EXTRACOLONIC CANCER IN LYNCH SYNDROME
Endometrial cancer is the fifth most common cancer in women in the UK, accounting for 7 % of invasive cancers in women, occurring in 1 in 100 women by 75 years of age. The commonest histological type (90 %) is adenocarcinoma. Women with Lynch syndrome have a very high lifetime risk of endometrial cancer. Tumours characteristically demonstrate MSI + (due to impaired repair of mismatch DNA errors), and complex atypical endometrial hyperplasia appears to be the premalignant endometrial lesion (Lohse et al. 2002; Sutter et al. 2004). Carriers of MSH6 mutations have the highest endometrial cancer risk (Wijnen et al. 1999), and the risk is higher in MSH2 than MLH1 mutation carriers (Vasen et al. 2001; Huang et al. 2004). Women with Lynch syndrome have a lifetime risk of endometrial cancer of up to 60 %, with the highest incidence between 40 and 60 years of age, average 49.3 years. The characteristics of endometrial cancer in Lynch syndrome, which appear to be different from sporadic cancers, include more poorly differentiated histology (83 % versus 27 % in sporadic cancers) with Crohn’s-like lymphoid reaction (100 % versus 27 %), lymphangio-invasive growth (67 % versus 0 %), and Tumours invasion by lymphocytes (100 % versus 36 %) (Van den Bos et al. 2004).
The risk of ovarian cancer in women with Lynch syndrome is about 8%, the highest in MLH1 and MSH2 mutation carriers. There is an increased risk of pancreatic cancer in Lynch syndrome, RR of 8, with a cumulative risk of 4 % by the age of 70 years (Kastrinos et al. 2009). It is still unclear whether the risk of breast cancer is increased in individuals with Lynch syndrome. An increased risk of breast cancer has been reported recently, and the Tumours have been shown to be deficient in the relevant MMR protein, especially in MLH1 mutation carriers (Engel et al. 2012; Barrow et al. 2009; Jensen et al. 2009), although other studies have failed to demonstrate an increased risk (Watson et al. 2008). More recent studies have again suggested that there is an increased risk for breast cancer in MMR mutation carriers (Win et al. 2012). Engel et al. (2012) reported a significantly increased risk of prostate cancer in Lynch syndrome (SIR 2.5 (1.4–4)), highest in MSH2 mutation carriers, and similar small increases in risk were reported in two other studies (Grindedal et al. 2009; Barrow et al. 2012). Immunohistochemistry showed loss of the relevant MMR
gene protein in most Tumours tested. There is an increased risk of urothelial cancer in Lynch syndrome. The risk of gastric cancer is also increased, with a lower age at diagnosis than in the general population; the risk appears to be higher in countries where the background risk of gastric cancer is high.
First-degree relatives of individuals affected by Lynch syndrome should be offered screening for colorectal cancer and possibly for other cancers seen in their family. Since colorectal adenomas are assumed to be the premalignant lesions (for colorectal cancer), and the majority of lesions are right sided, colonoscopy is the screening method of choice (Hodgson et al. 1995; Vasen et al. 2007, 2013). Asymptomatic at-risk relatives (with an affected first- degree relative with Lynch syndrome) should be offered annual colonoscopy from the age of 25 (Umar et al. 2004b). Interval cancers have been detected in individuals screened at 2-yearly intervals, so annual examinations are probably optimal but often not very practical, and therefore a “compromise” has been made by starting 18-monthly colonoscopies from 20 to 25 years of age, since fewer than 1 % of patients with Lynch syndrome develop colorectal cancer before the age of 20 years. The adenoma-carcinoma progression rate appears to be very much increased in Lynch syndrome above that in the general population (Jass 1995). If adenomas are found, they are removed, and colonoscopy should be repeated annually. There is good evidence that such screening does reduce cancer morbidity and mortality in screened individuals (Jarvinen et al. 1995; Renkonen-Sinisalo et al. 2000) and lead to the detection of CRC at an earlier stage, with a reduction of the risk of CRC by 63 %, and reduced colorectal cancer mortality (Vasen et al. 2007, 2013).
