Richter Transformation PDF

Richter transformation Supervised by: DR sadiq khalf Presented by: malak Abdullatif 2nd year hematopathology resident  Richter transformation (RT) its defined as a histologic transformation of CLL to an aggressive lymphoma ▪ Commonly to diffuse large B-cell lymphoma, ▪ and rarely to cla...

Richter transformation Supervised by: DR sadiq khalf Presented by: malak Abdullatif 2nd year hematopathology resident  Richter transformation (RT) its defined as a histologic transformation of CLL to an aggressive lymphoma ▪ Commonly to diffuse large B-cell lymphoma, ▪ and rarely to classical Hodgkin lymphoma ▪ very rarely to plasmablastic lymphoma or other form of lymphoma and leukemia Incidence: RT occurs in 2–10% of CLL patients usually during the disease course rather than at presentation RT presents as DLBCL-RT in ~90% Hodgkin lymphoma (HL-RT; ~10%) Very rarely other form of lymphoma or leukemia (3 cm on physical examination 2- Biological characteristics of the CLL -B –cell Genetic and molecular chracterestic CLL patients with leukemic B cells that are IGHV-unmutated are at an approximate 4-fold risk of RS relative to IGHV-mutated patients Shorter telomere length, which is a marker of genetic instability, is also associated with increased risk of RS  Phenotypic chracterestic - CD38, and CD49d status, have been found to be associated with risk of future RS Cytogenetic abnormalities such as del(11q22.3), del(17p13), del(15q21.3), del(9p21), have been also associated with RS Heritable germline polymorphisms in BCL2 , CD38 , have been reported to impart a higher risk for transformation.  CLINICAL PRESENTATION Onset of RT tends to be heralded by accelerated, pronounced increase in lymphadenopathy (often abdominal), splenomegaly, and B symptoms (fevers, night sweats, weight loss) extra nodal involvement may be present, especially in the gastrointestinal tract, bone marrow, central nervous system (CNS), or skin. In some cases, RT could present merely as an extra nodal mass  Signs and symptoms of extranodal involvement may manifest such as early satiety, gastrointestinal bleeding, rash, pathologic fractures, headache, blurred vision, or dyspnea. Physical examination may capture asymmetric and rapid growth of bulky lymph nodes (> 3 cm) detected by physical examination or imaging studies, splenomegaly, and/or hepatomegaly Diagnosis Lab finding CBC: Anemia thrombocytopenia 2 mg/L. elevated LDH >1.5 times the upper limit of normal paraproteinemia hypercalcemia These findings may also be associated with progression of disease, so that a proper diagnostic workup should be done. Tissue biopsy The current gold standard for diagnosis of RT is the biopsy of an affected lymph node or involved extra nodal site Since RT onset is usually neither disseminated nor simultaneous in all lymphatic regions the decision whether to biopsy patients with clinical suspicion of RT – as well as the choice of optimal site for biopsy – is aided by imaging studies with fluorodeoxyglucose (18FDG) positron emission tomography (PET)/computed tomography (CT) which will detect a relative increase in metabolic activity, expressed quantitatively as standardized uptake value (SUV). (SUV > 5.0) by PET/CT is an indication for tissue evaluation Whereas the absence of lesions detectable by 18FDG-PET is highly sensitive in excluding RS T. biopsy should be directed at the index lesion (ie, the lesion displaying the most avid 18FDG uptake at PET/CT). An excision biopsy is considered the gold standard for RS diagnosis because samples obtained with fine-needle aspiration may not be representative of the pathologic architecture of the tumor Histologic Variants of Richter Transformation 1-Diffuse large B-cell lymphoma DLBCL is the most frequent histologic variant of transformation in patients with CLL The development of DLBCL occurs 1.8–4.0 years from the time of initial CLL diagnosis and can arise before or after CLL therapy. Among patients with newly diagnosed CLL, the annual incidence rate of DLBCL is 0.5%; whereas among patients who have received treatment for CLL the annual incidence rate of DLBCL is ∼1% DLBCL may arise in any demographic subset of CLL patients, but is most common in men over 60 years of age. Pathologic features of RS-DLBCL Most cases of RS-DLBCL show diffuse effacement of lymph nodes or extra nodal sites by sheets of large cells with centroblastic morphology; a minority of cases have immunoblastic features. Mitotic figures and apoptotic bodies are usually frequent, and a starry-sky pattern and tumor necrosis are common Adherence to two WHO histopathological criteria is important : ▪ DLBCL-RT is typified by the presence of sheets of large. B-lymphoid cells with a nuclear size equal to or exceeding that of normal macrophage nuclei or more than twice the size of a normal lymphocyte; and ▪ these cells must show a diffuse growth pattern and not be present in small foci throughout the neoplasm. Typically, the neoplastic cells phenotypically are positive for the B-cell markers—CD19, CD20, CD22, and PAX5—as well as monotypic surface immunoglobulin light chain. CD38, ZAP70, and CD49d are often positive whereas CD5 and CD23 expression is retained to a varying extent 80% of RS-DLBCL have a non-germinal center B-cell-like (non-GCB) immunophenotype (negative for CD10 and positive for MUM1), 20% have a GCB immunophenotype (positive for CD10 and/or BCL6+, MUM1−) Other features often seen in RS-DLBCL include TP53 overexpression and a high (>70%) Ki-67 proliferation index. Epstein-Barr virus (EBV)-encoded RNA transcripts may be detected in some cases Diffuse large B cell lymphoma transformation of CLL/SLL. (A, B) CLL involving the bone marrow. (A) CLL with cytologically atypical morphology in a bone marrow aspirate smear with a population of small and medium-sized cells. (B) (B) Bone marrow space replaced by sheets of small lymphocytes. A proliferation center is present (C–F) Concurrent nasal mass biopsy involved by DLBCL. (C) Diffuse growth of large neoplastic lymphoid cells and a conspicuous starry sky pattern. (D) Neoplastic cells with immunoblast-like and centroblast-like morphology. (E) The neoplastic cells are positive for PAX5 and negative for CD5. (F) Ki-67 immunohistochemistry demonstrates a high proliferation rate. (A, wright-giemsa stain; B–D, hematoxylin-eosin; E and F, IHC with hematoxylin counterstain). Clonal relationship to underlying CLL: About 70–80% of RS-DLBCL cases are clonally related to the underlying CLL and can have similar unmutated or mutated (IGVH) sequences Commonly, RS-DLBCL arises from a dominant CLL clone after having acquired additional somatic mutations Patterns of clonal evolution in CLL In the linear model (A) of transformation transformation, more common among patients with RS-DLBCL, DLBCL originates directly from the major clone following the acquisition of additional genetic alterations. In this model, the DLBCL and CLL clones show similar IGVH mutation profiles. n the branched model (B), clones derive directly from a common precursor cell (CPC) by way of acquiring distinct genetic lesions. Note that both clones share a subset of alterations with the CPC and with each other in addition to harboring distinct genetic lesions. In both models, a minor subclone arising from the CPC and already equipped with transformation-specific gene signatures may be present at the time of diagnosis and may later declare itself as RT. Hodgkin lymphoma Less than 1% of patients with CLL develop Hodgkin lymphoma (RS-HL) Patients are typically in the seventh decade of life (range 30–88 years) when they undergo transformation to RS-HL and most are men. Hodgkin transformation is characterized by Hodgkin and Reed-Sternberg (HRS) cells in a polymorphous inflammatory background distinct from the CLL The inflammatory background consists of T-cells and histiocytes, with or without abundant eosinophils. Tumor necrosis is a common finding Any of the histologic subtypes of HL can be seen, with the mixed cellularity subtype being most common ✓By immunohistochemistry, HRS cells express CD30, CD15, and PAX5 (dim), and these cells are commonly positive for EBV ✓ HRS cells may be positive for CD20, usually with variable intensity, in 20–30% of cases. Hodgkin lymphoma transformation of CLL/SLL (A and B) Lymph node involved by CLL (dark areas) and Hodgkin lymphoma (light/pale areas) indicating transformation. (C) Low-grade component composed of small lymphocytes (D) with CD5 expression. (E) HRS cells in a polymorphous inflammatory background composed of T cells, histiocytes, and eosinophils. (F) HRS cells are CD30+. (A–C, E, hematoxylin-eosin; D and F, IHC with hematoxylin counterstain).  In about 80% of patients with RS-HL, the CLL cells have mutated IGVH. it has been demonstrated that similar VH gene rearrangements can be seen in HRS and CLL cells, implying that the two populations of cells were derived from a common precursor B-cell  Plasmablastic lymphoma Plasmablastic lymphoma (PBL) is an aggressive B-cell malignancy, thought to be related to DLBCL, in which the lymphoma cells exhibit morphologic and immunophenotypic features of plasma cell differentiation These neoplasms most commonly arise de novo in the setting of immunodeficiency, however, a few cases of plasmablastic lymphoma (RS-PBL) arising in patients with CLL has been reported Most patients who develop RS-PBL are men, 52–77 years of age. A serum or urine paraprotein can be detected in some patients In addition to typical plasmablastic features, residual CLL cells may be identified in some areas.  