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

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University of Groningen

Gynaecological malignancies in Lynch syndrome

Woolderink, Jorien Maria

DOI:

10.33612/diss.84185340

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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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Jorien Woolderink

Gynaecological

malignancies

in

Lynch

Syndrome

surveillance

and cancer

characteristics

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ISBN: 978-94-034-1649-6

Cover design & lay-out: Esther Beekman (www.estherontwerpt.nl) Printed by: Ipskamp Printing, Enschede

All rights reserved. No part of this dissertation may be reprinted, reproduced, or utilized in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording or any information storage or retrieval system, without prior written permission of the author.

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Gynaecological

malignancies in

Lynch Syndrome

surveillance and cancer

characteristics

Proefschrift

ter verkrijging van de graad van doctor aan de

Rijksuniversiteit Groningen

op gezag van de

rector Magnificus Prof. dr. E. Sterken

en volgens besluit van het college van Promoties

De openbare verdediging zal plaatsvinden op

27 november 2019 om 14.30 uur

door

Jorien Maria Woolderink

geboren op 11 maart 1975

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Promotores

Prof. dr. M.J.E. Mourits, UMC Groningen Prof. dr G.H. de Bock, UMC Groningen Prof. dr. H Hollema, UMC Groningen Beoordelingscommissie

Prof. dr. C.J. van Asperen, LUMC Leiden

Prof. dr. M.Y. Bongers, Maxima MC Veldhoven, Maastricht UMC Prof. dr. H.W. Nijman, UMC Groningen

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Paranimfen

Anne Uyttenboogaart Justine Briët

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9

23

39

55

69

93

113

140

144

150

152

Chapter 1

General introduction

Chapter 2

The additional value of endometrial sampling in the early detection of endometrial cancer in women with Lynch syndrome.

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

Chapter 3

Pain evaluation during gynaecological surveillance in women with Lynch syndrome.

Fam Cancer. 2017;16(2):205-210

Chapter 4

Feasibility of endometrial sampling by vaginal tampons in women with Lynch syndrome.

Submitted for publication

Chapter 5

Ovarian cancer in Lynch syndrome; a systematic review.

Eur J Cancer. 2016;55:65-73

Chapter 6

Characteristics of Lynch syndrome associated ovarian cancer. Gynecol Oncol. 2018;150(2):324-330

Chapter 7

General discussion and future perspectives

Chapter 8

Nederlandse samenvatting Dankwoord

Curriculum Vitae List of Publications

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General introduction

1

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

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Chapter 1 | General introduction

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LYNCH SYNDROME

Lynch syndrome (LS), previously called hereditary non-polyposis colorectal cancer syndrome, is an autosomal dominant genetic predisposition for cancer, caused by mutations in the mismatch repair (MMR) genes. (1) These MMR genes in LS are MLH1 (on chromosome 3), MSH2 (on chromosome 2), MSH6 (on chromosome 2), PMS2 (on chromosome 7) and the EPCAM gene, which inactivates the MSH2 gene. (2,3) When mutations in the MMR genes will develop, disruption of the open frame of the genes involved and an accumulation of small repetitive abnormalities of the DNA (micro satellites) occur. This is called microsatellite instability (MSI-high). Cells with this DNA-repair deficient MSI-high phenotype are prone to neoplastic changes and development of cancer. (3,4) LS is associated with early onset of colorectal cancer and several extra colonic malignancies of which endometrial cancer in female LS carriers is the most frequent. (4,5) Other, less common extra colonic malignancies in LS are ovarian, stomach, small intestine, pancreas, kidney, ureter, brain, kerato-acanthoma and biliary tract cancer. (4-6) In patients with LS, mutations in MLH1 and MSH2 genes contribute to 80-90% of all gene mutations, MSH6 contributes to 5-10% and PMS2 and the EPCAM mutation causing the remaining 5%. (2,7-10)

In this introduction the criteria for referral to a clinical geneticist because of a high probability of LS will be described. Patients can be referred to the clinical geneticist when they have a LS associated tumour at a young age or a positive family history for LS associated tumours. All criteria are formulated in the Dutch guideline hereditary colon cancer (11) and are shown in Table 1. LS is highly associated with the occurrence of colon cancer and gynaecological cancers as endometrial and, to a lesser extent, ovarian cancer. The characteristics of these gynaecological cancers in women with LS and the differences with sporadic endometrial and ovarian cancer are further described in this introduction. A woman with LS or a first degree relative with 50% risk of LS, will be advised for annual gynaecological surveillance. The (dis)advantages of gynaecological surveillance in women with LS are discussed in this introduction and are subject of study in part I of this thesis.

