University of Groningen Gynaecological malignancies in Lynch syndrome Woolderink, Jorien Maria

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Gynaecological malignancies in Lynch syndrome

Woolderink, Jorien Maria

DOI:

10.33612/diss.84185340

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Publication date:

2019

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Woolderink, J. M. (2019). Gynaecological malignancies in Lynch syndrome: surveillance and cancer

characteristics. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.84185340

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The additional value of

endometrial sampling

in the early detection

of endometrial cancer

in women with Lynch

syndrome

Helder-Woolderink JM

1

_{, De Bock GH}

2

_{, Sijmons RH}

3

_{, Hollema H}

4

_,

Mourits MJE

1

1_{Department of Gynecologic Oncology, University Medical Center Groningen}

²_{Department of Epidemiology, University Medical Center Groningen}

3_{Department of Genetics, University Medical Center Groningen}

4_{Department of Pathology, University Medical Center Groningen}

Gynecol Oncol. 2013;131(2):304-8

2

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P MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6

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M PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MS

M MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpC 2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH 2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 LH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH

M H6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 P

CAM MLH1 MSH2 MSH6 P EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM

ML SH2 MSH6 PMS2 EpCAM MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 S2 EpCAM MLH1 MSH2 M

M MS2 EpCAM MLH1 MSH PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCA LH1 MSH2 MSH6 PMS2 Ep

Ep MLH1 MSH2 MSH6 PM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MS H6 PMS2 EpCAM MLH1

SH6 PMS2 EpCAM M MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS M MLH1 MSH2 MSH6 PM

pCAM MLH1 MSH2 M EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM ML 2 MSH6 PMS2 EpCAM M

SH2 MSH6 PMS2 Ep MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MS

MS2 EpCAM MLH1 6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 Ep

MLH1 MSH2 MSH6 AM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1

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CAM MLH1 MSH PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM

SH2 MSH6 PMS2 M MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2

MS2 EpCAM MLH1 H2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6

MLH1 MSH2 MSH6 MS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 SH6 PMS2 EpCAM LH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 Ep CAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 M SH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS

2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH

LH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MS PMS2 EpCAM MLH1 MSH2 MSH6 PM

M PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCA MLH1 MSH2 MSH6 PMS2 EpCAM M

M MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 M

2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpC M MLH1 MSH2 MSH6 PMS2 EpCA

EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MS M MLH1 M

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6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 M

P CAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6

H2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM

S2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2

LH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 P

PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM ML

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ABSTRACT

Objective

Based on previous studies, standard gynecological screening consisting of annual transvaginal ultrasonography (TVU) was extended with endometrial sampling in women with Lynch Syndrome (LS).

The aim of this study was to evaluate the additional value of endometrial sampling in detecting (pre)malignancies of the endometrium in women with LS or first-degree relatives.

Methods

All women above 30 years of age with LS or first-degree relatives at 50% risk of LS are offered annual gynecological screening in our family cancer clinic. Endometrial screening results from January 2003-December 2007 (period I: standard screening by transvaginal sonography and serum CA125) were compared with screening results from January 2008-June 2012 (period II: standard screening added with endometrial sampling).

Results

Seventy five women (300 patient years) were screened annually. There were 266 screening visits, 117 in period I and 149 in period II. In period I, four premalignant endometrial lesions were detected and one endometrial carcinoma (FIGO stage IB). In period II, two premalignancies were found. None of the lesions would have been missed without standard endometrial sampling. No interval endometrial cancers were detected in this study.

Conclusion

In this study, annual endometrial screening seems an effective screening tool in the detection of premalignancies and early endometrial cancer in women with LS. Adding standard endometrial sampling to annual TVU has no additional value in the early detection of (pre)malignant endometrial lesions in women with LS in this study.

