Neuroendocrine Carcinomas of the Digestive Tract: What Is New?

Abstract

Neuroendocrine carcinomas (NEC) are rare tumors with a rising incidence. They show poorly differentiated morphology with a high proliferation rate (Ki-67 index). They frequently arise in the lung (small and large-cell lung cancer) but rarely from the gastrointestinal tract. Due to their rarity, very little is known about digestive NEC and few studies have been conducted. Therefore, most of therapeutic recommendations are issued from work on small-cell lung cancers (SCLC). Recent improvement in pathology and imaging has allowed for better detection and classification of high-grade NEN. The 2019 World Health Organization (WHO) classification has described a new entity of well-differentiated grade 3 neuroendocrine tumors (NET G-3), with better prognosis, that should be managed separately from NEC. NEC are aggressive neoplasms often diagnosed at a metastatic state. In the localized setting, surgery can be performed in selected patients followed by adjuvant platinum-based chemotherapy. Concurrent chemoradiotherapy is also an option for NEC of the lung, rectum, and esophagus. In metastatic NEC, chemotherapy is administered with a classic combination of platinum salts and etoposide in the first-line setting. Peptide receptor radionuclide therapy (PRRT) has shown positive results in high-grade NEN populations and immunotherapy trials are still ongoing. Available therapies have improved the overall survival of NEC but there is still an urgent need for improvement. This narrative review sums up the current data on digestive NEC while exploring future directions for their management.

Somatostatin and Its Receptor System in Colorectal Cancer

“…Separate subgroups of NET G3 and NECs are not anymore distinguished because they are genetically unrelated. There are also so-called mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) or MANECs (old terminology), in which each component is arbitrarily assumed to account for at least 30% of the tumor [ 123 , 186 , 187 , 188 ]. MiNENs rarely contain a well-differentiated NET component in association with a non-neuroendocrine component [ 189 ].…”

“…Optimal therapy in NETs usually depends on the primary location and classification, morphologic features of differentiation, and tumor proliferation rates. Patients with highly differentiated (G1) hormonally active and hormonally inactive NENs, and/or slow rates of disease progression, and patients with high SSTR expression and low Ki-67 index are characterized with more favorable outcomes [ 107 , 123 , 187 , 243 ].…”

“…Antagonist derivatives have been shown to be more effective compared with agonists, which may broaden the group of applications of these therapeutics (reviewed in [ 216 ]). The most current research findings and treatment guidelines for GEP-NETs are the subject of numerous publications [ 180 , 187 , 217 ].…”

Survival Analysis in Gastrointestinal Neuroendocrine Carcinoma With Bone Metastasis at Diagnosis

“…Although NECs are commonly considered as rare, they have a rising incidence in recent years (2)(3)(4). NECs are characterized by poorly differentiated morphology as well as a high proliferation capacity (Ki−67 proliferation index > 20%) (5). Moreover, NECs are often presented with metastasis at diagnosis or advanced status and have a poor prognosis (6)(7)(8).…”

Enhancer of Zeste Homolog 2 (EZH2) Is a Marker of High-Grade Neuroendocrine Neoplasia in Gastroenteropancreatic and Pulmonary Tract and Predicts Poor Prognosis

“…Therefore, Ki67 has established itself as a cell proliferation marker and is crucial for grading neuroendocrine neoplasia, especially GEP-NEN [ 11 ]. However, the Ki67 index alone is not sufficient for distinguishing between NEN-G3 and NEC; the morphology and expression of various markers are also required [ 12 ]. Chromogranin A is a glycoprotein secreted by neuroendocrine cells, and its expression is usually maintained in well-differentiated NETs but frequently lost in NECs [ 13 , 14 , 15 ].…”