Synovial Sarcoma with Extensive Rhabdoid Differentiation: A Rare Aggressive and Deceptive

doi:10.21203/rs.3.rs-4816439/v1

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Case Report

Synovial Sarcoma with Extensive Rhabdoid Differentiation: A Rare Aggressive and Deceptive

https://doi.org/10.21203/rs.3.rs-4816439/v1

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Background:Synovial sarcoma usually presents with spindle cell morphology with or without epithelial differentiation. Extensive rhabdoid differentiation is a very rare feature with only few cases has been described in literature.

Case Presentation: We present two cases of synovial sarcoma with rhabdoid differentiation along with their clinical follow-up. Both cases had tumor in the vicinity of joints and showed lung metastasis during follow-up inspite of R0 resection. We emphasised that extensive rhabdoid differentiation can be deceptive and challenging for diagnosis in small biopsies and also show an aggressive clinical course with dismal prognosis.

Conclusion:Awareness of this rarely described unusual and aggressive histomorphological subtype is prudent due to its distinct diagnostic, prognostic and therapeutic implications.

Aggressive

Metastasis

Rhabdoid

SSX18

Synovial Sarcoma

Synovial sarcoma (SS) is a spindle cell sarcoma with variable epithelial differentiation and has been classified as tumor of uncertain differentiation. The majority of SS arises in deep soft tissue of extremities, followed by trunk and head & neck regions. On histology, majority of SS are monophasic tumors comprising of blue spindled tumor cells followed by biphasic pattern with both epithelioid and spindle cell components. The neoplastic spindle cell component show characteristic monomorphic appearance and provides histological clue for diagnosis. At molecular level SS exhibits unique and characteristic t(X;18) (p11:q11) translocation which is a hallmark for definite diagnosis [1, 2].

Although rarely, SS can show myxoid change, extensive glandular differentiation, epithelioid cells, small round cells or metaplastic bone or cartilage formation, however an extensive rhabdoid differentiation is very unusual and rare feature described in SS, which can prompt an erroneous diagnosis [3]. We present two cases of SS with this unusual rhabdoid features which posed a diagnostic challenge during needle biopsy interpretation. Also both cases had aggressive course of disease which may be attributed to its rhabdoid morphology.

Case 1

A 49-year-old woman presented initially at some other institute with complaints of swelling in foot, progressively and slowly increasing in size for 4 months. Magnetic resonance imaging (MRI) and biopsy was suggestive of a malignant vasoformative tumor. The patient was referred to our tertiary cancer care centre. MRI was reviewed, which revealed a lobulated solid cystic infiltrative mass in both ventral and dorsal aspect extending through the first web space [Figure 1].

The submitted paraffin blocks of the biopsy showed an epithelioid tumor with areas of haemorrhage and vasoformative pattern evident at places [Figure 2a]. Significant areas showed large polygonal cells with eccentric nucleus and dense eosinophilic cytoplasm with hyaline inclusion evocative of rhabdoid differentiation [Figure 2b]. Mitosis was significant in both epithelioid and rhabdoid areas. The histomorphological differential diagnosis in germane to the clinical features were epithelioid malignant peripheral nerve sheath tumor (MPNST), epithelioid sarcoma, rhabdomyosarcoma (RMS), primary extrarenal malignant rhabdoid tumor and malignant melanoma with rhabdoid differentiation.

All the immunohistochemistry (IHC) markers in the primary panel [CK, SMA, S100, HMB-45, Desmin, MyoD1, SOX10] were negative; while INI-1 expression was significantly reduced, however not completely absent in the tumor cells [Figure 2c]. On further IHC panel, TLE-1 and TRPS-1 exhibited diffuse and strong nuclear positivity. Subsequently, the tumor cells were positive for SS18 gene rearrangement by break-apart fluorescent in situ hybridization (BA-FISH) [Figure 2d]. Hence, a diagnosis of SS with extensive rhabdoid differentiation was rendered.