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2 INTRODUCTION

Women with Lynch Syndrome (LS), previously called Hereditary Non Polyposis Colorectal Cancer (HNPCC), have an autosomal dominant inherited mutation in one of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. LS is characterized by a high risk and early occurrence of colorectal cancer and extra colonic cancers. (1) The second most common cancer in female LS patients is endometrial cancer. The estimated cumulative lifetime risk to develop endometrial cancer in women with LS varies in different reports between 21-71%. MLH1 and MSH2 mutation carriers have a lifetime risk up to 60% to develop endometrial cancer; carriers of an MSH6 mutation have a risk up to 71%, (1,2-5) although lower risks (24%) have been reported as well. (6) For PMS2 mutation carriers, a risk of 15% has been reported. (7) However, series of

PMS2 mutation carriers are significantly smaller than those for the other mismatch repair

genes and cancer risk therefore less well established. The overall annual incidence rate of developing endometrial cancer after the age of 40 years in LS is 2,5%. (8)

The high risk of endometrial cancer in LS and the earlier age of onset, together with a well-detectable and treatable premalignant or early malignant stage, is the reason to consider endometrial cancer screening in these women and their first degree relatives at 50% risk of LS. (1-2, 9-10) A few studies have investigated the optimal gynecological screening protocol in women with LS. (1,4,11-13) Interval endometrial carcinomas occurred with annual screening of TVU alone in two studies. (4,11) In a study by Renkonen et al, mutation carriers were screened with TVU and standard endometrial sampling of the endometrial tissue at an interval of 2-3 years. (1) In their study, eight of fourteen carcinomas and premalignant lesions were diagnosed by endometrial sampling alone. However, despite endometrial sampling during most of the screening visits in this study, three interval carcinomas occurred. The tumour stage and the survival curve were more optimal in the group of patients who underwent screening than in 83 mutation positive endometrial cancers patients who had not attended screening. (1) In 2009 Gerritzen et al. also found significantly more (pre)malignancies in women with standard endometrial sampling together with annual TVU, than in women with screening by TVU alone. (12) It was concluded that TVU alone is insufficient to detect early endometrial cancer in all cases, especially among premenopausal women, and that adding endometrial sampling improves the effectiveness of gynecological screening in women with LS. (1,12) Recently Manchandra et al found four (pre) malignant lesions with TVU and outpatient hysteroscopy with endometrial sampling

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in 41 women with LS. TVU alone detected two of four lesions. (13) In our hospital, the screening protocol was changed in women with LS or first-degree relatives at 50% risk of carrying the LS mutation and endometrial sampling was added as a standard screening tool to annual TVU from January 1st 2008. During endometrial sampling, some patients experience painful cramping but data about this symptom are lacking from other studies. Data about effectiveness of annual gynecological screening by TVU in women with LS or first degree relatives in our hospital between 1991-2002 have been published by Rijcken et al. (4) In the current study screening data were analyzed of all women with LS or first degree relatives, who were annually screened between January 2003 and June 2012.

The aim of the present study is to evaluate the additional value of endometrial sampling to annual TVU as a standard screening procedure in detecting (pre)malignant endometrial lesions in women with LS or first-degree relatives at 50% risk of carrying the LS mutation.

PATIENTS AND METHODS

Setting

Since 1991, a gynecological screening program for females with LS and first-degree relatives at 50% risk of carrying the LS mutation was introduced at the Family Cancer Clinic (FCC) of the University Medical Center Groningen at a recommended age to start of 30 years. (14) In all women with LS, a pathogenic mutation in either MLH1,

MSH2, MSH6 or PMS2 had been detected using methods published previously. (15-17)

All clinical data from LS carriers and first-degree relatives at 50% risk of carrying the LS mutation are prospectively registered in a database. The first-degree relatives at 50% risk of carrying the LS mutation were women who did not wanted to be screened because of implications for life insurance. In some other patients the genetic results were not available yet. All first degree relatives at 50% of carrying the LS mutation were regarded as a carrier until the genetic test showed no genetic mutation.

During Period I (2003-2007) annual gynecological screening was performed by TVU and serum CA125 measurement. Endometrial tissue sampling by endometrial sampling or hysteroscopy and endometrial biopsy was performed only in symptomatic women (irregular, postcoïtal or postmenopausal bleeding), or in women with increased endometrial thickness on TVU (double layer above 12 mm in premenopausal women, or above 4 mm in postmenopausal women). (18,19)

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2

From 2008, when the new Dutch guideline for LS was introduced which recommended annual endometrial sampling after TVU as the standard gynecological screening procedure in women with LS, annual endometrial sampling was added to the screening protocol. (14) During Period II (2008-2012), gynecological screening was performed according to this new guideline. If endometrial sampling was too painful or not possible, in case of symptoms or an increased endometrial thickness, a hysteroscopy and curettage under general anesthetics was offered. (14) Histopathological examinations were performed by one dedicated gynaeco-pathologist (HH).

