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While most carcinoids are asymptomatic through the natural lifetime and are discovered only upon surgery for unrelated reasons (so-called "coincidental carcinoids"), all carcinoids are considered to have malignant potential.
About 10% of carcinoids secrete excessive levels of a range of hormones, most notably serotonin (5-HT), causing:
- Flushing (serotonin itself does not cause flushing). Potential causes of flushing in carcinoid syndrome include bradykinins, prostaglandins, tachykinins, substance P, and/or histamine, diarrhea, and heart problems. Because of serotonin's growth-promoting effect on cardiac myocytes,[14] a serotonin-secreting carcinoid tumour may cause a tricuspid valve disease syndrome, due to the proliferation of myocytes onto the valve.
- Diarrhea
- Wheezing
- Abdominal cramping
- Peripheral edema
The outflow of serotonin can cause a depletion of tryptophan leading to niacin deficiency. Niacin deficiency, also known as pellagra, is associated with dermatitis, dementia, and diarrhea.
This constellation of symptoms is called "carcinoid syndrome" or (if acute) "carcinoid crisis". Occasionally, haemorrhage or the effects of tumor bulk are the presenting symptoms. The most common originating sites of carcinoid is the small bowel, particularly the ileum; carcinoid tumors are the most common malignancy of the appendix. Carcinoid tumors may rarely arise from the ovary or thymus.
They are most commonly found in the midgut at the level of the ileum or in the appendix. The next most common affected area is the respiratory tract, with 28% of all cases — per PAN-SEER data (1973 – 1999). The rectum is also a common site.
Carcinoid (also carcinoid tumor) is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum, ileum, appendix, and cecum) are associated with carcinoid syndrome.
Carcinoid tumors are the most common malignant tumor of the appendix, but they are most commonly associated with the small intestine, and they can also be found in the rectum and stomach. They are known to grow in the liver, but this finding is usually a manifestation of metastatic disease from a primary carcinoid occurring elsewhere in the body. They have a very slow growth rate compared to most malignant tumors. The median age at diagnosis for all patients with neuroendocrine tumors is 63 years.
Some PanNETs do not cause any symptoms, in which case they may be discovered incidentally on a CT scan performed for a different purpose. Symptoms such as abdominal or back pain or pressure, diarrhea, indigestion, or yellowing of the skin and whites of the eyes can arise from the effects of a larger PanNET tumor, either locally or at a metastasis. About 40% of PanNETS have symptoms related to excessive secretion of hormones or active polypeptides and are accordingly labeled as "functional"; the symptoms reflect the type of hormone secreted, as discussed below. Up to 60% of PanNETs are nonsecretory or nonfunctional, in which there is no secretion, or the quantity or type of products, such as pancreatic polypeptide (PPoma), chromogranin A, and neurotensin, do not cause a clinical syndrome although blood levels may be elevated. In total, 85% of PanNETs have an elevated blood marker.
Functional tumors are often classified by the hormone most strongly secreted, for example:
- gastrinoma: the excessive gastrin causes Zollinger–Ellison syndrome (ZES) with peptic ulcers and diarrhea
- insulinoma: hypoglycemia occurs with concurrent elevations of insulin, proinsulin and C peptide
- glucagonoma: the symptoms are not all due to glucagon elevations, and include a rash, sore mouth, altered bowel habits, venous thrombosis, and high blood glucose levels
- VIPoma, producing excessive vasoactive intestinal peptide, which may cause profound chronic watery diarrhea and resultant dehydration, hypokalemia, and achlorhydria (WDHA or pancreatic cholera syndrome)
- somatostatinoma: these rare tumors are associated with elevated blood glucose levels, achlorhydria, cholelithiasis, and diarrhea
- less common types include ACTHoma, CRHoma, calcitoninoma, GHRHoma, GRFoma, and parathyroid hormone–related peptide tumor
In these various types of functional tumors, the frequency of malignancy and the survival prognosis have been estimated dissimilarly, but a pertinent accessible summary is available.
PanNETs are sometimes abbreviated as PETs or PNETs: such use should not to be confused with the primitive neuroectodermal tumor (PNET).
The majority of PanNETs are benign, while some are malignant. The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories, which emphasize the tumor grade rather than the anatomical origin. In practice, those tumors termed well or intermediately differentiated PanNETs in the WHO scheme are sometimes called "islet cell tumors." The high grade subtype, termed neuroendocrine cancer (NEC) in the WHO scheme, is synonymous with "islet cell carcinoma".
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 tumours, 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 categories depends on well-defined histological features: size, lymphovascular invasion, mitotic counts, Ki-67 labelling index, invasion of adjacent organs, presence of metastases and whether they produce hormones.