No other lesion was found on metastatic work up on positron emission tomography-computed tomography (PET-CT) scan, hence, patient underwent below knee amputation. The gross findings were in resonance with the MRI findings [Figure 3a]. On histology, the tumor revealed epithelioid to spindle cell morphology with extensive rhabdoid differentiation [Figure 3b-c]. Mitosis was brisk [Figure 3c] and necrosis was evident. On IHC, SSX18 exhibited diffuse and strong nuclear positivity [Figure 3d]. A final diagnosis of SS with extensive rhabdoid differentiation was rendered, FNCLCC Grade 3. All the left inguinal and single intrapelvic lymph nodes were free of tumor. The case was discussed in multispeciality tumor board (MTB) meeting and was advised adjuvant chemotherapy (CT). Subsequently, patient received six cycles of adriamycin and ifosfamide based CT.

During regular follow up at 14 months, patient was found to developed left sided pleural effusion. Low dose CT chest showed left hemi thorax nodular heterogeneous density along costal, mediastinal and diaphragmatic pleura with gross pleural effusion and collapse of underlying lung and mass effect in form of mediastinal shift of heart towards right side [Figure 3e]. Biopsy of pleural nodule showed metastatic SS with extensive rhabdoid differentiation [Figure 3f]. During this admission patient suddenly had shortness of breath and upper back pain and was shifted to ICU for supportive care. The poor prognosis, complications and high chances of mortality was explained in details to patient’s attendants. However, they decided to continue further supportive care at local native place.

Case 2

A 35-year-old male who underwent complete work up at some other institute for swelling in knee was diagnosed as SS of the soft tissue in popliteal fossa. Patient took three cycles of neoadjuvant chemotherapy (gemcitabine and docetaxel) and was followed by surgical resection of the tumor. The tumor was reported as high grade SS. Patient did not take adjuvant treatment and came again two months after surgery for pain in right leg along with cough. MRI limb showed a lobulated hyperintense mass in popliteal fossa displacing the popliteal vessels [Figure 5a]. Restaging PET-CT was done suggestive of local disease recurrence/residual disease with new bilateral pulmonary nodules [Figure 4a] and suspicious inguinal lymph nodes.

Patient was referred to our hospital and underwent trucut biopsy from right subpleural nodule which revealed a blue spindle cell tumor with areas of rhabdoid differentiation [Figure 4b-c]. TLE-1, TRPS-1 and SSX18 [Figure 4c (inset)] exhibited diffuse and strong nuclear positivity in tumor cells, thus the histological findings were consistent with metastatic SS. INI-1 immunoexpression was significantly reduced, however not completely absent in tumor cells [Figure 4d]. Patient underwent limb salvage surgery and ilioinguinal lymph node dissection. HPE revealed morphology of monophasic SS, FNCLCC grade 3 with rhabdoid differentiation [Figure 5b-c]. No nodal metastasis was found. Patient also underwent bilateral video assisted thoracoscopic surgery (VATS) metastatectomy for metastatic SS.

The case was discussed in MTB meeting and patient was advised ifosfamide and adriamycin based adjuvant CT. After 4 cycles of adjuvant CT, follow-up PET-CT showed no evidence of disease. Patient is due for next planned cycles of CT regimen.

SS represents 5–10% of the entire soft tissue tumors and occurs predominantly in young patients with a marked predilection for the upper and lower extremities and tends to occur in the vicinity of joints. [1, 4, 5]

On histology, the majority of SS are monophasic while upto one quarter to one third of the cases are biphasic with epithelial differentiation; the latter can display variable histological pattern like nests, cords or well-formed glands [1]. The spindle cell component in monophasic or biphasic SS is characteristically monomorphic with scant cytoplasm, giving an appearance of blue spindle cell tumor. The mitosis is variable and is required for FNCLCC grading of SS. These characteristic histological features provide a clue for the diagnosis which is further worked up by IHC for confirmation.

The unusual histological pattern in SS like rhabdoid differentiation is sparsely described in literature with only handful of cases [3–6] and authors have attributed this morphological subtype as challenge for diagnosis. This histological pattern is extremely rare and deceptive during histomorphological assessment and often precludes possibility of SS in formulating the list of differential diagnosis. In the presented two cases, the clinical features especially, the site of tumor in the vicinity of joints provoked us to rule out the possibility of SS inspite of very unusal histology.

