**5. Managing Lynch syndrome cancer risks**

Any discussion with individuals and family members at risk for hereditary cancer must occur in the context of a high risk cancer clinic with available medical interventions or referral made to address these risks. The benefits and limitations of surveillance and risk reducing surgery should be individualized, and when possible, evidence based. Over the past few years, a number of studies and recommendations have been published that document the available strategies to guide management of these at-risk individuals with LS (Lindor et al., 2006; NCCN Practice Guidelines 2011; Schmeler et al., 2006; Winawer et al., 2003).

#### **5.1 Surveillance**

Both EC and ovarian cancer are likely to develop before the menopause in women diagnosed with LS. Endometrial cancer screening in women with LS who are asymptomatic consists of annual endometrial sampling beginning at age 30 to 35 or five to ten years prior

CRC rates to be 2.1% and 1.7% between *MLH1* and *MSH2* families, respectively, as compared to 0.33% for the general population (Lin et al., 1998). In a study by Lu et al., dual primary cancers (CRC and gynecologic-endometrial or ovarian) were reported in 16 women (14%) of 117 women with LS (Lu et al, 2005). An earlier study found synchronous and metachronous cancers: endometrial (21 patients), CRC (28 patients), and either gastric, small bowel, or urinary tract cancers (6 patients), in 80 women with LS-associated ovarian cancer

The Society of Gynecologic Oncologists Education Committee published guidelines to identify women with a personal or family history of EC or ovarian cancer, and synchronous or metachronous CRC, whom may benefit from genetic risk assessment for LS (Lancaster et

**EC or CRC and meet AC II criteria; EC or CRC diagnosed < age 50;** 

Table 3. Society of Gynecologic Oncologist: Guidelines for Lynch Syndrome Risk

\* LS-associated cancers include: CRC, EC, stomach, ovarian, ureter/renal pelvis, pancreas, hepatobiliary tract, brain (glioblastomas as seen in Turcot syndrome), small bowel, sebaceous adenomas and

Any discussion with individuals and family members at risk for hereditary cancer must occur in the context of a high risk cancer clinic with available medical interventions or referral made to address these risks. The benefits and limitations of surveillance and risk reducing surgery should be individualized, and when possible, evidence based. Over the past few years, a number of studies and recommendations have been published that document the available strategies to guide management of these at-risk individuals with LS (Lindor et al., 2006; NCCN

Both EC and ovarian cancer are likely to develop before the menopause in women diagnosed with LS. Endometrial cancer screening in women with LS who are asymptomatic consists of annual endometrial sampling beginning at age 30 to 35 or five to ten years prior

**Genetic risk assessment may be HELFUL: Patients with >5-10% chance of** 

**EC or ovarian cancer with synchronous or metachronous CRC or other LS-associated cancers\* with the first cancer diagnosed at** 

**EC or CRC with 2 or more first or seconddegree relatives with LS-associated** 

**First or second-degree relative that meets** 

**having LS** 

**any age;** 

**cancers\*;** 

**the above criteria.** 

(Watson et al., 2001).

al., 2007) (see Table 3).

**having LS** 

**diagnosed < age 50;** 

Assessment.

**5.1 Surveillance**

**Genetic risk assessment RECOMMENDED: Patients with >20-25% chance of** 

**EC or ovarian cancer with a synchronous or metachronous CRC with the first cancer** 

**First or second-degree relative with a known** 

keratoacanthomas (seen in Muir-Torre syndrome).

**5. Managing Lynch syndrome cancer risks** 

Practice Guidelines 2011; Schmeler et al., 2006; Winawer et al., 2003).

**germline mutation in a MMR gene.** 

(adapted from Lancaster et al., 2007).

to the earliest age of the family member diagnosed with a LS-associated cancer (Lindor et al., 2006; NCCN Practice Guidelines 2011). A recent Finnish study evaluated the efficacy of screening with endometrial biopsy and transvaginal ultrasound (TVUS) among 175 mutation-positive women age 35 or older with LS (Renkonen-Sinisalo et al., 2007). They found that surveillance intrauterine biopsy detected 8 women with EC and 4 ECs were indicated by TVUS. Although no statistically significant differences were observed in cancer stage or survival when compared with 83 women with EC who did not undergo surveillance, this strategy detected earlier cancers and there were no deaths in the surveillance group.

Studies have shown that endometrial thickness measurement to detect EC has a high falsepositive rate in women with LS, and in particular premenopausal women where endometrial thickness is highly variable (Dove-Edwin et al., 2002). Conversely, in postmenopausal women, atypical endometrial thickness is less variable. In this population, TVUS and endometrial sampling have similar sensitivities, and early detection is common because most women present with abnormal uterine bleeding (Dijkhuizen et al., 2000).

