Abstract
Background
Because of increased risk of metachronous colorectal cancer (CRC), all Lynch Syndrome (LS) patients are offered a total colectomy. However, since metachronous CRC rate by MMR gene is uncertain, and total colectomy negatively impacts quality of life, it remains unclear whether segmental resection is indicated for lower penetrance MMR genes. We evaluated metachronous CRC incidence according to MMR gene in LS patients who underwent a segmental colectomy.
Study Design
Single-center, retrospective cohort study in patients with a prior colectomy for CRC and an MMR germline mutation in MLH1, MSH2, MSH6, or PMS2 followed prospectively in a Hereditary CRC Family Registry. All patients underwent surveillance colonoscopy. Metachronous CRC was defined as one detected more than 1 year after index resection. Primary outcome was cumulative incidence of metachronous CRC overall and by MMR gene.
Results
110 patients were included: 35 with MLH1 likely pathogenic/pathogenic (LP/P) variants (32%), 42 MSH2 (38%), 20 MSH6 (18%), and 13 PMS2 (12%). Median follow-up 4.26 years (range 0.53 to 19.92). Overall, 22 patients (20%) developed metachronous CRC. At 10-year follow-up, incidence was 12% (95% CI 6 to 23%), with no metachronous CRC detected in patients with a PMS2 or MSH6 LP/P variant.
Conclusion
After index segmental resection, LS patients with a MSH6 or PMS2 LP/P variant are less likely to develop metachronous CRC than MLH1 or MSH2 carriers. Our data support segmental resection and long-term colonoscopic surveillance rather than a total colectomy in carefully selected, well-informed LS patients with a MSH6 or PMS2 LP/P variant.
Keywords: Colorectal Neoplasms, Hereditary Nonpolyposis, Colectomy, Germ-Line Mutation, Neoplasms, Second Primary
Precis
After a segmental colectomy for an index colorectal cancer, Lynch syndrome patients with an MSH6 or PMS2 mismatch repair likely pathogenic/pathogenic variant are less likely to develop a metachronous colorectal neoplasm than MLH1 or MSH2 carriers.
Introduction
Lynch syndrome (LS) is an autosomal-dominant inherited condition, caused by germline mutations in mismatch repair (MMR) genes that results in an inability to correct errors during the process of DNA replication. Likely Pathogenic/pathogenic (LP/P) variants in specific MMR genes (MLH1, MSH2, MSH6, and PMS2) are associated with a significantly increased risk of developing a number of solid cancers, with colorectal cancer (CRC) being the most common.(1) Along with the increased risk of developing an index CRC, there is also an increased lifetime risk of developing a metachronous CRC.(2) For this reason, an extended colonic resection (subtotal or total colectomy) has been advocated in LS patients with a LP/P MMR gene. (2–5) However, although this strategy is effective in reducing the risk of a metachronous neoplasm, functional consequences, such as increased frequency of bowel movements and possible negative impact on quality of life, temper the enthusiasm of some providers—and LS patients, who tend to be younger—to pursue this approach.(6) An alternative strategy is a segmental resection and frequent surveillance colonoscopy. However, this approach has its own limitations, since a fraction of patients will develop an invasive metachronous CRC despite regular surveillance colonoscopy. Furthermore, recent studies of clinically unaffected individuals with confirmed LS showed that more frequent colonoscopic surveillance (every 1 to 2 years rather than every 3 years) did not reduce CRC incidence or stage at detection (7) suggesting that more frequent surveillance colonoscopy after segmental resection is not likely to significantly reduce the risk of metachronous CRC. Nonetheless, in the US, NCCN guidelines (8), continue to recommend colonoscopic surveillance every 1–2 years for individuals affected with Lynch Syndrome.
Recent population data on unaffected patients with LP/P MMR genes demonstrate differential penetrance for cancer development and survival according to type of MMR gene harbored suggesting that individuals with confirmed LS may be risk-stratified according to type of MMR gene and offered a tailored surveillance protocol with more or less frequency depending on level of risk (9–13). Conversely, since the use of surveillance colonoscopy does not fully reduce the risk of developing a metachronous CRC, risk stratification by type of MMR gene may help identify LS CRC patients at high risk of metachronous CRC. For these patients, awareness of their increased risk may make an upfront total colectomy a more palatable option. Previously, we demonstrated the value of targeted genetic testing of MSH2 A636P mutation in Ashkenazi Jewish patients for helping determine the extent of colon resection. (14)Due to the paucity of data on rates of metachronous CRC after a segmental colectomy in LS CRC patients, our study aimed to evaluate the risk of metachronous CRC according to MMR gene in LS patients after segmental colectomy for an index colorectal cancer.
