GEP NET is one of the most increasingly diagnosed tumors in the world today. The incidence & pickup is on the rise in India too. It is one of the few potentially malignant / malignant tumors where long term survival is possible even in advanced stage of detection. Hence it is very important for all the patients with this disease to understand various aspects of this disease.
Neuroendocrine tumor is a tumor arising from specialised neuroendocrine cells distributed or located in various organs of the body. These special cells have capacity to secrete certain hormones like gastrin, insulin, epinephrine and many more depending on organ of origin. Hence tumors arising from these cells can also sometimes secrete these hormones. However not all NETs have capacity to secrete hormone. These secreted hormones can play a role in the symptoms / manifestations of the patient.
Functioning NETs are often called by the names of the hormone secreted by the tumor e.g. gastrinoma (gastrin secretion), insulinoma (insulin secretion), pheochromocytoma (catecholamine secretion) etcetera.
NET can be entirely benign (very low or low risk) or at high risk of cancer (potentially malignant) or be a cancer to begin with. This depends on the grade of the tumor decided by certain histopathological features not shared by other cancers of GI tract. Patients with low / intermediate risk NETs can also spread to other parts of the body like another cancer but will grow at a very low speed, will respond to multiple treatment modalities and thereby have long life.
NE cells are located in various organs like lung, thymus, bronchi, GI tract, pancreas, adrenal gland. Hence NETs arise in these organs. Sometimes it is impossible to locate the exact origin. However our discussion will be restricted to GI & pancreatic NETs. Since liver often is involved due to spread of this disease from any organ, we will cover liver metastasis from NETs too.
There is no specific cause for NET. Occasionally hereditary associations / genetic changes are seen. This is especially true for pancreatic NETs. Important to note that all genetic changes are not inherited, actually majority are de novo (in that patient). Hence majority of the NETs are sporadic / isolated in occurrence.
Symptoms of NET depends upon location, size, spread and whether it is secreting any hormone. When small in size, it is detected during routine check-up or during workup for unrelated complaints. Stomach NETs may be picked up during investigations for dyspepsia / acidity complaints. When large in size commonest symptom is abdominal pain. Pain could be nonspecific & vague or could be colicky when tumor is causing an obstruction as in small or large intestine. When causing intestinal obstruction, NET can cause vomiting too. Pancreatic NET can cause an attack of acute pancreatitis and hence acute pain. Large NET can cause weight loss, loss of appetite, vomiting, intestinal obstruction, GI bleeding. Sometimes NET is detected only after it has spread widely as in liver and symptoms are due to liver dysfunction (pain, nausea, vomiting, weight loss, jaundice)
When a NET secretes a hormone which in turn cause symptoms, it is called functioning tumor. Symptoms due to the hormone secreted depend upon the effect of the particular hormone like insulin causes low blood sugar, gastrin causes peptic ulcer & diarrhoea, some hormones cause flushing, diarrhoea & cardiac symptoms (carcinoid syndrome). Many of these hormone effects can be life threatening and hence need to be addressed.
Not all NETs secrete a hormone, these are called non-functioning tumors. In them the symptoms are due to location, size & spread as mentioned before.
NET is rarely a clinical diagnosis as that is possible only in functioning (hormone / chemical producing) NETs. Functioning NETs produce symptoms which are distinctly recognisable. Hence mostly NET is a diagnosis of imaging like CT scan / MRI / PET etcetera done for other symptoms as mentioned above. When a NET is suspected on USG / CT / MRI a dedicated PET -CT (DOTA / FDG / both) is performed. Along with that blood test like tumor markers (serum chromogranin levels) are done. When symptoms of functioning NET are present, levels of relevant hormone (gastric, insulin, c-peptide etcetera) are checked in the blood. For small intestinal NET, 24 hour collected urine is subjected to test for level of biproducts / metabolites of tumor products (5-HIAA).
Whenever possible an attempt is made to obtain a biopsy to confirm the histopathological diagnosis. This may be done under USG or CT scan guidance if tumor has already spread to the liver or when possible through endoscope if tumor is in stomach / duodenum / colon & is accessible. Small intestinal NETs are difficult to access for biopsy and only rarely biopsied through an enteroscope.
Screening for NET is not advised as it is not a very common tumor, investigations for screening are expensive and often involve radiation.
NETs are classified on various criteria i.e. location (gastroenteropancreatic vs bronchial vs adrenal ), grade (low vs high grade), nature (benign vs malignant). However grade is the most important criteria. Grade is decided by certain pathological criteria. Low grade tumors are usually benign. Occasionally this does not hold true (well differentiated high grade)
Benign / low risk asymptomatic NETs are often picked up in stomach during endoscopy done for dyspepsia (common term-hyperacidity). These are usually incidental, not responsible for the patient complaints & most of the times these patients will only be observed with regular endoscopy and only if the tumor shows growth, then it will be removed. Depending on the size and location of this tumor in the stomach, it is removed endoscopically or by a laparoscopic surgery when possible or by an open surgery when needed. Sometimes a hybrid / combined laparo-endocopic approach is chosen. Symptomatic or large gastric NET will usually be managed by a laparoscopic / open surgery.
