Serrated Polyposis Syndrome: A Narrative Review from Clinical Recognition to Risk-Adapted Cancer Prevention

Abstract

Serrated polyposis syndrome (SPS) is a clinically defined colorectal polyposis syndrome characterized by multiple and/or large serrated lesions and an increased risk of colorectal cancer (CRC). Its diagnosis remains challenging because it depends on cumulative endoscopic and histopathological findings rather than a single germline marker, and it remains under-recognized in routine practice. The biological basis of SPS is heterogeneous: serrated tumorigenesis commonly involves BRAF or KRAS activation, CpG island methylation, and MLH1 silencing, yet most cases are not explained by classic Mendelian inheritance and SPS-associated CRC may arise through serrated or conventional adenoma-carcinoma pathways. This narrative review integrates current evidence on clinical recognition, WHO diagnostic criteria, cancer risk, biological heterogeneity, endoscopic clearance, surveillance, surgery, and family screening. After high-quality clearance, surveillance can be adapted dynamically using the most recent clinical, endoscopic, and pathological findings, including polyp burden, advanced serrated lesions, dysplasia, advanced adenomas, prior CRC, and completeness of resection. At present, these conventional variables and guideline-based intervals constitute current practice; germline, epigenetic, microbiome, metabolomic, and other non-invasive biomarkers remain investigational and should not determine routine surveillance. A phase-based approach combining cumulative diagnosis, effective clearance, risk-adapted 1- or 2-year surveillance, selective surgery, and screening of first-degree relatives provides a pragmatic framework for CRC prevention.

Introduction

Serrated polyposis syndrome (SPS) has emerged as a clinically important colorectal polyposis syndrome at the intersection of serrated neoplasia, cancer predisposition, and endoscopic prevention. Serrated lesions, particularly sessile serrated lesions (SSLs), are now recognized as important precursors of colorectal cancer (CRC), especially in the proximal colon, and the serrated pathway may account for a substantial proportion of CRCs.^1–5 SPS, defined by the accumulation of multiple and/or large serrated polyps, represents the most clinically overt manifestation of this pathway and is associated with a markedly increased CRC risk.^6–8 Therefore, SPS is not merely a numerical polyp phenotype, but a clinically relevant model for understanding serrated pathway carcinogenesis and CRC prevention.

Despite its clinical importance, SPS remains frequently under-recognized. The diagnosis is based on cumulative endoscopic and histopathological findings rather than on a single germline mutation, and the World Health Organization (WHO) diagnostic criteria have evolved to capture patients with either multiple large proximal serrated polyps or a high cumulative serrated polyp burden.^7,9–13 This cumulative nature is critical: patients may meet diagnostic criteria only after several colonoscopies, and failure to integrate polyp counts across procedures is a major reason for missed diagnosis.^14–17 In addition, SSLs are often flat, subtle, proximally located, and difficult to detect or completely resect, further contributing to diagnostic delay and potentially to post-colonoscopy CRC.^3,4,18,19 Thus, one of the central challenges in SPS is not the absence of diagnostic criteria, but their inconsistent application in routine clinical practice.

The biological basis of SPS is heterogeneous and remains incompletely explained. Unlike classical Mendelian polyposis syndromes such as familial adenomatous polyposis or MUTYH-associated polyposis, most SPS cases do not have an identifiable high-penetrance germline cause.^9,20–25 RNF43 is currently the best validated germline gene associated with a small subset of SPS, but its prevalence is low and its penetrance appears variable.^26–30 At the somatic level, SPS-associated lesions frequently involve MAPK pathway activation through BRAF or KRAS mutations, widespread CpG island methylation, and, in some cases, MLH1 silencing with microsatellite instability.^{2,5,27,31–33} However, SPS-associated CRCs are not biologically uniform; accumulating evidence indicates that cancers in SPS may arise through both serrated and conventional adenoma-carcinoma pathways.^34–38 This molecular and pathological diversity supports the view that SPS is better understood as a heterogeneous clinical phenotype than as a single-gene or single-pathway disorder.

These diagnostic and biological complexities have direct implications for management. The main goal of care is durable CRC prevention through high-quality colonoscopy, complete removal of clinically relevant lesions, and long-term surveillance after initial endoscopic clearance.^39–41 Unlike reviews centered primarily on diagnostic criteria, molecular biology, or general management,^1,7,42,43 this narrative review organizes the evidence around sequential clinical phases: recognition, cumulative diagnosis, clearing, post-clearance interval assignment, surgical escalation, and family screening. Its distinctive contribution is to compare major international recommendations within a single actionable framework and to separate established clinical practice from promising but unvalidated molecular and multi-omics findings.

Diagnostic Criteria and the Problem of Under-Recognition

Evolution of WHO Diagnostic Criteria

The diagnosis of SPS remains fundamentally clinical, relying on cumulative endoscopic and histopathological findings rather than on a single molecular or germline marker. This distinguishes SPS from many classical hereditary polyposis syndromes and makes accurate diagnosis dependent on the systematic recognition, documentation, and aggregation of serrated lesions over time.^7,9,10 The WHO criteria have therefore served as the practical foundation for diagnosis. The 2010 WHO criteria defined SPS by any of three conditions: at least five serrated polyps proximal to the sigmoid colon, with at least two measuring ≥10 mm; any number of serrated polyps proximal to the sigmoid colon in an individual with a first-degree relative with SPS; or more than 20 serrated polyps of any size distributed throughout the colon.

The 2019 WHO update simplified this framework into two diagnostic criteria. Criterion I requires at least five serrated lesions/polyps proximal to the rectum, all measuring ≥5 mm, with at least two measuring ≥10 mm. Criterion II requires more than 20 serrated lesions/polyps of any size distributed throughout the large bowel, with at least five located proximal to the rectum. Importantly, the previous family-history-based criterion was removed, reflecting the fact that familial risk is clinically relevant but insufficiently specific as an independent diagnostic criterion. Studies evaluating the impact of this change suggest that most patients meeting the older criteria still meet the updated criteria, although a minority may be reclassified depending on lesion size, location, and cumulative polyp burden.^13,44 Table 1 summarizes the principal differences between the 2010 and 2019 criteria. Thus, the revised criteria preserve the core concept of SPS as a phenotype defined by multiplicity, size, and distribution of serrated lesions, while aiming to improve clinical applicability.

Table 1.

