Asymptomatic Multicentric Castleman Disease: A Potential Early Stage of Idiopathic Mcd

Introductions: In 2017, the Castleman Disease Collaborative Network (CDCN) published the first international, evidence-based consensus diagnostic criteria for HHV-8 (human herpesvirus-8) negative/idiopathic multicentric Castleman disease (MCD), a rare and sometimes life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, as well as multiple organ system dysfunction. According to this consensus, HHV-8 negative MCD was regarded as idiopathic MCD (iMCD) due to unknown etiology. However, there was a group of HHV-8 negative MCD patients who did not exhibit symptoms indicative of a hyperinflammatory state and therefore did not meet the minor criteria of iMCD proposed by CDCN. It was still unknown whether this subgroup of patients, regarded as asymptomatic MCD (aMCD), represented a ‘pre-stage’ of iMCD, which would eventually suffer from clinical and laboratory abnormalities over time, or if these patients belonged to a unique subset of MCD patients. Herein, we conducted a multicenter, retrospective study focusing on the follow-up information and potential transformation of aMCD patients, trying to figure out whether these patients would eventually exhibit inflammatory symptoms and laboratory abnormalities and transform into iMCD.

Methods: This observational, retrospective study enrolled aMCD patients from 2000 to 2021 in 26 Chinese medical centers. The inclusion criteria for aMCD patients who were eligible for this study were: HHV-8 negative MCD patients who met both major criteria (histopathologic evidence plus ≥ 2 lymph node stations involvement) but did not fulfill the minimal requirements of minor diagnostic criteria (at least 2/11 minor criteria with ≥ 1 laboratory criterion) proposed by CDCN. Demographic, clinical, laboratory data, including age, gender, medical history, histopathologic subtypes, symptoms and signs, radiological findings, treatment options at the stage of aMCD, were extracted from medical records. Patient follow-up information was collected from medical record systems and via telephone contacts. Patients were followed until March 31, 2023 and survival status was documented. The time-point when a patient developed symptoms and/or new laboratory abnormalities and fulfilled the CDCN diagnostic criteria of iMCD was recorded. Chi-square tests and t tests were used to compare dichotomous variables and continuous variables, respectively. The Kaplan-Meier method was used to depict survival curves and log-rank test was utilized to compare.

Results: A total of 114 patients with aMCD were enrolled. Among them, there were 60 (52.6%) males and 54 (47.4%) females. The median age at diagnosis of aMCD was 45.5 years (range: 10-79 years). Adult patients (≥18 y/o) accounted for 92.1%. After diagnosis of MCD, although the patients did not have inflammatory symptoms or laboratory abnormalities, 43 patients (37.7%) received treatment targeting MCD. Notably, the majority of patients received lymphoma-like intensive chemotherapy (eg. CHOP, R-CHOP) for this asymptomatic entity. With a median follow-up time of 46.5 months (range: 4-279 months), 6 patients (5.3%) transformed to iMCD. The median time between diagnosis of aMCD and iMCD in these 6 patients was 28.5 months (range: 3-60 months). Gender, age at diagnosis of aMCD, extent of lymph node involvement (the same side or both sides of diaphragm), pathological subtype and systemic therapy targeting MCD were not associated with the probability of transformation to iMCD. During follow-up, 7 patients died; three of them died from progression of MCD. Despite that 37.7% patients received systemic treatment targeting MCD, this strategy was neither associated with a lower probability of iMCD transformation nor a lower death rate. The 5-year estimated survival rate of patients who maintained aMCD was 94.9% while the 5-year estimated survival rate of patients who ultimately transformed to iMCD was 83.3%. Transformation to iMCD was an important predictor of death (log-rank p=0.01).

Conclusions: aMCD might be regarded as a potential early stage of iMCD that does not need immediate treatment but should be closely monitored.