Benign / low risk asymptomatic NETs in the pancreas are also observed when small in size. However symptomatic NETs (even when small), NET showing growth or large NETs are always treated by surgery whenever possible.
Benign / low risk NETs from duodenum, small intestine & large intestine are always treated. The approach (endoscopy / laparoscopy / open surgery / transanal surgery) depends on location, size, availability of expertise / experience, infrastructure etcetera.
NETs when functioning (producing hormones that cause symptoms) are always treated irrespective of size, location or risk.
High grade or frankly malignant NET are usually discovered at a late stage i.e. advanced stage with multiple metastasis to liver, lung and often to the intraabdominal peritoneal surface. These tumors are then rarely suitable for surgery. Also they are not responsive to certain other treatment modalities used in lower grade tumors (PRRT).
When detected at early stage, surgery is the only curative treatment and should be done ASAP. If detected with limited spread a surgery or a combination treatment involving surgery / interventional radiology / radiation / RFA / chemotherapy is used. However when detected with significant spread, chemotherapy is the mainstay of treatment. Few patients may undergo a surgery at a later stage depending on the response to chemotherapy. However many of these patients may also need palliative surgery for gastric or intestinal obstruction.
Treatment of metastatic disease depends upon the organ/s involved and extent / pattern of involvement. It is a complex multipronged treatment & should be done only in select centers with experience & expertise.
Liver is the commonest organ to which tumor spreads. If the disease is limited it can be treated by surgery (liver resection –one or multistaged, with or without RF ablation). Sometimes liver metastasis are pretreated with chemotherapy & /or embolization (blockade of tumor blood supply—TACE / TARE). Very few well selected patients are candidates for a liver transplantation for liver metastasis from NET.
Lungs are also caught up sometimes in the metastatic disease and are treated on the same lines like liver.
Peritoneal disease when present is a very bad omen. Limited disease can be removed surgically, however diffuse disease can only be treated with chemotherapy. When treatment for NET is planned an extensive search for metastatic disease is done and then a comprehensive treatment is charted.
Nature of surgery depends on the primary organ involved (stomach / duodeneum / small intestine / colon-rectum / pancreas / liver / peritoneum / lung), size of the tumor, lymph node involvement, grade etcetera.
When stomach is the primary organ, the extent of surgery can vary from endoscopic removal, a small wedge resection of stomach or partial gastrectomy to total gastrectomy. Sometimes surrounding organs like colon, spleen, pancreas may also need removal. With larger (>2 cms) or high grade tumor, lymph node clearance will also be required. Where feasible the surgery will be done laparoscopically.
When duodenum is the primary organ of origin, surgery extends from enucleation of the tumor / s from the wall or limited duodenal resection or a combined pancreatoduodenal resection (Whiple). An effort is made to avoid a pancreatoduodenectomy where possible. Again lymph node removal may also be necessary. In select cases, surgery is done laparoscopically.
Small intestinal NETs are fairly common after the stomach NET. The surgery involves removal of a portion of small intestine with all the draining lymph nodes. Sometimes right colon also needs to be removed depending on the location of tumor in the small intestine. Precaution is taken to identify multiple tumors, adequate intestine is preserved and proper lymph node clearance is done
Appendicular NETs are often seen especially after an appendicectomy. The treatment depends on the size of the lesion and patient may need an appendicectomy or a right colon removal.
Colon NET is quite uncommon and may require resection of a portion of large intestine depending on location. A wedge resection, segmental resection or a wide colectomy with lymph node removal is done.
Rectal NET is now seen often and is usually treated with endoscopic treatment if size permits. Rarely a transanal resection or transanal endoscopic microsurgery or transanal minimally invasive surgery or an open rectal resection may be needed. Enucleation is also an option in few cases.
When it is possible to completely remove metastasis to liver, they are removed by either a small or multiple metastatectomies, sometime minor hepatic resection or a major hepatic resection (in single stage or 2 stage). Occasional patient is a suitable candidate for liver transplantation if disease is restricted to liver, but nothing short of transplantation is an option.
For peritoneal disease, very rarely surgery is an option.
Surgery could be an endoscopic surgery, laparoscopic surgery or open surgery.
The endoscopic surgery may be an endoscopic removal of a submucosal polypoidal lesion whether in the stomach, duodenum, colon or rectum. The procedure is either a snaring of the polyp, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). Small intestinal, pancreatic or difficult locations in the stomach, duodenum & colon are not / cannot be removed by an endoscopic surgery. Occasionally endoscopy is supported by laparoscopic surgery in these situations. (endo-laparo hybrid procedure)
Laparoscopic surgery is suitable for selected gastric, duodenal, small intestinal, colonic & rectal NETs.
