Abstract
Background: Approximately 5% of colorectal cancers (CRCs) are associated with hereditary cancer syndromes. The natural history of these syndromes differs from sporadic cancers, and due to their increased risk of metachronous carcinomas, surgical approaches also differ. This review focuses on the current recommendations for surgical treatment and what evidence has led to these recommendations in the most clinically relevant hereditary CRC syndromes: Lynch syndrome (LS) and (attenuated) familial adenomatous polyposis (FAP). Summary: LS has no common phenotype and is caused by individual germline variants in one of the mismatch repair genes (MLH1, MSH2, MSH6, or PMS2). Because each gene is associated with a different risk of metachronous cancer, guidelines now differentiate between genes in their recommendations for oncology interventions. Classical and attenuated FAP are caused by germline mutations in the APC gene and have a characteristic phenotype. Although correlations exist between phenotype and genotype, the indication for surgery is predominantly based on clinical manifestation rather than specific gene mutations. Key Message: Currently, the recommendation on the two diseases tends to go in opposite directions: while some forms of FAP may require less extensive surgery, in some LS patients, more sophisticated knowledge of metachronous carcinoma risk leads to more extensive surgery.
Introduction
There is a familial and a hereditary component to about 20–35% of colorectal cancers (CRCs), as has been shown in particular by large kindred and twin studies [1]. Population studies have shown various risk groups.
First, one of the most common but less conspicuous constellations are familial non-syndromic colorectal carcinomas. As no specific genetic markers are currently available for these common familial colorectal carcinomas, screening and surveillance arise from family history [2]. Thus, first-degree relatives of a bowel cancer patient who is >50 years of age are 2–3 times more likely to develop bowel cancer themselves compared to the normal population [3]. The risk of developing CRC increases 3-6-fold if the first patient was under 45 years old or if two first-degree relatives had CRC [4]. Meanwhile, it should be noted that if the index patient is diagnosed after the age of 60 years, the CRC risk for first-degree relatives is only slightly increased and that, according to the latest guidelines, the routine national screening programs might be sufficient [4‒7].
Second, there is the group of well-defined or increasingly well-defined hereditary cancer syndromes, which account for about 5% of cases, characterized by a high penetrance of known genetic mutations [2]. In the early-onset of carcinomas (in patients <50 years of age), the link to a hereditary cause can be established in about 13% (prevalence range in different reports: 9–26%). In these cases, genome-wide association studies are often carried out [8]. In recent years, the threshold for systematic genetic testing has not only decreased due to lower costs and easier availability of automated panels but also due to growing public awareness so that the proportion of detected hereditary causes might increase in the coming years [9].
With the increasing knowledge of the range of penetrance and course of individual hereditary diseases, the indication and determination of the scope of surgery is becoming more and more complex. This narrative review attempts to provide a structured approach to the current state for the surgical treatment of the most clinically relevant hereditary cancer predispositions for CRC, Lynch syndrome (LS) and familial adenomatous polyposis (FAP)/attenuated FAP (AFAP) (Table 1).
