Richter's transformation (RT), also known as Richter's syndrome, is the conversion of chronic lymphocytic leukemia (CLL) or its variant, small lymphocytic lymphoma (SLL), into a new and more aggressively malignant disease. CLL is the circulation of malignant B lymphocytes with or without the infiltration of these cells into lymphatic or other tissues while SLL is the infiltration of these malignant B lymphocytes into lymphatic and/or other tissues with little or no circulation of these cells in the blood. CLL along with its SLL variant are grouped together in the term CLL/SLL.
RT is diagnosed in individuals who have CLL/SLL that converts to a malignancy with the microscopic histopathology of diffuse large B-cell lymphoma (DLBCL) or, less commonly, Hodgkin's lymphoma (HL). There are rare cases of: CLL/SLLs that convert into lymphoblastic lymphoma, hairy cell leukemia, or a high grade T cell lymphoma such as anaplastic large-cell lymphoma, angioimmunoblastic T-cell lymphoma, or plasmablastic lymphoma; CLL/SLLs that convert into acute myeloid leukemia; CLL/SLLs that convert into or develop non-hematological malignancies such as lung cancer, brain cancer, melanoma of the eye or skin, salivary gland tumors, and Kaposi's sarcomas; conversion of follicular lymphoma, lymphoblastic lymphoma, or marginal zone lymphoma into other types of hematological malignancies.. While some of these conversions have been termed RTs, the World Health Organization and most reviews have defined RT as a conversion of CLL/SLL into a disease with DLBCL or HL histopathology. Here, RTs are considered to be CLL/SLLs which convert into a disease with either DLBCL histopathology (here termed DLBCL-RT) or Hodgkin's lymphoma histopathology (here termed HL-RT).
CLL/SLL is the most common adult leukemia in Western countries, accounting for 1.2% of the new cancers diagnosed each year in the United States. It usually occurs in older adults (median age at diagnosis 70) and follows an indolent course over many years. About 1-10% of CLL/SLLs develop a Richter's transformation at a rate of 0.5–1% per year. In earlier studies, the transformed disease was reported to be far more aggressive than CLL/SLL with overall median survival times (i.e. times in which 50% of cases remain alive) between 1.1 and 16.3 months. Newer therapeutic regimens are improving the prognosis of DLBCL-RT and HL-RT.
History In 1928, Maurice Richter reported that a patient with CLL developed an aggressive generalized swelling of his lymph nodes, liver, and spleen due to their infiltration by rapidly growing "sarcoma-like cells." The patient died of this disease 22 days after his presentation. Richter termed the disorder "generalized reticular cell sarcoma." In 1964, Lortholary et al. described the occurrence of DLBCL in CLL patients and named the condition Richter's transformation. Subsequent studies have combined SLL with CLL and included HL-RT with DLBCL-RT in the definition of CLL/SLL RTs.
Presentation Studies have reported that CLL/SLL transforms into DLBCL-RT in ~90% and into HL-RT in 0.7-15% of all RTs. These transformations can occur at any point in the course of CLL/SLL. In a study of 77 individuals, DLBCL-RT and HL-RT were diagnosed simultaneously with CLL/SLL in 6 cases or 3–171 months after being diagnosed with CLL/SLL in 71 cases. A study of 10 RT cases reported that one individual presented with transformed CLL/SLL and 9 transformed 12 to 111 months after being diagnosed with CLL/SLL. The median time between the diagnosis of CLL/SLL and RT has varied between 1.8 and 5 years in 5 other studies.
Individuals with CLL/SLL that develop RT typically present with a rapid increase in the size of their superficial (i.e. cervical, axillary, inguinal, and/or retropharyngeal) lymph nodes; this may be the only sign of the transformation. Other symptoms may include B symptoms (i.e. fever in the absence of infection, drenching night sweats, and/or unexplained weight loss), and/or deterioration in general health. These symptoms are often accompanied by the development of extra-nodal disease, i.e. swelling or tumors due to the infiltration of malignant B lymphocytes into the gastrointestinal tract, bone, skin, central nervous system, spleen, liver, urinary bladder, thyroid gland, and/or pulmonary pleurae. Abnormal laboratory findings include elevation in blood lactate dehydrogenase levels in 50–80% of cases, progressively worsening anemia (i.e. decreases in red blood cells), thrombocytopenia (i.e. decreases in blood platelets), and/or hypercalcemia (i.e. elevation in serum calcium levels often due to bone involvement). FDG-positron emission tomography–computed tomography (i.e. FDG-PET-CT) can determine the sites of tissue invasion, the best sites to biopsy, and in some cases suggest the diagnosis of DLBCL-RT by showing that the involved tissues have distinctively high levels of FDG uptake. Individuals presenting with RT at the time of CLL/SLL diagnosis will show these symptoms and signs along with microscopic histopathological evidence of CLL/SLL concurrently with DLBCL-RT or HL-RT.
Risk factors for developing Richter's transformation Individuals with CLL/SLL are considered to be at an increased risk for developing RT if they have one or more of these elements: enlarged lymph nodes, liver, and/or spleen; advanced stage disease; low blood platelet counts and/or elevated serum beta-2-microglobulin levels; CLL/SLL cells which develop deletions in the CDKN2A gene, disruptions of the TP53 gene, activation of the C-MYC gene, trisomy (i.e. extra) chromosome 12, or mutations in the NOTCH1 gene; prior CLL/SLL treatment with chemotherapy regimens combining purine analogues and alkylating agents, multiple different types of chemotherapy, and/or combinations of fludarabine, cyclophosphamide, and rituximab (the latter regimen has been associated with a 2.38-fold higher risk of CLL/SLL developing an RT).
