NET & NEC

Question 1

Carcinoid syndrome

Answer 1

• Carcinoid syndrome is most common in the setting of disseminated disease, particularly liver metastases, but it can occur in apparently locoregional disease.
• carcinoid syndrome is associated with metastatic tumors originating in the midgut (jejunum, ileum, and cecum)
• The most prominent of these are serotonin, histamine, tachykinins, kallikrein, and prostaglandins
• Altered metabolism of tryptophan occurs in almost all patients with carcinoid syndrome, 1 percent of dietary tryptophan is converted to serotonin; however, this value may increase to 70 percent or more in patients with carcinoid syndrome. Serotonin is then metabolized to 5-hydroxyindoleacetic acid
• lack the aromatic amino acid decarboxylase that converts 5-hydroxytryptophan to serotonin, produce 5- hydroxytryptophan (and histamine) instead of serotonin
• distal colon and rectum, rarely secrete serotonin or any other bioactive hormones, unassociated with hormonal syndromes, even when metastatic
• widely metastatic tumors may result in niacin deficiency, decreased protein synthesis and hypoalbuminemia, with or without the clinical manifestations of pellagra (rough scaly skin, glossitis, angular stomatitis, and mental confusion)
• Serotonin stimulates intestinal secretion and motility and inhibits intestinal absorption, Serotonin does not cause flushing
• Histamine > Primary gastric NETs can produce histamine, responsible for the atypical flushing and pruritus associated with these tumors
• Kallikrein» is a potent vasodilator and may be responsible for flushing in some carcinoid patients
• Venous telangiectasia — These purplish vascular lesions, similar to those seen in acne rosacea, appear late in the course of carcinoid syndrome. They are due to prolonged vasodilatation and most often occur on the nose, upper lip, and malar areas

