Colic carcinoid

　　1. Pathophysiology

　　In colonic carcinoids, 68% are located in the right half of the colon, with the cecum accounting for 50%. The right half of the colon, cecum, and ileum originate from the midgut. 65% of the carcinoid cell types in the right half of the colon are argentaffin, and 35% are argyrophil. The difference between argentaffin and argyrophil cells is that the former secretes 5-HT, while the argyrophil cells secrete other functional active substances. Therefore, the right half colon carcinoids originating from the midgut can produce carcinoid syndrome in the late stage of the disease or with liver metastasis, which is due to the 5-HT secretion of argentaffin carcinoid cells exceeding the body's degradation capacity. At this time, the blood 5-HT level is higher than normal, and after the serotonin in the body is decomposed, the amount of 5-hydroxyindoleacetic acid (5-HIAA) in the urine over 24 hours also increases. The carcinoid cell lines in the left half colon and rectum derived from the hindgut are non-argentaffin and do not secrete 5-HT, so even in the late stage of rectal carcinoids with liver metastasis, carcinoid syndrome does not occur.

　　1. Histological Origin: The histogenesis of colonic carcinoids is generally believed to originate from Kulchitsky cells of the endoderm by most scholars. According to the classification by Williams and Sandler, colonic carcinoids belong to a subgroup derived from the hindgut. With the increasing reports of colonic carcinoids year by year, their occurrence seems to have exceeded the distribution area of endodermal epithelium, and in addition, the presence of neuroendocrine granules in the cytoplasm of tumor cells, as well as the fact that some tumor cells can produce functional serotonin (a substance with no difference in function from the neurotransmitter serotonin in the normal central nervous system), recent data more strongly support the origin of colonic carcinoids from the neuroendoderm, and they are classified as neuroendocrine tumors.

　　2. Morphological Appearance: Colonic carcinoids are mostly located in the deep mucosa, presenting as spherical or lentil-shaped, protruding into the intestinal lumen as nodular or polypoid, with a broad base and no pedicle, and a few with pedicle formation. They are usually small in size, with a diameter generally less than 1.5 cm, and occasionally larger than several centimeters. The tumor is relatively hard, with clear boundaries, covered by normal mucosa, and a few may appear with ulcers, forming a umbilical-like appearance. The cross-section is grayish yellow or white, with clear boundaries. Some cases may only show submucosal localized thickening, or present as broad-based polyps rising into the intestinal lumen. Colonic carcinoids can be multiple, and the mucosa covering the tumor is generally intact, with mucosal ulcers or bleeding less common than in adenocarcinoma. Rectal carcinoids are less commonly discovered, with the tumor diameter often less than 1 cm, being movable. Tumors larger than 1 cm often protrude into the intestinal lumen to form mushroom-like masses, accompanied by ulcers, and occasionally, intestinal stenosis may occur, with nodular and polypoid types being more common.

　　3. Tissue morphology: The cell morphology of colonic cancer also varies in differentiation. Typical carcinoids are composed of well-differentiated cells, which are small, polygonal, oval, or low columnar in shape, with moderate cytoplasmic quality, eosinophilic, with round or oval nuclei, not deeply stained, located centrally in the cell, without obvious nucleoli, and with rare nuclear division. The nuclear shape and cell shape are relatively uniform, often arranged in clusters, strips, or tubular glands. In a single tumor, tumor cells can appear in one arrangement, or all three of the above forms can coexist. Under electron microscopy, spherical neuroendocrine granules can be found in the cytoplasm of tumor cells. These neurosecretory granules have a core with different electron density and morphology located centrally or off-center, surrounded by a membrane, with a halo of different widths between the core and the membrane. The morphology and size of the secretory granules vary greatly, and the diameter of the secretory granules of colonic carcinoid cells is mostly between 100 and 300nm.

　　4. Histological characteristics: The pathological histochemical detection method for colonic carcinoids is mainly argyrophilic staining, where black granules can be seen in the cytoplasm. Different locations of carcinoids have different responses to silver staining. Carcinoids occurring in the hindgut have large, round, and uniform-sized cytoplasmic granules, and some are argyrophilic staining-positive. The argyrophilic staining of rectal carcinoids is approximately 55% negative, but there are also those that show positive response to argyrophilic staining (28%).

　　5. Immunohistochemical characteristics: The most sensitive immunohistochemical marker is chromogranin, and the positive expression of this marker is the most reliable basis for diagnosing carcinoids, in addition to histological morphology. The positive expression of other markers, such as neuron-specific enolase (NSE) and cytokeratin, also has supporting significance for the diagnosis of carcinoids. Immunohistochemical analysis shows that 90% of midgut carcinoids are serotonin-positive, and 90% of hindgut carcinoids are pancreastatin-positive. Rectal carcinoids can show positivity for cytokeratin, NSE, chromogranin A, and synaptophysin.