Comparison of the 2010 and 2019 WHO Diagnostic Criteria for Serrated Polyposis Syndrome

Feature	WHO 2010	WHO 2019	Practical Implication
Criteria structure	Diagnosis by any of three criteria.	Diagnosis by either of two criteria.	The former family-history diagnostic route was removed.
Large/proximal phenotype	≥5 serrated polyps proximal to the sigmoid colon, with ≥2 measuring >10 mm.	≥5 serrated lesions/polyps proximal to the rectum, all ≥5 mm, with ≥2 measuring ≥10 mm.	The 2019 criterion adds a 5-mm minimum for all lesions and uses the rectum as the boundary.
High-count phenotype	>20 serrated polyps of any size distributed throughout the colon.	>20 serrated lesions/polyps of any size throughout the large bowel, with ≥5 proximal to the rectum.	The updated criterion requires a documented proximal component.
Family-history criterion	Any number of serrated polyps proximal to the sigmoid colon in a person with a first-degree relative with SPS.	Removed as an independent diagnostic criterion.	Familial risk is addressed through screening of relatives rather than diagnosis based on family history alone.
Counting and histology	Cumulative use was inconsistently emphasized in abbreviated criteria.	All serrated histological subtypes count; counts are cumulative across colonoscopies.	Longitudinal endoscopy and pathology records should be reconciled before excluding SPS.

Notes: WHO criteria and subsequent clarification^7,9–13,44.

Abbreviations: SPS, serrated polyposis syndrome; WHO, World Health Organization.

SPS as a Cumulative Diagnosis

A key feature of SPS is that diagnosis is often cumulative. Patients may not meet WHO criteria at a single colonoscopy, particularly if the initial examination is incomplete, bowel preparation is suboptimal, proximal serrated lesions are missed, or prior pathology reports are not reviewed. The requirement to count serrated lesions across the patient’s lifetime is therefore not a technical detail but a central diagnostic principle.^10,17 In routine practice, this cumulative nature creates a major vulnerability: unless endoscopy and pathology reports from previous procedures are actively integrated, patients who already meet diagnostic thresholds may remain unrecognized.

This issue is especially important because serrated lesions are heterogeneous and often difficult to detect. SSLs, which are among the most clinically important serrated precursors, are frequently flat, pale, mucus-covered, and located in the proximal colon, making them more likely to be missed than conventional adenomas.^3,4,18,19 Pathological classification also matters. Distinguishing hyperplastic polyps (HP), SSLs with or without dysplasia, and traditional serrated adenomas (TSA) is essential not only for cancer risk assessment but also for determining whether WHO criteria are fulfilled.^3,4 Consequently, SPS diagnosis requires coordination between high-quality colonoscopy, accurate pathology, and longitudinal record review.

Why SPS Is Missed in Clinical Practice

Despite the availability of diagnostic criteria, SPS remains substantially under-recognized. Several studies have shown that many patients ultimately diagnosed with SPS had already accumulated enough serrated lesions to meet WHO criteria before the diagnosis was made. In one tertiary-center cohort, only a small proportion of patients eventually diagnosed with SPS had been specifically recognized as having SPS by their referring physicians, despite prior records showing sufficient polyp burden.¹⁴ Another analysis of patients with large sessile colorectal polyps found that SPS was rarely suspected by referring physicians, and even in a tertiary setting the diagnosis was initially missed in a substantial proportion of cases.¹⁵ These observations suggest that the problem is not simply lesion detection but failure to apply criteria consistently across repeated procedures.

The causes of under-recognition are multifactorial. First, serrated lesions, particularly SSLs, are technically challenging to identify endoscopically because of their subtle morphology and frequent proximal location.^3,4,18,19 Second, SPS is often not apparent at the index colonoscopy; one study reported that patients underwent a median of four colonoscopies before meeting diagnostic criteria, underscoring the cumulative nature of the syndrome.¹⁷ Third, pathology reports may document serrated lesions without prompting clinicians to reassess cumulative counts or consider SPS. Fourth, the phenotype is heterogeneous: some patients present with a smaller number of large proximal lesions, whereas others have numerous serrated polyps distributed throughout the colon.^31,45–47 This heterogeneity can obscure recognition, particularly when lesions are removed over multiple examinations by different endoscopists.

The clinical consequences of missed diagnosis are important. Failure to identify SPS may delay clearing colonoscopy, shorten opportunities for risk-adapted surveillance, and prevent appropriate counseling and screening of first-degree relatives. Because SPS is associated with increased CRC risk, including cancers diagnosed before or at recognition of the syndrome, missed diagnosis may contribute to preventable colorectal neoplasia.^8,14 Therefore, improving recognition should be considered a core component of cancer prevention rather than merely a matter of diagnostic labeling.

Strategies to Improve Recognition

Improving SPS recognition requires systematic approaches at the endoscopic, pathological, and health-system levels. At the endoscopic level, certain findings should trigger active reassessment for SPS, including multiple serrated lesions, large proximal SSLs, recurrent serrated polyps, or referral for resection of large serrated lesions.^19,48–50 Patients with several serrated polyps at an index colonoscopy or with one large serrated lesion may warrant careful review of prior reports and planned reassessment, even if they do not yet meet formal WHO criteria.^19,48 This approach is particularly relevant because patients with multiple large serrated lesions who fall short of formal SPS thresholds may still have a clinically meaningful synchronous polyp burden.⁵⁰

Pathologists also have an important role. Reports that identify multiple serrated lesions, large SSLs, dysplasia within serrated lesions, or mixed serrated and adenomatous polyposis should prompt communication with the treating clinician and consideration of SPS.⁴⁸ In atypical or overlapping cases, expert pathological review may be necessary, because patients initially labeled as SPS may occasionally be reclassified as having another polyposis syndrome after detailed review.^51,52 This reinforces the need for multidisciplinary collaboration among gastroenterologists, pathologists, geneticists, and surgeons.

Health-system interventions may further reduce missed diagnoses. Natural language processing tools that extract and integrate colonoscopy and pathology data across a patient’s history have shown high accuracy for identifying individuals who meet WHO criteria, including many who were not previously recognized by clinicians.⁵³ Such tools are conceptually well suited to SPS because the syndrome is defined by cumulative data that are often dispersed across multiple reports. Until automated systems are widely implemented, a pragmatic approach is to encourage structured reporting of serrated lesion number, size, location, and histology, combined with explicit alerts when cumulative findings approach or meet WHO criteria. In this sense, SPS diagnosis should be viewed not as a single-event decision but as a longitudinal process requiring repeated reassessment.

Epidemiology, Natural History, and Risk Stratification

Prevalence Estimates and Ascertainment Bias

Estimating the true prevalence of SPS is challenging because reported rates vary substantially according to population setting, endoscopic quality, pathological classification, and the consistency with which WHO criteria are applied. Although SPS was historically regarded as rare, contemporary studies suggest that it is increasingly encountered in colonoscopy practice and may represent one of the most clinically relevant colorectal polyposis syndromes.^1,7,54 However, the wide range of reported prevalence estimates indicates that SPS frequency cannot be interpreted without considering ascertainment bias.

