Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly, but not only, occur in the intestine, where they are often called carcinoid tumors.
Although there are many kinds of NETs, they are treated as a group of tissue because the cells of these neoplasms share common features, including a similar histological appearance, having special secretory granules, and often producing biogenic amines and polypeptide hormones.
The term "neuro" refers to the dense core granules, similar to those in serotonergic neurons that store monoamines. The term "endocrine" refers to the synthesis and secretion of these monoamines. The neuroendocrine system includes endocrine glands such as the pituitary, the parathyroids and the neuroendocrine adrenals, as well as endocrine islet tissue embedded within glandular tissue such as in the pancreas, and scattered cells in the exocrine parenchyma. The latter is known as the diffuse endocrine system.
There are several treatments available for neuroendocrine tumors, including surgery, systemic treatments such as chemotherapy and peptide receptor radionuclide therapy, and others. Treatments may be aimed at curing the disease or at relieving symptoms.
Classification
WHO The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories, which emphasize the tumor grade rather than the anatomical origin: well-differentiated neuroendocrine tumors, further subdivided into tumors with benign and those with uncertain behavior well-differentiated (low grade) neuroendocrine carcinomas with low-grade malignant behavior poorly differentiated (high grade) neuroendocrine carcinomas, which are the large cell neuroendocrine and small cell carcinomas.
Additionally, the WHO scheme recognizes mixed tumors with both neuroendocrine and epithelial carcinoma features, such as goblet cell cancer, a rare gastrointestinal tract tumor.
Placing a given tumor into one of these categories depends on well-defined histological features: size, lymphovascular invasion, mitotic count, Ki-67 labelling index, invasion of adjacent organs, presence of metastases and whether they produce hormones.
The WHO grading from 2022 endorses a three-tiered grading system for most NETs, in particular NETs of the gastrointestinal or pancreaticobiliary tract, as well as NETs of the upper aerodigestive tract and the salivary glands. The grading system is based on proliferation assessed by mitotic rate and Ki-67 index and stratifies NETs into grade 1 (G1, low-grade), grade 2 (G2, intermediate-grade) and grade 3 (G3, high-grade). Tumor necrosis, although recognized as a factor associated with a potentially worse prognosis, is not included in the grading of NETs of the gastrointestinal or pancreaticobiliary tract. However, the absence or presence of tumor necrosis is a component of the grading of NETs of many other origins, such as the upper aerodigestive tract, the lung and the thymus.
Neuroendocrine carcinomas are poorly differentiated high-grade neuroendocrine neoplasms and a designation of tumor grade is therefore redundant. Lung and thymic neuroendocrine neoplasms are classified in a similar manner, including typical and atypical carcinoids, small cell and large cell neuroendocrine carincomas.
Furthermore, the 2022 WHO classification introduces a two-tiered grading system for medullary thyroid carcinomas based on mitotic count, Ki-67 index and the absence or presence of tumor necrosis. Here, it may be noted that different cut-offs than with tumors of gastrointestinal, aerodigestive and lung origin are applied.
Anatomic distribution Traditionally, neuroendocrine tumors have been classified by their anatomic site of origin. NETs can arise in many different areas of the body, and are most often located in the intestine, pancreas or the lungs. The various kinds of cells that can give rise to NETs are present in endocrine glands and are also diffusely distributed throughout the body, most commonly Kulchitsky cells or similar enterochromaffin-like cells, that are relatively more common in the gastrointestinal and pulmonary systems.
NETs include certain tumors of the gastrointestinal tract and of the pancreatic islet cells, certain thymus and lung tumors, and medullary carcinoma of the parafollicular cells of the thyroid. Tumors with similar cellular characteristics in the pituitary, parathyroid, and adrenomedullary glands are sometimes included or excluded.
Within the broad category of neuroendocrine tumors there are many different tumor types, representing only a small proportion of the tumors or cancers in most of these tissues: Pituitary gland: Neuroendocrine tumor of the anterior pituitary Thyroid gland: Neuroendocrine thyroid tumors, particularly medullary carcinoma Parathyroid tumors Thymus and mediastinal carcinoid tumors Pulmonary neuroendocrine tumors bronchus pulmonary carcinoid tumors: typical carcinoid (TC; low-grade); atypical carcinoid (AC; intermediate-grade) small-cell lung cancer (SCLC) large cell neuroendocrine carcinoma of the lung (LCNEC) Extrapulmonary small cell carcinomas (ESCC or EPSCC) Gastroenteropancreatic neuroendocrine tumors (GEP-NET) Foregut GEP-NET (foregut tumors can conceptually encompasses not only NETs of the stomach and proximal duodenum, but also the pancreas, and even thymus, lung and bronchus) Pancreatic endocrine tumors (if considered separately from foregut GEP-NET) Midgut GEP-NET (from distal half of 2nd part of the duodenum to the proximal two-thirds of the transverse colon) appendix, including well differentiated NETs (benign); well differentiated NETs (uncertain malignant potential); well differentiated neuroendocrine carcinoma (with low malignant potential); mixed exocrine-neuroendocrine carcinoma (goblet cell carcinoma, also called adenocarcinoid and mucous adenocarcinoid) Hindgut GEP-NET Liver and gallbladder Adrenal tumors, particularly adrenomedullary tumors Pheochromocytoma Peripheral nervous system tumors, such as: Schwannoma paraganglioma neuroblastoma Breast Genitourinary tract urinary tract carcinoid tumor and neuroendocrine carcinoma ovary neuroendocrine tumor of the cervix Prostate tumor with neuroendocrine differentiation testes Merkel cell carcinoma of skin (trabecular cancer) Inherited conditions: multiple endocrine neoplasia type 1 (MEN1) multiple endocrine neoplasia type 2 (MEN2) von Hippel-Lindau (VHL) disease neurofibromatosis type 1 tuberous sclerosis Carney complex
Grading Neuroendocrine lesions are graded histologically according to markers of cellular proliferation, rather than cellular polymorphism. The following grading scheme is currently recommended for all gastroenteropancreatic neuroendocrine neoplasms by the World Health Organization:
G Mitotic count (per 10 HPF) Ki-67 index (%) GX Grade cannot be assessed G1 < 2 < 3% G2 2 to 20 3–20% G3 > 20 > 20%
If mitotic count and Ki-67 are discordant, the figure which gives the highest grade is used.
