphadenectomy. The uterus, bilateral ovaries and fallopian tubes demonstrated no gross or microscopic lesions. During the operation, the right inguinal mass was adherent to the periosteum on the symphysis pubis at ~2 cm from the midline. Grossly the mass measured 3.5×2.5×1.6 cm, was well encapsulated with a dense tan-white cut surface. Similar to the previous core biopsy, tumor cells showed 2 different components including monotonous spindle and epithelioid cells. The spindle cells were arranged in dense cellular sheets and vague fascicles with hyperchromatic nuclei, high nuclear/cytoplasm (N/C) ratio, granular chromatin, and inconspicuous nucleoli. Mitotic figures were sparse, about 1 to 2/10 HPF. The epithelioid component was arranged in cords, sheets, and solid nests, and tumor cells were uniform with clear cytoplasm and round to oval nuclei with inconspicuous nucleoli. Prominent bands of hyalinized sclerotic collagen were seen in the background. Tumor cells were positive for CK7, PAX8, ER, and EMA, patchy positive for BCL2 and negative for S100, MSA, SMA, p53, WT-1, CK5/6, CD10, inhibin, calretinin, and melanin A (Fig. 3). The differential diagnosis based on the morphology and immunohistochemical profile includes SS, sclerosing epithelioid fibrosarcoma and sarcomatoid carcinoma. RT-PCR for SS18-SSX t(X;18) translocation was performed and was positive, which confirmed the diagnosis of biphasic SS.
Based on patient’s age, clinical, and radiologic presentations, diagnosis, stage (pT1bN0) and positive surgical margin, a plan of adjuvant radiation therapy was established by medical oncology. She underwent radiotherapy to the pelvic tumor bed and regional lymph nodes. The patient was doing well without evidence of recurrence 5 yr after surgery.
A 54-year-old woman presented with a solid mass in the left lower abdominal quadrant which increased in size for 8 months. Ultrasound showed a hypoechoic 7×5.3×4.8 cm solid mass located in the left anterior lower pelvis. Patient underwent excision of the mass lesion.
Grossly it presented as a 10×7.5×5.8 cm subcutaneous mass of the anterior abdominal wall. Microscopically it showed an encapsulated mass with a pushing border. Serially sectioning of the mass revealed a flesh-tan lobulated cut surface. Pathologic examination showed a biphasic malignant neoplasm with malignant spindle cell fascicles mixed with epithelioid component. Immunohistochemistry showed that the epithelioid cells were positive for AE1/AE3, Cam5.2, EMA, PAX-8, CK7, and CD10, weakly positive for ER, while the spindle cells were positive for BCL-2, PAX-8, CD10, and TLE-1. Calretinin, inhibin, CD99, WT-1, and D2-40 were all negative (Fig. 4). The overall features raised a differential diagnosis between biphasic SS and mixed Müllerian tumor. Fluorescence in situ hybridization was performed and was positive for SS18 (SYT) (18q11) gene rearrangement, which supports the diagnosis of biphasic SS. Because the tumor presented 0.1 cm from the deep margin, the patient underwent three cycles of chemotherapy with doxorubicin and ifosfamide. The patient was lost to lost follow-up after the chemotherapy.
SS is a diagnostic challenge especially in rare anatomic locations, and aberrant expression of some markers such as PAX8 and ER may lead to misdiagnosis of other neoplasms including those of the female genital tract. The antibody information for PAX8 and ER used in current study is provided in Table 1.
TABLE 1 -
The relevant antibody information for PAX-8 and ER
||Roche Ventana Ulatrastainer
||Roche Ventana Ulatrastainer
||Dako Autostainer link 48
||Dako Autostainer link 48
To date, only limited publications in the English literature reported PAX8 positivity in SSs, with most cases of renal origin 12,14,18, 1 case of sub-diaphragm location 13 and 1 case in the wrist 19. PAX-8 and ER expression in SS from the current English literature review are summarized in Table 2. Rose and colleagues described 11 cases of renal SS and found PAX 8 focally positive in 1 monophasic SS, and diffusely positive in both the spindle and epithelial components in 1 biphasic SS. In their literature review they found about 20% of renal SS can have PAX8 expression and PAX8 could be a potential diagnostic pitfall for diagnosing renal neoplasm, especially when interpreting small renal biopsy specimens 12. The pattern of PAX8 positivity varies among different cases. A subdiaphragmatic biphasic SS showed strong PAX8 in both spindle and epithelial components 13, and a wrist biphasic SS 19 was strongly positive in the epithelial component but weak patchy positive in the spindle cell component 19. Karafin et al. 14 reported 6 of the 23 cases of monophasic SS showed PAX8 expression in the spindle cell component, while only 3 of the 8 cases of biphasic SS demonstrated weak to moderate PAX8 positivity in the epithelial component. In our current 2 cases, the PAX8 positivity is similar in both spindle and epithelioid components.
