Risk of Metachronous Colorectal Cancer in Lynch Syndrome: Who Needs an Extended Resection?

Abstract

Lynch syndrome (LS) is the most common genetic condition associated with early-onset colorectal cancer. It is inherited in an autosomal dominant fashion. The increased cancer risk is due to a germline mutation in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene. This leads to a deficient DNA mismatch repair mechanism, resulting in the accumulation of nucleotide changes and microsatellite instability, providing phenotypical evidence that MMR is not functioning normally. LS is associated with a high risk of early-onset colorectal cancer and recurrence. Thus, when undergoing surgery for primary colorectal cancer, extended resection should be discussed with the patient. This review provides an overview of current surgical risk-reducing strategies in LS-associated colorectal cancer. Surgical treatment for LS carriers with colorectal cancer needs to be highly individualized, based on patient and disease characteristics. Strategies are presented to guide decision making in pathologic MMR gene mutation carriers undergoing surgery for colorectal cancer.

1. Introduction

Lynch Syndrome (LS) is a hereditary cancer predisposition syndrome associated with an elevated lifetime risk of several cancers. These include colorectal, endometrial, ovarian, gastric, small intestine, hepatobiliary, urinary, brain, and skin cancer. About 3% of all cases of colorectal cancer (CRC) are associated with LS [1]. It was formerly called hereditary non-polyposis colorectal cancer (HNPCC) due to the perceived absence of characteristic colorectal polyps and to differentiate it from the polyposis form of hereditary cancer. LS is now known to be associated with a pathologic germline mutation in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or loss of EPCAM, resulting in hypermethylation of the MSH2 promoter [2,3]. LS is inherited in an autosomal dominant manner. It was traditionally identified in symptomatic cancer patients fulfilling a set of clinical criteria which are known as the Amsterdam or Bethesda criteria [4,5]. Additionally, several prediction models were presented that help estimate the probability of LS based on clinical parameters [6]. Current guidelines, however, recommend screening for evidence of mismatch repair deficiencies in all colorectal and endometrial cancer patients. This is usually performed by starting with immune histochemistry (IHC) of the MMR genes in tumor tissue followed by further sequential testing for LS in cases with loss of gene expression [7]. If LS is confirmed in an index patient, direct family members can be offered germline testing to identify mutation carriers at an early age and to inform surveillance. Many cases of LS are only identified after diagnosis of an index cancer, and since sequential testing leading to confirmation of a germline mutation is not always readily available, mutational status is often not known at index surgery. Thus, for discussing extended surgery mutation status should be available. Therefore, guidelines recommend performing IHC screening for defunct MMR genes on preoperative cancer biopsies or direct germline genetic testing for path_MMR [7]. The incidence of primary and metachronous colorectal cancer varies depending on the affected path_MMR gene and probably also on the gender [8]. The goals for surgical treatment of CRC in patients with LS are to maximize life expectancy while preserving the quality of life. In the following paragraphs, the surgical strategies for CRC in LS carriers are outlined considering patient and disease characteristics.

2. Defining the Risk of Metachronous Cancer in Lynch Syndrome Patients

To establish an individual patient’s metachronous cancer risk, several variables need to be considered. It is now known that cancer risk is not equal for all mismatch repair genes. Genotype–phenotype correlations have been described in LS families for some time [9,10]. Several study groups have since published their data from large cohorts from national and international databases, suggesting a higher CRC risk for path_MLH1 and path_MSH2 carriers compared to path_MSH6 and path_PMS2 carriers [11,12]. These findings have led to the recommendation of extended surgery (either subtotal colectomy with ileosigmoidal anastomosis or total colectomy with ileorectal anastomosis) for high-risk path_MLH1 and path_MSH2 but not for path_MSH6 and path_PMS2 carriers by European expert groups [7]. A recent meta-analysis found a 22.8% and 6% metachronous colorectal cancer rate in the segmental and extended colectomy groups, respectively, resulting in a four-fold risk of metachronous CRC in patients that received segmental colectomy only (OR 4.02, 95% CI: 2.01–8.04, p < 0.0001) [13]. Metachronous cancer occurred in patients despite 1–2 yearly endoscopic surveillance. Two other meta-analyses also found an increased metachronous cancer risk for patients after segmental colectomy but no statistical difference in mortality [14,15]. The main findings from the meta-analyses are outlined in

Table 1. Systematic reviews and meta-analyses on the risk of metachronous colorectal cancer following segmental vs. extended colectomy.

