A subset of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) show complex karyotype (CK), and these cases include a relatively high proportion of cases of therapy-related myeloid neoplasms and TP53 mutations. We aimed to evaluate the clinicopathologic features of outcome of 299 AML and MDS patients with CK collected from multiple academic institutions. Mutations were present in 287 patients (96%), and the most common mutation detected was in TP53 gene (247, 83%). A higher frequency of TP53 mutations was present in therapy-related cases (P = .008), with a trend for worse overall survival (OS) in therapy-related patients as compared with de novo disease (P = .08) and within the therapy-related group; the presence of TP53 mutation strongly predicted for worse outcome (P = .0017). However, there was no difference in survival between CK patients based on categorization of AML vs MDS (P = .96) or presence of absence of circulating blasts ≥1% (P = .52). TP53-mutated patients presented with older age (P = .06) and lower hemoglobin levels (P = .004) and marrow blast counts (P = .02) compared with those with CK lacking TP53 mutation. Multivariable analysis identified presence of multihit TP53 mutation as strongest predictor of worse outcome, whereas neither a diagnosis of AML vs MDS nor therapy-relatedness independently influenced OS. Our findings suggest that among patients with MDS and AML, the presence of TP53 mutation (in particular multihit TP53 mutation) in the context of CK identifies a homogeneously aggressive disease, irrespective of the blast count at presentation or therapy-relatedness. The current classification of these cases into different disease categories artificially separates a single biologic disease entity.

Acute myeloid leukemia (AML) is a neoplasm of immature myeloid cells and is associated with a wide variety of clinical presentations, morphological features, immunophenotypes, and genetic findings. Recent advances in identification of cytogenetic abnormalities and mutations have provided novel insights into the pathogenesis of AML. Based on the above‐mentioned parameters, the World Health Organization (WHO) classified AML into 25 subtypes, including 2 provisional entities, which differ in prognosis and treatment. In addition, certain mutations are associated with germline predisposition and increase the risk of inherited AML, which warrants family screening. Therefore, precise diagnosis and classification of AML are the most important steps in patient management. Both these steps require incorporation of history, clinical presentation, and laboratory results with studies performed by a pathologist. Pathologist‐initiated studies include morphologic evaluation on the bone marrow aspirate and/or core biopsy, immunophenotyping by flow cytometry and/or immunohistochemistry, cytogenetic analysis by karyotyping and/or fluorescence in situ hybridization, and molecular testing using gene panels and/or next‐generation sequencing. A similar approach is employed during follow‐up of patients after beginning treatment. Here, we describe in detail the various aspects of the workup, including purpose, limitations, and practice guidelines for the different studies. The process of choosing appropriate materials for the different studies is also addressed. We also provide an algorithm for the workup and risk stratification of AML based on guidelines recommended by the WHO, College of American Pathologists, National Comprehensive Cancer Network, American Society of Clinical Oncology, European Society of Medical Oncology, and the European LeukemiaNet.

Key Points: Nonacute NPM1-mutated myeloid neoplasms are biologically distinct from nonacute NPM1 wild-type myeloid neoplasms. Nonacute NPM1-mutated myeloid neoplasms are associated with poorer survival compared with NPM1-mutated AML and NPM1-WT myeloid neoplasms.

Objectives: The 2008 World Health Organization (WHO) classification system grouped bilineal and biphenotypic acute leukemias together under a new heading of mixed phenotype acute leukemia (MPAL). The lineage-specific marker criteria have also changed for a diagnosis of MPAL. The goal of this study was to characterize clinical significance of this new group. Methods: Sixty-one patients diagnosed with MPAL using either European Group for the Immunological Classification of Leukaemias (EGIL) criteria or 2008 WHO criteria were included in this study. Results: Sixteen patients (26%) diagnosed with acute biphenotypic leukemia using EGIL criteria did not fulfill 2008 WHO criteria for MPAL. Cytogenetic data were available for 32 patients, and the most common abnormality was t(9;22) (five of 32 cases). Clinical outcome data suggested that younger patients with MPAL (≤21 years) had better overall survival (OS) in both the EGIL and WHO groups (EGIL, P = .0403; WHO, P = .0601). Compared with 177 patients with acute myeloid leukemia (AML), MPAL patients had better OS (P = .0003) and progression-free survival (P = .0001). However, no difference in OS between MPAL and 387 patients with acute lymphoblastic leukemia was present (P = .599). Conclusions: As defined by the 2008 WHO classification, fewer patients are now classified as having MPAL than with the EGIL criteria. In this study, patients with MPAL have a better clinical outcome compared with patients with AML.

Loss of the Y chromosome (LOY) is one of the most common somatic genomic alterations in hematopoietic cells in men. However, due to the high prevalence of LOY as the sole cytogenetic finding in the healthy older population, differentiating isolated LOY associated with clonal hematologic processes from aging-associated mosaicism can be difficult in the absence of definitive morphological features of disease. In the past, various investigators have proposed that a high percentage of metaphases with LOY is more likely to represent expansion of a clonal myeloid disease-associated population. It is unknown whether the proportion of metaphases with LOY is associated with the incidence of myeloid neoplasia-associated genomic alterations. To address this question, we identified marrow samples with LOY as isolated cytogenetic finding and used targeted next generation sequencing-based molecular analysis to identify common myeloid neoplasia-associated somatic mutations. Among 73 patients with median age of 75 years (range 29-90), the percentage of metaphases with LOY was <25% in 23 patients, 25-49% in 10, 50-74% in 8 and ≥75% in 32. A threshold of ≥75% LOY was significantly associated with morphologic diagnosis of myeloid neoplasm (p = 0.004). Further, ≥75% LOY was associated with a higher lifetime incidence of diagnosis of myelodysplastic syndromes (MDS; p < 0.0001), and in multivariate analysis ≥75% LOY was a statistically significant independent predictor of myeloid neoplasia [OR 6.17; 95% CI = 2.15-17.68; p = 0.0007]. Higher LOY percentage (≥75%) was associated with greater likelihood of having somatic mutations (p = 0.0009) and a higher number of these mutations (p = 0.0002). Our findings indicate that ≥75% LOY in marrow is associated with increased likelihood of molecular alterations in genes commonly seen in myeloid neoplasia and with morphologic features of MDS. These observations suggest that ≥75% LOY in bone marrow should be considered an MDS-associated cytogenetic aberration.