In primary colonoscopy screening populations, SPS appears uncommon. A systematic review suggested that the prevalence in screening cohorts is likely below 0.09%.⁵⁵ By contrast, higher rates have been reported in selected colonoscopy cohorts, including a single-center Australian study in which SPS prevalence reached 2.94%.⁵⁴ FIT-positive screening populations also show higher reported prevalence than unselected primary screening cohorts, with estimates ranging from 0.34% to 0.66%.^55,56 European screening data similarly demonstrated substantial variation in the detection of clinically relevant serrated polyps and SPS, with SPS rates increasing after follow-up colonoscopy.⁵⁶ These differences likely reflect not only true population variation but also differences in bowel preparation, endoscopist awareness, detection of subtle proximal serrated lesions, pathological interpretation, and cumulative application of WHO criteria.

Thus, SPS should not be described simply as either “rare” or “common.” A more accurate interpretation is that SPS is under-ascertained in routine practice and becomes more visible when endoscopic detection is optimized and cumulative diagnostic criteria are systematically applied. This epidemiological uncertainty has direct clinical implications: low apparent prevalence may reflect missed diagnoses rather than true absence of disease, particularly in settings where serrated lesion detection and longitudinal polyp counting are inconsistent.^{14–16,53,57}

Colorectal Cancer Risk at Diagnosis and During Surveillance

The central clinical concern in SPS is CRC risk. Available evidence consistently indicates that patients with SPS have a substantially increased risk of CRC, particularly before or at the time of diagnosis. A 2022 meta-analysis including 36 studies and 2788 patients reported an overall CRC risk of 19.9% in SPS.⁸ Importantly, this risk was concentrated around the time of diagnosis, with a pooled synchronous CRC prevalence of 14.7% and a personal history of CRC before SPS diagnosis in 7.0% of patients.⁸ Large cohort studies have reported similar concerns, with CRC prevalence estimates of 15.8% in a multicenter cohort of 296 patients and 29.3% in another cohort of 434 patients.^58,59 These data reinforce the importance of early recognition: many cancers appear to occur before SPS has been formally identified and placed under structured surveillance.

The risk profile changes after diagnosis and effective endoscopic management. In the same meta-analysis, the risk of CRC during surveillance was substantially lower, estimated at 2.8%, or approximately 7 cases per 1000 person-years.⁸ Prospective and long-term surveillance cohorts support the view that intensive endoscopic management can markedly reduce CRC incidence. In a specialized center with more than 10 years of prospective follow-up after initial polyp clearance, the 5-year CRC incidence during surveillance was only 1.0%.⁶⁰ Another prospective study using annual surveillance with removal of all polyps ≥3 mm reported no CRC during a median follow-up of 3.1 years.³⁹ A long-term single-center study similarly found no CRC during surveillance after endoscopic clearance over a median follow-up of 5.0 years.⁶¹

These findings should be interpreted carefully. Surveillance does not eliminate neoplastic risk, and the low incidence of CRC in well-managed cohorts likely reflects both effective clearing colonoscopy and close follow-up in expert settings. Nevertheless, the contrast between high CRC prevalence at or before diagnosis and low CRC incidence during structured surveillance supports a clinically important conclusion: timely diagnosis and durable endoscopic control are central to cancer prevention in SPS.

Advanced Neoplasia as the Persistent Clinical Challenge

Although CRC incidence can be markedly reduced after effective endoscopic clearance and surveillance, advanced colorectal neoplasia remains common in SPS. Advanced neoplasia generally includes advanced adenomas, advanced serrated lesions—typically defined by size ≥10 mm or the presence of dysplasia—and CRC. This composite endpoint is clinically important because it captures the persistent neoplastic activity that continues even when invasive cancer is prevented.

Several studies demonstrate that advanced neoplasia remains a frequent outcome during follow-up. A multicenter study reported a 3-year cumulative incidence of advanced neoplasia of 42.0%, although the CRC component was relatively low at 3.1%.⁶² Other cohorts have reported lower but still clinically meaningful rates; for example, one long-term study found a 5-year cumulative advanced neoplasia incidence of 21.6%, with variation according to the WHO criterion fulfilled.⁶¹ Longitudinal data further suggest that the polyp burden in SPS may remain relatively stable over many years, rather than disappearing after the initial clearing phase.⁶⁰ These findings indicate that SPS should be viewed as a chronic neoplasia-prone condition requiring long-term control rather than a one-time polypectomy problem.

This distinction between CRC prevention and advanced neoplasia control is important for management. Low CRC incidence during surveillance should not be misinterpreted as justification for abandoning follow-up. Instead, it suggests that surveillance is effective because it repeatedly identifies and removes lesions before malignant progression. Therefore, advanced neoplasia, rather than CRC alone, may be the more practical endpoint for risk stratification and surveillance planning in SPS.

Risk Factors for CRC and Advanced Neoplasia

The heterogeneity of CRC and advanced neoplasia risk in SPS has prompted efforts to identify clinical and endoscopic predictors that can guide surveillance intensity. Several factors have been associated with higher risk. Serrated polyps containing dysplasia are among the most consistent markers of increased CRC risk.^58,59 The presence of advanced adenomas also confers increased risk, emphasizing that conventional adenoma-carcinoma biology can coexist with serrated neoplasia in SPS.⁵⁹ High cumulative polyp burden is another important risk signal. Patients fulfilling more than one WHO criterion appear to have greater risk of CRC or advanced neoplasia than those fulfilling a single criterion.^59,62

Characteristics of sessile serrated lesions (SSLs) also matter. More than two SSLs proximal to the splenic flexure and the presence of at least one proximal SSL with high-grade dysplasia have been identified as independent CRC risk factors.⁵⁸ Other variables linked to dysplastic SSLs include older age at SPS diagnosis, personal history of CRC, size of the largest SSL removed, and total SSL count.⁵⁴ These findings suggest that risk assessment should not rely only on whether SPS criteria are met, but should incorporate lesion number, size, location, histology, dysplasia, conventional adenoma burden, and prior CRC history.

This risk-factor evidence supports a shift from uniform surveillance toward risk-adapted management, but the associations are not fully consistent across retrospective and prospective cohorts. High polyp burden, dysplastic serrated lesions, advanced adenomas, proximal large SSLs, and prior CRC should therefore be treated as clinical modifiers rather than components of a validated universal risk score.^{58,59,61–63} Selected patients with a low burden at the most recent high-quality examination may be candidates for a 2-year interval after complete clearing, whereas higher-risk findings or uncertainty about examination quality justify closer reassessment.