Criteria to refer to the clinical geneticist because of high probability of LS

If a patient develops a LS associated tumour or has a family history meeting one of the LS criteria, (see Table 1), there is a suspicion of LS and these patients are eligible for genetic counselling, genetic testing and/or surveillance. (6,11)

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11

1

For patients without a malignancy, with a positive family history for LS associated tumours, or a known mutation in the family of one of the LS mismatch repair genes, counselling by a clinical geneticist and a DNA test is recommended.

Since the updated guideline in 2015, in patients diagnosed with a LS associated tumour (endometrial cancer < 70 years, colorectal cancer < 50 years), immunohistochemical (IHC) staining for four MMR proteins (MLH1, MSH2, MSH6 and PMS2) is performed. (11) IHC shows the absence of MMR protein expression in women with LS. (12) If loss of

MLH1 protein is found, a MLH1 hypermethylation test is added. Hypermethylation of MLH1 results in an inactivated MLH1 protein, which is not associated with LS. When IHC

of the tumour shows loss of MSH2, MSH6, PMS2 or MSH1 (without hypermethylation of MLH1) there is a strong suspicion of LS and a DNA test is recommended to test for a germ line mutation. When IHC is inconclusive, a microsatellite instability (MSI) test can be accomplished. MSI testing demonstrates the end-result of a deficiency in the mismatch repair genes with evaluation of the accumulation of mismatches, insertions and deletions in highly repetitive DNA segments. If the tumour displays micro satellite instability, there is also a strong suspicion of LS and a DNA test is recommended to test for a germ line mutation. Also in young patients diagnosed with a LS associated tumour (endometrial or colon cancer < 40 years of age) a DNA test is recommended regardless of the IHC/MSI results or the family history. (6,11)

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Endometrial cancer

Endometrial cancer is one of the most common cancers in women in the Western world. In the Netherlands, endometrial cancer is diagnosed in about 1900 women yearly and around 400 women die of this disease each year. (13) Postmenopausal bleeding is an early symptom of the disease and 75% of the patients are diagnosed with early stage endometrial cancer. Risk factors are obesity, older age, late start of the menopause, nulliparity, unopposed exogenous estrogen suppletion, use of tamoxifen or a genetic predisposition. (14) The mean age at diagnosis in the general population is 60-65 years. (13)

TABLE 1 Criteria for referral to the clinical geneticist because of suspicion of Lynch syndrome (11) 1: Patients without a malignancy and a positive

family history for malignancies 2: Patients with colorectal- or endometrial cancer with abnormal immunohistochemical (IHC) fi ndings or microsatelite instability (MSI) in the tumour

• A fi rst-degree relative with colon cancer < 50 years of age.

• Or three or more fi rst or second-degree relatives with a Lynch syndrome associated tumour < 70 years of age.

• Or a mutation in one of the LS mismatch repair genes in the family.

• < 40 years of age, regardless the IHC/MSI results.

• Or < 70 years of age with abnormal IHC/MSI results (except hypermethylation of the MLH1- promotor-gene).

3: Patients with endometrial cancer 4: Patients with colorectal- or endometrial cancer without results of IHC/MSI in the tumour • Endometrial cancer < 40 years of age, (regardless

the results of IHC/MSI

• Or endometrial cancer < 70 years of age, with occurrence of MSI/IHC (except hypermethylation of the MLH1-promotor gene).

• Or endometrial cancer and colorectal cancer, or a LS associated malignancy* in the same patient, < 70 years of age.

