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Management of ovarian and endometrial cancers in women belonging to HNPCC carrier families: review of the literature and results of cancer risk assessment in Polish HNPCC families

  • Tadeusz Dębniak1Email author,
  • Tomasz Gromowski1,
  • Rodney J Scott2,
  • Jacek Gronwald1,
  • Tomasz Huzarski1,
  • Tomasz Byrski1,
  • Grzegorz Kurzawski1,
  • Dagmara Dymerska1,
  • Bohdan Górski1,
  • Katarzyna Paszkowska-Szczur1,
  • Cezary Cybulski1,
  • Pablo Serrano-Fernandez1 and
  • Jan Lubiński1
Hereditary Cancer in Clinical Practice201513:3

https://doi.org/10.1186/s13053-015-0025-2

Received: 1 October 2014

Accepted: 5 January 2015

Published: 16 January 2015

Abstract

Background

Over half the cancer deaths in HNPCC families are due to extra-colonic malignancies that include endometrial and ovarian cancers. The benefits of surveillance for gynecological cancers are not yet proven and there is no consensus on the optimal surveillance recommendations for women with MMR mutations.

Methods

We performed a systematic review of the literature and evaluated gynecological cancer risk in a series of 631 Polish HNPCC families classified into either Lynch Syndrome (LS, MMR mutations detected) or HNPCC (fulfillment of the Amsterdam or modified Amsterdam criteria).

Results

Published data clearly indicates no benefit for ovarian cancer screening in contrast to risk reducing surgery.

We confirmed a significantly increased risk of OC in Polish LS families (OR = 4,6, p < 0.001) and an especially high risk of OC was found for women under 50 years of age: OR = 32,6, p < 0.0001 (95% CI 12,96-81,87). The cumulative OC risk to 50 year of life was calculated to be 10%. Six out of 19 (32%) early-onset patients from LS families died from OC within 2 years of diagnosis. We confirmed a significantly increased risk of EC (OR = 26, 95% CI 11,36-58,8; p < 0,001). The cumulative risk for EC in Polish LS families was calculated to be 67%.

Conclusions

Due to the increased risk of OC and absence of any benefit from gynecological screening reported in the literature it is recommended that prophylactic oophorectomy for female carriers of MMR mutations after 35 year of age should be considered as a risk reducing option. Annual transvaginal ultrasound supported by CA125 or HE4 marker testing should be performed after prophylactic surgery in these women.

Due to the high risk of EC it is reasonable to offer, after the age of 35 years, annual clinical gynecologic examinations with transvaginal ultrasound supported by routine aspiration sampling of the endometrium for women from either LS or HNPCC families. An alternative option, which could be taken into consideration for women preferring surgical prevention, is risk reducing total hysterectomy (with bilateral salpingo-oophorectomy) for carriers after childbearing is complete.

Keywords

HNPCC Lynch syndrome Ovarian cancer Endometrial cancer Adnexectomy

Background

Lynch syndrome, also referred to as hereditary non-polyposis colorectal cancer (HNPCC), accounts for somewhere between 2 and 5% of all CRC [1],[2]. It has been shown that Lynch Syndrome (LS) is a result of germline mutations in genes involved in DNA mismatch repair (MMR) MSH2, MLH1, MSH6, and PMS2, whereas as HNPCC refers to families that adhere to the Amsterdam criteria or iterations of it. Mutations within MSH2 and MLH1 are the most frequently observed in Lynch syndrome [3]-[6]. More recently, it has been reported that loss of EPCAM is associated with Lynch syndrome, by virtue of it changing the epigenetic status of the promoter region of MSH2 [7]. Mutation carriers are at high risk of developing colorectal cancer (CRC), and endometrial cancer (EC) at unusually young ages [8]. Other, extra-colonic tumor types such as ovarian, small bowel, urinary, biliary tract, gastric, and brain tumors, have also been associated with HNPCC [9],[10]. Due to the high cumulative risk of CRC colonoscopy is recommended in LS families [11]. This strategy has been documented to decrease CRC mortality [12]. Over half the cancer deaths in HNPCC families are due to extra-colonic malignancies [13]. The benefit of surveillance for gynecological cancers is not yet proven and there is no consensus on the optimal surveillance recommendations for women with MMR mutations. The aim of this study was to perform a systematic review of the literature and to evaluate and compare cancer risk in our series of 631 Polish HNPCC families including 279 families with identified mismatch repair (MMR) gene mutations (referred as Lynch syndrome (LS) families) in order to suggest optimal management of ovarian and endometrial cancer for female MMR mutation carriers and their close relatives.

Material and methods

The relevant literature articles were found after a comprehensive search of the Medline (Pubmed) database from its inception to 17 September 2014 by inputting “HNPCC”; 4298 publications were identified. A refined search using combinations of terms: “HNPCC”, “tumor spectrum”, “ovarian cancer”, “endometrial cancer”, “screening”, “cancer risk”, “surveillance” and “prophylactics” identified reference used herein.

During 2002-2014 631 HNPCC families studied herein were classified into either LS or HNPCC at the International Hereditary Cancer Center (IHCC) Szczecin, Poland, due to 1): identification of pathogenic MMR gene mutations -278 LS families (1176 women, 1507 men); or 2): fulfillment of Amsterdam criteria (144 families, 240 affected individuals and 750 their first-degree relatives) or HNPCC suspected criteria (at least 2 first degree relatives affected with CRC/EC and at least one of them diagnosed < 50 yrs- 209 families, 348 affected patients and 1092 their first-degree relatives) – total 353 families referred as HNPCC families (with no MMR mutations) (1285 females, 1145 males). There were 1433 mutation carriers and 1250 first-degree relatives in LS families: 1371 individuals coming from 142 MLH1 families, 946 individuals from 98 MSH2 families, 347 persons from 36 MSH6 families, 19 individuals from 2 EPCAM families.