Environmental Factors, Special Populations, and Uncertain Extracolonic Risk

The etiology of SPS remains incompletely understood, but epidemiological studies have identified several environmental and host-associated factors. Cigarette smoking is one of the most consistently reported risk factors for SPS.^64,65 Higher body mass index, particularly early-adulthood BMI, and female biological sex have also been associated with SPS in some studies.^64,66 Conversely, some data suggest potential inverse associations between CRC risk and factors such as non-steroidal anti-inflammatory drug use, hormone replacement therapy, or higher dietary folate and calcium intake, although these findings require cautious interpretation and should not yet be translated into SPS-specific preventive recommendations without further validation.⁶⁴

Certain clinical populations may deserve special attention. Survivors of Hodgkin lymphoma treated with abdominal radiotherapy and/or alkylating agents have been reported to have increased risk of SPS and advanced serrated lesions.⁶⁷ SPS-like phenotypes have also been described in long-standing inflammatory bowel disease and in therapy-associated polyposis among survivors of childhood and young adult cancers.^68,69 These settings may mimic or overlap with SPS while carrying distinct mechanisms of carcinogenesis and surveillance considerations. Because the evidence is derived from small or selected populations, these associations should be interpreted as hypothesis-generating and should not be generalized to the broader SPS population.

The risk of extracolonic cancer in SPS remains uncertain. Some studies have reported extracolonic malignancies among SPS patients or their relatives, but the evidence is less consistent and less robust than the established association with CRC.^57,70 Therefore, extracolonic cancer risk should be presented as an area requiring further study rather than as a definitive component of SPS clinical management. At present, CRC prevention remains the principal evidence-based focus of SPS surveillance and family screening.

From Cancer Risk to Risk-Adapted Prevention

Taken together, the epidemiological and natural history data support three key conclusions. First, SPS is likely under-ascertained, and reported prevalence depends heavily on endoscopic detection, pathological classification, and cumulative application of diagnostic criteria. Second, CRC risk is substantial before or at SPS diagnosis but appears markedly reduced after high-quality clearing colonoscopy and structured surveillance. Third, advanced neoplasia remains common during follow-up, indicating that SPS requires long-term management even when invasive cancer is prevented.

These conclusions justify a risk-adapted prevention framework. The clinical question is no longer simply whether SPS is associated with CRC risk; that association is well established. The more relevant question is how to identify patients at highest risk, determine appropriate surveillance intervals after endoscopic control, and integrate lesion burden, histology, dysplasia, conventional adenoma coexistence, prior CRC, and family history into individualized care. This risk-stratified perspective provides the bridge to the following section, which examines the biological heterogeneity underlying SPS-associated neoplasia.

Limitations and Generalizability of the Evidence Base

The SPS evidence base has important geographic and referral-center limitations. Much of the evidence supporting intensive clearing and 1- to 2-year surveillance comes from European specialist centers with experienced endoscopists, centralized or expert pathology review, and structured recall systems.^{39,60,62,63,71,72} The low CRC incidence achieved in these cohorts may therefore reflect both treatment efficacy and setting-specific expertise, and it may not be directly reproducible in community practice, lower-resource settings, or populations with limited access to high-quality colonoscopy. Evidence from non-European regions and ancestrally diverse populations remains comparatively limited.

Apparent discrepancies among studies also arise from methodological heterogeneity. Reported CRC and advanced-neoplasia rates vary with referral selection, use of the 2010 versus 2019 WHO criteria, inclusion or exclusion of synchronous cancers, definitions of advanced neoplasia, clearing thresholds, colonoscopy quality, and follow-up duration.^8,60,62,63 Genetic testing yield likewise depends on age and family-history referral criteria, panel composition, variant classification, and ancestry.²⁴ These differences limit direct comparison and can produce apparently conflicting estimates without implying true biological disagreement.

Accordingly, the management framework proposed here is a guideline-supported clinical approach, not a universally validated risk score. Clinical, endoscopic, and pathological features can support interval assignment in current practice, whereas germline, epigenetic, microbiome, metabolomic, and organoid findings remain exploratory. Prospective multicenter validation across diverse geographic regions and routine clinical settings is required before molecularly informed surveillance or longer intervals can be adopted.

Biological Heterogeneity of SPS-Associated Neoplasia

Histological Spectrum of Serrated Lesions

The biological heterogeneity of SPS begins with the histological diversity of serrated lesions themselves. Modern pathological classification recognizes HPs, SSLs with or without dysplasia, and TSAs as distinct entities with different morphological features, anatomical distributions, and malignant potential.^3,4,73 Among these, SSLs are considered the principal serrated precursors of CRC, particularly in the proximal colon, whereas TSAs are less common but also premalignant.^3,4,73 By contrast, most small distal HPs have low malignant potential, although their distinction from small or subtle SSLs can be challenging in practice.^3,4,74,75

This histological heterogeneity has direct clinical relevance in SPS. First, the diagnostic criteria for SPS depend on accurate classification and cumulative counting of serrated lesions. Second, lesion subtype influences cancer risk: SSLs with cytological dysplasia represent a more advanced step toward malignant transformation and are regarded as direct precursors to invasive carcinoma.^76,77 Third, misclassification or under-recognition of subtle serrated lesions may contribute to delayed SPS diagnosis and inadequate surveillance intensity. Therefore, pathology in SPS is not merely descriptive; it is central to diagnosis, risk stratification, and cancer prevention.

Somatic Serrated Pathway: MAPK Activation, CIMP and MLH1 Silencing

The classical serrated neoplasia pathway is characterized by early activation of the mitogen-activated protein kinase pathway, most commonly through BRAF V600E mutation and less frequently through KRAS mutation.^2,5,78 These alterations are followed by widespread epigenetic dysregulation, particularly the CpG island methylator phenotype (CIMP), which can silence tumor suppressor genes and DNA repair genes.^2,5,79 In a subset of lesions, methylation-induced silencing of MLH1 leads to mismatch repair deficiency and high-level microsatellite instability (MSI-H), providing a molecular route from SSL to dysplasia and eventually CRC.^27,34,35

SPS provides a unique human model for studying this pathway because affected patients often harbor multiple serrated lesions at different stages of progression. A systematic review reported that BRAF mutations were present in approximately 73% of serrated polyps from SPS patients but in only about 49% of SPS-associated CRCs, whereas KRAS mutations were less frequent in both polyps and cancers.³⁵ These data support the central role of the BRAF-driven serrated pathway in SPS-associated neoplasia, but also suggest that BRAF mutation alone cannot explain all cancers arising in SPS.