• Or endometrial cancer < 70 years of age and a fi rst degree relative with endometrial cancer, (or a LS associated malignancy*): both under < 70 years of age and one < 50 years of age. • Or endometrial cancer < 70 years of age and

two or more fi rst- or second degree) relatives with endometrial cancer or a LS associated malignancy*,all < 70 years of age.

• < 50 years of age.

• Or < 70 years of age and a second primary colorectal or Lynch syndrome associated malignancy* < 70 years of age, (at the same patient).

• Or < 70 years of age and a fi rst degree relative with colorectal cancer < age 70, and one of them under age 50.

• Or < 70 years of age and two or more (fi rst or second degree) relatives with colorectal cancer or a LS associated malignancy*, all under age 70. • Or < 70 years of age and many polyps or

unusual polyps:

* Or cancer of the endometrial tissue, stomach, small intestine, pancreas, biliary tract, ureter, urethra, ovary, brain or sebaceous gland adenoma (carcinoma) or kerato acanthoma. (11)

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1

TABLE 1 Criteria for referral to the clinical geneticist because of suspicion of Lynch syndrome (11) 1: Patients without a malignancy and a positive

family history for malignancies 2: Patients with colorectal- or endometrial cancer with abnormal immunohistochemical (IHC) fi ndings or microsatelite instability (MSI) in the tumour

• A fi rst-degree relative with colon cancer < 50 years of age.

• Or three or more fi rst or second-degree relatives with a Lynch syndrome associated tumour < 70 years of age.

• Or a mutation in one of the LS mismatch repair genes in the family.

• < 40 years of age, regardless the IHC/MSI results.

• Or < 70 years of age with abnormal IHC/MSI results (except hypermethylation of the MLH1- promotor-gene).

3: Patients with endometrial cancer 4: Patients with colorectal- or endometrial cancer without results of IHC/MSI in the tumour • Endometrial cancer < 40 years of age, (regardless

the results of IHC/MSI

• Or endometrial cancer < 70 years of age, with occurrence of MSI/IHC (except hypermethylation of the MLH1-promotor gene).

• Or endometrial cancer and colorectal cancer, or a LS associated malignancy* in the same patient, < 70 years of age.

• Or endometrial cancer < 70 years of age and a fi rst degree relative with endometrial cancer, (or a LS associated malignancy*): both under < 70 years of age and one < 50 years of age. • Or endometrial cancer < 70 years of age and

two or more fi rst- or second degree) relatives with endometrial cancer or a LS associated malignancy*,all < 70 years of age.

• < 50 years of age.

• Or < 70 years of age and a second primary colorectal or Lynch syndrome associated malignancy* < 70 years of age, (at the same patient).

• Or < 70 years of age and a fi rst degree relative with colorectal cancer < age 70, and one of them under age 50.

• Or < 70 years of age and two or more (fi rst or second degree) relatives with colorectal cancer or a LS associated malignancy*, all under age 70. • Or < 70 years of age and many polyps or

unusual polyps:

* Or cancer of the endometrial tissue, stomach, small intestine, pancreas, biliary tract, ureter, urethra, ovary, brain or sebaceous gland adenoma (carcinoma) or kerato acanthoma. (11)

In endometrial cancer several histological types are distinguished. The most frequent type is endometrioid adenocarcinoma, and less common types are mucinous adenocarcinoma, serous adenocarcinoma, clear cell adenocarcinoma, undifferentiated carcinoma and mixed type carcinoma (composed of more than one type, with at least 10% of each component). (15) These carcinomas are grouped in two different subtypes. Type 1 carcinoma; representing 80% of all endometrial carcinomas, occurs around age 60, present at an early stage with symptoms of abnormal uterine bleeding. These carcinomas are linked to unopposed estrogen stimulation, which may result in the development of simple hyperplasia of the endometrial tissue. This may progress to atypical hyperplasia, finally resulting in well-differentiated endometrioid adenocarcinoma. This type of endometrial carcinoma is characterized by good survival rates. Type 2 carcinomas often occur around age 70, representing the other 20% of the endometrial carcinomas. These tumours show non-endometrioid histology like high grade serous and clear cell carcinomas. They are not linked to estrogen stimulation, have a higher risk of lymph vascular invasion and lymphatic and metastatic spread, and behave more clinically aggressive with a decreased survival rate when compared to Type 1. (16-19)

