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Primary synovial sarcoma of the kidney: a case report of complete pathological response at a Lebanese tertiary care center
BMC Urology volume 18, Article number: 40 (2018)
Primary synovial sarcoma of the kidney is a rare type of soft tissue sarcoma. Its presenting features can resemble those of other renal tumors; rendering its early diagnosis, a dilemma. Several cases of renal synovial sarcoma have been reported in the literature with varying treatment options and outcomes. This article describes a rare case of primary renal synovial sarcoma and reviews all cases in the literature.
A 26-year-old male presented with flank pain and hematuria. Initially diagnosed with Wilm’s tumor, revision of pathology and histology, along with the immunohistochemical profile, confirmed, nevertheless, the diagnosis of primary monophasic synovial sarcoma of the kidney with the SYT-SSX2 fusion transcript. Follow-up, post nephrectomy, revealed recurrence within the lungs and at the surgical bed. Surgical resection followed by adjuvant chemotherapy regimen constituting of Doxorubicin and Ifosfamide, achieved complete pathological response.
In this case report, we emphasize the need for accurate diagnosis and prompt treatment. We propose multimodality treatment approach including surgery along with anthracycline-based chemotherapy to induce complete remission.
Soft tissue sarcoma (STS) is a rare malignant tumor of mesenchymal origin having an incidence of 2–3 cases per 100,000, thus contributing to less than 1% of all adult malignancies [1, 2]. Synovial sarcoma (SS), or sarcoma of tissues adjacent to joints, is a rare type of STS, and represent 5 to10% of all STSs . SS is commonly found in the proximal limb of young adults and has a male predominance . Other unusual sites of occurrence include the head and neck, heart, lungs, and kidneys . Very few reports have tackled this tumor due to its rarity and difficulty to distinguish from other renal pathologies. The first case of primary SS of the kidney has been reported by Faria et al. in 1999 . We present a case of primary synovial sarcoma of the kidney, initially thought to be a Wilm’s tumor, along with patient follow-up, showing complete pathological response to treatment, followed by a literature review of this disease entity.
A 26-year-old male experienced recurrent flank pain and gross hematuria over several months duration. Kidney ultrasound showed a lower pole mass concerning for renal cell carcinoma. After confirmation of a right kidney tumor, measuring 6 cm, by an enhanced CT scan, he underwent right radical nephrectomy with para-caval lymph node dissection, at another institute, with pathology there, read initially as adult type Wilm’s tumor. After referral to our institute for rereading of the pathological slides, the morphological and immunostaining profiles were analyzed, and results came out to be consistent with synovial sarcoma of the right kidney. The tumor was monophasic and showed a cellular spindle cell proliferation with a prominent perivascular growth pattern and partial necrosis. It was positive for vimentin, BCL-2, CD56, MCK (partial), and negative for CD10, 31, 34, 99, 117, CK7, Desmin, SMA, MyoD1, EMA, WT-1, S100, RCC, PAX8, GATA-3, and Synaptophysin (Fig. 1).
Molecular studies on the paraffin-embedded blocks were performed to test for the t(X; 18) SYT/SSX fusion transcript, using RT-PCR, at the University of Michigan Health System. RT-PCR amplification was performed using fluorescent dye-labeled primers, specific for the SYT-SS18 and SYT-SSX genes. The PCR products were then detected and sized by capillary electrophoresis to identify the presence of chimeric transcripts. A concurrent internal control was run to ensure the integrity of the mRNA. FISH analysis was also performed using a break-apart style probe. The results were unfortunately negative due to the low quality samples.
According to these findings, a diagnosis of primary monophasic SS of the kidney was made. It was elected for serial follow up and no adjuvant treatment, thereafter. Six months later, a follow up CT scan detected a 1.5cmx1.7 cm left lower lobe lung nodule suggestive of metastasis. Consequently, he underwent a smooth left lower lobe wedge resection. Fusion gene product analysis on the resected lung tissue, via FISH, revealed SYT-SSX 2 gene rearrangement confirming the SS diagnosis. Three months afterwards, CT scan of the chest, abdomen, and pelvis revealed another disease recurrence in the nephrectomy surgical bed, with tumor invasion of the inferior vena cava and the presence of conglomerate suspicious aorto-iliac lymph nodes. A multidisciplinary team approach decided to start the patient on Doxorubicin 50 g/m2 and Ifosfamide 5 g/m2 chemotherapeutic regimen. Following the third cycle, CT scan and MRI showed a 30 to 50% interval decrease in size of tumor masses in the right nephrectomy bed and adjacent retroperitoneum, IVC tumor, and distal aortocaval lymph nodes, indicating partial treatment response. The patient were received a total of 5 cycles, with no adjunct side effects.
