Lymphoma & related disorders
Mature B cell neoplasms
Small B cell lymphomas with a circulating component
Richter syndrome


Minor changes: 23 March 2021

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PubMed Search: Richter syndrome[TI] pathology

Sepideh Nikki Asadbeigi, M.D.
 Chelsey D. Deel, M.D.
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Page views in 2021 to date: 1,011
Cite this page: Asadbeigi SN, Deel CD. Richter syndrome. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomarichtersyndrome.html. Accessed May 16th, 2021.
Definition / general
  • Transformation of a chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) into an aggressive lymphoma, primarily diffuse large B cell lymphoma (DLBCL), with rare cases developing into Hodgkin lymphoma
  • Rare cases of plasmablastic lymphoma (PBL) or B lymphoblastic leukemia / lymphoma have been reported (Eur J Haematol 2001;67:322)
Essential features
  • Progression of a chronic lymphocytic leukemia / small lymphocytic lymphoma into an aggressive lymphoma, most commonly diffuse large B cell lymphoma, with rare cases transforming into Hodgkin lymphoma (Hum Pathol 2016;55:108)
  • Common clinical presentation: sudden clinical deterioration, development of systemic symptoms, rapid lymph node enlargement and extranodal manifestations
  • Association with CDKN2A, NOTCH1, MYC, TP53 mutations (Curr Hematol Malig Rep 2014;9:294)
  • Poor overall prognosis: prognosis improved with clonally unrelated diffuse large B cell lymphoma (Blood 2011;117:3391)
Terminology
  • Richter syndrome
  • Richter transformation
ICD coding
  • ICD-10: C91.10 - chronic lymphocytic leukemia of B cell type not having achieved remission
Epidemiology
  • Typically older adults
  • Occurs in approximately 2 - 10% of patients with chronic lymphocytic leukemia (Ann Hematol 2018;97:1859, Adv Clin Exp Med 2018;27:1683)
  • Richter syndrome of Hodgkin lymphoma type is a rare disease, occurring in 0.4 ‐ 0.7% of chronic lymphocytic leukemia patients (Hum Pathol 2016;55:108, Med Hypotheses 2006;66:577)
  • Association between EBV and Hodgkin type Richter syndrome
  • May occur during various times after diagnosis, with some reports of chronic lymphocytic leukemia and Richter syndrome diffuse large B cell lymphoma type being diagnosed simultaneously
  • Incidence increased in patients undergoing heavy pretreatment
Sites
Pathophysiology
  • 80% of cases derived from underlying chronic lymphocytic leukemia clone, while 20% of cases are described as unrelated clones (Hemasphere 2020;4:e473)
  • 2 common genetic pathways responsible for transformation (Immunotargets Ther 2019;8:1)
    • Cell cycle deregulation by TP53 and CDKNA2 mutations in over 50% of cases
    • NOTCH1 mutations and trisomy 12 in almost 33% of cases
  • Genetic instability and loss of cell cycle control, related to c-MYC abnormalities, may explain the mechanisms of transformation
