Análise imuno-histoquímica de fatores relacionados à resistência terapêutica em neoplasias de glândula salivar

Abstract

Introduction: Therapeutic resistance in cancer is a complex and multifactorial process, in which tumors are intrinsically resistant to therapies or acquire resistance over the course of treatment. In this context, the role of ABC transporters (a large family of ATP-dependent transmembrane proteins associated with drug efflux) and transcription factors involved in the epithelialmesenchymal transition (EMT) process is highlighted. Objective: To evaluate the immunohistochemical expression of ABCB1, ABCG2, Twist1, and Snail1 in salivary gland neoplasms and correlate them with clinical-pathological and prognostic parameters. Methodology: The sample consisted of 20 cases of mucoepidermoid carcinoma (MEC), 19 cases of adenoid cystic carcinoma (AdCC), 14 cases of acinic cell carcinoma (ACC), and 20 cases of pleomorphic adenoma (PA). Clinical-demographic, morphological, and immunohistochemical analyses were performed using ABCB1, ABCG2, Twist1, and Snail1 antibodies. The collected data were submitted for descriptive and statistical analysis (p≤0.05). Results: All cases of AdCC, ACC, and PA were negative for ABCB1, while only 35% of MEC cases showed positivity for this transporter. Significantly higher expression of ABCG2 was observed in MEC and PA cases compared to ACC cases (p<0.01). Increased expression of Twist1 (nuclear) was found in MEC compared to AdCC and ACC (p<0.05). Furthermore, significantly higher expression of Twist1 (cytoplasmic) was noted in ACC and MEC when compared to both AdCC and PA (p<0.01). Regarding Snail1, higher nuclear expression was observed in AdCC compared to ACC (p<0.0001), while its cytoplasmic staining was increased in MEC compared to other tumors (p<0.01). In AdCC cases, significantly higher immunoexpression of Twist1 (nuclear and cytoplasmic) was found in cases with necrosis (p<0.05) and grade III/high-grade tumors (p<0.05). In MEC, significantly higher expression of Snail1 (nuclear) was observed in older patients (p=0.028) and major salivary glands (p=0.045), while its lower cytoplasmic expression was associated with distant metastasis (p=0.021) and death (p=0.021). Furthermore, in MEC, positive and significant correlations were found between ABCG2 with ABCB1, and with Twist1 (nuclear) (p<0.05), as well as negative correlations between Twist1 (cytoplasmic) and Snail1 (nuclear and cytoplasmic) (p<0.05). Five-year survival analyses showed that the presence of metastases (lymph node and distant) and advanced clinical stage significantly impacted the reduction of overall and disease-free survival in patients with AdCC and MEC, whereas the expression of Twist1 (cytoplasmic) was associated with poorer disease-free survival in MEC. Conclusions: It is suggested that the ABCG2 transporter may play a role in intrinsic chemoresistance, while ABCB1 does not seem to be directly involved in this process. Additionally, the transcription factors Twist1 and Snail1, crucial for EMT, likely play a significant role in the chemoresistance of malignant salivary gland neoplasms.