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
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