Neuroendocrine neoplasms (NENs) are a group of neuroendocrine cells of embryonic origin with neuroendocrine markers and peptide hormone-producing tumors that can occur in the pancreas, gastrointestinal tract, lung, adrenal glands, etc. The symptoms, screening tools and treatment vary widely from site to site. For a long time, NENs have been considered a rare disease, but in recent years, with the increasing awareness of the disease, the incidence of NENs is statistically increasing fivefold, for example, Steve Jobs, the former CEO of Apple, whom we know well, died of pancreatic NENs. So although it is a rare disease, it should also attract the attention of doctors and the general public.
Is NENs a malignant tumor?
There are benign and malignant tumors, and all NENs are tumors with malignant potential, which means that once NENs are diagnosed, the vast majority of patients need to be treated. However, NENs are a large group of diseases, unlike the treatment and prognosis of stomach and intestinal cancers that we usually imagine are relatively single, NENs can be classified into G1, G2 and G3 according to the degree of differentiation and proliferation of the tumor.
Patients with G1/G2 can achieve radical cure through resection, and if resection is not possible, they can also achieve long-term survival with tumor under close observation or pharmacological intervention, while tumors of G3 patients develop very rapidly, with high chance of recurrence after surgery and poor effect of pharmacological treatment, even less than 1 year from diagnosis to death. Therefore, do not panic if you are diagnosed with NENs, and be sure to communicate with your doctor in a timely manner to understand the specifics.
Why are NENs easily misdiagnosed?
The chance of misdiagnosis has long been extremely high due to the low incidence of NENs and the variety of ways it develops.
There are several reasons for this.
1. Since the current global understanding and even naming of the disease is not uniform and perfect, not to mention the general public, even clinicians have very limited experience with this disease. In addition, all tumors require pathological confirmation of diagnosis, and NENs have no specific histological features and need to be diagnosed by immunohistochemistry. This may result in misdiagnosis if the pathologist is inexperienced. These reasons cause many patients to take 3-5 years just to confirm the diagnosis.
2. Some patients with NENs have no clinical symptoms and some have hormone-induced related symptoms (this is due to the fact that NENs secrete hormones themselves), such as hypoglycemia, diabetes, intractable ulcers, abdominal pain and diarrhea, as well as Cushing’s syndrome and carcinoid syndrome. Carcinoid syndrome mainly manifests as facial flushing, secretory diarrhea, and carcinoid heart disease. Most of these patients wander between multiple departments such as endocrinology, oncology, and gastroenterology, but are unable to receive effective treatment. All these reasons lead to about 50% of patients with NENs being locally advanced or showing metastasis by the time they are diagnosed.
What tests are available to help us diagnose NENs?
For patients with symptoms, doctors will perform hormonal tests according to the symptoms to clinically determine whether NENs is considered, but the final diagnosis must be confirmed by various means, whether the patient has symptoms or not, by obtaining pathological tissues and immunohistochemistry such as CgA and Syn, and finally confirming the diagnosis and grading (G1/G2/G3). When NENs are suspected or confirmed, systemic examinations must be refined to clarify whether the tumor has developed distant metastases.
Routine CT and MRI are very important examinations, and ultrasound endoscopy is recommended for NENs in the pancreas as well as in the stomach, which also helps to obtain pathological specimens. In addition, there are specific tests for NENs: octreotide scan and 68 gallium-labeled PET-CT, which are more sensitive and specific than conventional CT and MRI for identifying systemic metastases, but some patients may have negative octreotide scans. Only a few hospitals in the country are currently performing these two tests.
What should I do if I have NENs?
The global understanding of this disease has been limited to the last 10 years: Europe and the United States have developed guidelines since 2005 and 2008, while the understanding of this disease in China is just beginning. Considering the current status of diagnosis and treatment in China, the Chinese Anti-Cancer Association established a neuroendocrine tumor expert committee in 2012, with Director Xu Jianming as the chief member.
As the leader of the committee, our department took the task of writing the first edition of the Chinese expert consensus on gastroenteropancreatic neuroendocrine tumors this year. The consensus integrates the four major international guidelines related to neuroendocrine tumors and will be released at the National Cancer Conference in September this year. The consensus is a synthesis of four major international guidelines related to neuroendocrine tumors and will be released at the National Cancer Conference in September this year, with the aim of popularizing the basic diagnostic procedures and treatment protocols for this disease among physicians nationwide.
NENs, like other tumors, can be cured by resection if detected in time. Early stage gastric NENs can be cured by endoscopic resection, while NENs in other areas require laparoscopic or open surgery to remove the tumor. Since NENs are essentially malignant tumors, even after radical resection, some patients will experience recurrence and should be followed up regularly after surgery according to medical advice.
Treatment for patients who cannot undergo radical resection mainly includes local and systemic treatment. Since the most common metastatic site of NENs is the liver, local treatment such as radiofrequency ablation, laser thermotherapy, arterial embolization and selective internal radiation therapy can be adopted to control liver metastases, which can effectively reduce tumor load and hormone secretion, thus improving the quality of life of patients.
Systemic treatment includes symptom control and anti-proliferative palliative treatment. For patients with symptoms caused by tumor secretion of hormones, there are corresponding drugs for different symptoms, in addition to which octreotide treatment can be considered. For patients who cannot be controlled by drugs, local treatment with needles or tumor reduction surgery can be taken to relieve symptoms after multidisciplinary discussion.
Currently, long-acting octreotide and two targeted drugs (sunitinib and everolimus) are preferred for the anti-proliferative treatment of G1/G2 NENs. Long-acting octreotide has been included in Beijing’s medical insurance, but the drug is more effective in controlling the symptoms associated with tumor-secreting hormones and has a lower chance of shrinking the tumor. Among the targeted drugs sunitinib has been approved for pancreatic NENs in China, and everolimus is not yet available in China. The disadvantage of targeted drugs is that they are more costly and not covered by medical insurance.
So in this case, it is recommended to enroll in a suitable clinical study to try a newly developed but unmarketed drug, which can reduce a large financial burden and may benefit from it at the same time. Chemotherapy can be used in rapidly progressing G2 patients as well as G3 patients. It is generally not preferred in G2 patients, while G3 patients are mainly treated with chemotherapy, to which targeted drugs such as bevacizumab can be added.
In general, NENs are a large group of diseases, and the biological behavior varies greatly between different tumor species. The understanding of these diseases in China is just beginning, and the level of treatment for NENs varies greatly across the country. As it involves multiple specialties such as oncology, endocrinology, gastroenterology and surgery, it is recommended to decide the treatment plan through a multidisciplinary discussion.