Methods
Study design and participants
This was a single-center retrospective cohort study that included patients who were enrolled into a prospectively maintained Hereditary Colorectal Cancer Family Registry between August 21, 2001, and November 30, 2017. The Hereditary Colorectal Cancer Family Registry at Memorial Sloan Kettering Cancer Center (MSK) is an institutional review board (IRB)-approved study (IRB protocol # 01–110) that prospectively enrolls patients with various forms of hereditary CRC, including early-onset CRC (younger than 40 years of age at time of diagnosis), syndromic polyposis, non-syndromic polyposis (gene-negative), or a germline-confirmed diagnosis of a known inherited syndrome such as Lynch Syndrome.
We included all patients who had undergone a segmental colectomy for a CRC with a confirmed LP/P MMR variant in one of four specific genes: MLH1, MSH2, MSH6, and PMS2. Exclusion criteria included lack of a follow-up colonoscopy after an initial CRC, or any synchronous colorectal carcinoma diagnosed within a year after resection of the index lesion. Data on demographics, familial history of cancers, number of follow-up colonoscopies, and surgical and pathologic histories were obtained from patients’ medical records and the Hereditary Colorectal Cancer Family Registry database. This study was approved by the MSK IRB, and a waiver of informed consent was obtained (IRB #16–1656).
A metachronous CRC was defined as a new CRC diagnosed one year after the index CRC. The primary outcome was to determine the cumulative incidence of metachronous CRC after index CRC according to MMR gene. If no event was observed, the patientś follow-up was censored on the date of last colonoscopy.
Clinicopathologic criteria
In addition to standard pathological variables, patient data were also evaluated according to both the Amsterdam II Criteria and the revised Bethesda Guidelines. The Amsterdam criteria are used to identify patients who may have LS and the Bethesda Guidelines are used to identify patients who should undergo tumor testing for microsatellite instability (MSI). (15, 16)
Statistical analysis
Categorical variables are presented as frequencies while continuous variables are presented as medians with ranges. The Kaplan-Meier method is used to describe and estimate metachronous CRC free rates-overall and by MMR gene. One minus the Kaplan Meier estimates were used to graph cumulative incidence. All statistical tests are two-sided and p-values of <0.05 are considered statistically significant. All statistical analyses are performed using R version 3.6.0 Software (R Foundation for Statistical Computing, https://R-project.org).
Results
A total of 202 LS patients were identified as potentially eligible for our study. Of these, 92 patients were excluded: 53 had no follow-up colonoscopy, 32 had undergone an extended resection, and 7 had a synchronous lesion at the time of the index surgery (Fig. 1). Demographic data on the final cohort of 110 patients is presented in Table 1.
Figure 1.
Patient flow chart of the study
Table 1.
Patient, Disease, and Surgical Characteristics
| Characteristic | Data (n = 110) |
|---|---|
| Age, y, median (range) | 44.5 (7–74) |
| Sex, female, n (%) | 53 (48) |
| Positive Amsterdam II Criteria, n (%) | 40 (36) |
| Positive Bethesda Criteria, n (%) | 83 (75) |
| HNPCC-related tumors, total, n (%) | 27 (25) |
| Endometrium, n | 23 |
| Ovary, n | 1 |
| Urothelium, n | 1 |
| Other, n | 2 |
| LP/P MMR variant, n (%) | |
| MLH1 | 35 (32) |
| PMS2 | 13 (12) |
| MSH2 | 42 (38) |
| MSH6 | 20 (18) |
| Primary tumor location, n = 103, n (%) | |
| Right colon | 58 (56) |
| Left colon | 31 (30) |
| Rectum | 14 (14) |
| Median number of follow-up colonoscopies (range) | 3 (1–8) |
HNPCC, hereditary nonpolyposis colorectal cancer; LP/P likely pathogenic/pathogenic; MMR, mismatch repair.
