In this study, the tumor grade defined using immunopathological tests was the most significant predictor for metastasis in patients with 10–20 mm sized rectal NET. Ki-67 index itself was also meaningful; however, it was less significant than the tumor grade. Tumor size and muscularis propria involvement were significant based on the EUS results in univariate analysis. Pathological tumor size, lymphovascular invasion, and perineural invasion showed no statistically significant differences.
It is surprising that tumor size, as determined by EUS, was a more significant factor than the pathological tumor size in predicting metastasis. There is a possibility that the biopsy results may not accurately reflect the original tumor properties since tissue deformation may occur during and after resections. On the other hand, it can be thought that EUS retains the original shape before the manipulation and better reflects the original size of the tumor. This reasoning seems to be more conspicuous as the accuracy of the measurements obtained with the EUS machine has been improved according to technological advancement [1]. Moreover, the risk of metastasis can be assessed before treatments such as endoscopic resection. Thus, the tumor size defined by EUS could be considered more significant to determine radical resection than pathological tumor size.
Among immunochemical examinations, the tumor grade was the most significant to predict metastasis in the present study. Several previous studies and guidelines stated that each of these factors mitotic count and Ki-67 index were significant in predicting metastasis risk and prognosis [10, 13]. On the other hand, different studies also reported that the tumor grade assessed by combining these two factors was a significant predictor [6, 11]. In the present study on 10–20 mm sized rectal NET, the grade defined based on the two factors combined was independent predictive factor for metastasis in multivariate analysis. In particular, 67% of the patients with the metastasis had a tumor grade 2. The remaining two patients with tumor grade 1 were suspected of lymph node metastasis based on lymphovascular and perineural invasion, or lymph node enlargement on EUS. Therefore, it seems that the proper treatment would be determined if the tumor grade had been used as the main factor to predict metastasis in post-operative biopsy while referring to the results of imaging and other pathological tests.
Lymphovascular invasion and perineural invasion had no statistical significance; however, they were observed in 33.3% of the patients with the metastasis (vs. 6% in non-metastatic group), therefore, an increase in sample size may demonstrate a statistical significance for these factors. As mentioned above, one case with metastasis was determined as tumor grade 1, in which lymphovascular invasion and perineural invasion were identified. The significance may be lower than that of the tumor grade, but it may certainly be considered as a clinically meaningful test.
Immunochemical methods for diagnosis of rectal NET include chromogranin A, B, synaptophysin, CD56, CD57, p53, and neuron-specific enolase [4]. There is no consensus regarding the need for immunochemical examinations in all cases of NET. However, immunochemical testing is encouraged when the tumor presents with histologically unclear characteristics. Tests for chromogranin A and synaptophysin are considered as a standard [4]. Other tests are not recommended for routine staining. p53 may be used as a marker for hypodifferentiated tumors, but it is not recommended as part of the routine [14]. In the present study, tests for chromogranin A, synaptophysin, and CD56 were performed. In addition, this study also investigated whether immunochemical tests can be used not only for diagnosis but also for determining the treatment method. However, none of the above immunochemical tests for NET diagnosis could be identified to have an association with lymph node metastasis. Synaptophysin and CD56 were expressed in all of the patients in metastatic and non-metastatic groups. Chromogranin A was expressed in only a few cases, and no statistically significant difference was observed between the groups.
This study focused on the controversy in the appropriate treatment choice for 10–20 mm sized rectal NET. Since previous studies have focused on various sizes of rectal NET, the predictors of metastasis of 10–20 mm sized rectal NET could not be directly identified. The current study suggests that tumor grade is the most important factor in determining the radical treatment of 10–20 mm sized rectal NET. In addition, it is considered essential to examine the tumor size, lymph node enlargement, and muscularis propria involvement using EUS, and lymph node enlargement using CT. Thereafter, if the tumor size defined with EUS is 15 mm or larger, muscularis propria has been infiltrated, and lymph node enlargement has been identified in EUS and CT results, radical resection should be considered for the first option. In other cases, endoscopic resection may be considered at first; afterward, radical resection is suggested for tumor grade 2 or higher in pathologic examination.
This study has a few limitations. First, small numbers of patients were included in the study. The incidence of 10–20 mm sized rectal NET was low, and that of metastasis was even lower, which led to the limitation of the small sample size. To compensate for this limitation, we extended the study period to 11 years. Another limitation was a retrospective of this study; therefore, the possibility for selection bias existed. In the future, prospective studies could obtain more significant results. The other limitation is that lymph node metastasis was not pathologically confirmed in all patients. To exclude potential errors that could not be identified with imaging, even though there was lymph node metastasis, only those patients who were followed-up for at least two years after receiving endoscopic resection with no pathologically identified lymph node metastasis, were included in the study. Patients who underwent only endoscopic resection with a follow-up duration of fewer than two years were excluded.