Phenotypes and genotypes of LS (data from www.plsd.eu; attended on 10. Jan 2023) and polyposis syndromes FAP and AFAP [22]
Hereditary CRC syndromes . | Nonpolyposis syndrome . | Polyposis syndromes . | ||||
---|---|---|---|---|---|---|
adenomatous polyposis syndromes . | ||||||
LS . | FAP . | AFAP . | ||||
Inheritance pattern | Autosomal dominant | Autosomal dominant | Autosomal dominant | |||
Colorectal phenotype | No specific phenotype | >100 polyps, typically first in the rectum/sigma | <100 polyps, often first appearance in the right hemicolon | |||
Genotype/mutation | path_MLH1 | path_MSH2 | path_MSH6 | path_PMS2 | APC gene, consisting of 15 exons, 2,384 codonsa | |
Most mutationsCodon 157–1,595, including MCR 1,250–1,464 | Most mutations5′ end of APC (codon 1–233)Alternative spliced region of exon 9 (codon 311–412)3′ of codon 1,595 | |||||
Calculated lifetime risk for CRC | 48–57%b | 47–51%b | 18–20%b | ∼10%‡ | 100% | ∼70% |
Risk for metachronous CRC | ||||||
When first CRC at age <40 years | 47% | 48% | 23% | |||
When first CRC at age <50 years | 39% | 36% | 23% |
Hereditary CRC syndromes . | Nonpolyposis syndrome . | Polyposis syndromes . | ||||
---|---|---|---|---|---|---|
adenomatous polyposis syndromes . | ||||||
LS . | FAP . | AFAP . | ||||
Inheritance pattern | Autosomal dominant | Autosomal dominant | Autosomal dominant | |||
Colorectal phenotype | No specific phenotype | >100 polyps, typically first in the rectum/sigma | <100 polyps, often first appearance in the right hemicolon | |||
Genotype/mutation | path_MLH1 | path_MSH2 | path_MSH6 | path_PMS2 | APC gene, consisting of 15 exons, 2,384 codonsa | |
Most mutationsCodon 157–1,595, including MCR 1,250–1,464 | Most mutations5′ end of APC (codon 1–233)Alternative spliced region of exon 9 (codon 311–412)3′ of codon 1,595 | |||||
Calculated lifetime risk for CRC | 48–57%b | 47–51%b | 18–20%b | ∼10%‡ | 100% | ∼70% |
Risk for metachronous CRC | ||||||
When first CRC at age <40 years | 47% | 48% | 23% | |||
When first CRC at age <50 years | 39% | 36% | 23% |
aCave! genotype and phenotype do not strictly correlate, but approximate distinctions may be made.
bRisks differ gender-related.
cDue to the low number of patients with path_PMS2, there are no reliable numbers.
Non-Polypous Syndromes
Lynch Syndrome
In contrast to polyposis syndromes (especially FAP), LS lacks a conspicuous phenotype from which a suspected clinical diagnosis could be derived. For this reason, the Amsterdam criteria were defined as so-called familial environment criteria (such as the number and degree of relationship of family members affected by LS-associated carcinomas), which can be used indirectly to derive a tentative diagnosis [6].
LS is caused by pathogenic germline variants in one of the mismatch repair genes: MLH1, MSH2, MSH6, or PMS2 (and with epigenetic silencing of MSH2 by deletion of EPCAM). Since LS has an autosomal dominant inheritance pattern, the presence of at least one allele of pathological variance is sufficient to cause the disease, but penetrance varies by affected gene and sex. It is the most common cause of inherited CRC (prevalence 1:370–440) [10], although a much higher prevalence has been described in the Icelandic population (1:226), the highest reported so far [11]. But even if the prevalence is estimated to be lower, a staggering number of cases must be assumed to have remained undetected.
The data from the Prospective Lynch Syndrome Database (PLSD), an initiative of the European Hereditary Tumorgroup (EHTG) that collects registry data from specialized LS centers from many countries, are best suited for risk assessments of cancer development in relation to the individual genes (www.plsd.eu) [12]. Thus, the prevalence of LS in the general population cannot be derived from this data, but the incidence of cancer development of the individual genes in proven LS for different organs and separated by sex can be estimated best from them. The PLSD website currently indicates the overall cancer incidence from 25 to 75 years of age as high as 71–81% for path_MLH1, 75–84% for path_MSH2, and 41–62% for path_MSH6, depending on sex. For PMS2, the overall cancer incidence for both sexes combined in the same age range is 34%; due to the less frequent occurrence (and therefore the paucity of data), it is not possible to separate by sex. Thus, the highest cancer risks were found in path_MLH1 and path_MSH2 carriers.
In a prospective analysis, looking at data from 6,350 mutation carriers, the cumulative incidence for CRC between the ages of 25 and 75 years was 48–57% for path_MLH1, 47–51% for path_MSH2, and 18–20% for path_MSH6, depending on gender. For path_PMS2, the cumulative incidence of CRC between 25 and 75 years was for both sexes combined 10% (Table 2) [13].