Only 36% of patients met the modified Amsterdam II Criteria. Most patients (75%) met the revised Bethesda Guidelines. In terms of LP/P MMR genes, 42 patients (38%) had MSH2 variants, 35 (32%) had MLH1, 20 (18%) had MSH6, and 13 (12%) had PMS2 variants.
More than half (56%) of patients had a primary right CRC, with only 14% of the cancers located in the rectum. The median number of follow-up colonoscopies in the cohort was 3 (range 1 to 8). The pathologic specimen characteristics of the primary tumor was available for 97 patients: according to American Joint Committee on Cancer (AJCC) staging guidelines, 33 patients had stage Tis/I disease, 36 had stage II, 27 had stage III, and only 1 had stage IV. Other pathologic characteristics of the primary tumors are summarized in Table 2.
Table 2.
Primary Tumor Characteristics
| Characteristic | Data (n = 97) |
|---|---|
| AJCC pathological stage, n (%) | |
| Tis | 5 (5) |
| I | 28 (29) |
| II | 36 (37) |
| III | 27 (28) |
| IV | 1 (1) |
| Mucinous tumor, n (%) | 50 (52) |
| Tumor budding, n (%) | 4 (4) |
| Lymphocyte infiltration, n (%) | 16 (16) |
| Lymphovascular infiltration, n (%) | 18 (19) |
| Large venous invasion, n (%) | 1 (1) |
| Perineural invasion, n (%) | 4 (4) |
| Lymph node harvested, n, median (range) | 24.5 (1–105) |
AJCC, American Joint Committee on Cancer.
Rate and time to metachronous CRC according to pathogenic MMR gene
The median time of follow-up was 4.26 years (range 0.53 to 19.92). As shown in Table 3, 22 (20%) patients developed a metachronous CRC: 9 with mutations in MLH1, 10 with mutations in MSH2, 2 with mutations in PMS2, and only 1 with a mutation in MSH6. Sixteen pathology reports are available, showing that most patients had stage I (38%) or II (31%) disease at the time of diagnosis. In addition, 25% of the metachronous lesions were stage III at diagnosis. Half of the patients had at least one more adenoma in the surgical specimen.
Table 3.
Metachronous Colon Adenocarcinomas Characteristics
| Characteristic | Data |
|---|---|
| MMR gene, n = 22, n (%) | |
| MLH1 | 9 (26) |
| MSH2 | 10 (24) |
| PMS2 | 2 (15) |
| MSH6 | 1 (5) |
| AJCC pathological stage, n = 16, n (%) | |
| Tis | 1 (6) |
| I | 6 (38) |
| II | 5 (31) |
| III | 4 (25) |
| Any other adenoma in surgical specimen, n (%) | 8 (50) |
AJCC, American Joint Committee on Cancer; MMR, mismatch repair.
The metachronous CRC cumulative incidence rate for the whole cohort was 7% (95% confidence interval [CI] 3 to 15%) at 5 years and 12% (95% CI 6 to 23%) at the 10-year follow-up (Fig. 2). Patients with MLH1 and MSH2 LP/P variants had a 10-year cumulative incidence of 23% (95% CI 10 to 49%) and 10% (95% CI 3 to 29), respectively. No metachronous CRCs were observed in patients with MSH6 and PMS2 LP/P variants during a 10-year follow-up (Fig. 3). Two patients with a PMS2 LP/P variant developed a metachronous CRC at 20 and 37 years after index segmental resection. The only patient with a MSH6 LP/P variant who developed a metachronous CRC did so at 46 years after the index resection.
Figure 2.
Overall metachronous colorectal cancer (CRC) cumulative incidence in 20 years period of observation. Cumulative incidence at 5 years = 7% (95% CI 3 to 15), 10 years = 12% (95% CI 6 to 23)
Figure 3.
Metachronous colorectal cancer (CRC) cumulative incidence by mismatch repair gene through 20 years of observation. During a 10-year follow-up, no events were observed in patients with a likely pathogenic/pathogenic PMS2 or MSH6 variant. Cumulative incidence for MLH1 and MSH2 at 5 and 10 years is shown.