Patients included in the here presented analysis

From January 2003 until June 2012, 98 women with LS or first-degree relatives at 50% risk of carrying the LS mutation were included (flowchart 1). Twenty three women were excluded from the study: 18 patients underwent a hysterectomy before January 2003 and in five patients no sufficient clinical information was available. A total number of 75 women fulfilled all inclusion criteria and were enrolled in the here presented analysis. All relevant data were entered into a separate password protected database. Protection of a patient’s identity was guaranteed by assigning study specific unique patient numbers. Only two dedicated data managers, who also have daily responsibility for the large database, know the patient numbers. Therefore, according to the Dutch law no further Institutional Review Board approval was needed for this study.

Data collection

For each woman, patient characteristics and clinical data including the age at the first surveillance, menopausal status, time since first screening, clinical symptoms, number of screening visits, extra visits because of symptoms, findings and number of TVU´s, findings and number of endometrial sampling, pathology reports, Ca 125 levels and clinical data on histopathological results were collected.

Data analysis

Data analysis was performed with SPSS statistics version 18. In period I and II, results of all screening visits were collected and analyzed if the endometrial lesions was found by TVU (enlarged endometrial thickness) and/or by endometrial sampling. The findings of the screening in period I (January 2003-December 2007: annual TVU and only endometrial sampling in case of enlarged endometrial thickness or symptoms) with screening visits in period II (January 2008-June 2012: standard annual TVU and endometrial sampling) were compared. We also analyzed if the lesions in period II would have been picked up if we had not introduced the standard endometrial

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sampling in period II. The occurrence of interval carcinomas during both study periods was analyzed.

RESULTS

From 2003 to 2012, 61 women were premenopausal and 14 were postmenopausal. The median age at the first gynecological screening was 38 years (range 26-61) and 41 years (range 23-67 years) in periods I and II, respectively. However three women (23-26-26 years of age) received information about the screening program starting from age 30, and asked to be screened during the first visit. At that visit standard gynecological screening was performed. Two 26 year old women returned for screening according to the protocol at age 30. The women of 23 years returned after one year and asked to TABLE 1 Patient characteristics before (I) and after (II) the introduction of standard endometrial sampling Patients in screenings period I * (n=44) Patients in screenings period II # (n=63) All patients (n=75) Menopausal status n (%) Premenopausal Postmenopausal 38 (86%) 6 (14%) 49 (78%)14 (22%) 61 (81%)14 (19%) Age at fi rst visit in years

median (range)

38 (26-61) 41 (23-67) 40 (23-67) Mutation status, n (%)

First-degree relatives at 50% risk of carrying the LS mutation Mutation carrier MSH1 MSH2 MSH6 PMS2 Epcam 19 (43%) 25 (57%) 9 9 6 1 21 (33%) 42 (67%) 13 10 10 6 3 28 (37%) 47 (63%) 15 11 12 6 3

* Period I (2003-2007): Screening included annual transvaginal ultrasonography and CA125 measurement (data not shown)

# Period II (2008-2012): Screening included annual transvaginal ultrasonography, endometrial sampling and CA125 measurement (data not shown)

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2

TABLE 2 Results of annual screening before (I) and after (II) the introduction of standard endometrial sampling

Period 1 (2003-2007)*

Period II (2008-2012) # Screening visits and period

Number of screening visits

Screening visits per patient median (range) Screening period in months median (range)

117 3 (1-6) 36 (1-60) 149 2 (1-3) 28 (2-51) Screening procedures TVU n (%) Endometrial samplings n (%) 117 (100%) 14$_(12%) 149 (100%) 117 (79%) Number of screening positives

Abnormal fi ndings with TVU

Abnormal fi ndings with endometrial sampling

14 (12%) 5 (4%)

22 (15%) 1 (0,6%) &

* Period I: Screening included annual TVU and serum CA125 measurement (data not shown) # Period II: Screening included annual TVU, endometrial sampling and serum CA125

measurement (data not shown)

