An update on the development of concepts, diagnostic criteria, and challenging issues for neuroendocrine neoplasms across different digestive organs

Couvelard, Anne; Cros, Jérôme

doi:10.1007/s00428-022-03306-7

Cited by 8 publications

(3 citation statements)

References 125 publications

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“…Ki‐67 alone cannot be used, although a recent report shows that the 55% cutoff is best to discriminate NEC from NET G3 27 . When morphology is ambiguous, immunohistochemistry (IHC) can be performed with a panel of antibodies: ATRX/DAXX (loss of expression favors pancreatic NET), Menin (loss of expression favors pancreatic/lung NET), Somatostatin receptor‐2 (high expression favors NET), TTF1 (high expression in digestive primary favors NEC), Rb (loss of expression favors NEC) and p53 (either strong and diffuse expression or complete loss of expression favors NEC) 28 . Some of these markers could be analyzed by NGS testing, especially in case of unclear IHC result, but IHC‐NGS correlation data on large series are so far lacking.…”

Section: Diagnosismentioning

confidence: 99%

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma

Sørbye

Grande

Pavel

et al. 2023

J Neuroendocrinology

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This ENETS guidance paper, developed by a multidisciplinary working group, provides up‐to‐date and practical advice on the diagnosis and management of digestive neuroendocrine carcinoma, based on recent developments and study results. These recommendations aim to pave the road for more standardized care for our patients resulting in improved outcomes. Prognosis is generally poor for digestive NEC, most are advanced at diagnosis and median survival in metastatic disease is 11–12 months. Surgery can be of benefit for localized disease after extensive preoperative imaging. Carboplatin in combination with etoposide is recommended as first‐line treatment for metastatic disease. Irinotecan with fluoropyrimidines has the best evidence as second‐line treatment. Immunotherapy plays a minor role in biomarker‐unselected patients. Molecular profiling if available is encouraged to identify new targets. More prospective clinical trials are highly needed to fulfil the unmet needs in this field, especially on new predictive and prognostic biomarkers and to improve survival of patients with advanced disease.

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Section: Diagnosismentioning

confidence: 99%

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma

Sørbye

Grande

Pavel

et al. 2023

J Neuroendocrinology

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“…In addition to the traditional neuroendocrine markers synaptophysin and chromogranin A, insulinoma‐associated protein 1 (INSM1), a zinc‐finger transcription factor that regulates neuroendocrine cell differentiation [ 9 ], has been established as a complementary marker for the diagnosis of neuroendocrine neoplasms [ 10 ]. While high sensitivity and specificity [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ] of INSM1 expression have been reported for neuroendocrine neoplasms from various anatomic sites, a specific evaluation of INSM1 expression in colorectal MANECs/NECs is still lacking. Furthermore, there are no data regarding the frequency and prognostic relevance of INSM1 expression in conventional CRCs and it is also not known whether INSM1 expression in conventional CRCs and MANECs/NECs is fully comparable to the expression of the traditional neuroendocrine markers synaptophysin/chromogranin A.…”

Section: Introductionmentioning

confidence: 99%

High expression of insulinoma‐associated protein 1 (INSM1) distinguishes colorectal mixed and pure neuroendocrine carcinomas from conventional adenocarcinomas with diffuse expression of synaptophysin

Litmeyer,

Konukiewitz,

Kasajima

et al. 2023

The Journal of Pathology CR

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Complementary to synaptophysin and chromogranin A, insulinoma‐associated protein 1 (INSM1) has emerged as a sensitive marker for the diagnosis of neuroendocrine neoplasms. Since there are no comparative data regarding INSM1 expression in conventional colorectal adenocarcinomas (CRCs) and colorectal mixed adenoneuroendocrine carcinomas/neuroendocrine carcinomas (MANECs/NECs), we examined INSM1 in a large cohort of conventional CRCs and MANECs/NECs. In conventional CRC, we put a special focus on conventional CRC with diffuse expression of synaptophysin, which carry the risk of being misinterpreted as a MANEC or a NEC. We investigated INSM1 according to the immunoreactive score in our main cohort of 1,033 conventional CRCs and 21 MANECs/NECs in comparison to the expression of synaptophysin and chromogranin A and correlated the results with clinicopathological parameters and patient survival. All MANECs/NECs expressed INSM1, usually showing high or moderate expression (57% high, 34% moderate, and 9% low), which distinguished them from conventional CRCs, which were usually INSM1 negative or low, even if they diffusely expressed synaptophysin. High expression of INSM1 was not observed in conventional CRCs. Chromogranin A was negative/low in most conventional CRCs (99%), but also in most MANECs/NECs (66%). Comparable results were observed in our independent validation cohorts of conventional CRC (n = 274) and MANEC/NEC (n = 19). Similar to synaptophysin, INSM1 expression had no prognostic relevance in conventional CRCs, while true MANEC/NEC showed a highly impaired survival in univariate and multivariate analyses (e.g. disease‐specific survival: p < 0.001). MANECs/NECs are a highly aggressive variant of colorectal cancer, which must be reliably identified. High expression of INSM1 distinguishes MANEC/NEC from conventional CRCs with diffuse expression of the standard neuroendocrine marker synaptophysin, which do not share the same dismal prognosis. Therefore, high INSM1 expression is a highly specific/sensitive marker that is supportive for the diagnosis of true colorectal MANEC/NEC.

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“…More clinical trials modulating the TME for NENs are underway. Moreover, different digestive organs show site-specific characteristics, such as changes in typical proteins, the proportion of disease subtypes, and survival time [ 12 ]. Hence, the mechanism by which the TME induces NEN tumor cells to express a broad functional spectrum and associated clinical application deserve further study in diverse gastrointestinal sites.…”

Section: Introductionmentioning

confidence: 99%

The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

Chen

et al. 2022

Cancers

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Gastroenteropancreatic neuroendocrine neoplasms feature high heterogeneity. Neuroendocrine tumor cells are closely associated with the tumor microenvironment. Tumor-infiltrating immune cells are mutually educated by each other and by tumor cells. Immune cells have dual protumorigenic and antitumorigenic effects. The immune environment is conducive to the invasion and metastasis of the tumor; in turn, tumor cells can change the immune environment. These cells also form cytokines, immune checkpoint systems, and tertiary lymphoid structures to participate in the process of mutual adaptation. Additionally, the fibroblasts, vascular structure, and microbiota exhibit interactions with tumor cells. From bench to bedside, clinical practice related to the tumor microenvironment is also regarded as promising. Targeting immune components and angiogenic regulatory molecules has been shown to be effective. The clinical efficacy of immune checkpoint inhibitors, adoptive cell therapy, and oncolytic viruses remains to be further discussed in clinical trials. Moreover, combination therapy is feasible for advanced high-grade tumors. The regulation of the tumor microenvironment based on multiple omics results can suggest innovative therapeutic strategies to prevent tumors from succeeding in immune escape and to support antitumoral effects.

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An update on the development of concepts, diagnostic criteria, and challenging issues for neuroendocrine neoplasms across different digestive organs

Cited by 8 publications

References 125 publications

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma

High expression of insulinoma‐associated protein 1 (INSM1) distinguishes colorectal mixed and pure neuroendocrine carcinomas from conventional adenocarcinomas with diffuse expression of synaptophysin

The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

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