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Keywords: chromogranin-A , carcinoid tumors , neuroendocrine tumors , computered tomography , ultrasonography , octreotide scintigraphy , somatostatin receptors , radioimmunoassay. Often silent and benign, GET may also be aggressive when sporadic and may sometimes mimic the course of gastric adenocarcinoma. Yearly age-adjusted incidence is around 0. Gastric carcinoids ECLomas develop from gastric enterochromaffin-like cells ECL cells in response to chronically elevated gastrin.

Type 1 tumors ECLomas in the course of atrophic gastritis may occur in conditions of achlorhydria secondary to auto-immune atrophic fundic gastritis. It occurs mostly in women and they are non-functioning tumors, typically found during upper GI endoscopy performed for dyspepsia. Type 1 tumors are almost exclusively benign lesions with little risk of deep invasion of the gastric parietal wall.

The neoplastic ECL cells become progressively dedifferentiated with an increasing number of Ki immunoreactive IR cell nuclei.

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In addition, there is a substantial decrease in argynophil and IR NE cells that can be visualized by conventional methods. ECLomas secondary to hypergastrinemia should be closely followed for signs of clinical and histopathological tumor progression. Such ECLomas deserve early, active, radical surgical treatment. NENs arise at almost any anatomical site, including paraganglia, and are distributed throughout the body in organs of all types, as well as in soft tissues;.

NENs express a variable spectrum of proteins, shared with their normal cell counterparts at specific anatomical locations, including markers of general neuroendocrine differentiation such as chromogranin A, chromogranin B, and synaptophysin as well as site-specific markers such as hormones and transcription factors [ 4 ]. Existing classification systems vary widely in terminology and criteria between sites, with robust data supporting grading systems in some anatomic sites e.

In addition, some NETs have been subjected to careful cell-type classification most well-known in the pituitary, but also in the rectum and pancreas that has prognostic and predictive value, whereas others have not, e. The relative prevalence of different NEN categories also varies by anatomic site. The panorama of genetic knowledge regarding NENs is patchy, with well-defined traits defined by high-throughput studies for some anatomic sites and relatively scarce information for other sites. The term NENs encompasses both well-differentiated NETs and poorly differentiated NECs, as they both share common histologic, immunophenotypic, and ultrastructural neuroendocrine features.

However, genetic evidence at specific anatomic sites supports the dual morphological subdivision that distinguishes poorly differentiated NECs from well-differentiated NETs [ 5 , 6 , 7 , 8 , 9 ]. Although they can have overlapping histologic features, their inclusion together in a single classification framework may incorrectly lead to the presumption that well-differentiated NETs and poorly differentiated NECs are closely related neoplasms; in most organs where these families of neoplasms have been studied, the data suggest that they are not biologically closely related [ 7 , 8 , 9 ].

In addition, to have different degrees of biological aggressiveness, and different responses to medical therapy, NETs and NECs have different risk factors, hereditary predispositions, relationships to non-NE neoplasia, and underpinning genetics. This is well supported by data in the pulmonary and the digestive systems, as described below, with limited data as yet in other systems.

Six major points of discussion were identified by the expert group: 1. Anatomy : It is recognized that every anatomical site has its own individuality and clinical—pathological features, which often form the basis for historical classification systems. Anatomic site-specific features must be considered when devising any common classification system in order to avoid potential confusion. It was proposed and agreed that current WHO definitions i.

It was noted that the recently proposed new terminology for pituitary tumors is more in line with this proposal than the current WHO terminology [ 10 ].

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  • Use of this new terminology for pituitary NENs, rather than the WHO terminology may be helpful to allow for a clear and smooth transition in the classification to assist those using it. It was acknowledged that the expression of neuroendocrine markers can vary depending on anatomic site and degree of differentiation, and that different general neuroendocrine markers to define neuroendocrine differentiation are currently used in different organ systems e.

