A Semiquantitative Scoring System May Allow Biopsy Diagnosis of Pulmonary Large Cell Neuroendocrine Carcinoma

Experience With Tissue Microarrays

Marina K Baine, MD, PhD; John H. Sinard, MD, PhD; Guoping Cai, MD; Robert J. Homer, MD, PhD


Am J Clin Pathol. 2020;153(2):165-174. 

In This Article

Abstract and Introduction


Objectives: The aim of this study was to devise reproducible biopsy criteria for distinguishing pulmonary large cell neuroendocrine carcinoma (LCNEC) from non-small cell lung carcinoma (NSCLC).

Methods: Tissue microarrays of LCNEC and NSCLC were generated from resection specimens and used as biopsy surrogates. They were stained for neuroendocrine markers, Ki-67, napsin-A, and p40, and independently analyzed by standardized morphologic criteria by four pathologists. Tumors were scored based on morphology, neuroendocrine marker expression, and Ki-67 proliferative index.

Results: The average total score for LCNEC was significantly higher than for NSCLC (5.65 vs 0.51, P < .0001). Utilizing a cutoff score of 4 or higher showed 100% sensitivity and 99% specificity for LCNEC diagnosis, with an excellent agreement among four pathologists (98%).

Conclusions: The proposed semiquantitative approach based on a combination of specific morphologic and immunophenotypic features may be a useful tool for biopsy diagnosis of LCNEC.


Large cell neuroendocrine carcinoma (LCNEC) of the lung is considered a rare entity, representing approximately 3% of primary lung malignancies.[1] Although originally considered a subtype of pulmonary large cell carcinoma,[2] in the 2015 World Health Organization (WHO) classification[3] LCNEC has been grouped with other neuroendocrine tumors, as its clinical and molecular features are more closely related to small cell lung carcinoma (SCLC). Current diagnostic criteria include: (1) non-small cell cytologic features, (2) high mitotic rate of more than 10 mitoses per 2 mm2, and (3) neuroendocrine differentiation by morphology and immunohistochemistry, with the former characterized by organoid nesting, trabecular growth pattern, peripheral palisading, and/or rosette-like structures.[3] Although additional frequently encountered features of LCNEC include extensive necrosis, prominent nucleoli, and a Ki-67 labeling index (LI) greater than 40%,[3] they are not currently required for the diagnosis of LCNEC. Molecular analysis suggests two major subtypes, one more closely related to small cell carcinoma and one more closely related to adenocarcinoma, but with distinct differences from each.[4,5]

Among neuroendocrine tumors, the distinction between SCLC and LCNEC is considered the most difficult.[6] However, among an unselected population of lung carcinomas diagnosed on biopsy, the distinction is most commonly between non-small cell carcinomas vs LCNEC because LCNEC shares cytologic features such as large cell size and prominent nucleoli with non-small cell lung carcinoma (NSCLC) by definition. In this differential, neuroendocrine stains are not generally recommended because generic NSCLC can express these markers as well. More specific features of LCNEC such as palisading and organoid appearance are difficult to visualize on small biopsies. Immunohistochemistry for p40 largely resolves the problem of distinction with a nonkeratinizing basaloid squamous cell carcinoma. However, the problem of distinction from a solid poorly differentiated adenocarcinoma and large cell carcinoma remains.

Watanabe et al[7] were able to diagnose LCNEC on biopsy specimens, as evidenced by concordance with six corresponding resected cases using a combined scoring system that included morphology, neuroendocrine stains, and Ki-67. However, that study did not provide guidelines as to the minimum number of criteria that must be met to make the LCNEC diagnosis. Furthermore, to our knowledge, this approach has not been validated in a larger independent cohort. We report here a more detailed evaluation of this approach using a larger cohort, taking advantage of a tissue microarray as a biopsy surrogate. In our hands, this approach is generally accurate and reproducible for diagnosis of LCNEC in small tissue samples.