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Medullary thyroid carcinoma (MTC) represents 4–10 % of all thyroid carcinomas; MTCs arise from the parafollicular cells (C cells). Around 20–25 % of MTCs are part of inherited multiple endocrine neoplasia type 2 (MEN2) syndromes, while the rest are sporadic. Most are MEN2 syndromes that are divided in MEN2A and MEN2B. MEN2A represents 95 % of all MEN2 cases and is subdivided in 4 variants: classical MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung’s disease (HD), and familial medullary thyroid carcinoma (FMTC). Codon 634 in exon 11 is found mutated in 80–93 % of MEN2A patients. MEN2B are 5 % of all patients with MEN2 syndromes. MEN2B is characterized by the presence of MTC, pheochromocytoma, ganglioneuromatosis of the intestine and oral mucosa, neuromas of the tongue, marfanoid habitus, and medullated corneal nerve fibers. The mutation M918T in exon 16 is found in 95–100 % of MEN2B cases. Two thirds of sporadic MTCs have somatic mutations in RET: M918T in exon 16, the most common mutation; 8–68 % of the RET mutation-negative cases have somatic mutations in HRAS and KRAS. RET germline mutations should be offered to all patients with C-cell hyperplasia, familial MTC, and apparently sporadic MTC. These molecular studies are very helpful in characterizing these tumors.

In recent years, a number of therapeutic agents have been tested in clinical trials and approved for neuroendocrine tumors (NETs), including an antiangiogenic agent (sunitinib) and an mTOR inhibitor (everolimus). Despite this clinical success, we still do not have biomarkers that can predict efficacy and provide clinically relevant information on potential resistance mechanisms against various antiangiogenic therapies (AA-Rxs). In order to address this important clinical challenge, there is an urgent need for pathologists to implement robust biomarker strategies to evaluate the expression of various members of the VEGF/VEGF receptor pathway and other relevant targets/biomarkers in human NET tissues. This will provide valuable biologic insights into pathologic angiogenesis, antiangiogenesis, and various resistance mechanisms in human NETs. Furthermore, selection of NET patients based on relevant biomarker or target expression in a given NET subtype will enable the current and emerging antiangiogenic therapies to be tailored to the right NET patients and will help achieve highest levels of clinical efficacy for these agents. An emerging approach to overcome resistance against AA-Rxs is concurrent targeting of VEGF and transcription factors or of multiple angiogenic pathways, such as VEGF and FGF.

Neuroendocrine system is not well developed in the esophagus, and as a result esophageal neuroendocrine tumors (NETs) are extremely rare. Anatomically esophageal NETs are classified under foregut neuroendocrine neoplasm (NENs) category, and their grading and staging follows the general rule as for foregut NETs of elsewhere. Several genetic and epigenetic alterations and molecular pathway dysregulations have been proposed to be involved in the pathogenesis of esophageal NENs including mTOR pathway. The most common presenting symptom of esophageal NET is dysphagia. Cases of typical carcinoid syndrome in NET of esophagus are very rare, and as its lung counterpart, syndrome of inappropriate secretion of antidiuretic hormone (SIADH) can be seen in association with esophageal NET in extremely rare occasions as well. The 2010 WHO classification system divides NENs of esophagus into low- to intermediate-grade (grade 1–2) neuroendocrine tumors (NETs) and high-grade (grade 3) neuroendocrine carcinomas (NECs, large or small cell type), according to their histopathologic characterization and proliferation rate. Esophagus is the most common site of small cell carcinoma in the gastrointestinal tract and histologically indistinguishable from its counterpart in the lung. However, small cell neuroendocrine carcinoma (SCNEC) of esophagus may have a much more aggressive clinical course and tends to metastasize early. Despite combination radio-chemotherapies, the overall survival is very poor.

Primary neoplasms of the appendix showing neuroendocrine differentiation include neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and mixed adenoneuroendocrine carcinomas (MANECs), including goblet cell carcinoids. NETs comprise 50–77 % of all appendiceal neoplasms and 19 % of all gastrointestinal (GI) NETs. Primary NECs of the appendix are extremely rare and exhibit immunohistopathologic profile similar to NECs at other sites within the GI tract. MANECs arise from a pre-existing goblet cell carcinoid (GCC) and consist of a mixture of exocrine (signet ring type or poorly differentiated) and endocrine carcinoma components, with one component exceeding 30 %. Appendiceal NETs are more frequent in females, and most are diagnosed incidentally in the distal third (75 %) of the appendix. Mean age at presentation is 32–43 years; tubular NETs occur at younger age compared to goblet cell carcinoids. Most appendiceal neoplasms are clinically silent or may simulate acute appendicitis with intermittent abdominal pain or pain localized in the right lower abdomen. Carcinoid syndrome is rare and suggests extensive metastatic disease. Most appendiceal NETs are enterochromaffin cell (EC cell) serotonin-producing neoplasms. Less frequent subtypes include L cell NETs and tubular carcinoids. The latter can be misdiagnosed as metastatic adenocarcinoma as it lacks direct contact with the appendiceal mucosa. GCCs are relatively rare, while primary NECs, or MANECs, are extremely rare, but can pose diagnostic challenges for practicing pathologists and need careful sampling, review, and workup. The vast majority of patients with NETs of the appendix have favorable prognosis, with 88–94 % 5-year survival for localized disease and 25–31 % with distant metastatic disease. Prognosis of GCC is intermediate between carcinoids and appendiceal adenocarcinomas with an overall 5-year survival of 76 %. Since patients with appendiceal NETs are at increased risk for other GI malignancies, follow-up with colonoscopic screening is warranted.

