The Role of 2-[18F]-FDG PET/CT in Detecting Richter Transformation in Chronic Lymphocytic Leukemia: A Systematic Review

Abstract

Richter transformation (RT) is a condition wherein B cell chronic lymphocytic leukemia (CLL) transforms into a more aggressive lymphoma variant. The incidence and the significance of RT detected by 2-[18F]-FDG PET/CT is a clinical challenge and it is not widely investigated in the literature. The aim of this systematic review was to analyze published data about the potential role of 2-[18F]-FDG PET/CT in detecting RT. A comprehensive computer literature search of the PubMed/MEDLINE, Embase and Cochrane library databases was conducted up to December 2020. Thirteen studies (1336 patients with CLL) were selected. The maximum standardized uptake value (SUVmax) was the most common metabolic parameter used to detect RT. An SUVmax of 5 had an average overall sensitivity of 87% (range: 71–96%), an average overall specificity of 49% (range: 4–80%), an average positive predictive value of 41% (range: 16–53%) and an average negative predictive value of 84% (range: 33–97%). Other metabolic variables were only marginally investigated, with promising results. 2-[18F]-FDG PET/CT imaging may play an important role in the detection of RT in CLL, based on the high metabolic activity of the nodal lesions that transformed into aggressive lymphomas. 2-[18F]-FDG PET/CT has high negative predictive value for evaluating RT.

Unusual Illustration of Richter Transformation in Chronic Lymphocytic Leukemia on FDG PET/CT

“…Richter transformation most commonly occurs in the lymph nodes. In rare cases, involvements of extranodal sites such as bone marrow, central nervous system, pleura, lung, skin, and gastrointestinal tract were also reported 9,10 . FDG PET/CT images of this case illustrated the most severe and most disseminated involvements of Richter transformation in CLL.…”

Approach to relapsed CLL including Richter Transformation

“…In my own practise in patients with relapsed CLL I will consider the following issues (Table 1): Re‐assessment of biological risk profile; especially karyotype (looking for the development of karyotypic complexity) 4 /FISH panel, 5 TP53 mutational status if previously wild‐type, 6–8 presence of resistance mutations for specific targeted therapies if previously exposed ( BTK, PLCG2, BCL2 ), 9–11 and for academic interest where available, repeat genetic mutational profile for such genes as ATM, BIRC3, BRAF, SF3B1, NOTCH, FBXW7, POT1, ASXL1, MyD88. 12 Consider whether there are features present concerning for the development of Richter syndrome 1 ; new onset high fevers, marked elevation of serum LDH, new onset hypercalcemia, dominant bulky adenopathy, atypical extranodal sites of involvement (e.g., bone, CNS, …), or discordant or generalized marked elevation of 18‐F‐Deoxy‐Glucose (FDG) SUVmax (maximum standardized uptake value) on positron emission tomography (PET) scanning 13 Aware of the potential need for future therapy initiation in the medium‐term, and the potential immune suppression associated with such therapy, evaluation of other health issues such as ensuring vaccinations up‐to‐date including seasonal influenza, COVID‐19, pneumococcus, and Varicella zoster , 14 recommended community cancer screening including thorough skin check, 15 cardiovascular risk profile especially hypertension, smoking cessation if applicable, and optimization of physical activity/fitness. Importantly, then closer serial monitoring every 2–4 months of the patient including PB lymphocytosis and levels of normal blood cell parameters (Hb, Neutrophils, and Plts), extent of adenopathy clinically and on imaging, general well‐being and frequency of infections, IgG levels and other indirect laboratory parameters of disease burden (LDH, β 2 ‐microglobulin (β 2 M), albumin, urate) which in aggregate will influence my assessment of kinetics of disease progression and potential triggers for initiation of next line of therapy.…”

“…Consider whether there are features present concerning for the development of Richter syndrome 1 ; new onset high fevers, marked elevation of serum LDH, new onset hypercalcemia, dominant bulky adenopathy, atypical extranodal sites of involvement (e.g., bone, CNS, …), or discordant or generalized marked elevation of 18‐F‐Deoxy‐Glucose (FDG) SUVmax (maximum standardized uptake value) on positron emission tomography (PET) scanning 13 …”

“…Richter syndrome diagnosis requires tissue confirmation, and must be carefully distinguished from “accelerated” CLL 33 . In the context of disease progressing after prior CIT, and SUVmax of >5 on FDG PET had a high specificity for RT (∼80%) 13 . However, among patient treated with novel agents, especially BTKi, higher FDG avidity is typically seen, and the specificity of an elevated SUVmax for RT (even using a cut‐point of 10) is much lower (∼50%), 34 however I still have a low threshold for acquiring an image‐guided core biopsy of a dominant or discordant site of high SUV (>10) to exclude RT, in any patient potentially suitable for intensive therapy, if safe to do so.…”

“…12 -Consider whether there are features present concerning for the development of Richter syndrome 1 ; new onset high fevers, marked elevation of serum LDH, new onset hypercalcemia, dominant bulky adenopathy, atypical extranodal sites of involvement (e.g., bone, CNS, …), or discordant or generalized marked elevation of 18-F-Deoxy-Glucose (FDG) SUVmax (maximum standardized uptake value) on positron emission tomography (PET) scanning. 13 -Aware of the potential need for future therapy initiation in the medium-term, and the potential immune suppression associated with such therapy, evaluation of other health issues such as ensuring vaccinations up-to-date including seasonal influenza, COVID-19, pneumococcus, and Varicella zoster, 14 recommended community cancer screening including thorough skin check, 15 cardiovascular risk profile especially hypertension, smoking cessation if applicable, and optimization of physical activity/fitness.…”