Surgery in different genotypes of LS
LS . | path_MLH1 . | path_MSH2 . | path_MSH6 . | path_PMS2 . | |
---|---|---|---|---|---|
Indication for surgery | Absolute indication: CRCNo relative indication and no prophylactic surgery | ||||
Primary colon cancer | |||||
ESCP guidelines [16] | Subtotal colectomy + ileosigmoidal (ileorectal) anastomosis | Segmental colectomy (e.g., right hemicolectomy) | |||
British guidelines [7] | Subtotal colectomy + ileosigmoidal (ileorectal) anastomosis | Segmental colectomy (e.g., right hemicolectomy) | |||
NCCN [14] | Subtotal colectomy + ileosigmoidal (ileorectal) anastomosis | Segmental colectomy (e.g., right hemicolectomy) | |||
Primary rectal cancer | |||||
ESCP guidelines [16] | (Low) Anterior resection/APR | (Low) Anterior resection/APR | |||
British guidelines [7] | (Low) Anterior resection/APR | (Low) Anterior resection/APR | |||
NCCN [14] | Proctectomy or total proctocolectomy depending on the clinical scenario and factors such as age, pathogenic variant, relationship to the anal sphincter, and anticipated need for pelvic radiation | ||||
Rectal cancer after previous colon cancer | |||||
ESCP guidelines [16] | Proctectomy/proctocolectomy with ileoanal anastomosis with pouch or APR with permanent ileostomy | - |
LS . | path_MLH1 . | path_MSH2 . | path_MSH6 . | path_PMS2 . | |
---|---|---|---|---|---|
Indication for surgery | Absolute indication: CRCNo relative indication and no prophylactic surgery | ||||
Primary colon cancer | |||||
ESCP guidelines [16] | Subtotal colectomy + ileosigmoidal (ileorectal) anastomosis | Segmental colectomy (e.g., right hemicolectomy) | |||
British guidelines [7] | Subtotal colectomy + ileosigmoidal (ileorectal) anastomosis | Segmental colectomy (e.g., right hemicolectomy) | |||
NCCN [14] | Subtotal colectomy + ileosigmoidal (ileorectal) anastomosis | Segmental colectomy (e.g., right hemicolectomy) | |||
Primary rectal cancer | |||||
ESCP guidelines [16] | (Low) Anterior resection/APR | (Low) Anterior resection/APR | |||
British guidelines [7] | (Low) Anterior resection/APR | (Low) Anterior resection/APR | |||
NCCN [14] | Proctectomy or total proctocolectomy depending on the clinical scenario and factors such as age, pathogenic variant, relationship to the anal sphincter, and anticipated need for pelvic radiation | ||||
Rectal cancer after previous colon cancer | |||||
ESCP guidelines [16] | Proctectomy/proctocolectomy with ileoanal anastomosis with pouch or APR with permanent ileostomy | - |
APR, abdominoperineal resection.
Two crucial pieces of information should be taken into consideration:
While both genders with path_MSH6 variant had similar, modestly increased risk for CRC, females with path_MSH6 variants had shown to have high risks for gynecological cancers (41% for endometrium cancer between the ages 25 and 75 years) [13]. Thus, family history is of limited use in male MSH6 mutation carriers [13], and the overall term “cancer risk” inadequately delineates the specific risks.
The overall cancer risk for path_PMS2 carriers is not increased before age 45 years; the risk for CRC only increases after age 70 years, and even then, only reaches the 10% just mentioned, which is not significant [13].
Surveillance
LS carriers should undergo colonoscopy from 25 years of age; depending on the guideline, the current recommendation is every 1–2 years [7, 14].
