Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities

Abstract

Background: Successful multimodality management of advanced soft tissue sarcomas (STS) remains a clinical challenge. Although immune checkpoint blockade has shown great promise, only a minority of patients respond. Improved biomarkers could benefit the treatment choice, since cytotoxic therapies and radiotherapy (RT) can alter the immune milieu. The objective of this study was to characterize PD-L1 expression in locally advanced STS with or without preoperative RT. Design: Tissue microarrays (TMA) were constructed using formalin-fixed, paraffin-embedded STS cases (N=17). A composite H-scoring system was applied to analyze/ quantify the protein expression. TMA sections were immunostained using a rabbit anti-human PD-L1 antibody (Sino Biological, Clone: 015). The intensity and percentage of PDL-1-positive cells were calculated and scored blindly. Patients were categorized into PD-L1 high and low-expressing based on H-score above or below the median. Parametric and non-parametric statistics were used as appropriate. Results: Mean age was 55±21, 82% were female, and 53% of STS tumors were located on the extremity. Median tumor size was 15.5 cm (range 2.4-24.8 cm). Half of the cases received preoperative RT. We observed 9 recurrences, and 5 sarcoma deaths. Overall, PD-L1 expression was significantly lower among RT patients (62.5±23.1 vs 139±90.5, p=0.04), and tumor stem cell markers EGFR/CD44 were also significantly lower among chemotherapy patients (p < 0.05). Distant recurrences were more common in PDL-1 high patients (5/8, 62%) than PDL-1 low patients (2/9, 22%). Conclusions: RT is associated with decreased PD-L1 expression in locally advanced STS, and lower PD-L1 expression is associated with improved longterm outcome. The modulation of PDL-1 expression by RT and the impact on prognosis in STS warrants further study. Background: Dedifferentiated liposarcoma (DDLPS) sometimes exhibit heterologous differentiation, and its influence on prognostic outcome is still controversial. As for ossification, it is also not clear whether the bone component means heterologous differentiation or it can be formed by reactive (non-neoplastic) mesenchymal cells. We aimed to investigate the neoplastic nature of the bones formed in DDLPS, and make clear the clinical and pathological characteristics of DDLPS with ossification. Design: We examined 27 cases of DDLPS with ossification by comparing them with 24 cases of DDLPS without ossification and 17 cases of primary extraskeletal osteosarcoma (ESOS) without MDM2 amplification or overexpression. The clinical and pathological findings were reviewed. Histological grade was determined using 'modified' FNCLCC grading system proposed before emphasizing the importance of tumor differentiation scoring. Results: MDM2 amplification was confirmed in osteocytes and/or osteoblastic cells in all DDLPS cases with ossification where Fluorescence In-Situ Hybridization (FISH) was successfully performed in bone forming area (22/22). The bones found in DDLPS were mainly mature in most cases (20/27), and ...

Cytologic Features of SMARCA4-Deficient Thoracic Sarcoma: A Case Report and Comparison with Other SWI/SNF Complex-Deficient Tumors

“…The cytologic features described here recapitulate the histology of SMARCA4-DTSs [2, 3]. These tumors have been shown to be histologically similar among cases, displaying diffuse sheets of poorly cohesive, relatively monotonous undifferentiated ovoid/epithelioid cells with vesicular chromatin, and prominent nucleoli.…”

“…Schaefer et al [6] performed immunohistochemistry for claudin-4 on various tumors and found that the expression of claudin-4 was frequent in carcinomas (including SWI/SNF complex-deficient ones) and epithelial components of synovial sarcomas, whereas almost all the sarcomas investigated were negative for this marker. Indeed, a uniform lack of claudin-4 expression in SMARCA4-DTS was observed in a case series by Yoshida et al [2] as well as in our case, suggesting that SMARCA4-DTSs are true sarcomas and do not represent the least differentiated variants of lung carcinomas.…”

“…Gene expression analysis revealed that these tumors are transcriptionally related to other SWI/SNF complex-deficient tumors – such as malignant rhabdoid tumors (MRTs) and small cell carcinomas of the ovary, hypercalcemic type (SCCOHTs) – but distinct from lung cancers with or without SMARCA4 mutations [1]. Subsequent studies [2, 3] also identified tumors corresponding to this new category, supporting the distinctiveness of SMARCA4-DTS from other potentially related entities.…”

“…Differences in CD34 expression may also distinguish SMARCA4-DTS from lung carcinomas: CD34 is expressed in the majority (60–83%) of SMARCA4-DTSs [1-3], whereas this marker is not usually expressed in lung carcinomas, including SMARCA4-deficient ones [2]. However, in endometrial carcinomas, Shah et al [7] recently reported that CD34 was not uncommonly expressed in undifferentiated components of dedifferentiated carcinomas, suggesting that CD34 cannot be used to exclude epithelial neoplasms.…”

Uterine mesenchymal tumours: recent advances

“…Loss of SMARCA4 expression through truncating mutations or deep deletions of the SWI/SNF‐related, matrix‐associated, actin‐dependent regulator of chromatin, subfamily A, member 4 ( SMARCA4 ) gene have recently been detected in a subset of UUS . These tumours share overlapping clinicopathological and genetic features with other SMARCA4‐deficient cancers, such as ovarian small cell carcinoma of hypercalcaemic type, atypical teratoid/rhabdoid tumours and thoracic sarcomas . SMARCA4‐deficient UUS are large bulky masses involving the endomyometrium that are composed of sheets of large discohesive and uniformly atypical epithelioid cells with eccentric round to oval nuclei, vesicular chromatin, prominent nucleoli and scant to abundant eosinophilic cytoplasm.…”