Update on gene fusions and the emerging clinicopathological landscape of peritoneal and pleural mesotheliomas and other neoplasms

Abstract

Background: Mesothelioma is a rare and aggressive malignant neoplasm arising from mesothelial cells, which occasionally manifests recurrent fusions. EWSR1/FUS-CREB, YY1, MAP3K8, NR4A3, and ALK-rearranged proliferations have been reported in limited series with no clear histological or clinical correlations, limiting clinicians' ability to assess prognosis and integrate these new entities into therapeutic decisions. The aim of this study was to better characterize these rearranged proliferations histologically, molecularly, and clinically.

Methods: Clinical, pathological, and comprehensive transcriptome and mutation data were collected for each case.

Results: A total of 41 tumors were included, encompassing 7 ALK, 10 MAP3K8, 4 NR4A3, 8 ESWR1/FUS::ATF1, 8 EWSR1::YY1, and 4 SUFU-fused cases. We found a female predominance, except for cases harboring NR4A3 and SUFU; and most patients were around 60 years of age, but those harboring ALK or EWSR1/FUS::ATF1 gene fusions were younger. Each group exhibited distinct histological, immunohistochemical, molecular features, and oncological courses. Specifically, MAP3K8 and ALK presented PAX8+ papillary proliferations, ESWR1/FUS::ATF1 and EWSR1::YY1 displayed angiomatoid fibrous histiocytoma-like patterns, while SUFU showcased 'tissue culture'-like spindle cell proliferation. Poor prognosis factors were the pleural site, male sex, Ki67 ≥10%, and ESWR1/FUS::ATF1 or SUFU gene fusions.

Conclusions: This study significantly broadens the spectrum of mesothelial tumors associated with fusions, offering insight into novel epithelioid (mesothelial) proliferations with distinctive histological appearances, molecular profiles, and prognoses to guide adapted treatments for patients.

Keywords: ALK; EWSR1; MAP3K8; SUFU; gene fusion; mesothelioma.

Graphical abstract

Figure 1

Presentation of cohort and analysis of overall survival of cohort. (A) Presentation of cohort. (B-E) Analysis of overall survival of cohort. The univariate analysis found that being female (P value: 0.0346, B), having a peritoneum or vaginal testicular (VT) site (P value: <0.001, C), harboring ALK, MAP3K8, or NR4A3-rearranged fusions (P value: 0.016, D), or exhibiting a Ki67 <10% (P value: <0.001, E) were associated with longer overall survival.

Figure 2

Histological patterns and immunophenotype of mesothelioma rearranged- ALK or MAP3K8.ALK-rearranged cases (A-H) displayed extensive papillary proliferation of mesothelial cells, featuring hyaline or edematous papillae infiltrated by small-sized psammoma bodies and foamy cells. The mesothelial cells around the papillary axes appeared cuboidal or cylindrical with a consistent appearance (A-D). These cases exhibited classical mesothelial differentiation (E and F), conserving BAP1 and PAX8+ expression with a Ki67 proliferation index <5% (G-H). MAP3K8-rearranged peritoneal/vaginal testicular (VT) cases (I-O) resembled the ALK counterpart but showed a fringe-like cellular distribution around the papillae and a myxoid stroma within the papillae, distinguishing them (I-K). They also exhibited classical mesothelial differentiation (L and M), conserving BAP1 and PAX8+ expression, and a Ki67 proliferation index of <5% (N and O). MAP3K8-rearranged pleural cases (P-V) showed marked atypia, diffuse infiltration, and a doubtful mesothelial differentiation profile (S and T), yet maintained BAP1 and PAX8 expression with a Ki67 proliferation index of 40% (U and V).

Figure 3

Histological patterns and immunophenotype of neoplasms rearranged-ATF1, ESWSR1, NR4A3, and SUFU.EWSR1/FUS::ATF1-rearranged cases (A-K) displayed well-circumscribed neoplasms within a fibrous capsule and dense lymphoid cuffing (A and B). The predominant solid architectural pattern was observable alongside macrocysts and microcysts containing serous fluid (C-E). Mesothelial differentiation was doubtful (F-I). BAP1 was retained, PAX8 was negative, and the Ki67 proliferation index ranged from <5% to 10%-20% (J and K). ESWSR1::YY1-rearranged cases (L-V) displayed scattered tumor nodules and epithelioid cells arranged in cords and trabeculae (L-P). Some cases resembled angiomatoid fibrous histiocytoma-like tumors (L). Immunohistochemically, 75% exhibited classical mesothelial profile, while 25% had a doubtful profile (Q-T). BAP1 was retained, PAX8 was negative, and Ki67 proliferation ranged between <10% and 15%-30% (U and V). NR4A3-rearranged cases (W-AD) displayed a constant microcystic architecture (W-AA) without atypia, mitotic activity, or necrosis. The transition into spindle cell proliferation occupied <10% of the tumor surface (W). These cases showed a classical mesothelial differentiation profile (AB and AC). BAP1 was retained, PAX8 was negative, and the Ki67 proliferation index was <5% (AD). SUFU-rearranged cases (AF-AL) exhibited a uniform appearance with hypo- and hypercellular areas (AF-AG), occasionally displaying a chevron-like pattern. Spindle-shaped cells arranged in a bland fashion within a fibrous or myxoid stroma were moderately atypical (AH and AI). BAP1 was retained, PAX8 was positive in one case, and the Ki67 index ranged from 40% to 60% (AJ-AL).

Figure 4

Analysis of UMAP projection. The clustering analysis using gene expression profiling grouped: cases with gene fusions (N = 41) versus control cases without gene fusions (N = 160). The distinct subgroups emerged: ALK, NR4A3, or MAP3K8-rearranged mesotheliomas formed separate clusters based on histology and site. EWSR1/FUS::ATF1-rearranged epithelioid tumors constituted a distinct group from angiomatoid fibrous histiocytoma, while EWSR1::YY1-rearranged mesotheliomas formed their unique cluster. SUFU-rearranged sarcomatoid mesothelioma clustered with some pleural mesotheliomas, distinctly different from sarcomas and carcinomas in the database. Papillary and solid mesothelial tumors exhibited a unique transcriptomic profile compared with other rearranged proliferations. Ctrl, control; EM, epithelioid mesothelioma; SM, sarcomatoid mesothelioma; UMAP, Uniform Manifold Approximation and Projection.