There are many endocrine cells diffusely distributed in the mucosa of normal gastrointestinal tract, which secrete many gastrointestinal hormones, and it can also be said that gastrointestinal tract is the largest endocrine organ in human body. Malignant tumors of endocrine cell origin in the gastrointestinal tract are collectively referred to as gastrointestinal neuroendocrine tumors, including those occurring in the stomach, small intestine, rectum and colon. Gastrointestinal neuroendocrine tumors are pathologically divided into highly differentiated neuroendocrine tumors (G1/G2) and poorly differentiated neuroendocrine carcinomas G3, which differ in malignancy and have very different treatment strategies.
Gastrointestinal neuroendocrine tumors and carcinoid syndromes
Gastrointestinal neuroendocrine tumors (carcinoid tumors) can secrete many kinds of hormones, such as gastrin, 5-hydroxytryptamine, histamine, and tachykinin. Some patients can develop hormone-related symptoms called carcinoid syndrome, typically manifesting as diarrhea, episodes of skin flushing, abdominal pain, etc. Patients with carcinoid syndrome often have obvious liver metastases. When the patient’s diarrhea is not cured for a long time, he/she should be alert to gastrointestinal carcinoid tract and pay attention to check the small intestine and liver in addition to doing gastroscopy and colonoscopy. And about 70% of patients with gastrointestinal neuroendocrine tumors do not present with carcinoid syndrome.
Gastrointestinal tract carcinoid tumor, gastrointestinal neuroendocrine tumor and neuroendocrine carcinoma
Gastrointestinal tract carcinoid tumors, gastrointestinal neuroendocrine tumors and neuroendocrine carcinoma are confusingly conceptualized by many people including many patients and families, partly due to the inconsistent terminology used in pathology reports.
Gastrointestinal neuroendocrine tumors, according to pathological grading, are classified as grade 1 (G1), grade 2 (G2) and grade 3 (G3). Highly differentiated gastrointestinal neuroendocrine tumors grade 1, formerly called carcinoid tumors, are still in use, such as gastric carcinoid tumors, rectal carcinoid tumors, and small bowel carcinoid tumors belong to this category. Highly differentiated gastrointestinal neuroendocrine tumors include G1 and G2, which are relatively slow-growing and less malignant. Lowly differentiated gastrointestinal neuroendocrine carcinoma G3, with high malignancy and poor prognosis. In other words, highly differentiated neuroendocrine tumors are, in most cases, the same meaning as carcinoid tumors of the gastrointestinal tract, but hypofractionated neuroendocrine carcinomas cannot be called carcinoid tumors. According to the latest WHO pathological diagnostic criteria, highly differentiated neuroendocrine tumors G2, also cannot be called carcinoid tumors. Both neuroendocrine tumor G1G2 and neuroendocrine carcinoma G3 are malignant tumors, only with different degrees of malignancy.
Prognosis and survival
The clinical stage and pathological grading of patients determine their prognosis and survival. Clinical staging is based on the size of the tumor at the time of diagnosis, whether there is lymph node spread and liver-lung-bone metastasis, etc. Clinical staging is divided into 4 stages, stage 1 and stage 2 are considered early stage, stage 3 and stage 4 are middle and late stage. Generally speaking, the later the stage of tumor, the shorter the survival period of the patient. However, the prognosis and survival of patients should be combined with the pathological grading of the tumor. Gastrointestinal neuroendocrine tumors are classified into grade 1 (G1), grade 2 (G2) and grade 3 (G3), and the higher the grade, the greater the malignancy. As an example, small intestinal neuroendocrine tumor grade 1, which is small intestinal carcinoid tumor, has slow tumor development, and even if the patient has developed significant liver metastasis, long-term survival may be obtained through standardized treatment. Similarly, for small intestinal neuroendocrine tumor with liver metastasis, if the pathological grading is grade 3, the prognosis is poor and the patient’s survival is only about 1 year.
Diagnosis, staging and examination items
The widely carried out routine examinations such as gastroscopy, colonoscopy, ultrasound, CT, MRI, etc. can be used to clarify the primary site of tumor and whether there is distant metastasis. For patients suspected of small intestinal carcinoid tumor, capsule endoscopy or small intestinal microscopy is recommended.
Routine blood tumor markers such as CEA, CA125, CA19-9, AFP, etc. are of little value for gastrointestinal neuroendocrine tumors. Laboratory tests for neuroendocrine tumors include serum CgA, serum NSE and 24h urine 5-HIAA, which are meaningful for monitoring the condition of patients with advanced disease and assessing the effect of treatment. serum CgA and 24h urine 5-HIAA are currently available in only a few hospitals.
Nuclear medicine tests include growth inhibitor receptor imaging (octreotide scan) and PET-CT. Octreotide scan is a whole-body scan for neuroendocrine tumors and is suitable for patients with highly differentiated gastroenteropancreatic neuroendocrine tumors, and is especially meaningful for detecting metastatic lesions. The sensitivity of octreotide scan to detect neuroendocrine tumors is only about 80%, and false negative results may occur for tumors smaller than 1 cm in the gastrointestinal tract.
