Richter Transformation in CLL
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Questions and Answers

What percentage of patients with CLL are likely to develop Hodgkin lymphoma?

  • 15%
  • 10%
  • 5%
  • Less than 1% (correct)

    • In which age range do patients typically undergo transformation to RS-HL?

  • 40–70 years
  • 30–88 years (correct)
  • 20–50 years
  • 50–90 years

    • Which cell type is commonly found in the inflammatory background of Hodgkin transformation?

  • B-cells
  • Plasma cells
  • Histiocytes (correct)
  • Natural killer cells

    • What is the most common histologic subtype of Hodgkin lymphoma?

    <p>Mixed cellularity</p> Signup and view all the answers

    Which of the following cell markers is NOT typically expressed by Hodgkin and Reed-Sternberg (HRS) cells?

    <p>CD10</p> Signup and view all the answers

    Which characteristic finding is common in Hodgkin transformation?

    <p>Tumor necrosis</p> Signup and view all the answers

    In which type of immunohistochemistry are HRS cells commonly positive?

    <p>CD20</p> Signup and view all the answers

    What type of precursor cell do clones in the branched model derive from?

    <p>Common precursor cell (CPC)</p> Signup and view all the answers

    What is the primary type of lymphoma to which chronic lymphocytic leukemia (CLL) commonly transforms?

    <p>Diffuse large B-cell lymphoma</p> Signup and view all the answers

    Which of the following genetic characteristics increases the risk of Richter transformation?

    <p>Shorter telomere length</p> Signup and view all the answers

    What clinical symptoms typically herald the onset of Richter transformation?

    <p>Accelerated lymphadenopathy and systemic B symptoms</p> Signup and view all the answers

    What percentage of CLL patients is estimated to experience Richter transformation?

    <p>2-10%</p> Signup and view all the answers

    What characteristic is typically associated with accelerated/progressed CLL (a/pCLL)?

    <p>Increased mitotic activity</p> Signup and view all the answers

    Which cytogenetic abnormality is NOT commonly associated with Richter transformation?

    <p>Del(2p16)</p> Signup and view all the answers

    Which laboratory finding is commonly associated with the diagnosis of Richter transformation?

    <p>Elevated LDH levels</p> Signup and view all the answers

    What distinguishes clonal unrelated DLBCL from clonally related DLBCL regarding survival outcomes?

    <p>Prolonged survival averaging around 5 years</p> Signup and view all the answers

    Which of the following neoplasms may coexist with CLL but is considered rare?

    <p>Marginal zone lymphoma</p> Signup and view all the answers

    What is the most rare form of lymphoma or leukemia that can result from Richter transformation?

    <p>Plasmablastic lymphoma</p> Signup and view all the answers

    Which symptom could indicate extranodal involvement in a patient with Richter transformation?

    <p>Early satiety</p> Signup and view all the answers

    What is a common diagnostic tool used to confirm HSV lymphadenitis?

    <p>Immunohistochemistry</p> Signup and view all the answers

    What impact does misclassification of lymphomas in CLL have on patient care?

    <p>It affects treatment decisions negatively</p> Signup and view all the answers

    What procedure is considered the gold standard for the diagnosis of Richter Transformation (RT)?

    <p>Tissue biopsy of affected lymph nodes</p> Signup and view all the answers

    What does a standardized uptake value (SUV) greater than 5.0 indicate in 18FDG-PET scanning?

    <p>Need for tissue evaluation</p> Signup and view all the answers

    Which markers are typically positive in neoplastic cells of RS-DLBCL?

    <p>CD19, CD20, CD22, PAX5</p> Signup and view all the answers

    Which of the following histologic variants is the most frequent in patients with Richter Transformation?

    <p>Diffuse large B-cell lymphoma</p> Signup and view all the answers

    What percentage of RS-DLBCL cases exhibit a non-GCB immunophenotype?

    <p>80%</p> Signup and view all the answers

    What demographic is most commonly associated with the development of diffuse large B-cell lymphoma in CLL patients?

    <p>Men over 60 years</p> Signup and view all the answers

    What feature is characteristic of RS-DLBCL according to WHO criteria?

    <p>Presence of sheets of large B-lymphoid cells</p> Signup and view all the answers

    Which of the following immunophenotypic characteristics would indicate a GCB RS-DLBCL?

    <p>Positive for CD10 and/or BCL6+</p> Signup and view all the answers

    Which genetic feature is commonly tested in RS-DLBCL cases?

    <p>TP53 activation</p> Signup and view all the answers

    What is the mean time frame for DLBCL development from the initial diagnosis of CLL?

    <p>1.8–4.0 years</p> Signup and view all the answers

    Which of the following statements about fine-needle aspiration is true regarding tissue sampling for Richter Transformation?

    <p>Samples may not be representative of the tumor's architecture.</p> Signup and view all the answers

    What is the majority relationship between RS-DLBCL and underlying CLL?

    <p>About 70-80% of cases are clonally related</p> Signup and view all the answers

    In which model of transformation is DLBCL more commonly observed in patients?

