Extramedullary Chronic Lymphocytic Leukemia: Systematic Analysis of Cases Reported Between 1975 and 2010

Extramedullary Chronic Lymphocytic Leukemia (EM-CLL) is reported in the literature as case reports and series. The prognosis, patient characteristics, and treatment approaches to EM-CLL have not been fully analyzed in a comprehensive fashion. We therefore conducted a systematic review to better understand EM-CLL and how it might affect patients' clinical course and overall survival.

A comprehensive PubMed search for English-language articles published between 1975 and 2010 in peer-reviewed journals was performed. EM-CLL was defined as CLL identified pathologically in these reports outside the bone marrow. Search terms included “EM-CLL, CLL outside the bone marrow, and CLL with each system [central nervous system (CNS), genitourinary (GU/GYN), gastrointestinal (GI), cardiac, pulmonary, head and neck (H+N), skin, and vascular]. Data regarding location, sex, age at diagnosis, systemic CLL disease setting (relapsed vs. initial diagnosis), laboratory studies/prognostic factors (when available), treatment for CLL (yes or no), use of chemotherapy (yes or no), use of radiation (yes or no), use of rituximab (R), use of purine analogues, outcome (alive or deceased), and follow-up were collected. A z-test was used for assessing proportion differences for gender, stage (Rai 0, 1, 2 vs. Rai 3, 4), and chemotherapy (yes or no). Univariate analyses were performed via the Chi-square test. A backward stepwise logistic regression analysis was performed to identify whether disease location, disease setting, age, and sex influence overall survival (OS). No other multivariate analyses were performed due to large percent of missing data for different variables of interest. A two-tailed P level of 0.05 was considered statistically significant in all analyses; which were performed using SPSS for windows, version 19.0 (SPSS Inc.) and StarStat (DataStar, Inc.).

A total of 192 cases were identified [63 (33%) skin, 51 (27%) CNS, 26 (14%) GI, 20 (10%) GU/GYN, 10 (5%) lung, 10 (5%) ocular, 6 (3%) heart, 5 (3%) H+N, and 1(0.5%) vascular]. Median age at detection of EM-CLL was 62 (range, 25–89); significantly more men were diagnosed with EM-CLL versus women (61% vs. 35%; z = 3.51, P <.001); more patients were at early stage (Rai 0, 1, 2) versus advanced (Rai 3 and 4) at time of EM-CLL but this difference was not statistically significant (22% vs. 18%; z = .43, P =.665). More patients with EM-CLL were treated with chemotherapy for their underlying systemic CLL than not (65% vs. 15%, z = 6.25, P <.001); very few patients received radiotherapy which was delivered for their EM-CLL (n=35; 18%) but treatment information was missing from approximately 20% of cases. Our analysis showed that there was no significant difference with regard to number of patients treated with chemotherapy before and after the contemporary chemoimmunotherapy era (defined here as before and after the year 2000) (87% vs. 78%, p =.171). As far as systemic therapy for CLL, 12% of pts received R and 14% received purine analogues. Tissue sites such as CNS (45%), ocular (33%), H+N (25%), and skin (19%) were significantly more likely to receive XRT (p <.001) but no significant differences between the sites were reported for chemotherapy (p =.106), R (p =.237), and purine analogues (p =.090) usage. OS data was missing in 56 cases (29%), 79 were alive (41%), and 54 (28%) were dead at the time of case reporting. Backward stepwise logistic regression analysis, which included data for 102 (53%) patients showed that EM-CLL detected in patients with systemic relapse had worse OS compared to those with EM-CLL at time of initial CLL diagnosis (p =.027), while no significant effect on OS was found for tissue site (p =.085), age (above or below 70, p =.796), and sex (p =.791). All other variables were not significant.

To our knowledge, this analysis represents the largest collection of EM-CLL series examined comprehensively. EM-CLL is not an uncommon presentation in the spectrum of CLL/SLL with skin and CNS being the most commonly affected organs (33% and 27% respectively). Patients who develop EM-CLL in the relapsed setting have significantly worse OS compared to those who manifest EM-CLL at the time of initial diagnosis. We propose that this subset of CLL needs a prospective and robust accumulation of prognostic and clinical data as it will be critical in defining how extramedullary presentation affects the biology and natural course of CLL.

No relevant conflicts of interest to declare.