Patients originated from different regions of Poland. All adult LS mutation carriers or first-degree relatives were included, as well as probands and their adult first degree-relatives from HNPCC families. We investigated the tumor spectrum, age of onset of ovarian cancer (OC) and endometrial cancer (EC), the risk of OC and EC and survival from OC in these families. Observed (OF) and expected frequencies (EF) were calculated by the evaluation of the total number of family members and affected individuals in different age groups (range of 5 years) in LS and HNPCC families and compared to age-specific incidence rates in the different age groups (range 5 years) per 100,000 people. These calculations were matched by site with the individuals registered in the Polish general population [14]. Statistical analyses including evaluation of expected and observed frequencies and cumulative risk were performed using Cox regression, chi-square with Yates correction and T-test analysis.

All participants signed an informed consent document prior to entering the study. The study was approved by the institutional review board of the Pomeranian Medical University.

For 10-year survival analysis a comparison with follow-up data from a consecutive ovarian cancers was performed. This group consisted of 608 unselected ovarian cancer patients (there were no HNPCC- and LS-associated OC in this series of cases) from the registry of International Hereditary Cancer Centre in Szczecin, Poland, who were diagnosed from 1998 to 2006 in cooperating Oncology Centers in Szczecin, Poznań and Rzeszów. All cases were histologically or cytologically confirmed.

Results

Tumor spectrum

Literature data

Recent analysis of the cancer spectrum in 368 MMR genes mutation carriers (mainly non-Hispanic white US citizens) from 176 families confirmed that the two most common LS cancers were: CRC (58% of all cancers) in both sexes and EC (14%) followed by ovarian cancer (OC) as the third most common malignancy (3,5%). Cancers of the urogenital tract (kidney/uterus/bladder) constituted 3,1%, stomach/small intestine 2,7%, breast 1,9% and prostate 1.1% of all malignancies in these families [15]. Another study from Europe performed on 2118 German and Dutch MMR gene mutation carriers revealed a similar tumor spectrum and a high incidence of gynecological cancers: CRC 50%, EC 16%, OC 4,4%, breast 4,4%, urological 3,6%, stomach 1,6% [16]. LS-associated OC has been reported to exhibit a variety of histopathological subtypes, mostly invasive, with 22% presenting with synchronous primary EC [17].

Polish data

Consistent with reports in the literature, a comparison of the cancer spectrum between 278 LS families and 353 HNPCC families diagnosed at the IHCC confirmed the high incidence of gynecological cancers in Polish HNPCC families. There were 21 OCs among 573 tumors (3,6%) in LS families and 18 OCs among 588 tumors (3,1%) in the HNPCC families. EC was more prevalent among LS families (138/573 tumors, 24% of all cancers) compared to HNPCC families (81/588 tumors, 14% of all cancers). There were no major differences in the distribution of other tumors between either the LS or HNPCC families (Table 1).
Table 1

Cancer spectrum in MMR genes mutation positive and negative HNPCC families

  

Mutation positive

    

Mutation negative

  
 

N

Mean age

%

<50

≥50

 

N

Mean age

%

<50

≥50

CRC

289

48,2

50,4 [289/573]

171

118

CRC

345

53,4

58,6 [345/588]

156

189

EC

138

49,8

24,1 [138/573]

69

69

EC

81

51

13,7 [81/588]

41

40

OC

21

42,6

3,66 [21/573]

19

2

OC

18

54,6

3,06 [18/588]

5

13

KI

6

52,2

1,04 [6/573]

3

3

KI

13

57,3

2,21 [13/588]

3

10

BL

5

55,4

0,87 [5/573]

3

2

BL

6

49

1,02 [6/588]

3

3

LC

3

60

0,52 [3/573]

1

2

LC

2

68,5

0,34 [2/588]

0

2

ST

12

52,6

2,09 [12/573]

6

6

ST

9

49,2

1,53 [9/588]

6

3

PC

6

55,2

1,04 [6/573]

2

4

PC

5

56,4

0,85 [5/588]

1

4

Liv

8

47,6

1,39 [8/573]

5

3

Liv

4

60

0,68 [4/588]

1

3

FGT

36

50,7

6,28 [36/573]

17

19

FGT

32

51,4

5,44 [32/588]

14

18

BR

28

52

4,88 [28/573]

9

19

BR

32

51

5,44 [32/588]

16

16

BONES

4

59,2

0,70 [4/573]

1

3

Thr

1

51

0,17 [1/588]

0

1

Gallbladder

1

50

0,17 [1/573]

0

1

SS

1

58

0,17 [1/588]

0

1

CSU

9

51,4

1,57 [9/573]

4

5

CSU

25

52,3

4,25 [25/588]

10

15

SKIN

2

48,5

0,35 [2/573]

1

1

SKIN

2

59,5

0,34 [2/588]

1

1

MM

1

44

0,17 [1/573]

1

0

MM

1

72

0,17 [1/588]

0

1

Lx

1

52

0,17 [1/573]

0

1

OUN

2

35,5

0,34 [2/588]