    <p>Linear model of transformation</p> Signup and view all the answers

    What are common pathologic features of RS-DLBCL when examined histologically?

    <p>Starry-sky pattern and tumor necrosis</p> Signup and view all the answers

    Which characteristic is associated with the proliferation of neoplastic cells in RS-DLBCL?

    <p>High Ki-67 proliferation index</p> Signup and view all the answers

    What is a potential indicator of Epstein-Barr virus activity in RS-DLBCL?

    <p>Detection of EBV-encoded RNA transcripts</p> Signup and view all the answers

    What immunophenotypic marker is consistently positive in HRS cells?

    <p>CD30</p> Signup and view all the answers

    What is a common characteristic feature of plasmablastic lymphoma cells?

    <p>Morphological features of plasma cell differentiation</p> Signup and view all the answers

    Which of the following is NOT a typical marker expressed by neoplastic cells in RS-PBL?

    <p>PAX5</p> Signup and view all the answers

    What is the typical age range for patients diagnosed with RS-PBL?

    <p>52-77 years</p> Signup and view all the answers

    What type of leukemia is derived from progenitor B-lymphoid cells?

    <p>B-lymphoblastic leukemia/lymphoma (B-LBL)</p> Signup and view all the answers

    What distinguishes RS-LBL from typical cases of CLL?

    <p>Acute lymphoblastic transformation</p> Signup and view all the answers

    In which area are B-lymphoblastic leukemia/lymphoma typically found?

    <p>Bone marrow and peripheral blood</p> Signup and view all the answers

    Which of the following features is characteristic of the neoplastic cells in RS-LBL?

    <p>Numerous intermediate-sized lymphoblasts</p> Signup and view all the answers

    Study Notes

    Richter Transformation (RT)

    • Defined as a histological transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma
    • Commonly transforms to diffuse large B-cell lymphoma (DLBCL)
    • Less often, it transforms to classical Hodgkin lymphoma
    • Very rarely transforms to plasmablastic lymphoma or other lymphoma/leukemia types

    Incidence

    • RT occurs in 2-10% of CLL patients
    • Usually during the disease course, not at presentation
    • Most commonly presents as DLBCL-RT (~90%)
    • Hodgkin lymphoma-RT (~10%)
    • Other lymphoma/leukemia types are very rare (<1%)

    Risk Factors at CLL Diagnosis

    • Advanced Rai stage (III-IV)
    • Lymph nodes >3 cm on physical examination

    Biological Characteristics of CLL-B-cells

    • CLL B-cells that lack IGHV somatic mutations are at a 4-fold increased risk of RT compared to those with IGHV mutated B-cells
    • Shorter telomere length (marker of genetic instability) is associated with an increased risk of RT
    • CD38 and CD49d status have been linked to the risk of future RT
    • Cytogenic abnormalities (e.g., del(11q22.3), del(17p13), del(15q21.3), del(9p21)) may be associated with RT

    Heritable Germline Polymorphisms

    • Polymorphisms in BCL2 and CD38 have been reported to increase RT risk

    Clinical Presentation

    • RT onset is marked by an accelerated, pronounced increase in lymphadenopathy (often abdominal), splenomegaly, and B symptoms (fever, 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 may only present as an extra-nodal mass

    Clinical Signs and Symptoms

    • Extranodal involvement may manifest as early satiety, gastrointestinal bleeding, rash, pathologic fractures, headache, blurred vision, or dyspnea
    • Physical examination may reveal asymmetric and rapid growth of bulky lymph nodes (>3 cm), splenomegaly, and/or hepatomegaly

    Lab Findings

    • Complete Blood Count (CBC):
      • Anemia
      • Thrombocytopenia (<100 x 109/L often present)
      • New onset of absolute lymphocytosis (≥5.0 x 109/L)

    Biochemical Investigations

    • Elevated serum beta-2 microglobulin (B2M) level (>2 mg/L)
    • Elevated lactate dehydrogenase (LDH) levels (>1.5 times upper limit of normal)
    • Paraproteinemia
    • Hypercalcemia

    Tissue Biopsy

    • The gold standard for RT diagnosis is a biopsy of an affected lymph node or extra-nodal site
    • RT onset is usually not disseminated or simultaneous in all lymphatic regions
    • Imaging studies like FDG-PET/CT aid in the decision to biopsy and optimal site selection
    • SUV (standardized uptake value) >5.0 by PET/CT indicates a need for tissue evaluation
    • Biopsy should target the index lesion (lesion with highest FDG uptake)
    • Excisional biopsy is the gold standard, as fine-needle aspirations may not capture the entire pathological architecture of the tumor

    Histologic Variants of Richter Transformation (RT): DLBCL

    • DLBCL is the most common histologic variant in CLL patients
    • DLBCL occurs 1.8-4.0 years after initial CLL diagnosis and can develop before or after CLL treatment
    • Annual incidence rate of DLBCL in newly diagnosed CLL patients is 0.5%. It is ~1% in CLL patients with prior therapies

    Pathologic Features of RS-DLBCL

    • Most cases show diffuse effacement of lymph nodes or extra-nodal sites by large cells with centroblastic morphology
    • A minority of cases may show immunoblastic features
    • Mitotic figures, apoptotic bodies, a starry-sky pattern, and tumor necrosis are common
    • WHO criteria dictate that B-lymphoid cells showing diffuse growth pattern and a nuclear size equal to or exceeding that of a normal macrophage nucleus should be considered.