A follow-up MRI, several months later, showed continued decrease in the size of 3 masses at the previous surgical site, IVC tumor invasion, and aortocaval lymph nodes, indicating continued response to treatment. One of the small masses in the nephrectomy bed almost completely resolved, on imaging, with no new progression. It was then decided to have the patient undergo surgical resection of the residual masses at the previous surgical bed with removal of the aorto-caval lymph nodes, thrombectomy with vena caval repair. All surgical margins were negative. Final pathology came out to be necrosis, with no viable tumor identified. Thus, a complete pathological response was achieved using the Adriamycin/Ifosfamide regimen, a year after the initial nephrectomy. A sample of the kidney lysate was again tested for the (X; 18) SYT/SSX fusion transcript via RT-PCR and FISH, and results were negative, suggestive of complete treatment response.
Synovial sarcoma is a mesenchymal spindle cell tumor which displays variable epithelial differentiation and has a specific chromosomal translocation t(X; 18) (p11; q11), which results from the fusion of the SYT gene on chromosome 18 to exon 5 of either SSX1 or SSX2 genes on chromosome X . It was recently reported that the SSX4 gene is also involved in such a translocation [6, 7].Nonetheless, SS of the kidney can be first misdiagnosed as a renal cell carcinoma due to similar clinical presentation . The identification of the monophasic type of renal SS is also controversial as it has similar microscopic features to other spindle cell tumors, such as fibrosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumors, adult Wilm’s tumor, spindle cell carcinoma and spindle cell melanoma . While monophasic SS of the kidney is made up exclusively of monomorphic spindle cells, the biphasic type is a mixture of both spindle-shaped cells and epithelial cells. SS of the kidney is a rare disease such as 64 cases have been reported since the Faria et al. cases up to 2012 . We conducted a literature review using Embase and PubMed databases and included all cases (even those published in languages other than English) till the year 2016. This yielded a total of 114 cases (Table 1) constituting the largest series of renal SS cases to be reported. Noteworthy, our case is the first to be reported from the Middle East.
The median age of patients with renal SS was 40.5 (15–78) years, which is half the median age for diagnosis of renal cell carcinoma . The female to male ratio was 1:1. Regarding the predominant presentation symptoms, data was only available for 82 cases. The most frequently reported symptom on presentation was isolated flank/lumbar pain which was found in 20 patients (24.4%).This is in concordance with a review conducted on older data where this same predominant symptom occurred in 55.5% of cases . Hematuria was present in 37 patients (44%) upon presentation. Kohle et al. reported similar data, albeit smaller sample size, where 98% of their patients were symptomatic at the time of presentation, with 67% having pain and 38% having hematuria . These figures are in concordance with our analysis of the world literature.
According to our analysis, the leading fusion variant was the SYT-SSX 2, detected in 42 (36.8%) patients, as opposed to the SYT-SSX 1 variant, detected in 23 (20.2%) patients, in total (Table 1).
Data on metastasis and disease recurrence was available for 70 and 57 patients, respectively. 19 (27.1%) patients had metastasis, whereas 14 (24.6%) patients had tumor recurrence on follow-up. These numbers are similar to what was published in previous series .
A 30 to 50% of the patients who underwent surgical resection of their primary tumor were reported to witness metastasis to the lungs or liver . Our patient is of no exception. In terms of median survival for patients with localized disease, size represents an important prognostic factor . A retrospective analysis was done on 135 consecutive patients with extremity and truncal variant of synovial sarcomas, seen at three institutions in Boston, between years 1961 and 1996. Patients with localized synovial sarcomas, less than 5 cm in longest diameter, had a survival at 10 years equivalent to 88%, compared with a 10-year survival of 38 and 8% for 5 to 10 cm and greater than 10 cm sarcomas, respectively . Similar results were reported by Singer et al. on 48 consecutive patients with extremity and truncal synovial sarcomas, seen between years 1966 and 1994 .
SS of the kidneys presents a diagnostic dilemma, as it resembles renal cell carcinoma amongst other tumors. Diagnosis can be based on morphological (spindle cell) and immunological tumor profile. It can also be established by genetic analysis via FISH and RT-PCR, demonstrating the SYT18-SSX gene translocation. Demonstrating which translocation, the tumor possesses, has been a delicate matter. For instance, a SS case that was previously shown to be negative for SYT/SSX1 and SYT/SSX2 gene expression by conventional RT-PCR, was instead found to be SYT/SSX4 positive, as the sole fusion transcript expressed in this tumor sample, when the RT-PCR was redesigned . This might have explained our negative results, when trying to identify the translocations, since our RT-PCR was only designed to detect SYT/SSX1 and SYT/SSX2 fusion gene variants.
Moreover, the value of TLE1 antibody in the diagnosis of SS has also been examined. TLE1 was found to be an excellent discriminator of SS from other sarcomas, in a study by Terry et al. . They reported that TLE1 monoclonal and polyclonal antibodies gave intense and/or diffuse nuclear staining in 91 out of 94 molecularly confirmed synovial sarcoma patients. In contrast, TLE1 staining has been detected much less frequently and at lower levels, if et al.l, in 40 other mesenchymal tumors; thereby making this a robust immunohistochemical marker for SS. Jagdis et al. also supported this view as their findings confirmed that TLE1 was more sensitive and specific for synovial sarcoma, than any other currently available immunohistochemical kits . Kosemehmetoglu et al. confirmed the sensitivity, but not the specificity, of TLE1 antibodies in diagnosing synovial sarcomas .