$_{Only if indicated (symptoms or enlarged endometrial thickness on TVU)} &_{This abnormal fi nding was detected by endometrial sampling as well as by TVU}

be screened because her sister developed cancer at a very young age. Fifteen women were carrier of a MLH1 gene mutation, 14 MSH2 (of which 3 EPCAM), 12 MSH6, 6 PMS2, and 28 women were first-degree relatives at 50% risk of carrying the LS mutation (Table 1). The participants had a total of 266 screening visits in 300 patient years, and 13 extra visits because of symptoms of abnormal bleeding. In period I, 44 women underwent the annual screening program and 117 screening visits were recorded in which annual TVU was the standard screening tool. In period II, a total of 63 women underwent 149 screening procedures in which TVU was followed by standard endometrial sampling (Table 2).

Screening period I

In 14 of 117 (12%) women TVU showed an enlarged endometrial thickness and endometrial tissue was collected for histopathological examination (Table 3). In three symptomatic patients the endometrial thickness was normal during the screening visit, but due to the reported symptoms of irregular bleeding, endometrial sampling was performed. Nine endometrial samples showed no abnormalities, however in five patients histopathology showed hyperplasia (three simple hyperplasia and one

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TABLE 3 Histological fi ndings in patients with an abnormal TVU Endometrial sampling Period 1 (03-07) *

(n=14) Period 2 (08-12) # (n=22) Endometrial sampling

Normal

Simple hyperplasia

Complex hyperplasia and loss of MSH1

Complex hyperplasia and loss of MSH2

Endometrioid adenocarcinoma No micro curettage performed (possible pregnancy)

Hysteroscopy and endometrial sampling Simple Hyperplasia

Simple Hyperplasia and loss of MSH2 and MSH6 9 (65%) 1 (7%) 1 (7%) 0 1 (7%) 0 1 (7%) 1 (7%) 19 (85%) 1 (5%) 0 1 (5%) 0 1 (5%)

* Period I: Screening included annual TVU and serum CA125 measurement (data not shown): endometrial sampling was performed in case of abnormal endometrial fi ndings by TVU or abnormal vaginal bleeding.

# Period II: Screening included annual TVU, endometrial sampling and serum CA125 measurement (data not shown)

TABLE 4

Clinical details of women with a (pr

e)malignant endometrial lesion at scr

eening Patient age Mutation Year of diagnosis Symptoms TVU

Diagnostic endometrial sampling

Tr eatment Histology uterus 1 (37 y) MSH2 2004 none polyp

Simple hyperplasia and loss of

MSH2 and MSH6 TLH 1 No (pr e)malignancy 2 (48 y) MSH6 2006 Irr egular

and postcoital bleeding

9 mm

MSH2 and MSH6 expr ession TAH 2 Simple hyperplasia 3 (42 y) MSH6 2006 Irr egular bleeding 6 mm Endometrioid adenocar cinoma grade 2 TAH

Endometrioid type adenocar

cinoma

stage Ib grade II

4 (42 y)

Unknown genetic test will follow

2007 none 14 mm Simple hyperplasia Follow-up -5 (39 y) MLH1 2007 Irr egular bleeding 11mm

Complex atypical hyperplasia and loss of MSH1

TLH

Complex atypical hyperplasia

6 (48 y) MSH2 2009 Irr egular bleeding 6 mm

TLH No (pr e) malignancy 7 (49 y) MSH2 2011 none 9 mm Simple hyperplasia Follow-up -1 T otal lapar oscopic hyster

ectomy and bilateral salpingo-oophor

ectomy

2 T

otal abdominal hyster

ectomy

complex atypical hyperplasia) or endometrioid adenocarcinoma (stage IB grade 2) (Table 3). In three women endometrial tissue was collected by endometrial sampling and in two by hysteroscopy and curettage. All five patients were premenopausal. The mean age of developing endometrial (pre)malignancies in these five women was 42 years (37-48) in this analysis (Table 4).

