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

Abstract

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.

Keywords: Biopsy diagnosis; Large cell neuroendocrine carcinoma of the lung; Scoring criteria.

Image 1

Morphologic and immune phenotypes of sample large cell neuroendocrine carcinoma (LCNEC) and non-LCNEC tumors (original magnification, ×20). Total score for LCNEC was 7 (architecture = 2, necrosis = 1, neuroendocrine marker positivity = 3, high Ki-67 labeling index [≥40%] = 1). Total score for non-LCNEC was 3 (architecture = 2, necrosis = 0, neuroendocrine marker positivity = 0, high Ki-67 labeling index [≥40%] = 1).

Figure 1

Average total scores in large cell neuroendocrine carcinoma (LCNEC) and non-small cell lung carcinoma (NSCLC). Each dot represents an individual case but cases with overlapping total scores (average from four pathologists) are displayed as a single dot. The mean total scores (long solid lines) with the corresponding values (μ) and the standard deviations (short solid lines) for each phenotypic category are displayed on the graph. The mean total score for LCNEC (5.65) was significantly higher than that for NSCLC (0.51, P < .0001).

Figure 2

Intratumor heterogeneity and reproducibility of the proposed large cell neuroendocrine carcinoma (LCNEC) scoring system. Each dot represents an individual case and the bars represent standard errors of the mean (SEM). A horizontal dotted line is drawn at a mean score of 4, which is the diagnostic cutoff for LCNEC based on the proposed scoring criteria.