Συσχέτιση και αξιολόγηση ιστοπαθολογικών ευρημάτων και βιολογικής συμπεριφοράς των κακοήθων νεοπλασμάτων των σιαλογόνων αδένων

Abstract

Introduction: The incidence of malignant neoplasms of the salivary glands varies among researchers, with an estimated incidence of 0.4-2.6:100,000, accounting for 3-6% of head and neck malignancies and less than 1% of all malignancies. Despite their rarity, salivary gland neoplasms exhibit a diversity unmatched by any other organ, with more than 20 different types of malignant glandular tumors. This histological diversity may contribute to the variable clinical behavior and prognosis of salivary gland malignancies. Potential prognostic factors in malignant salivary gland neoplasms include staging, histologic type of tumor with its differentiation, perineural infiltration (PNI), location and status of surgical margins. The incidence of perineural infiltration (PNI) in malignant salivary gland neoplasms ranges from 23-96% with a mean of 55.7%, with a recent study reporting the incidence of PNI in various histologic types of salivary gland carcinoma. Epithelial cell adhesion molecule EpCAM is a type I transmembrane protein. EpCAM is expressed in most epithelial cells and during embryogenesis. The frequent and high expression of EpCAM in various carcinomas (98 out of 131 tested) and in metastases and a correlation with clinical outcome have made EpCAM both a prognostic marker and a therapeutic target. The aim of this study was to identify possible biological factors that influence the clinical course, recurrence probability, and disease-related mortality in patients with salivary gland cancer. Specifically, the marker EpCAM was used and its immunohistochemical expression was studied in malignant neoplasms of the salivary glands in all tumors included in the study. Material and Methods: The study examined 65 cases of patients with various histopathologic subtypes of malignant salivary gland tumors treated at the Department of Oral and Maxillofacial Surgery of "G. Papanikolaou" General Hospital of Thessaloniki from 2007 to 2016. Demographic and clinical data were collected from medical records, and histopathologic diagnosis was confirmed using WHO 2017 criteria. An immunohistochemical study of epithelial cell adhesion molecule (EpCAM) protein expression was performed using an automated immunohistochemistry system and the MOC-31 antibody. The statistical analysis of the data was performed using the statistical program SPSS 27.0, IBM® SPSS® Statistics. The significance level was set at 5%. All results were considered significant at p≤0.05.Results65 cases of malignant salivary gland neoplasms of different histopathologic subtypes were included in our study. Of the total number of patients, 35 were female (53.8%) and 30 were male (46.2%). The mean age were 58.7 years. Regarding the location, 30 (46.15%) cases involved the major salivary glands and 35 (53.85%) cases involved the minor salivary glands. The salivary gland tumors studied are: adenocystic carcinoma with 18 cases (27.7%), mucoepidermoid carcinoma with 20 cases (30.8%), adenocarcinoma multiforme with 9 cases (13.8%), adenocarcinoma (NOS) with 4 cases (6. 2%), intraductal carcinoma with 5 cases (7.7%), epithelial-myoepithelial with 5 cases (7.7%), adenocarcinoma with 2 cases (3.1%) and carcinoma from pleomorphic adenoma with 2 cases (3.1%). Of the total 65 cases studied, perineural infiltration was present in 29 cases (42.62%) and lymphatic infiltration in 27 cases (41.53%). In terms of location, the majority of tumors with perineural infiltration involved the major salivary glands (20/29). Perineural infiltration of minor salivary gland malignancies was observed in 9/29 (25.71%) cases. In terms of histological type, the majority of tumors with perineural infiltration were intraductal carcinoma in 5/5 cases (100%) and adenocystic carcinoma in 13/18 (72.22%) cases. The immunohistochemical evaluation was performed by calculating the total immunostaining score (TIS) as the product of the proportion score (PS) and the intensity score (IS) according to Allred scoring system used in the evaluation of oestrogen receptor positivity. Among the 65 malignant neoplasms studied in the salivary glands, Epithelial cell adhesion molecule (EpCAM) expression was detected in 81.5% of cases, showing correlations with tumor type, staining intensity, and location. Notably, significant associations were identified between EpCAM expression and recurrence, metastasis, and infiltration. These findings underscore the intricate nature of malignant salivary gland neoplasms and suggest a potential prognostic significance of EpCAM expression in predicting disease progression and outcomes. Discussion: There is a consensus regarding certain factors like stage, neck lymph node infiltration, and perineural infiltration in different studies examining the prognosis of salivary gland cancer. These factors are typically considered consistent across various research contexts, and in our study, we treated them as such. Specifically, our investigation found a significant association between perineural infiltration and lymphovascular infiltration, aligning with findings from previous research. However, the impact of perineural infiltration on patient survival has been a topic of debate. While some studies have not found it to be a predictor of worse survival, our study, despite its limited sample size and variations in salivary gland pathologies, demonstrated a strong correlation between perineural infiltration and 5-year overall and disease-free survival in patients with salivary gland carcinoma. This finding is in line with earlier reports suggesting that perineural infiltration holds prognostic significance in malignant salivary gland carcinoma. Moreover, epithelial cell adhesion molecule (EpCAM) expression, detectable in various human epithelial tissues including the salivary glands, presents a potential avenue for further investigation into the biological mechanisms underlying salivary gland malignancies. Regarding the effect of EpCAM expression on survival, our study showed that tumors with high EpCAM expression had reduced disease-free survival (RFS) (p<0.001) and overall survival (OS) (p<0.001) compared to patients with low-grade EpCAM expression. Finally, it should be noted that in our study, a statistically significant reduction in overall survival (OS) (p<0.001) and disease-free survival (RFS) (p<0.001) was observed in tumors with both perineural infiltration and high EpCAM expression (PNI+/EpCam+) compared to patients with PNI-/EpCam- tumors. In addition, the concurrent presence of perineural infiltration and positive EpCAM expression appeared to be associated with shorter disease-free survival and overall survival. However, due to the small number of patients with two positive markers, this specific finding needs to be verified in a larger group of patients. In conclusion, the clinical prognostic factors of salivary gland cancer (histologic type, differentiation) are well established in the literature, while evidence for a number of biological factors is mixed. Our study confirmed the prognostic value of detection of perineural infiltration and EpCAM expression. Further studies with more samples will help to document the potential utility of EpCAM as an immunohistochemical marker in the study of prognosis in salivary gland malignancies.