Question 2

generalidades net y nec

Answer 2

*neuroendocrine tumor (NET)” refers to well-differentiated neuroendocrine neoplasms, and “neuroendocrine carcinoma (NEC)” refers to poorly differentiated neuroendocrine cancers
*Radiographic staging and tumor localization –CT, RNM, CT PET gallium Ga-68 DOTATATE
*Mesenteric masses are usually indicative of a primary tumor located in the small intestine
*Appendix // 1. The prognosis of appendiceal NETs is best predicted by tumor size // 2. tumors less than 2 cm in diameter (95%) low likelihood of metastases at diagnosis// 3. up to 30 percent of larger tumors have already metastasized at diagnosis, mostly to regional nodes// 4. a right hemicolectomy has been traditionally recommended for tumors greater than 2 cm or those with mesoappendiceal invasion, completion right colectomy for tumors <2 cm only if there is evidence of mesoappendiceal invasion or positive or unclear margins, tumors less than 1 cm can usually be treated by simple appendectomy
* NETs of the small intestine are most commonly found in the ileum within 60 cm of the ileocecal valve. All small intestinal NETs have the potential to metastasize, irrespective of size// patients with non-metastatic tumors of any size should be treated with wide local excision that includes resection of the involved segment and small bowel mesentery // multiple NETs are present in approximately 25 to 55 percent of cases // resection of the primary tumor may be advised even in patients with known distant metastases in order to reduce the potential for bowel obstruction or bleeding, or to palliate abdominal pain // five-year overall survival rates range from 40 to 85 percent; 10-year survival rates of 40 to 60 percent are reported // Ten-year disease-specific survival :
* ●Stage I – 95 percent (95% CI 93-97 percent)
●Stage IIA – 95 percent (95% CI 90-96 percent)
●Stage IIB – 77 percent (95% CI 71-83 percent)
●Stage IIIA – 68 percent (95% CI 58-77 percent)
●Stage IIIB – 77 percent (95% CI 74-80 percent)
●Stage IV – 42 percent (95% CI 38-46 percent)
* Prognosis among surgically treated patients also depends on margin status
* in pancreas»>high likelihood of nodal metastases with ampullary NETs, even with tumor size <2 cm
*in rectum metastases were found in 2 percent of patients with tumors <1 cm, 10 to 15 percent in patients with tumors measuring 1.0 to 1.9 cm, and 60 to 80 percent in tumors measuring >2 cm, additional prognostic factors, including mitotic index and lymphovascular invasion (LVI), which could portend a poorer prognosis // Observation alone results in inferior outcomes, even for small tumors <1 cm, mucosa or submucosa (T1) can generally be treated by standard endoscopic resection // Large tumors (>2 cm) or those that invade the muscularis propria (≥T2) are generally treated with radical surgical resection (LAR or APR, five-year overall survival rates were 92, 88, 59, and 15 percent for stage I, II, III, and IV disease
* colon»_space;> five-year survival rates were only 62 percent across all stages (compared with 88 percent for rectal NETs) // Well-differentiated colonic NETs have the worst prognosis of any gastrointestinal tract well-differentiated NET: more aggressive behavior may be that colonic NETs are frequently right sided // two-thirds have evidence of nodal or distant metastases at the time of diagnosis // tumors are >2 cm and/or invasive through the muscularis propria»_space; formal partial colectomy and regional lymphadenectomy
* Stomach — Gastric NETs are subdivided into three categories, with differing biologic behavior and prognoses // Type 1 gastric NETs, which represent 70 to 80 percent of all gastric NETs»_space; associated with chronic atrophic gastritis, serum gastrin rises, most are ST I no mortality with prolonged follow-up // Type 2 gastric NETs, which represent approximately 5 percent of gastric NETs rise serum gastrin, The underlying cause of type 2 gastric NETs is a pancreatic or duodenal gastrinoma // Type 3 (sporadic) gastric NETs occur in the absence of atrophic gastritis or the Zollinger-Ellison syndrome, 20 percent of gastric NETs and are the most aggressive, local or hepatic metastases are present in up to 65 percent of patients who come to resection // type 3 partial or total gastrectomy with local lymph node resection is the treatment, endoscopic therapy alone only well-differentiated (grade 1) gastric NET no larger than 1.5 cm and without lymphovascular invasion// For type 1 and 2 gastric NETs smaller than 1 to 2 cm, endoscopic resection represents adequate therapy
* nonhormonal biomarkers such as chromogranin A (CgA) in surveillance is controversial // 24-hour measurements of urinary 5-hydroxyindoleacetic acid (5-HIAA) are not recommended for postoperative surveillance of tumors that are unlikely to produce serotonin
* for rectal, gastric, and appendiceal NETs >2 cm :
●3 to 12 months postresection: Abdominal or abdominopelvic multiphasic CT or MRI scan for gastrointestinal NETs, chest CT with or without contrast for lung/thymus NETs. Assay of biochemical markers as clinically indicated.
●>1 year postresection: Every 12 to 24 months abdominal or abdominopelvic multiphasic CT or MRI scan for gastrointestinal NETs, chest CT with or without contrast for lung/thymus NETs. Assay of biochemical markers as clinically indicated.
●>10 years postresection: Continue surveillance as clinically indicated.
* median survival durations are longer among patients with metastatic (stage IV) NETs of the small intestine compared with metastatic tumors originating in other sites
* five-year survival rates for metastatic gastrointestinal NETs of low-, intermediate-, or high-grade histologic differentiation were 87, 38, and 0 percent, respectively
* Other prognostic factors: Tumor burden five-year survival rates for those with <5 and ≥5 metastases were 79 and 47 percent, respectively, Carcinoid heart disease , Hormone production, Metastatic site liver metastasis had worse survival than did those with brain and bone metastasis