The CIMP-MLH1-MSI axis is particularly important for understanding progression from SSL to cancer. Promoter hypermethylation can silence MLH1, resulting in MSI-H CRC, a hallmark of many serrated pathway cancers.^27,34,35 However, not all SPS-associated cancers are MSI-H, and not all arise through the same molecular sequence. This distinction is important because it prevents oversimplification of SPS as a uniform BRAF-mutant/CIMP-high disease.

SPS-Associated CRC Is Not Molecularly Uniform

A major conceptual advance in recent SPS research is the recognition that SPS-associated CRCs are molecularly heterogeneous. Although the serrated pathway is central to SPS, available evidence indicates that cancers in SPS may arise through both serrated and conventional adenoma-carcinoma pathways.^34–38 Roughly half of CRCs in SPS patients have been reported to harbor BRAF V600E mutation, consistent with a serrated pathway origin, whereas the remainder are BRAF wild-type and more likely to reflect conventional or mixed adenoma-carcinoma biology.^36,37

This dual carcinogenic landscape has clinicopathological correlates. BRAF-mutant SPS-associated CRCs tend to be proximal and are often MSI-H due to MLH1 loss, whereas BRAF wild-type cancers are more frequently distal and microsatellite stable.^36,38 In addition, patients with BRAF wild-type CRCs may have a higher ratio of conventional adenomas to serrated polyps, and adenomas themselves have been identified as risk factors for CRC in SPS cohorts.^36,37 These observations challenge the earlier assumption that SPS-related cancers arise exclusively through the serrated pathway and provide a biological explanation for why conventional adenoma burden remains clinically relevant in SPS.

Germline Predisposition: Validated Genes, Candidate Genes and Limitations

Unlike classical Mendelian polyposis syndromes, the germline basis of SPS remains largely unexplained. Large cohort studies have reported a low diagnostic yield from germline testing, supporting the concept that most SPS is not caused by a single high-penetrance inherited mutation.^{22–25,51,80} In one cohort of 258 tested SPS patients, pathogenic germline variants were found in only 2.9%, including incidental Lynch syndrome diagnoses and one RNF43 variant.²⁴ Another study found pathogenic variants in a minority of tested patients, involving genes such as MUTYH, SMAD4, CHEK2, POLD1 and RNF43, but these findings underscore heterogeneity rather than a single dominant genetic cause.⁸¹

RNF43 is currently the best validated germline gene associated with a small subset of SPS. RNF43 encodes a negative regulator of Wnt signaling, and germline pathogenic variants have been identified in families with serrated polyposis.^26,27 However, RNF43 explains only a small proportion of SPS cases, with estimated prevalence around 1.5–2.5%, and its penetrance appears variable.^28–30 Somatic RNF43 mutations are also seen in sporadic serrated lesions and MSI-H CRCs with MLH1 methylation, often in association with BRAF mutation.^27,82 Thus, RNF43 is biologically relevant to the serrated pathway but should not be presented as the principal cause of SPS.

Other candidate genes and pathways have been proposed, including genes involved in DNA interstrand crosslink repair, WNK2, BUB1, POLD1 and others.^83–88 However, many of these findings come from small cohorts, individual families, or single-case reports and require independent validation. Similarly, overlap with other polyposis syndromes can occur; for example, MUTYH-associated polyposis may present with numerous serrated lesions, and some patients initially classified as SPS may ultimately be reclassified after expert pathological or genetic review.^51,89–94 Therefore, germline testing in SPS is best viewed as a tool to identify rare actionable variants or alternative syndromic diagnoses, not as a replacement for phenotype-based diagnosis.

Field Effect, Epigenetics, Microbiome and Metabolome

The incomplete explanation provided by germline genetics has shifted attention toward field effects and non-mutational mechanisms. Several observations suggest that the apparently normal colonic mucosa in SPS may already harbor molecular alterations that predispose to the emergence of multiple serrated lesions. Whole-exome sequencing studies of polyps from individuals with unexplained polyposis have shown that serrated polyps often carry BRAF mutations but relatively few APC/CTNNB1 alterations, supporting their distinction from conventional adenomas.⁹⁵ In addition, early serrated lesions may have a relatively low somatic mutation burden, suggesting that epigenetic changes rather than accumulated coding mutations may be important early drivers.⁹⁶

Epigenetic field effects are particularly relevant. Epigenome-wide methylation profiling of normal mucosa from SPS patients has identified hypermethylation of genes such as HLA-F as a potential biomarker candidate, suggesting either a constitutional epigenetic predisposition or an acquired mucosal field defect.⁹⁷ CIMP-high methylation is also highly prevalent in the serrated pathway and may drive progression through silencing of genes such as MLH1 and MGMT.^2,27,31,33 These findings provide a plausible mechanism by which multiple lesions may arise across the colon in SPS, even in the absence of a clear monogenic cause.

Emerging data also implicate the colonic microenvironment, microbiota and metabolome. Preliminary studies suggest that mucosa-associated microbiota profiles in SPS may differ from those in adenomatous polyposis and that stool metabolite patterns, such as altered leucine-to-tyrosine ratios, may help distinguish polyposis phenotypes.⁹⁸ Patient-derived organoid models have also begun to explore therapeutic vulnerabilities of serrated lesions, including sensitivity to EGFR pathway inhibition in SSL-derived organoids.⁹⁹ These findings remain exploratory and should not yet be interpreted as clinically validated biomarkers or chemopreventive strategies. Nevertheless, they broaden the biological model of SPS from a purely genetic disorder to a multifactorial phenotype shaped by somatic, epigenetic, microbial, metabolic and environmental influences.

SPS as a Heterogeneous Clinical Phenotype

The accumulated evidence supports a revised biological model of SPS. Rather than a single-gene syndrome or a uniform serrated pathway disorder, SPS should be understood as a clinically defined phenotype with multiple biological layers. At the lesion level, HPs, SSLs, SSLs with dysplasia and TSAs differ in malignant potential. At the somatic level, BRAF/KRAS activation, CIMP and MLH1 silencing drive the classical serrated pathway, but SPS-associated CRCs may also arise through BRAF-wild-type, microsatellite-stable, conventional or mixed pathways. At the germline level, RNF43 and other rare variants explain only a minority of cases. At the mucosal level, field effects, methylation changes, microbiota and metabolomic alterations may help explain multiplicity and recurrence.

This heterogeneity has practical consequences. It explains why SPS diagnosis cannot rely solely on genetic testing, why conventional adenomas remain relevant in SPS risk assessment, and why surveillance strategies should eventually incorporate not only the number of serrated lesions but also lesion histology, dysplasia, adenoma burden, molecular features and family history. The next section therefore turns from biological heterogeneity to its clinical implication: risk-adapted management.