1

1

OUN

3

42

0,52 [3/573]

2

1

LEUC

6

50,7

1,02 [6/588]

2

4

LEUC

2

63

0,35 [2/573]

0

2

Salivary gland

1

33

0,17 [1/588]

1

0

LYMPH

1

60

0,17 [1/573]

0

1

      

SS-soft tissue sarcoma, CRC-colorectal cancer, EC-endometrial cancer, BL-bladder cancer, KI- kidney cancer, OC- ovarian cancer, LC- lung cancer, ST- stomach cancer, PC- prostate cancer, Liv- liver cancer, FGT- female genital tract, BR- breast cancer, Thr- thyroid cancer, CSU- cancer suspected unknow, MM- malignant melanoma, Lx- larynx cancer, OUN- central nervous system cancer, LEUC- leukemia, LYMPH- lymphoma.

In the LS families individual at risk for CRC was 10,7% (289 CRC among 2683 individuals), for EC 12% (138 cases among 1176 females), for OC 1,7% (21 patients among 1176 women) and 2,8% for early-onset cases (19 cases among 661 women before 50). In the HNPCC families individual at risk for CRC was 14,1% (345 CRC among 2430 individuals), for EC 6,3% (81 cases among 1285 females) and 1,4% for OC (18 patients among 1285 women).

Risk of ovarian cancer

Literature data

For female LS patients, the lifetime risk of developing OC is estimated to be somewhere between 3% and 20% with a standardized incidence ratio (SIR) ranging from 7 to 14 [18]-[22]. The mean age of OC has been reported to be between 40 and 47 years of age [16],[21],[22]. In a recent Danish study the mean age of OC was reported to be lower in LS families (41 years) compared to HNPCC families (66 years) or HNPCC-suspected families (64 years) [23].

Polish data

Statistical analysis of the age of onset of gynecological cancers in Polish LS patients reported herein confirmed that the mean age of OC was significantly lower in these families (43 years, age range 31-52) when compared to the general Polish population (54 years, p < 0.0001) and to HNPCC families (53 years, age range 27-80, p < 0.001).

Statistical analyses of the observed (OF = 21 cases) and expected frequency (EF = 4,6) of OC in our series of LS families showed a significantly increased risk of OC (OR = 4,6, 95% CI 2,75-7,78; p < 0.001) in comparison to the general population estimates. An especially high risk of OC was found for women under 50 years of age: OR = 32,6, 95% CI 12,96-81,87; p < 0.0001 (OF = 19 and EF = 0,6). The cumulative OC risk to 50 year of age was calculated to be 10% for Polish female LS patients.

Statistical comparison of the OF (n = 18) and EF (n = 5,4) of OC in our series of HNPCC families showed also significantly, although to a lesser degree than in LS families, increased risk of OC (OR = 3,6, 95%CI 1.34-9.82; p = 0.012). The cumulative OC risk to 85 year of life was calculated to be 6% for Polish females from HNPCC families.

Out of 21 patients affected by OC in the LS families 11 patients harboured MSH2 mutations, 8 females were MLH1 mutations carriers and 2 carried MSH6 mutations.

Risk of endometrial cancer

Literature data

For female LS patients, the lifetime risk of developing EC is estimated to be between 30% and 70% with a standardized incidence ratio (SIRs) ranging from 10 to 62 [21],[22],[24],[25]. The mean age of diagnosis for EC has been reported to be 48, 49 and 54 years in MLH1, MSH2 and MSH6 mutation carriers respectively [26],[27].

Polish data

The mean age of EC diagnosed in our LS families was 50 years of age (range 27-78). The mean age of EC detected in HNPCC families was 51 years (range 20-75). Statistical analyses of the observed (OF = 138 cases) and expected frequency (EF = 5,5 cases) of EC in our series of LS families showed a significantly increased risk of EC when compared to general population (OR = 26, 95% CI 11,36-58,8; p < 0,001). The cumulative risk for EC in Polish LS families was calculated to be 67%. Similarly, although to a lesser extent than in LS families, statistical analyses of the OF (n = 81) and EF (n = 6,5) of EC in our HNPCC families revealed a significantly increased risk of EC (OR = 14, 95%CI 6,23-32,98; p < 0,0001). The cumulative risk for EC in Polish HNPCC families was calculated to be 36%.

Cancer deaths

Literature data

In a recent study of 179 Finnish LS families from 1069 mutation carriers 151 had succumbed - 97 (64%) to cancer. From these 55,3% cancer deaths were due to extra-colonic, extra-endometrial cancers; CRC accounted for 36,4% of the deaths; 8.2% due to EC. Only 7.9% of the patients with CRC had died from CRC and 5% of those with EC, respectively; 61% of the extra-colonic, extra-endometrial cancer patients died from their primary disease [13].

Conflicting data regarding prognosis of OC in the HNPCC exists in the literature. A comparison of 26 OC from Dutch HNPCC families versus 52 sporadic OC matched for age, stage and year of diagnosis, derived from the Dutch population revealed that the survival rate was not significantly different between patients with OC-HNPCC and the controls with sporadic OC [28]. There is, however, a second report suggesting that a better prognosis of OC in LS, with a 10-year survival of 81%, than in BRCA1/2 mutation carriers or in the general population [29].

