Objective: To establish reproducible electron microscopic criteria for identifying the four major types of neuroendocrine tumors of the lung: carcinoid; atypical carcinoid; large cell neuroendocrine carcinoma; and small cell carcinoma. Methods: Measurements were made on electron micrographs using a digital image analyzer. Sixteen morphometric variables related to tumor cell differentiation were assessed in 27 tumors. The examination under electron microscopy revealed that all of the tumors could be classified as belonging to one of the four categories listed above. Cluster analysis of the morphometry variables was used to group the tumors into three clusters, and Kaplan-Meier survival function curves were employed in order to draw correlations between each cluster and survival. Results: All three clusters of neuroendocrine carcinomas were found to be associated with survival curves, demonstrating the prognostic significance of electron microscopic features. The tumors fell into three well-defined clusters, which represent the spectrum of neuroendocrine differentiation: typical carcinoid (cluster 1); atypical carcinoid and large cell neuroendocrine carcinoma (cluster 2); and small cell carcinoma (cluster 3). Cluster 2 represents an intermediate step in neuroendocrine carcinogenesis, between typical carcinoid tumors and small cell carcinomas. Conclusions: Our findings confirm that electron microscopy is useful in making the diagnosis and prognosis in cases of lung tumor.

Keywords: Neuroendocrine tumors/lung; Microscopy, electron; Cluster analysis; Survival analysis.