TABLE 2 -
and ER expression in synovial sarcoma
from English literature
||SS case number/type (location)
|Rose et al. 12
||11 SS (renal)
||2/11 +: 1 monophasic SS spindle cell
Positive (2+); 1 biphasic SS both spindle and epithelial cells positive (3+)
|Lordello et al. 13
||1 biphasic SS (subdiaphragm)
||1/1 +: both spindle and epithelial cell positive (weak to moderate, multifocal)
|Karafin et al. 14
||23 monophasic SS
8 biphasic SS
|6/23 +: spindle cell positive (3 moderate, 3 strong)
3/8 +: only epithelial cell positive
(1 moderate, 2 weak)
|Cai et al. 18
||1 monophasic SS (renal)
||1/1 +: spindle cell positive
|Fewtrell et al. 19
||1 biphasic SS (wrist location)
||1/1 +: spindle cell moderate and patchy positive (20%–30%), and epithelial cells strong diffusely positive
||2 biphasic SS (pelvic mass)
||2/2: both spindle and epithelial cells positive
ER indicates estrogen receptor; SS, synovial sarcoma.
The dual positivity of PAX8 and ER further complicated the diagnosis of the current cases. The combined PAX8, ER and cytokeratin positivity in our first case led to the misdiagnosis of metastatic carcinoma of Müllerian origin. Our careful search of the English literature only reveals one case of biphasic SS with dual expression of PAX8 and ER in the subdiaphragm of a female patient 13. In their case, the tumor presented with biphasic morphology with nests of epithelial-like cells forming variably sized cyst-like space alternating with spindle cells forming intersecting fascicles.
Biphasic SS is defined as harboring variable amounts of epithelial and spindle cell components. The epithelial cells are arranged in solid nests or cords, or in glands with a tubular or sometimes alveolar or papillary architecture. The glandular component is often a pitfall of a misdiagnosis of adenocarcinoma or carcinosarcoma. In case 1, the core biopsy showed spindle cell infiltration with a rare epithelioid component in the biopsy in the background of stromal fibrosis with focal calcification. The positive pancytokeratin, CAM 5.2, PAX8, and CK7 pointed to the diagnosis of metastatic carcinoma of Müllerian tract. On resection, the epithelioid cell proliferation with vague glandular formation also made carcinosarcoma a possible diagnosis. However, carcinosarcoma in the female genital tract is usually a high-grade malignancy with both high-grade carcinoma and high-grade sarcoma. The carcinomatous component can be high-grade endometrioid carcinoma, serous or clear cell carcinoma, or undifferentiated carcinoma, and the sarcoma component can be high-grade leiomyosarcoma, undifferentiated sarcoma or heterologous component such as rhabdomyosarcoma. Most of the epithelioid cells in the current cases are arranged in cords and sheets with pseudoalveolar pattern, which is not commonly seen in the classic carcinosarcoma. Furthermore, the spindle cell component in the current cases shows monotonous morphology arranged as hypercellular fascicular architecture with little intervening stroma. The mitotic count was low with 1 to 2/10 HPF.
Approximately 95% of SS’s are characterized by the t(X;18)(p11;q11) translocation involving the SS18 gene on chromosome 18 and SSX genes on the X chromosome, leading to a chimeric SS18-SSX gene fusion 20. Majority of cases involve the SSX1 and SSX2 genes, with two-thirds of cases attributed to the SSX1 gene 21. Literature has found the SS18-SSX gene fusion to be a hallmark only in SSs and has not been reported in other neoplastic conditions 22. A literature search via COSMIC (Catalogue of Somatic Mutations in Cancer) was conducted for both the SS18-SSX1 and SS18-SSX2 fusions. The articles dated back to the 1990s and included 91 curated articles, with various tissue sites included in the search results for tissue distribution. For the SS18-SSX1 fusion, there were a total of 1167 samples identified and with a 49% mutation rate for this fusion and 1168 samples with a 30% mutation rate for the SS18-SSX2 fusion among the curated articles 23. All mutated samples were soft tissue samples, specifically with a diagnosis of SS. No samples with either of these fusions were reported outside this category in our literature search.
The prognosis of pelvic SS is largely unknown due to the limited cases previously reported. Fishers et al. 2 described a series of 11 intra-abdominal SS cases. They found it mainly occurs in middle-aged patients as a large intra-abdominal/pelvic mass which is difficult to excise and recurs locally. Chatzipantelis et al 24 studied 6 cases of retroperitoneal SS and found all tumors are biphasic, with recurrence and metastasis within the abdomen. In our first case, the patient underwent radiation therapy due to positive surgical margin, and she is recurrence-free at 5-year follow-up. Valkov and colleagues studied 249 soft tissue sarcomas and found ER positivity was a significant favorable indicator for disease specific survival in women. It is not clear if ER expression is a prognosticator in the current case.
In conclusion, we report 2 cases of primary pelvic and abdominal biphasic SS in female patients with co-expression of PAX8 and ER. PAX8 expression along with ER could be a potential diagnostic pitfall in female patients with biphasic tumor, especially when interpreting small biopsy specimen. PAX8 and ER staining in soft tissue sarcoma has been little studied, and the current cases demonstrate its potential positivity in soft tissue tumors in female patients. Careful morphologic examination together with immunohistochemistry and molecular studies can help to render a correct diagnosis.
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