Polish data

In our series of 21 OC from Polish LS families (3 OC were excluded from survival calculations due to incomplete follow up data) the 10-year survival rate was 61%. It was significantly higher when compared to 5% of 10-year survival rate of 600 consecutive patients with OC (HNPCC patients were excluded) diagnosed at our center (Figure 1). This indicates a better prognosis of Lynch syndrome-associated OC. However, 6 out of 19 (32%) affected patients from LS families died due to OC within 2 years of diagnosis. All but one patient was diagnosed after their 37th year of age (the youngest woman was 31 at the time of cancer detection). The 10-year survival rate of OC in our HNPCC subgroup was 21% (Figure 1).
Figure 1

Survival comparison of the HNPCC associated ovarian cancers and unselected OC from general Polish population.

Discussion

Management of ovarian cancer

Majority of LS-associated ovarian cancers show non-serous histology- an association between endometrioid and clear cell ovarian carcinomas and hereditary predisposition due to MMR gene mutation has been reported [30],[31]. There is limited evidence to establish whether routine screening with serum CA125 levels for the high-risk population would result in a decrease in mortality from OC. CA125, mostly associated with serous OCs, has been reported to to be elevated in around 11% of the Lynch syndrome or hereditary carcinoma of the breast/ovary cases; during the premenopausal period rising values of CA125 were associated with benign pelvic diseases,such as endometriosis, adenomyosis and myomas [32]. However, current guidelines for gynecological screening in HNPCC recommend transvaginal ultrasound (TVUs) and CA125 testing, every 1-2 years starting at 30-35 years of age [33]-[35]. Recently it has been suggested that HE4 marker might be useful for diagnosing OC due to its high specificity, especially in the premenopausal population and combining of HE4 and CA125 could be considered as an option in the OC management [36],[37].

We found four published studies that included a total of 585 women screened for the screening method included both TVUS and CA125 (applied in three studies) or TVUS only (one study). Taken together, 5 OC were diagnosed in these studies; only 1 OC during surveillance (stage IIIC), the other 4 OC were detected accidentally because of bleeding or surgery performed due to unrelated reasons and not by surveillance [38]-[41]. In all studies no benefit was shown for OC surveillance or the diagnosis of early stage ovarian cancer OC (Table 2).
Table 2

Literature data regarding gynecological cancer management in Lynch syndrome families

Author

Year

Patients

Methods

Outcome/drawback

References

Ketabi Z

2014

236 women from LS families/8 years

Biennial TVUs/ CA125/ES

1 OC (II B) and 3 interval OCs diagnosed

[23]

Gerritzen LH

2009

100 LS carriers or AMS members/2,5 years

TVUs/CA125/ES

1 OC diagnosed (III C)

[38]

Rijcken FE

2003

41 LS carriers or AMS members/5 years

TVUs/CA125/optional ES

1 interval EC detected

[39]

Dove-Edwin I

2002

269 AMS females/826 person-years

TVUS only

2 cases of EC- neither case detected by surveillance

[40]

Renkonen-Sinisalo L

2007

175 LS carriers/759 person-years

TVUs/CA125/routine ES

4 OC occured, none detected by surveillance

[41]

Stuckless S

2013

174 MSH2 carriers/5 years

TVUs/CA125/ES

3 deaths due to OCs both in screened and unscreened females

[42]

Schmeler KM

2006

315 LS carriers/10 years

Surgery

OC: 0/47 cases bilat salpino-oophorect. (0%) vs 12/223 no surgery (5.5%) EC: 0/61 hysterectomy (0%) vs 69/210 no surgery (33%) Surgical complication rate 1.6 percent, no data regarding overall survival

[43]

Manchandra R

2012

41 women from LS families/8 years

TVUs/routine ES

TVU alone missed 1 EC and 1 premalignant lesion

[56]

TUV – transvaginal ultrasound.

ES – endometrial sampling.

A second retrospective study reported on impact of gynecological screening in 174 MSH2 carriers [42]. Six of the 54 women in the screened group (TVUS + CA125/5 years) developed OC and there were 2 deaths due to OC within the first 2 years after diagnosis. The same number (six) of 54 matched women (taking into account age at entry into screening program) in the non-screened group developed OC, which lead to 3 deaths. In total, 16 OC among 120 unscreened women occurred, from which 5 deaths had occurred within 2 years. The authors concluded that screening did not result in any earlier cancer detection and despite screening, 2 young women died from OC. The authors suggest that prophylactic surgery be considered in female mutation carriers who have completed childbearing [42] to reduce their risk of presenting with incurable disease.

Recently an impact of gynecological screening (biennial TVUS + CA125 in case of abnormal findings/8 years) was retrospectively evaluated in 236 women (2067 women years) from Danish LS families. Four cases of OC were diagnosed: only one OC in a woman with no symptoms was detected by surveillance (highly differentiated endometrioid adenocarcinoma, stage II B); three other OCs were diagnosed as interval cancers due to symptoms [23]. Consistently with previous reports, the study showed OC screening in female LS patients to be futile.

In 2006 risk-reducing bilateral salpingo-oophorectomy has been shown to be an effective strategy for preventing OC [43]. Modeling studies of prophylactic surgery versus gynecologic surveillance for LS women showed that risk-reducing surgery is associated with the lowest costs and would increase life-expectancy [44]-[46].

According to the revised guidelines for the clinical management of Lynch syndrome prophylactic oophorectomy can be an option to be discussed with mutation carriers who have completed their families especially after the age of 40 years [11].

