Although p16INK4a and other diagnostic biomarkers have been established as sensitive and accurate diagnostic biomarkers for cervical squamous cell carcinoma (SCC) and endocervical adenocarcinoma, they have limited power to predict the survival of patients following the diagnosis of cervical cancer. By contrast, we discovered by laser capture microdissection and mass spectrometry, that keratin 17 (K17) could predict the overall survival of patients with squamous cell carcinoma (SCC) more accurately than grade, stage, or any other clinicopathologic features1,2. K17 status, however, has not been previously evaluated in glandular neoplasms of the endocervical mucosa. Based on the concept that both squamous and glandular lesions of the cervix are driven by similar pathogenetic mechanisms, we hypothesized that K17 overexpression could also be a prognostic biomarker for endocervical glandular neoplasia.
Cases of endocervical adenocarcinoma, adenocarcinoma in situ (AIS), benign glandular lesions, and normal endocervical mucosa were selected from the archival collections of formalin-fixed, paraffin-embedded tissue blocks from the Departments of Pathology at Stony Brook Medicine and the University of Massachusetts. Immunohistochemical staining for K17 was performed by an indirect immunoperoxidase method and K17 expression was scored based on the PathSQ score, the proportion of cells that showed strong (2+) staining.
K17 was highly expressed in 21/32 (65.6%) cases of adenocarcinoma in situ (AIS) and in 75/90 (83%) of adenocarcinoma cases. K17 staining was detected in a mean of 33.94% of malignant cells and was strongest at the periphery of pseudoglandular groups and at the invasive front of tumors. K17 was not detected in benign glandular lesions but was found in subcolumnar reserve cells, most notably in microglandular hyperplasia. High levels of K17 expression were significantly associated with decreased patient survival. While the 40-89% K17+ category did not significantly differ from the <40% category (HR = 2.03, p=0.13), those with a 90%-100% K17+ scores had 3.47 times higher risk of death as compared to the risk of death for those with a <40% K17 score (p=0.01).
In summary, K17 expression in normal endocervix was limited to subcolumnar reserve cells while expression in the columnar endocervical epithelium was highly specific for glandular neoplasia of the cervix. Most importantly, we further determined that high K17 expression is a powerful, negative prognostic biomarker that can be used to identify patients that have the shortest survival probability following the diagnosis of endocervical adenocarcinoma.
1. Escobar-Hoyos LF, Yang J, Zhu J, et al. Keratin 17 in premalignant and malignant squamous lesions of the cervix: proteomic discovery and immunohistochemical validation as a diagnostic and prognostic biomarker. Mod Pathol 27: 621-30, 2014.
2. Escobar-Hoyos LF, Shah R, Roa-Pena L, et al. Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility. Cancer Res 75:3650-62, 2015.