  • Infection with EBV associated with dysregulating the immune system in Hodgkin type Richter syndrome (Adv Clin Exp Med 2018;27:1683)
Etiology
  • Clinical: advanced Rai stage at diagnosis and lymph node size > 3 cm, heavily pretreated chronic lymphocytic leukemia (Ann Hematol 2018 ;97:1859)
  • Increased risk of Richter syndrome associated with adverse prognostic factors, including del(11q), del(17p), unmutated immunoglobulin heavy chain variable region genes (IGHV) and a high expression of ZAP70, CD38 and CD49d at diagnosis
  • Increased risk of transformation with NOTCH1 mutation (Leukemia 2013;27:1100)
Clinical features
Diagnosis
Laboratory
  • Elevated LDH level
  • Anemia, neutropenia and thrombocytopenia
  • Hypercalcemia with or without lytic bone lesion
  • Paraproteinemia in 44% of patients (Cancer 2005;103:216)
Radiology description
  • Radiologic assessment demonstrates higher predictive value over clinical criteria
  • Computerized tomography (CT) scan helpful criteria (Ann Hematol 2018;97:1859)
    • Rapid disproportionate enlargement of a single group of lymph nodes
    • Inhomogeneous attenuation of lymph nodes, reflecting central necrosis
    • Evidence of extranodal involvement
  • PET / CT scan findings (Blood 2018;131:2761)
    • Evaluation of lymph nodes with SUVmax > 5 demonstrates high sensitivity but lower specificity for detecting Richter syndrome
    • Usefulness of PET / CT with its high negative predictive value (97 - 98%)
Prognostic factors
Case reports
Treatment
  • Richter syndrome - diffuse large B cell lymphoma type (DLBCL RS):
    • R-CHOP or R-CHOP-like regimens (i.e. R-EPOCH) are widely used as first line treatment option (Blood 2018;131:2761)
    • Stem cell transplantation an available option in young, fit patients
    • Emerging role of immunotherapy, including BTK inhibitors (ibrutinib, acalabrutinib), BCL2 inhibitors (venetoclax), PD-1 receptor inhibitors (pembrolizumab), among others (Blood 2018;131:2761, Immunotargets Ther 2019;8:1)
  • Richter syndrome - Hodgkin lymphoma type (HS RS):
Microscopic (histologic) description
  • Diffuse large B cell lymphoma type:
    • Diffuse effacement of lymph nodes or extranodal sites with sheets of large cells with centroblastic, immunoblastic or anaplastic morphology
    • Proposed criteria to distinguish from aggressive chronic lymphocytic leukemia (Immunotargets Ther 2019;8:1):
      • Presence of large B cells with nuclear sizes either equal to the nucleus of macrophages or more than twice that of a normal lymphocyte
      • Diffuse growth pattern of large cells
  • Hodgkin lymphoma type:
    • Presence of classic Reed-Sternberg cells in an appropriate polymorphous background of small T cells, histiocytes, eosinophils and plasma cells
Microscopic (histologic) images