Given the published evidence and our own data showing a high risk of OC for young women from LS families and the absence of any positive effect of screening we conclude that it is justified to recommend the option of prophylactic oophorectomy for female carriers of MMR mutations after 35 year of age. Since three cases of primary peritoneal cancers after prophylactic bilateral salpingo-oophorectomy in HNPCC patients have been reported [47],[48] and previous studies involving women with BRCA mutations have also reported an incidence of primary peritoneal cancer after prophylactic bilateral salpingo-oophorectomy of 0.8 to 1.0 percent. [49],[50], annual TVUS and CA125 screening might be considered as an option of the follow-up after prophylactic surgery in these women. Conflicting data regarding the prognosis of HNPCC-associated OC can be found in the literature [28],[29]. But even if the results of a comparison of the 10-year survival between our LS-OC and Polish consecutive OCs pointed at a better prognosis for OC associated with MMR gene mutations, risk-reducing surgery performed at the age of 35 would save at least 6 young women from our HNPCC mutation families. Preventive oophorectomy was reported to be associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality [51], even if it has been observed that BRCA1/2-associated OC patients have a longer progression-free survival and overall survival compared with women with sporadic OC [52],[53]. Approximately one-third of Polish LS-associated OC patients died within two years after diagnosis, most probably due to different chemosensitivity of their tumors. Ovarian cancers are usually treated by platinium-based therapy. Contrary to serous sporadic OC and BRCA1-related OC, decreased susceptibility to cisplatin therapy has been suggested to be characteristic feature for Lynch syndrome-associated OC [54].

Management of endometrial cancer

We found six reported studies that included a total of 1518 women screened for EC [23],[38]-[41],[55]. In the studies that used TVUS as the only screening method, interval ECs were diagnosed [40],[55]. In the studies in which protocols also included endometrial biopsies the detection of premalignant lesions and EC was significantly improved. A comparison of the results of routine endometrial biopsy [38],[41] and optional biopsy (performed in cases with abnormalities - bleeding, irregular endometrium, endometrium thickness >4 mm [23],[39] or >5 mm [38] in postmenopausal women) revealed better efficiency in disease detection in the protocols that included routine biopsies where the EC detection rate exceeded 70% in comparison to a 50% detection rate when optional sampling was performed.

Additionally, in another recent report two endometrial carcinomas and two premalignant lesions were identified in 41 women who underwent 69 annual visits with standard TVU and outpatient hysteroscopy with endometrial sampling. Screening with TVU alone would have missed one endometrial carcinoma and one premalignant lesion in that study [56].

Unlike others, Helder-Woolderink et al.[57] reported a lack of additional value in endometrial sampling for EC detection. 75 LS patients or their first-degree relatives at 50% risk of carrying the MMR mutation were analysed in this study, including women who underwent annual screening program based upon TVUS alone and women screened by both TVUS and routine endometrial sampling. No interval EC was diagnosed.

A large meta-analysis of sporadic endometrial cancers advocated Pipelle endometrial sampling as an equally effective, if not superior, method compared with transvaginal ultrasound for detecting endometrial cancer in both pre- and postmenopausal women [58]. A recent prospective study showed that conducting endometrial sampling at the time of colonoscopy (for colorectal cancer risk assessment) is a patient-centered option that is feasible, acceptable, and may improve adherence to LS screening recommendations [59].

Comparison of the results of the screening performed in 236 LS patients revealed that EC surveillance should only be targeted to this group of women [23].

Until now no prospective study has evaluated the impact of the EC screening on the survival of LS or HNPCC patients and the efficiency of screening for EC that generally presents with symptoms at an early stage is not clear. However, given the high risk of EC in female LS patients, according to the revised guidelines for the clinical management of LS, transvaginal ultrasound and aspiration biopsy (starting from the age of 35-40 years) should be offered as an appropriate risk reducing strategy [11]. Recently a retrospective study was published on the impact of gynecological screening in 174 MSH2 female carriers [42]. Nine of 54 women in the screened group (TVUS + endometrial sampling/5 years) developed EC, with no deaths due to this malignancy. Twenty of 54 matched women (taking into account age at entry into screening program) in the non-screened group developed EC, which resulted in 3 deaths. In total, 44 ECs among 120 unscreened women occurred, leading to 11 deaths [42]. The authors argued that risk-reducing hysterectomy and bilateral salpingo-oophorectomy after childbearing is complete is the most effective risk reduction strategy.

Modeling studies have shown that prophylactic hysterectomy and bilateral salpingo-oophorectomy can increase life expectancy and can also be a cost-effective strategy [44]-[46]. Total hysterectomy was shown to significantly reduce the risk of EC in women with Lynch syndrome [43]. However, given better outcomes than those observed for OC, the screening efficiency in detecting EC and high survival rates for this cancer [60] it remains unclear whether surgical prevention of EC in MMR carriers would significantly impact on morbidity and mortality.

In conclusion, our present knowledge on Lynch syndrome indicates that special prevention and treatment options should be applied to patients with LS. Due to the increased risk of OC, conflicting data regarding the prognosis of this disease in HNPCC and lack of any benefit from gynecological screening, it is recommended that prophylactic oophorectomy for female carriers of MMR mutations after 35 year of age should be considered as a risk reducing option. Annual transvaginal ultrasound (TVUS) supported by CA125 or HE4 marker might be considered as an option of the follow-up after prophylactic surgery in these women.