Endometrial cancer and LS

The lifetime risk of developing endometrial cancer in LS is 15-55% depending on the type of gene mutation compared with 3% in the general population. (4,9,20-23) The mean age of women who develop endometrial cancer in LS is 50-55 years. (5,20,22,23) This is ten years earlier than in the general population. The most frequently reported symptom is irregular or postmenopausal bleeding and/or increased bleeding during menstrual periods. This can be confusing and misdiagnosed at this age, as many healthy women have this perimenopausal bleeding pattern around age 50. In 75% of the women with LS, endometrial cancer is diagnosed at an early stage, which is the same as in the general population. The five years overall survival of endometrial cancer in women with LS is around 85%, which is also comparable with the survival of endometrial cancer in the general population. (15,24-27)

Ovarian Cancer

Ovarian cancer is a less common and more lethal malignancy, with 1300 new cases in the Netherlands each year and around 1000 of these women will die of ovarian cancer. (13) Ovarian cancer is a disease with none, a-specific or late symptoms. Therefore ovarian cancer is most often diagnosed in an advantaged stage with a poor survival. Risk factors are nulliparity, no use of oral contraceptives, or a genetic predisposition

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of which BRCA1/2 or LS mutations are most prevalent. The mean age at diagnosis of ovarian cancer in the general population is 60-65 years. (13) The most frequent histological type of ovarian cancer in the general population is the high grade serous type. (28,29) The fallopian tube is being suggested as the primary site of origin of pelvic high grade serous ovarian cancer and non invasive serous tubal intraepithelial carcinoma’s (STICs) have been identified in prophylactically removed Fallopian tubes in BRCA carriers. (30-32) Most sporadic ovarian cancers and cancers in BRCA 1/2 mutation carriers are diagnosed as FIGO stage III-IV with a five year overall survival rate of 20-40% although a progression free survival above 50% was reported in BRCA

1-2 carriers who used Olaparib additional to standard surgical treatment and platinum

based chemotherapy after four years. (13,29,33) Ovarian cancer and LS

About 10-15% of all ovarian cancers develop in women with a BRCA1/2 or LS mutation. The majority of inherited ovarian cancers are caused by a BRCA1/2 gene mutation and ovarian cancer in LS is not a very common trait. (34-35) The lifetime risk of developing ovarian cancer in LS is 6-12% depending on the type of gene mutation. (36-42) However, in most studies on ovarian cancer, only a small number of women with LS have been included. Therefore the information about the incidence and clinical aspects of ovarian cancer in women with LS is scattered and incomplete. (21-22,36,43) The mean age of a few studies reporting on women with LS who developed ovarian cancer, was at a young age and most patients were diagnosed at an early stage (FIGO stage I/II). (44-46) Due to few studies and limited data on ovarian cancer in LS, the contribution of annual gynaecological surveillance to this early stage disease cannot be established yet.

Gynaecological surveillance and LS

Annual gynaecological surveillance in women with LS consisting of a transvaginal ultrasound and endometrial sampling in case of increased endometrial thickness to detect endometrial abnormalities in an early malignant stage is effective. (5,47-48) However the additional value of standard endometrial sampling to annual transvaginal ultrasound (irrespective of endometrial thickness), in detecting more (pre)malignant endometrial lesions in women with LS is unknown.

The value of annual gynecological surveillance for early detection of ovarian cancer in LS has never been studied systematically, due to small numbers and is still under debate. (5,48-49) In general, ovarian cancer surveillance has not been proven effective, in reducing ovarian cancer mortality in the general population (29) and not even among

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women with a BRCA 1/2 mutation. (29,50-53) Even during surveillance, most ovarian cancers are found in an advanced stage and interval ovarian cancers develop between two surveillance visits. (50,52-56) As most ovarian cancers in women with LS tend to be detected at an early stage, some ascribe it to annual surveillance in LS. (57) However, there are only a few studies and no solid data to confirm this. Others assume that the good prognosis can be attributed to another biology, as the tumour type of ovarian cancer in LS (more often endometrioid or clear cell) is different from ovarian cancer in sporadic cases and BRCA1/2 mutation carriers (mostly high grade serous).