Open surgery is suitable for most large / multiple NETs, significant lymph node disease, pancreatic NETs, NET with small bowel obstruction etcetera. Small intestinal NET is often not suitable for a laparoscopic surgery as one needs to rule out multiple tumors and need to remove the associated lymph node disease.
Rectal NET (which are picked up more frequently now), tumor may removed by transanal surgery.
An endoscopic / robotic / laparoscopic / open resection may be attempted depending on size, location, depth, extent, pathology, stage, availability of expertise, experience, knowledge of the subject and infrastructure .
Occasional patient is a suitable candidate for liver transplantation if metastatic disease is restricted to liver, i.e. there is no extrahepatic disease; but nothing short of transplantation is an option because liver is massively involved.
Gastric, rectal & rarely duodenal /colonic NETs are the only ones considered for endoscopic treatment. Gastric NETs are the most commonly treated by endoscopy. But endoscopic approaches are restricted by size and location.
Large NETs, difficult location (duodenum / colon / small intestine / gastroesophageal junction), metastasis are some situations where endoscopic approach is not feasible.
Simple biopsy or snaring is usually not associated with complications except rare chance of bleeding which is usually controlled easily through endoscope. However special procedures like EMR / CAP EMR / ESD done for larger NETs have more risk of bleeding and perforation.
Most gastric, small intestinal, colonic & sometimes even rectal NET will be suitable for a laparoscopic approach. This is especially true when size is small, lymph nodes are small & limited & there is no metastatic disease.
Large NETs, difficult location (some parts of duodenum), large lymph node disease are some situations where laparoscopy is not an option.
Small intestinal NET often lead to intestinal obstruction through their lymph node disease. Due to this it is always important that small intestinal NET is removed immediately when diagnosed.
Multiple NETs are especially common in small intestines, pancreas & stomach. Elsewhere it is not so common.
Nonsurgical treatment is only used when patient is not suitable for surgical treatment or sometimes in combination with surgery (before / after). The unsuitability for surgery could be due to patient fitness, functioning tumor or distant tumor spread.
Many of the NETs express special receptors called somatostatin receptors on their cells. They are used in the treatment planning. Special medications called SSRA (somatostatin short or long acting) are used and they block these receptors thereby reducing the substances the tumor produces. Usually somatostatin will not shrink the tumor but often reduce the symptoms.
The same SSRs are used to attach radioisotopes to the tumor. The radioisotopes (leuticium 177) get attached to the SSRs and then destroy the cells. This is called peptide receptor radionuclide therapy (PRRT).The problem is that the tumors that do not express the SSRs cannot be treated by this modality. This is often seen in high grade NETs or NE cancers.
Transarterial treatments like chemoembolization (TACE) or radioembolization (TARE) are used for select liver metastasis to shrink the tumor and make it suitable for surgery or just to reduce tumor related symptoms like pain, occasionally bleeding or to reduce production of hormones.
Percutaneous interventions like radiofrequency ablation of the tumor is used in isolation or in combination with other treatment modalities.
Lastly systemic chemotherapy is used for select cases of neuroendocrine cancer. There are multiple drugs and regimens available now. But most carry significant drug related toxicity.
Functioning NETs cause symptoms through the hormones they secrete. Hence they manifest early. They also need to be always treated against the observation / follow up policy. Treatment is complete surgical removal whenever possible. Sometimes the clinical complaints due to the secreted hormones need a control before surgery. At such time the SSRAs are useful to control the hormones before a surgery is performed. When a complete removal is not feasible then at least a cytoreduction / partial removal is done if possible and later SSRAs are continued. The remaining treatment approach / principals remain same.
Patients in early stage are suitable candidates for upfront surgery and a surgery is accordingly performed. Occasionally the histopathology shows a higher stage / risk factors than expected in which case patient needs postoperative chemotherapy.
Some patients are not suitable for immediate surgery due to local or systemic spread or as a protocol based on stage of disease. These patients need chemotherapy or embolization / PRRT / SSRA as a pre-surgery treatment (neoadjuvant) or as a palliative treatment. When used as pre-surgery this course may take 2-3 months or longer followed by a restaging / reassessment for surgery. The restaging involves many blood and imaging investigations. If suitable, patient undergoes surgery and it is followed by further course of therapy. Most patients except those in very early stage will require postoperative chemotherapy for 3-6 months.
Those patients that do not respond to initial line of therapy are then shifted to second line therapy. Some patients require expensive special anticancer drugs (monoclonal antibodies). This is often seen in patients with widespread / metastatic disease. In patients with locally advanced disease sometimes a major resectional procedure involving multiple organs is needed which has significant risk of complications (anastomotic leak, bleeding, infections etcetera) and risk to life.