TLE-1 is a highly sensitive IHC marker for the diagnosis of SS; however, lacks specificity as the immunoexpression can be seen in MPNST, solitary fibrous tumor and angiomatoid fibrous histiocytoma [1]. Hence, the gold standard for the diagnosis of SS is unique t(X;18) (p11;q11) translocation which is routinely demonstrated by BA-FISH for SS18 gene rearrangement. SS18 gene on chromosome 18 is fused to one of the SSX gene; SSX2 or SSX4 on X chromosome, which is genetic hallmark of SS [7].

Recently, new IHC markers like TRPS-1 & novel SS18-SSX fusion specific antibody have emerged with latter being 100% specific for the diagnosis of SS and can obviate the need of translocation (FISH) studies [8, 9]. Cloutier et al [8] have evaluated 165 cases of SS with TRPS-1 IHC and the expression was evident in 86% of the cases, however the specificity of this marker for diagnosis of SS is not well documented

Kohashi et al [2] have evaluated INI-1 immunoexpression in 95 cases of SS and 30 cases of other soft tissue sarcoma. They found reduced expression in 69% (66/95) cases of SS while the protein expression was preserved in remaining cases of SS and all (100%) cases of other soft tissue sarcoma. The study also concluded that status of INI-1 immunoexpression did not affect the prognosis of patients of SS (p = 0.46) and none of the case showed complete loss of INI-1 protein expression. Hence, pattern of INI-1 expression had limited efficacy for prognostication of SS and was more useful for in identifying histological tumor categories. In our both cases exhibiting rhabdoid differentiation, we found significant reduced expression of INI-1 which served as a clue to rule out SS, along with clinical features.

The prognostic implication of rhabdoid differentiation on SS in uncertain due to paucity of cases, however, both our cases had poor prognosis and both cases presented with lung metastasis within 1-1.5 years indicating a more aggressive behaviour of synovial sarcomas with rhabdoid morphology. Wen et al [4] and Machen et al [10] have also attributed the rhabdoid morphology with systemic metastasis and poor prognosis in their findings.

To conclude, rhabdoid differentiation is a rare occurrence in SS, however awareness of this unusual histological feature espoused with correlation of clinical features can help the pathologist to consider SS in the differential diagnosis which can be subsequently confirmed by fusion specific IHC or translocation studies by FISH. The accurate diagnosis is prudent due to distinct prognostic and therapeutic implication of this entity. We propose rhabdoid differentiation in SS is an unfavourable and aggressive histological feature.

Ethics approval and consent to participate: All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Board (Rajiv Gandhi Cancer Institute & Research Centre); vide the ethical approval letter number RES/SCM/60/2023/76. Informed consent was obtained from all individual participants included in the study.

Consent for publication: Consent for publication was given as per institutional policy.

Funding: This study was not supported by any funding.

Conflicts of interest: The authors declare that they have no conflict of interest.

Availability of data and material: Not applicable.

Authors Contributions:

SP, DB, HR, RO, MG, AM: Substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data

SP, DB: Drafting the article and revising it critically for important intellectual content.

SP, DB, HR, RO, AS, GG, SR, GD, MK, VT, MG, IS, AM: Final approval of the version to be published. All authors confirm they have meaningfully contributed to the research and read and approved the final manuscript.

Acknowledgements: None

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Hartel PH, Fanburg-Smith JC, Frazier AA, Galvin JR, Lichy JH, Shilo K, Franks TJ. Primary pulmonary and mediastinal synovial sarcoma: a clinicopathologic study of 60 cases and comparison with five prior series. Mod Pathol. 2007;20(7):760–9.
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Cloutier JM, Ingram DR, Wani K, Lazar AJ, Wang WL. Frequent TRPS1 expression in synovial sarcoma is associated with SS18-SSX fusion oncoprotein activity. Hum Pathol. 2022;130:88–94.
Baranov E, McBride MJ, Bellizzi AM, Ligon AH, Fletcher CDM, Kadoch C, Hornick JL. A Novel SS18-SSX Fusion-specific Antibody for the Diagnosis of Synovial Sarcoma. Am J Surg Pathol. 2020;44(7):922–33.
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No competing interests reported.

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Synovial Sarcoma with Extensive Rhabdoid Differentiation: A Rare Aggressive and Deceptive

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Case Presentation

Case 1

Case 2

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