Contributed by Shahbaz Khan, M.D. and Sepideh Nikki Asadbeigi, M.D.
H&E of Richter syndrome H&E of Richter syndrome

Diffuse large B cell lymphoma type

Extranodal Richter syndrome Extranodal Richter syndrome

Extranodal

Peripheral smear description
  • Richter syndrome malignant cells are occasionally seen in the bone marrow and very rarely in the peripheral blood (J Hematol. 2014;3:86)
  • Morphology of transformed cells may show enlarged cells with pleomorphic nuclei, less condensed chromatin, prominent nucleoli and scant cytoplasm (Plant Physiol 2016;171:1569)
  • Background circulating chronic lymphocytic leukemia cells present (small lymphocytes with condensed / clumped chromatin)
Positive stains
Negative stains
  • Diffuse large B cell lymphoma type:
    • Rare germinal center phenotype (CD10, BCL6 expression) (positive in 5 - 10% of cases)
    • EBV negative
  • Hodgkin type:
    • Reed-Sternberg cells: negative for CD20
Flow cytometry description
Molecular / cytogenetics description
  • Most molecular findings / knowledge based on research of diffuse large B cell lymphoma type Richter syndrome (findings in Hodgkin type Richter syndrome are less known)
  • Deregulation of cell cycle control, proliferation and damage to DNA repair and target genes via somatic mutations of TP53 (60 - 80%), CDKNA2 (30%) or MYC itself (30%) or by affecting their regulatory functions, e.g. NOTCH1 (30%) and MGA (10%)
  • 2 common genetic pathways responsible for transformation (Immunotargets Ther 2019;8:1)
    • TP53 and CDKNA2 mutations in over 50% of cases
    • NOTCH1 mutations and trisomy 12 in almost 33% of cases
  • Increased risk of Richter syndrome associated with adverse prognostic factors, such as del(11q), del(17p), unmutated immunoglobulin heavy chain variable region genes (IGHV) and a high expression of ZAP70, CD38 and CD49d
  • Cytogenetic analysis of Richter syndrome: predominantly complex karyotype
Sample pathology report
  • Lymph node, right level II, excision:
    • Diffuse large B cell lymphoma, nongerminal center subtype (see comment)
    • Comment: In light of the patient's clinical history of chronic lymphocytic leukemia with a recent rapidly enlarging cervical lymph node, this lesion would be best classified as Richter transformation of the patient's chronic lymphocytic leukemia / small lymphocytic lymphoma to diffuse large B cell lymphoma.
Differential diagnosis
  • Aggressive chronic lymphocytic leukemia (CLL):
    • Increase in size and proliferative activity of the CLL cells with confluent expansion of the proliferation centers in the lymph nodes (proliferation centers broader than a 20x field)
    • Proposed criteria to distinguish from aggressive CLL (Immunotargets Ther 2019;8:1):
      • Presence of large B cells with nuclear sizes either equal to the nucleus of macrophages or more than twice that of a normal lymphocyte
      • Diffuse growth pattern of large cells
    • Distinction requires pathologist expertise
  • De novo diffuse large B cell lymphoma (DLBCL):
    • Morphologically indistinguishable
    • PD-1 negative
    • Distinct molecular signature: typical recurrent mutations of de novo DLBCL affecting NFκB (e.g. CARD11, TNFAIP / A20, CD79A, CD79B, BCL6, BCL2, PRDM1 and EZH2) or genes associated with CLL chemorefractoriness and progression (e.g. BIRC3, MYD88, DDX3X, SF3B1 and RPS15) not seen in Richter syndrome DLBCL
  • Hodgkin-like lesion:
    • Hodgkin/Reed-Sternberg (HRS) cells in the setting of chronic lymphocytic leukemia (CLL) (HRS-CLL) and Hodgkin lymphoma variant of Richter transformation (CHL-RT) can show similar morphology (Hum Pathol 2016;55:108)
    • HRS-CLL has potential to progress to CHL
    • Only 27% of patients have a prior diagnosis of HRS-CLL, as opposed to 73% of CHL-RT patients
    • Cytologic features are typical of CLL in most cases of HRS-CLL with rare mixed inflammatory cells, in contrast to CHL-RT, which shows polymorphous inflammatory background
    • CHL-RT shows a moth-eaten or segregated pattern of CHL in background of CLL
    • Immunophenotype and EBV status of the HRS cells are similar in both HRS / CLL and CHL / RT cases (Hum Pathol 2016;55:108)
    • Both majority of HHR-CLL and CHL-RT patients are EBV+
Board review style question #1

A 75 year old man with a history of CLL / SLL presents with a rapidly enlarging cervical lymph node. A representative microscopic section is seen above. Which factor is indicative of a favorable prognosis in this patient?

  1. Immunoglobulin heavy chain gene rearrangement of lymph node tissue is clonally unrelated to the concurrent CLL / SLL clone
  2. Laboratory work up showing platelet count of 75,000 / μL with normal WBC count
  3. PET / CT scan showing a 6 x 3 cm cervical lymph node with SUV of 7
  4. TP53 mutation in the biopsied tissue
  5. Positive PD-1 immunohistochemical expression in the biopsied tissue
Board review style answer #1
A. Immunoglobulin heavy chain gene rearrangement of lymph node tissue is clonally unrelated to the concurrent CLL / SLL clone

Comment Here

Reference: Richter syndrome
Board review style question #2
In cases of Richter syndrome of diffuse large B cell lymphoma subtype, which of the following is a common genetic alteration?

  1. JAK2
  2. CD79B
  3. TP53
  4. MYD88
  5. SF3B1
Board review style answer #2
C. TP53

Comment Here

Reference: Richter syndrome
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