Patients with spread to liver often benefit from surgery & / or ablative therapy (Radiofrequency ablation) & / or PRRT & /or SSRAs if the disease is suitable for surgical treatment / ablation / combination. Sometimes surgery for metastasis is done simultaneously with the surgery for the primary tumor. However often this has to be done in multiple stages.
Patients with NET are followed up at regular intervals (3-6 months / 6-12 months / yearly / 3 yearly / 5 yearly / 10 yearly) based on risk assessment (size & grade).
Patient will need physical check-up, blood investigations (routine tests lie CBC, LFT & specific tests like chromogranin A, specific hormone levels if tumor is functioning), imaging investigations (USG / CT / MRI / PET-CT) during surveillance.
Patients with NET liver metastasis are a special group. If the disease is very limited in liver at the time of 1st diagnosis, an upfront surgery / ablation can be done separately or along with the surgery for primary tumor. However this is possible in very few cases. The nature of surgery could extend from a small metastatectomy to a major liver resection
Most patients with liver metastasis (whether diagnosed initially or at a later stage) will require some nonsurgical therapy (PRRT / chemotherapy) as the initial treatment and depending on the response, a surgery / ablation may be considered at a later stage. The surgery includes various types of liver resections from minor to major to extensive liver resection. Sometimes percutaneous vascular interventions are needed before surgery to enlarge the portion of liver that will remain with the patient after the surgery. In such cases surgery is performed in stages. In very rare cases liver transplantation may be considered. Patient will require chemotherapy after liver resection too. Occasionally internal radiation therapy may also be used, via percutaneous intervention. All this makes the treatment extremely expensive.
Few patients are suitable candidates for surgery even when there is peritoneal disease, which can be surgically removed. Some of these patients present with intestinal obstruction and may need bowel resection with or without a stoma. This is followed by chemotherapy. However extremely spread peritoneal metastasis with ascites is often a terminal disease and family should be convinced that one should accept the fate.
Pathology specimen needs assessment from a skilled gastrointestinal pathologist just the way the endoscopy / surgery is done by specialized gastrointestinal surgeon. Hence a second opinion & further tests may be asked on biopsy / surgery specimen.
Chemotherapy has a very important role in treatment of high grade NET or NE cancer. It is used either after a surgery or in patients with metastasis which cannot be removed or treated by surgery / Ablation / PRRT. Many drugs are available. However results of chemotherapy show limited response. Very rarely chemotherapy is used / successful to downstage the locally advanced disease and surgery is useful in such patients.
Multidisciplinary cancer care involves aggressive chemotherapy in the postoperative period or to downstage the disease (inoperable & / or unresectable disease to operable & resectable disease – neoadjuvant treatment) before any surgery. A chemoport (surgery) is inserted for delivering the chemotherapy to avoid problems of venous access. In neoadjuvant setting, chemotherapy is followed by a curative surgery where possible. Surgery is again followed by multiple cycles & lines (1st line, 2nd line etcetera) of chemotherapy. It is especially useful in young &/or fit patients with aggressive cancer disease. These patients can withstand the demanding nature of this treatment regime and may have better survival. A typical neoadjuvant chemotherapy goes on for 3 months and then patient is reassessed for a possible surgery. Post-surgery chemotherapy is restarted as early as possible (4-5 weeks) and goes on for further 3-4 months.
Chemotherapy is also used in palliative setting for inoperable advanced disease
Grade of the tumor, size, stage of disease (extent of tumor spread), patient’s general condition / fitness / performance score, tumor biology (aggressiveness / grade) are the most important factors that decide the survival.
Patients are followed up at interval of 3 months in 1st year with blood investigations & imaging (CT / MRI / DOTAPET-CT). Intensive follow up is done in 1st 2 years and is less frequently later.
Recurrence could be in the same location or in another part of intestine (especially in case of stomach / small intestine), or in the nodes, liver, peritoneum etcetera. Recurrence risk is higher in patients with high grade NET, incompletely removed NET, or NE cancer.
Whenever possible, surgery should be considered. When not possible for any reason, other options like SSRAs (medications), RFA, TACE, TARE, PRRT, chemotherapy are considered.
Recurrence in liver or lungs are treated as previously discussed with a combination of PRRT, chemotherapy, surgery, & ablation. Selectively radiotherapy is also used. For recurrence at local site (intestine / pelvis), a combination of chemotherapy, surgery and selectively radiotherapy is used. If surgery is possible a major resectional procedure involving multiple organs is needed which has significant risk of complications (anastomotic leak, bleeding, infections, need to live with a stoma, urinary and sexual dysfunction) and risk to life.
Many more questions can come to the mind of a patient or relatives depending on the situation and the treating doctor would be in the best position to answer them.
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