Two myeloid leukemia cases with rare FLT3 fusions.

Genetic rearrangements involving FLT3 are rare and only recently have been detected in myeloid/lymphoid neoplasms associated with eosinophilia (MLN-eos) and chronic myeloproliferative disorders. Here we report two cases with FLT3 fusions in patients demonstrating mixed features of myelodysplastic/myeloproliferative neoplasms. In the first case, FLT3 was fused with a new fusion partner MYO18A in a patient with marrow features most consistent with atypical chronic myeloid leukemia; the second case involving ETV6-FLT3 fusion was observed in a case with bone marrow features most consistent with chronic myelomonocytic leukemia. Notably, we observed that samples from both patients demonstrated FLT3 inhibitor (quizartinib and sorafenib) sensitivity in ex vivo drug screening assay.

DNMT3A co-mutation is required for FLT3-ITD as an adverse prognostic indicator in intermediate-risk cytogenetic group AML.

This single institution cohort study of 132 AML patients investigated the clinical implications of co-mutations detected with a 42-gene NGS panel. In the intermediate-risk cytogenetic group, FLT3-ITD is an adverse prognostic indicator only in the presence of a DNMT3A co-mutation, regardless of NPM1 mutation status. In the absence of a concomitant DNMT3A mutation, there was no significant difference in overall survival between FLT3-ITD positive and FLT3-ITD negative patients. Furthermore, mutation analysis on post-induction specimens showed that residual FLT3-ITD and/or DNMT3A mutations were associated with a high frequency of therapy resistance or relapse in AML. While FLT3-ITD positive patients are currently considered high risk, incorporation of DNMT3A mutation status may be needed to refine prognostication and guide clinical management in AML. Multi-gene mutation testing is essential to provide novel insights related to diagnostic and prognostic information.

The Prognostic Significance of c-MET and EGFR Overexpression in Resected Gastric Adenocarcinomas.

OBJECTIVES: Epidermal growth factor receptor (EGFR) and c-MET are tyrosine kinase growth factor receptors implicated in gastric cancer (GC), and their pathways appear to be interdependent. The aim of this study was to investigate the prognostic value of EGFR and c-MET protein overexpression by immunohistochemistry in Canadian patients with resected GC and correlate it with clinicopathologic characteristics and overall survival (OS). MATERIALS AND METHODS: Tissue microarray blocks were constructed from 120 resected GCs stained with EGFR and c-MET and scored semiquantitatively (0 to 3+). Each receptor's expression was compared with clinicopathologic characteristics and survival. Descriptive statistics, Kaplan-Meyer, and Cox regression were used for statistical analyses. RESULTS: Of the 113 interpretable cases, overexpression of EGFR and c-MET was noted in 17 (15%) and 65 (57%), respectively; coexpression of EGFR and c-MET was observed in 12 (10%) of GC. EGFR and c-MET overexpression correlated with poor OS: median 13 versus 30 months in EGFR positive versus negative GC (hazard ratio [HR]=1.67, P=0.11); 27 versus 49 months in c-MET positive versus negative GC (HR=1.17, P=0.49), respectively. GC coexpressing EGFR and c-MET was significantly correlated with poor survival: 12 versus 29 months in double-positive versus rest of tumors both in univariate (HR=2.62, P=0.003) and multivariate analyses (HR=2.58, P=0.01). CONCLUSIONS: This study describes the prevalence and prognostic value of EGFR and c-MET in a Canadian population of patients undergoing curative intent resection for GC. Both c-MET and EGFR overexpression trended toward poor OS, but only the group with EGFR+/c-MET+ GC reached statistical significance on multivariate analysis.

Squamous cell carcinomas of the anterior oral cavity are commonly associated with simplex (or differentiated) oral intraepithelial neoplasia: clinical and pathologic significance.

INTRODUCTION: We investigated the occurrence of differentiated oral intraepithelial neoplasia (DOIN) that met the criteria for differentiated intravulvar neoplasia, associated with invasive squamous cell carcinoma (SCC) of the anterior oral cavity, and its clinicopathologic significance. MATERIALS AND METHODS: Sixty-nine consecutive cases of SCC of the anterior oral cavity were categorized into 2 groups: group A comprised SCC associated with DOIN; Group B consisted of cases associated with classical SCC in situ. RESULTS: Fifty-five cases (80%) were classified as group A, or DOIN lesions, with only 14 (20%) as group B. All cases were associated with invasive SCC, except 2 cases in group B. Squamous epithelium continuous or adjacent to invasive SCC displayed consistent changes in the parabasal and basal layers with (1) cytologic atypia with proliferation of parabasal cells in downward expansion causing reactive proliferation of the basal cell layer in early stage and invading the basal layer in late stage, (2) disordered nuclear/cytoplasmic arrangement, and (3) a "cobblestone" appearance characterized by prominent intercellular spaces and cytoplasmic density involving the entire cell (dyskeratosis) of the parabasal layer. p53 and Ki67 immunostaining revealed linear reactivity mainly in the parabasal layer. CONCLUSIONS: DOIN lesions are frequently associated with invasive SCC of anterior oral cavity. Due to the subtle histopathologic changes, DOIN lesions pose potential diagnostic difficulty with differentiation from mild dysplasia or reactive atypia.