Role of PET/CT in the Diagnostic Work-up of Patients with Chronic Lymphocytic Leukemia (CLL) and Clinical Signs of Disease Progression
Authors: Mauro Francesca R , Riminucci Mara , Rossi Davide , Paoloni Francesca , Laurenti Luca , Frustaci Anna M , Cimino Giuseppe , Santopietro Michelina , Spadafora Chiara , Rago Angela , Autore Francesco , Matteo Molica , Simonetta Brocchieri , Nicolai Emanuele , Gaidano Gianluca , Guarini Anna , Paolo Bianco , Foà Robin 
Published: October 2019

Abstract
Abstract 3888
Chronic lymphocytic leukemia (CLL) is a heterogeneous leukemia with a very variable outcome. The occurrence of a second malignancy (SM) or of a disease transformation (DT) may complicate the course of the disease. An aggressive diffuse large B-cell lymphoma (DLBCL) and, less frequently, a Hodgkin's lymphoma (HL) are the most commonly observed forms of DT, defined as Richter's syndrome (RS). Since the presence of enlarged “bulky nodes”, as well as the observation of extra-nodal lesions, can lead both to the suspicion of a CLL progression and to the possibility of a DT or of a SM, a biopsy of the involved tissue is the only appropriate approach for a correct diagnosis. Positron emission tomography/computed tomography (PET/CT) is currently used for the initial staging and restaging of HL and DLBCL, as well as for the identification of other malignancies. In a previous report by Bruzzi et al. (JNM, 2006), PET/CT showed a high predictive value in demonstrating or excluding DT. The same finding has been observed in single case reports, where in patients with CLL a high 18F-FDG uptake was associated with the presence of a DLBCL. With the aim of discriminating the presence of a DT or a SM malignancy, between June 2008 and June 2012, a PET/CT exam followed by the biopsy of the involved tissue was performed in CLL patients from 4 Italian centers. Patients included in this study showed disease progression requiring treatment according to the 2008 revised IWCLL criteria and clinical signs suggestive of the presence of a more aggressive disease, such as rapidly enlarging or bulky lymph nodes (diameter ≥5 cm) and/or extra-nodal lesions associated with at least one additional sign including B systemic symptoms, increased serum lactate dehydrogenase (LDH), increased β2 microglobulin (B2M). The 18F-FDG uptake was correlated with the histologic findings and, for the purpose of this study, a maximum standardized uptake value (SUVmax) ≥5 was considered highly suggestive of a more aggressive disease. Data on 64 CLL patients (median age, 66 years, range, 35–85) were retrospectively analyzed. At the time of PET/CT, the median follow-up from CLL diagnosis was 73 months (range, 3– 227 months) and a Binet C stage was observed in 16 cases (25%). Twenty-three (36%) patients were treatment-naïve and 41 (64%) had been previously treated (median number of prior treatments, 2; range, 1–4), including 14 (22%) refractory cases. Systemic symptoms were recorded in 25% of cases, LDH was increased in 41% and B2M in 72%. The majority of patients (61%) were IGVH unmutated, 45% CD38 positive and 56% ZAP-70 positive. Bulky lymph nodes (diameter ≥5 cm) and/or marked splenomegaly (longitudinal diameter ≥17 cm) were observed in 30 cases (47%). Evidence of extra-nodal disease was recorded in 8 cases (12.5%): thyroid, 2 cases; uterine fundus, 1; gastric,1; bone, 1; nasopharynx, 1; skin infiltrates, 2. The biopsy confirmed a SLL/CLL diagnosis in 44 cases, a DT in 15 (DLBCL, 10; HL, 5) and SM in 5 (thyroid cancer + SLL/CLL, 2 cases; lymph node metastasis of carcynoid + SLL/CLL, 1; lymph-node metastasis of a squamous cancer, 1; lejomioma of the uterine fundus,1). Sites of abnormal 18F-FDG uptake having a SUVmax ≥5 were recorded in a total number of 30 cases, in 13/44 cases (30%) with a SLL/CLL histology, in 13/15 with DT (87%), including 9/10 (90%) cases of DLBCL and 4/5 (80%) HL. An abnormal uptake was recorded also in 4/5 patients with SM. Based on these results, for the diagnosis of a DT or SM, PET/CTPET/CT showed an overall sensitivity, specificity, positive and negative predictive values of 85% 70%, 57% and 91%, respectively, while for the diagnosis of a DT (DLBCL+HL) the sensitivity, specificity, positive and negative predictive values were 87%, 65%, 43% and 94%, respectively. The cases with a SLL/CLL histology having a SUVmax ≥5 were characterized by a higher Ki-67% expression (p=0.0001) suggesting a high rate of cell turnover. Our results show that a PET/CT performed in CLL patients at the time of disease progression can detect cases with a high likelihood of DT or SM, representing therefore a very helpful imaging technique in guiding the appropriate site that should be considered for biopsy.

Disclosures:
No relevant conflicts of interest to declare.