The prognostic implication of SYT-SSX fusion type in synovial sarcomas is still under debate. The SYT-SSX fusion type and the presence of metastasis, at diagnosis, were both proven to be important prognostic indicators . Kawai et al. analyzed SYT–SSX fusion transcripts in 45 synovial sarcomas by reverse-transcriptase polymerase chain reaction, and compared the results with relevant clinical and pathological data . SYT- SSX2 fusion type carried a significant positive prognosis for overall survival . This was thought to be due to an association with a lower prevalence of metastatic disease at diagnosis, in patients having this rearrangement . In another study by Ladanyi et al., the SYT–SSX2 fusion transcript had a significantly longer metastasis-free survival . On the contrary, Japanese patients, with synovial sarcoma, having positive SYT-SSX fusion transcript, were retrospectively analyzed . They concluded that SYT-SSX fusion type was not found to be a significant prognostic factor, unlike tumor size and histological grading, for patients with localized synovial sarcoma . Another study by Guillou et al. also confirmed that histologic grading, and not SYT-SSX fusion type, was a stronger predictor of survival, by collecting retrospective data on 165 SS patients .
In our sample, staging information was available for 46 patients, based on the 7th edition TNM staging for soft tissue sarcomas. Among the patients having the SYT-SSX2 fusion protein. 53.8% were stage II and 34.6% were of stage III. 33 and 25% of patients with SYT-SSX1 transcript were stage II and III, respectively. 25% of patients with SYT-SSX1 were of stage IV, versus only 7.7% for SYT-SSX2 patients.
Lungs were the most common metastatic site, regardless of the fusion type. However, 50% of patients with SYT-SSX2 fusion type had metastasis to the liver. Although lungs and liver are common sites for metastasis for renal SS [19, 20], it was not reported before whether there is a relation between the site of metastasis and the type of fusion transcript. From the above, it appears that SYT-SSX 1 behaves more aggressively. However, studies with a larger number of patients and longer follow-up periods are needed to verify these observations, especially in the light of the contradicting data, presenting on the prognostic value of the SYT-SSX fusion protein.
Although SS is considered an aggressive form of STS where metastasis can occur in 50% of the cases, it was found to be sensitive to Anthracycline based chemo-therapy . However, due to the rarity of the tumor, a standard therapy has not been established. Treatment modalities include surgical resection and chemotherapy. A combination of chemotherapy (Ifosfamide and Doxorubicin) and surgery has yielded positive results [6, 9, 12, 13]. Based on our review of the literature, 10 patients took Ifosfamide and Doxorubicin, either together or in combination with other chemotherapeutic agents. 5 out of 10 cases were reported to have complete remission. This further corroborates the effectiveness of giving Ifosfamide and Doxorubicin as a regimen to treat primary renal SS. The basis for chemotherapy was tumor volume reduction, mainly attributed to Ifosfamide. In one case report, the combination of Ifosfamide and Doxorubicin lead to a 50% reduction of the tumor before consequent resection . The controversy of the impact of adjuvant chemotherapy on overall survival, in SS patients, is limited by randomized clinical trials’(RCTs) sample size and varied chemotherapy regimens with discrepant results . The Sarcoma Meta-analysis Collaboration (SMAC) group performed a meta-analysis of all known randomized clinical trials in 1997. Their results indicated that doxorubicin-based chemotherapy served to significantly improve time to local and distant recurrence, as well as overall recurrence-free survival in comparison to patients who were just observed . An increase in overall survival was not statistically significant . Another meta-Analysis of RCTs of adjuvant chemotherapy for localized resectable STS was conducted by Pervais et al. where they built on the results of the SMAC study and narrowed the confidence intervals . This meta-analysis demonstrated marginal efficacy of doxorubicin based chemotherapy with respect to local recurrence, distant recurrence, overall recurrence, and overall survival, in comparison to those who did not receive adjuvant chemotherapy .
In conclusion, primary SS of the kidney is an aggressive rare disease that can be mistaken for other types of renal cell carcinomas. Its diagnosis is based on morphological and molecular studies demonstrating spindle cells and the SYT-SSX translocation. However, establishing a correct diagnosis may be difficult. Prognosis can be enhanced by use of anthracycline based chemotherapy. Moreover, the combination of surgery and chemotherapy has shown positive results. Particularly, we propose the use of Ifosfamide and Doxorubicin as a standard chemotherapy to induce complete remission. Since the disease may have rapid course with unfavorable outcomes, clinicians need to be aware of the existence of this rare entity, so that timely and appropriate therapy can be initiated.
fluorescence in situ hybridization
Inferior vena cava
Magnetic resonance imaging
Randomized clinical trials
reverse transcriptase-polymerase chain reaction
Soft tissue sarcoma
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El Chediak, A., Mukherji, D., Temraz, S. et al. Primary synovial sarcoma of the kidney: a case report of complete pathological response at a Lebanese tertiary care center. BMC Urol 18, 40 (2018) doi:10.1186/s12894-018-0358-z
- Synovial sarcoma
- Pathological response