　　6. The determination of the colonic carcinoid nature mainly relies on its biological behavior rather than histological morphology. Most colonic carcinoids, although growing slowly and with a long course, still have the characteristics of invasive growth of malignant tumors. The cancer tissue invades and destroys the local tubular wall, invades surrounding tissues, and invades lymphatic and blood vessels, forming local lymph nodes and even distant organ metastasis. Hematogenous metastasis often forms metastatic foci in the liver, followed by the lung. The rate of metastasis is related to the size of the primary lesion and the location of the primary tumor. For primary tumors of 1cm, more than 50% develop metastasis, and almost all those >2cm are accompanied by regional lymph node and intrahepatic metastasis. The metastasis rate of colonic carcinoids is the highest, reaching 52% to 72%, and most have local lymph node or liver metastasis at surgery, with poor prognosis; the metastasis rate of rectal carcinoids is 17% to 35%. The metastatic foci of carcinoids, especially well-differentiated carcinoids, grow slower than those of other malignant tumors, and even those with metastasis can survive for several years. Therefore, surgical treatment can achieve good results in most carcinoid cases, including those with metastasis.

　　Second, pathological type

　　1. Williams divides gastrointestinal carcinoids according to embryological development and blood supply:

　　(1) Foregut carcinoid: Including the stomach, 1st and 2nd segments of the duodenum, and pancreas.

　　(2) Midgut carcinoid: Including the 3rd and 4th segments of the duodenum, jejunum and ileum, cecum, and ascending colon.

　　(3) Hindgut carcinoid: Including the left half colon and rectum.

　　2. According to the difference in the silver staining reaction of cancer cells, carcinoids are divided into argentaffin and non-argentaffin types. The cells of the foregut carcinoid produce a variety of hormones, and due to the small amount, symptoms are rarely seen in clinical practice. The cells of the midgut carcinoid mainly secrete serotonin, etc., and the amount of secretion exceeds the degradation capacity of the liver, especially when there is liver metastasis, the symptoms of carcinoid syndrome often appear. The cells of the hindgut carcinoid can secrete various peptide substances, such as somatostatin, enkephalin, and substance P, and rarely show the symptoms of carcinoid syndrome.

　　3. Carcinoids are divided into typical carcinoids and atypical carcinoids according to pathological type, with atypical carcinoids being poorly differentiated carcinoids, often indicating more malignant behavior. The prognosis of typical carcinoids is significantly better than that of atypical carcinoids.

　　4. The histological structure of colon carcinoid can be divided into 4 types:

　　(1) Adenoid type: The cancer cells are connected in strings to form adenotubular or adenofollicular, daisy-like, or strip-like structures, and the cells are mostly low columnar.

　　(2) String type: The cancer cells are arranged in solid strings, or in parallel strings of double rows of cells arranged in a ribbon-like manner, with less connective tissue between the strings, and the stromal reaction is obvious, resembling hard cancer.

　　(3) Solid mass type: The cancer cells are arranged in solid masses composed of polygonal tumor cells of uniform size, separated by a small amount of connective tissue containing capillaries.

　　(4) Mixed type: The above three types can be mixed arbitrarily.

　　5. Metastasis routes: The biggest difference between colon carcinoid and carcinoid in other parts is its high metastasis rate. The carcinoid found in the colon is larger than that in other parts, with an average diameter of 4.9 cm. Part of the reason is that the right half colon lumen is large and not easy to be discovered early. The metastatic sites are the regional lymph nodes most, followed by the liver, lung, and ovary. About 60% have local lymph node or liver metastasis during surgery.

　　1. Paroxysmal skin erythema:Generally occurring above the chest, such as the face, neck, and upper chest. It is manifested as scattered, clear, skin patchy erythema, which usually lasts for 2 to 5 minutes and can regress spontaneously. If the duration is prolonged (such as several hours), it may turn purple-red, with local edema, increased heart rate, and decreased blood pressure. Skin erythema is often induced by emotional excitement, overwork, or eating, and is one of the most common symptoms of carcinoid syndrome.

　　2. Diarrhea:Diarrhea is mostly loose stools or watery diarrhea, occurring 5 to 6 times a day, with the maximum reaching 20 to 30 times. Severe cases can lead to electrolyte imbalance. Diarrhea often accompanied by transient abdominal pain, occasionally appearing simultaneously with other symptoms. Some people have diarrhea after eating or in the morning.