The current guideline for LS in the Netherlands advises annual endometrial surveillance by transvaginal ultrasound, measurement of the endometrial thickness and performance of a standard endometrial sampling in women from 40-60 years. (11) The choice for endometrial surveillance at this peri-menopausal age (when irregular bleeding is common and often misinterpreted) is not to miss early endometrial cancer. A surveillance advice for ovarian cancer in women with LS could not be given, due to a lack of firm data on surveillance and a certain age-range of appearance. It is advised to evaluate the ovaries while performing the transvaginal ultrasound to check the endometrial thickness for endometrial surveillance, although there is lack of evidence for annual ovarian surveillance alone in women after hysterectomy. (11)

Aim of the thesis:

The aim of this thesis is to study aspects of gynaecological surveillance in women with LS in order to improve counselling and find evidence for continuation or cessation of the various aspects of annual gynaecological surveillance in female LS carriers. In part I we evaluated the additional value of endometrial sampling to transvaginal ultrasound. We also studied the pain scores during this procedure and whether endometrial sampling can be replaced by a less invasive and less painful procedure (vaginal tampons). In part II of the thesis, the clinical and histopathological characteristics of ovarian cancer in women with LS were evaluated and the possible role of surveillance in early detection of these cancers was studied.

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OUTLINE OF THE THESIS

Part I: endometrial cancer and LS

In chapter two of this thesis, the additional value of standard endometrial sampling in detecting (pre)malignancies of the endometrial tissue in women with LS or first degree relatives (FDR) was evaluated. In this study, two different surveillance programs were compared. We investigated the results of annual screening in a group of women with LS or FDR who underwent annual transvaginal ultrasound and endometrial sampling in case of symptoms or a thickened endometrial response only (period I), versus women with LS or FDR who underwent transvaginal ultrasound and standard endometrial sampling at every surveillance visit, irrespective of endometrial thickness (period II). The rate of (pre)malignancies of the endometrial tissue detected in both groups was evaluated.

Endometrial sampling during annual surveillance in women with LS is an outpatient procedure, which only takes a few minutes. However, the disadvantage is that it is an invasive procedure during which many women report substantial pain and the annual repetition induces fear for this examination, although the magnitude has never been studied. Chapter three describes the perceived pain on a visual analogue scale (VAS) during repetitive annual endometrial sampling. We also studied pain scores in symptomatic women who underwent a single endometrial sampling procedure. We evaluated if asymptomatic women who underwent annual endometrial sampling reported more pain than the symptomatic group who underwent single endometrial sampling, and if the VAS score aggravated during subsequent annual procedures in women with LS. If women with LS decided for preventive surgery or to quit annual gynaecological surveillance, the reason was examined.

As endometrial sampling at annual surveillance is perceived as a painful procedure by a substantial proportion of the women with LS (median VAS score 5.0) we investigated whether a less invasive procedure would be feasible to collect endometrial cells, which is reported in chapter four. It describes a pilot study in which 25 asymptomatic women with LS or FDR were asked to insert a tampon vaginally 2-4 hours before the annual surveillance visit. At the outpatient clinic, before starting the physical examination, the tampon was removed by the patient, handed to the gynaecologist, swopped in fixation fluid and send to the pathology lab for analysis. Subsequently, the standard annual gynaecological surveillance was performed, including endometrial sampling. The aim of the study was to analyse if endometrial cells can be obtained by using

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vaginal tampons and if so, if the cells are of enough good quality to analyse. The level of pain of both procedures was evaluated with VAS scores.

Part II: ovarian cancer and LS

In chapter five of this thesis a literature review is presented about the clinical and pathological characteristics of ovarian cancer in women with LS and we evaluated the role of surveillance in the detection of ovarian cancer in LS.

