Gynecological Surveillance and Surgery Outcomes in Dutch Lynch Syndrome Carriers

Abstract

Lynch syndrome (LS) is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, predisposing female carriers for endometrial cancer (EC) and ovarian cancer (OC). Since gynecological LS surveillance guidelines are based on little evidence, we assessed its outcomes. Data regarding gynecological tumors, surveillance, and (risk-reducing) surgery were collected from female LS carriers diagnosed in our center since 1993. Of 505 female carriers, 104 had a gynecological malignancy prior to genetic LS diagnosis. Of 264 carriers eligible for gynecological management, 164 carriers gave informed consent and had available surveillance data: 38 MLH1, 25 MSH2, 82 MSH6, and 19 PMS2 carriers (median follow-up 5.6 years). Surveillance intervals were within advised time in >80%. Transvaginal ultrasound, endometrial sampling, and CA125 measurements were performed in 76.8%, 35.9%, and 40.6%, respectively. Four symptomatic ECs, one symptomatic OC, and one asymptomatic EC were diagnosed. Endometrial hyperplasia was found in eight carriers, of whom three were symptomatic. Risk-reducing surgery was performed in 73 (45.5%) carriers (median age 51 years), revealing two asymptomatic ECs. All ECs were diagnosed in FIGO I. Gynecological management in LS carriers varied largely, stressing the need for uniform, evidence-based guidelines. Most ECs presented early and symptomatically, questioning the surveillance benefit in its current form.

Endometrial cancer in Lynch syndrome

“…[92][93][94] Helder-Woolde et al found no additional benefit for combined use compared to annual TVS, which was attributed to the differences in surveillance interval and ages of enrolled patients. 95 In addition, the pain and invasiveness of endometrial biopsy affects its acceptability among MMR PVs carriers, 96,97 and the different methods of endometrial biopsy influence its diagnostic accuracy. 98 Other alternative surveillance tools are also under investigation, including vaginal tampon-based endometrial sampling, Pap test and urinary biomarkers for the detection of EC.…”

“…Helder‐Woolde et al found no additional benefit for combined use compared to annual TVS, which was attributed to the differences in surveillance interval and ages of enrolled patients 95 . In addition, the pain and invasiveness of endometrial biopsy affects its acceptability among MMR PVs carriers, 96,97 and the different methods of endometrial biopsy influence its diagnostic accuracy 98 …”

Screening and risk reducing surgery for endometrial or ovarian cancers in Lynch syndrome: a systematic review

“…Eighteen studies of endometrial cancer screening detected a total of 104 cancers among 2688 women (3.9%), diagnosed between at ages 36–72 years (Figure 1). 10–27 A total of 1193 of 2688 (44.4%) patients had confirmed mismatch repair/ EPCAM mutations and 1495 of 2688 (55.6%) were identified through Amsterdam criteria (Figure 1).…”

“…Fourteen studies detected 29 cancers among 2224 women (1.3%), diagnosed between 35 and 83 years old (Online Supplemental Figure 3). 11 12 14 15 20 21 23–30 Twenty-eight of 1458 (1.9%) mismatch repair/ EPCAM carriers were diagnosed with ovarian cancer, representing 96.6% of all ovarian cancers found. Twelve of 28 (42.9%) were in asymptomatic women detected through screening at their first or subsequent screening visit (Online Supplemental Figure 3).…”

“…Of the 13 studies included, three were prospective cohort studies31–33 and 10 were retrospective histopathological analyses24 27 34–41 (Online Supplemental Table 6). Eight studies reported preoperative screening results.…”