　　3. Symptoms caused by fibrous tissue hyperplasia:Fibrous tissue hyperplasia often occurs in serous or endocardial membranes, such as peritoneum, right endocardium (tricuspid valve, pulmonary artery valve), pleura, pericardium, and the outer membranes of some small blood vessels. Due to the above lesions, carcinoid patients have corresponding symptoms and signs, such as tricuspid or pulmonary artery murmur, chest pain, and so on.

　　4. Asthma:It often occurs with diarrhea or paroxysmal skin flushing, lasting about 10 minutes, and related to bronchial smooth muscle spasm.

　　First, general symptoms

　　1. The vast majority of carcinoids are asymptomatic when they are small, and are often found incidentally in clinical practice. If the tumor grows to a certain size or grows in a special location, it often causes some intestinal dysfunction, abdominal pain, or varying degrees of obstruction symptoms. Appendiceal carcinoids have appendicitis symptoms and are often misdiagnosed as appendicitis and operated on. Rectal carcinoids may appear early signs of bleeding, mucous blood stools, or changes in defecation habits, but these symptoms have no obvious distinction from those caused by colorectal adenocarcinoma in the same location, so it is difficult to make a correct clinical diagnosis.

　　2. In addition to the general symptoms similar to colorectal adenocarcinoma, a few cases, regardless of the size of the tumor, may present with some specific syndromes known as carcinoid syndrome. Observing and studying the presence of carcinoid syndrome can be helpful for clinical preoperative diagnosis and determination of treatment methods.

　　Second, carcinoid syndrome

　　1. Paroxysmal skin flushing: Generally occurs above the chest, such as the face, neck, upper chest, etc., manifested as scattered, clear, skin patchy redness, usually lasting 2 to 5 minutes, which can subside spontaneously. If the duration is prolonged (such as several hours), it may turn purple-red, with local edema, increased heart rate, and decreased blood pressure. Skin flushing is often induced by emotional excitement, overexertion, or eating, and is one of the most common symptoms of carcinoid syndrome.

　　2. Diarrhea: Diarrhea is mostly loose stools or watery diarrhea, occurring 5 to 6 times a day, with the maximum reaching 20 to 30 times. Severe cases can lead to skin flushing, electrolyte imbalance, and diarrhea often accompanied by transient abdominal pain. Occasionally, it appears simultaneously with other symptoms. Some people have diarrhea after eating or in the morning.

　　3. Symptoms caused by fibrous tissue hyperplasia: Fibrous tissue hyperplasia often occurs in serous or endocardial membranes, such as peritoneum, right endocardium (tricuspid valve, pulmonary artery valve), pleura, pericardium, and the outer membranes of some small blood vessels. Due to the above lesions, carcinoid patients have corresponding symptoms and signs, such as tricuspid or pulmonary artery murmur, chest pain, and so on.

　　4. Asthma: Often accompanied by diarrhea or transient skin flushing, lasting about 10 minutes, and related to bronchial smooth muscle spasm.

　　How to prevent colonic carcinoid?

　　1, colonic carcinoid:It is a slowly growing, low-grade, long-term malignant tumor with a relatively good prognosis. It can survive with the tumor for a long time. The prognosis of colonic carcinoid depends on its primary site, depth of invasion, tumor size, whether there is lymph node and liver metastasis, symptoms at the time of consultation, and surgical method, etc. A report by Chen's 31 cases of colonic carcinoid using flow cytometry proves that aneuploid tumors have poor clinical prognosis. It is also reported that P53 expression in colonic carcinoid suggests poor prognosis for patients and is considered a potential indicator of advanced carcinoid. Generally, the cause of death of patients is carcinoid crisis and carcinoid involvement of the heart with heart failure, shock, loss of fluid and electrolytes, extreme malnutrition, etc. Therefore, the prognosis of patients with typical carcinoid syndrome is often worse than that of patients without syndrome.

　　2, colonic carcinoid:The prognosis is worse than that of other gastrointestinal tract tumors, with a 5-year survival rate of 33% to 52%. The prognosis is related to whether there is metastasis at the time of surgery. The 5-year survival rate of patients without metastasis is 77%, 65% with regional lymph node metastasis, and 17% with distant lymph node metastasis. The prognosis of rectal carcinoid is better than that of colorectal cancer. Generally, the 5-year survival rate reaches more than 80%.

　　One, urine 5-hydroxyindoleacetic acid determination

　　The normal urine 5-hydroxyindoleacetic acid is 2-9mg, and its content is helpful for the diagnosis of carcinoid syndrome when it exceeds 50mg. Some individuals may excrete up to 2000mg.

