TCL-239: Clinical, Pathological, and Prognostic Implications of RHOAG17V Mutation in Peripheral T-Cell Lymphomas

Abstract

Context RHOAG17V mutation has been implicated in peripheral T-cell lymphomas (PTCL), characteristically angioimmunoblastic T-cell lymphomas (AITL). However, the association of the dominant-negative control with clinicopathological profile of the neoplasm is yet not clear. Objective To study the impact of RHOAG17V on the clinicopathological presentation and prognostication of T-follicular helper (TFH) cell-derived PTCL and PTCL-NOS. Design This was an ambispective study over six years (2015–2020), including 88 patients with diagnoses of PTCL-NOS (44), AITL (37), PTCL-TFH phenotype (P-TFH; 6), and follicular T-cell lymphoma (1) from the archives of Department of Pathology (AIIMS, New Delhi). Mutational analysis was performed using allele-specific polymerase chain reaction (PCR), validated by the sequencing of cloned products, along with conventional Sanger sequencing. Detailed clinicopathological correlation was done. Main Outcome Measures The association between the presence of mutation and diagnosis, clinical factors (demographics, performance status, organomegaly, IPI/PIT score, stage, marrow involvement), histologic and immunophenotypic presentation (pattern, high endothelial venules [HEV], immunopositivity for TFH markers [CD10, ICOS, PD1, BCL6, and others], CD30, and EBER ISH), and survival (overall and progression-free survival) was analyzed. Results RHOAG17V mutation was present in association with diagnosis of AITL (51.35%) in comparison to PTCL-NOS (25%) and P-TFH (16.67%; p-value=0.027). Sanger sequencing of conventional PCR did not yield any mutations, and the results were based on allele-specific PCR. Mutant cases of AITL had an overall worse performance status at presentation (p-value=0.045), along with a diffuse pattern of nodal involvement (p-value=0.046). Two diffuse large B-cell lymphoma-transformed cases harbored the mutation. Amongst the PTCL-NOS patients, immunopositivity for ICOS (p-value=0.045), along with the presence of increased HEV (p-value=0.035), was noted. None of these factors showed any association with P-TFH. On multivariate analysis, wild-type status predicted an inferior OS (p-value=0.029) in AITL, whereas no significant difference was noted in PFS. Mutation did not confer a survival advantage in PTCL-NOS or P-TFH. Conclusions RHOAG17V mutation, though not specific, shows an association with diagnosis of AITL and has been studied as a lineage-assigning marker for the TFH phenotype, as implicated by ICOS immunopositivity and HEVs in PTCL-NOS. Low variant allelic frequency could lead to false-negative results with conventional PCR products. Mutant status can have prognostic implications with translational relevance and requires larger cohorts for validation. Funding Thanks to Science Engineering Research Board and AIIMS Research section (SERB-EEQ/2016/402, AIIMS A-653).