Surgery
The determination of the ideal surgical therapy and its extent should consider the risk of developing metachronous carcinoma in the colorectum. In relation to the individual genes, the evaluation of the PLSD shows that in patients who had their first carcinoma before the age of 40 years, the development of a subsequent colorectal carcinoma was 46% for path_MLH1, 48% for path_MSH2, and 23% for path_MSH6. If the first carcinoma occurred later, the risk of a second carcinoma was also reduced [15] (Table 1). However, crude 10-year survival even after a second CRC was 91% overall, 89% for pat_MLH1, 92% for pat_MSH2, and 100% for path_MSH6[15].
These specific gene dependencies in the risks for metachronous CRC have now led to adjustments in some of the most recent guidelines. The European Guidelines from the European Hereditary Tumor Group (EHTG) and ESCP (European Society for Coloproctology) now recommends performing a colectomy with an ileorectal or ileosigmoidal anastomosis for both MLH1 and MSH2 mutations [16] (Table 2).
With an ileosigmoid anastomosis, there is still a little more colon to monitor, but the quality of life seems to be somewhat better compared to an ileorectal anastomosis (IRA) [17, 18]. The UK guidelines encourage the decision to perform a segmental or near-total/total colectomy in patients with path_MLH1 or path_MSH2 to be made after considering the risks of metachronous cancer, the functional consequences of surgery, the age of the patient, and his/her wishes [7]. Conversely, the authors of the guidelines do not see sufficient evidence to make the same recommendation for path_MSH6 and path_PMS2 patients but always advocate segmental colon resection in these cases [7].
This contrasts with the latest NCCN guidelines, which, with the exception of path_PMS2 carriers, always recommend a discussion on the possible performance of an “extended” colectomy [14]. “Extended” is not defined more precisely.
A further difference in the guidelines concerns the procedure in the presence of rectal cancer. While for rectal cancer the NCCN guidelines recommend total proctocolectomy or proctectomy depending on age, gene variant, distance to the sphincter, and possible need for radiation, the EHTG and the UK guidelines recommend standard surgery in the sense of a (low) anterior resection or APR [7, 14, 16].
Chemoprevention in LS
In the prospective, placebo-controlled CAPP2 study of over 850 LS patients, 600 mg aspirin/day for at least 2 years was found to significantly reduce the likelihood of new-onset CRC (per-protocol HR: 0.56; 95% CI: 0.34–0.91; intention-to-treat HR: 0.65; 95% CI: 0.43–0.97), without significantly increasing the likelihood of adverse events [19]. Whether 600 mg is indeed necessary or whether lower doses would be sufficient (as suggested by observation data from the general population) is currently being clarified in a follow-up study, the data from which are not expected for several years (CAPP3).
The European Guideline of ESCP and EHTG recommend that all LS patients should take 100 mg of acetylsalicylic acid, while higher doses may be considered for overweight individuals [16]. The British guidelines recommend 150 mg of acetylsalicylic acid daily and 300 mg daily for a BMI over 25 kg/m2[7]. The latest NCCN guidelines have also included the recommendation to take aspirin but without specifying a dosage [14]. Before starting the medication, H. pylori colonization should be excluded or eradicated [7].
Polyposis Syndromes
According to the predominant type of polyps, polyposis syndromes can be subclassified into adenomatous polyposis (e.g., FAP), hamartous polyposis (e.g., Peutz-Jeghers syndrome), and serrated polyposis.
Familial Adenomatous Polyposis
Genotype-Phenotype Correlations
APC is located on chromosome 5q21; the gene consists of 15 exons and 2,843 codons. Most germline mutations are located in the 5′ half of the gene, particularly in codons 1,061 and 1,309. Classical FAP shows full penetrance of its pathogenic variant and has a life-time-risk for CRC of 100% with a median age of onset without treatment of 39 years [14]. Germline variants in the central part of the gene are often associated with classical FAP (codon 157–1,595). Variants between codons 1,250–1,464 are said to be in the mutation cluster region (MCR) and are associated with profuse polyposis [22]. A milder phenotype with less penetrance shows AFAP. Mutations concerning the 5′ or 3′ end of the gene are causing about 78% of AFAP cases (e.g., 5′ end [codons 1–233], the alternative spliced region of exon 9 [codons 311–412], or 3′ end of codon 1,595) [22]. Nevertheless, in a cohort study, 35% of the patients with mutations in these regions clinically showed the picture of classical FAP, and doubts have therefore arisen as to whether genotype can be a reliable indicator of AFAP at all [23].
