Is the sum of positive neuroendocrine immunohistochemical stains useful for diagnosis of large cell neuroendocrine carcinoma (LCNEC) on biopsy specimen?

Abstract

Purpose

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is underdiagnosed on biopsy specimen. We evaluated if routine neuroendocrine immunohistochemical (IHC) stains are helpful in the diagnosis of LCNEC on biopsy specimen.

Methods

Using the Dutch pathology registry (PALGA) surgically resected LCNEC with matching pre‐operative biopsy specimen were identified and Haematoxylin and IHC slides (CD56, Chromogranin‐A, Synaptophysin) requested. Subsequently, three pathologists assigned 1) the presence or absence of the WHO 2015 criteria and 2) cumulative size of all (biopsy) specimen. For validation, a tissue micro array (TMA) of non‐small cell lung cancer (NSCLC) (77) and LCNEC (19) was used.

Results

LCNEC was confirmed on the resection specimen in 32/48 re‐reviewed cases. In 47% (n=15/32) LCNEC was also confirmed in the paired biopsy specimen. Neuroendocrine morphology was absent in 53% (n=17/32) of paired biopsy specimen, more often when fewer amount of tissue was available for evaluation ((29% <5mm (n=14) versus 67% ≥5mm (n=18) P=0.04). Combined with current WHO criteria, positive staining for ≥2 out of 3 neuroendocrine IHC markers increased the sensitivity for LCNEC from 47% to 93% on paired biopsy specimen. Further validated using an independent TMA of LCNEC and NSCLC with sensitivity and specificity of 80 and 99%, respectively.

Conclusions

LCNEC is difficult to diagnose because neuroendocrine morphology frequently is absent in biopsy specimen. In NSCLC devoid of obvious morphological squamous or adenocarcinoma features, positive staining in ≥2 out of three neuroendocrine IHC stains support the diagnosis of LCNEC.

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