    Colon and rectum neuroendocrine tumors: experience of the National Cancer Institute in Brazil

    Tumor family definition : It was proposed and agreed that two families or classes of epithelial NENs be recognized, well-differentiated and poorly differentiated. It was acknowledged that the two families may not exist in all anatomical sites, and that their relative prevalence also varies widely by site of origin. As this is primarily a classifier for NEN of epithelial origin, it was further suggested that paragangliomas i.

    Tumor sub-type definition : Tumor sub-types variants can be defined morphologically or by other criteria, and some may have their own ICD-O codes.

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    Tumor grade : It was proposed and agreed that well-differentiated neoplasms NETs should usually be graded in three tiers as G1, G2, and G3 Table 1 , corresponding to low-grade, intermediate-grade, and high-grade. In some organs, the current nomenclature inherently reflects the grade e. It is not necessary to grade NEC as these are always high grade.

    In practice, tissue availability may restrict areas available for counting. It may also be best practice to specify the number of mitoses counted within the total area assessed for each case i.

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    Necrosis may be focal punctate or diffuse geographic. Mitotic counts have in the past been expressed as the number per high-powered field HPF as the unit of area within the tumor. Unfortunately, different combinations of microscopes and lenses result in HPFs of variable area [ 11 , 12 , 13 ]. Grade may therefore differ, simply based on the microscope being used. While it is possible to at least define the exact size of these fields in scientific publications, this does not allow an accurate grade to be assigned in routine practice. It is arguable that there is little excuse for the use of HPFs, when international standard SI units such as mm 2 are available, and we have chosen to express the mitotic count per mm 2 , in line with WHO Blue Book policy.

    It was agreed that the specific basis for grading should continue to be contingent on anatomic site, based on current practices for each site. It was proposed and agreed that poorly differentiated neoplasms NEC be i of high grade by definition; ii of two separate morphologic types and iii defined as small cell neuroendocrine carcinoma SCNEC or large cell neuroendocrine carcinoma LCNEC.

    Some tumor types may have organ-specific names: e. It was proposed and agreed that tumor classes be site-specific and different, and site-specific grading parameters cut-offs be defined for each anatomic subgroup. NENs in some anatomic sites are further characterized based on their production of bioactive substances peptide hormones or bioamines , and in a number of anatomic sites, clinically functional NENs exist in which a hormonal or paraneoplastic syndrome may be the dominant clinical manifestation of the neoplasm.

    It was acknowledged that the detection of secretory products, either in the serum or using immunohistochemistry to assay the tumor cells, may be of relevance for classification i. However, given the variety of different bioactive substances produced in NENs of different locations, no general recommendations for assaying them could be developed. In many anatomic sites, neoplasms exist that exhibit both neuroendocrine and non-neuroendocrine elements, which can be present in morphologically distinct cell populations or more intimately intermixed.

    Designations such as combined small cell carcinoma in the lung mixed adenoneuroendocrine carcinoma MANEC; in the tubular gastrointestinal tract , or mixed neuroendocrine-non-neuroendocrine neoplasm MiNEN; in the pancreas have been proposed for this family. While this conceptual category is recognized as an important member of the NEN family, these complex neoplasms were not included in the present classification framework, though they are mentioned in the site-specific sections below where they may be a cause of confusion.

    Another scenario in which neuroendocrine differentiation can occur in neoplasms is in non-NECs following chemotherapy, molecularly targeted therapy, or radiotherapy. In some instances, a small cell carcinoma may arise following treatment of an adenocarcinoma such as in the prostate or lung and such poorly differentiated NECs can be considered within the present classification framework. In other scenarios, however, treated carcinomas may display apparent well-differentiated neuroendocrine elements, such as in the Paneth-like cell features of treated prostatic adenocarcinoma [ 17 , 18 ], or the well-differentiated neuroendocrine cell nests in rectal carcinomas following chemoradiotherapy [ 19 ].

