Blasts With Cup‐Like Nuclear Morphology: When the First Impression Could Be Misleading

A 53-year-old man was referred to the hematology department for evaluation of newly diagnosed pancytopenia. He was undergoing maintenance therapy with lenalidomide following autologous stem cell transplantation (ASCT) for multiple myeloma (MM), diagnosed 4 years earlier. Bone marrow aspiration revealed 90% blasts, some with cup-like nuclear morphology, a feature classically associated with certain acute myeloid leukemia (AML) harboring NPM1 and/or FLT3 mutations (Figure 1A, May–Grunwald–Giemsa stain, original magnification ×1000). However, immunophenotyping demonstrated a B-cell precursor acute lymphoblastic leukemia (B-ALL) phenotype. The blasts were CD19+/CD10partial/CD20−/CD22+/CD33+/CD34+/cytoplasmic CD79a+/TdT+/cytoplasmic IgM+/MPO− (Figure 1C). No monoclonal plasma cells were detected, and kappa/lambda light chains were assessed only by flow cytometry, where they were detected in a few polyclonal lymphocytes but not on the blasts. Molecular analyses identified a complete deletion of the CDKN2A-CDKN2B locus, with no mutations detected in NPM1 or FLT3. Cytogenetic testing revealed a normal karyotype, while the patient's initial MM was characterized by hypotriploidy with gains of chromosomes 3, 5, 6, 7, 9, 11, 15, 17, 19, and 20. Immunohistochemistry (IHC) demonstrated diffuse cytoplasmic IgM positivity (Figure 1B, IHC, original magnification ×1000). This finding could raise a differential diagnosis with Dutcher bodies, which are cytoplasmic immunoglobulin inclusions typically found in plasma cells and mature B cells. However, the diffuse IgM staining pattern observed in our case does not fit with Dutcher bodies, which appear as well-defined, localized inclusions that stain strongly positive. Instead, the perinuclear clearing observed could suggest unstained Golgi zones. The patient achieved complete remission after 2 months of B-ALL-directed chemotherapy, followed by allogeneic bone marrow transplantation. Cup-like nuclear morphology has been well-described in AML, particularly in cases with NPM1 and/or FLT3 mutations, but has been rarely reported in B-ALL. Few cases in the literature describe B-ALL with similar nuclear features, including cases associated with IGH::DUX4 fusion, BCR-ABL1 translocation, or t(4;11) rearrangement. Notably, our case lacked these alterations, suggesting that cup-like nuclear morphology in B-ALL may not be restricted to a single molecular mechanism. This case also highlights the role of genetic instability in secondary hematologic malignancies. While no shared cytogenetic abnormalities were identified between the initial multiple myeloma and the secondary leukemia, the presence of hypotriploidy in the MM clone and the occurrence of a CDKN2A-CDKN2B deletion in the B-ALL clone suggest a clonal evolution process. Lenalidomide exposure and prior ASCT have been associated with an increased risk of secondary hematologic neoplasms, including B-ALL. This case underscores the importance of molecular surveillance in long-term MM survivors, as well as the need for comprehensive immunophenotypic and genetic analyses in secondary leukemias to distinguish B-ALL from AML in cases with overlapping morphological features. D.N. wrote the manuscript. M.V. provided care for the patient and reviewed the manuscript. H.F. designed and supervised the project. H.F., D.P., and M.F. were involved in cytological and immunophenotyping analysis and results interpretation. A.-L.T. performed histological and immunohistochemical analysis and results interpretation. P.H. performed molecular analysis and results interpretation. All authors discussed the results and contributed to the final manuscript. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. Data are available upon request from the corresponding author at [email protected].