The neoplastic cells of RS-PBL often express CD38, ZAP-70, CD138, BLIMP1, IRF4/MUM1, and XBP1. CD5, CD20, PAX5, and IRF8 are commonly negative. Molecular studies have shown monoclonal IGH and MYC rearrangement The prognosis of patients with RS-PBL is grim. B-lymphoblastic leukemia/lymphoma ▪ B-lymphoblastic leukemia/lymphoma (B-LBL) is a neoplasm derived from progenitor B-lymphoid cells often involving bone marrow, peripheral blood, and less commonly lymph nodes ▪ Acute lymphoblastic transformation of CLL (RS-LBL) is rare, ▪ Most patients are men, with a reported age range of 42–76 years. ▪ The reported interval between CLL diagnosis and RS-LBL ranges from 2 months to 7 years; although simultaneous presentation of CLL and RS-LBL may occur RS-LBL is characterized by numerous lymphoblasts ,The blasts are intermediate size, with indented nuclei, fine chromatin, one or two small nucleoli, and scant cytoplasm The neoplastic cells express HLA-DR, surface Ig, pan-B cell markers, and TdT ; a TdT-negative case also has been reported. There is variable expression of CD5, CD10, CD22, and CD23  T-cell lymphomas Rarely patients with CLL develop T-cell lymphomas. In general, the relationship between CLL and these neoplasms is poorly understood Differential diagnosis: Accelerated/progressed CLL (a/pCLL), : Features expanded proliferation centers and increased mitotic activity but lacks diffuse sheets of large cells typical of RT. Pseudo-Richter: Seen after ibrutinib discontinuation; responds well to restarting therapy. Characterized by a high Ki-67 index and preserved CD5/LEF-1 expression. HSV Lymphadenitis: Mimics RT with necrosis and high proliferation rates but features viral inclusions. Diagnosed via immunohistochemistry and treated with antivirals. Other Lymphomas in CLL/SLL: Rare T-cell and B-cell lymphomas, such as mantle cell and marginal zone lymphomas, may coexist with CLL  Despite not falling into the category of RT, the existence of lymphomas with a tendency to develop in patients with CLL is well documented and can potentially mimic RT clinically Misclassification can affect treatment; expert hematopathology and advanced diagnostics (FISH, IHC) are essential  prognosis ▪ Prognosis different for each histological variant ▪ For DLBCL ,most important prognostic factor is the clonal relationship between the CLL and the DLBCL clones ▪ Despite similar clinical features at presentation, clonally unrelated DLBCL are characterized by a significantly longer survival (~5 years), that is in the range of that of de novo DLBCL, compared to clonally related cases (8–16 months). ▪ Such differences in clinical outcome between clonally related and clonally unrelated DLBCL reflect differences in the genetics ▪ For patients diagnosed with HL-type RT seem to present a better overall survival (OS) than DLBCL-type RT although inferior to those with de novo HL, with median OS reported of 2.6–3.9 years management of DLBCL-type Richter syndrome For clonally unrelated CLL and DLBCL ( different immunoglobulin gene rearrangements) , treat the disease as a de novo DLBCL because( the DLBCL is a second malignancy ) R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) as first line reserving SCT only in the case of lack of response or relapse after R-CHOP) For clonally related CLL and DLBCL ( sharing of identical immunoglobulin gene rearrangements) –(true transformation) treat with chemoimmunotherapy ( R-CHOP) followed by consolidation with reduced-intensity conditioned allogeneic or autologous SCT depending on whether a donor is available, and the patient is fit for transplant.  Reference: Eyre, T. A., Riches, J. C., Patten, P. E. M., Walewska, R., Marr, H., Follows, G., Hillmen, P., & Schuh, A. H. (2021). Richter transformation of chronic lymphocytic leukaemia: A British Society for Haematology Good Practice Paper. British Journal of Haematology, 196(4), 864–870. https://doi.org/10.1111/bjh.17882 Abrisueta, P., Nadeu, F., Bosch, J., Iacoboni, G., Serna, A., et al. (2023). From genetics to therapy: Unraveling the complexities of Richter transformation in chronic lymphocytic leukemia. Cancer Treatment Reviews, 120, Article 102619. https://doi.org/10.1016/j.ctrv.2023.102619 Broadway-Duren, J. (2022). An approach to diagnosis of Richter transformation in chronic lymphocytic leukemia. Journal of the Advanced Practitioner in Oncology, 13(5), 535–538. https://doi.org/10.6004/jadpro.2022.13.5.7 Rossi, D., Spina, V., & Gaidano, G. (2018). Biology and treatment of Richter syndrome. Blood, 131(25), 2761–2772. https://doi.org/10.1182/blood-2018- 01-791376 Rossi, D., & Gaidano, G. (2016). Richter syndrome: Pathogenesis and management. Seminars in Oncology, 43(2), 311–319. https://doi.org/10.1053/j.seminoncol.2016.02.012 Parikh, Sameer A., Neil E. Kay, and Tait D. Shanafelt. "How We Treat Richter Syndrome." Blood, vol. 123, no. 11, 2014, pp. 1647–1657. DOI: https://doi.org/10.1182/blood-2013-11-516229 Thank you