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2

TABLE 4

Clinical details of women with a (pr

e)malignant endometrial lesion at scr

eening Patient age Mutation Year of diagnosis Symptoms TVU

Diagnostic endometrial sampling

Tr eatment Histology uterus 1 (37 y) MSH2 2004 none polyp

MSH2 and MSH6 TLH 1 No (pr e)malignancy 2 (48 y) MSH6 2006 Irr egular

and postcoital bleeding

9 mm

MSH2 and MSH6 expr ession TAH 2 Simple hyperplasia 3 (42 y) MSH6 2006 Irr egular bleeding 6 mm Endometrioid adenocar cinoma grade 2 TAH

Endometrioid type adenocar

cinoma

stage Ib grade II

4 (42 y)

Unknown genetic test will follow

2007 none 14 mm Simple hyperplasia Follow-up -5 (39 y) MLH1 2007 Irr egular bleeding 11mm

Complex atypical hyperplasia and loss of MSH1

TLH

6 (48 y) MSH2 2009 Irr egular bleeding 6 mm

TLH No (pr e) malignancy 7 (49 y) MSH2 2011 none 9 mm Simple hyperplasia Follow-up -1 T otal lapar oscopic hyster

ectomy

2 T

otal abdominal hyster

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Screening period II

Twenty-two of 149 (15%) TVU procedures revealed an enlarged endometrial thickness and endometrial sampling showed no abnormalities in 19. Two endometrial samples showed hyperplasia. In one 48 year old premenopausal woman complex atypical hyperplasia was found (Table 3). This woman had irregular bleeding with a normal endometrial thickness on TVU and endometrial sampling was performed because of her symptoms. The other premalignancy (simple hyperplasia) was found in a postmenopausal woman (49 years). She had no symptoms, the ultrasound showed an endometrial thickness of 9 mm. Besides, she was diagnosed with an undifferentiated thyroid carcinoma later (Table 4). During period I there were seven (16%) extra visits in 44 women. Only one of seven TVU procedures showed an enlarged endometrial thickness. Three endometrial samplings were performed because of abnormal bleeding, all related pathology reports were normal. In period II, six (10%) extra surveillance visits in 63 women were performed because of symptoms. All six women underwent a TVU of which two had an enlarged endometrial thickness. Also all women underwent endometrial sampling and no histological abnormalities were found (Table 5).

TABLE 5 Clinical details of women with interval visits

Period 1 (03-07) * Period 2 (08-12) # Interval visits due to symptoms (n)

TVU performed

Endometrial sampling performed 7 7 (100%) 3 (43%) 6 6 (100%) 6 (100%) Abnormal fi ndings with TVU

Abnormal fi ndings with endometrial sampling

1 (14%)

0 2 (33%) 0

* Screening included annual TVU and CA125 measurement

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Interval cancers

In this study of 300 women years no interval carcinomas or premalignant endometrial lesions were found between two screening visits in both periods. No patient died of endometrial cancer during this study period. Ten (13%) women underwent a preventive hysterectomy during the study period. Eight preventive operations were performed because of cancer worries and/or anxiety for invasive and painful endometrial sampling procedures annually. Two patients developed colorectal cancer (in situ) during the study period and in both women a preventive hysterectomy and bilateral salpingo-oophorectomy was performed in the same setting as the colorectal surgery. Histological examinations of the uterine and ovarian specimens revealed no (pre)malignancies. In this study 266 TVUs showed eight ovarian cysts in six patients, all with normal CA125 levels. 218 serum CA125 levels were determined, ranging from 3-64 kU/L with a median of 17. In study period I, (2003-2007) one woman had a CA125 level above 35 kU-L (38 kU-L). She was postmenopausal and TVU showed normal ovaries. Two women had an ovarian cyst (3,5 and 4,0 cm) with a normal CA125 level.

In study period II (2008-2012) six women had an elevated CA125 level. TVU of these women showed no ovarian abnormalities. Six ovarian cysts (range 4-7 cm) in five women were found. They all had a normal CA125 level. No further diagnostic procedures were performed. No ovarian cancers were detected during surveillance and no interval ovarian cancers or Lynch related cancers were diagnosed between 2003-2012.