When colorectal cancer is detected in an affected individual, many centers advocate subtotal or even total colectomy because of the significant risk of a second colorectal cancer, but the evidence for and against such management options is still lacking, and there is currently a European trial to evaluate this (Olschwang et al. 2005). Prophylactic hysterectomy and subtotal colectomy may be considered in certain cases of Lynch syndrome (Celentano et al. 2011). Lifetime surveillance for rectal cancer should be continued after such surgery. The risk of rectal cancer has been assessed at 12 % over a 12- year follow-up period (Jarvinen et al. 2000). Such surgery could also be offered to MMR gene mutation carriers who have been found to have recurrent or dysplastic adenomas. Carrier women found to have colon cancer require careful preoperative assessment of ovarian and uterine cancer. Even if there is no evidence of current malignancy, prophylactic hysterectomy and bilateral oophorectomy at the time of colon surgery should be considered when there is a strong family history of these neoplasms. In view of the substantial risk of a second CRC after partial colectomy, the option of subtotal colectomy should be considered when undertaking surgery for a first colorectal cancer.
Aspirin significantly reduces the incidence of cancer in Lynch syndrome, so treatment with regular small doses may be advisable, but the pros and cons of such treatment should be carefully discussed in view of the side effects of such treatment.
It has been claimed that individuals with Lynch syndrome may have a survival benefit from treatment with adjuvant chemotherapy (Elsaleh et al. 2001), although the evidence for this is conflicting; current evidence suggests that Tumours demonstrating MMR deficiency are resistant to chemotherapeutic agents including 5-FU, methylating agents, and antimetabolites (Bignami et al. 2003; Clark et al. 2004).
Because of the increased risk of gynecological cancers (ovarian and endometrial) in females with Lynch syndrome (possibly up to a half of total cancer risk), women with this disease and those at high risk of inheriting it should probably be followed up with annual bimanual pelvic examination and transvaginal ultrasound scan for ovarian and uterine cancers from 30 years of age. Transvaginal ultrasound with Doppler examination may delineate ovarian lesions, and a serum CA125 is also suggested annually (Jacobs and Lancaster 1996), but the efficacy of such surveillance is still unproven. Regular endometrial aspiration and biopsy (pipette or hysteroscopic biopsy) is more sensitive than ultrasound for the detection of premalignant lesions such as atypical endometrial hyperplasia and endometrial cancer (Wood and Duffy 2003), but since endometrial cancer has a relatively good prognosis, and the efficacy of surveillance is as yet unknown, screening would be best performed in the setting of a prospective study (Vasen et al. 1996, 2013).
Hysterectomy and bilateral oophorectomy largely prevent the development of endometrial and ovarian cancer and may be considered in women with Lynch syndrome after childbearing age, especially if colorectal cancer surgery is scheduled.
A high incidence of other Lynch syndrome-associated cancers in particular families may be an indication for screening for specific cancer within that kindred showing an increased frequency of these extracolonic cancers. Thus, dermatological surveillance may be offered in Muir–Torre families. The estimated risk of urothelial cancer in Lynch syndrome varies from 5 to 20 %, highest in MSH2 mutation carriers. These usually present with painless hematuria, and the prognosis is relatively good. Surveillance for urological malignancy could be offered by abdominal ultrasound and cytological examination of an early-morning urine sample for red blood cells and cytology, and Tumours-specific markers, from 30 to 35 years of age, although this is controversial and not of proven efficacy (Myrhoj et al. 2008).
Most gastric cancers in Lynch syndrome are of the intestinal type, so regular upper GI endoscopy may lead to early detection of precursor lesions and early cancer. Precursor lesions have been ascertained in MMR gene mutation carriers: H. pylori infection was observed in 26 %, atrophy in 14 %, and intestinal metaplasia also in 14 % (Renkonen-Sinisalo et al. 2000).
Gastroscopies annually, with eradication of Helicobacter pylori infection, when present, could, therefore, be considered from the age of 35 years in individuals with a strong family history of gastric cancer (Park et al. 2000) or those in areas with a high background risk of gastric cancer such as Japan, although the efficacy of such screening has not yet been established. (For more discussion, Renkonen-Sinisalo et al. 2002; ten Kate et al.
2007; Vasen et al. 2007).
Because some studies have found a slight increase in the risk of prostate cancer in men with Lynch syndrome, screening by PSA analysis could be considered, but as no evidence exists for the benefits of screening for prostate cancer in MMR gene mutation carriers at the present time, this should only be considered as part of a research study.
Screening for pancreatic cancer has not been shown to be of benefit, so any surveillance should only be performed as part of a research study.