Myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDS) are a group of conditions characterized by abnormal production of blood cells in the bone marrow. MPNs typically involve an increased number of blood cells, while dysfunctional blood cells are typically seen in MDS (Khoury et al., 2022). While MDS and MPNs generally have distinct clinical and laboratory features, there is overlap in some patients. For example, abnormal findings on a complete blood count might include leukocytosis, anemia, and thrombocytopenia. Diagnosing specific types of MDS, MPNs, and MDS/MPN overlap conditions can be challenging given overlapping clinical features and nebulous boundaries between exact diagnoses. Molecular testing has particular relevance for this group of conditions as it can be helpful in the initial diagnosis as well as prognosis and treatment planning (Prakash et al., 2023; Arber et al., 2022; Khoury et al., 2022; Smith et al., 2019; Elmariah and DeZern, 2019). 

Atypical chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML) are hematopoietic neoplasms that are characterized by a combination of myelodysplastic and myeloproliferative features. Unlike typical chronic myeloid leukemia, aCML and CMML do not exhibit the common BCR::ABL1 translocation. aCML and CMML often have overlapping histopathological features and clinical presentation, and can be difficult to differentiate (Smith et al., 2019). According to classification criteria from the World Health Organization (WHO), molecular testing for genes associated with other MPNs can have utility to help rule out other diagnoses. For example, the presence of typical MPN driver pathogenic/likely pathogenic (P/LP) variants (JAK2, CALR, and MPL) can exclude a diagnosis of aCML, but ASXL1, SETBP1, or ETNK1 P/LP variants support a potential diagnosis of aCML (Patnaik and Tefferi, 2023; Wong and Pozdnyakova, 2019). TET2, SRSF2, ASXL1, EZH2, and SETBP1 are also frequently associated with CMML and have been used to confirm this diagnosis or predict prognosis (Elmariah and DeZern, 2019). However, caution should be taken in the interpretation of genetic results in this group of conditions, given the potential for some common P/LP variants to be age-related or present only in subclones (Tanaka and Bejar, 2019). Importantly, this group of conditions can also progress or transition into other types of hematologic malignancies via clonal evolution. Thus, regular follow-up and additional genetic testing may be necessary for these patients (Faisal et al., 2019). Hematopoietic stem cell transplant is the only curative therapy for these conditions, though this is not recommended for patients deemed to be at low risk for progression (Khoury et al., 2022).

Refractory Anemia with Ring Sideroblasts and Thrombocytosis (RARS-T) is a form of MDS/MPN overlap that is characterized in over 80% of cases by the presence of an SF3B1 P/LP variant. P/LP variants are also frequently observed, similar to the P/LP variant profile of essential thrombocythemia (Tanaka and Bejar, 2019). Cytogenetic abnormalities are uncommon. RARS-T tends to have a good prognosis overall, and most patients demonstrate excellent response to lenalidomide therapy (Smith et al., 2019).

Systemic Mastocytosis

Mast cell activation disease (MCAD) is a group of disorders characterized by the accumulation of genetically altered mast cells and/or abnormal release of mast cell mediators that affect the function of multiple organ systems (Molderings et al., 2011). Mast cell disease was first classified as a myeloproliferative neoplasm (MPN) as part of the 2008 World Health Organization (WHO) criteria, but is no longer considered a subgroup of the MPNs due to its unique clinical and pathologic features (Khoury et al., 2022). Traditional subclasses of MCAD include mass cell activation syndrome (MCAS), systemic mastocytosis (SM), and mast cell leukemia (MCL). Classifications of mastocytosis include cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma (MCS) (Leguit et al., 2023; Arber et al., 2022; Khoury et al., 2022).

SM is characterized by the proliferation and hyperactivation of clonal mast cells (Khoury et al., 2022). Individuals with SM can have various clinical manifestations of the condition including cutaneous lesions, gastrointestinal symptoms, osteoporosis, anaphylaxis, involvement of the bone marrow with cytopenias, and more rarely, other organs, by infiltrating neoplastic mast cells (Khoury et al., 2022). In 2022, the WHO updated the diagnostic criteria for SM (Khoury et al., 2022). The criteria include a combination of major and minor features; one minor criteria is the identification of a pathogenic variant of the codon 816 of cKIT gene (in most cases D816V) (Khoury et al., 2022). A diagnosis of SM is established when an individual has the major criterion and one minor criterion, or three minor criteria (Khoury et al., 2022). Molecular testing for cKIT (preferably on bone marrow) thus has clinical utility. Furthermore, other molecular biomarkers (such as SRSF2, ASXL1, RUNX1, and FIP1L1::PDGFRA fusion) have been shown to be useful in confirming diagnosis and/or determining prognosis (Khoury et al., 2022; Jawhar et al., 2016).