Utility of contrast-enhanced harmonic endoscopic ultrasonography for predicting the prognosis of pancreatic neuroendocrine neoplasms

概要

BACKGROUND AND AIMS:
The annual incidence of pancreatic neuroendocrine neoplasm （PanNEN） ranges between 0.32 and 0.43/100,000 and is increasing. However, PanNEN grade and tumor aggressiveness are not necessarily correlated17, 18. The present study examined the enhancement patterns on CH-EUS related to the degree of clinical malignancy, and pathological features of the tumor in PanNEN, compared with those on CE-CT.
Pancreatic neuroendocrine neoplasms （PanNENs）, including Grade 1 （G1） or G2 tumors, can have a poor prognosis. This study investigated the value of contrast-enhanced harmonic endoscopic ultrasonography （CHEUS） for predicting the prognosis of PanNENs.

METHODS:
This single-center, retrospective study included 47 consecutive patients who underwent CH-EUS and were diagnosed with PanNEN by surgical resection or EUS- guided fine needle aspiration between December 2011 and February 2016. Patients were divided into aggressive and non-aggressive groups according to the degree of clinical malignancy. CH-EUS was assessed regarding its capacity for diagnosing aggressive PanNEN, the correspondence between contrast patterns and pathological features, and its ability to predict the prognosis of PanNEN.

RESULTS:
There were 19 cases of aggressive PanNEN and 28 cases of non- aggressive PanNEN. The aggressive group included three G1, four G2, three G3 tumors, three mixed neuroendocrine nonneuroendocrine neoplasms, and six neuroendocrine carcinomas. CH-EUS was superior to contrast-enhanced computed tomography for the diagnosis of aggressive PanNEN （P < 0.001）: hypo-enhancement on CH-EUS was an indicator of aggressive PanNEN, with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 94.7%, 100%, 100%, 96.6%, and 97.9%, respectively. Among G1/G2 PanNENs, cases with hypo- enhancement on CH-EUS had a poorer prognosis than those with hyper/iso-enhancement （P=0.0009）. Immunohistochemical analyses, CH-EUS findings, and tumor aggressiveness shows the results of immunohistochemical analyses of 36 resected cases. The percentage of Sirius Red and α-SMA positivity, both of which are strong indicators of tissue fibrosis, was significantly higher in cases with hypo-enhancement on CH-EUS （P < 0.001 and P < 0.001） and aggressive PanNENs （P < 0.001 and P < 0.001） than in cases with hyper/iso- enhancement on CH-EUS and non-aggressive PanNENs . By contrast, MVD was significantly lower in cases with hypo-enhancement on CH- EUS （P < 0.001） and aggressive PanNENs （P < 0.001） than in cases with hyper/iso- enhancement on CH-EUS and non-aggressive PanNENs . Vessel diameter and vessel area were significantly smaller in cases with hypo-enhancement on CH-EUS （P=0.015 and P=0.049） and aggressive PanNENs （P=0.005 and P=0.028） than in cases with hyper/iso-enhancement on CH-EUS and nonaggressive PanNENs .

Discussion:
Intratumoral MVD is a prognostic parameter in malignant tumors and several studies show that MVD is lower in malignant PanNEN than in benign PanNEN. MVD is considered to be associated with the expression of vascular endothelial growth factor （VEGF） and α-SMA, which affects the degree of differentiation of the tumor. Moreover, VEGF is an important factor for the metastatic process in PanNENs. MVD is significantly lower in PanNENs with distant metastasis than in those without distant metastasis regardless of the PanNEN WHO grade, and decreased MVD is correlated with increased stromal fibrosis in the tumor. Similarly, in the present study, α-SMA and Sirius Red positive staining revealed that the intratumoral degree of fibrosis were stronger in aggressive than in non-aggressive tumors. By contrast, intratumoral MVD, vessel diameter, and vessel area were lower in aggressive PanNENs than in nonaggressive PanNEN.

CONCLUSION:
CH-EUS may be useful for predicting the prognosis of PanNENs.