Risk-Adapted Management: Endoscopic Control, Surgery, and Family Screening

Detection and Clearing Colonoscopy

The primary goal of SPS management is CRC prevention through high-quality detection, complete removal of clinically relevant lesions, and durable endoscopic control. Because serrated lesions, particularly SSLs, are often flat, pale, mucus-covered, and proximally located, their detection requires meticulous colonoscopic technique rather than routine examination alone.^3,4,42,76,79 Adequate bowel preparation, careful mucosal inspection, sufficient withdrawal time, and awareness of the subtle endoscopic features of SSLs are essential components of effective surveillance.^43,100 In patients with suspected or confirmed SPS, colonoscopy should therefore be approached as a targeted clearing procedure, not simply as a diagnostic examination.

Enhanced imaging may improve lesion detection in selected settings. High-definition white-light endoscopy is generally considered a minimum standard, while dye-based chromoendoscopy has shown benefit in detecting additional polyps, particularly small proximal serrated lesions, in SPS surveillance.^101,102 The role of virtual chromoendoscopy, such as narrow-band imaging, is more nuanced: it may help characterize lesion borders and surface patterns, although randomized data have not consistently shown superiority over high-resolution white-light endoscopy for overall miss rates.^103–105 Mechanical devices such as Endocuff have not clearly improved serrated lesion detection in SPS surveillance.¹⁰⁶ Thus, the emphasis should remain on high-quality technique, careful inspection, and complete mucosal assessment, with adjunctive technologies used according to local expertise and patient-specific risk.

The initial clearing phase is particularly important. Patients with large serrated lesions, especially lesions ≥20 mm, have a high prevalence of synchronous lesions and may meet SPS criteria upon careful reassessment.⁴⁹ Therefore, the discovery of a large serrated lesion should prompt a high-quality clearing colonoscopy of the entire colon, both to exclude synchronous advanced neoplasia and to evaluate for SPS.⁴⁹ In this context, clearing colonoscopy serves two purposes: cancer prevention and syndrome recognition.

Complete Resection and Endoscopic Control

Once serrated lesions are detected, complete resection is essential. Incomplete resection has been implicated in post-colonoscopy CRC, particularly for subtle serrated lesions that may have indistinct borders.^76,79 The resection approach should be tailored to lesion size, morphology, location, and endoscopist expertise. For diminutive and small serrated lesions, cold snare polypectomy is generally preferred because of its favorable safety profile and effectiveness.^41,43 For larger SSLs, particularly those ≥10 mm, cold snare endoscopic mucosal resection or conventional EMR may be appropriate depending on lesion characteristics and local practice.^41,43 Very large, flat, fibrotic, recurrent, or anatomically challenging lesions may require advanced resection techniques in expert centers.^41,49,107

The concept of “endoscopic control” is central to SPS management. Rather than focusing only on the number of colonoscopies performed, clinicians should determine whether clinically relevant lesions can be consistently detected and cleared. Studies suggest that endoscopic control is achievable in most patients after a limited number of clearing procedures, although the number of procedures required depends on baseline polyp burden, lesion size, and distribution.^41,108–110 Once control is achieved, management shifts from initial clearance to maintenance surveillance.

This distinction is important because it separates two clinical phases that are often conflated. During the clearing phase, short intervals may be necessary to remove synchronous lesions and reduce immediate neoplastic risk. During the maintenance phase, surveillance intervals may be individualized according to ongoing polyp burden and advanced neoplasia risk. This framework prevents both undertreatment of high-burden patients and unnecessary over-surveillance of patients with stable disease after effective clearing.

Risk-Adapted Surveillance After Clearing

Major recommendations share the goals of high-quality clearing and lifelong colonoscopic follow-up but differ in interval detail (Table 2). The 2015 ACG guideline recommends colonoscopy every 1–3 years with removal of all polyps >5 mm. ESGE uses findings from the most recent high-quality examination to assign 1- or 2-year surveillance, whereas BSG/ACPGBI/UKCGG recommends annual surveillance after clearance of lesions >5 mm with extension to 2 years when no lesion ≥10 mm is found. Australian eviQ similarly recommends 1- to 2-year surveillance after a structured clearing phase.^20,71,72,111 These differences reflect guideline age, evidentiary thresholds, and local care pathways rather than a fully resolved optimal interval.

Table 2.

Selected International Recommendations for Management of Serrated Polyposis Syndrome

Guideline	Clearing Target	Post-Clearance Surveillance	Surgery and First-Degree Relatives
ACG 201520	Attempt removal of all polyps >5 mm.	Colonoscopy every 1–3 years; no explicit 1- versus 2-year finding-based algorithm.	Surgery: inability to control polyp growth or CRC. FDR: individualized because evidence was considered unclear.
ESGE 201971	Remove all polyps ≥5 mm and smaller polyps suspicious for dysplasia.	1 year after ≥1 advanced polyp or ≥5 relevant polyps; 2 years otherwise, based on the most recent examination.	Surgery: consider when endoscopic control is not feasible. FDR: baseline at 45 years, then every 5 years if no earlier indication.
BSG/ACPGBI/UKCGG 202072	Clear the colon of all lesions >5 mm.	Annual surveillance; extend to 2 years if no polyp ≥10 mm is identified at subsequent surveillance.	Surgery: MDT referral when disease is not endoscopically manageable. FDR: baseline at 40 years or 10 years before index-case diagnosis; every 5 years if appropriate.
eviQ 2025111	Repeat at 3–6 months until two examinations are clear of relevant polyps.	Every 1–2 years; annual if >1 advanced serrated polyp, >1 advanced adenoma, or >5 relevant lesions; repeat sooner after inadequate preparation.	Surgery: consider if clinically relevant polyps cannot be controlled endoscopically. FDR: start at 40 years, youngest SPS age, or 10 years before youngest CRC in an affected FDR; subsequent interval by findings.

Notes: Guidelines differ in definitions and evidentiary grading; this table summarizes clinically relevant points rather than replacing the full source documents^20,71,72,111.

Abbreviations: ACG, American College of Gastroenterology; ESGE, European Society of Gastrointestinal Endoscopy; BSG, British Society of Gastroenterology; ACPGBI, Association of Coloproctology of Great Britain and Ireland; UKCGG, United Kingdom Cancer Genetics Group; FDR, first-degree relative.

A practical post-clearance algorithm can nevertheless be derived from the best prospective evidence and current guidance. After a high-quality colonoscopy with complete resection, a 1-year interval should follow detection of at least one advanced polyp (advanced serrated lesion or advanced adenoma) or at least five clinically relevant polyps. A 2-year interval may be considered when no advanced polyp and fewer than five relevant polyps are found.^63,71,72,111 In this context, relevant polyps include adenomas or SSLs of any size, TSAs, and hyperplastic polyps ≥5 mm. This rule translates risk adaptation into a reproducible decision while retaining reassessment after every examination.

