Recent studies identified germline HAVCR2 (TIM-3) mutations as the specific genetic predisposition to subcutaneous panniculitis-like T-cell lymphoma (SPTCL). However, distinction between HAVCR2-mutated and HAVCR2-wildtype SPTCLs remains elusive. We studied the prevalence of HAVCR2 mutation in a nation-wide cohort of SPTCL and investigated clinical and molecular distinction between HAVCR2-mutated and HAVCR2-wild-type SPTCLs. A multicenter nationwide cohort of 53 SPTCL cases was established; patients were diagnosed at seven Korean institutions between 2003 and 2020. Histologic features were reviewed by experienced hematopathologists and clinical features were retrospectively reviewed. Whole-exome sequencing (WES) and RNA-seq were performed using formalin-fixed, paraffin-embedded (FFPE) samples of 8 patients diagnosed in Seoul National University Hospital (SNUH), with matched non-neoplastic tissue samples from two patients. Direct sequencing of HAVCR2 exon 2 was successfully carried out using FFPE samples from 33 of the remaining 45 patients. Among 41 patients with available HAVCR2 mutation status, 28 (68.3%) were women, and the median age at diagnosis was 30 years (range 11–74). Ten patients (10/40; 25.0%) suffered hemophagocytic syndrome (HPS) or HPS-like systemic illness during the clinical course, and 14 patients (14/40; 35.0%) progressed during the follow-up. Six patients (6/41; 14.6%) died of disease progression or HPS. We found 18 patients (18/41; 43.9%) with HAVCR2 mutation; 15 patients harbored biallelic HAVCR2 Y82C mutation and 3 patients were noted for heterozygous HAVCR2 Y82C mutation. HAVCR2-mutated SPTCLs occurred in younger patients (median age 26.5 versus 37; Mann-Whitney p-value = 0.003), and were more often complicated by HPS or HPS-like systemic illness (10/18 versus 0/22; Fisher's exact p-value < 0.001), compared to HAVCR2-wild-type SPTCLs. Survival analysis using log-rank test revealed that HAVCR2-mutated SPTCLs had shorter progression-free survival, though statistical significance was not achieved (p-value = 0.081) WES results did not show recurrent genetic alteration other than HAVCR2 Y82C in 4 out of 8 patients. Mutations in genes involved in T/NK cell-associated inflammation (PVRL1, PVRL2, TICAM1, GZMA), epigenetic modification (BAZ2A, KMT2C, KMT2D, SETD1A), JAK-STAT signaling (IFNL2, PIAS3), and NF-kB pathway (PDCD11) were observed in individual cases. Gene set enrichment analyses (GSEA) using RNA-seq results showed significant enrichment of pathways involving TNF-alpha signaling via NF-kB (FDR q-value = 0.008), hypoxia (FDR q-value = 0.009), IL6-JAK-STAT3 signaling (FDR q-value = 0.026), apoptosis (FDR q-value = 0.121), and MTORC1 signaling (FDR q-value = 0.188) in HAVCR2-mutated SPTCLs. HAVCR2 Y82C hotspot mutation frequently occurs in Korean patients with SPTCL, which was characterized by unique clinicopathologic features. SPTCL with HAVCR2 Y82C was enriched with distinct cellular pathways, which remains to be further validated.

Citation Format: Jiwon Koh, Insoon Jang, Seungchan Mun, Cheol Lee, Hee-Jung Cha, Young Ha Oh, Jin Man Kim, Young Hyeh Ko, Jae Ho Han, Heounjeong Go, Jooryung Huh, Kwangsoo Kim, Yoon Kyung Jeon. Subcutaneous panniculitis-like T-cell lymphoma with HAVCR2 mutation shows unique clinicopathologic features and gene expression profile [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-34.