Healthcare Quiz on CLL Features

Richter Transformation (RT)

• RT is a histologic transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma
• Common transformation is to diffuse large B-cell lymphoma (DLBCL), less often to classical Hodgkin lymphoma.
• Very rare transformation to plasmablastic lymphoma or other lymphoma/leukemia types
• Occurs in 2-10% of CLL patients, usually during the disease course rather than at presentation
• DLBCL-RT occurs in approximately 90% of cases, Hodgkin lymphoma-RT in ~10%
• Less than 1% of CLL cases transform into Hodgkin lymphoma

Risk Factors for RT

• Advanced Rai stage (III-IV) at CLL diagnosis
• Lymph nodes greater than 3 cm on physical exam

Biological Characteristics of CLL-B Cells

• Patients with IGHV-unmutated leukemic B cells have a 4-fold increased risk of RT compared to IGHV-mutated patients
• Shorter telomere length (marker of genetic instability) is associated with increased risk of RT
• CD38 and CD49d status can be associated with increased risk of future RT.
• Cytogenetic abnormalities (del(11q22.3), del(17p13), del(15q21.3), del(9p21)) also associated with increased risk of RT
• Heritable germline polymorphisms in BCL2 and CD38 have been shown to increase the risk of transformation.

Clinical Presentation of RT

• Onset is often characterized by accelerated, increased lymphadenopathy (often abdominal), splenomegaly, and B symptoms (fever, night sweats, weight loss)
• Extra-nodal involvement may occur, especially in the gastrointestinal tract, bone marrow, central nervous system (CNS), or skin
• In some cases, RT presents solely as an extra-nodal mass
• Early signs and symptoms of extranodal involvement may include 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) detected by physcial exam or imaging studies, accompanied by splenomegaly and/or hepatomegaly.

Diagnosis of RT

• Laboratory Findings/CBC:
  • Anemia
  • Thrombocytopenia (<100 x 10⁹/L) is often observed
  • New onset of absolute lymphocytosis (≥5.0 × 10⁹/L)
• Biochemical Investigations:
  • Elevated serum beta-2 microglobulin (B2M) (>2 mg/L)
  • Elevated LDH (lactate dehydrogenase) levels (greater than 1.5 times the upper limit of normal)
  • Paraproteinemia
  • Hypercalcemia

Tissue Biopsy

• Gold standard for RT diagnosis is biopsy of affected lymph node or extra-nodal site.
• RT onset is uncommonly disseminated or simultaneous in all lymphatic regions.
• 18FDG-PET/CT imaging is useful to guide biopsy site selection.
• Positive findings (SUV >5.0) in PET/CT scans would indicate that a tissue evaluation is necessary.
• Biopsy should be directed at the index lesion, the lesion showing the most avid 18FDG uptake at PET/CT

Histologic Variants of Richter Transformation

• Diffuse large B-cell lymphoma (DLBCL): The most frequent histologic variant of transformation.
  • Development of DLBCL occurs within 1.8-4.0 years following the initial CLL diagnosis, occurring sometimes before or after CLL therapy.
  • DLBCL incidence rate among newly diagnosed CLL patients is about 0.5% while in patients previously treated for CLL is around 1%.
  • DLBCL most commonly arises in men over 60 years of age
• Pathologic features of RS-DLBCL: Most cases show diffuse effacement of lymph nodes/extra nodal sites by large cells with centroblastic morphology.
  • Immunoblastic features are seen in a minority of cases. Often exhibit mitotic figures and apoptotic bodies with a starry sky pattern. Tumor necrosis is common
• Adherence to WHO criteria is important: Cells must exhibit diffuse growth throughout the neoplasm and have a nuclear size equal to or exceeding that of normal macrophage nuclei or twice the size of a normal lymphocyte;
• Phenotypic characteristics: positive for B-cell markers (CD19, CD20, CD22), PAX5, monotypic surface immunoglobulin light chain; CD38, ZAP70, and CD49d are often positive, but CD5 and CD23 expression may be retained to a varying extent