In the Netherlands, a Dutch Cancer Registry (STOET) has been collecting clinical data of LS mutation carriers since 1987. Clinical data on all LS associated ovarian cancers from this registry and all LS associated ovarian cancers from the University Medical Center Groningen who were not in the STOET database, were studied in chapter six. For these women the following data was collected: data on gynaecological surveillance, age at diagnosis, mutation type, histological type, FIGO stage, treatment and follow-up data. The aim of this study was to describe clinical characteristics of LS associated ovarian cancer and the efficacy of surveillance in the early detection of these ovarian cancers.

In chapter seven, the results of the different studies are discussed and some future perspectives are given. A Dutch summary of all results is given in chapter eight.

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18. Olawaiye AB, Boruta DM. Management of women with clear cell endometrial cancer. a Society of Gynecologic Oncology (SGO) review. Gynecol Oncol. 2009 ;113(2).277-83. 19. Murali R, Soslow RA, Weigelt B. Classification of endometrial carcinoma. more than two

types. Lancet Oncol. 2014 Jun;15(7).e268-78.

20. Dowty JG, et al. Cancer risks for MLH1 and MSH2 mutation carriers. Humn mutation. 2013; 34(3).490-7.

21. Barrow E, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome. a report of 121 families with proven mutations. Clinical genetics, 2009. 75(2).141-9.

22. Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. the journal of The American Medical Association. 2011;305(22).2304-10.

23. 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;102.193-201. 24. Vasen H.F, Watson P, Mecklin J.P, Jass J.R. Green J.S, Nomizu T, et al. The epidemiology of

endometrial cancer in hereditary nonpolyposis colorectal cancer. Anticancer Res. 1994;14.1675-8.

25. Broaddus R.R, Lynch H.T, Chen L.M, Daniels MS, Conrad P, Munsell MF et al. Pathologic features of endometrial carcinoma associated with HNPCC. Cancer. 2006;106.87-94. 26. Boks D.E, Trujillo A.P, Voogd A.C, Morreau H, Kenter GG, Vasen HF. Survival analysis of

endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. Int J Cancer. 2002;102.198-200.

27. Møller P, Seppälä T, Bernstein I, Holinski-Feder E, Sala P, Gareth Evans D, et al. in collaboration with The Mallorca Group (http.//mallorca-group.eu). Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance. first report from the prospective Lynch syndrome database. Gut. 2015 Dec 9. pii. gutjnl-2015-309675.

28. De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, et al. EUROCARE-5 Working Group. Cancer survival in Europe 1999-2007 by country and age. results of EUROCARE--5-a population-based study. Lancet Oncol. 2014 Jan;15(1).23-34.

29. Jacobs I, Menon U, Ryan A, Gentry-Maharaj A, Burnell M, Kalsi JK, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). a randomised controlled trial. Lancet 2016;387. 945–956.

30. Leeper K, Garcia R, Swisher E, Goff B, Greer B, Paley P. Pathologic findings in prophylactic oophorectomy specimens in high-risk women. Gynaecol Oncol. 2002;87(1).52-6.

31. Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE, et al. Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol. 2007;1(25).3985-90.

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32. Reitsma W, de Bock GH, Oosterwijk JC, Bart J, Hollema H, Mourits MJ. Support of the ‘fallopian tube hypothesis’ in a prospective series of risk-reducing salpingo-oophorectomy specimens. Eur J Cancer. 2013; 49(1).132-41.

33. Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M. et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2018 27;379(26).2495-2505.

34. Pal T, Permuth-Wey J, Betts JA, Krischer JP, Fiorica J, Arango H, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 2005;104.2807-2816.

35. Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108(44).18032-7.

36. Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999;81.214-8.

37. Boilesen AE, Bisgaard ML, Bernstein I. Risk of gynecologic cancers in Danish hereditary nonpolyposis colorectal cancer families. Acta Obstet Gynecol Scand. 2008;87.1129-35.

38. Vasen HF, Wijnen JT, Menko FH, Kleibeuker JH, Taal BG, Griffioen G et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. 1996;110.1020-7.

