Myelodysplastic/Myeloproliferative Neoplasm (MDS/MPN) with Isolated Isochromosome 17q [i(17q)]: An Aggressive Entity with Prominent Multilineage Dysplasia and Wild Type NPM1.
Rashmi Kanagal Shamannna, CCameron Yin, Gary Lu, Martin Nguyen, Daniela Hoehn, Guillermo Garcia-Manero, Saroj Vadhan-Raj, L Jeffrey Medeiros, Carlos Bueso-Ramos. UT MD Anderson Cancer Center, Houston
Background: Isolated i(17q) is a rare cytogenetic abnormality in myeloid neoplasms with distinctive clinicopathologic characteristics. It is an MDS/MPN characterized by hyper-condensed pseudo-Pelger-Huët (PPH) nuclei in neutrophils and a high rate of progression to acute myeloid leukemia. However, frequency of genetic mutations in NPM1, FLT3, RAS, and JAK2 is unknown. We report clinicopathologic and molecular genetic features of 19 cases of MDS/MPN with isolated i(17q).
Design: We searched pathology database for myeloid neoplasms with isolated i(17q). No case was positive for BCR-ABL1. Clinical data was obtained and histopathological slides were reviewed. Immunohistochemical stains for p53, Ki67 and caspase 3 were done on bone marrow (BM) biopsies. Genomic DNA from BM aspirates was amplified by PCR followed by mutational screening for NPM1 (exon 12), FLT3 (direct sequencing), JAK2V617F (pyrosequencing) and RAS (capillary electrophoresis).
Results: A total of 19 patients with isolated i(17q) myeloid neoplasm were identified. There were 12 women and 7 men, median age of 62 years (24-90). Initial blood counts revealed median hemoglobin level of 10.3 g/dL, white cell count of 5.4 and platelet count of 47. Nine patients had splenomegaly. Morphologically, all cases showed features of MDS/MPN. BM was hypercellular (median, 90%) with a median blast count of 18% at presentation. There was significant dysplasia in granulocytes including hyper-condensed PPH neutrophils in 14/15 cases. Megakaryocytes were small and monolobated in 13/14. Erythroid dysplasia was present in 8/16. P53 immunostain was positive in all cases tested. Ki67 revealed a median MIB1 proliferative index of 25% and caspase 3 showed 4% apoptotic cells. Mutational analysis showed no evidence of NPM1 (n=16), JAK2 V617F (n=8) or RAS (n=8) mutations. 2 of 11 (18%) cases had FLT3 mutations (1 ITD and 1 ITD with D835 point mutation). Survival data was available for 15 patients. Median overall survival was 7.43 months. 13 patients died, 3 are alive in remission, 1 was lost for follow-up.
Conclusions: MDS/MPN with isolated i(17q) is a distinctive clinicopathologic entity characterized by prominent multilineage dysplasia and poor prognosis. Strong p53 expression in conjunction with a low proliferation and brisk apoptosis implies that p53 on the normal allele is functional. Unmutated NPM1 may contribute to p53 stabilization and activation. These neoplasms are uncommonly associated with FLT3 mutations. NPM1, JAK2V617F and RAS mutations are absent or rare.
Monday, February 28, 2011 1:00 PM
Poster Session II # 175, Monday Afternoon