Other Features

• Non-germinal center B-cell-like (non-GCB) immunophenotype is seen in about 80% of RS-DLBCL cases (negative for CD10 and positive for MUM1)
• 20% of cases have a GCB immunophenotype, positive for CD10 and/or BCL6+, MUM1-
• TP53 overexpression and a high Ki-67 proliferation index are frequent findings
• Epstein-Barr virus (EBV) has been detected in some cases

Hodgkin Lymphoma

• Less than 1% of CLL patients will transform to RS-HL
• Transformation typically occurs during the seventh decade of life (range 30-88), primarily in men.
• Hodgkin transformation is distinguished by the presence of Hodgkin and Reed-Sternberg cells in a polymorphic inflammatory background, different from that characteristic of CLL
• Inflammatory background contains T-cells, histiocytes, potentially with abundant eosinophils
• Immunohistochemistry commonly shows CD30, CD15, and PAX5 positivity.

Plasmablastic Lymphoma (PBL)

• RS-PBL is aggressive B-cell malignancy related to DLBCL
• Most common origin is de novo in the setting of immune deficiency
• Fewer cases noted in CLL/SLL patients
• Patient demographics and clinical characteristics:
  • Majority of patients are men, age 52-77
  • Serum/urine protein commonly detectible in some cases
  • Typical plasmablast features exist along with residual CLL cells in some samples
• Immunohistochemistry would show positivity for CD38, ZAP-70, CD138, BLIMP1, IRF4/MUM1, and XBP1
• CD5, CD20, PAX5, and IRF8 are typically negative

B-lymphoblastic Leukemia/Lymphoma (LBL)

• RS-LBL arises from progenitor B-lymphoid cells.
• Primarily involves bone marrow, peripheral blood, and less commonly lymph nodes
• Acute lymphoblastic transformation of CLL is rare
• Age range most commonly reported is 42-76, with a majority of patients being men.
• Typical interval between CLL diagnosis and RS-LBL is 2 months to 7 years

T-cell lymphomas

• Rare in CLL patients, relationship poorly understood

Differential Diagnosis

• Accelerated/progressed CLL (a/pCLL): Characterized by expanded proliferation centers and increased mitotic activity, but lacks diffuse sheets of large cells
• Pseudo-Richter: Presents after discontinuation of ibrutinib. Responds well to therapy restarting characterized by high Ki-67 (proliferation) index and preserved CD5/LEF-1 expression.

Other Types of Lymphomas

• Other rare T-cell and B-cell lymphomas (mantle cell and marginal zone lymphomas) may occasionally coexist with CLL.
• HSV Lymphadenitis: mimics RT with necrosis high proliferation rates but features of viral inclusions. Diagnosed by immunohistochemistry and treated with antivirals.

Prognosis

• Prognosis differs based on the histologic variant.
• DLBCL: The most significant factor for prognosis is the presence or absence of a clonal relationship between CLL and the DLBCL clone
  • Clonally unrelated cases present with longer survival (~5 years).
  • Clonally related cases have a shorter survival (8-16 months)
• HL-type RT: Patients tend to have better overall survival compared to DLBCL-type RT, though inferior to those who have de novo Hodgkin lymphomas
  • Median OS in HL-type RT cases is reported to be between 2.6-3.9 years.

Management

• DLBCL-type RT: For clonally unrelated CLL and DLBCL, treat as de novo DLBCL, usually with R-CHOP as first-line therapy, followed by SCT if needed
• HL-type RT: The treatment approach is similar to DLBCL-type RT
• Clonally related CLL and DLBCL: Initiate chemoimmunotherapy (R-CHOP), followed by a consolidation with reduced-intensity conditioned allogeneic or autologous SCT if an appropriate donor/fitness is available.

Test your knowledge on the characteristics of accelerated/progressed Chronic Lymphocytic Leukemia (a/pCLL) and pseudo-Richter syndrome. This quiz will challenge your understanding of these conditions and their unique features. Perfect for healthcare professionals or students in hematology.