FAP accounts for less than 1% of CRC [24]. Additionally, up to 25% of the germline mutations are de novo mutations [25]. It has a prevalence of 1/8,300–1/21,500 and manifests equally in both sexes [24, 26]. Regarding the phenotype and clinical presentation of the FAP, two major types have been described: classical and attenuated FAP.
Classical FAP
Classical FAP is characterized by the presence of hundreds to thousands adenomatous polyps throughout the large intestine with first appearance in the rectum and sigmoid colon. By the age of 15 years, 50% of the patients have developed adenomas and by the age of 35 years, over 95% [27].
Clinical Presentation and Identification
The diagnosis of FAP is suspected prior to the proving positive genetic test by the presence of either >100 colorectal adenomas or <100 adenomas at a young age with a positive APC gene mutation in the family history. The main objective of surveillance and treatment in FAP patients is the prevention of CRC, while maintaining a good quality of life. In other words, endoscopic monitoring must be reliable, and prophylactic surgery must not miss its moment of indication.
Endoscopic screening and genetic testing in patients with FAP-positive family members should be initiated at the age of 10–15 years. In classical FAP, occurrence of adenomas never begins in the proximal colon but in the sigma or rectum. Therefore, annual rectosigmoidoscopy is sufficient but should be replaced by complete colonoscopy after appearance of the first adenomas [6, 28]. Absolute indications for surgery are CRC or colorectal symptoms. Since CRC is rare in the asymptomatic youth, prophylactic colorectal surgery can in most cases be evaluated after puberty or in the early twenties. Relative indications for surgery are listed in Table 3.
Surgery in polyposis syndromes
Polyposis syndromes (FAP and AFAP) . | ||
---|---|---|
indication for surgery . | absolute indication: CRC or symptomsrelative indications: (increase in) polyp burden, large polyps >10 mm, high-grade dysplasia, endoscopic surveillance not possible . | |
. | proctocolectomy (IPAA) . | total colectomy + IRA . |
Indication for extent* | ||
NCCN [14] | Severe disease in the colon and/or rectumCurable rectal cancerAfter TAC/IRA: endoscopically unmanageable disease in the rectumPatient not reliable for follow-up surveillance of retained rectum | Rectum polyps amenable to endoscopic surveillance and resection |
British guidelines [7] | Rectal polyp number >20, the presence of high-grade dysplasiaSevere phenotype (>1,000 synchronous adenomas)Large (>10 mm) adenomasGenotype (APC pathogenic variant codon 1,250–1,450)Poor compliance with follow-up surveillance | Relative rectal sparing (<20 polyps)All rectal adenomas are <5 mm in diameterAny polyps >5 mm can be endoscopically removed |
St. Mark’s practice [23] | Pathogenic variant outside of the MCR (codon 1,250–1,464)Colonic adenoma burden <500Fewer than 20 rectal adenomas, all of which must be endoscopically manageable | |
Recommended follow-up | Annual pouchoscopy [1, 2] | Flexible sigmoidoscopy every 6–12 months depending on polyp burden [1] |
Polyposis syndromes (FAP and AFAP) . | ||
---|---|---|
indication for surgery . | absolute indication: CRC or symptomsrelative indications: (increase in) polyp burden, large polyps >10 mm, high-grade dysplasia, endoscopic surveillance not possible . | |
. | proctocolectomy (IPAA) . | total colectomy + IRA . |
Indication for extent* | ||
NCCN [14] | Severe disease in the colon and/or rectumCurable rectal cancerAfter TAC/IRA: endoscopically unmanageable disease in the rectumPatient not reliable for follow-up surveillance of retained rectum | Rectum polyps amenable to endoscopic surveillance and resection |
British guidelines [7] | Rectal polyp number >20, the presence of high-grade dysplasiaSevere phenotype (>1,000 synchronous adenomas)Large (>10 mm) adenomasGenotype (APC pathogenic variant codon 1,250–1,450)Poor compliance with follow-up surveillance | Relative rectal sparing (<20 polyps)All rectal adenomas are <5 mm in diameterAny polyps >5 mm can be endoscopically removed |
St. Mark’s practice [23] | Pathogenic variant outside of the MCR (codon 1,250–1,464)Colonic adenoma burden <500Fewer than 20 rectal adenomas, all of which must be endoscopically manageable | |
Recommended follow-up | Annual pouchoscopy [1, 2] | Flexible sigmoidoscopy every 6–12 months depending on polyp burden [1] |
*Colectomy with IRA to be considered if all “low rectal disease burden” factors are fulfilled; proctocolectomy if one risk factor for severe disease is fulfilled.
