Prognostic significance of laterality in lung neuroendocrine tumors

Abstract

Purpose: Well-differentiated lung neuroendocrine tumors (Lu-NET) are classified as typical (TC) and atypical (AC) carcinoids, based on mitotic counts and necrosis. However, prognostic factors, other than tumor node metastasis (TNM) stage and the histopathological diagnosis, are still lacking. The current study is aimed to identify potential prognostic factors to better stratify lung NET, thus, improving patients' treatment strategy and follow-up.

Methods: A multicentric retrospective study, including 300 Lung NET, all surgically removed, from Italian and Spanish Institutions.

Results: Median age 61 years (13-86), 37.7% were males, 25.0% were AC, 42.0% were located in the lung left parenchyma, 80.3% presented a TNM stage I-II. Mitotic count was ≥2 per 10 high-power field (HPF) in 24.7%, necrosis in 13.0%. Median overall survival (OS) was 46.1 months (0.6-323), median progression-free survival (PFS) was 36.0 months (0.3-323). Female sex correlated with a more indolent disease (T1; N0; lower Ki67; lower mitotic count and the absence of necrosis). Left-sided primary tumors were associated with higher mitotic count and necrosis. At Cox-multivariate regression model, age, left-sided tumors, nodal (N) positive status and the diagnosis of AC resulted independent negative prognostic factors for PFS and OS.

Conclusions: This study highlights that laterality is an independent prognostic factors in Lu-NETs, with left tumors being less frequent but showing a worse prognosis than right ones. A wider spectrum of clinical and pathological prognostic factors, including TNM stage, age and laterality is suggested. These parameters could help clinicians to personalize the management of Lu-NET.

Keywords: Ki67 index; Lung neuroendocrine tumors; Mitotic count; Necrosis; Prognostic factors.; Tumor location.

Fig. 1

Patients’ selection flowchart

Fig. 2

a Pathological features of the study population. b Surgical data (intervention yes/no, resection margins and type of surgery) of the study population

Fig. 3

a–c Typical lung carcinoid. Endobronchial, right-sided, lesion (a) showing an organoid architecture (b) and low Ki-67 proliferative index (c). d–f Atypical carcinoid lung carcinoid. Peripheral, left-sided, lesion (d) with well-differentiated morphology (e) and high Ki-67 proliferative index (exceeding 20%) (f) a, d: original magnification x100; b, c, f: original magnification x200; e: original magnification x400

Fig. 4

a Kaplan–Meier survival curves of the clinic-pathological variables with significant impact on patient’s survival in terms of PFS. p-values have been considered as significant if <0.05 and are reported according to the corresponding univariant Cox regression analysis. b Kaplan–Meier survival curves of the clinic-pathological variables with significant impact on patient’s survival in terms of OS. p-values have been considered as significant if <0.05 and are reported according to the corresponding univariant Cox regression analysis

Fig. 4

a Kaplan–Meier survival curves of the clinic-pathological variables with significant impact on patient’s survival in terms of PFS. p-values have been considered as significant if <0.05 and are reported according to the corresponding univariant Cox regression analysis. b Kaplan–Meier survival curves of the clinic-pathological variables with significant impact on patient’s survival in terms of OS. p-values have been considered as significant if <0.05 and are reported according to the corresponding univariant Cox regression analysis