G1 and G2 neuroendocrine neoplasms are called neuroendocrine tumors (NETs) – formerly called carcinoid tumours. G3 neoplasms are called neuroendocrine carcinomas (NECs).
It has been proposed that the current G3 category be further separated into histologically well-differentiated and poorly-differentiated neoplasms to better reflect prognosis.
Regarding pulmonary Carcinoids/NET, a similar classification with slightly different cutoffs has recently been proposed by the a working group from the International Association for the Study of Lung Cancer (IASLC) Pathology Committee:
G Mitotic count per 2 mm2 and Necrosis Ki-67 index (%) NOS Biopsy specimens lacking a Ki-67, with the exception of instances in which mitoses and/or necrosis are present, which can be called at least carcinoid/NET G2 Carcinoid/NET G1 < 2 and no necrosis < 5% Carcinoid/NET G2 2 to 10 and/or necrosis 5–20% Carcinoid/NET G3 > 10 > 20%
Staging
Currently there is no one staging system for all neuroendocrine neoplasms. Well-differentiated lesions generally have their own staging system based on anatomical location, whereas poorly differentiated and mixed lesions are staged as carcinomas of that location. For example, gastric NEC and mixed adenoneuroendocrine cancers are staged as primary carcinoma of the stomach.
TNM staging of gastroenteropancreatic Grade 1 and Grade 2 neuroendocrine tumors are as follows:
Stomach Primary Tumor (T) T Category Tumor Criteria TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Invades the lamina propria or submucosa, and less than or equal to 1 cm in size T2 Invades the muscularis propria, or greater than 1 cm in size T3 Invades through the muscularis propria into subserosal tissue without penetration of overlying serosa T4 Invades visceral peritoneum (serosal) or other organs or adjacent structures Regional Lymph Node (N) N Category N Criteria NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant Metastasis (M) M Category M Criteria M0 No distant metastasis M1 Distant metastasis M1a Metastasis confined to liver M1b Metastasis in at least one extra-hepatic site M1c Both hepatic and extra-hepatic metastases AJCC Prognostic Stage Groups Stage Criteria I T1, N0, M0 II T2 or T3, N0, M0 III Any T, N1, M0; T4, N0, M0 IV Any T, any N, M1
Duodenum / Ampulla of Vater Primary Tumor (T) T Category Tumor Criteria TX Primary tumour cannot be assessed T1 Invades the mucosa or submucosa only, and less than or equal to 1 cm in size (duodenal tumors)Confined within the sphincter of Oddi, and less than or equal to 1 cm in size (ampullary tumors) T2 Invades the muscularis propria, or is > 1 cm (duodenal)Invades through sphincter into duodenal submucosa or muscularis propria, or is > 1 cm (ampullary) T3 Invades the pancreas or peripancreatic adipose tissue T4 Invades visceral peritoneum (serosal) or other organs Regional Lymph Node (N) N Category N Criteria NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant Metastasis (M) M Category M Criteria M0 No distant metastasis M1 Distant metastasis M1a Metastasis confined to liver M1b Metastasis in at least one extra-hepatic site M1c Both hepatic and extra-hepatic metastases AJCC Prognostic Stage Groups Stage Criteria I T1, N0, M0 II T2 or T3, N0, M0 III T4, N0, M0; Any T, N1, M0 IV Any T, any N, M1
Jejunum and IleumAJCC, 8th edition: Primary Tumor (T) T Category Tumor Criteria TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Invades the lamina propria or submucosa, and less than or equal to 1 cm in size T2 Invades the muscularis propria, or greater than 1 cm in size T3 Invades through the muscularis propria into subserosal tissue without penetration of overlying serosa T4 Invades visceral peritoneum (serosal) or other organs or adjacent structures Regional Lymph Node (N) N Category N Criteria NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis less than 12 nodes N2 Large mesenteric masses (> 2 cm) and / or extensive nodal deposits (12 or greater), especially those that encase the superior mesenteric vessels Distant Metastasis (M) M Category M Criteria M0 No distant metastasis M1 Distant metastasis M1a Metastasis confined to liver M1b Metastasis in at least one extra-hepatic site M1c Both hepatic and extra-hepatic metastases AJCC Prognostic Stage Groups Stage Criteria I T1, N0, M0 II T2 or T3, N0, M0 III Any T, N1 or N2, M0; T4, N0, M0; IV Any T, any N, M1