    Immunophenotypic Characteristics of RS-DLBCL

    • Neoplastic cells typically express B-cell markers (CD19, CD20, CD22, PAX5) and monotypic immunoglobulin light chain
    • CD38, ZAP70, and CD49d are often positive
    • CD5 and CD23 expression is retained to a varying extent

    Non-GCB and GCB Immunophenotypes

    • 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-)
    • TP53 overexpression and a high Ki-67 proliferation index (>70%) are also common in RS-DLBCL

    Clonal Relationship to Underlying CLL

    • About 70-80% of RS-DLBCL cases are clonally related to the underlying CLL (sharing similar IGVH sequences)
    • RS-DLBCL often arises from a dominant CLL clone after acquiring additional somatic mutations
    • Differences are present in both clinical outcome and genetics which affect treatment.

    Hodgkin Lymphoma

    • Less than 1% of CLL patients develop Hodgkin lymphoma (RS-HL)
    • Typically occurs in the seventh decade of life (range 30-88 years)
    • Characterized by Hodgkin and Reed-Sternberg (HRS) cells in a polymorphous inflammatory background distinct from CLL
    • This background contains T-cells and histiocytes and may include abundant eosinophils
    • HRS cells commonly express CD30, CD15, and PAX5 (dimmish) and are frequently positive for EBV by immunohistochemistry
    • HRS cells may also express CD20, but intensity is usually variable
    • Clonal relationship to underlying CLL has been shown with similar immunoglobulin gene rearrangements in about 80% of cases.

    Plasmablastic Lymphoma (PBL)

    • Aggressive B-cell malignancy, thought to be related to DLBCL, characterized by morphologic and immunophenotypic plasma cell features
    • Commonly arises de novo in an immunocompromised state, however, a minority of RS-PBL cases are reported in CLL.
    • Most patients are men (~52–77 years of age)
    • Serum or urine paraprotein may be detectable
    • Residual CLL cells might be present in certain areas
    • Neoplastic cells usually express CD38, ZAP70, CD138, BLIMP1, IRF4/MUM1, and XBP1
    • CD5, CD20, PAX5, and IRF8 are usually negative
    • Molecular studies show monoclonal IGH and MYC rearrangements
    • Prognosis for RS-PBL is poor

    B-lymphoblastic Leukemia/Lymphoma (B-LBL)

    • Neoplasm derived from progenitor B-lymphoid cells, affecting bone marrow, peripheral blood, and less commonly lymph nodes
    • Acute lymphoblastic transformation of CLL (RS-LBL) is a rare presentation
    • Predominantly affects men (42–76 years of age)
    • Presentation interval between CLL diagnosis and RS-LBL is widely diverse (2 months to 7 years)
    • Characterized by numerous lymphoblasts with intermediate size, indented nuclei, fine chromatin, and scant cytoplasm
    • Neoplastic cells express HLA-DR, surface Ig, pan-B cell markers, and TdT, although TdT-negative cases are also documented
    • CD5, CD10, CD22, and CD23 expression is variable

    T-cell Lymphomas

    • Rare in patients with CLL
    • Relationship between CLL and these neoplasms is not fully understood

    Differential Diagnoses

    • Accelerated/progressed CLL (A/P CLL): Expanded proliferation centers but lacks diffuse large cell features
    • Pseudo-Richter: Seen after ibrutinib discontinuation; responds well to therapy resumption. Characterized by high Ki-67 index and preserved CD5/LEF-1 expression
    • HSV Lymphadenitis: Mimics RT with necrosis and high proliferation rates; features viral inclusions, often diagnosed with immunohistochemistry and treated with antivirals
    • Other Lymphomas: Mantle cell and marginal zone lymphomas may coexist with CLL; less common T and B subtypes exist

    Prognosis

    • Prognosis varies depending on the histological subtype of RT
    • In DLBCL-RT, clonal relationship between CLL and DLBCL is important in prognostication
    • Clonally unrelated DLBCL cases have a significantly longer survival (~5 years) compared to clonally related cases (8–16 months)

    Management of DLBCL-type Richter Syndrome

    • Clonally unrelated CLL and DLBCL: Treated as de novo DLBCL

    • First Line: R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)

    • Second Line (if needed): Stem cell transplant (SCT) reserved for lack of response or relapse post-R-CHOP

    • Clonally related CLL and DLBCL: treated with chemoimmunotherapy (R-CHOP) followed by consolidation with reduced-intensity conditioned allogeneic/autologous SCT based on fit and donor availability.

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    Explore the biological characteristics and incidence of Richter Transformation (RT) in chronic lymphocytic leukemia (CLL). This quiz covers its transformation types, risk factors, and histological implications. Test your understanding of this critical aspect of hematologic malignancies.

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