Due to the high risk of EC it is reasonable to offer, after the age of 35 years, annual clinical gynecologic examinations with transvaginal ultrasound (TVUS) supported by routine aspiration sampling of the endometrium to women from either LS or HNPCC families. Another option that could be taken into consideration for women preferring surgical prevention as a risk reducing alternative is total hysterectomy (with bilateral salpingo-oophorectomy) for carriers after childbearing is complete.

Declarations

Authors’ Affiliations

(1)
Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University
(2)
Discipline of Medical Genetics, Faculty of Health, University of Newcastle and Hunter Medical Research Institute

References

  1. Aaltonen L, Johns L, Järvinen H, Mecklin JP, Houlston R: Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors. Clin Cancer Res 2007, 13: 356–61. 10.1158/1078-0432.CCR-06-1256View ArticlePubMedGoogle Scholar
  2. Aarnio M: Clinicopathological features and management of cancers in lynch syndrome. Patholog Res Int. 2012, 12: 1–6. 10.1155/2012/350309View ArticleGoogle Scholar
  3. Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, et al.: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993, 75: 1027–38. 10.1016/0092-8674(93)90546-3View ArticlePubMedGoogle Scholar
  4. Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, et al.: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993, 75: 1215–25. 10.1016/0092-8674(93)90330-SView ArticlePubMedGoogle Scholar
  5. Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 1994, 371: 75–80. 10.1038/371075a0View ArticlePubMedGoogle Scholar
  6. Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, et al.: Mutation of a mutL homolog in hereditary colon cancer. Science 1994, 263: 1625–9. 10.1126/science.8128251View ArticlePubMedGoogle Scholar
  7. Tutlewska K, Lubinski J, Kurzawski G: Germline deletions in the EPCAM gene as a cause of Lynch syndrome - literature review. Hered Cancer Clin Pract 2013, 11: 9. 10.1186/1897-4287-11-9View ArticlePubMedPubMed CentralGoogle Scholar
  8. Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 2003, 348: 919–32. 10.1056/NEJMra012242View ArticlePubMedGoogle Scholar
  9. Watson P, Vasen HF, Mecklin JP, Bernstein I, Aarnio M, Järvinen HJ, et al.: The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 2008, 123: 444–9. 10.1002/ijc.23508View ArticlePubMedPubMed CentralGoogle Scholar
  10. Lin-Hurtubise KM, Yheulon CG, Gagliano RA Jr, Lynch HT: Excess of extracolonic non-endometrial multiple primary cancers in MSH2 germline mutation carriers over MLH1. J Surg Oncol 2013, 108: 433–7. 10.1002/jso.23413View ArticlePubMedGoogle Scholar
  11. Vasen HF, Blanco I, Aktan-Collan K, Gopie JP, Alonso A, Aretz S, et al.: Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 2013, 62: 812–23. 10.1136/gutjnl-2012-304356View ArticlePubMedPubMed CentralGoogle Scholar
  12. Järvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomäki P, et al.: Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000, 118: 829–34. 10.1016/S0016-5085(00)70168-5View ArticlePubMedGoogle Scholar
  13. Pylvänäinen K, Lehtinen T, Kellokumpu I, Järvinen H, Mecklin JP: Causes of death of mutation carriers in Finnish Lynch syndrome families. Fam Cancer 2012, 11: 467–71. 10.1007/s10689-012-9537-3View ArticlePubMedGoogle Scholar
  14. Wojciechowska U, Didkowska J, Zatoński W: Cancer in Poland in 2010. The Maria-Skłodowska-Curie Memorial Cancer Center, Department of Epidemiology and cancer Prevention, Polish National Cancer Registry, Warsaw; 2012.Google Scholar
  15. Pande M, Wei C, Chen J, Amos CI, Lynch PM, Lu KH, et al.: Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry. Fam Cancer 2012, 11: 441–7. 10.1007/s10689-012-9534-6View ArticlePubMedPubMed CentralGoogle Scholar
  16. 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. 10.1200/JCO.2012.43.2278View ArticlePubMedGoogle Scholar
  17. Watson P, Bützow R, Lynch HT, Mecklin JP, Järvinen HJ, Vasen HF, et al.: The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2001, 82: 223–8. 10.1006/gyno.2001.6279View ArticlePubMedGoogle Scholar
  18. Hampel H, Stephens JA, Pukkala E, Sankila R, Aaltonen LA, Mecklin JP, et al.: Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 2005, 129: 415–21. 10.1016/j.gastro.2005.05.011View ArticlePubMedGoogle Scholar
  19. Barrow E, Robinson L, Alduaij W, Shenton A, Clancy T, Lalloo F, et al.: Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet 2009, 75: 141–9. 10.1111/j.1399-0004.2008.01125.xView ArticlePubMedGoogle Scholar
  20. Stuckless S, Parfrey PS, Woods MO, Cox J, Fitzgerald GW, Green JS, et al.: The phenotypic expression of three MSH2 mutations in large Newfoundland families with Lynch syndrome. Fam Cancer 2007, 6: 1–12. 10.1007/s10689-006-0014-8View ArticlePubMedGoogle Scholar
