Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) in patients with pulmonary carcinoid tumours: Prevalence and prognosis of an under-recognised disease

Background: DIPNECH is considered a rare condition and the natural history is poorly described. Its prevalence is likely underestimated given the absence of routine reporting on histopathology and often insufficient background lung parenchyma in the setting of lung biopsy. It is thought to give rise to pulmonary carcinoids (PCs) (>5 mm) or tumourlets (≤5 mm). We aimed to assess the prevalence and characteristics of DIPNECH in the PC population and to investigate predictors of progression-free (PFS) and overall survival (OS). Methods: We identified patients with PCs plus histologically-proven DIPNECH and/or high suspicion of DIPNECH on imaging. The relationship between baseline characteristics and PFS and OS was analysed using the Kaplan-Meier method and curves were compared using the logrank test. Results: 46/233 (20%) patients with well-differentiated PCs and DIPNECH were identified (91% female, 52% never smokers, 50% cough and/or dyspnoea at time of diagnosis, 76% typical carcinoids (TC), 24% atypical carcinoids (AC), 9% both TC and AC) had median follow-up 37 mo (range 2-138 mo). Multicentric carcinoids were demonstrated in 11 (24%) patients on histopathology and a further 26 (57%) patients had synchronous carcinoids suggested on enhanced CT (multiple nodules >5 mm). Median PFS was 10.4 years. Six (13%) patients developed regional or distant metastases after a median of 25 months (8-125 mo) and most patients had higher proliferative indices on biopsy of metastases compared to histopathology at diagnosis. Atypical carcinoid morphology (PFS p-value 0.0006, OS p-value 0.03) and carcinoid TNM stage (PFS p-value p < 0.0001, OS p-value 0.006) was associated with shorter PFS and poorer OS. Of the entire cohort, ten year survival rate was 87%. Median OS was not reached. Conclusions: DIPNECH may be more prevalent in the PC population than previously appreciated, especially in women. Whilst our results confirm DIPNECH is predominantly an indolent disease associated with TCs, up to one quarter of patients may develop ACs and these patients may warrant closer observation. Median PFS is long and lifelong follow-up is recommended. Legal entity responsible for the study: Aimee Hayes. Funding: Has not received any funding. Disclosure: A. Grossman: Lecture fees: Novartis, Ipsen, HRA Pharma, Pfizer, but none for the past 12 months. C. Toumpanakis: Speaker honoraria: Ipsen, Novartis, AAA. M. Caplin: Advisory board and speaker honoraria: Novartis, Ipsen, AAA, Lexicon. All other authors have declared no conflicts of interest.