Stage IV lung carcinoids: spectrum and evolution of proliferation rate, focusing on variants with elevated proliferation indices

Abstract

The spectrum and evolution of proliferation rates in stage IV lung carcinoids is poorly defined. In particular, there are limited data on the prevalence and characteristics of tumors exceeding the standard upper proliferative criteria – as defined largely based on early-stage carcinoids – in metastatic setting.Sixty-six patients with stage IV lung carcinoids were identified, and all evaluable samples (n=132; mean 2 samples per patient) were analyzed for mitotic counts and Ki-67 rate. Clinicopathologic and genomic features associated with elevated proliferation rates (>10 mitoses per 2 mm2 and/or >20% hot-spot Ki-67), and evolution of proliferation rates in serial specimens were analyzed.We found that mitoses and/or Ki-67 exceeded the standard criteria in 35 of 132 (27%) samples, primarily (31/35 cases) from metastatic sites. Although neuroendocrine neoplasms with >10 mitoses per 2 mm2 are currently regarded as de facto neuroendocrine carcinomas, the notion that these cases are part of the spectrum of carcinoids was supported by 1) well-differentiated morphology, 2) conventional proliferation rates in other samples from same patient, 3) genetic characteristics, including the lack of RB1/TP53 alterations in all tested samples (n=19), and 4) median overall survival of 2.7 years, compared to <1 year survival of stage IV neuroendocrine carcinomas in the historic cohorts. In patients with matched primary/metastatic specimens (48 pairs), escalation of mitoses or Ki-67 by ≥10-points was observed in 35% of metastatic samples; clonal relationship in one pair with marked proliferative progression was confirmed by next-generation sequencing. Notably, escalation of proliferation rate was documented in a subset of metastases arising from resected typical carcinoids, emphasizing that the diagnosis of typical carcinoid in primary tumor does not assure low proliferation rate at metastatic sites.In conclusion, stage IV lung carcinoids frequently exceed the standard proliferative criteria established for primary tumors, and commonly exhibit proliferative escalation at metastatic sites. Despite the overlap of proliferation rates, these tumors show fundamental morphologic, genomic and clinical differences from neuroendocrine carcinomas, and should be classified separately from those tumors. Awareness of the increased proliferative spectrum in metastatic carcinoids is critical for their accurate diagnosis. Further studies are warranted to explore the impact of proliferation indices on prognosis and therapeutic responses of patients with metastatic carcinoids.

Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology

“…A molecular study by next-generation sequencing (NGS) also found a "carcinoid-like" subgroup among highly proliferative LNET [7]. This entity was also observed in a recent large study of stage IV carcinoids, accounting for 27% of the samples [8]. There is still no consensus concerning the name of this entity and the terms "high-grade lung carcinoids," "grade 3 atypical carcinoids," "high-grade lung NET," "lung NET G3," "lung well-differentiated neuroendocrine neoplasms with a Ki-67 > 20%," "lung carcinoid with a Ki-67 > 20%," or "high-grade NEC of the lung with carcinoid morphology" have been discussed [6,[9][10][11].…”

“…Lung neuroendocrine neoplasms with morphologic features of carcinoid tumours but of high grade have recently been reported. They are rare tumours, the largest recent series describing the pathological aspect of 12 and 28 cases [6,8]. Their definition does not reach consensus yet and they are not included in the official WHO classification.…”

“…Several reports suggest that they could evolve from a previously low-grade (G1 or G2) NET and that they may simultaneously display heterogeneous areas of grading [13][14][15][16][17]. These characteristics may be shared with their thoracic counterparts [8]. The genomic alterations underlying the pathogenesis of these rare tumours in the lung have not been characterised so far.…”

Effect of metastatic site on survival in patients with neuroendocrine neoplasms (NENs). An analysis of SEER data from 2010 to 2014

“…Our approach in this paper is similar to other large SEER studies [3 24] but can definitely alter the reported results. The GI NEN literature is moving to a more uniform grading of neoplasms and there is a trend to use proliferation markers to predict outcomes in lung NENs as well [25,26] but this is far from a settled argument. Another issue is that classification of pancreatic NENs (and most recently other GI NENs) has changed to include a category of "well differentiated, high grade" with a prognosis intermediate between G2 and G3.…”

Large cell neuroendocrine carcinoma with a solitary brain metastasis and low Ki-67: a unique subtype

“…1). This subgroup might comprise high-grade NET, which has been recently described in several studies although not recognized in current WHO classification (19, 20, 21). However, in those series, the tumors had a carcinoid morphology and absence of TP53 and RB1 mutations.…”