　　Two, histopathological examination

　　The morphological characteristics of carcinoid under light microscopy are:

　　(1) The nuclear morphology, size, and staining of carcinoid tumor cells are relatively uniform, with fewer mitotic figures, little anisotropy, and inconspicuous nucleoli.

　　(2) The cytoplasm of carcinoid tumor cells is transparent or acidophilic fine granular, and can have argyrophilic and argentaffin staining reactions.

　　(3) The cells of carcinoid tumors are polygonal or somewhat round, arranged in a special ribbon-like, wreath-like, daisy-like, or antler-like solid nests or glandular structures, with uniform spacing between the cells and orderly arrangement.

　　(4) The stroma of carcinoid tumors often has fibrous tissue hyperplasia, and the stroma fibrous tissue hyperplasia is more obvious in patients with carcinoid syndrome.

　　Three, barium and air double-contrast imaging

　　The localization diagnosis of the primary lesion has high value. The examination not only can clarify the location of the tumor but also detect multiple foci. Double-contrast barium and air examination can detect the diameter of the tumor.

　　(1) Mass type: Presents as multiple nodules fused together.

　　(2) Polypoid type: Shows a filling defect-like change.

　　(3) Infiltrative type: The intestinal segment is infiltrated and narrowed.

　　(4) Obstructive type: Barium passes through受阻.

　　Four, colonoscopy

　　For patients suspected of having colonic adenocarcinoma, routine colonoscopy should be performed. Colonoscopy is currently the most effective, safest, and most reliable method for diagnosing colonic lesions. The vast majority of early lesions can be detected through colonoscopy. Under colonoscopy, colonic adenocarcinoma presents as a hemispherical pedunculated polyp-like mass protruding into the intestinal lumen, with a rigid wall, most of the mucosal surface smooth, grayish white, with common malformation concave in the central part, and partial mucosal congestion, edema, superficial erosion, or ulceration may be present nearby, which is easily misdiagnosed as colorectal cancer. Colonoscopy can not only observe the lesion directly but also take biopsies for pathological examination.

　　5. Ultrasound and CT scan

　　It is of great value for understanding the extent of the lesion, the depth of invasion, whether there is metastasis, and estimating the extent of surgery, but it is not very helpful for the differential diagnosis of carcinoid.

　　6. Somatostatin receptor scintigraphy

　　For tumor diameter

　　In most cases: after surgery, patients must pay attention to eating light and easily digestible food with reasonable nutrition. As the condition improves, gradually return to normal diet. Foods such as garlic, onions, green onions, leeks, beer, and lamb, which are easy to cause bloating and unpleasant odors, should be eaten as little as possible. Drinking a glass of cool water in the morning can stimulate defecation, or a small amount of normal saline can be injected into the artificial anus to induce defecation. Appropriate physical exercise also helps regulate defecation.

　　1. Treatment

　　1. Once colon carcinoid is diagnosed, surgical treatment should be the main approach. In cases with liver metastasis, efforts should be made to resect them; otherwise, hepatic artery ligation or embolization can be performed, which has a certain mitigating effect on carcinoid syndrome. Emergency surgery is required when colon carcinoid is complicated with hemorrhage and compression of adjacent organs. Currently, the commonly used method is endoscopic resection. For submucosal lesions that are difficult to resect by electrocoagulation, it is possible to first inject normal saline locally in the mass to make the mass bulge and perform 'mucosal stripping resection'. For tumors with a diameter greater than 2cm, suspected of being malignant or not amenable to endoscopic resection, surgical resection should be performed, including the intestinal segment and lymph nodes 5cm away from the tumor margins. Carefully seek and resect any other possible tumors. For patients who have missed the opportunity for surgery or have extensive metastasis, simple bypass surgery can be performed to relieve obstruction, allowing for survival for several years. Even if only palliative resection of most of the tumor is possible, it can help extend the patient's life. For suspected carcinoid without carcinoid syndrome (CS), 5-HIAA should be measured before surgery to help judge postoperative recurrence, metastasis, and progression. It is preferable to perform radical resection for colon carcinoid, as the metastasis rate is high, and some cases require extended radical resection. For those with extensive metastasis that cannot be completely resected, surgery should not be abandoned. Efforts should be made to resect as much of the metastatic tumor tissue as possible, even if the resection margin passes through cancer tissue, as it is not a problem. After this palliative resection treatment, symptoms are often significantly alleviated, and patients can survive for many years. There are also reports of the use of octreotide to treat residual lesions, the efficacy of which is yet to be observed. For liver metastases, wedge resection or resection of the liver segment or lobe can be performed. For those that cannot be resected, hepatic artery ligation or embolization can be chosen, which can often reduce the size of the liver metastases and alleviate carcinoid syndrome. Embolization can be performed repeatedly, especially for patients who cannot tolerate surgery.

