Mutational analysis of cervical cytology improves diagnosis of endometrial cancer: A prospective multicentre cohort study

Abstract

Endometrial carcinoma (EC) is traditionally diagnosed by a histopathological assessment of an endometrial biopsy, leaving up to 30% of patients undiagnosed due to technical failure or an inadequate amount of tissue. The aim of the current study is to assess whether mutational analysis of cervical cytology or pipelle endometrial biopsies improves the diagnostic accuracy of traditional histopathological diagnosis of EC. This prospective multicentre cohort study included patients surgically treated for EC or a benign gynaecological condition (control group). A Pap brush sample, cervicovaginal self‐sample, pipelle endometrial biopsy and surgical specimen of either the EC or normal endometrium were obtained. A targeted next‐generation sequencing panel was used to analyse these samples for mutations in eight genes. Sensitivity, specificity and predictive values were calculated. Fifty‐nine EC patients and 31 control patients were included. In these patients, traditional histopathological diagnosis by pipelle had a sensitivity of 79% and a specificity of 100%. For EC patients, 97% of surgical specimens contained at least one mutation. Mutational analysis of Pap brush samples, self‐samples and pipelle endometrial biopsies yielded a sensitivity of 78, 67 and 96% with a specificity of 97, 97 and 94%, respectively. Combining one of these three methods with histopathological pipelle endometrial biopsy evaluations yielded a sensitivity of 96, 93 and 96%, respectively. Our study has shown that mutational analysis of either cervical cytology or pipelle endometrial biopsies improves diagnosis of EC. Prospective validation will support implementation in clinical practice.

Diagnostic accuracy of cytology for the detection of endometrial cancer in urine and vaginal samples

“…Endometrial cancer is known to shed malignant cells through the cervix into the lower genital tract. Tumour DNA collected from cervical brushes and vaginal tampons demonstrate methylation levels and mutational profiles matching those of the endometrial cancer resected at hysterectomy [11][12][13] . Tumour cells have also been reported on routine cervical cytology samples in 45% of women with endometrial cancer 14 although cytology has not been formally tested in this regard.…”

Cancer‐associated mutations in normal human endometrium: Surprise or expected?

“…The use of Sanger sequencing targeting representative cancer‐associated genes has frequently revealed somatic mutations in 80%‐90% of endometrial cancer specimens, but rarely in normal endometrial samples 40,41 . A targeted NGS panel for 8 genes ( ARID1A , CTNNB1 , KRAS , MTOR , PIK3CA , POLE , PTEN and TP53 ) detected somatic mutations in over 90% of endometrial cancer specimens, while only 6% of women without cancer exhibited PIK3CA mutations 42 …”

An Integrated Approach for the Early Detection of Endometrial and Ovarian Cancers (Screenwide Study): Rationale, Study Design and Pilot Study

“…Thus, cervical cytology is repeatedly recognized as a potential source of information about gynecological tumors, and molecular approaches (genomic, epigenomic, and proteomic) have been evaluated to detect EC and OC with considerable sensitivity and specificity [ 30 , 31 , 32 ]. Other minimally invasive methods to detect EC/OC using molecular approaches have been evaluated, such as blood samples, tampons, and vaginal self-samples, with promising results [ 33 , 34 , 35 ]. These recent findings offer an exciting perspective on the early detection of EC/OC.…”