Discussion
Our data suggest that, after a segmental colectomy for an index CRC, LS patients with an MSH6 or PMS2 LP/P variant are less likely to develop a metachronous colorectal neoplasm than MLH1 or MSH2 carriers. Our results, which are similar to those in MMR carriers undergoing surveillance as reported by Vasen et al,(17) support biological data demonstrating that MLH1 and MSH2 LP/P variants represent a stronger mutator phenotype.(18, 19) Also consistent with other reports,(2, 20) a long time interval between the index CRC and the metachronous CRC was noted in our patients with a PMS2 LP/P variant.
The rate of metachronous CRC in our cohort (20%) was similar to some other reports,(2, 20) although Anyla et al (21) reported a rate of 32%. This higher rate could be explained by the fact that they defined metachronous CRC as all cancers that had not been diagnosed at the time of the index cancer. Therefore, it is likely that they included synchronous CRC, which occurs more frequently in LS patients.(22) Parry et al (2) reported an overall rate of metachronous CRC of 22% and a 10-year cumulative risk of CRC of 16%, both of which are similar to our results. In addition, they concluded that metachronous CRC risk did not differ by the MMR gene, although they stated that the numbers for MSH6 and PMS2 variants were too low to draw any conclusions. Our study found no incidence of metachronous CRC at 10 years in patients with MSH6 and PMS2 LP/P variants. These findings are in concordance with those of Møller et al and the Mallorca Group (13), which demonstrate that cancer risks differ according to MMR mutation. They reported cumulative incidences of CRC of 46%, 43%, and 15% in MLH1, MSH2, and MSH6 carriers at 75 years of age.(13) The same group reported that LS-related cancers were detected beyond 25 years of age in carriers of MLH1 and MSH2 LP/P variants, and from about 40 years of age in carriers of MSH6 and PMS2 LP/P variants. They further commented that among first cancer detected, the CRC cumulative incidences at 70 years by LP/P variant were 46%, 35%, 20%, and 10% for MLH1, MSH2, MSH6 and PMS2, respectively.(11) These observations demonstrate that different MMR genes are associated with significant differences in patterns of penetration and expression, with MSH6 and PMS2 having a lower risk.
Contrary to what is reported in the literature,(3, 21) we observed metachronous CRC in some patients with PMS2 LP/P variants, albeit many years after treatment of the index CRC. This may be explained by the observation that PMS2 mutations have a lower penetrance than other MMR genes, with a cumulative CRC risk of 15%−20% up to age 70.(23–25) Our findings may also be explained by the development of sporadic non-LS CRC during the prolonged follow-up period.
Current guidelines recommend intensive surveillance for germline-confirmed LS patients as a way to diminish the persistent incidence of CRC despite frequent colonoscopy.(1, 8) However, recent prospective studies on LS patients under colonoscopic surveillance have demonstrated that CRCs occur despite regular colonoscopy with polypectomy.(11) Seppälä el al reported that cancer incidence in carriers of MLH1 variants did not change despite the use of different colonoscopy surveillance strategies.(26) In a separate study, Seppälä et al also showed that CRC stage was not dependent on the interval time from last colonoscopy (27). Engel et al similarly showed no significant reduction in CRC incidence or stage of detection in Germany, which uses annual colonoscopic surveillance, when compared with countries using longer surveillance intervals (the Netherlands, with 1- to 2- year intervals, and Finland, with 2- to 3-year intervals). (7)This growing body of evidence supports what has been long suspected, which is that in some LS patients, CRC may develop via a pathway that does not include a visible precursor polyp, allowing it to go undetected till large and invasive. Recently, Ahadova et al described three possible molecular pathways in the development of CRC in LS patients: MMR-proficient adenomas that later lose MMR function (Pathway 1), MMR-deficient crypt foci that later develop into an adenoma (Pathway 2), or MMR-deficient crypt foci that develop into a nonpolypous lesion with immediate invasive growth (Pathway 3).(28) This raises the possibility that frequent colonoscopy surveillance may be more beneficial in some group of LS patients than others, and that these groups may be defined by the MMR gene involved.
