Prognostic significance of pulmonary multifocal neuroendocrine proliferation with typical carcinoid

Background: Clinical significance of multifocal pulmonary neuroendocrine proliferation (MNEP), including tumorlets and pulmonary neuroendocrine cell hyperplasia, in association with Typical Carcinoid (TC), is still debated. Methods: A retrospective series of TC with long-term follow-up data prospectively collected from two institutions was evaluated, and the outcome comparison between TC alone and MNEP+TC was investigated. Several baseline covariates were imbalanced between the MNEP+TC and TC groups, therefore, we have conducted 1:1 propensity score matching and inverse probability of treatment weighting (IPTW) in the full sample. In the matched group, association of clinical, respiratory and work-related factors with group was determined through univariable and multivariable conditional logistic regression analysis. Results: 234 TC patients have undergone surgery: 41 MNEP+TC(17.5%) and 193 TC alone(82.5%). In the MNEP+TC group older age(p<0.001), peripheral tumors(p=0.0032), smaller tumor size(p=0.011) and lymph-nodal spread(p=0.02) were observed in comparison with TC group. Relapses occurred in 8 patients (19.5%) of MNEP+TC group and in 7(3.6%) of TC group. After matching, in 36 pairs of patients a significantly higher 5-years progression-free rate was observed for TC group(p<0.01). Similar results were observed using IPTW in the full sample. Odds of being in the MNEP+TC group was higher with work-related exposure to inhalant agents(p=0.008), asthma/bronchitis(p=0.002), emphysema, fibrosis and inflammatory status(p=0.032), micronodules on the chest CT scan and respiratory insufficiency(p=0.036). Conclusions: The association with MNEP seems to represent a clinically and prognostic relevant factor in TC. Hence, careful pre-operative workup, systematic pathological evaluation, including non-tumorous lung parenchyma, and long-term postoperative follow-up should be recommended in these patients.