Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden’s syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome–hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden’s syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management. The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden’s syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome–hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden’s syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management. The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. Nevertheless, there has been tremendous progress in recent years, both in understanding the underlying genetics that underpin these disorders and in elucidating the biology of associated premalignant and malignant conditions. Emerging data in affected populations focus increasingly on those with defined cancer susceptibility germline pathogenic variants leading to less heterogeneity in terms of quantifying cancer risk. The US Multi-Society Task Force on Colorectal Cancer (USMSTF) is a group of colorectal cancer (CRC) content experts appointed by the American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy, supplemented at times by other experts to complement existing expertise. In this USMSTF Consensus Statement, the gastrointestinal hamartomatous polyposis syndromes were chosen because of recent progress in understanding these diseases. The following entities reviewed are: Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), PTEN hamartoma tumor syndrome (PHTS, including Cowden’s syndrome [CS] and Bannayan-Riley-Ruvalcaba syndrome [BRRS]), and hereditary mixed polyposis syndrome (HMPS). Germline alterations are known to cause each of these disorders, but the diagnosis can also be made on the basis of clinical criteria. Although there are essentially no long-term prospective controlled studies of comparative effectiveness of management strategies for these syndromes, there have been consensus statements by expert panels that made management recommendations for these disorders. The goal of this USMSTF Statement was to review the literature focusing on the most recent data, synthesize both the data and the suggested approaches to diagnosis and management by other expert groups, and present the consensus recommendations of the USMSTF (Table 1). Review of summary tables, conference calls, and revisions of iterative drafts, including recommendation statements, were used to reach consensus, at which time documents were forwarded to Governing Boards for approval. As our USMSTF is a group of individuals with expertise in gastroenterology and gastrointestinal malignancies, we have reserved our management recommendations to these areas and defer to other expert groups’ recommendations for other cancers (which are reviewed here). This document therefore recommends clinical approaches to diagnosing and managing these conditions that affect children and adults, focuses on cancer risk, and provides insights into future research opportunities.Table 1Questions and Recommendations of Best PracticeWhich individuals with hamartomatous polyps should be referred for genetic evaluation? We recommend patients with any of the following undergo a genetic evaluation: 2 or more lifetime hamartomatous polyps, a family history of hamartomatous polyps, or a cancer associated with a hamartomatous polyposis syndrome in first or second-degree relatives. Genetic testing (if indicated) should be performed using a multigene panel test. (Strong recommendation, low quality of evidence)Peutz-Jeghers syndrome Who should undergo a genetic evaluation for Peutz-Jeghers syndrome?We recommend genetic evaluation for any individual with the following: 1) 2 or more histologically confirmed Peutz-Jeghers polyps, 2) any number of Peutz-Jeghers polyps in an individual who has a family history of Peutz-Jeghers syndrome in a first-degree relative, 3) characteristic mucocutaneous pigmentation in a person with a family history of Peutz-Jeghers syndrome, 4) any number of Peutz-Jeghers polyps in a person with the characteristic mucocutaneous pigmentation of Peutz-Jeghers syndrome. (Strong recommendation, low quality of evidence) Which organs should undergo surveillance when caring for a patient with Peutz-Jeghers syndrome?Patients with Peutz-Jeghers syndrome are at increased risk for cancer in multiple organs including cancer of the breast, small bowel, colon, stomach, pancreas, ovaries, testes, and lungs.Given this risk, we recommend a multidisciplinary approach to cancer surveillance in these organs (Strong recommendation, low quality of evidence) How and when should small bowel surveillance be performed in Peutz-Jeghers syndrome?We recommend that baseline small bowel surveillance using video capsule endoscopy or magnetic resonance enterography be performed between ages 8-10 years or earlier if the patient is symptomatic. If no polyps are found at the initial examination, surveillance should resume at age 18. Because of the risk of small bowel intussusception, small bowel surveillance in adulthood is recommended to continue throughout life every 2-3 years. (Strong recommendation, low quality of evidence) What is the recommended approach to endoscopic surveillance of the colon, stomach, and duodenum in Peutz-Jeghers syndrome?We suggest a baseline upper gastrointestinal endoscopy between the ages of 8 and 10 years, which could be performed at the time of capsule placement for small bowel surveillance or if polyps are identified on magnetic resonance enterography. Although the initiation age for colonoscopy remains uncertain, we also suggest initiation of colonoscopy at same time as esophagogastroduodenoscopy. In those in whom characteristic polyps are detected, both colonoscopy and esophagogastroduodenoscopy should be repeated every 2–3 years. In those in whom there are no Peutz-Jeghers polyps at baseline, surveillance is repeated at age 18 years, or sooner should symptoms arise, and then every 3 years. (Weak recommendation, very low quality of evidence) What size polyps found on small bowel imaging in Peutz-Jeghers syndrome should be removed?We recommend polypectomy of small bowel polyps that are symptomatic or ≥10 mm to prevent intussusception and other complications, such as bleeding.