Therapy-related myeloid neoplasms with normal karyotype show distinct genomic and clinical characteristics compared to their counterparts with abnormal karyotype.

Therapy-related myeloid neoplasms (t-MNs) are a complication of treatment with cytotoxic chemotherapy and/or radiation therapy. The majority of t-MNs show chromosomal abnormalities associated with myelodysplastic syndrome (MDS) or KMT2A rearrangements and are characterized by poor clinical outcomes. A small but substantial subset of patients have normal karyotype (NK) and their clinical characteristics and mutational profiles are not well studied. We retrospectively studied patients diagnosed with t-MN at three institutions and compared the mutational profile and survival data between t-MNs with NK and t-MNs with abnormal karyotype (AK). A total of 204 patients with t-MN were identified including 158 with AK and 46 with NK. NK t-MNs, compared to AK, were enriched for mutations in TET2 (p < 0.0001), NPM1 (p < 0.0001), ASXL1 (p = 0.0003), SRSF2 (p < 0.0001), RUNX1 (p = 0.0336) and STAG2 (p = 0.0099) and showed a significantly lower frequency of TP53 mutations (p < 0.0001). Overall survival (OS) was significantly lower in AK t-MNs as compared to NK cases (p = 0.0094). In our study, NK t-MNs showed a significantly better OS, a higher prevalence of MN-associated mutations and a lower frequency of TP53 mutations compared to their AK counterparts. The distinct clinical and mutational profile of NK t-MNs merits a separate classification.

Renal Neoplasms with Concurrent Castleman-Like Regional Lymphadenopathy.

INTRODUCTION: Renal cell neoplasms are known to be associated with paraneoplastic syndromes, and the association with Castleman-like regional lymphadenopathy has been rarely reported. We aim to characterize the association between renal neoplasms and Castleman-like lymphadenopathy. METHODS: A search for renal neoplasms with concurrent Castleman-like lymphadenopathy in one single medical institution from 2000 to 2023 resulted in 4 specimens. A literature search for "Castleman" and "renal neoplasm" resulted in 8 reports. Patients' demographics, clinical presentation, gross and histologic features, results of ancillary studies, treatment, and follow-up were evaluated. RESULTS: Our patients included 3 men and 1 woman, with a mean age of 60 years. Four different subtypes of renal neoplasms were diagnosed, including clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, and mucinous cystadenoma of the renal pelvis. For Castleman-like regional lymphadenopathy, 2 were plasma-cell predominant, and 2 were hyaline-vascular. After a median follow-up of 84 months, all patients were alive with no recurrence or progression of Castleman-like features following nephrectomies. CONCLUSION: Castleman-like regional lymphadenopathy should be considered in patients with renal tumors and lymphadenopathy. Although more prevalent in clear cell RCC, it can be also associated with other renal neoplasms. The concurrent lymphadenopathy was remitted following the renal tumor resections.

Survival outcomes of diffuse large B-cell lymphoma by association with concurrent or antecedent follicular lymphoma and double hit status.

Diffuse large B-cell lymphoma (DLBCL) transformed from follicular lymphoma (FL) (tDLBCL) has been traditionally associated with an aggressive course, but more recent studies have shown longer survivals. The clinical significance of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) is less clear. We compared outcomes of tDLBCL, cDLBCL/FL, and de novo DLBCL (dDLBCL) and then evaluated the impact of double hit (DH) rearrangements (MYC with BCL2 and/or BCL6) in these subgroups' outcomes. The progression free survival (PFS) and overall survival (OS) were not significantly different among the three groups (dDLBCL, tDLBCL, and cDLBCL/FL). The effect of DH on survival was then analyzed in two subgroups: (1) dDLBCL and (2) tDLBCL + cDLBCL/FL. PFS and OS were significantly shorter in lymphomas with DH in each of these two subgroups. We conclude that DH status drives outcomes in all DLBCLs, regardless of their transformation status.

Concurrent Mutations in ATM and Genes Associated with Common γ Chain Signaling in Peripheral T Cell Lymphoma.

Peripheral T cell lymphoma (PTCL) is a heterogeneous malignancy with poor response to current therapeutic strategies and incompletely characterized genetics. We conducted whole exome sequencing of matched PTCL and non-malignant samples from 12 patients, spanning 8 subtypes, to identify potential oncogenic mutations in PTCL. Analysis of the mutations identified using computational algorithms, CHASM, PolyPhen2, PROVEAN, and MutationAssessor to predict the impact of these mutations on protein function and PTCL tumorigenesis, revealed 104 somatic mutations that were selected as high impact by all four algorithms. Our analysis identified recurrent somatic missense or nonsense mutations in 70 genes, 9 of which contained mutations predicted significant by all 4 algorithms: ATM, RUNX1T1, WDR17, NTRK3, TP53, TRMT12, CACNA2D1, INTS8, and KCNH8. We observed somatic mutations in ATM (ataxia telangiectasia-mutated) in 5 out of the 12 samples and mutations in the common gamma chain (γc) signaling pathway (JAK3, IL2RG, STAT5B) in 3 samples, all of which also harbored mutations in ATM. Our findings contribute insights into the genetics of PTCL and suggest a relationship between γc signaling and ATM in T cell malignancy.