Use of Cervical Mucus to Screen for Gynecological Malignancies

A Pilot Study

Ihab Lamzabi; Lela Buckingham; Mezgebe Gebrekiristos; Richa Jain; Paolo Gattuso; Vijaya Reddy; Alfred Guirguis; Summer Dewdney; Jacob Rotmensch; Pincas Bitterman

Disclosures

Mod Pathol. 2013;26(11):1508-1513. 

In This Article

Abstract and Introduction

Abstract

High-grade malignancies are the leading cause of death from gynecological tumors. Unfortunately, no efficient screening method is available for these tumors. In this paper we report the results of a pilot study based on the frequency of TP53 mutations in these cancers. Mucus from the cervix of 32 hysterectomy specimens with no grossly visible cervical or serosal involvement were included in this study. TP53 exons 5–9 mutations were screened for mutations using single strand conformation polymorphism (SSCP). Immunostain for p53 protein was performed in all fallopian tubes and in a sample from the tumors that were identified prospectively. A total of 32 cases including 19 malignant, and 13 benign cases were included. P53 immunostain was positive in only 5 cases including 3 high grade malignant tumors and 2 precancerous lesions (serous tubal intraepithelial lesion or p53 signature) in the fallopian tubes. A TP53 mutation band pattern was detected by SSCP in 2/3 and 2/2 cases respectively. Twenty-seven cases were negative for p53 imunostain, 4 of which were positive for TP53 mutation by SSCP including 3 low-grade malignancies. The results of this study provide evidence that DNA from precursor lesions of high grade ovarian, fallopian tube and endometrial carcinomas can be detected in cervical mucus. Further studies using different markers, in preoperative setting and large scale screening studies will determine the utility of using cervical mucus to screen for gynecological malignancies.

Introduction

High-grade malignancies are the leading cause of death from gynecological tumors.[1–4] These tumors can arise from different locations including peritoneum, ovaries, fallopian tubes and endometrium, and show molecular aberrations with TP53 gene mutation being the most common and one of the earliest events in their carcinogenesis.[5–8]

High-grade epithelial ovarian cancers are highly aggressive tumors that represent 75% of all ovarian carcinomas, and account for 90% of deaths. They display high chromosomal instability and show TP53 mutations in >95% of cases. Recent studies suggest that most high-grade ovarian epithelial carcinomas arise from epithelial implantS originating from the fimbriated end of the fallopian tubes. In addition, high-grade epithelial ovarian tumors are commonly associated with tubal intraepithelial carcinomas and tubal p53 signature. Tubal intraepithelial carcinomas are positive for p53 immunostain, show epithelial stratification, high proliferative activity by Ki67 immunostain, and harbor TP53 mutation in most of the cases. P53 signature also called serous tubal intraepithelial lesion (STILs) shows positivity with p53 immunostain but does not show epithelial stratification or high proliferative activity. They are also associated with TP53 mutations in about 50% of the cases.[6–10] High-grade endometrial carcinomas also harbor TP53 mutations and have the worst prognosis among endometrial carcinomas.[5]

All high-grade gynecological malignancies share the tendency to become symptomatic only at advanced stages, especially the ovarian high-grade carcinomas.[1–4] Interest in early detection has been centered on ovarian carcinomas in an effort to reduce their mortality and several large-scale studies have been undertaken. Most of these studies used serum tumor markers associated with ovarian malignancies (particularly CA125) and/or ultrasound as a screening method. However, Serum markers and ultrasound are not sensitive nor specific for carcinomas. Furthermore, some studies found that screening using these methods did not reduce the mortality from ovarian cancers.[11,12] Similarly, screening for endometrial carcinoma using Pap smears or liquid based cytology showed low sensitivity.[13]

In this paper, we describe the results of a pilot study that may open a new era for the screening and early diagnosis of high-grade gynecological malignancies and perhaps all gynecological cancers. The idea behind this study is based on the usual path of an ovocyte from the ovary entering the uterus through the fallopian tubes, and perhaps ending most of the time in the cervical mucus. This path suggests that DNA molecules from neoplastic cells may also take the same route and be found in the cervical mucus. Testing the mucus has several advantages. First, getting a sample from the mucus is not invasive and has no side effects. Second, most women in the reproductive age are screened for cervical cancer, and the mucus can be taken at the same time as a Pap smear. Third, the viscosity of the mucus might help trap molecules from the upper gynecologic tract. Finally, the molecules in the mucus would provide information mainly about the gynecologic tract, which will make further investigation and surveillance more targeted.

When we began the study, there was no publication in the English literature about using cervical mucus as a screening tool for gynecological malignancies.

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