    Finally, tumors of the paraganglia are designated paraganglioma and are classified based on criteria for these neoplasms: they are mentioned in passing, but are not the focus of this paper. The above classification framework criteria Fig. It was recognized that NENs at different anatomic sites may fit variably into the above-defined framework. Accordingly, the site-specific applications for the classification are further defined below.

    Necrosis, though recognized as a potential adverse prognostic factor, is not included in the grading parameters. Pancreatic neuroendocrine carcinomas PanNECs are usually large cell-type and may contain components of adenocarcinoma, typically not found in NETs. Progression from G1 or G2 NETs to G3 may occur, both within a primary tumor and between sites of disease, particularly over time as the tumor evolves clinically.

    In the gastrointestinal tract, G3 NETs are also reported, though less commonly than in the pancreas. The value of determining the hormone secretion profile of pancreatic NENs is debated, although insulinomas are usually less aggressive, and gastrinomas more so. In the gastrointestinal tract, the classification of NENs has not been updated by WHO since [ 14 ], though this is now in progress.

    In fact, G3 NETs in the gastrointestinal tract have also been reported [ 25 ], although less commonly than in the pancreas. Therefore, it has been proposed that a three tier system G1—G3 should be adopted for NETs in the gastrointestinal tract as well [ 2 ]. Instead, epigenetic dysregulation appears to have a major role in the pathogenesis of small bowel NETs [ 35 ]. NECs of the gastrointestinal tract may exhibit components of adenocarcinoma or, in the esophagus or anus, squamous cell carcinoma, again emphasizing the close relationship of NECs to non-NECs.

    Use of this terminology and the WHO criteria were recommended by a recent ENETS guideline based upon a systematic literature review and consensus of an international, multidisciplinary panel of experts and endorsed by the International Association for the Study of Lung Cancer [ 38 ]. This is particularly important in small biopsies with crush artifact, where carcinoids can be misdiagnosed as SCLC [ 41 , 42 ].

    No reliable cut-off has been established for Ki in the distinction between typical carcinoid and atypical carcinoid [ 43 ], although reported ranges for typical carcinoid are 2. Although some studies have suggested usefulness of Ki in grading lung carcinoids, others have shown limited additive value over histologic criteria, particularly mitotic counts [ 44 , 45 ]. Some studies have evaluated the entire spectrum of neuroendocrine lung neoplasms with various proposals of how to incorporate Ki proliferation rates and mitotic counts, but there is no consensus on the optimal approach [ 38 , 43 , 46 , 47 ].

    There is a great need for further research on this topic both on the issue of separating typical carcinoid from atypical carcinoid and carcinoids from the high-grade LCNEC and SCLC. The category of G3 atypical carcinoid in the lung is not a validated entity and not recognized in the WHO classification, although a few studies suggest these cases may exist [ 48 , 49 ]. Poorly differentiated NECs typically present in older patients, with strong association with cigarette smoking and a very poor prognosis.

    Current evidence suggests these tumors show less benefit from traditional platinum-based chemotherapy, however everolimus, an MTOR pathway inhibitor, is now approved, and recent evidence shows temozolamide may have some effect. Global genomic studies have demonstrated extensive genetic alterations in SCLC and large cell carcinoma including LCNEC , consisting of amplifications, deletions, and mutations in contrast to very few genetic changes in lung carcinoids [ 53 ]. These data demonstrate that, although pulmonary NETs typical carcinoid and atypical carcinoid are regarded as part of the spectrum of pulmonary NE neoplasms, they are only distantly related to poorly differentiated NECs SCLC and LCNEC because these groups of tumors have major clinical, epidemiologic, histologic, genetic, and prognostic differences.

    The current WHO classification consists only of well-differentiated neoplasms classified as adenomas or well-differentiated carcinomas based on the presence of distant metastasis and sub-classified depending on hormone production. However, despite the rarity of distant metastatic spread, these tumors are recognized to have a high incidence of invasion of surrounding tissues. Clinically and pathologically, these aggressive tumors and carcinomas with metastasis were very similar [ 61 , 62 , 63 ]. Therefore, it has been proposed that pituitary tumors be classified as NETs, i.