Carcinoids most commonly affect the small bowel, particularly the ileum, and are the most common malignancy of the appendix. Many carcinoids are asymptomatic and are discovered only upon surgery for unrelated causes. These coincidental carcinoids are common; one study found that one person in ten has them. Many tumors do not cause symptoms even when they have metastasized. Other tumors even if very small can produce adverse effects by secreting hormones.
Ten per cent (10%) 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:
- flushing
- diarrhea
- asthma or wheezing
- congestive heart failure (CHF)
- abdominal cramping
- peripheral edema
- heart palpitations
A carcinoid crisis with profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure can occur if large amounts of hormone are acutely secreted, which is occasionally triggered by factors such as diet, alcohol, surgery chemotherapy, embolization therapy or radiofrequency ablation.
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. However, valve replacement is rarely needed. The excessive outflow of serotonin can cause a depletion of tryptophan leading to niacin deficiency, and thus pellagra, which is associated with dermatitis, dementia, and diarrhea. Many other hormones can be secreted by some of these tumors, most commonly growth hormone that can cause acromegaly, or cortisol, that can cause Cushing's syndrome.
Occasionally, haemorrhage or the effects of tumor bulk are the presenting symptoms. Bowel obstruction can occur, sometimes due to fibrosing effects of NET secretory products with an intense desmoplastic reaction at the tumor site, or of the mesentery.
Diffuse stomach cancer is characterized by the presence of poorly differentiated tumor cells. Microscopic appearance is signet ring cell carcinoma, which is tumor cells with mucin droplet that displaces the nucleus to one side.
The appearance of the stomach is like a "leather bottle". It is characterized by a thick, rigid stomach wall caused by diffuse infiltration of tumor cells and extensive fibrosis.
Diarrhea may be a presenting symptom.
Most patients with fundic gland polyps (FGPs) do not have any symptoms, and the diagnosis is made on gastroscopy done for other reasons. Retrospective analysis of patients with sporadic FGPs shows that a high percentage do have symptoms, but that this is more likely to be related to the underlying disease responsible for the polyposis. These symptoms include:
- epigastric pain
- nausea
- vomiting
- weight loss
The polyps on endoscopy are usually tiny, numerous and sessile, and usually scattered throughout the fundus of the stomach, where parietal cells are more numerous. They have the same colour as the gastric mucosa, and never have a stalk.
When the polyps are biopsied, the pathology typically shows shortened gastric pits, and both superficial and deep cystic lesions in the fundic glands, lined by all three types of cells of acid-producing mucosa: mucous, parietal and chief cells. As sometimes parietal cell hyperplasia may develop deep dilations of gland, one should be really strict in the diagnosis of FGPs (i.e. the presence of deep and superficial dilations). Infrequently, the two lesions may coexist. Foci of dysplasia can sometimes be seen.
The carcinoid syndrome occurs in approximately 5% of carcinoid tumors and
becomes manifest when vasoactive substances from the tumors enter the systemic circulation escaping hepatic degradation. Interestingly, if the primary tumor is from the GI tract (hence releasing serotonin into the hepatic portal circulation), carcinoid syndrome generally does not occur until the disease is so advanced that it overwhelms the liver's ability to metabolize the released serotonin.
- Flushing: The most important clinical finding is flushing of the skin, usually of the head and the upper part of thorax.
- Diarrhea: When the diarrhea is intense and explosive, it may lead to electrolyte disturbance and dehydration.
- Abdominal pain: Due to desmoplastic reaction of the mesentery or hepatic metastases.
- Bronchoconstriction, which may be histamine-induced, affects a smaller number of patients and often accompanies flushing.
- Secondary restrictive cardiomyopathy: About 50% of patients have cardiac abnormalities classically of the restrictive-type caused by serotonin-induced fibrosis of the valvular endocardium, notably the tricuspid and pulmonary valves, called cardiac fibrosis. This results in a heart with normal rhythm and contractility, but reduced preload and end-diastolic volume. "TIPS" is an acronym for Tricuspid Insufficiency, Pulmonary Stenosis (fibrosis of tricuspid and pulmonary valves).
- Nausea and Vomiting
Pancreatic islet cell tumors occur in 60 to 70% of patients. Tumors are usually multicentric. Multiple adenomas or diffuse islet cell hyperplasia commonly occurs; such tumors may arise from the small bowel rather than the pancreas. About 30% of tumors are malignant and have local or distant metastases. Malignant islet cell tumors due to MEN 1 syndrome often have a more benign course than do sporadically occurring malignant islet cell tumors.About 40% of islet cell tumors originate from a β-cell, secrete insulin (insulinoma), and can cause fasting hypoglycemia. β-cell tumors are more common in patients 40 years of age. Non-β-cell tumors are somewhat more likely to be malignant.
