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A Subset of Large Cell Neuroendocrine Carcinomas in the Gastroenteropancreatic Tract May Evolve from Pre-existing Well-Differentiated Neuroendocrine Tumors

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Abstract

In the gastro-entero-pancreatic (GEP) tract, neuroendocrine neoplasms (NENs) include well differentiated neuroendocrine tumors (NETs) and high-grade NE carcinomas (NECs), which are thought to make up separate and mutually exclusive tumor entities. Little is known, however, as to whether there may be any pathogenetic link between them. Clustering analysis of a 10-gene panel generated from a previously reported next-generation sequencing analysis on 48 GEP-NENs with clinical annotations was used in the study. Unsupervised cluster analysis showed three histology-independent clusters, namely, C1, C2, and C3, which accounted for 44% of patients but the entire array of mutations. All but two NECs fell into the clusters, yet with different prevalence rates (p < 0.0001). A model was devised according to which NETs were likely to evolve into NECs upon progression of C3 into C1 and C2, despite different morphology. The median Ki-67 labeling index was 5% in C3 showing better prognosis and 50% in C1 and C2 experiencing worse prognosis, with an impressive intra-tumor heterogeneity of diversely proliferating tumor areas. This study suggests that a subset of large cell NECs in the gastroenteropancreatic tract may evolve from pre-existing well-differentiated NETs.

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Data Availability

All data and materials being used and presented in this study are available as Supplemental Table 1.

Abbreviations

APC :

APC regulator of WNT signaling pathway

ATM :

ATM serine/threonine kinase

ATRX :

ATRX Chromatin Remodeler

BRAF :

B-Raf proto-oncogene, serine/threonine kinase

CTNNB1 :

Catenin beta 1

DAXX:

Death Domain Associated Protein

IDH1 :

Isocitrate dehydrogenase [NADP(+)] 1

KRAS :

KRAS proto-oncogene, GTPase

PIK3CA :

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

PTEN :

Phosphatase and tensin homolog

RB1 :

RB transcriptional corepressor 1

TP53 :

Tumor protein p53

DNA:

Deoxyribonucleic acid

GEP:

Gastroenteropancreatic

IHC:

Immunohistochemistry

LCNEC:

Large cell neuroendocrine carcinoma

NE:

Neuroendocrine

NEC:

Neuroendocrine carcinoma

NEN:

Neuroendocrine neoplasm

NET:

Neuroendocrine tumor

NGS:

Next-generation sequencing

TNM:

Tumor node metastasis

WD:

Well differentiated

WHO:

World Health Organization

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Acknowledgments

This work is dedicated to the memory of Carlotta, an extraordinarily lively girl who died an untimely death due to cancer in the prime of her life. The authors are indebted with Ms. Cecilia Pelosi for accurate proofreading of the manuscript.

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Author notes

  1. Giuseppe Pelosi and Fabrizio Bianchi are equally contributed to the work.

Authors and Affiliations

  1. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Giuseppe Pelosi

  2. Inter-Hospital Pathology Division, IRCCS MultiMedica, Milan, Italy

    Giuseppe Pelosi & Marco Barella

  3. Cancer Biomarker Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy

    Fabrizio Bianchi & Elisa Dama

  4. Department of Oncology, University of Turin, Turin, Italy

    Jasna Metovic & Mauro Papotti

  5. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy

    Angelica Sonzogni

  6. Laboratory of Vascular Biology and Angiogenesis, IRCCS MultiMedica, Milan, Italy

    Adriana Albini

  7. Department of Pathology, Fox Chase Cancer Centre, Philadelphia, PA, USA

    Yulan Gong

  8. Department of Medical Oncology, Fox Chase Cancer Centre, Philadelphia, PA, USA

    Namrata Vijayvergia

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GP conceived and designed the study, drafted and finalized the manuscript, and shared all statistical analyses; FB carried out clustering analysis, supervised all statistical procedures, shared the study design, and contributed to draft and finalize the manuscript; ED performed all statistical analyses; JM, AS, AA, MP, YG, and NV critically revised the manuscript and finalized the manuscript. All authors approved the submitted version.

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Correspondence to Giuseppe Pelosi.

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Disclosures and Declarations

F.B is a recipient of grants from the Associazione Italiana Ricerca sul Cancro (AIRC) [IG-22827], the Italian Ministry of Health [GR-2016-02363975 and CLEARLY]. N.V. was supported by Cancer Center Support Grant (CCSG) P30 CA006927 to Fox Chase Cancer Center. All the other authors declare that there are no sources of funding. All authors declare that there are no financial or non-financial interests and that the study does not involve humans and/or animals for which specific approval by the ethics committee and/or informed consent are required. Moreover, the study does not have implications for public health or general welfare.

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Approval and Consent to Participate

As this study dealt with reappraisal of previously generated and authorized molecular data by the Fox Chase Cancer Centre’s ethics committee, no further release was necessary. In particular, no new information about patients was collected and no protected health information was used in the current study. The study was performed in keeping with the Declaration of Helsinki and, remarkably, does not contain any individual person’s data, but only aggregated information.

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Pelosi, G., Bianchi, F., Dama, E. et al. A Subset of Large Cell Neuroendocrine Carcinomas in the Gastroenteropancreatic Tract May Evolve from Pre-existing Well-Differentiated Neuroendocrine Tumors. Endocr Pathol 32, 396–407 (2021). https://doi.org/10.1007/s12022-020-09659-6

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