  21. Aarnio M, Mecklin JP, Aaltonen LA, Nyström-Lahti M, Järvinen HJ: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995, 64: 430–3. 10.1002/ijc.2910640613View ArticlePubMedGoogle Scholar
  22. 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. 10.1136/jmg.2004.024299View ArticlePubMedPubMed CentralGoogle Scholar
  23. Ketabi Z, Gerdes AM, Mosgaard B, Ladelund S, Bernstein I: The results of gynecologic surveillance in families with hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2014, 133: 526–30. 10.1016/j.ygyno.2014.03.012View ArticlePubMedGoogle Scholar
  24. 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: 437–44. 10.1111/j.1600-0412.2011.01091.xView ArticlePubMedGoogle Scholar
  25. Barrow PJ, Ingham S, O’Hara C, Green K, McIntyre I, Lalloo F, et al.: The spectrum of urological malignancy in Lynch syndrome. Fam Cancer 2013, 12: 57–63. 10.1007/s10689-012-9573-zView ArticlePubMedGoogle Scholar
  26. Rodriguez-Bigas MA, Möeslein G: Surgical treatment of hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome). Fam Cancer 2013, 12: 295–300. 10.1007/s10689-013-9626-yView ArticlePubMedGoogle Scholar
  27. Hendriks YM, Wagner A, Morreau H, Menko F, Stormorken A, Quehenberger F, et al.: Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology 2004, 127: 17–25. 10.1053/j.gastro.2004.03.068View ArticlePubMedGoogle Scholar
  28. Crijnen TE, Janssen-Heijnen ML, Gelderblom H, Morreau J, Nooij MA, Kenter GG, et al.: Survival of patients with ovarian cancer due to a mismatch repair defect. Fam Cancer 2005, 4: 301–5. 10.1007/s10689-005-6573-2View ArticlePubMedGoogle Scholar
  29. Grindedal EM, Renkonen-Sinisalo L, Vasen H, Evans G, Sala P, Blanco I, et al.: Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds. J Med Genet 2010, 47: 99–102. 10.1136/jmg.2009.068130View ArticlePubMedGoogle Scholar
  30. Chui MH, Ryan P, Radigan J, Ferguson SE, Pollett A, Aronson M, et al.: The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-specific screening strategy. Am J Surg Pathol 2014, 38: 1173–81. 10.1097/PAS.0000000000000298View ArticlePubMedGoogle Scholar
  31. Niskakoski A, Kaur S, Renkonen-Sinisalo L, Lassus H, Järvinen HJ, Mecklin JP, et al.: Distinct molecular profiles in Lynch syndrome-associated and sporadic ovarian carcinomas. Int J Cancer 2013, 133: 2596–608.PubMedGoogle Scholar
  32. Karlan BY, Platt LD: Ovarian cancer screening. The role of ultrasound in early detection. Cancer 1995, 76: 2011–5. 10.1002/1097-0142(19951115)76:10+<2011::AID-CNCR2820761318>3.0.CO;2-LView ArticlePubMedGoogle Scholar
  33. Lindor NM, Petersen GM, Hadley DW, Kinney AY, Miesfeldt S, Lu KH, et al.: Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 2006, 296: 1507–17. 10.1001/jama.296.12.1507View ArticlePubMedGoogle Scholar
  34. Schmeler KM, Lu KH: Gynecologic cancers associated with Lynch syndrome/HNPCC. Clin Transl Oncol 2008, 10: 313–7. 10.1007/s12094-008-0206-9View ArticlePubMedGoogle Scholar
  35. Meyer LA, Broaddus RR, Lu KH: Endometrial cancer and Lynch syndrome: clinical and pathologic considerations. Cancer Control 2009, 16: 14–22.PubMedPubMed CentralGoogle Scholar
  36. Wang J, Gao J, Yao H, Wu Z, Wang M, Qi J: Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: a meta-analysis. Tumour Biol 2014, 35: 6127–38. 10.1007/s13277-014-1811-6View ArticlePubMedGoogle Scholar
  37. Ghasemi N, Ghobadzadeh S, Zahraei M, Mohammadpour H, Bahrami S, Ganje MB, et al.: HE4 combined with CA125: favorable screening tool for ovarian cancer. Med Oncol 2014, 31: 808. 10.1007/s12032-013-0808-0View ArticlePubMedGoogle Scholar
  38. Gerritzen LH, Hoogerbrugge N, Oei AL, Nagengast FM, van Ham MA, Massuger LF, et al.: Improvement of endometrial biopsy over transvaginal ultrasound alone for endometrial surveillance in women with Lynch syndrome. Fam Cancer 2009, 8: 391–7. 10.1007/s10689-009-9252-xView ArticlePubMedPubMed CentralGoogle Scholar
  39. Rijcken FE, Mourits MJ, Kleibeuker JH, Hollema H, van der Zee AG: Gynecologic screening in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2003, 91: 74–80. 10.1016/S0090-8258(03)00371-8View ArticlePubMedGoogle Scholar
  40. Dove-Edwin I, Boks D, Goff S, Kenter GG, Carpenter R, Vasen HF, et al.: The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer 2002, 94: 1708–12. 10.1002/cncr.10380View ArticlePubMedGoogle Scholar
  41. Renkonen-Sinisalo L, Bützow R, Leminen A, Lehtovirta P, Mecklin JP, Järvinen HJ: Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome. Int J Cancer 2007, 120: 821–4. 10.1002/ijc.22446View ArticlePubMedGoogle Scholar
