Rosai–Dorfman disease is a histiocytic disorder with a poorly defined pathogenesis. Recent molecular studies have revealed recurrent mutations involving genes in the MAPK/ERK pathway in Langerhans cell histiocytosis and Erdheim–Chester disease. However, cases of Rosai–Dorfman disease have rarely been assessed. We performed next-generation sequencing to assess 134 genes on 21 cases of Rosai–Dorfman disease, including 13 women and 8 men with a median age of 43 years (range, 3–82). In all, 13 had extranodal, 5 had nodal, and 3 had coexistent nodal and extranodal disease. The head and neck region was the most common area involved (n=7). Mutation analysis detected point mutations in 7 (33%) cases, including KRAS (n=4) and MAP2K1 (n=3). No mutations were identified in ARAF, BRAF, PIK3CA, or any other genes assessed. Immunohistochemistry demonstrated p-ERK overexpression in 3 cases, all harboring MAP2K1 mutations. Patients carrying mutated genes were younger (median age, 10 vs 53 years, P=0.0347) with more pediatric patients (4/7 vs 1/14, P=0.0251). The presence of mutations correlated with location being more common in the head and neck region; 6/7 (86%) mutated vs 1/14 (7%) unmutated cases (P=0.0009). All 5 (100%) mutated cases with available staging information had a multifocal presentation, whereas only 3/11 (27%) unmutated patients had multifocal disease (P=0.0256). Treatment information was available in 10 patients, including radical resection (n=4), resection and radiation (n=3), and cladribine-based chemotherapy (n=3). With a median follow-up of 84 months (range, 7–352), 7 remained in clinical remission and 3 had persistent disease. No correlation between mutation status and clinical outcome was noted. In summary, we detected mutually exclusive KRAS and MAP2K1 mutations in one-third of cases of Rosai–Dorfman disease suggesting this subgroup are clonal and involve activation of MAPK/ERK pathway. Our data contribute to the understanding of the biology of Rosai–Dorfman disease and point to potential diagnostic and therapeutic targets.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is uncommon in the United States. We report 73 patients with ENKTL, including 49 men and 24 women (median age, 46 y). Sixty-three patients had nasal/upper aerodigestive tract disease; 10 had extranasal disease involving skin, small intestine, epiglottis, testis, adrenal glands, kidney, and breast. Complete staging data were available for 68 patients: 44 stage I/II and 24 stage IV. Fifteen of 69 (22%) had lymphadenopathy and 10/63 had bone marrow involvement. Histologically, 67/73 (92%) showed necrosis, and 48/70 (69%) had an angiocentric/angiodestructive growth pattern. The neoplastic cells showed a wide spectrum: medium sized (n=34), mixed small and large (n=21), large (n=13), and small (n=5). In situ hybridization for Epstein-Barr virus–encoded small RNA was positive in every case. Immunohistochemical studies showed expression of cytotoxic markers (100%), T-bet (96%), CD2 (96%), CD3 (93%), CD56 (90%), and ETS-1 (64%). Ki-67 was ≥60% in 46% cases. Therapy was known for 64 patients; 14 received only chemotherapy, 8 radiation alone, and 42 received combined radiation and chemotherapy. Median survival was 4.2 years, and 5-year overall survival was 46% (median follow-up, 3.8 y). Extranasal disease, high International Prognostic Index score, and high proliferation rate correlated with poorer prognosis. We conclude that ENKTL cases in the United States are similar to those reported in Asia and other countries. Absence of the angiocentric/angiodestructive pattern and presence of lymphadenopathy, features underemphasized in the literature, occurred in appreciable subsets of patients. The International Prognostic Index score, anatomic site of disease, and proliferation rate had prognostic value in this patient cohort.

BACKGROUND: Isolated isochromosome (17q) is a rare cytogenetic abnormality in Philadelphia chromosome‐negative myeloid neoplasms, usually myelodysplastic and/or myeloproliferative neoplasms (MDS/MPN). De novo acute myeloid leukemia (AML) with isochromosome 17q has rarely been reported. The frequency of genetic mutations is unknown.METHODS: The authors assessed clinicopathologic, immunophenotypic, and molecular genetic features of 22 myeloid neoplasms with isolated isochromosome 17q.RESULTS: Fourteen patients presented as MDS/MPN; 8 as de novo AML. Most presented with leukocytosis, anemia, thrombocytopenia, and splenomegaly. Morphologically, all showed myelodysplastic and myeloproliferative features, including pseudo‐Pelger‐Huet‐like neutrophils, micromegakaryocytic hyperplasia, hypercellularity, fibrosis, and osteosclerosis. Blasts were increased (median, 40% in de novo AML; 9% in MDS/MPN). Immunohistochemical assessment of proliferation and apoptosis rates in AML were similar to a matched group without isochromosome 17q. In most patients, isochromosome 17q occurred at time of blast transformation or disease progression. DNA sequencing revealed no mutation in the uninvolvedTP53allele. Mutational analyses showed rare mutations inNRAS(3 of 10),FLT3(2 of 16), andJAK2(1 of 18), and no mutations inNPM1(0 of 15),KIT(0 of 4), andCEBPA(0 of 4). The median overall survival was 14.5 months for de novo AML, and 11.0 months for MDS/MPN. With a median follow‐up of 8.5 months (range, 1.5‐107 months), 15 died of disease, 6 had persistent disease, and 1 was in remission after bone marrow transplantation.CONCLUSIONS: The authors conclude that myeloid neoplasms with isolated isochromosome 17q represent a distinct clinicopathologic entity with myelodysplastic and myeloproliferative features, high risk of leukemic transformation, and wild‐typeTP53. Cancer 2011;. © 2011 American Cancer Society.

Acute myeloid leukemia (AML) with ≥2% plasmacytoid dendritic cells (pDC) has been recently described as AML with pDC differentiation (pDC-AML) characterized by pDC expansion with frequent RUNX1 mutations. In this study, we investigated a cohort of 53 pDC-AML cases representing about 3% of all AML cases. We characterized their immunophenotype and genetic profiles and compared these findings with blastic plasmacytoid dendritic cell neoplasm (BPDCN). pDC-differentiation/expansion was preferentially observed in AML with an immature myeloid or myelomonocytic immunophenotype, where myeloblasts were frequently positive for CD34 (98%), CD117 (94%), HLA-DR (100%) and TdT (79%), with increased CD123 (89%) expression. The median number of pDCs in pDC-AML was 6.6% (range, 2% to 26.3%) and their immunophenotype reminiscent of pDCs in early or intermediate stages of differentiation. The immunophenotype of pDCs in pDC-AML was different from BPDCN (n = 39), with major disparities in CD34 (96% vs. 0%), CD56 (8% vs. 97%) and TCL1 (12% vs. 98%) and significant differences in frequency of CD4, CD13, CD22, CD25, CD36, CD38, CD117 and CD303 expression. At the molecular level, the genetic landscapes of pDC-AML and BPDCN also differ, with RUNX1 mutations detected in 64% of pDC-AML versus 2% of BPDCN. Disparities in TET2 (21% vs. 56%), FLT3 (23% vs. 0%), DNMT3A (32% vs. 10%) and ZRSR2 (2% vs. 16%) (all p < 0.05) were also detected. The distinct immunophenotypic and mutation profiles of pDC-AML and BPDCN indicate that the neoplastic pDCs in pDC-AML and BPDCN derived from different subsets of pDC precursors.