Histopathology DLBCL-RT histopathology The microscopic histopathology of DLBCL-RT in involved lymph nodes and other tissues stained with hemotoxylin and eosin generally shows confluent sheets of large malignant B lymphocytes that resemble centroblasts in ~80% of cases or immunoblasts in the remaining ~20% of cases. These malignant B lymphocytes express CD20 surface membrane protein in almost all cases, PD-1 surface membrane protein in up to 80% of cases (high PD-1 levels help cancer cells evade host immune systems), CD5 surface membrane protein in ~30% of cases, and CD23 surface membrane protein in ~15% of cases. In 90-95% of cases, these cells also express IRF4 (a transcription factor that regulates the development of lymphocytes including B lymphocyte) or in the other 5-10% of cases CD10 (an enzyme found in the neoplastic cells of pre-B cell leukemias and some cases of CLL/SLL).
HL-RT histopathology
The histopathology of the involved tissues in HL-RT is diagnosed based on the presence of Reed-Sternberg cells (here termed RS cells). The adjacent micrograph shows a typical RS cell, surrounded by normal lymphocytes. RS cells are distinctively large and have multiple nuclei, as in his case, or one nucleus with two lobes. RS cells express CD30 cell surface protein (a member of the tumor necrosis factor receptor family) and CD15 (a blood group antigen carbohydrate on the cell surface). One study reported the RS cells in HL-RT do not express CD20 but another reported that ~35% do. These cells also express a protein located in the cell nucleus, lymphoid enhancer-binding factor 1, in ~80% of cases. The RS cells in HL-RT are spread throughout 1) a CLL/SLL-like background of variably shaped, small lymphocytes or 2) an inflammatory cell-like background of epithelioid histiocytes, eosinophils, and plasma cells that is similar to that found in many cases of Hodgkin's lymphoma not due to RT (here termed HL-not RT). HL-RT cases with the CLL/SLL-like background are termed type 1 (or type I) HL-RT and those with the inflammatory cell-like background are termed type 2 (or type II) HL-RT. While some studies have regarded lesions with the type 1 histopathology as not true HL-RTs, one study reported that, among 26 type 1 and 51 type 2 cases, 3 showed an evolution of type 1 into a type 2 histopathology on serial biopsies and the two types were similarly responsive to chemotherapy regimens used to treat Hodgkin's lymphoma-not RT. A second study reported that the type 1 and 2 histopathology can occur not only in succession but also in the same lesion. Finally, a study of 51 type 2 HL-RT cases showed that the RS cells expressed PAX5 in 100%, CD30 in 100%, CD15 in 92%, CD20 in 47%, and ZAP-70 in 32% of case while 26 type 1 cases had RS cells that expressed these respective proteins in 100%, 100%, 78%, 52%, and 57% of the cases. Here, HL-RT is regarded as consisting of leukemic cells with type 1, type 2, or a mixture of the type 1 with type 2 histopathology.
Epstein-Barr virus in RT More than 90% of the world's population is infected with the Epstein-Barr virus (EBV). During the infection, EBV enters B lymphocytes and may cause infectious mononucleosis, minor non-specific symptoms, or no symptoms. The virus then goes into a latency phase in which infected individuals become lifetime asymptomatic carriers of EBV in their B lymphocytes. Long after its initial infection and latency, EBV may again become active in the B lymphocytes and cause a wide range of EBV-associated diseases including various Epstein–Barr virus–associated lymphoproliferative diseases. EBV reactivation can occur in the B lymphocytes of CLL/SLL and lead to a severer form of CLL/SLL and/or to Richter's transformation. RT transformation has been reported to rarely underlie the development of DLBCL-RT but is associated with the development of type 1 HL-RT in 75% of 51 type 2 cases and 65% of 26 type 1 cases. EBV is detected in 30% to 50% of HL-not RT cases (see Epstein–Barr virus-positive Hodgkin lymphoma). EBV infection in CLL/SLL malignant B lymphocytes is often diagnosed using In situ hybridization to detect Epstein–Barr virus–encoded small RNAs (i.e. EBERs) made by the virus.
Gene abnormalities DLBCL-RT gene abnormalities The malignant B lymphocytes in DLBCL-RT but not DLBCL unrelated to RT (i.e. DLBCL-not RT) carry an inactivated TP53 tumor suppressor gene in 50–60% of cases and often abnormalities in their NOTCH1, MYC, and CDKN2A genes. DLBCL-RT cells usually do not have abnormalities in the genes regulating cell signaling or B lymphocyte differentiation pathways that are often found in the malignant B lymphocytes of DLBCLs-not RT. DLBCL-RT malignant B lymphocytes also lack gene abnormalities commonly found in DLBCLs-not RT such as inactivated acetyltransferase, CREB-binding protein, EP300, beta-2 microglobulin genes; translocations of the BCL6 and BCL2 genes; and losses of PRDM1 and TNFAIP3 genes.