Surgical Concept
There are 3 surgical options treating classical FAP [14]:
Total proctocolectomy with or without mucosectomy and ileal pouch-anal anastomosis (IPAA)
Total colectomy with IRA
Total proctocolectomy with ileostomy
For most patients, the decision will be between total proctocolectomy with ileal pouch formation and total colectomy with IRA. According to UK guidelines, the choice of surgical intervention depends on the number of rectal polyps, the size and presence of high-grade dysplasia, the genotype, and the functional consequences of surgery [7]. The NCCN guidelines recommend somewhat more generally that the decision to remove the rectum depends on whether the polyps are amenable to endoscopic surveillance and resection. Rectal cancer and severe rectal disease (size or the number of polyps) preclude preservation of the rectum [14].
However, preserving the rectum in FAP patients bares the imminent risk of future adenoma or dysplasia development or even cancer in it. There are large cohort studies from St. Mark’s Hospital investigating the course of FAP after IRA [23, 29]. In a more historical cohort overlooking 427 FAP patients, they identified that individuals with >500 polyps in the resected colon, APC pathogenic variant in the MCR, and age under 25 years at the time of primary surgery are independent factors for proctectomy over time [29]. In this large cohort, the rectal failure rate was as high as 18%. According to the data, St. Mark’s Hospital refined the selection criteria and has been offering colectomy with ileorectostomy for over 10 years to those patients who have their pathogenic variant outside the MCR, a colonic adenoma burden of <500 adenomas and less than 20 adenomas in the rectum [23]. In their recently published cohort of 191 FAP patients, the percentage of those who had to undergo proctectomy during a median follow-up of 8.6 years was as low as 5.2%. Therefore, the option of ileorectostomy should be considered carefully as it promises to preserve quality of life. According to a meta-analysis of non-randomized trials comparing IRA and IPAA, the preservation of the rectum has reasonable advantages: lower stool frequency over 24 h, lower need for defecation at night and incontinence [30]. However, IPAA was not significantly different from IRA with regard to stool frequency at night, daytime incontinence, and need for antidiarrheal medication [30].
For further fine-tuning, studies are currently investigating whether, with close monitoring, a near-total colectomy and the creation of an ileo-distal sigmoidal anastomosis would be sufficient as the quality of life would presumably be significantly better than after an IRA [23]. It is far too early to take a position on this.
None of the guidelines address the situations in which a mucosectomy with hand suturing of the pouch-anal anatomy might be electively indicated. The British guidelines highlight that there is a very small risk for adenocarcinoma after an IPAA but confirm that most cancers develop in residual rectal or in the anal transition zone [7].
In a cohort study including 206 FAP patients that had either stapled IPAA or mucosectomy and overlooking a follow-up of 10.3 years, 51% of the individuals developed adenoma after stapled IPAA but no patient developed cancer [31]. The Dutch polyposis registry confirmed these results with 45% of the patients showing an adenoma development after 10 years and 1.9%, a cancer [32]. However, a study on the 92 published cases of pouch-related cancers revealed a significant correlation between the type of surgery (stapling vs. hand-sewn) and cancer incidence [33].