Given the probability of metachronous CRC development in patients with LS, the limitations of surveillance colonoscopy to fully prevent such an event, and the ability of extended resection to eliminate the risk in that segment of bowel,(20) it is reasonable to recommend an extended rather than segmental resection for LS patients. However, many variables—including location, stage of index cancer, age of patient, comorbidities, and individual patient preference—may tip a patient’s decision towards or away from choosing an extended colectomy to prevent a metachronous CRC while accepting the possibility of worse bowel function and quality of life.
There is a growing body of literature that documents the impact of an extended colectomy on function and quality of life, especially in active young patients. A median daily stool frequency of four after an ileosigmoid anastomosis and five after an ileorectal anastomosis has been reported, despite considerable dietary restrictions and medication use.(29) Similarly, a study using quality-of-life questionnaires and the Colorectal Functional Outcome questionnaire (30) demonstrated that when compared to patients with segmental colectomy, patients with subtotal colectomy had more problems with defecation, including a significantly higher stool frequency and higher score on stool-related aspects and social impact.
Our data suggest that LS patients considering an extended versus a segmental colectomy may now begin to use knowledge of their specific MMR gene as they weigh risks and benefits. Given that 25% of metachronous CRC were Stage III at diagnosis, LS patients undergoing an index segmental colectomy should consider the potential need for adjuvant therapy in these metachronous cases. This would be of particular concern for patients with a LP/P MLH1 or MSH2 variant. Conversely, patients with a LP/P MSH6 or PMS2 variant, who have a significantly lower risk of metachronous CRC, may be more inclined to pursue a segmental colectomy.
Our study limitations include retrospective study design, small sample size, few events per group, and lack of quality-of-life data. Also, follow-up is limited as our registry data includes only patients treated at MSK and may not include extended follow-up from patients not returning to MSK. In addition, we may be under-detecting metachronous neoplasms detected elsewhere. Furthermore, since we have neither the average number of colonoscopies over time nor mean/median time from last colonoscopy to metachronous CRC development, we are unable to demonstrate that metachronous CRC developed irrespective of surveillance colonoscopy. In addition, our definition of metachronous neoplasm does not include advanced adenomas.
The main strengths of our study are that it is a single-center experience allowing for increased likelihood of improved follow-up and standardized care. Furthermore, our institution conducts formal germline testing to determine MMR pathogenic variance and thus we see a higher number of patients with MSH6 and PMS2 LP/P variants, which have been limited in other reports.
Conclusion
Our results suggest that highly informed, carefully counseled LS patients with a MSH6 or PMS2 likely pathogenic/pathogenic variant who are interested in optimizing their bowel function and quality of life may be offered a curative segmental resection for an index, isolated colon cancer in conjunction with a strict, optimized colonoscopic surveillance protocol for the remaining colon. Prospective, multicenter studies with larger sample size and follow-up are needed to validate these findings.
ACKNOWLEDGMENTS
We gratefully acknowledge the following individuals for valuable contributions to this article: Sujata Patil, Frederick Heller, Emmanouil Pappou, Iris Wei, Garrett Nash, Philip Paty, Arnold Markowitz, Margaret McPartland, and Arthur Gelmis.
Support: This work was supported in part by the National Cancer Institute, grant number P30 CA008748. Dr Guillem received lecture payments from Moffit Cancer Center, Stony Brook Cancer Center, and Louisiana State University Health Sciences Center.
Abbreviations and Acronyms
- AJCC
American Joint Committee on Cancer
- CRC
colorectal cancer
- LP/P
likely pathogenic/pathogenic
- LS
Lynch syndrome
- MMR
mismatch repair
Footnotes
Disclosure Information: Nothing to disclose.
Disclosures outside the scope of this work: Dr Guillem received payment for a speaker tour from Roche Pharmaceuticals. Dr Garcia-Aguilar received honoraria payments from Intuitive Surgical Inc, Medtronic, and Johnson & Johnson. Dr Smith received travel support from Intuitive Surgical Inc and payment for serving as a clinical advisor for Guardant Health Inc. Dr Stadler has an immediate family member who received payment from Allergan Inc, Adverum Biotechnologies Inc, Alimera Sciences Inc, BioMarin Pharmaceutical Inc, Fortress Biotech Inc, Genentech Inc/Roche Pharmaceuticals, Novartis, Optos, Regeneron Pharmaceuticals Inc, REGENXBIO Inc, and Spark Therapeutics Inc.
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