The impact of histopathology and NAB2–STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/hemangiopericytoma

Abstract

Meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is a rare tumor with propensity for recurrence and metastasis. Although multiple classification schemes have been proposed, optimal risk stratification remains unclear, and the prognostic impact of fusion status is uncertain. We compared the 2016 WHO CNS tumor grading scheme (CNS-G), a three-tier system based on histopathologic phenotype and mitotic count, to the 2013 WHO soft-tissue counterpart (ST-G), a two-tier system based on mitotic count alone, in a cohort of 133 patients [59 female, 74 male; mean age 54 years (range 20–87)] with meningeal SFT/HPC. Tumors were pathologically confirmed through review of the first tumor resection ( n = 97), local recurrence ( n = 35), or distant metastasis ( n = 1). A STAT6 immunostain showed nuclear expression in 132 cases. NAB2 – STAT6 fusion was detected in 99 of 111 successfully tested tumors (89%) including the single STAT6 immunonegative tumor. Tumors were classified by CNS-G as grade 1 ( n = 43), 2 ( n = 41), or 3 ( n = 49), and by ST-G as SFT ( n = 84) or malignant SFT ( n = 49). Necrosis was present in 16 cases (12%). On follow-up, 42 patients had at least one subsequent recurrence or metastasis (7 metastasis only, 33 recurrence only, 2 patients had both). Twenty-nine patients died. On univariate analysis, necrosis ( p = 0.002), CNS-G ( p = 0.01), and ST-G ( p = 0.004) were associated with recurrence-free (RFS) but not overall survival (OS). NAB2 – STAT6 fusion type was not significantly associated with RFS or OS, but was associated with phenotype. A modified ST-G incorporating necrosis showed higher correlation with RFS ( p = 0.0006) and remained significant ( p = 0.02) when considering only the primary tumors. From our data, mitotic rate and necrosis appear to stratify this family of tumors most accurately and could be incorporated in a future grading scheme. Electronic supplementary material The online version of this article (10.1007/s00401-018-1952-6) contains supplementary material, which is available to authorized users.

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

“…32 In fact, the association between the fusion variants and malignant potential is still unclear, and few studies have evaluated whether malignant SFTs have additional alterations compared to nonmalignant SFTs. 9,[31][32][33]39,41,45 Recent reports have suggested that TERT promoter mutations ( Fig. 4d) are associated with poor prognosis in SFTs.…”

“…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 …”

“…Nevertheless, few studies have evaluated the role of molecular alterations in malignant SFTs compared to nonmalignant SFTs . Currently, mitotic activity (≥4/10 HPFs), telomerase reverse transcriptase gene (TERT) promoter mutations, and/or TP53 mutations are considered to better correlate with tumor aggressiveness, although inclusion of molecular alterations in the widely‐used risk stratification models is still pending . In this study, the authors review and discuss current knowledge on SFT, including their wide morphologic spectrum, immunohistochemical and molecular findings and differential diagnosis.…”

“…In fact, the association between the fusion variants and malignant potential is still unclear, and few studies have evaluated whether malignant SFTs have additional alterations compared to nonmalignant SFTs …”