　　2. Chemotherapy Chemotherapy is generally not sensitive and is mainly used for patients with extensive metastases, who cannot undergo surgical resection or palliative resection. In patients without CS, combined chemotherapy may occasionally show efficacy. Commonly used drugs include fluorouracil, streptozocin (STZ), carmustine (BCNU), lomustine (CCNU), doxorubicin (ADM), methotrexate (MTX), cyclophosphamide, busulfan (Myleran), and dacarbazine (dacarbazine, DTIC). Fluorouracil and streptozocin or fluorouracil and lomustine (CCNU) are relatively effective. Unfortunately, tumors that are sensitive to chemotherapy are prone to severe and even fatal CS attacks during chemotherapy, so patients with active CS are not suitable for chemotherapy. Some people believe that preoperative chemotherapy for 3 to 9 months, followed by percutaneous hepatic artery catheter embolization chemotherapy, and then ligating the hepatic artery and other collateral circulation a few weeks later, is effective for patients with CS. If the antagonist or blocker of serotonin, alpha-adrenaline, and prostaglandin is effective in chemotherapy, a long-term individualized chemotherapy plan can be formulated. The dosage should be lower than that of conventional chemotherapy to reduce adverse reactions. A positive adrenaline test before treatment and a negative adrenaline test after treatment indicate efficacy. The initial treatment plan should be determined in the hospital, and then changed to outpatient treatment and follow-up.

　　3. Radiotherapy has a certain effect on liver metastases and can also alleviate pain caused by bone metastases, with the commonly used dose being 4000 to 4500 Gy.

　　4. The treatment of carcinoid syndrome and other complications varies according to the symptoms and severity, and is individualized. High-protein diet, niacin, and vitamin supplementation should be provided. Except for methoxamine and angiotensin being cautiously used in severe hypotension and shock, adrenaline-containing drugs, including all vasoconstrictors, are contraindicated. Monoamine oxidase inhibitors and sympathomimetic drugs should be strictly restricted, and the release of endogenous catecholamines should be blocked, with smoking, avoiding physical stimulation, and emotional tension prohibited. Even if the patient undergoes surgery with minimal risk, anesthesia should be administered with caution, otherwise serious complications may occur. Antiserotonin and antiprostaglandin drugs should be kept on hand before surgery, and the use of thiopental, palfium, and nitrous oxide (laughing gas) can significantly reduce the risk. Opiate preparations such as phenylbutylpiperidine and loperamide can effectively control diarrhea, and the administration of adequate anticholinergic drugs may be helpful occasionally. Somatostatin and interferon can alleviate flushing and diarrhea, and have certain therapeutic effects on metastatic carcinoids. Pancreatic enzyme preparations can also improve steatorrhea and malabsorption. If biliary malabsorption is present, colestyramine (cholestyramine) may be used. During surgery, 90Yi mixed with plastic microspheres is injected into the hepatic artery, and its beta radiation can also effectively control CS.

　　Second, prognosis

　　2. Colon carcinoid is a slowly growing, low-grade malignant tumor with a long course. Generally, the prognosis is good, and it can survive with the tumor for a long time. The prognosis of colon carcinoid depends on its primary site, depth of invasion, tumor size, presence or absence of lymph node and liver metastasis, symptoms at the time of consultation, and surgical method. A report by Chen's family in Taiwan on 31 cases of colon carcinoid proved that aneuploid tumors have poor clinical prognosis by flow cytometry. It was also reported that P53 expression in colon carcinoid suggests poor prognosis for patients and is considered a potential indicator of advanced carcinoid. Generally, the cause of death of patients is carcinoid crisis and carcinoid involvement of the heart with concurrent heart failure, shock, loss of fluid and electrolytes, extreme malnutrition, etc. Therefore, the prognosis of patients with typical carcinoid syndrome is often worse than that of those without the syndrome.

　　1. The prognosis of colon carcinoid is worse than that of other gastrointestinal tract diseases, with a 5-year survival rate of 33% to 52%. Its prognosis is related to whether there is metastasis at the time of surgery. The 5-year survival rate of patients without metastasis is 77%, 65% with regional lymph node metastasis, and 17% with distant lymph node metastasis. The prognosis of rectal carcinoid is better than that of colorectal cancer. Generally, the 5-year survival rate reaches above 80%.