Neuroendocrine tumor (NETs) is a relatively rare tumor, the incidence of neuroendocrine tumors in the United States was 5.25/100000 in 2004. According to the SEER database, the incidence of gastrointestinal NETs is increasing in recent years. The incidence of rectal NETS rates is the highest in the gastrointestinal tract, accounting for about 29%of gastrointestinal NETs. However, most NETs seem to be sporadic, and risk factors for sporadic NETs are poorly understood.
There are few studies that focus on rectal NETs and these studies contain limited patient cohorts[14–16]. Our study included 310 patients with rectal NETs and is the
largest Chinese cohort up to date.
With the application and popularization of endoscopic techniques, the rectal neuroendocrine tumors are diagnosed earlier nowadays, and most of them are treated with endoscopic surgery. Of course, if the tumor size is large or involves the metastatic lymph nodes, more extensive surgery is indicated. We can see that the tumor size or lymph node involvement will influence the surgery procedure and furthermore influence patient outcomes. However, there are several clinicopathological features that can influence patients’ outcome. According to published data and our analysis, grade, the depth of tumor invasion (T), the number of metastatic lymph nodes(N), distant metastases(M) and age at diagnosis are the most common factors that influence outcomes. Chi et al. found that tumor grade was an independent prognostic factor, while Weinstock et al. found that tumor stage was a independent prognostic factor; Chagpar et al. found that the depth of tumor invasion, tumor size, lymph node metastasis and distant metastasis were independent
When we discuss prognosis, all elements above should be taken into consideration. However, the most common predictive systems, TNM classification and grade only focus on a portion of these variables and sometimes these two conflict. For example, if a patient has a grade 1 tumor with liver metastasis, according to the grade predictive system, this patient is low-grade and has a good prognosis. On the contrary ,when we put this patient into the TNM system, it is late-stage and has a poor prognosis. Conclusively, these two systems are limited in predicting outcomes.
But nomograms can take into account these variables in a Cox PHs regression. However, only a few nomogram studies focus on NETs. Modlin et al. focused on small-intestinal neuroendocrine tumors and Ye L et al. built a nomogram to predict outcomes for pancreatic neuroendocrine tumors. However, these studies have relatively small samples and do not include rectal NETs. This study presents the first
nomogram for predicting the prognosis of rectal NETs.
In our studies, four clinicopathological factors were independently correlated with prognosis in both the Chinese and SEER databases including age, tumor size, grade and TNM classification, according to the Cox PHs regression model. Thus, we
used these four factors when designing the nomogram.
This nomogram includes both grade and TNM stage were included, thereby addressing some of the limitations of the other predictive models. As expected, the predictive accuracy of the nomogram was superior to both predictions of TNM classification and WHO grade guidelines, with concordance indices of 0.907
compared with 0.829 and 0.809, p < 0.001 respectively.
As for the age and tumor size, we also found that they are both important elements that influence prognosis. Zhang X et al. reported that young age was a favorable prognostic factor while Li P et al. reported that lymph node metastasis was related to the tumor diameter and further more influence the prognosis of the rectal NETs. In our study, we found that patients likely have a decreased rate of
survival with increasing tumor size.
It seems that Ki-67 or mitotic rate per 10 high-power fields could be the better variable, because they are continuous variables which have a wider range prediction and be more individual compared with the categorical variables. However, we combine these two variables as grade, in order to simplify this model and make sure this nomogram can be used easily. Another reason is that Ki-67 (G classification) was categorized as “well differentiated”, “moderately differentiated”, or “poorly differentiated/undifferentiated” in the SEER database. Once an external validation is undertaken, it might be necessary to treat the parameters consistently between the training and validation sets. We hypothesize that the nomogram will improve if the cutoff of the Ki-67 index is changed in the future. Thus, the use of a continuous Ki-67
index variable might be better for establishing the nomogram.
This study has some limitations. One is that we did not include the functional status and medical treatment as variables. According to the NCCN guidelines,
patients with metastatic neuroendocrine tumor and carcinoid syndrome should be treated with somatostatin analogues. However, even though our 5 hospitals are the biggest centers in southern China, medical resources are limited. Some patients could not wait to receive the continuous therapy and went to the other hospitals. Others declined treatment secondary to cost or lack of understanding. Given these limitations, we opted to not include these variables so as to not compromise the nomogram.
Another limitation was that most of the patients were diagnosed within the last 3 years as this disease was better realized. With the routine use of endoscopy, the incidence of rectal NETs is increasing in recent years, but given the lack of numbers, we could not perform 5-year overall survival rate. With time, we can collect more
patients and variables and improve upon the nomogram.