  42. Stuckless S, Green J, Dawson L, Barrett B, Woods MO, Dicks E, et al.: Impact of gynecological screening in Lynch syndrome carriers with an MSH2 mutation. Clin Genet 2013, 83: 359–64. 10.1111/j.1399-0004.2012.01929.xView ArticlePubMedGoogle Scholar
  43. Schmeler KM, Lynch HT, Chen LM, Munsell MF, Soliman PT, Clark MB, et al.: Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 2006, 354: 261–9. 10.1056/NEJMoa052627View ArticlePubMedGoogle Scholar
  44. Yang KY, Caughey AB, Little SE, Cheung MK, Chen LM: A cost-effectiveness analysis of prophylactic surgery versus gynecologic surveillance for women from hereditary non-polyposis colorectal cancer (HNPCC) Families. Fam Cancer 2011, 10: 535–43. 10.1007/s10689-011-9444-zView ArticlePubMedGoogle Scholar
  45. Kwon JS, Sun CC, Peterson SK, White KG, Daniels MS, Boyd-Rogers SG, et al.: Cost-effectiveness analysis of prevention strategies for gynecologic cancers in Lynch syndrome. Cancer 2008, 113: 326–35. 10.1002/cncr.23554View ArticlePubMedGoogle Scholar
  46. Chen LM, Yang KY, Little SE, Cheung MK, Caughey AB: Gynecologic cancer prevention in Lynch syndrome/hereditary nonpolyposis colorectal cancer families. Obstet Gynecol 2007, 110: 18–25. 10.1097/01.AOG.0000267500.27329.85View ArticlePubMedGoogle Scholar
  47. Schmeler KM, Daniels MS, Soliman PT, Broaddus RR, Deavers MT, Vu TM, et al.: Primary peritoneal cancer after bilateral salpingo-oophorectomy in two patients with Lynch syndrome. Obstet Gynecol 2010, 115: 432–4. 10.1097/AOG.0b013e3181b6f4f9View ArticlePubMedPubMed CentralGoogle Scholar
  48. Ghezzi F, Uccella S, Cromi A, Bogani G, Donadello N, Riva C: Primary peritoneal cancer in Lynch syndrome: a clinical-pathologic report of a case and analysis of the literature. Int J Gynecol Pathol 2013, 32: 163–6. 10.1097/PGP.0b013e31825ac5c9View ArticlePubMedGoogle Scholar
  49. Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van’t Veer L, Garber JE, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engel J Med 2002, 346: 1616–22. 10.1056/NEJMoa012158View ArticleGoogle Scholar
  50. Kauff ND, Satagopan JM, Robson ME, Scheuer L, Hensley M, Hudis CA, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002, 346: 1609–15. 10.1056/NEJMoa020119View ArticlePubMedGoogle Scholar
  51. Finch AP, Lubinski J, Møller P, Singer CF, Karlan B, Senter L, et al.: Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 2014, 32: 1547–53. 10.1200/JCO.2013.53.2820View ArticlePubMedPubMed CentralGoogle Scholar
  52. Chetrit A, Hirsh-Yechezkel G, Ben-David Y, Lubin F, Friedman E, Sadetzki S: Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer. J Clin Oncol 2008, 26: 20–5. 10.1200/JCO.2007.11.6905View ArticlePubMedGoogle Scholar
  53. Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, et al.: “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 2008, 26: 5530–6. 10.1200/JCO.2008.16.1703View ArticlePubMedGoogle Scholar
  54. Marcelis CL, van der Putten HW, Tops C, Lutgens LC, Moog U: Chemotherapy resistant ovarian cancer in carriers of an hMSH2 mutation? Fam Cancer 2001, 1: 107–9. 10.1023/A:1013865323890View ArticlePubMedGoogle Scholar
  55. Lécuru F, Le Frère Belda MA, Bats AS, Tulpin L, Metzger U, Olschwang S, et al.: Performance of office hysteroscopy and endometrial biopsy for detecting endometrial disease in women at risk of human non-polyposis colon cancer: a prospective study. Int J Gynecol Cancer 2008, 18: 1326–31. 10.1111/j.1525-1438.2007.01183.xView ArticlePubMedGoogle Scholar
  56. Manchanda R, Saridogan E, Abdelraheim A, Johnson M, Rosenthal AN, Benjamin E, et al.: Annual outpatient hysteroscopy and endometrial sampling (OHES) in HNPCC/Lynch syndrome (LS). Arch Gynecol Obstet 2012, 286: 1555–62. 10.1007/s00404-012-2492-2View ArticlePubMedGoogle Scholar
  57. Helder-Woolderink JM, De Bock GH, Sijmons RH, Hollema H, Mourits MJ: The additional value of endometrial sampling in the early detection of endometrial cancer in women with Lynch syndrome. Gynecol Oncol 2013, 131: 304–8. 10.1016/j.ygyno.2013.05.032View ArticlePubMedGoogle Scholar
  58. Dijkhuizen FP, Mol BW, Brölmann HA, Heintz AP: The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis. Cancer 2000, 89: 1765–72. 10.1002/1097-0142(20001015)89:8<1765::AID-CNCR17>3.0.CO;2-FView ArticlePubMedGoogle Scholar
  59. Huang M, Sun C, Boyd-Rogers S, Burzawa J, Milbourne A, Keeler E, et al.: Prospective study of combined colon and endometrial cancer screening in women with lynch syndrome: a patient-centered approach. J Oncol Pract 2011, 7: 43–7. 10.1200/JOP.2010.000038View ArticlePubMedPubMed CentralGoogle Scholar
  60. Lu KH, Daniels M: Endometrial and ovarian cancer in women with Lynch syndrome: update in screening and prevention. Fam Cancer 2013, 12: 273–7. 10.1007/s10689-013-9664-5View ArticlePubMedGoogle Scholar

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