Most islet cell tumors secrete pancreatic polypeptide, the clinical significance of which is unknown. Gastrin is secreted by many non–β-cell tumors (increased gastrin secretion in MEN 1 also often originates from the duodenum). Increased gastrin secretion increases gastric acid, which may inactivate pancreatic lipase, leading to diarrhea and steatorrhea. Increased gastrin secretion also leads to peptic ulcers in > 50% of MEN 1 patients. Usually the ulcers are multiple or atypical in location, and often bleed, perforate, or become obstructed. Peptic ulcer disease may be intractable and complicated. Among patients presenting with Zollinger-Ellison syndrome, 20 to 60% have MEN 1.
A severe secretory diarrhea can develop and cause fluid and electrolyte depletion with non–β-cell tumors. This complex, referred to as the watery diarrhea, hypokalemia and achlorhydria syndrome (VIPoma) has been ascribed to vasoactive intestinal polypeptide, although other intestinal hormones or secretagogues (including prostaglandins) may contribute. Hypersecretion of glucagon, somatostatin, chromogranin, or calcitonin, ectopic secretion of ACTH resulting in Cushing's syndrome, and hypersecretion of somatotropin–releasing hormone (causing acromegaly) sometimes occur in non–β-cell tumors. All of these are rare in MEN 1.Nonfunctioning pancreatic tumors also occur in patients with MEN 1 and may be the most common type of pancreatoduodenal tumor in MEN 1. The size of the nonfunctioning tumor correlates with risk of metastasis and death.
Linitis plastica, also known as Brinton's disease or leather bottle stomach, is a morphological variant of diffuse (or infiltrating) stomach cancer.
Causes of linitis plastica could be lye ingestion or metastatic infiltration of the stomach, particularly breast and lung carcinoma. It is not associated with H. pylori infection or chronic gastritis. The risk factors are undefined, except for rare inherited mutations in E-cadherin, which are found in about 50% of diffuse-type gastric carcinomas.
Signet ring cell carcinoma (SRCC) is a rare form of highly malignant adenocarcinoma that produces mucin. It is an epithelial malignancy characterized by the histologic appearance of signet ring cells.
Primary SRCC tumors are most often found in the glandular cells of the stomach (SRCC originates in the stomach in 90 percent of patients), and less frequently in the breast, gallbladder, urinary bladder, and pancreas. SRCCs do not normally form in the lungs, though a few incidences have been reported.
Among colorectal cancers, the prevalence of SRCC is less than one percent. Though incidence and mortality of gastric cancer has declined in many countries over the past 50 years, there has been an increase in occurrences of gastric SRCC-type cancers.
SRCC tumors grow in characteristic sheets, which makes diagnosis using standard imaging techniques, like CT and PET scans, less effective.
Hyperparathyroidism is present in ≥ 90% of patients. Asymptomatic hypercalcemia is the most common manifestation: about 25% of patients have evidence of nephrolithiasis or nephrocalcinosis. In contrast to sporadic cases of hyperparathyroidism, diffuse hyperplasia or multiple adenomas are more common than solitary adenomas.
Patients with Zollinger–Ellison syndrome may experience abdominal pain and diarrhea. The diagnosis is also suspected in patients who have severe ulceration of the stomach and small bowel, especially if they fail to respond to treatment.
- Chronic diarrhea, including steatorrhea (fatty stools)
- Pain in the esophagus, especially between and after meals at night
- Nausea
- Wheezing
- Vomiting blood
- Malnourishment
- Loss of appetite
Gastrinomas may occur as single tumors or as multiple small tumors. About one-half to two-thirds of single gastrinomas are malignant tumors that most commonly spread to the liver and to lymph nodes near the pancreas and small bowel.
Nearly 25 percent of patients with gastrinomas have multiple tumors as part of a condition called multiple endocrine neoplasia type 1 (MEN 1). MEN I patients have tumors in their pituitary gland and parathyroid glands, in addition to tumors of the pancreas.
Fundic gland polyposis is a medical syndrome where the fundus and the body of the stomach develop many polyps. The condition has been described both in patients with familial adenomatous polyposis (FAP) and attenuated variants (AFAP), and in patients in whom it occurs sporadically.
Krukenberg tumors often come to the attention when they cause abdominal or pelvic pain, bloating, ascites, or pain during sexual intercourse. Krukenberg tumors can occasionally provoke a reaction of the ovarian stroma which leads to hormone production, that results in vaginal bleeding, a change in menstrual habits, or hirsutism, or occasionally virilization as a main symptom.
All these symptoms are non-specific and can also arise with a range of problems other than cancer, and a diagnosis can only be made following confirmatory investigations such as computed tomography (CT) scans, laparotomy and/or a biopsy of the ovary.
