Loss of p16 and high Ki67 labeling index is associated with poor outcome in esophageal carcinoma

Abstract

The p16 tumor suppressor is coded by CDKN2A (9p21) and plays an important role during carcinogenesis and tumor progression in numerous tumor entities. The aim of our study was to evaluate the prognostic role of p16 expression and CDKN2A deletion in esophageal cancer (EC). Therefore, we analyzed p16 and KI67 expression by immunohistochemistry and 9p21 deletion by fluorescence in-situ hybridization on a tissue microarray including 398 adenocarcinomas (AC) and 293 squamous cell carcinomas (SCC) with clinical follow up-data. p16 positivity was found in 30.2% of AC and 13.9% of SCC and CDKN2A deletion in 32.1% of AC and 33.5% of SCC. In SCC p16 immunostaining correlated with low tumor stage (P = 0.014). In AC Ki67 positivity was associated with high tumor stage (P = 0.001), presence of lymph node metastasis (P = 0.009), high UICC stage (P = 0.001) and poor grading (P = 0.005). Overall survival (OS) was shorter for patients with high Ki67 labeling index (Ki67LI; P = 0.009) and negative p16 immunostaining (P = 0.026). In both histological tumor types, CDKN2A deletion showed no association with phenotype or outcome. Proportional cox-regression modeling revealed patients' age, tumor stage, lymph node metastasis and Ki67 labeling index as independent prognostic markers in AC. In SCC, only patients' age and tumor stage proved to be independent prognosticators. In summary, our study shows that loss of p16 expression and high Ki67LI is linked to shortened OS in AC. CDKN2A deletion shows no relevant association with tumor phenotype and patient outcome.

Clinical–morphological profiles of esophageal carcinoma’s main types

“…The assessment of the degree of differentiation of the two types of carcinoma was present only in the American study mentioned above and in the German study of Jacobsen et al [28]. In both studies the trend was somehow balanced, more inclined toward poorly differentiated pattern in the American study [29], trend that was also present but more pronounced in our study.…”

“…In studies that analyzed both ECs and their subtypes [ 25 , 27 , 28 , 29 ], the values of EACs M/F ratio were higher than those of ESCCs and the values of ECs taken as a whole were placed between the values of the two main types. However, there were two exceptions: our study and the Korean study [ 26 ] in which the M/F ratio value of ESCCs was higher than that of EACs.…”

“… Comparison of M/F ratio with other studies. EC: Esophageal cancer; EAC: Esophageal adenocarcinoma; ESCC: Esophageal squamous cell carcinoma; M: Male; F: Female; OS: Our study; 1: [ 29 ]; 2: [ 25 ]; 3: [ 24 ]; 4: [ 27 ]; 5: [ 28 ]; 6: [ 26 ]; 7: [ 32 ]; 8: [ 30 ]; 9: [ 31 ]; 10: [ 35 ]; 11: [ 34 ]; 12: [ 33 ]; 13: [ 22 ]; 14: [ 21 ]; 15: [ 5 ] all cases; 16: [ 5 ] surgery; 17: [ 23 ] …”

“…Regarding the ESCCs, most of these studies [ 24 , 28 , 31 , 35 ] revealed a higher incidence of squamous tumors in elderly persons. Only the Swedish study [ 25 ] reported younger ages for patients with ESCCs – many patients in the 7 th decade of life (60–69 years) but followed by the 8 th decade (70–79 years).…”

“…Local invasion was assessed for both ECs as a whole and their main histological variants only in the German and American studies mentioned above [28,29]. In both studies, both ECs and their types showed a trend toward an invasion limited to the esophageal wall (pT3), more pronounced in the German study [28]. 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% In our study, the situation was somehow different, with a more obvious trend toward the aggressive stages (T4) for both ECs and the two histological types (Figure 14a).…”