Interval assignment is conditional on examination quality and durable endoscopic control. Inadequate bowel preparation, incomplete examination, uncertain or piecemeal resection of a complex lesion, unresolved pathology, residual lesions, prior CRC, or unreliable follow-up should prompt earlier or individualized reassessment rather than automatic use of the nominal 1- or 2-year interval. Conversely, a lower polyp count cannot justify extension when clearance quality is uncertain. These quality modifiers are particularly important when applying expert-center data in routine practice.

Evidence does not currently support routine surveillance beyond 2 years. A 2026 multicenter randomized non-inferiority trial enrolled 131 low-risk patients with no advanced neoplasia and fewer than five relevant polyps at the preceding examination. Advanced neoplasia was detected in 6.9% at 2 years and 13.6% at 3 years; because the confidence interval crossed the prespecified non-inferiority margin, the non-inferiority of the 3-year strategy remained inconclusive. Diagnosis within the preceding 3 years was also associated with higher advanced-neoplasia risk.¹¹² Thus, 3-year surveillance should remain investigational pending larger prospective validation.

When is Surgery Needed?

Most patients with SPS can be managed endoscopically, but surgery remains necessary in a subset. Guideline-consistent indications include CRC, dysplasia or a complex lesion not amenable to curative endoscopic resection, and a polyp burden that cannot be safely or completely controlled despite expert clearing attempts.^{20,39,40,62,71,72,111} No single numeric polyp threshold defines failure of endoscopic management; feasibility depends on lesion size, distribution, recurrence, procedure burden, local expertise, and patient preference. Multidisciplinary review is therefore appropriate before elective colectomy whenever immediate oncologic surgery is not required.

When surgery is performed, the operation should be individualized according to lesion distribution, cancer status, rectal involvement, patient age, comorbidities, and expected postoperative surveillance burden. Subtotal colectomy with ileorectal or ileosigmoid anastomosis is commonly considered when the polyp burden is diffuse or endoscopic control is not feasible.^62,113 Importantly, surgery reduces but does not abolish future neoplasia risk. Advanced neoplasia may still occur in retained rectum or residual colon, making postoperative surveillance mandatory.^62,113

Surgery should therefore be framed not as failure of management, but as one component of CRC prevention when endoscopic control is no longer realistic or safe. Early referral to an experienced colorectal surgeon may be appropriate when repeated clearing attempts fail, when complex lesions recur, or when malignant transformation is suspected. Multidisciplinary discussion is especially valuable in borderline cases, where the balance between continued endoscopic management and prophylactic surgery may be difficult.

Screening and Counseling of First-Degree Relatives

Management of SPS extends beyond the index patient. First-degree relatives have an increased risk of CRC and serrated lesions, even though most SPS families do not have an identifiable germline mutation.^{40,57,114–118} This familial aggregation supports proactive screening of relatives based on family history and the proband’s diagnosis, rather than waiting for a molecular explanation.

Guidelines differ modestly in the starting age for first-degree relatives (Table 2). ESGE recommends baseline colonoscopy at age 45 years, whereas BSG/ACPGBI/UKCGG recommends age 40 years or 10 years before the index case was diagnosed; eviQ recommends age 40 years, the age of the youngest SPS diagnosis in the family, or 10 years before the youngest CRC diagnosis in an affected first-degree relative, whichever is earliest.^71,72,111 If the baseline examination is normal, a 5-year interval is commonly used in European guidance; subsequent timing should be shortened according to detected adenomas or serrated lesions. The older ACG guideline leaves family screening individualized because evidence was then limited.²⁰

Genetic counseling may be appropriate for SPS patients and families, particularly when there is early-onset CRC, multiple affected relatives, adenomatous polyposis, extracolonic cancer clustering, or an atypical phenotype suggesting overlap with another hereditary syndrome.^9,119 However, genetic testing should not be used to exclude SPS, because the diagnosis remains phenotype-based and most cases are genetically unexplained. The role of counseling is therefore twofold: to identify rare actionable germline variants or alternative syndromic diagnoses, and to ensure that family members receive appropriate colonoscopic prevention.

A Practical Management Framework

Contemporary SPS management can be organized into sequential clinical phases (Figure 1). First, suspect SPS when multiple serrated lesions, large proximal SSLs, recurrent serrated polyps, or a large serrated lesion prompt review of prior records. Second, establish the diagnosis using cumulative WHO 2019 criteria and consider alternative hereditary syndromes when the phenotype is atypical. Third, perform high-quality clearing colonoscopy until clinically relevant lesions are completely resected and endoscopic control is documented. Fourth, apply the quality gate and choose 1- or 2-year surveillance from the most recent findings. Fifth, refer for advanced endoscopy or multidisciplinary surgical evaluation when control is uncertain or unachievable. Finally, initiate guideline-based screening and counseling for first-degree relatives.

Figure 1.

Phase-based management pathway for serrated polyposis syndrome.

The framework deliberately distinguishes current practice from research. Cumulative lesion counts, polyp burden, size, histology, dysplasia, advanced adenomas, prior CRC, completeness of resection, bowel preparation, and follow-up reliability can inform management now. Germline, methylation, microbiome, metabolomic, organoid, and other non-invasive biomarkers may refine future prediction but should not override guideline-based clinical decisions until prospectively validated.

Future Directions

Beyond Phenotype-Based Diagnosis

The current diagnostic criteria for SPS are pragmatic and clinically useful, but they remain primarily phenotype-based. They define SPS according to the cumulative number, size, and distribution of serrated lesions, rather than according to a specific biological mechanism. This approach is necessary because most SPS cases lack an identifiable high-penetrance germline cause, but it also means that patients meeting the same diagnostic criteria may differ substantially in underlying biology, polyp behavior, and CRC risk.^{22–25,51,79}

Future work should therefore move beyond diagnosis alone and focus on risk prediction. The key clinical question is not simply whether a patient meets WHO criteria, but whether that patient is likely to develop advanced neoplasia or CRC despite endoscopic control. Existing studies already suggest that risk is not uniform: dysplastic serrated lesions, advanced adenomas, high cumulative polyp burden, proximal SSL burden, fulfillment of multiple WHO criteria, and prior CRC history have all been associated with higher neoplastic risk.^54,58,59,62 Conversely, selected lower-burden patients may be safely managed with longer surveillance intervals after effective clearing colonoscopy, as suggested by prospective risk-adapted surveillance data.⁶³ These observations provide the foundation for a more refined SPS classification that integrates clinical, endoscopic, pathological, and eventually molecular variables.

