#00066498

A 55-year-old male with a history of chronic lymphocytic leukemia (CLL), for which only IGVH mutation status (unmutated) was assessed at diagnosis, status post obinutuzumab/venetoclax therapy, presented with rapidly progressive generalized lymphadenopathy and new-onset leukocytosis. Peripheral blood smear demonstrated numerous large atypical cells (up to 56%) with irregular nuclear contours, open vesicular chromatin, prominent nucleoli, and deeply basophilic cytoplasm, morphology consistent with centroblasts/immunoblasts rather than prolymphocytes. 

Right inguinal lymph node core biopsy showed sheets of medium-to-large lymphoid cells, morphologically consistent with DLBCL. Immunohistochemistry revealed positivity for CD79a, PAX5, MYC, and BCL2, with loss of CD20; CD10, BCL6, CD30, MUM1, and Cyclin D1 were negative. Ki-67 proliferation index was 60–70%. Bone marrow biopsy demonstrated a diffuse and interstitial infiltrate of atypical B cells comprising approximately 40–50% of marrow cellularity (CD79a/PAX5), with reduced trilineage hematopoiesis. Flow cytometry identified an abnormal B-cell population (69.55% of events) expressing CD5, CD19, CD20, CD49d, CD200, FMC7, and dim surface kappa light chain restriction, consistent with the patient's known CD5+ B-cell lymphoma. This immunophenotype—including dim kappa restriction—was concordant between the peripheral blood and lymph node, atypical for B-prolymphocytic leukemia (B-PLL), which characteristically shows bright surface immunoglobulin, and instead supporting a shared clonal origin. Together with the centroblast/immunoblast-like morphology, these findings support the circulating large cells in the peripheral blood as the leukemic/circulating phase of the same DLBCL clone identified in the lymph node, representing an unusual leukemic dissemination of Richter transformation, rather than a distinct B-PLL-type transformation.

At transformation, FISH was negative for TP53 deletion, ATM deletion, 13q14 deletion, and trisomy 12; CCND1::IGH was negative, excluding mantle cell lymphoma, while IGH gain (favor trisomy 14) was identified. NGS revealed an FBXW7 mutation (Tier II, VAF 33.66%) and a BCL2 variant of undetermined significance (Tier III, VAF 31.1%). Bone marrow chromosome analysis showed a complex karyotype (17/20 cells) with additional material on 5p and 15q, a derivative chromosome 10 from an unbalanced t(1;10)(q25;q22), and a pericentric inversion of chromosome 12. FISH/NGS/karyotype were not performed at baseline CLL diagnosis.

Richter transformation occurs in 2–10% of CLL patients and carries a poor prognosis. Although bone marrow and tissue involvement by transformed large cells is well described, abundant circulating transformed blasts in the peripheral blood are distinctly uncommon. This case lacked TP53 disruption, the alteration most classically linked to Richter transformation, but demonstrated a complex karyotype and an FBXW7 mutation—FBXW7 regulates NOTCH1 stability, and NOTCH1 pathway activation is a well-established mechanism of Richter transformation, supporting a TP53-independent, NOTCH1-related route. Recognition of these large atypical cells on routine peripheral smear, particularly in a CLL patient with new lymphadenopathy, is a critical morphologic clue that should prompt urgent tissue biopsy and immunophenotyping.