ABSTRACT
DNMT3A mutations play a prominent role in clonal hematopoiesis and myeloid neoplasms with arginine (R)882 as a hotspot, however the clinical implications of R882 vs. non-R882 mutations in myeloid neoplasms like myelodysplastic syndrome (MDS) is unclear. By data mining with publicly accessible cancer genomics databases and a clinical genomic database from a tertiary medical institution, DNMT3A R882 mutations were found to be enriched in AML (53% of all DNMT3A mutations) but decreased in frequency in clonal hematopoiesis of indeterminate potential (CHIP) (10.6%) or other myeloid neoplasms including MDS (27%) (p<.001). Next with the largest cohort of patients with DNMT3A R882 mutant MDS known to date from multiple institutions, DNMT3A R882 mutant MDS cases were shown to have more severe leukopenia, enriched SRSF2 and IDH2 mutations, increased cases with excess blasts (47% vs 22.5%, p=.004), markedly increased risk of AML transformation (25.8%, vs. 1.7%, p=.0001) and a worse progression-free survival (PFS) (median 20.3, vs. >50 months, p=.009) than non-R882 mutant MDS cases. DNMT3A R882 mutation is an independent risk factor for worse PFS, and importantly the differences in the risk of AML transformation between R882 vs. non-R882 mutant patients cannot be explained by different treatment approaches. Interestingly the higher risk of AML transformation and the worse PFS in DNMT3A R882 mutant MDS cases are mitigated by coexisting SF3B1 or SRSF2 mutations. The unique clinicopathologic features of DNMT3A R882 mutant MDS shed light on the prognostic and therapeutic implications of DNMT3A R882 mutations.
ABSTRACT
OBJECTIVE: The aim of this is to provide an updated review of the literature and to report our institutional experience with this rare gynecologic malignancy. METHODS: The medical records of patients with diagnosis of non-Hodgkin lymphoma of the female genital tract from 1980 to 2013 at the Yale-New Haven Hospital were reviewed retrospectively. Histological classification and staging were determined by the World Health Organization and Ann Arbor systems, respectively. Kaplan-Meier was used to calculate the survival. RESULTS: There were 36 patients with diagnosis of non-Hodgkin lymphoma of the female genital tract and followed for a median of 61 months (0-361 months). The median age of diagnosis was 44 years (19-87 years), and 76% (n = 28) were classified as stage IV.Of these, 4 patients were asymptomatic on presentation, and 13 were identified incidentally during surgery/radiography (n = 9), on prenatal ultrasound (n = 1), and on Papanicolaou test (n = 3). The location of the disease included the ovary (n = 6), uterine corpus and cervix (n= 9), vagina (n = 1), a pelvic mass (n = 7), isolated pelvic/para-aortic lymph nodes (n = 3), and/or multiple sites (n = 9). There were 6 cases that were concomitant with other gynecologic malignancies.Diffuse large B-cell lymphoma (n= 18) was the most common histologic type. A total of 28 patients underwent surgery. Combination chemotherapy was used in 34 patients, with concomitant radiation therapy in 7 and stem cell transplantation in 3. A total of 5 patients had recurrent disease.The overall median survival from the diagnosis of lymphoma was 70 months (0.3-361 months) with a 91% 1-year survival, 86% 5-year survival, and a 79% 10-year survival. CONCLUSIONS: Our report is the largest published single-institution experience of this disease. It demonstrates a more favorable prognosis and proposes that with early diagnosis and appropriate therapy, radical gynecologic surgery can be avoided.
