Carcinoid tumors

Most frequent neuroendocrine tumor of the G.I. tract.

Generally, slow-growing tumors.

May be symptomatic or asymptomatic.

Peak incidence 50-70 years of age.

Incidence has been steadily rising over the last 30 years.

Comprise 0.49% of all malignancies (Modlin IM).

Occurs in 1-2 persons per 100,000 population per year.

The incidence is 2-5 cases per one hundred thousand/year.

Updated incidence of 35 per 100,000 people.

More common than pancreatic and gastric cancers, and was diagnosed similarly to Hodgkin’s disease.

Revised estimated annual incidence of clinically relevant disease is 5.25 per 100,000 population prevalence >100,000 in the US (Yao JC et al).

About 11-12,000 carcinoid tumors are diagnosed in the United States every year.

May originate anywhere in the body but most commonly in bronchi, stomach, small intestine, appendix or rectum.

Diagnosis depends on the site of origin, secretion patterns, the presence of carcinoid syndrome.

Incidence rates generlly higher among black population.

Incidence rates are double among men older than 50 years of age and in women younger than age 50.

Recent decrease in the incidence of appendicieal carcinoids.

Majority of lesions arise in the gastrointestinal tract (67.5%) or the bronchopulmonary system (25.3%).

Many cases are diagnosed incidentally during routine appendectomy, endoscopy, or CT scan.

Approximately 10% of patients have tumors that secrete bioactive mediators that provide clinical characterisitics of the carcinoid syndrome.

Most cases of carcinoid syndrome likely to occur in patients with tumors that originate in the small intestine or appendix.

Carcinoid syndrome occurs in 8-35% of patients with such tumors and occurs mostly in patients with hepatic metastases.

Metabolic products released by intestinal carcinoid are rapidly destroyed by blood and liver enzymes, and explains why carcinoid syndrome is not seen unless hepatic metastasis are present.

Have the ability to secrete peptides and hormones, such as serotonin.

Symptoms of carcinoid syndrome are in a large part related to the secretion of serotonin.

Gastrointestinal tumors present with abdominal pain, intestinal obstructive symptoms, diarrhea, constipation, the presence of an abdominal mass and gastrointestinal bleeding.

Ten per cent or less of carcinoids, primarily some midgut carcinoids, secrete excessive levels of a range of hormones, most notably serotonin (5-HT) or substance P, causing a constellation of symptoms called ((carcinoid syndrome)).



Carcinoid syndrome symptoms:









asthma or wheezing



congestive heart failure (CHF)



abdominal cramping



peripheral edema



heart palpitations



A carcinoid crisis presents with profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure with large amounts of hormone are acutely secreted.



Hormone release in carcinoid tumors is occasionally triggered by diet, alcohol, surgery, chemotherapy, embolization therapy or radiofrequency ablation.

Increased 5 HIAA levels generally indicate the presence of liver metastases, may be associated with the carcinoid syndrome and carcinoid heart disease.

Chronic exposure to high levels of serotonin causes thickening of the heart valves, particularly the tricuspid and the pulmonic valves, and over a long period can lead to congestive heart failure.

Elevated levels of 5 HIAA associated with shorter survival times.

Urinary 5 HIAA is a byproduct of serotonin breakdown and is therefore indicative of serotonin levels.

Chromogranin A (CgA) levels are specific to confirm the diagnosis of such tumors and are useful to monitor disease.

Chromogranin A levels indicative of tumor burden an correlates with the severity of disease.

Chromogranin A has a lower specificity then 5 HIAA for the diagnosis of carcinoid, 86% and 100%, respectively, but has a higher sensitivity than 5-HIAA, 68% and 35%, respectively.

Retroperitoneal or less commonly pleural or pulmonary fibrosis may occur.

May be associated with mesenteric fibrosis with impaired intestinal motility and obstruction of the bowel.

66% of tumors arise from the gastrointestinal tract.

Classification: foregut, midgut or hindgut depending on the embryonic origin.

Forgut tumors develop in the respiratory tract, Siamese, stomach, duodenum and pancreas.

Most gastrointestinal lesion develop in the small bowel 41.8%, rectum 27.4% or stomach 8.7%.

Carcinoid tumors of the rectum are more prevalent in Black and Asian populations in the U.S.

Midgut develop in the small bowel, appendix, and ascending colon.

Hindgut tumors develop in the transverse colon, descending colon or rectum.

In women, the primary tumor site are the lungs, stomach, appendix, and cecum.

In men, the primary sites are the thymus, duodenum, pancreas, jejunum/ileum or rectum.

Rectal carcinoids are rare, accounts for less than 15% of all gastrointestinal tract carcinoids.

Rectal carcinoids account for 1.3% of all rectal tumors.

Rectal carcinoids less aggressive than carcinoids of other sites.

Rectal carcinoids 5 year survival ranges from 62-100%, compared to small intestine lesions of 52-77% and for colon 33-75%.

Rectal carcinoids-risk of metastases correlates with size.

Outcomes have changed little in the last 30 years: median survival in patients diagnosed 1973-2004 with local, regional, with distant metastases was 223 months, 111 months, and 33 months, respectively (Jao JC).

5-year survival for localized disease is greater than 75% and the 5 year survival rate for patients with distant metastases is <40%.

Carcinoid tumors of the small bowel are more frequently diagnosed at a later stage.

Thymic carcinoid primarily affects men age 40-60 years.

Have somatostatin receptors on the cell membranes making radiolabeled octreotide helpful in the diagnosis and staging of the disease.

Scintigraphy with radiolabeled octreotide has a sensitivity between 80-90%.

Surgical resection of the primary tumor should always be considered, we have a wide resection and negative margins and resection of regional lymph node basins.

In clinical situations where there is multifocal midgut carcinoids they should be resected, if adequate bowel length can be left to prevent short bowel syndrome.

DTIC associated with a response rates of 16%-33%.

Everolimus is efficacious in carcinoid tumors.

Bevacizumab, has a response rate of about 25% in neuroendocrine tumors.

Sunitinib can block metabolic targets in a neuroendocrine tumors and inhibit tumor growth, inhibits vascular endothelial growth factor receptor, and platelet derived growth factor receptor, which play a role in angiogenesis: a randomized trial utilizing this agent increased progression free survival in pancreatic neuroendocrine tumors from 5.5 to 11.1 months.

Axitinib is a a treatment option for unresectable and metastatic carcinoid tumors.

The 12 month progression-free survival (PFS)] rate associated with axitinib in advanced carcinoid tumors is promising when compared to results observed in phase 2 studies of other antiangiogenic TKIs such as sunitinib or pazopanib.

5 mg Axitinib twice daily in metastatic carcinoid was associated with a PFS rate of 65% at 12 months, ans a 1-year overall survival (OS) rate of 93%.

Somatostatin analogues can stop the growth of neuroendocrine cells: PROMID study of 85 patients with mid gut carcinoids comparing octreotide to placebo, the average progression free survival was 14.3 months versus six months, respectively and at six months 64% of the patients treated with octreotide remained without progressive disease versus 37.2% in the placebo group (Arnold R et al).

Pazopanib significantly improved progression-free survival (PFS) in patients with progressive carcinoid tumors who were enrolled in a prospective randomized phase 3 trial.

Median PFS was 11.6 months for patients receiving the small molecule VEGF inhibitor, versus 8.5 months for those receiving placebo.

Toxicity risks, including an excess of hypertension.

Despite the improved PFS in the pazopanib arm, there was no improvement in overall survival.

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