BCOR Overexpression in Renal Malignant Solitary Fibrous Tumors

Abstract

BCOR immunoreactivity is a sensitive and highly specific marker for clear cell sarcoma of the kidney (CCSK). However, a subset of adult renal sarcomas which overexpress BCOR are negative for BCOR genetic alterations, including BCOR gene fusions or BCOR-internal tandem duplication, and thus remain unclassified. We report five such undifferentiated renal/perirenal sarcomas which raised the differential diagnosis of CCSK due to their morphologic appearance and strong BCOR immunoreactivity, but which on RNA sequencing (RNA-Seq) proved to be malignant solitary fibrous tumors (SFTs). The neoplasms occurred in patients at an age range of 30-62 years. Three patients were females and two male. Four were primary renal neoplasms while one was perirenal. All five neoplasms were cellular, non-pleomorphic, undifferentiated sarcomas with branching capillary vasculature composed of primitive round to ovoid neoplastic cells with scant cytoplasm and nuclei having fine, evenly-dispersed chromatin. None of the cases demonstrated the typical hyperchromatic fusiform nuclei, prominent collagen deposition, or hemangiopericytomatous vasculature of SFT. All five cases were strongly immunoreactive for BCOR. Three cases were CD34 negative, where the other two were only focally CD34 positive. STAT6 was subsequently found to be positive by immunohistochemistry in all five cases. In summary, we report a previously unrecognized mimic of CCSK: malignant SFTs with an undifferentiated/small round cell phenotype along with branching capillary vasculature, strong immunoreactivity for BCOR, and minimal or no immunoreactivity for CD34. As CCSK is treated with a specific chemotherapy regimen, this distinction has therapeutic implications.

Lessons learned from the developmental origins of childhood renal cancer

“…Rather, 90% of CCSK patient samples carry internal tandem duplications (ITDs) in BCOR, which plays essential roles in epigenetic silencing (Astolfi et al, ; Roy et al, ; Ueno‐Yokohata et al, ). Subsequent studies have also described a gene fusion of BCOR with Cyclin B3 (CCNB3), a positive regulator for cyclin‐dependent kinase and cell cycle control, resulting from inv(X)(p11q11), an X chromosomal pericentric inversion in CCSK samples (Argani et al, , ; Kao et al, ). Interestingly, BCOR‐ITD overexpression is also not exclusive to CCSK, and is described in other neoplasms, such as renal malignant solitary fibrous tumor, and high‐grade uterine sarcoma, suggesting its role as potential oncogene and implying that lessons learned in those diseases may also be applicable to CCSK (Argani et al, ; Mariño‐Enriquez et al, ).…”

“…Subsequent studies have also described a gene fusion of BCOR with Cyclin B3 (CCNB3), a positive regulator for cyclin‐dependent kinase and cell cycle control, resulting from inv(X)(p11q11), an X chromosomal pericentric inversion in CCSK samples (Argani et al, , ; Kao et al, ). Interestingly, BCOR‐ITD overexpression is also not exclusive to CCSK, and is described in other neoplasms, such as renal malignant solitary fibrous tumor, and high‐grade uterine sarcoma, suggesting its role as potential oncogene and implying that lessons learned in those diseases may also be applicable to CCSK (Argani et al, ; Mariño‐Enriquez et al, ). Additionally, a chromosomal translocation affecting t(10;17)(q22;p13), resulting in a YWHAE‐NUTM2B fusion, is strongly implicated as the primary initiating pathogenic event for 5% of CCSK (O'meara et al, ; Punnett, Halligan, Zaeri, & Karmazin, ; Rakheja et al, ; Table ).…”

Controversial issues in soft tissue solitary fibrous tumors: A pathological and molecular review

“…The NAB2–STAT6 fusion is the molecular hallmark (Fig. d) of SFTs . Although Barthelmess et al detected a significant association between the NAB2ex6‐ STAT6ex16/17 variant and malignancy in SFTs, other authors have reported that no fusion variants are associated with malignancy …”

“…Many of the histological variants reveal a focal patternless architecture, and variably fibro‐collagenous stroma . NAB2‐STAT6 was discovered as a novel fusion gene of SFTs, and STAT6 immunoexpression has been established as a surrogate marker of the NAB2‐STAT6 gene fusion, expression of this protein representing a very sensitive and specific diagnostic tool …”

“…Special mention should be made of those tumors with frequent CD34 immunoexpression, such as spindle cell lipoma, dermatofibrosarcoma protuberans, myofibroblastoma, myofibroblastic tumors, metastatic low grade endometrial sarcoma, NTRK ‐tumors/infantile fibrosarcoma, or gastrointestinal stromal tumors (GIST) . Other soft tissue spindle cell tumors with uncommon CD34 expression (synovial sarcoma or BCOR‐sarcomas) should also be included in the differential diagnosis since BCOR immunoexpression has also been reported in SFT …”