The examination is not suitable for all neuroendocrine tumors, and it is only applicable to patients with low-differentiated neuroendocrine cancer. PET-CT is not recommended for highly differentiated neuroendocrine tumors, including carcinoid tumors, because conventional PET-CT examination is not sensitive to carcinoid tumors. PET-CT using special tracer (crop 68 labeled octreotide) abroad is more sensitive to neuroendocrine tumors, but it is still in the research stage in China.
Pathological diagnosis
Clinicians get the clinical stage of tumor based on endoscopy, ultrasound, CT, MRI and other examinations, however, pathological diagnosis from pathologists is needed to confirm the diagnosis of neuroendocrine tumor. For pathological diagnosis of gastrointestinal neuroendocrine tumors, it is essential to do immunohistochemical testing for CgA and Syn. The pathological report should also indicate the tumor grade, which is determined as grade 1, 2 or 3 based on Ki-67 index and nuclear splitting image count. Therefore, pathological grading is given by the pathologist and reflected in the pathology report. Some patients or family members always confuse pathological grading with clinical staging. Pathological tissue can come from endoscopic biopsies, surgical resection specimens, or can be taken from metastatic lesions such as supraclavicular lymph node biopsies, liver puncture biopsies, etc.
Treatment method
Early gastrointestinal neuroendocrine tumors can be resected endoscopically or surgically depending on the situation. After tumor resection, highly differentiated neuroendocrine tumors (including carcinoid tumors) do not need chemotherapy and are monitored regularly; low-differentiated neuroendocrine cancers need chemotherapy after surgery to prevent metastasis.
Treatment of advanced gastrointestinal neuroendocrine tumors has different treatment strategies depending on the pathological grading of the patient’s tumor. Neuroendocrine carcinoma with low differentiation (pathological grade 3) has high malignancy and poor prognosis, chemotherapy is preferred for treatment, which is sensitive and has an efficiency of about 70%, but the maintenance of efficacy is short; neuroendocrine tumors with high differentiation (pathological grade 1 or 2) have relatively slow tumor development, and treatment methods include octreotide, everolimus, as well as interventional treatment for liver metastases and Chinese herbal medicine, etc. Chemotherapy is not the first choice, but only when other treatment methods have failed.
Octreotide
Octreotide is the first-line treatment choice for highly differentiated advanced gastrointestinal neuroendocrine tumors, with or without carcinoid syndrome. Octreotide is not part of chemotherapy, it is an analogue of growth inhibitor and acts as a suppressor of pathological secretion of other gastrointestinal hormones by binding to growth inhibitor receptors on neuroendocrine tumors, thus controlling carcinoid syndrome. In addition to effective symptom control, octreotide has the effect of inhibiting tumor growth, and most patients with advanced disease have obtained long-term disease stabilization (SD), and only about 10% of patients with tumor shrinkage.
For advanced gastrointestinal neuroendocrine tumors, long-acting octreotide (santoprene), 20-40 mg, is administered by deep intramuscular injection every 4 weeks, and the dose and interval of santoprene can be adjusted according to the condition. For the first time, short-acting octreotide (sennin) can usually be used for 7-14 days to observe the efficacy and side effects. Zanlon is well tolerated and is acceptable to most patients.
It is worth mentioning that Seron is not suitable for the treatment of patients with hypofractionated neuroendocrine carcinoma.
Everolimus
Everolimus belongs to the class of targeted therapeutic agents, which is an mTOR inhibitor. The FDA and the EU have approved everolimus for the treatment of advanced pancreatic neuroendocrine tumors, which can significantly prolong the progression-free survival of patients. For advanced gastrointestinal neuroendocrine tumors, an international multicenter phase 3 clinical study is currently underway.
Traditional Chinese Medicine (TCM)
Chinese herbal medicine is effective in improving patients’ own immunity and inhibiting tumor growth, which is suitable for highly differentiated advanced gastrointestinal neuroendocrine tumors. These tumors develop slowly, and in the absence of conditions to receive treatment with Zanlon and everolimus, Chinese herbal medicine can be tried, and we are currently conducting research on the application of Chinese herbal medicine to control this aspect of neuroendocrine tumors.
Chemotherapy
Chemotherapy can be considered for patients with advanced hypofractionated neuroendocrine carcinoma and some highly differentiated neuroendocrine tumors G2. It is worth mentioning that chemotherapy is not advocated for advanced gastrointestinal carcinoid tumors because of the low efficiency and high side effects of chemotherapy for this type of tumors, while Sunlong, everolimus, and Chinese herbal medicine can effectively control the growth of carcinoid tumors, maintain patients’ quality of life, and prolong disease-free progression survival time.