Keratin 17 Is a Prognostic Biomarker in Endocervical Glandular Neoplasia

Daniel Mockler, MD; Luisa F. Escobar-Hoyos, PhD; Ali Akalin, MD, PhD; Jamie Romeiser, MPH; A. Laurie Shroyer, PhD; Kenneth R. Shroyer, MD, PhD

Disclosures

Am J Clin Pathol. 2017;148(3):264-273. 

In This Article

Abstract and Introduction

Abstract

Objectives. Previous work in our laboratory identified keratin 17 (K17) as a specific and sensitive biomarker for high-grade squamous intraepithelial lesions and cervical squamous cell carcinoma (SCC). K17, however, has not been previously evaluated in endocervical glandular neoplasia. Based on the similar pathogenesis of squamous and glandular lesions of the cervix, we hypothesized that K17 overexpression could also be a diagnostic and/or prognostic biomarker for endocervical neoplasia.

Methods. Cases of endocervical adenocarcinoma (n = 90), adenocarcinoma in situ (AIS) (n = 32), benign glandular lesions (n = 36), and normal endocervical mucosa (n = 5) were selected from Stony Brook Medicine and the University of Massachusetts from 2002 to 2013. Immunohistochemical staining for K17 was performed by an indirect immunoperoxidase method and was scored based on the proportion of cells that showed strong (2+) staining.

Results. K17 was highly expressed in 21 (65.6%) of 32 AIS and in 75 (83.0%) of 90 adenocarcinoma cases. In adenocarcinomas, K17 staining was detected in a mean of 33.9% of malignant cells. Staining tended to be strongest at the periphery of pseudoglandular groups and at the invasive front of tumors. K17 was not detected in the epithelial cells of benign glandular lesions, but groups of cuboidal cells, residing beneath the epithelial layer of benign glands, were frequently positive for K17, especially in cases of microglandular hyperplasia. High levels of K17 expression were significantly associated with decreased patient survival.

Conclusions. K17 is highly expressed in most cases of both invasive adenocarcinoma and in AIS and is a powerful, negative prognostic marker for patient survival.

Introduction

Uterine cervical cancer is a significant health concern, being the second most common cancer and the third leading cause of cancer mortality in women worldwide.[1] However, incidence and mortality rates have declined in the United States and other developed countries due largely to the introduction of the Papanicolaou stain in the 1940s and the implementation of screening programs that detect preinvasive lesions.[2–4]

Cervical cancer has multiple histologic subtypes, with squamous cell carcinoma (SCC) accounting for approximately 75% of cases and invasive adenocarcinoma accounting for 10% to 15% of cases.[5] It has been shown that histologic type is an independent prognostic factor in cervical cancer, with adenocarcinoma subtypes being associated with a poorer prognosis compared with SCC.[6,7] When adenocarcinomas are present, they tend to be larger in size and have a propensity for early lymphatic and hematogenous metastasis. Although screening programs have been very effective in decreasing the incidence of SCC by as much as 80%,[8] studies have shown a contrasting increase in the incidence of cervical adenocarcinoma, particularly in younger women.[5,9,10]

Although p16INK4a has been well established as sensitive and accurate diagnostic biomarker for endocervical adenocarcinoma in situ and invasive adenocarcinoma in histologic sections and in cervical cytology specimens, clinical and diagnostic features alone have limited power to predict the survival of patients with endocervical adenocarcinoma.[11–13] By contrast, we discovered, using laser capture microdissection and mass spectrometry, that keratin 17 (K17) could predict the overall survival of patients with cervical squamous cell carcinoma more accurately than grade, stage, or any other clinicopathologic features.[14] Subsequent work in our laboratory demonstrated that K17 serves as a nuclear shuttle of p27KIP1, resulting in sustained cell cycle progression.[15] Other studies have shown K17 to be a negative prognostic indicator in gastric adenocarcinoma, bladder carcinoma, epithelial ovarian carcinoma, and triple-negative breast carcinoma.[16–20] There remains a critically important, unmet clinical need, however, to identify prognostic (as opposed to diagnostic) biomarkers of endocervical adenocarcinoma. Thus, the goal of this study was to determine if K17 expression is a negative prognostic biomarker associated with decreased survival of patients with endocervical adenocarcinoma.

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