The Significance of Tumor Budding and Immunohistochemical Axl Expression in Gallbladder Adenocarcinomas.

Background: Tumor budding is a histopathological finding that is accepted as an indicator of epithelial-mesenchymal transformation in many solid tumors. Axl is a Receptor Tyrosine Kinase (RTK) family member and contributes to epithelial-mesenchymal transformation. It has been reported that its overexpression in various solid cancer cells is associated with a poor prognosis. It is claimed that Axl RTK may be the targeted molecule in treating some cancers due to its location in the cell membrane.

Aims: To investigate the relationship between immunohistochemical (IHC) Axl expression with tumor budding on the histopathological level and their prognostic significance in patients with gallbladder carcinoma. Thus, it is aimed to contribute to the emergence of a molecular option for targeted, personalized therapy in these patients.

Study Design: A retrospective cross-sectional study.

Methods: Thirty-eight gallbladder cancer patients who underwent surgery between 2000 and 2017 were included in the study. The expressions of Axl RTK in tumor tissues were evaluated by the IHC method. Demographic data (age, sex) of patients, histopathological features (size, growth pattern), tumor differentiation, pathological T staging, lymphovascular invasion, perineural and serosal invasion, surgical margin, tumor infiltrated lymphocyte, and tumor budding were examined. The tumor budding of the tumor was made according to the International Tumor Budding Consensus Conference and was classified as low (0-4 buds), intermediate (5-9 buds), high (≥ 10 buds). The relationship between clinical pathologic features, the survival rate, and Axl expression was analyzed with Person’s chi-square, Cox regression tests, and the Kaplan-Meier method.

Results: Tumor budding was determined as low in 12, intermediate in 10, and high in 16 cases. The increased degree of tumor budding was associated with focal-diffuse Axl expression ( = 0.018), infiltrative growth patterns ( = 0.031), poor differentiation ( = 0.006), advanced pathological stage ( = 0.002), and serosal ( = 0.040), perineural ( = 0.008), and lymphovascular invasion ( < 0.0001). Overall survival time was shorter in patients with intermediate to high tumor budding compared with those with low tumor budding ( = 0.011).

Conclusion: Axl expression appears to be associated with tumor budding capacity, which may be a poor prognostic criterion for patients with gallbladder cancer. It may be a good target to prevent tumor budding to reduce tumor invasion and metastasis.