Τα νεοπλάσματα των σιελογόνων αδένων, αν και σπάνια, εκπροσωπούν ένα ευρύ φάσμα μορφών κακοήθων όγκων κεφαλής και τραχήλου. Η ετερογένεια στην ιστολογία και η μεγάλη ποικιλομορφία τους αποτελούν σημαντικούς παράγοντες που επηρεάζουν την κλινική συμπεριφορά και πρόγνωση τους. Η έκφραση του επιθηλιακού παράγοντα προσκόλλησης EpCAM σε αυτούς τους όγκους δεν έχει μέχρι στιγμής χαρακτηριστεί λεπτομερώς στη βιβλιογραφία, αλλά η υψηλή έκφρασή του τον καθιστά υποψήφιο ως προγνωστικό δείκτη και θεραπευτικό στόχο. Η παρούσα διδακτορική διατριβή ασχολείται με την αναζήτηση πιθανών βιολογικών παραγόντων που επηρεάζουν την κλινική πορεία, την πιθανότητα υποτροπής και τη σχετιζόμενη με τη νόσο θνητότητα σε ασθενείς με καρκίνο των σιελογόνων αδένων. Για τον σκοπό αυτό, μελετήθηκε ο δείκτης EpCAM και η ανοσοϊστοχημική έκφρασή του σε κακοήθη νεοπλάσματα των σιελογόνων αδένων. Συμπεριλήφθηκαν 65 περιπτώσεις ασθενών με κακοήθη νεοπλάσματα των σιελογόνων αδένων ποικίλων ιστοπαθολογικών υποτύπων. Αναλύθηκαν δημογραφικά στοιχεία και παράγοντες όπως η περινευρική και λεμφαγγειακή διήθηση, καθώς και η έκφραση του EpCAM. Τα αποτελέσματα έδειξαν σημαντική συσχέτιση της έντασης της χρώσης του EpCAM με τον ιστολογικό τύπο του καρκινώματος και την πιθανότητα υποτροπής, ενώ επίσης παρατηρήθηκε συσχέτιση με την περινευρική και αγγειακή διήθηση.