    Poorly differentiated NECs do not occur in the pituitary. PitNET prognosis and prediction relies more on cell type and degree of cell differentiation than on proliferative markers [ 10 ]. However, grading of these tumors as G1, G2, and G3 is currently not possible based on available data. Mitoses are uncommon in these tumors and there are no data on the value of mitotic counts in the classification of PitNETs. Necrosis is rare and related to vascular thrombosis.

    There is some evidence that different mutations underlie tumors of different cell types. In contrast, AIP mutations may be implicated in some sparsely granulated somatotroph tumors with epigenetic silencing in those tumors without mutation. Early studies suggested that TP53 inactivation and RAS mutations were features of carcinomas [ 68 , 69 ].

    However, the genetic factors underlying the majority of sporadic PitNETS remain unknown and epigenetic alterations are thought to be common. Paragangliomas arising in and around the sella turcica should be distinguished from PitNETs and classified as a separate family. Epithelial neuroendocrine neoplasms in the Head and Neck WHO tumor blue book are categorized into well-differentiated typical carcinoid , moderately differentiated atypical carcinoid and poorly differentiated small and large cell neuroendocrine carcinomas.

    Well-differentiated NEN typical carcinoid , NET-G1, display organoid formation composed of monotonous cells with minimal mitotic figures [ 71 ]. The differential diagnoses include paraganglioma and medullary thyroid carcinoma [ 72 , 73 , 74 ]. Moderately differentiated atypical carcinoid , NET-G2, carcinoma retains organoid architecture and manifest cellular pleomorphism, moderate numbers of mitoses, and occasional necrosis and amyloid-like deposition. Although not widely practiced, Ki scoring can be helpful.

    The main differential diagnoses are medullary thyroid carcinoma and paraganglioma [ 75 , 76 , 77 ]. The differential diagnosis of this entity is broad and includes neuroblastoma, embryonal rhabdomyosarcoma, sinonasal undifferentiated, NUT carcinoma, pituitary NETs, paraganglioma, mucosal melanoma, and primitive neuroectodermal tumors. Lineage-associated immunohistochemical markers are needed in the diagnosis and categorization of these entities. Undifferentiated sinonasal carcinomas do not express neuroendocrine markers, while paraganglioma, neuroblastoma, rhabdomyosarcoma and melanoma are keratin negative.

    MCC commonly express dot-like CK20 staining [ 78 ]. Metastasis from skin and other sites must be excluded. The prognosis of MTC is heavily influenced by the stage of the disease, by serum calcitonin and carcinoembryonic antigen levels, and in MEN2 cases by the type of RET mutation [ 80 ]. RET mutations influence the tumor microenvironment and angiogenesis, and among sporadic cases p. Interestingly, however, there is evidence that immunohistochemical loss of calcitonin expression with retention of CEA is considered an unfavorable sign, pointing to the potential value of biomarkers, including hormones, in defining MTC prognosis [ 75 ].

    Improved biomarker and grade profiling offers a great opportunity for the optimal selection of patients to be treated with the tyrosine kinase inhibitors Vandetanib, Cabozantinib currently approved for advanced MTC [ 80 ]. Mixed medullary and follicular cell carcinomas, where neoplastic C-cells are closely intermixed with other types of non-neuroendocrine follicular cell-derived tumors usually papillary carcinoma , are extremely rare but well documented.

    They correspond to the mixed neuroendocrine-non-neuroendocrine tumors of other organs e. Equally rare are intrathyroidal NEN with the features of paraganglioma, that need to be distinguished from the paraganglioma-like MTC variant [ 87 ]. The current classification includes well-differentiated neoplasms classified as adenomas, atypical adenomas, or carcinomas parathyroid NETs ; poorly differentiated, aggressive carcinomas corresponding to parathyroid NECs are extremely unusual. The diagnosis of malignancy is based on invasive growth, evidenced by vascular invasion, full penetration of the tumor capsule with extension into the surrounding non-neoplastic tissues, or metastases [ 88 , 89 ].

