Distribution of gastrointestinal neuroendocrine tumors in Europe: results from a retrospective cross-sectional study

Gastrointestinal (non-pancreatic) neuroendocrine tumors represent a rare but in recent years more frequent tumor entity (Rindi and Wiedenmann 2020). The diagnosis requires the availability of technically advanced procedures, which could potentially distort the measured epidemiology of these tumors (Pavel et al. 2020). Therefore, we compared clinical and histopathological characteristics of patients diagnosed with a GI-NET in four different European countries, all of which feature highly developed healthcare systems. In our analyses including 1354 patients, we found that, although patient characteristics are comparable between countries, there are notable regional differences, e.g., in tumor grading and tumor origin.

One of the major findings of our study is that more than 80% of patients with GI-NET are diagnosed in a metastasized disease stage with the liver representing the most common site of metastases. This finding is highly relevant because for almost all patients with stage IV disease no curative therapy options are available, and the life expectancy of many of these patients is reduced accordingly (Strosberg et al. 2015). For many patients with metastatic NET, the administration of somatostatin analogs represents the current standard of care. In addition to an antisecretory effect, this therapy is also considered to have antiproliferative properties, and in numerous studies the time to tumor progression and overall survival were better than with placebo therapy (Stueven et al. 2019). Newer therapeutic options include the administration of targeted therapies such as the mTOR antagonist Everolimus. In contrast, cytotoxic chemotherapy is ineffective in GI-NET. Just recently, the so-called peptide receptor radionuclide therapy (PRRT) was established as a novel therapeutic option in NET patients refractory to other treatments (Kratochwil et al. 2015; Stueven et al. 2019). Despite this progress, the prognosis in metastatic disease remains poor. Our data, therefore, point to the need for intensive efforts for early detection of neuroendocrine tumors. Such efforts could lead to detection of the disease at earlier disease stages and, thus, greatly simplify and improve the clinical management of these patients.

Another major finding of our study is that a significant proportion of patients with GI-NET feature a G3 histology. Such G3 differentiated neuroendocrine tumors (G3 NET) have to be distinguished from low-to-intermediate grade (G1–G2) NETs, as well as from highly malignant, poorly differentiated neuroendocrine carcinomas (NEC) (Pavel et al. 2020). Today, limited data exist on high-grade neuroendocrine tumors (NETs G3) which represent a new category among neuroendocrine neoplasms (NEN) (Kasajima et al. 2021). Recently, Kasajima et al. analyzed 1513 NEN from a consultation series regarding prevalence, tumor origin, and metastases (Kasajima et al. 2021). Based on the WHO classification of digestive system tumors, 130 NET G3 (9%) were identified, which is similar to the frequency of NET G3 in our analysis. Notably, in our database, 9.3% of all G3 tumors were found in the small intestine, 46% within the large intestine and 26.7% within stomach and gut. Due to the rarity of NET G3, there are currently no data from randomized trials on the optimal treatment of this entity (Pavel et al. 2020). However, there is consensus that cytotoxic chemotherapy should be administered. However, the objective response rate (ORR) with cisplatin-based chemotherapy in NET G3 (Ki-67 < 55%) is much lower than in NEC and cisplatin/etoposide is not recommended and temozolomide-based chemotherapies or STZ-based chemotherapy in the case of pancreatic origin are mostly recommended (Pavel et al. 2020). Nevertheless, the prognosis of patients with G3 NET is much worse compared to patients with well-differentiated NET (G1/G2). Our data regarding regional differences in the frequency of G3 differentiation among NET from different countries might be explained by a different awareness for this specific entity (Pelosi and Travis 2021). Moreover, in Germany, well-differentiated NEN (G1/G2) are mostly treated by endocrinologists, poorly differentiated NEN (G3) rather by oncologists. Due to the design of the database, it seems likely that G3 NET are artificially overrepresented in the German arm of the analysis. Nevertheless, since both biological behavior and optimal treatment is tremendously different from other NET, our results should trigger further efforts to optimize the clinical management of patients with G3 NET.

The main strength of the present study is the use of data from a large number of patients from several countries, enabling the understanding of the intercountry variation. However, our study is subject to some limitations, some of which are specific to NET, others of which reflect general imitations of the database. Regarding NET, data on a potential hereditary background are lacking. Moreover, no data on the functional activity are available. Finally, it is impossible to fully exclude that NEC G3 have been misclassified as NET G3; thus, it seems possible that the database might not be representative for the whole spectrum of GI-NET. Regarding the database, it is important to note that only drug-treated patients were included and that the original questionnaire was not designed for the concrete research purpose. Missing variables such as genetic factors and socioeconomic status are further limitations. Finally, no causal relationships but only associations can be estimated in studies like this and comparison with other established data bases are lacking. Nevertheless, the database was used for many different studies and has demonstrated it suitability for research purpose in many different clinical analyses. Therefore, the differences in clinical and histopathological characteristics identified within this analysis should trigger further epidemiological research allowing to better understand the pathophysiology of NET and to optimize the management of patients with these tumors in different European countries.

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