Author: Artūrs Truškovs
What animal comes to mind when You hear hoofbeats? Probably a horse, right? Of course, it is so simple! Well, not exactly. In the medical world it’s not so black and white. Not all diagnoses are horses, or the most likely possibility. Sometimes when You hear hoofbeats, it’s a zebra- the less likely scenario. In the cancer world, neuroendocrine tumors (NETs) are the zebras.
NET Cancer Day
“When you hear hoofbeats, think of horses not zebras” is an old saying coined in the late 1940s by Dr. Theodore Woodward who instructed his medical interns to think logically and focus on the likeliest possibilities when making a diagnosis. However, physicians need to remember that an unlikely diagnosis is a possibility, thinking: “Sometimes it is a zebra”. Represented by this analogy because of their rarity, NETs are also called “the forgotten cancer” making up less than 2 percent of digestive tract malignancies.  As a result, The International Neuroendocrine Cancer Alliance (INCA) created NET Cancer Day on the 10thof November to raise awareness about NETs and alert to the need for timely diagnosis, access to treatment and care for all NET patients.  Although the term “zebra” does not have the same terrifying effect as the “silent killer” pancreatic cancer, it would be a mistake to think of it as the striped, fluffy, herbivore You can see and pet in the Zoo. Why?
NET is the umbrella term for a group of unusual cancers which develop from the cells of the neuroendocrine system. The neuroendocrine cells are a combination of hormone-producing endocrine cells and nerve cells, which all together perform specific tasks throughout the body, such as controlling blood pressure and heart rate, regulating air and blood flow through the lungs, managing food movement through the gastrointestinal tract and other vital functions. 
“NETs can arise almost anywhere in the body.”
Because the neuroendocrine system is so diffuse, NETs are found in the gastrointestinal system, lungs, reproductive system and other organs. NETs affect people in different ways in terms of tumor growth, the symptoms produced, whether they spread and how they spread.  NETs can affect both men and women, people of any age, and although often small, even less than a centimeter in size, in some cases they can be very aggressive. Symptoms can vary, depending on the location and biological properties of the tumor.
“NETs can give rise to a wide variety of symptoms that often mirror more common diseases.”
Depending on where they are in the body and the ability of some functional tumors to produce extra hormones, symptoms associated with NETs are abdominal pain, bowel obstruction, rash or flushing, diarrhea, cough, wheezing, bloody sputum, intermittent low blood sugar or diabetes.  These symptoms can be similar to those of Irritable Bowel Syndrome, Crohn’s disease, peptic ulcer disease, gastritis, asthma, pneumonia and so on.  NETs are difficult to diagnose and are often misdiagnosed for up to 5-7 years. 
There are several ways of detecting NETs, including blood tests for certain NET markers (chromogranin A and B) and evidence of a rise in certain peptides and hormones, elevated levels of the main metabolite of serotonin (5-HIAA) in urine tests, and different imaging techniques (CT, MRI, PET and others). Examining tissue samples under a microscope (histopathology) and testing for certain antigens (immunohistochemistry) is the definitive tool to confirm the diagnosis.  Early detection is vital to improve patient outcomes. The treatment depends on the size and location of the tumor, whether the cancer has spread, and the patient’s overall health.  If detected early, NETs can often be cured with surgery.
“At present, however, more than 50% of NETs are diagnosed at a later stage, when they have already spread to other parts of the body.” 
In these cases, they can rarely be cured, although often can be managed successfully for several years using somatostatin analogs, which work by slowing down the production of hormones responsible for unpleasant symptoms, particularly growth hormone and serotonin.  Other treatment methods include: chemotherapy or radiotherapy depending on the histological properties on location of the tumor, hepatic artery embolization (HAE) if the tumor has spread to the liver, and peptide receptor radionuclide therapy (PRRT). 
Zebras in Latvia
Data on NETs is difficult to obtain and is mainly based on national cancer registries. Considering that no specific data regarding NET patients is available in the Latvian Cancer registry, in 2015 a national Latvian registry of gastroenteropancreatic tumors (GEP-NETs) was launched by the cooperation of the EU based international endocrine surgical quality registry EUROCRINE and two Latvian University Hospitals: Riga East Clinical University Hospital and Pauls Stradins Clinical University Hospital. The registry is continuously being updated and can serve as a map into a world relatively unknown. According to the registry data the occurrence is approximately 2.3 times higher in womenthan men, and most patients are between the ages of 52 and 70 years. Although patients present with a variety of non-specific symptoms, abdominal pain is the characteristic clinical manifestation in more than ¾ of patients. The most common site of origin is the pancreas, followed by the stomach, small bowel and other sites. Although most of the diagnosed NETs are histologically well-differentiated (low grade), meaning cancer cells look more like normal cells under a microscope, tend to grow and spread more slowly than poorly differentiated cancer cells and generally indicate a better prognosis, more than ¼ of patients are diagnosed or treated in advanced stages of cancer, when the disease has spread to other organs. Treatment options include a surgical removal of the tumor and oncological treatment: chemotherapy, radiotherapy or therapy with somatostatin analogs. Although an operation with curative intent has been performed in more than ¾ of patients and oncological treatment was used in approximately ¼ of patients, this disease proved lethal in ¼ of the registry population. Further collection and critical analysis of GEP-NET data in accordance to European levels can serve as a solid background for improving surgical and non-surgical treatment thus influencing long term results in the future. 
Article sources: Cancer Treatment Centers of America. Incidence of NETs. Retrieved from: https://www.cancercenter.com/neuroendocrine-tumors  International Neuroendocrine Cancer Alliance (INCA). Let’s Talk About NETs.Retrieved from: http://incalliance.org/lets-talk-about-nets  Cancer.Net. (2016). About endocrine and neuroendocrine tumors. Retrieved from: https://www.cancer.net/cancer-types/neuroendocrine-tumor/introduction  International Neuroendocrine Cancer Alliance (INCA). Why do NET cancers behave differently in different people?Retrieved from: http://incalliance.org/what-is-net-cancer  NET Cancer Day. Retrieved from: https://netcancerday.org/symptoms  NET Cancer Day. Diagnosis and misdiagnosis. Why are NET cancers so often misdiagnosed? Which tests are used in helping to diagnose NET cancers? Which scans are used in helping to diagnose NET cancers?Retrieved from: https://netcancerday.org/diagnosis-and-misdiagnosis-2  Canadian Society of Intestinal Research. Retrieved from: https://www.badgut.org/information-centre/a-z-digestive-topics/neuroendocrine-tumours  NET Cancer Day. Treatment options. Retrieved from: https://netcancerday.org/treatment  Cancer Treatment Centers of America. Stages of neuroendocrine tumors.Retrieved from: https://www.cancercenter.com/neuroendocrine-tumors  Cancer Research UK. Why you have them. Retrieved from: https://www.cancerresearchuk.org/about-cancer/carcinoid/treatment/somatostatin  Plaudis, H., Ozolins, A., Ptasnuka, M., Truskovs, A., Liepina, E., Pavars, M., Geriņa-Bērziņa, A., Purkalne, G. 2018. First results of gastroenteropancreatic neuroendocrine tumour (GEP-NET) multi-institutional registry [abstract]. Rīga Stradiņš University International Student Conference “Health and Social Sciences”. 2018. 187 (abstr.)
Cover picture: Photo by Geran de Klerk on Unsplash NET Cancer Day. Retrieved from: https://netcancerday.org/  Ksenija Mirošņika. Starptautiskā NET diena 2017, Latvia.
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