The primary role of TVUS appears to be in ovarian cancer screening in women with LS. LS is associated with an increased risk of ovarian cancer, estimated at 12% by age 70 compared with 1.5% in the general population (Barrow et al., 2009). Although there are no data regarding ovarian cancer screening in women with LS, most experts recommend an annual pelvic exam, TVUS, and CA125 serum tumor marker, every 6 to 12 months, starting at age 30 to 35 or five to ten years prior to the earliest age of the family member diagnosed with a LS-associated cancer (Lindor et al., 2006; NCCN Practice Guidelines 2011). Since ovarian cancer is much less common than EC in women with LS, it is unknown whether these screening strategies decrease morbidity and mortality.

Although not the emphasis of this chapter, CRC surveillance recommendations in individuals with LS include, colonscopy every one to two years, beginning at age 20 to 25 or two to five years prior to the earliest diagnosis if it is before age 25 (Lindor et al, 2006; NCCN Practice Guidelines 2011). For *MSH6* and *PMS2* mutation positive carriers, colonoscopy is recommended at age 30 to 35 or 10 years prior to the youngest age of diagnosis in the family, whichever comes first (NCCN Practice Guidelines 2011; Senter et al., 2008). In support of this strategy, one study showed that colonoscopy every 3 years reduced the CRC risk by 50% and decreased overall mortality by about 65% (Jarvinen et al., 2000). In a further study, the cumulative risk of CRC after a 10-year follow-up was 6% with a surveillance interval of 1-2 years compared to a 2-3 year surveillance (Vasen et al., 2010).

Lynch syndrome is associated with an increased risk for other cancers as well, including, gastric, small bowel, urothelial, pancreatic, and brain. It is imperative that the clinician caring for these individuals and their families with LS, refer to the National Comprehensive Cancer Network (NCCN) Guidelines for management options for these cancer risks.

#### **5.2 Risk reducing surgery**

Women with LS may consider prophylactic hysterectomy and bilateral salpinooophorectomy (BSO) to substantially reduce the risk of endometrial and ovarian cancers (Guillem et al., 2006; NCCN Practice Guidelines 2011). In a large retrospective case-control study of 315 mutation-positive (*MLH1, MSH2*, or *MSH6*) women, risk-reducing hysterectomy with BSO proved to be an effective strategy for preventing endometrial and ovarian cancer (Schmeler et al., 2006). No women who had a hysterectomy developed EC compared with 69 of 210 (33%) of the controls (no hysterectomy). Further, no women who underwent a BSO developed ovarian cancer compared with 12 of 233 (5%) of the controls (no BSO). One ovarian cancer was diagnosed in a woman who underwent a hysterectomy. Risk-reducing surgery may take place at the time of CRC diagnosis or once child-bearing is completed. In addition, there are no recommendations for chemopreventive strategies in LS to decrease gynecologic cancer risks. Studies from Lu et al., suggest oral contraceptive pills or medroxyprogesterone acetate (Depo-Provera) may have the potential to prevent EC and/or ovarian cancer associated with LS (Lu et al., 2010).

Counseling regarding prophylactic surgery of this kind should include not only the risks inherent in surgery, but also premature menopause and its associated risks; menopausal vasomotor symptoms, estrogen therapy, osteoporosis, urogenital atrophy, and less clear, heart disease (Chen et al., 2007; Schmeler et al., 2006). Preoperative assessment should include colonoscopy, endometrial sampling, TVUS and a CA125 tumor marker. Preparation for a complete surgical staging should be available if occult carcinoma is found.

Cost-effectiveness decisions must be reviewed with the patient when embarking on a management strategy for surveillance or prevention of LS-associated cancers. One study compared different strategies in a hypothetical cohort of women with LS: 1) no prevention, 2) prophylactic hysterectomy and BSO at age 30, 3) prophylactic surgery at age 40, 4) annual screening with endometrial biopsy, TVUS and CA125 from age 30, and 5) annual screening from age 30 until prophylactic surgery at age 40 (combined strategy) (Kwon et al., 2008). The authors found that annual screening followed by prophylactic surgery at age 40 was the most effective gynecologic cancer prevention strategy, but the incremental benefit over riskreducing surgery alone came with a substantial cost. Thus, a careful review of different strategies to improve the effectiveness and decrease the lifetime costs of these interventions is warranted in patients with LS.