    Mitoses, atypical mitoses, macronucleoli, thick intersecting fibrous bands, and necrosis are potential signs of malignancy [ 89 , 90 ]. Therefore, although the Ki labeling index, mitotic counts, and necrosis are often used as markers of aggressive behavior, they are not part of a formally defined diagnostic grading scheme.

    Neuroendocrine Neoplasms: Dichotomy, Origin and Classifications

    The parafibromin gene CDC73, previously HRPT2 is frequently inactivated in malignant tumors, and loss of function mutations are identified in the germline of patients with apparently sporadic parathyroid carcinoma as well as in other CDC73 related disorders, such as hyperparathyroidism-jaw tumor syndrome and familial isolated hyperparathyroidism.

    Lack of immunohistochemical expression of parafibromin combined with immunoreactivity for PGP9. NENs of the breast are rare and poorly defined. Most are likely to represent mixed NENs. Clinical syndromes related to hormone production are extremely rare in breast NENs and the classic organoid features of carcinoid tumors of the lung and gastrointestinal tract i. The current classification also acknowledged the presence of a third category which comprises a subset of breast carcinomas with neuroendocrine differentiation as determined by histochemical and immunohistochemical analysis.

    These include breast carcinoma of no special type NST as well as special types such as solid papillary carcinoma and the hypercellular variant of mucinous carcinoma of any histological grade. Therefore, distinction between well-differentiated NETs and grade 1 or 2 breast carcinomas expressing neuroendocrine markers should be based on the presence of histological features characteristic of neuroendocrine differentiation.

    Assessment of prognostic variables including mitotic count and Ki labeling index is used as a marker of aggressive behavior, although in a way similar to other breast carcinomas and not as a formally defined grading system for NENs. Unlike most other sites, necrosis is not used as a well-established prognostic factor in NENs of the breast [ 97 ]. Tumor stage and histological grade, which encompass mitotic counts, are used as the main prognostic parameters.

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    Currently, there are no data from prospective clinical trials on optimal management of NENs of the breast and these tumors are usually treated with the same strategy used for the other types of invasive breast cancer. Thus, outside of the context of the exceedingly rare small cell carcinoma of the breast, neuroendocrine differentiation in breast neoplasms is not regarded to have therapeutic significance.

    The terms carcinoid, typical and atypical carcinoid are not recommended. The classification in all locations is based on morphology but proliferation markers as well as necrosis are not formally included in the classification parameters. NETs in the kidney, formerly designated carcinoid tumors, are extremely rare, and high-grade NENs arising from the renal pelvic mucosa must be excluded before the diagnosis of NEN of renal parenchyma because they are more common than tumors of renal origin [ 98 ].

    In cases of renal paraganglioma, tumors arising from the perihilar sympathetic ganglia must also be excluded. Some studies have correlated poor patient prognosis with increased mitotic activity, presence of necrosis and cytological atypia, but stage at presentation is the strongest predictor of survival. Poorly differentiated NECs small cell and large cell types are aggressive with most patients dying of metastasis. For a tumor to be classified as NEC, the typical neuroendocrine histology must constitute the majority of the tumor.

    Some reported cases were associated with a lesser component of conventional urothelial carcinomas. Most acinar prostate adenocarcinomas demonstrate scattered neuroendocrine cells by immunohistochemistry. Prostatic NETs must be distinguished from prostatic adenocarcinomas showing extensive Paneth-like differentiation, which can be present initially or following androgen deprivation therapy [ ]. It is therefore thought that SCNECs represent transdifferentiation from usual prostate adenocarcinoma. NENs are uncommon or rare at all sites in the female genital tract.

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    • They are most common in the ovary where most are clinically benign, morphologically corresponding to carcinoid tumors, and arise in dermoid cysts.