Question 3

tumor biomarkers in gastroenteropancreatic neuroendocrine tumors

Answer 3

• Nonhormonal secretory products, such as chromogranin A, pancreastatin, and pancreatic polypeptide are often produced by both functional and nonfunctional NETs
• Biomarkers can be diagnostic, prognostic, or predictive
• CgA is a glycoprotein secreted by neurons and neuroendocrine cells, high sensitivity, and specificity for CgA in patients with advanced NETs, both functional and nonfunctional, Test performance is better with advanced than with localized disease, Several medications, notably proton pump inhibitors (PPI), and some foods increase CgA levels, CgA levels are often elevated in nonneoplastic conditions such as chronic atrophic gastritis, renal failure, and inflammatory diseases, CgA as a marker indicative of changing tumor burden in patients treated with somatostatin analogs. These agents significantly reduce plasma CgA levels, and this change may reflect diminished hormonal synthesis and release from tumor cells rather than a reduction in tumor mass, CgA in patients with newly diagnosed NETs is now considered a category III recommendation by the nccn
• Pancreatic polypeptideis most commonly elevated in patients with pancreatic NETs and when elevated, it can serve as a tumor marker
• the role of these tumor markers in surveillance after surgical resection of a NET is limited due to their relatively poor sensitivity and specificity
• serial measurements of CgA and/or other nonhormonal tumor markers are most useful in patients with metastatic NETs
• Serotonin and 5 -hydroxyindoleacetic acid (5-HIAA) — Serotonin (5-hydroxytryptamine) is an amine derivative secreted by the enterochromaffin cells of the small intestine, and is the main hormone implicated in the carcinoid syndrome, elevated circulating serotonin levels occur only in patients with metastatic disease, Other conditions such as malabsorption, celiac disease, and renal failure can affect 5-HIAA levels, Elevation in excretion of urinary 5-HIAA is highly sensitive and specific for midgut tumors that have metastasized to the liver
• Gastrin — Gastrin is a peptide hormone secreted by the G-cells of the pyloric antrum, duodenum, and pancreas. It is involved in the stimulation of gastric acid release, A serum gastrin value greater than 10 times the upper limit of normal (1000 pg/mL) in the presence of a gastric pH below 2 is diagnostic of ZES, If the gastrin level is between the upper limit of normal and 1000 pg/mL, a secretin test can be performed, and is considered positive if gastrin rises more than 120 pg/m, somatostatin receptor imaging positron emission tomography scans, and endoscopic ultrasound replace the secretin test.
• The gold standard test for diagnosis of an insulinoma is the 72-hour fasting test, which should measure insulin, proinsulin, and C-peptide. Insulin, C-peptide, and proinsulin are elevated in insulinoma
• Glucagonomas are rare functioning NETs that secrete glucagon. These pancreatic tumors are typically large (>3 cm) and most (50 to 80 percent) are metastatic at diagnosis. Glucagonoma syndrome is characterized by hyperglycemia, glossitis, cachexia, and the distinctive skin eruption necrolytic migratory erythema, diagnostic with elevated fasting glucagon levels

Question 4

Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system

Answer 4

gastroenteropancreatic (GEP) system by the WHO:
1. Well-differentiated neuroendocrine tumors (NETs) show a solid, trabecular, gyriform, or glandular pattern, with fairly uniform nuclei, coarsely stippled (“salt and pepper”) chromatin, and finely granular cytoplasm // NETs are graded as low (G1), intermediate (G2), and high (G3) grade
2. Poorly differentiated neuroendocrine carcinomas (NECs) are by definition high-grade carcinomas that resemble small cell carcinoma or large cell NEC
3. Morphology and immunohistochemistry : NETs produce abundant neurosecretory granules, as reflected in the strong and diffuse immunohistochemical expression of neuroendocrine markers such as synaptophysin and chromogranin, amyloid deposition in pancreas, glandular architecture with psammoma body formation is usually seen in duodenal or ampullary somatostatin-secreting NETs // NECs are sheet-like or diffuse architecture, irregular nuclei, and less cytoplasmic granularity. Immunohistochemical expression of neuroendocrine markers is generally more limited in extent and intensity
4. Classification: proliferative rate to stratify the grades and requires both a mitotic count and the Ki-67 labeling index to be assessed // Poorly differentiated neoplasms >20 percent Ki-67 labeling index, >20 per 2 mm2 mitotic rate, 40 percent of cases, poorly differentiated NECs contain non-neuroendocrine components, including conventional adenocarcinoma, signet ring cell carcinoma, and more rarely, squamous cell carcinoma, category of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) before called MANEC
5. the underlying genomic alterations persist in the higher-grade foci, and the specific mutations that are typical of poorly differentiated NEC, such as RB1 and TP53, are generally not found in well-differentiated NET G3. Progression from NET to NEC occurs extremely rarely
6. A mitotic rate greater than 20 per 2 mm2 usually indicates a NEC, since most NET G3 cases fall into the high-grade range solely based on their Ki-67 index
7.