Neuroendocrine neoplasms of the colon and rectum are derived from the same stem cell which gives rise to glandular cells and other cells lining the epithelium. Neuroendocrine carcinomas are more common in the colon, whereas neuroendocrine tumors are more common in the rectum. In the colon neuroendocrine carcinomas can be seen mixed with other types of tumors including adenocarcinomas. These tumors are mainly nonfunctional, but the neuroendocrine tumors in the cecum and right colon which composed of EC cells can be functional and in rare cases can cause carcinoid syndrome. These neoplasms share some of the molecular changes that are seen in these neoplasms in other parts of the GI system.

Neuroendocrine tumor (NET) is a family of neoplasms that arises from nervous (neuro-) system and hormonal (endocrine) cells of multiple organs and functions. NET cells in the GI tract share common histological characteristics typically associated with neuroendocrine differentiation. Immunohistochemically, NET cells produce common polypeptide hormones and a variety of biogenic amines related to modulating the biological functions of the organs where these tumors arise. The immunophenotypical profiles of these neoplasms are relatively specific: they are positive for markers of neuroendocrine differentiation and may produce various polypeptides and hormones unique to their subtypes. Immunohistochemical examination of these neuroendocrine markers, such as synaptophysin, chromogranin, CD56, and other markers such as neuron-specific enolase (NSE), as well as proliferative markers (Ki-67 labeling index), should be carried out for the proper classification and grading of any NET. Additionally, in this era of molecular medicine and personalized precision medicine, the molecular background and the involved molecules are gaining more recognition. The current knowledge on the molecular genetics of neuroendocrine tumors will be introduced at the end of this chapter. In short, this chapter will focus on immunophenotypical profile and currently understood molecular genetics of gastrointestinal neuroendocrine tumors.

Grading and differentiation are the terms used for the pathological classification of tumors. Grading of the tumor is a method to express the biological features and aggressiveness of the tumor. Conversely, the term differentiation is used to reflect the degree of tumor resemblance to its nonmalignant counterpart.

PD-NECs are high-grade epithelial malignancies, which include two main histologic entities: small cell carcinoma (SCC) and large-cell NEC (LCNEC). Most HG-NECs arising in the squamous-lined GI tract (esophagus and anal canal) are small cell type (78 %), while majority of those involving the glandular GI mucosa are large cell (53 %) or mixed (82 %). Colorectal NECs (especially SCCs) often show Rb protein loss and alterations in p53 and show higher frequency of allelic imbalances, especially involving the p53, CDKN2A/Rb pathway, FHIT (3p), DCC/SMAD4 (18q), and MEN1. PD-NEC patients with GI primaries tend to have more extensive disease and poorer prognoses than those with non-GI primaries. Pancreatic PD-NECs are mostly located in the pancreatic head and include large-cell, small-cell, or combined PD-NEC with a component of adenocarcinoma or well-differentiated NET. Well-differentiated NETs and acinar cell carcinoma can be misdiagnosed as PD-NEC and need careful application of morphologic criteria and IHC markers (like trypsin, chymotrypsin). Most (80 %) had nodal metastases at presentation with a median survival of 11 months. Diagnostically, IHC can be helpful in differentiating LC-NEC from its mimics, supporting PD-NEC based on ASH1 positivity and non-GI primary source for TTF-1-positive metastatic NEC, unknown primary. TMPRSS2-ERG gene rearrangement occurs in prostatic PD-NECs. Further advances in our understanding of the molecular basis of PD-NECs should lead to new diagnostic and therapeutic strategies and are an area of active investigation, as we implement the newer model of precision oncology.

Small intestine neuroendocrine neoplasms (SI-NENs) derive from enterochromaffin (EC) cells of the embryonic neural crest and anatomically have been categorized under the midgut neuroendocrine neoplasm (NENs) category. Midgut NETs are the most common type of neuroendocrine neoplasm. Although SI-NENs are rare, in general, they are the most common malignancy of the small bowel and about half of all small intestine neoplasms have neuroendocrine origin. The most common site of the gastrointestinal NET is ileum.

In recent years the field of Neuroendocrine Tumor Pathology has evolved into several key areas, especially with reference to their diagnoses and treatment. Here we would summarize some of those key advancements, many of which have been covered in greaer detail earlier in this book.

In recent years, molecular advances have improved our understanding of the biologic basis of genesis, growth, and progression of human NETs. Emerging therapies (VEGF and mTOR inhibitors) have shown clinical efficacy in unselected patient populations with advanced pancreatic NETS. These results suggest that further molecular characterization of human NETs may rationalize patient tailoring approaches for future clinical trials of targeted therapeutics. That will maximize clinical impact on NET patient management and further improve our understanding of the various resistance pathways. Therefore, future advances in continued discovery, validation, and qualification of promising molecular biomarkers will develop more personalized diagnostic and therapeutic options to make precision medicine a reality for patients with neuroendocrine tumors.