DISCUSSION

In this study in 75 women, 300 patient years, there was no additional value of endometrial sampling in the early detection of endometrial cancer in women with Lynch syndrome or their first-degree relatives at 50% risk of carrying the LS mutation. There were 266 standard screening visits. In period I (2003-2007), in 117 screening visits, four premalignant endometrial lesions were detected and one endometrial carcinoma (FIGO stage IB). In period II (2008-2012), in 149 screening visits, two premalignancies were found and no cancers. All seven (pre)malignant cases were picked up by TVU. None of the lesions would have been missed if endometrial samples would not have been performed. No interval endometrial cancer was detected. There was no additional value in CA 125 measurements for detection of ovarian pathology in this study.

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Unlike others no additional value of standard endometrial sampling to annual TVU was found in this study in detecting (pre)malignant endometrial lesions. Renkonen et al. screened 175 Finnish mutation carriers (759 patient years) with TVU and endometrial sampling in 90% of the visits, every two-three years. (1) Endometrial cancer occurred in 14 cases. Eleven were diagnosed by screening, eight by endometrial samplings. TVU indicated only four endometrial cancers. Endometrial sampling detected 14 additional cases of premalignancies. In 2009 Gerritzen et al. found significantly more (pre)malignancies (three atypical hyperplasia’s and one endometrial carcinoma) in 64 visits with standard ultrasound and endometrial sampling than in 221 visits (one atypical hyperplasia and two endometrial carcinomas) with standard TVU only (and 28 endometrial samples taken because of abnormal ultrasound findings). (12) In 2012 Manchandra er al. found two endometrial carcinomas and two premalignant lesions in 69 annual visits with standard TVU and outpatient hysteroscopy with endometrial sampling. Standard screening with TVU alone would have missed one endometrial carcinoma and one premalignant lesion in this study. (13) One explanation for the lack of additional value of endometrial sampling in our study as compared to the Renkonen, Gerritzen and Manchandra studies is that in our study the interval was one year instead of two-three years in the Renkonen study. In the studies of Gerritzen and Manchandra, women also underwent annual screening. Another explanation might be that the women in our study were younger at the time of detection the (pre)malignancy. In our study the mean age of developing endometrial premalignancies was 44 years (range 37-49 years). The mean age of women with a premalignancy in the study of Renkonen et al. was 48 years (range 37-57 years). (1) Gerritzen et al. found a mean age of 49 years (range 45-56 years) in the women with premalignant endometrial lesions (12) and Manchandra et al found one patient with atypical hyperplasia at the age of 37 years. (13) Younger age is related to a lower expected prevalence of (pre)malignancies. Another explanation could be that endometrial sampling in younger women is not as sensitive as it is in postmenopausal women. However there is no data about the difference in the sensitivity of an endometrial sampling biopsy between pre- and postmenopausal women. In the here presented study no interval carcinomas during annual screening were found. Dove Edwin et al. (11) found two interval carcinomas in 269 women (in 826 patient years) and Rijcken et al. (4) found one interval endometrial carcinoma in 41 patients (197 patient years). In both studies only annual TVU was used for standard screening. In the study of Renkonen et al. three interval carcinomas occurred in 175 Finnish mutation carriers (759 patient years).

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The possible reason for this difference in interval carcinomas is again the fact that we screened annually while Renkonen et al had a screening interval of two-three years. (1) During the study period 10/75 (13%) women choose to have preventive surgery. Two patients underwent a preventive hysterectomy and a bilateral salpingo-oophorectomy when treated for colorectal cancer. Another reason for a women to opt for preventive surgery was to stop the painful annual endometrial sampling. Only one study reported on patient acceptability of endometrial sampling in LS screening and they concluded that transvaginal ultrasonography was associated with less discomfort than hysteroscopy or endometrial sampling and would be the single test of choice for the majority. There was no significant difference between the pain scores for hysteroscopy and endometrial sampling. (20) In our study some women reported pain during endometrial sampling as a reason to opt for prophylactic surgery. Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be offered to women diagnosed with colon cancer during the same surgery. (21-23)

In conclusion, annual endometrial screening seems effective in the detection of premalignancies and early endometrial cancer in women with LS in this study. Adding standard endometrial sampling to annual TVU has no additional value in the early detection of (pre)malignant endometrial lesions in these women with LS. Patient acceptability of screening modalities should form an integral part of studies assessing the effectiveness of endometrial screening in the Lynch syndrome population.