A future risk model for SPS should ideally combine several domains: age at diagnosis, personal and family history of CRC, cumulative serrated and adenomatous polyp burden, lesion size and location, presence of dysplasia, quality and completeness of endoscopic clearance, and molecular features of representative lesions. Such a model would help distinguish patients who require intensive surveillance from those in whom colonoscopy burden may be safely reduced. However, before such models can be implemented, they require validation in large, prospective, multicenter cohorts with standardized colonoscopy quality, pathology review, and long-term outcomes.

Molecular and Non-Invasive Biomarkers

Molecular and non-invasive biomarkers are promising but remain investigational for SPS risk stratification. Germline testing can identify rare actionable variants or alternative hereditary syndromes, but its diagnostic yield is low and it should not be used to exclude a phenotype-based SPS diagnosis.^24,25,80,81 RNF43 is the best validated germline gene for a small subset, yet its low prevalence and variable penetrance preclude routine use for interval assignment.^26–30 Polygenic risk scores likewise lack SPS-specific clinical validation.^120,121 At present, none of these markers should determine routine surveillance.

Epigenetic and mucosal field-effect markers may be more directly relevant to the SPS phenotype. Hypermethylation signatures in normal-appearing mucosa, including candidate markers such as HLA-F, suggest that SPS may involve a constitutional or acquired field defect predisposing to multifocal serrated neoplasia.⁹⁷ Likewise, CIMP-related methylation, MLH1 silencing, and MGMT methylation contribute to serrated pathway progression and may help distinguish biologically distinct lesion subsets.^2,27,31,33 Future studies should determine whether these markers can predict recurrent advanced neoplasia, guide surveillance intervals, or identify patients who are likely to develop CRC despite apparent endoscopic control.

Microbiome and metabolome studies offer another exploratory direction. Differences in mucosa-associated microbiota and stool metabolite profiles, including altered amino acid ratios, have been reported in SPS and may help distinguish serrated from adenomatous polyposis phenotypes.⁹⁸ Patient-derived organoid models may also provide platforms for studying lesion biology and testing chemopreventive strategies.⁹⁹ However, these approaches remain research tools. They should not yet be presented as clinically validated biomarkers, and their future value will depend on reproducibility, assay standardization, cost-effectiveness, and ability to improve outcomes beyond high-quality colonoscopic surveillance.

Optimizing Surveillance While Reducing Patient Burden

Lifelong colonoscopic surveillance is central to SPS care but imposes physical, psychological, logistical, and economic burdens. Prospective data support dynamic 1- or 2-year intervals after high-quality clearing,⁶³ but the 2026 randomized comparison of 2 versus 3 years did not establish non-inferiority of the 3-year strategy and identified greater risk during the early years after diagnosis.¹¹² Therefore, reducing burden should focus on reliable identification of patients suitable for 2-year surveillance, efficient clearing, high-quality procedures, and patient-centered scheduling rather than routine extension beyond 2 years.

Future surveillance strategies should be patient-centered as well as risk-adapted. Patients with SPS may experience anxiety related to lifelong cancer risk, repeated procedures, and implications for family members. Surveillance colonoscopies can also lead to work-time loss, procedural burden, and healthcare resource use.¹²² Therefore, the goal should not be maximum surveillance intensity for all patients, but the minimum effective surveillance intensity required to maintain cancer prevention. This requires shared decision-making, clear communication of individualized risk, and attention to patient-reported outcomes.

The same principle applies after surgery. Colectomy may reduce CRC risk in patients with uncontrollable polyp burden or unresectable neoplasia, but retained rectum or residual colon remains at risk for advanced neoplasia.^62,113 Postoperative surveillance intervals should therefore be informed by residual bowel anatomy, previous polyp burden, findings at the first postoperative examination, and patient-specific risk factors. Prospective data are needed to define optimal follow-up after subtotal colectomy, ileorectal anastomosis, or ileosigmoid anastomosis.

Multidisciplinary and Family-Based Prevention

SPS management is inherently multidisciplinary. Gastroenterologists and endoscopists are responsible for detection, clearing, and surveillance; pathologists provide accurate classification of serrated lesions and dysplasia; geneticists and genetic counselors help identify overlapping hereditary syndromes and guide family counseling; surgeons manage patients with uncontrollable polyp burden or cancer; and primary care clinicians may help ensure adherence to long-term surveillance.

Family-based prevention remains a key component. First-degree relatives of SPS patients have increased risks of CRC and serrated lesions, even though most families lack an identifiable germline mutation.^{40,57,114–118} Current recommendations therefore rely on colonoscopic screening rather than genetic testing alone, typically beginning at age 40 or 10 years before the earliest SPS or CRC diagnosis in the family, with intervals adjusted according to findings.^40,43 Future studies should clarify whether family history, polyp phenotype, genetic background, and possibly polygenic or molecular markers can refine screening recommendations for relatives.

The broader goal is to integrate index-patient and family-level prevention. A diagnosis of SPS should trigger not only treatment of the proband but also systematic review of family history, communication with relatives, and appropriate colonoscopic screening. This is particularly important because the lack of a monogenic explanation may lead to underappreciation of familial risk. In SPS, absence of a pathogenic germline variant should not be interpreted as absence of inherited or shared risk.

Conclusions

Three messages are immediately actionable. First, SPS remains a phenotype-based and cumulative diagnosis: clinicians should aggregate colonoscopy and pathology findings across time and apply the 2019 WHO criteria as soon as they are met. Reliable lesion counting, size documentation, and pathology classification are therefore core cancer-prevention interventions rather than administrative details.

Second, management should proceed by phase. High-quality clearing and complete resection must precede maintenance surveillance. Thereafter, at least one advanced polyp or at least five relevant polyps supports a 1-year interval, whereas a 2-year interval may be considered after a high-quality examination showing no advanced polyp and fewer than five relevant polyps. Examination quality, resection completeness, prior CRC, complex lesions, and follow-up reliability can justify earlier reassessment. Surgery is appropriate when endoscopic control is unsafe or unachievable, and diagnosis of an index patient should trigger screening of first-degree relatives.

Third, the limits of current evidence should be explicit. Biomarker-informed surveillance and routine intervals beyond 2 years are not established. Larger prospective multicenter studies involving diverse geographic regions, community as well as expert settings, standardized clearance definitions, and patient-reported outcomes are required before newer risk models can enter routine practice. Until then, risk-adapted cancer prevention should remain anchored in cumulative diagnosis, colonoscopy quality, pathology, dynamic lesion burden, and reliable longitudinal care.

Ethics Approval and Informed Consent

Not applicable. This narrative review uses only previously published literature and includes no new human participants, animals, or identifiable patient data.

Disclosure

The authors declare that they have no competing interests.