In this study, we showed that the incidence of NETs increased from 0.244 per 100,000 in 1996 to 3.162 per 100,000 in 2015. Rectum, lung/bronchus, and pancreas were the most 3 common primary sites of NETs. The best survival of NETs was for NETs in rectum and small intestine and the worst survival was observed for NETs in esophagus and liver. During our study period, improved survival was only observed for pancreatic NETs.
Increasing incidence trends of NETs have been observed in many countries, including Taiwan. Several factors may have contributed to the increasing incidence trend of NETs in Taiwan. One possible reason is the increasing awareness of NETs by the physicians, particularly pathologists. Another possible explanation is the wide availability of diagnostic facilities in Taiwan, including endoscopy, sonography, and CT scan in clinics, regional hospitals and medical centers. Once a physician observes an abnormal finding, the physician will arrange additional examinations to make a final diagnosis. Additionally, cancer screening programs in Taiwan may have also contributed to the increased incidence, particular for NETs of gastrointestinal tract. National cancer screening program for cervical, breast, oral, and colon cancers in Taiwan began in 2010. People who have had a positive stool occult blood test would have received endoscopic examination for gastrointestinal tract, such as pan-endoscopy and/or colonoscopy. However, the incidence trends also increased for NETs located in sites other than the gastrointestinal tract, including NETs in sites not easily detectable through screening. In addition, if the increased physicians’ awareness of NETs is a major factor, one would expect the incidence of NETs to reach a plateau at some point, but our results indicated the contrary, showing a continued increase in NETs incidence. Taken together, our results suggest a real increase in the incidence of NETs in Taiwan.
Among the primary sites, the incidence of pancreatic NETs increased most rapidly. The result is consistent with the NET incidence in the US reported by Dasari et al . Our previous study found that although both pancreatic adenocarcinoma and pancreatic NETs showed increasing incidence, the increase in pancreatic NETs was more prominent, suggesting that the etiologies of adenocarcinoma and NETs might be partly different . Halfdanarson et al. conducted a case-control study of 263 pancreatic NET patients and 602 controls and showed that non-alcohol use, diabetes, obesity, and family cancer history of certain cancers (sarcoma, pancreatic NETs, gall bladder cancer, ovarian cancer, and gastric cancer) were risk factors of pancreatic NETs . Haugvik et al. performed a meta-analysis for risk factors of pancreatic NETs and reported that diabetes, family history of cancer, alcohol, and smoking were risk factors . The other risk factors for NETs in sites other than pancreas include family history of carcinoid or other cancers, race, sex, age, alcohol drinking, social economic status, obesity, smoking, and LDL-cholesterol level [17–21]. However, more investigations are needed to generate solid evidence.
In our updated analysis (data from 1996–2015), we observed that since our last analysis (data from 1996–2008), rectum and lung and bronchus have the remained the most and the second most common site of NETs occurring in Taiwan. The incidence of pancreatic NETs surpassed the incidence of gastric NETs since our last analysis to rank third after rectal and lung and bronchus NETs. Our results revealed an abrupt increase of rectal NETs in 2011, which might be partly due the initiation of the national cancer screening program in 2010 targeting four cancers, including colon cancer. The incidence trends of NETs in other sites in Taiwan were similar to those in the US reported by Dasari et al .
The common sites of NETs are different by races and geographic areas.3 NETs of lung and bronchus are common among white Americans, Europeans and Asians. NETs of rectum are more common among Asians and the African Americans whereas NETs of small intestine are more common among white Americans and Europeans. The site distribution of NETs in Oceania is also different. Wyld et al reported the incidence trends of NETs over three decades in Queensland, Australia and showed that the most common sites of NETs were small intestine (1.03 per 100,000), followed by <link rid="Sec8"><link rid="Sec9">appendix</link></link> (0.74 per100,000), lung (0.71 per 100,000), and rectum (0.69 per 100,000). Pancreatic NETs (0.25 per 100,000) was the sixth most common NETs in their analysis . Hallet et al also reported increasing incidence trends of NETs in Ontario, Canada from 1994 to 2009. In that study, the most common sites of NETs in 2009 were lung/bronchus (1.28 per 100,000), followed by small intestine (1.01 per 100,000), rectum (0.96 per 100,000), large intestine (0.69 per 100,000), and pancreas (0.6 per 100,000) . These studies showed that the most common sites of NETs are different by races and geographic areas, suggesting possible genetic and environmental differences in the etiologies of the NETs. Therefore, it would be crucial to survey the risk factors in different races and geographic areas to identify the potential genetic and environmental factors for the prevention of NETs.
In this study, we noticed that among the 6 common sites of NETs, only the survival of pancreatic NETs improved from T2 to T3. The survival of NETs in other sites showed no significant improvement. NETs of lung and bronchus had the worst survival among the NETs in the 6 most common sites with a 5-year survival rate of 32.6% (Table 3). There had been no specific novel agents approved for NETs in lung and bronchus until recently. Everolimus was approved to prolong the progression free survival of well differentiated pulmonary NETs due to the results of a successful phase III study  and the National Health Insurance of Taiwan began reimbursing everolimus for treating pulmonary NETs in October, 2019. However, there is still limited improvement for the treatment of high grade neuroendocrine carcinoma, including large cell neuroendocrine carcinoma. The prognosis of pulmonary large cell neuroendocrine carcinoma was poor with a 5-year cancer-specific survival of 20.7% according to the analysis from the Surveillance, Epidemiology, and End-Results (SEER) database from 2000 to 2013 . The overall survival of the high grade pulmonary large cell neuroendocrine carcinoma patients with distant stage was not different from that of small cell lung cancer . Most neuroendocrine carcinoma, including large cell neuroendocrine carcinoma, in lung or other sites have been treated as small cell lung cancer. Chemotherapy with etoposide and platinum is the standard first line treatment [26, 27]. There is no standard second line treatment for high grade neuroendocrine carcinoma after recurrence or refractory. Although many novel agents, such as pembrolizumab, topoisomerase-1-inhibiting antibody-drug conjugate (ADC) targeting Trop-2 (sacituzumab govitecan), temozolomide, and antibody-drug conjugate directed against delta-like protein 3 (rovalpituzumab tesirine), have been tested for their toxicity and clinical efficacy in recurrence or resistant small cell lung cancer [28–31], studies of novel agents in neuroendocrine carcinoma of other sites is limited. Further investigations are needed for the development of novel treatment to improve the survival of neuroendocrine carcinoma patients.
The treatment for low grade or intermediate grade NETs is different from that of high grade neuroendocrine carcinoma. For non-high grade NETs, several agents, including everolimus, sunitinib and lanreotide, have been shown to improve the progression free survival of advanced GEP and pulmonary NETs [6, 9–11]. In addition, chemotherapy with temozolomide alone or in combination with capecitabine has also been shown effective in treating advanced GEP and pulmonary NETs [32–34]. Because in Taiwan the targeted agents for non-pancreatic gastrointestinal tract and pulmonary NETs were approved and reimbursed later than those for pancreatic NETs, it was reasonable for our analysis to show that only pancreatic NETs had an improved overall survival from T2 to T3. However, we can expect that the survival of other gastrointestinal tract and pulmonary NETs will be improved in the near future. In addition to the common sites of NETs, NETs of some other less common sites had poor survival rates, including NETs of head and neck, female genital organs, liver, esophagus, biliary tract and prostate, with 5-year survival rates less than 40% (Table 3). Fewer studies have been conducted in these sites of NETs probably due to the rarity and difficulty for data and sample collection, leading to a paucity of information to improve their survival.