Since pouch-related carcinomas are a rare event, there will probably be no significance to the question of mucosectomy, considering all FAP patients after proctocolectomy. Conversely, if we look at those who develop carcinoma, the link to stapler anastomosis seems clearer. However, leaving a rectal cuff leads to superior functional outcome [34], and additionally, partially remaining rectal mucosa has been described in patients with hand-sewn anastomosis and total mucosectomy [35]. Therefore, total mucosectomy can only be recommended individually, e.g., with simultaneous rectal cancer, high-grade dysplasia, or massive polyp burden in the distal rectum.
Most importantly, annual endoscopic surveillance of any remaining rectal mucosa, anal transition zone mucosa, and ileal pouch is recommended for life [7]. Total proctocolectomy with formation of an end ileostomy is performed in cases with contraindications for creation of an ileoanal pouch, such as anal Crohn’s disease, mesenteric desmoid tumor, or dysfunctional sphincter.
Attenuated FAP
The AFAP shows a milder phenotype and is characterized by usually 10–100 adenomas with later development of adenomas (mean age of diagnosis 44 years) as well as later cancer appearance (mean age 56 years).
Diagnosis and Surveillance
CRC usually occurs 10–15 years later than in FAP patients, but the estimated cumulative lifetime risk is substantially higher at 70% [36]. Adenomas typically appear at first in the right hemicolon, making complete colonoscopy from the beginning inevitable. Screening should be initiated at age 18–20 years and be repeated every 2 years until first polyps arise. Then, colonoscopy should be carried out annually [37], endoscopic surveillance may be effective until later in life than in FAP patients.
Surgical Concept
Indication for surgery and its extent do not differ substantially from classical FAP. However, IRA is for most patients with AFAP an oncologically sufficient option.
Discussion
It is becoming increasingly evident that the hereditary diseases cannot be summarized under a uniform title but that gene or even codon variants should be taken into account in therapy decisions just as much as the phenotype, sex, and age of the affected person [38, 39]. However, it should also be mentioned that the current guidelines are still probably not yet complete. Thus, not only the risk of developing metachronous carcinoma should be considered in LS but it should also be considered that the prognosis of any colorectal carcinoma in LS is good due to its microsatellite unstable nature and the emergence of breakthrough drugs like immune checkpoint inhibitors. In addition, the risk figures for the development of metachronous colorectal carcinoma date back to before the use of aspirin medication, which might significantly reduce the risks although we do not yet know the exact dosage.
In addition, newly diagnosed LS, e.g., someone with diagnosis of pat_MLH1 after a right hemicolectomy, pose a particular difficulty. If we recommend a colectomy to patients with known LS prior to surgery, it follows that we might also recommend a completion colectomy to those with a postoperative diagnosis of LS. There is a logical gap in the current approach as to why we recommend extensive surgery from the outset for some patients, but not completion for others. With FAP, on the contrast, we aim to prospectively understand in detail which codons predict a severe course and for which patients a less extensive surgery is an option.
Conclusion
In summary, while in LS gene and gender may influence therapy decisions, in FAP, knowledge of the mutated codon is important for risk classes, but most importantly the individual phenotype should be considered in therapy decisions. On balance, the trend is that in FAP, with the help of genetics and better understanding of disease progression based on different phenotypes, less extensive surgery is required in some patients, while in LS, the differentiated recognition of metachronous carcinoma risk leads to more extensive surgery in some patients. In all these decisions, however, it must always be kept in mind that the weighing of risks is done on the basis of the given facts of gene and sex and the possible benefits, but above all, the shared decision-making with the patient is of utmost importance.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Author Contributions
Karoline Horisberger and Carolina Mann were responsible for conception and drafting of the work. Hauke Lang was responsible for critical revising. Karoline Horisberger finally approved the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Additional Information
Both Karoline Horisberger and Carolina Mann are first authors and contributed equally to this work.