The Development of Diagnostic Criteria and Utilization of Excisional Lymph Node Biopsies Shorten Time to Diagnosis for Idiopathic Multicentric Castleman Disease

Background:

Idiopathic multicentric Castleman Disease (iMCD) is a rare lymphoproliferative disorder defined by multifocal lymphadenopathy and systemic inflammation potentially causing end-stage organ failure and death. iMCD patients have either a severe TAFRO (thrombocytopenia, anasarca, fever/reticulin fibrosis, organomegaly) subtype or a milder NOS (Not Otherwise Specified) subtype. iMCD patients often endure a lengthy path to diagnosis, requiring imaging, a lymph node (LN) biopsy, and blood work in addition to the exclusion of more common disorders. We investigated the morbidity of delayed diagnosis, the impact of 2017 consensus diagnostic guidelines, differences in diagnostic time between subtypes, and impact of LN biopsies on diagnosis times.

Methods:

The ACCELERATE Natural History Registry identified 110 iMCD patients whose diagnoses were confirmed by a panel of expert clinicians and pathologists. Time to diagnosis was defined as days from the first day of a patient’s reported symptoms to the date of their diagnostic LN biopsy. We compared diagnosis times between iMCD subtypes before (2017 or earlier) and after (2018 or later) published diagnostic guidelines. We calculated the number and types of LN biopsies and pathology consultations required before an iMCD diagnosis.

Results:

The cohort of 110 iMCD patients consisted of 49 (45%) females and 61 males (56%) with a median (Interquartile Range, IQR) age of 37 (22, 48) years and a range of 2-75 years. Forty-three (39%) patients were classified as NOS and 67 (61%) were classified as TAFRO. Fifty-one (46%) patients were diagnosed following the development of diagnostic guidelines. The median (IQR) time to diagnosis for the full cohort of 110 patients was 51 (21, 153) days, with a range of 2-3626 days. NOS patients faced significantly longer diagnosis times than TAFRO patients, with median (IQR) days to diagnosis of 96 (45, 338) days compared to 31 (14, 85) days (W=2148, p=1.5 x 10^-5). Patients diagnosed before publication of the guidelines had a median (IQR) diagnosis time of 74 (24, 241) days, significantly longer than the 34 (19, 90) days it took for patients to be diagnosed following publication of the guidelines (W=1145, p= 0.03). This reduction in diagnosis times was driven almost entirely by a reduction in median diagnosis times for NOS patients diagnosed after publication (65 vs. 218 days, W=349, p=0.009).

We investigated the consequences of delayed diagnosis on patient outcomes. TAFRO patients with the longest time to diagnosis (upper two quartiles) spent more time hospitalized prior to diagnosis than those with the shortest time to diagnosis (bottom two quartiles), with a median (IQR) of 24 (6, 44) days hospitalized compared to 8 (4, 16) (W=748, p=0.006).

iMCD patients received a median (IQR) of 1 (1, 2) LN surgeries and 2 (1, 3) pathology consultations prior to diagnosis, with ranges of 1-6 and 1-7, respectively. Time to diagnosis was positively correlated with the number of pathology consults (r = 0.3772, p = 5.0 x 10^-5) and LN biopsies (r=0.35382, p = 1.5 x 10^-4). Thirty-two (29%) patients received a core needle biopsy before an excisional biopsy, while 78 (71%) patients began with an excisional biopsy. The median time from first biopsy to diagnosis was significantly shorter for patients who began with an excisional biopsy (W=1893, p=1.0 x 10^-6), indicating that core needle biopsies delay diagnosis. From the 110 iMCD patients, only 2 (2%) patients were diagnosed from a core biopsy.

Discussion:

iMCD patients frequently encounter diagnostic delays, which can lead to increased morbidity. NOS subtype patients faced longer diagnosis times than TAFRO patients, likely due to a more indolent presentation. Following the consensus diagnostic guidelines in 2017, there was a shortening in the time to diagnosis by 54% overall and by 70% for NOS patients, reducing the disparity between NOS and TAFRO. TAFRO patients who had longer times to diagnosis spent more time hospitalized, highlighting the morbidity of diagnostic delays. Lastly, we showed that core needle biopsies are rarely sufficient for an iMCD diagnosis and delay an accurate diagnosis. Altogether, our findings point to the morbidity of diagnostic delay and emphasize the importance of consensus diagnostic guidelines and excisional LN biopsies in reducing the time to diagnosis. Our findings also highlight the need for a serum biomarker or alternative diagnostic approach to reduce the time to diagnosis.