Predisposing Factors for Richter's Transformation
Extensive studies of genomic changes occurring in Richter's transformation were reported by Rossi et al.[11,21] Factors that were seen to predispose to Richter's transformation were different from the risk factors associated with CLL progression. Specific guidelines for interventions in patients having risk factors for Richter's transformation are not yet available.
A pilot study reported by Rossi et al in 2008 involving 185 CLL patients and paired samples (CLL and Richter's transformation in the same patient) has shown that the following factors predispose to Richter's transformation in a patient with CLL. (Detailed discussions of the pathological mechanisms behind these factors are beyond the scope of this article.)
1. CD38 expression (CD38 ≥ 30%)
2. Stereotyped B-cell receptor
3. IGHV4-39 gene usage
4. Telomere length < 5000 base pairs
5. Lymph node size > 3 cm
6. Absence of del13q14
Other studies have reported on polymorphisms with CD38 and LRP4 genes. CD38 GG homozygous patients had a 30.6% increased risk compared with the risk in patients having the GC or CC genotype and patients having the LRP4 TT genotype (which is related to Wnt signaling pathways in CLL).
NOTCH1 mutations were recently shown to predict for the development of Richter's transformation, while SF3B1 mutations did not.
Currently, there is no evidence that treatment with purine analogues (fludarabine, cladribine(Drug information on cladribine)), alone or in combination with cyclophosphamide(Drug information on cyclophosphamide) and rituximab(Drug information on rituximab) (Rituxan), can increase the risk of Richter's transformation in patients with CLL.
Prognostic Factors in Richter's Transformation
In 2006, one of the largest studies in patients with Richter's transformation (n = 148) proposed a prognostic scoring system (Richter's transformation Score). Five factors that significantly predicted for poor outcome in patients with Richter's transformation were:
• Zubrod performance status > 1
• Elevated lactate dehydrogenase (LDH) levels (> 1.5 times normal)
• Platelet count < 100 × 109/L
• Tumor size > 5 cm
• Prior therapies > 1
Patients were divided into low-, low-intermediate–, high-intermediate–, and high-risk categories based on the number of risk factors at the time of presentation (identified by scores of 0–1, 2, 3, and 4–5, respectively). Median survival of patients in low-, low-intermediate–, high-intermediate–, and high-risk categories was 1.12, 0.9, 0.33, and 0.2 years, respectively (Figure 2).
Histopathology of Richter's Transformation
Biopsy of the involved site (core needle/excisional) is necessary to confirm the diagnosis of RT. Morphologically, specimens from Richter's transformation show large atypical cells with centroblastic/immunoblastic morphology. The majority (about 80%) of diffuse large B-cell lymphoma cases in Richter's transformation displays a post–germinal center (GC) phenotype (MUM1/IRF4 expression) and only a few cases will show a GC variety (CD10 and BCL6 expression). CD20 expression is generally bright, while CD5 and CD23 expression may be dim to negative in Richter's transformation. The proliferation marker Ki-67 can be highly expressed in large cells of Richter's transformation. Rarely, Richter's transformation can also present with a Hodgkin's variant with Reed Sternberg (R-S) cells, with expression of CD15 and CD30 by the R-S cells similar to that seen in de novo Hodgkin's disease.
Approach to a Patient With Suspected Richter's Transformation
Suspect Richter's transformation when a patient with CLL presents with a rapidly deteriorating clinical profile and enlargement of lymph nodes, prominent B symptoms (night sweats, weight loss, fever without infection), and extranodal involvement (such as involvement of the central nervous system, skin, stomach, testes, eyes, or lungs). Pancytopenia is common. Elevated LDH levels are common. Hypercalcemia with or without lytic bone lesions and monoclonal gammopathy can also be seen.
PET-CT (positron emission tomography–computed tomography) scanning may be quite helpful in diagnosing Richter's transformation. An abnormal increase in uptake of the tracer 18F-FDG (18-fluorodeoxyglucose, a glucose analogue) on PET-CT with standardized uptake value (SUV) > 5 is highly suggestive of the development of Richter's transformation. In a study of 37 patients with CLL, 11 patients developed Richter's transformation, and PET-CT scanning detected Richter's transformation with a sensitivity, a specificity, and positive and negative predictive values of 91%, 80%, 53%, and 97%, respectively. Particular attention to the following factors is needed when examining results from PET-CT scans for evidence of suspected Richter's transformation:
• False-positive results can be caused by granulomas, additional malignancies, or infections.
• A uniform method of calculating SUV from the same instrument must be used.
• Poor scanner quality control can result in false-positives.
• Chemotherapy and other immunotherapies increase the likelihood of false-positive PET results.
• Attention must be paid to the type of chemotherapy administered: one study showed that a negative biopsy following a positive PET-CT scan was fairly common after dose-intense chemotherapy.
• Rigorous quality control must be maintained to compensate for variability in data acquisition and image reconstruction.
• Newer biologic agents may inhibit glucose uptake and thus may reduce SUV.
Routine use of PET-CT in clinical practice to detect Richter's transformation in CLL is not necessary. Nevertheless, PET-CT can indicate a site of Richter's transformation amenable to biopsy, since all nodes may not be involved. Biopsy with a pathologic diagnosis remains the gold standard for diagnosing Richter's transformation. Gallium-67 scanning was used in the past to differentiate Richter's transformation from CLL, but is of limited value in the current era.