Author and Year	Year of Publication of Included Studies	Number of Included Studies	Number of Included Cases Overall (SC/EC)	Metachronous CRC (SC vs. EC)	Overall Survival (SC vs. EC)
Heneghan et al. (2015) [14]	1993–2012	6	948 (780/168)	23.5% vs. 6.8% (OR: 3.69, 95% CI: 1.889–7.125, p < 0.005)	10-year: 90.7% vs. 89.7% (OR: 1.92, 95% CI: 0.915–4.035, p = 0.09)
Anele et al. (2017) [13]	2002–2015	6	871 (705/166)	22.6% vs. 6.0% (OR: 4.02, 95% CI: 2.01–8.04, p < 0.001)	Not reported
Malik et al. (2018) [15]	1993–2017	10	1389 (1119/270)	LS: OR: 8.56, 95% CI: 3.37–21.73, p < 0.01; HNPCC: OR: 3.04; 95% CI: 1.46–6.34, p < 0.01	OR: 1.65, 95% CI: 0.90–3.02

LS, Lynch syndrome; SC, segmental colectomy; EC, extended colectomy; HNPCC, hereditary nonpolyposis colorectal cancer. Modified from [22], with kind permission

. A recent prospective Lynch syndrome database (PLSD) study reported that the risk of metachronous colorectal cancer by age 70 was 36% (95% confidence interval 29 to 43.8) despite regular colonoscopies. Based on their data, the PLSD provides an online resource that allows for the calculation of cumulative risk for cancer by age, genetic variant, and gender that can be used for personal genetic counseling and decision-making. The resource is available at http://www.plsd.eu/ (accessed on 16 May 2022) [16]. The benefit of surveillance colonoscopy with polypectomy in the general population has been associated with a reduction in CRC risk and improved survival [17,18]. Several studies, however, independently demonstrated that a substantial proportion of LS carriers developed CRC despite regular colonoscopic surveillance [19]. While the reasons for this observation are not completely understood, it represents an important argument for the discussion of extended surgery [19]. Increasing evidence suggests that cancer risk is not only influenced by the path_MMR gene but also by gender, genetic modifiers, obesity, and lifestyle factors such as physical activity, smoking, alcohol consumption, diet, and even continent of residence [20,21]. Therefore, an individual’s risk assessment needs to consider the patient’s age, comorbidities, and genotype, as well as expected functional outcome and priorities. Other factors such as peritoneal adhesions due to prior (open) surgery and an elevated risk for repeat surgery or intolerance of surveillance endoscopy may also influence the informed decision for extended surgery. To facilitate interval colectomies, a laparoscopic approach should be preferred when performing segmental colectomy in LS patients whenever possible.

3. Extended Resection at Index Surgery for Colon Cancer in Path_MMR Carriers

As outlined in the previous paragraph, the risk of metachronous cancer was consistently shown to be reduced by subtotal colectomy at the time of diagnosis of first colon cancer in patients with LS. Consequently, subtotal colectomy reduced the need for subsequent surgery in LS [23]. The ideal extent of resection however is not defined. While European guidelines recommend subtotal colectomy with an ileosigmoidal anastomosis, American guidelines recommend a total abdominal colectomy with ileorectal anastomosis [7,24]. Current guideline recommendations on the operative strategy according to the affected gene are summarized in

Table 2. Surgical options for colorectal cancer in path_MMR carriers.

	Path_MLH1	Path_MSH2	Path_MSH6	Path_PMS2
Primary Colon Cancer	Subtotal colectomy	Subtotal colectomy	Segmental colectomy *	Segmental colectomy *
Metachronous colon cancer after segmental colectomy	Subtotal colectomy with ileorectal anastomosis	Subtotal colectomy with ileorectal anastomosis	Subtotal colectomy with ileorectal anastomosis	Subtotal colectomy with ileorectal anastomosis
Primary rectal cancer	Anterior resection/APR	Anterior resection/APR	Anterior resection/APR	Anterior resection/APR
Rectal cancer after previous segmental colectomy	Proctocolectomy with ileal pouch–anal anastomosis/APR with a permanent ileostomy	Proctocolectomy with ileal pouch–anal anastomosis/APR with a permanent ileostomy	Proctocolectomy with ileal pouch–anal anastomosis/APR with a permanent ileostomy	Proctocolectomy with ileal pouch–anal anastomosis/APR with a permanent ileostomy

APR, abdominoperineal resection, modified from [7]. * Note that current US guidelines recommend subtotal colectomy with ileorectal anastomosis for all path_MMR carriers irrespective of the affected gene. They also recommend consideration of less extensive surgery for patients above age 60–65 or with underlying sphincter dysfunction.

. The optimal reconstructive strategy for extended resection for CRC in LS patients is not defined. Reports comparing the rate of metachronous cancer in CRC patients with LS after subtotal colectomy with ileorectal or ileosigmoidal anastomosis are lacking. However, there is functional benefit for sigmoid colon preservation. In a retrospective study of 320 patients undergoing either ileorectal or ileosigmoidal anastomosis for different pathology, Duclos et al. reported ileorectal anastomosis as an independent factor to be associated with poor long-term function [25]. Other studies have found fewer bowel movements, better quality of life and lower rates of anastomotic leakage for ileosigmoidal compared to ileorectal anastomosis [26,27]. There is physiological rationale for preserving the rectosigmoid region, since retrograde motor patterns in the sigmoid region—termed the rectosigmoid brake—were demonstrated to limit rectal filling and thus may help preserve bowel function [28]. Taken together, it is conceivable that complete abdominal colectomy will result in somewhat lower rates of metachronous cancer at the cost of worse functional outcomes. Studies on the optimal operative strategy for CRC in LS are needed to clarify these points and guide surgeons and patients.