Primary gastric lymphoma (lymphoma that originates in the stomach itself) is an uncommon condition, accounting for less than 15% of gastric malignancies and about 2% of all lymphomas. However, the stomach is a very common extranodal site for lymphomas (lymphomas originating somewhere else with metastasis to stomach). It is also the most common source of lymphomas in the gastrointestinal tract.
Carcinoid syndrome is a paraneoplastic syndrome comprising the signs and symptoms that occur secondary to carcinoid tumors. The syndrome includes flushing and diarrhea, and less frequently, heart failure, emesis and bronchoconstriction. It is caused by endogenous secretion of mainly serotonin and kallikrein.
Most people affected by primary gastric lymphoma are over 60 years old. Symptoms include epigastric pain, early satiety, fatigue and weight loss.
A Krukenberg tumor refers to a malignancy in the ovary that metastasized from a primary site, classically the gastrointestinal tract, although it can arise in other tissues such as the breast. Gastric adenocarcinoma, especially at the pylorus, is the most common source. Krukenberg tumors are often (over 80%) found in both ovaries, consistent with its metastatic nature.
Zollinger–Ellison syndrome (ZES) is a disease in which tumors cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea.
The syndrome is caused by a gastrinoma, a neuroendocrine tumor that secretes a hormone called gastrin. The tumor causes excessive production of gastric acid, which leads to the growth of gastric mucosa and proliferation of parietal and ECL cells.
ZES may occur on its own or as part of an autosomal dominant syndrome called multiple endocrine neoplasia type 1 (MEN 1). The primary tumor is usually located in the pancreas, duodenum or abdominal lymph nodes, but ectopic locations (e.g., heart, ovary, gallbladder, liver, and kidney) have also been described.
Stomach cancer is often either asymptomatic (producing no noticeable symptoms) or it may cause only nonspecific symptoms (symptoms that may also be present in other related or unrelated disorders) in its early stages. By the time symptoms occur, the cancer has often reached an advanced stage (see below) and may have metastasized (spread to other, perhaps distant, parts of the body), which is one of the main reasons for its relatively poor prognosis. Stomach cancer can cause the following signs and symptoms:
Early cancers may be associated with indigestion or a burning sensation (heartburn). However, less than 1 in every 50 people referred for endoscopy due to indigestion has cancer. Abdominal discomfort and loss of appetite, especially for meat, can occur.
Gastric cancers that have enlarged and invaded normal tissue can cause weakness, fatigue, bloating of the stomach after meals, abdominal pain in the upper abdomen, nausea and occasional vomiting, diarrhea or constipation. Further enlargement may cause weight loss or bleeding with vomiting blood or having blood in the stool, the latter apparent as black discolouration (melena) and sometimes leading to anemia. Dysphagia suggests a tumour in the cardia or extension of the gastric tumour into the esophagus.
These can be symptoms of other problems such as a stomach virus, gastric ulcer, or tropical sprue.
Gastrointestinal cancer refers to malignant conditions of the gastrointestinal tract (GI tract) and accessory organs of digestion, including the esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus. The symptoms relate to the organ affected and can include obstruction (leading to difficulty swallowing or defecating), abnormal bleeding or other associated problems. The diagnosis often requires endoscopy, followed by biopsy of suspicious tissue. The treatment depends on the location of the tumor, as well as the type of cancer cell and whether it has invaded other tissues or spread elsewhere. These factors also determine the prognosis.
Overall, the GI tract and the accessory organs of digestion (pancreas, liver, gall bladder) are responsible for more cancers and more deaths from cancer than any other system in the body. There is significant geographic variation in the rates of different gastrointestinal cancers.
Primary signet ring cell carcinoma of the colon and rectum (PSRCCR) is rare, with a reported incidence of less than 1 percent. It has a poor prognosis because symptoms often develop late and it is usually diagnosed at an advanced stage. Five-year survival rates in previous studies ranged from nine to 30 percent. Average survival was between 20 and 45 months. It tends to affect younger adults with higher likelihood of lymphovascular invasion. It is worth noting that the overall survival rate of patients with SRCC was significantly poorer than that of patients with mucinous or poorly differentiated adenocarcinoma.
In advanced gastric cancers, the prognosis for patients with the SRCCs was significantly worse than for the other histological types, which can be explained by the finding that advanced SRCC gastric cancers have a larger tumor size, more lymph node metastasis, a deeper invasive depth and more Borrmann type 4 lesions than other types.
A gastrointestinal carcinoid tumor is a rare, slow-growing form of cancer that affects certain cells in the lining of the stomach and intestines. The cells it affects make hormones that regulate the production of digestive juices and muscles that move food through the stomach and intestines. This kind of cancer usually occurs in the appendix, small intestine, or rectum. Its presence is associated with an increased risk of cancers affecting the other parts of the digestive system. It is usually treated with surgery.