While Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies with various histology and nomenclature, they may include gastroenteropancreatic (GEP) cancer, Genitourinary (GU) tracts cancer and pulmonary cancer.
Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies with diverse and confusing histology and nomenclature, however, the term “neuroendocrine” refers to widely distributed cells with “neuro” and “endocrine” properties. In fact, the “neurological” characteristics are based on identifying dense nuclear granules (DCG1) located in serotonergic neurons that store monoamines. (However, unlike neurons, NE cells have no synapses.) Moreover, the “endocrine” properties refer to the synthesis and secretion of these monoamines. The neuroendocrine (NE) system includes scattered cells in the endocrine glands such as the pituitary gland, parathyroid glands, NE adrenal glands, and endocrine islet tissue and exocrine glandular tissue (thyroid gland or pancreas) as well as endocrine cells of the respiratory and digestive system, belonging to the so-called diffuse endocrine system2.
Because of the systemic proliferation of NE cells, NENs have been described in the central nervous system, larynx, respiratory tract, thyroid, gastrointestinal (GI), thoracic, skin, and genitourinary systems. In fact, the gastrointestinal tract and lungs are the most common primary sites for tumor3.
Gastroenteropancreatic (GEP)-NETs (Neuroendocrine tumors)
The GEP-NET, which is specific to people at 50-60 years of age, is difficult to diagnose. It is usually detected accidentally during surgery, especially for other reasons (such as appendectomy). In fact, the presence of abdominal discomfort may lead to considerable difficulty and delay in diagnosis. However, GEP-NETs are divided into carcinogenic tumors of the luminal GI tract and NETs of the pancreas.
In fact, diagnosis of these tumors usually happens after surgery using appendectomy specimens. While most of these tumors are benign, Carcinoid syndrome is rare (<1%)4.
Initially, these rare tumors are divided into type I associated with chronic atrophic gastritis with or without pernicious anaemia. After that type II is associated with Zollinger-Ellison syndrome and MEN-1 syndrome. Type III tumors are sporadic, large, isolated and aggressive tumors, sometimes resulting in atypical carcinoid syndrome due to histamine and serotonin. Consequently, unlike the diffuse rash of typical carcinoid syndrome, the flushing of type III tumors is red, patchy, and severely itchy5.
These rare tumors are associated with a more aggressive clinical course and worse prognosis than adenocarcinoma. In fact, they are divided into two disease types: small cell carcinoma and moderately differentiated NEC. Small and large colorectal carcinomas have similar morphological and immunohistochemical features to small cell lung cancer, whereas moderately differentiated colorectal NECs have similar morphology to large cell lung neuroendocrine labelling. Chemotherapy manages the former one, while surgery manages the latter one6.
Pancreatic NENs (traditionally called islet-cell carcinomas)
However, these tumors involve islet cells of the pancreas that may or may not produce various hormones. In fact, functional tumors associated with multiple clinical syndromes are:
- Insulinoma, a β-cell carcinoma of the pancreatic islets, and the most common GI NET, which can appear as part of MEN-1 syndrome, cause excessive insulin secretion, leading to symptoms of hypoglycemia and hypokalemia7.
- Gastrinoma, the second most common GI NET after insulinoma, is most commonly found in the pancreas and duodenum. They occur mainly in older men and often lead to Zollinger-Ellison syndrome or severe peptic ulcer disease8.
- In fact, tumors secreting pancreatic polypeptides (Ppomas) are the third most common type of pancreatic NETs. They are not associated with clinical syndromes, unlike gastrinomas, vasoactive intestinal peptide-releasing tumors (VIPomas) or glucagonomas. While people with Ppomas report weight loss, jaundice and abdominal pain, elevated pancreatic polypeptide level confirms diagnosis.
- In 90% of cases, pancreatic VIPomas secrete VIP64 autonomously, causing watery diarrhoea, hypokalemia and chlorine syndrome. However, first described by Werner and Morrison in 1958.65, Gastrinoma, Insulinoma, Glucagon and somatic cellomas, and VIPomas are associated with MEN-1. syndrome.
- In 90% of adult cases, pancreatic VIPomas secrete VIP autonomously, causing watery diarrhoea, hypokalemia and chlorine syndrome. Like gastrinoma, Insulinoma, Glucagon and somatic cellomas, VIPomas are associated with MEN-1 syndrome.
- Glucagonoma is an extremely rare tumor of the pancreas that overproduces the anti-regulatory hormone glucagon. Glucagon syndrome is a neoplastic phenomenon characterized by 4D: dermatitis (necrotic migratory erythema), diabetes mellitus, depression and deep vein thrombosis in approximately 1 in 20 million cases.
- Somatostatinoma is the most common NET, located mainly in the pancreas and duodenum. Somatostatin is an inhibitory hormone that inhibits pancreatic, bile, gastrointestinal secretions and gallbladder contraction. Hyperglycemia, cholelithiasis, and steatosis characterises Somatostatinoma syndrome. 68 Elevated somatostatin level (> 10 ng/ml) confirms the diagnosis5.
The presence of carcinoid syndrome due to hypersecretion of amines and peptides often facilitates the diagnosis of NET. In fact, Enterochromaffin or Kulchitzky cells, which are part of diffuse neuroendocrine cells in the gut, synthesize serotonin from dietary tryptophan.
The classical carcinoid syndrome with watery diarrhoea, bronchospasm, flushing, hypotension and right heart dysfunction is related to serotonin hypersecretion, as serotonin properties include bronchoconstriction, vasodilation, and smooth muscle contraction9.
NENs of the Genitourinary (GU) Tracts
GU tract NENs rare neoplasms, which primarily occur in the bladder and kidney and usually present with abdominal or flank pain, weight loss, abdominal bumps, and hematuria, are more common in females than in male GU tracts. However, the most common part of a woman’s genitals is the cervix, followed by the ovaries. Endometrial, vaginal and vulvar NEN has also been reported. In fact, male GU neoplasms are much less common. Moreover, the prostate is the most common site among men. Furthermore, other tumor localizations include testis and small cell NE carcinoma of the penis, testis, and penile urethra. Symptoms caused by hormone production or carcinoid syndrome are rare, occurring in less than 10% of cases10.
NETs in the lungs include typical and atypical carcinoids, such as LCNEC and SCLC. In fact, they result from the decarboxylation system of amine precursors and the origin of neuroendocrine (Kulchitsky) cells, which is similar to that of small cell lung carcinoma. Therefore, the clinical signs and symptoms depend on the tumour’s anatomic status and biological aggressiveness11.
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