Multiregion Comprehensive Genomic Profiling of a Gastric Mixed Neuroendocrine-Nonneuroendocrine Neoplasm with Trilineage Differentiation

Abstract

Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) are a group of rare tumors previously known as mixed adenoneuroendocrine carcinomas (MANECs). The neuroendocrine component is high-grade and may consist of small-cell carcinoma or large-cell neuroendocrine carcinoma. The nonneuroendocrine component may consist of adenocarcinoma or squamous cell carcinoma. We report a unique case of a MiNEN with trilineage differentiation: large-cell neuroendocrine carcinoma, squamous cell carcinoma, and adenocarcinoma. The reported patient presented with symptoms of an upper gastrointestinal bleed and was ultimately diagnosed with a MiNEN with trilineage differentiation. This is the first report of this exceedingly rare tumor type to include next-generation sequencing of the 3 separate tumor entities. In addition, we review the current literature and discuss the role of next-generation sequencing in classifying and treating MiNEN tumors.

Mixed Neuroendocrine Non-Neuroendocrine Neoplasms: A Systematic Review of a Controversial and Underestimated Diagnosis

“…In the majority of cases where the neuroendocrine and non-neuroendocrine components of MiNEN could be analysed separately, the two components exhibited a core of common alterations, supporting the hypothesis of their common clonal origin, but also alterations exclusively present in one or the other the two components [29,30,58,79,95,97], suggesting that at some point of the tumourigenic process, two distinct morphology entities emerge through the activation of separate genetic programmes. Usually, shared mutations involved well-characterised cancer drivers (e.g., TP53, APC, KRAS, BRAF) and have higher allele frequencies (compared to alterations which are exclusive of a single component), suggesting their occurrence in the earlier stages of the development of MiNENs [29,58,79,93,97]. In support of this, Yuan et al performed multiregional next-generation sequencing analysis on samples from spatially separated regions from two patients with oesophageal MiNEN to interrogate intra-tumour heterogeneity and clonal evolution; alterations in TP53, RB1, PTEN, PI3KCA, and KRAS were identified in all tumour samples/regions from both patients and had higher allele frequencies (compared to alterations not present in all samples/regions).…”

“…The quantitative composition of the primary tumour was described in 36 studies (n = 294) [12,15,17,19,21,[23][24][25]27,29,30,34,36,[39][40][41]45,46,[48][49][50][52][53][54]56,57,59,65,73,74,80,82,[84][85][86]92]; the two components were present in equal proportion in 27.9% (n = 82) of cases, whereas in the remaining 72.1% one of the two histologies was predominant; the neuroendocrine component in 42.2% (n = 124), the non-neuroendocrine component in 29.9% (n = 88).…”

“…Among 69 studies (n = 667) reporting the grade of differentiation of the neuroendocrine component [11][12][13][14][15][16][17][18][19][21][22][23][24][25][26][27][28][29][54][55][56][57][58][59][60][61][62]68,71,[73][74][75]79,80,82,[84][85][86][87]89,[91][92][93]96,97,100,101], a large proportion of MiNENs (92.5%; n = 617) had a grade 3 neuroendocrine component, whereas 4.3% (n = 29) and 3.1% (n = 21) had a grade 1 and a grade 2 neuroendocrine component, respectively. Among MiNENs with a grade 3 neuroendocrine component, the morphological subtype (large cell or small cell) was reported in 25 studies (n = 241) [11,…”

“…Twenty studies (n = 381) reported on the genetic/molecular alterations underlying MiNEN [29,30,35,58,59,64,67,71,72,77,79,81,82,85,89,[91][92][93]95,97]. In 49.1% of cases where genetic/molecular data was available, the site of origin of MiNEN was the colon-rectum.…”

<p>Clinicopathological Characteristics and Prognostic Factors of Patients with Gastric Cancer Accompanying Neuroendocrine Differentiation (NEDGC)</p>

“…According to the definition by the World Health Organization (WHO) in 2010, 1 NEDGC is a gastric neoplasm in which differentiated neuroendocrine (NE) cells are scattered as single cells or cell clusters among gastric carcinoma cells. NEDGC distinguishes itself from mixed adeno-neuroendocrine carcinoma (MANEC), which has been renamed to mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) in the WHO 2017 classification, 2,3 by the volume of epithelial and NE cells components within the same tumor tissue.…”