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Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome. Int J Cancer. 2006;120(4):821-24.

2. Koornstra JJ, Mourits MJE, Sijmons RH, Leliveld AM, Hollema HH, Kleibeuker JH. Management of extra-colonic tumours in patients with Lynch syndrome. Lancet Oncol. 2009;10(4):400-8.

3. STOET, VKGN, WKO: Erfelijke tumoren, richtlijnen voor diagnostiek en preventie 2010. 4. Rijcken FE, Mourits MJE, Kleibeuker JH, Hollema H, Van der Zee AGJ. Gynecologic

screening in heriditary nonpolyposis colorectal cancer. Gynecol Oncol. 2003;91(1):74-80. 5. Lu KH, Schorge JO, Rodabaugh KJ, Daniels MS, Sun CC, Soliman PT, et al. Prospective

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6. Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, et al. Risks of Lynch Syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102(3):193-201. 7. Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, et al. The clinical

phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135(2):419-28.

8. Grindedal E.M, Blanco I, Stormorken A, Maehle L, Clark N, Gonzalez S, et al. High risk of endometrial cancer in colorectal cancer kindred is pathognomonic for MMR-mutation carriers. Fam Cancer. 2009;8(2):145-51.

9. Lindor NM, Petersen GM, Hadley DW, Kinney AY, Miesfeldt S, Lu KH, et al.

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10. Obermair A, Youlden DR. Young JP, Lindor NM, Baron JA, Newcomb P, et al. Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma. Int J Cancer. 2010;127(11):2678-84.

11. Dove-Edwin I, Boks D, Goff S, Kenter GG, Carpenter R, Vasen HF, Thomas HJ. outcome of the endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer. 2002;94(6):1708-12.

12. Gerritzen LHM, Hoogerbrugge N, Oei ALM, Nagengast FM, Van Ham van MAPC, Massuger LFAG, De Hullu JA. Improvement of endometrial biopsy over transvaginal ultrasound alone for endometrial surveillance in women with Lynch syndrome. Fam Cancer. 2009;8(4):391-7.

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13. Manchandra R, Saridogan E, Abdelraheim A, Johnson M, Rosenthal A.N, Benjamin E, et al. Annual outpatient hysteroscopy and endometrial sampling (OHES) in HNPCC/Lynch syndrome (LS). Arch Gynecol Obstet. 2012;286(6):1555-62.

14. Richtlijn erfelijke darmkanker 2008 ISBN/EAN: 978-90-813077-1-0.

15. Niessen RC, Hofstra RM, Westers H, Ligtenberg MJ, Kooi K, Jager PO, et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer. 2009;48(8):737-44.

16. Niessen RC, Kleibeuker JH, Westers H, Jager PO, Rozeveld D, Bos KK, et al. PMS2 involvement in patients suspected of Lynch syndrome. Genes Chromosomes Cancer. 2009;48(4):322-9.

17. Niessen RC, Berends MJ, Wu Y, Sijmons RH, Hollema H, Ligtenberg MJ, et al. Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer. Gut. 2006;55(12):1781-8.

18. Blumenfeld ML Turner LP. Role of transvaginal sonography in the evaluation of endometrial hyperplasia and cancer. Clin Obstet Gynecol 1996;39:641-55.

19. Smith-Bindman R, Kerlikowske K, Feldstein VA, Subak L, Scheidler J, Segal M, Brand R, Grady D.Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA. 1998 4;280(17):1510-7.

20. Elmasry K, Davies AJ, Evans DG, Seif MN, Reynolds K. Strategies for endometrial screening in the Lynch syndrome population: a patient acceptability study. Fam Cancer. 2009;8(4):431-9.

21. Pistorius S, Kruger S, Hohl R, Plaschke J, Distler W, Saeger HD, Schackert HK. Occult endometrial cancer and decision making prophylactic hysterectomy in hereditary nonpolyposis colorectal cancer patients. Gynecol Oncol. 2006;102(2):189-94.

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23. Lu KH. Hereditary gynecologic cancers: differential diagnosis, surveillance, management and surgical prophylaxis. Fam Cancer. 2008;7(1):53-8.

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