4. Prophylactic (Risk-Reducing) Surgery in Asymptomatic Mutation Carriers

While prophylactic proctocolectomy is recommended in patients with a pathologic germline mutation in the APC gene leading to familial adenomatous polyposis (FAP), no such recommendation exists for path_MMR mutation carriers. To date, there is insufficient evidence to recommend prophylactic (risk-reducing) surgery for path_MMR carriers. No documented strategy exists to identify LS patients at higher risk than others based on gene, gender, or age. It is unclear whether concomitant risk factors warrant prophylactic surgery in LS patients. McNamara et al., in a small series of 12 patients with LS and concurrent inflammatory bowel disease, did not find a sufficiently increased CRC risk to recommend prophylactic surgery [29]. Further studies are needed to define whether cohorts within LS patients exist that benefit from prophylactic surgery. However, in patients not deemed suitable for colonoscopic surveillance or at very high familial risk, prophylactic surgery can be an option.

5. Surgery for Rectal Cancer in Lynch Syndrome

Studies have reported metachronous colon cancer after surgery for rectal cancer in path_MMR carriers. However, the number of reported cases is much lower than for colon cancer [30,31]. Consequently, there is insufficient evidence to support extended surgery for primary rectal cancers in path_MMR carriers. National and international guidelines thus recommend anterior resection or abdominoperineal resection (APR) as primary surgery in these cases [8,23,30]. In patients with rectal cancer after previous segmental colectomy, proctocolectomy with ileal pouch–anal anastomosis or abdominoperineal resection with permanent ileostomy is recommended by the European expert group; however, no data exist to support this recommendation [7].

6. Extended Resection for Lynch Syndrome Carriers at the Time of Recurrence

To date, no studies have reported the risk of a third colorectal cancer after a subsequent metachronous colorectal cancer. Studies addressing the addition of proctectomy to colectomy at CRC recurrence in LS are lacking. To establish the optimal surgical treatment in these patients, (prospective) studies are needed. Based on weak evidence and expert opinion led by understanding of the probability of metachronous CRC in LS patients, guidelines recommend extensive resection at CRC recurrence either as subtotal colectomy with ileorectal anastomosis in patients with metachronous colon cancer or proctocolectomy with ileal pouch–anal anastomosis in patients with metachronous rectal cancer [7,24,32].

7. Risk-Reducing Gynecologic Surgery at the Time of Colorectal Cancer Surgery

Although not within the scope of this article, risk-reducing prophylactic gynecologic surgery (RRS) should be briefly mentioned, as simultaneous risk-reducing surgery at the time of treatment for CRC may be advised in some cases. Women with LS have a 40–60% risk of endometrial cancer, which is similar to colorectal cancer risk. Additionally, they have a 12% risk of ovarian cancer [33]. There is no effective screening program for endometrial cancer. Risk-reducing surgery including total hysterectomy and bilateral salpingo-oophorectomy (BSO) prevents gynecological cancer in women with LS and is the only effective preventive approach [34,35]. Therefore, the Manchester International Consensus Group strongly recommends that risk-reducing total hysterectomy and BSO be offered to women, but no earlier than at age 35–40 after completion of childbearing in path_MLH1, path_MSH2, and path_MSH6 carriers [36]. There is insufficient evidence to strongly recommend RRS in path_PMS2 carriers. In women with CRC in whom these criteria are met, RRS should therefore be offered at the same time as colonic resection after “high-quality preoperative multidisciplinary counseling” [36]. Interestingly, a recent study on the uptake of RRS among 2292 female path_MMR carriers found that only 5% of the RRS (20/392) was performed simultaneously with CRC surgery [37].

8. Future Directions

In recent years, understanding of the role of the affected path_MMR gene for CRC risk has evolved, leading to refined recommendations for surveillance and treatment depending on gene and gender. Thus far, data on patients with MHS6, PMS2, or EPCAM are lacking. Improved understanding of these less frequent path_MMR types will help determine personalized treatment strategies for each LS patient. Additionally, improved understanding of individual risk will allow cancer risk-reduction to be weighed against functional outcomes. Further studies, particularly prospective studies, will help better define optimal operative strategies for each tumor localization, maximizing functional outcomes. Additionally, improvement in diagnostics and medical treatment will likely have an impact on the extent and timing of surgery.

9. Conclusions

Studies have shown no difference in overall survival between segmental and extended colectomy in CRC patients with LS. However, extended colectomy may still be the preferred option as it decreases the risk of metachronous CRC, especially in younger patients [38]. Data on postoperative quality of life after extended colectomy for CRC in LS are scarce. However, the available evidence suggests that while stool frequency was higher in patients with extended colectomy, leading to a loss in associated social function, overall quality of life was not affected. In conclusion, surgeons caring for patients with LS should be aware of the risk of metachronous CRC despite regular colonoscopic surveillance. Careful preoperative counseling is mandatory. Full preoperative workup including identification of path_MMR carriers should be available at the time of surgical planning in patients with a suspicion of LS associated CRC.