Lymphoma & related disorders
Mature B cell neoplasms
Small B cell lymphomas with a circulating component
Richter syndrome
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PubMed Search: Richter syndrome[TI] pathology
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Peripheral smear description | Positive stains | Negative stains | Flow cytometry description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Asadbeigi SN, Deel CD. Richter syndrome. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomarichtersyndrome.html. Accessed November 28th, 2024.
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)
- References: Cancer Genet Cytogenet 1996;86:143, Blood 1991;78:797, Blood 2018;131:1258
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 associated with EBV, occurring in 0.4 - 0.7% of chronic lymphocytic leukemia patients (Hum Pathol 2016;55:108, Med Hypotheses 2006;66:577)
- 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
- Primarily lymph nodes, bone marrow
- Can present in extranodal sites (40% of cases): gastrointestinal tract, testis, skin, central nervous system, eye, lung, kidney (Clin Nucl Med 2019;44:e87, IJU Case Rep 2019;2:232, Dermatol Online J 2020;26:13030, Medicine (Baltimore) 2018;97:e12701, Am J Ophthalmol 1996;122:266, Am Rev Respir Dis 1988;138:980)
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 (Am J Surg Pathol 1992;16:859, Am J Surg Pathol 1993;17:853, Br J Haematol 2005;129:199, Adv Clin Exp Med 2018;27:1683)
Etiology
- Risk factors for high grade transformation:
- 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
- Sudden clinical deterioration
- Development of systemic symptoms (B symptoms): fatigue, night sweats, weight loss, fever (Oncology (Williston Park) 2012;26:1146)
- Rapid, asymmetrical lymph node growth (Br J Haematol 2008;142:709)
- Extranodal manifestations / sites of disease
- Specificity of the above clinical signs is limited to 50 - 60% (Curr Treat Options Oncol 2017;18:75)
Diagnosis
- Laboratory assessment: lactate dehydrogenase (LDH), complete blood count, calcium level (Dermatology 2010;220:226)
- Radiologic imaging: CT, PET / CT for evaluation of suspicious sites of disease and biopsy planning (J Nucl Med 2006;47:1267)
- Biopsy of the involved lymph node or extranodal site is the gold standard for diagnosis (Int J Hematol Oncol 2019;7:IJH09)
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
- Overall poor prognosis, with survival ranging from 1 - 45 months depending on risk stratification (Blood 2018;131:2761)
- Favorable prognostic factors:
- Clonally unrelated chronic lymphocytic leukemia and Richter syndrome diffuse large B cell lymphoma: prognosis similar to de novo diffuse large B cell lymphoma (Ann Hematol 2018;97:1859)
- Unfavorable factors:
- Platelet count < 100,000/μL (J Clin Oncol 2006;24:2343)
- TP53 (Proc Natl Acad Sci U S A 2008;105:13520)
- Trisomy 12
- LDH > 1.5 times upper limit (J Clin Oncol 2006;24:2343)
- Tumor size > 5 cm (J Clin Oncol 2006;24:2343)
- > 1 prior treatment (J Clin Oncol 2006;24:2343)
- Failure to achieve complete remission after induction
Case reports
- 64 year old man with chronic lymphocytic leukemia and leukemic Richter syndrome occurring in peripheral blood (J Hematol 2014;3:86)
- 72 year old man with sudden scrotal swelling (IJU Case Rep 2019;2:232)
- 75 year old man presenting with enlarged cervical and subdiaphragmatic lymph nodes as well as diffuse wall thickening of the colon (Clin Nucl Med 2019;44:e87)
- 76 year old woman with ulcerated cutaneous Richter syndrome presenting as a 10 cm erythematous, infiltrative and irregular ulcer (Dermatol Online J 2020;26:13030)
- 77 year old man presenting with enlarging cervical lymph nodes and a preauricular mass (Onco Targets Ther 2019;12:1181)
- CLL patient with an unusual plasmablastic variant of Richter syndrome (Eur J Haematol 2001;67:322)
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):
- Most commonly used treatment regimen is ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) (Adv Clin Exp Med 2018;27:1683)
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.
Diffuse large B cell lymphoma type
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 (J Clin Oncol 2006;24:2343)
- Background circulating chronic lymphocytic leukemia cells present (small lymphocytes with condensed / clumped chromatin)
Positive stains
- Diffuse large B cell lymphoma type:
- Positive for B cell markers CD20 or CD79a
- Variable expression of CD5 (~30%), CD23 (~15%), MYC (30 - 40%) (Am J Surg Pathol 2007;31:1605, Int J Clin Exp Pathol 2015;8:7540, Am J Hematol 2016;91:1036)
- Majority have nongerminal center phenotype (positive for MUM1 / IRF4)
- Frequent expression of BCL2 (up to 80% of cases) (Haematologica 2020;105:765)
- High level of PD-1 expression in RS indicates clonal relation of CLL / SLL and DLBCL RS (Br J Haematol 2019;185:370, Am J Surg Pathol 2018;42:843)
- Hodgkin type:
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
- Most cases retain a chronic lymphocytic leukemia / small lymphocytic lymphoma immunophenotype (Am J Clin Pathol 2015;143:25)
- Transformation to Richter syndrome may demonstrate some minor modulations in antigen expression (Am J Clin Pathol 2015;143:25)
- Majority of DLBCL transformations from CLL / SLL retain the expression of CD5 and CD23 by flow cytometry (Am J Clin Pathol 2001;115:385)
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
- No characteristic chromosomal abnormality
- Monosomies of 9, 17 and losses of 9p, 17p can be seen (Am J Clin Pathol 2015;143:25)
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
- 27% of patients with HRS-CLL have a prior known diagnosis of CLL, as opposed to 73% of CHL-RT patient who had prior diagnosis of CLL
- 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+
- Ibrutinib related pseudo Richter transformation:
- Happens after a brief dose interruption of Ibrutinib or acute infection in CLL / SLL patients (Br J Haematol 2020;191:e22)
- Presents with lymphadenopathy, lymphocytosis or progressive cytopenia and tissue biopsy shows DLBCL transformation; return of LDH and lymphocyte count to normal after treatment resumption with rebiopsy showing CLL / SLL with no DLBCL left
- Large cells with the same immunophenotype as CLL / SLL
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?
- Immunoglobulin heavy chain gene rearrangement of lymph node tissue is clonally unrelated to the concurrent CLL / SLL clone
- Laboratory work up showing platelet count of 75,000 / μL with normal WBC count
- PET / CT scan showing a 6 x 3 cm cervical lymph node with SUV of 7
- TP53 mutation in the biopsied tissue
- 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
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?
- JAK2
- CD79B
- TP53
- MYD88
- SF3B1
Board review style answer #2