39. Vasen HF, Stormorken A, Menko FH, Kleibeuker JH, Taal BG, Griffioen G et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers. a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol. 2001;19.4074-80.

40. Quehenberger F, Vasen HF, Van Houwelingen HC. Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene. correction for ascertainment. J Med Genet. 2005;42.491-6.

41. Watson P, Vasen HF, Mecklin JP, Bernstein I, Aarnio M, Järvinen HJ et al. The risk of extracolonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer. 2008;123.444-9. 42. Brown GJ, St John DJ, Macrae FA, Aittomäki K. Cancer risk in young women at risk of hereditary nonpolyposis colorectal cancer. implications for gynecologic surveillance. Gynecol Oncol. 2001;80.346-9.

43. Engel C, Loeffler M, Steinke V, Rahner N, Holinski-Feder E, Dietmaier W et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol.

2012;30.4409-15.

44. Watson P, Bützow R, Lynch HT, Mecklin JP, Järvinen HJ, Vasen HF et al.; International Collaborative Group on HNPCC. The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecol Oncol. 2001;82.223-8.

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45. 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;8.145-51.

46. Ketabi Z, Bartuma K, Bernstein I, Malander S, Grönberg H, Björck E et al. Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors. Gynecol Oncol. 2011;121.462-5.

47. 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. 48. Gerritzen LHM, Hoogerbrugge N, Oei AL, Nagengast FM, Van Ham MA, Massuger LF,

de Hullu JA. Improvement of endometrial biopsy over transvaginal ultrasound alone for endometrial surveillance in women with Lynch syndrome. Fam Cancer. 2009;8.391-7. 49. Auranen A, Joutsiniemi T. A systematic review of gynecological cancer surveillance in women

belonging to hereditary nonpolyposis colorectal cancer (Lynch syndrome) families. Acta Obstet Gynecol Scand. 2011; 90(5).437-44.

50. Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C et al. Effect of screening on ovarian cancer mortality. the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011;305.2295-303.

51. Pinsky PF, Zhu C, Skates SJ, Black A, Partridge E, Buys SS, Berg CD. Potential effect of the risk of ovarian cancer algorithm (ROCA) on the mortality outcome of the Prostate, Lung, Colorectal and Ovarian (PLCO) trial. Int J Cancer. 2013;132(9).2127-33.

52. Hermsen BB, Olivier RI, Verheijen RH, van Beurden M, de Hullu JA, Massuger LF et al. No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study. Br J Cancer. 2007;96.1335-42.

53. Velde van der NM, Mourits MJ, Arts HJ, de Vries J, Leegte BK, Dijkhuis G et al. Time to stop ovarian cancer screening in BRCA1/2 mutation carriers? Int J Cancer. 2009;124.919-23. 54. J acobs IJ, Skates SJ, MacDonald N, Menon U, Rosenthal AN, Davies AP et al. Screening for

ovarian cancer. a pilot randomised controlled trial. Lancet 1999;353.1207-10.

55. Menon U, Gentry-Maharaj A, Hallett R, Ryan A , Burnell M, Sharma A et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers. results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol. 2009 Apr;10.327-40.

56. Rosenthal AN, Fraser L, Manchanda R, Badman P, Philpott S, Mozersky J et al. Results of annual screening in phase I of the United Kingdom familial ovarian cancer screening study highlight the need for strict adherence to screening schedule. J Clin Oncol. 2013;31.49-57. 57. Järvinen HJ, Renkonen-Sinisalo L, Aktán-Collán K, Peltomäki P, Aaltonen LA, Mecklin JP. Ten

years after mutation testing for Lynch syndrome. cancer incidence and outcome in mutation- positive and mutation-negative family members. J Clin Oncol. 2009 Oct 1;27(28).4793-7.

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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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Chapter 2 | The additional value of endometrial sampling in the early detection of endometrial cancer in women with Lynch syndrome

24

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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Chapter 2 | The additional value of endometrial sampling in the early detection of endometrial cancer in women with Lynch syndrome

26

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)