Gastric Large Cell Neuroendocrine Carcinomas: A Distinct Clinicopathologic Entity

Abstract

The current histologic classifications of gastric cancers define only carcinoids and small cell carcinomas in the neuroendocrine (NE) category. This study aimed to characterize the histologic and clinical features of high-grade gastric NE carcinomas of nonsmall cell type, tentatively named large cell neuroendocrine carcinoma (LCNEC). Tumors with histologic features suspicious of NE differentiation were selected by a histologic review of 2835 resected gastric cancers, and those with a NE phenotype in > 50% and 1% to approximately 50% tumor cells assessed by expressing chromogranin A and/or synaptophysin were defined as LCNEC and adenocarcinoma with neuroendocrine differentiation (ACNED), respectively. One hundred ninety-nine tumors were selected and of the 109 positive for chromogranin A and/or synaptophysin, 42 and 44 met the criteria for LCNEC and ACNED, respectively. Generally, LCNECs demonstrated less predominant NE morphology than carcinoids, and could be roughly divided into solid (30 cases), tubular (7 cases), and scirrhous (5 cases) subtypes with reference to their main growth pattern. The prognosis of LCNECs was significantly worse than that of conventional adenocarcinomas (P < 0.0001). Thus, this study shows that the spectrum of gastric NE tumors is broader than has previously been recognized and LCNEC is not only a distinct histopathologic entity, but also a distinct clinical entity. Furthermore, the prognosis of ACNEDs was also significantly worse than that of adenocarcinomas (P < 0.0001), and some ACNEDs might actually have been LCNECs, and survival analysis showed that > 20% positivity of NE markers could be enough to characterize LCNEC, as long as light microscopic NE morphology was present in the tumor.

Increased neuroendocrine cells in resected metastases compared to primary colorectal adenocarcinomas

“…Neuroendocrine differentiation has been described in human adenocarcinomas of the prostate, breast, stomach, lung, and colorectum, among others [1][2][3][4][5][6][7][8]. The clinical significance of this finding is debated and in any case differs among the various organs.…”

“…In the prostate, neuroendocrine differentiation has been demonstrated in therapy naïve cases but it has been specifically associated to hormone refractory cancers and indeed found associated to tumor progression and a worse prognosis [5]. At variance, in breast cancer neuroendocrine differentiation has been consistently demonstrated to lack any prognostic significance [9], whereas its association with a more aggressive disease is still controversial in lung [7,10] and stomach carcinomas [6].…”

Primary neuroendocrine carcinoma of the kidney

“…One such cavity occupied a considerable part of the tumor. Less frequently, large cell neuroendocrine carcinoma is seen 21,22 . Some authors 23,24 claim that neuroendocrine carcinoma of the renal pelvis is more frequently associated with transitional cell carcinoma, adenocarcinoma or squamous cell carcinoma than with the same tumors arising in the renal parenchyma.…”

Extrapulmonary neuroendocrine small and large cell carcinomas: a review of controversial diagnostic and therapeutic issues

“…They are rare or extremely rare outside the lung and can develop in virtually any location. Relatively large series were reported in the gastroenteropancreatic (GEP) area, including the esophagus [6], stomach [7,8], colon and rectum [9], and pancreas [10]. In addition, EPNECs of the small or large type were investigated in the prostate [11,12], bladder [13] and uterine cervix [14,15].…”

“…In the stomach, mixed tumors follow a behavior intermediate between pure LCNEC (the most aggressive subgroup) and conventional gastric adenocarcinoma [7]. In the colon and rectum, the extent of the NE component (within the 30% rule) is not a predictor of behavior, and even a minor high-grade NE cell population was found able to metastasize [50].…”