The potential of somatostatin receptor 2 as a novel therapeutic target in salivary gland malignant tumors

Abstract

Background: Treatment regimens for patients with metastatic or recurrent post-radiation, locoregional, unresectable salivary cancer are limited. An inverse correlation between somatostatin receptor 2 (SSTR2) and the proliferating marker Ki-67 in neuroendocrine tumors has enabled a treatment plan for metastatic disease, utilizing peptide receptor radionuclide therapy. Interestingly, healthy salivary glands express high levels of SSTR2. In this study, the presence of SSTR2, its correlation with Ki-67 in glandular salivary carcinomas and the clinical applicability thereof was determined.

Methods: In the retrospective part of this study, 76 adequate tumor tissue specimens obtained from patients diagnosed with primary or metastatic salivary carcinomas between 1988 and 2016, were collected for tissue array and histologically classified. Immunohistochemistry was performed to determine the presence, relative expression and potential correlation of SSTR2 and Ki-67. The clinical significance of SSTR2 expression was determined by prospectively assessing ⁶⁸Ga-DOTATATE uptake using PET-CT imaging, in patients diagnosed with metastatic salivary gland malignant tumors between 2015 and 2016.

Results: Sixty-three primary cancer tumors and 14 metastatic tumors were tested. All tumor subtypes were found to express SSTR2 to some extent. The highest expression was seen in Mucoepidermoid carcinoma (MEC) tissues where the majority of specimens (86.4%) expressed SSTR2. A relatively strong immunohistochemical staining score for SSTR2 was observed in MEC, adenoid cystic carcinoma and polymorphous adenocarcinoma. Interestingly, an inverse correlation between SSTR2 and Ki-67 expressions was observed (44%) in MEC tissue. Uptake of ⁶⁸Ga-DOTATATE was visualized using PET-CT imaging in 40% of patients, across metastatic MEC and ACC. All observations were found to be statistically significant.

Conclusion: This study confirms the expression of SSTR2 in glandular salivary carcinomas and an inverse correlation in expression levels between SSTR2 and Ki-67. This lays a foundation for novel treatment options in salivary metastatic cancers where SSTR2 may be a potential novel therapeutic target.

Keywords: 68Ga-DOTATATE; Ki-67; PET-CT; Peptide receptor radionuclide therapy; Salivary carcinomas; Somatostatin receptor.

Fig. 1

PET-CT imaging showing in vivo ⁶⁸Ga-DOTATATE uptake in metastases. Salivary carcinoma uptake of intravenous ⁶⁸Ga-DOTATATE is clearly visualized in the patient, indicative of somatostatin receptor 2 (SSTR2) expression. Metastases were detected in diverse organs including the pelvis, sacrum and groin