(Strong recommendation, low quality of evidence) What is the recommended pancreatic cancer surveillance in Peutz-Jeghers syndrome?We suggest annual pancreatic cancer surveillance with either magnetic resonance cholangiopancreatography or endoscopic ultrasound starting at age 35 years. (Weak recommendation, low quality of evidence)Juvenile Polyposis Syndrome Who should undergo a genetic evaluation for juvenile polyposis syndrome?We recommend genetic evaluation for any individual with 1) 5 or more juvenile polyps of the colon or rectum; or 2) 2 or more juvenile polyps in other parts of the gastrointestinal tract; or (3) any number of juvenile polyps and 1 or more first-degree relatives with juvenile polyposis syndrome. (Strong recommendation, low quality of evidence) Which organs should undergo surveillance when caring for a patient with juvenile polyposis syndrome?Juvenile polyposis syndrome patients are at increased risk for cancer in multiple organs including cancer of the colon and stomach.Given this risk, we recommend patients with juvenile polyposis syndrome undergo surveillance of the colon and stomach. (Strong recommendation, low quality of evidence) At what age should colonoscopic and upper endoscopic surveillance begin in individuals identified with juvenile polyposis syndrome?We suggest initiating colonoscopic and upper endoscopic surveillance at age 12–15 years, or earlier if symptomatic. Surveillance should be repeated every 1–3 years depending on polyp burden. (Weak recommendation, low quality of evidence) Which patients with juvenile polyposis syndrome should undergo screening for hereditary hemorrhagic telangiectasia?We suggest patients with SMAD4 pathogenic variants be clinically evaluated for HHT at the time of the diagnosis, including screening for and appropriate management of cerebral and pulmonary AVMs. (Weak recommendation, low quality of evidence)PTEN hamartoma tumor syndrome Which gastrointestinal findings should prompt a genetic evaluation for PTEN hamartoma tumor syndrome?We recommend individuals with multiple gastrointestinal hamartomas or ganglioneuromas undergo genetic evaluation for Cowden’s syndrome and related conditions. (Strong recommendation, low quality of evidence) Which organs should undergo surveillance for cancer when caring for a patient with PTEN hamartoma tumor syndrome?In PTEN hamartoma tumor syndrome, patients are at increased risk for cancer in multiple organs, including cancer of the breast, thyroid, kidney, uterus, colon, and skin.Given this risk, we recommend a multi-disciplinary approach to cancer surveillance in these organs. (Strong recommendation, low quality of evidence) What is the recommended colonoscopic surveillance in individuals identified with PTEN hamartoma tumor syndrome?We suggest colonoscopy surveillance to begin at age 35 years (or 10 years younger than age of any relative with colorectal cancer), repeated at intervals no greater than 5 years, depending on polyp burden. (Weak recommendation, low quality of evidence)NOTE. Specific circumstances may merit modification of the recommendations. In cases where very-early-onset cancers develop, the above statements may be modified to start surveillance 10 years earlier than the youngest cancer diagnosis in the family. Open table in a new tab NOTE. Specific circumstances may merit modification of the recommendations. In cases where very-early-onset cancers develop, the above statements may be modified to start surveillance 10 years earlier than the youngest cancer diagnosis in the family. A computer-aided PubMed search was performed from 2000 to 2018, with additional back searches as required, and consisted of the following search terms: hamartoma, hamartomatous polyp, hamartoma syndrome, Peutz-Jeghers syndrome, juvenile polyp, juvenile polyposis, Cowden’s syndrome, Cowden’s disease, PTEN-hamartoma, Bannayan-Riley-Ruvalcaba syndrome, hyperplastic polyposis, serrated polyposis, and hereditary mixed polyposis syndrome. Only English-language articles were reviewed. Published articles were selected on the basis of relevance to the diagnosis or clinical management of these diseases. Emphasis was placed on the risk for gastrointestinal cancer in these disorders to gain consensus on rational and reasonable strategies for management once these diseases are diagnosed in a family. The document was approved by the governing boards of each of the sponsoring gastroenterology societies. The USMSTF approach to an adapted use of Grading of Recommendations Assessment, Development and Evaluation (GRADE) has been described previously.1Guyatt G.H. Oxman A.D. Kunz R. et al.What is "quality of evidence" and why is it important to clinicians?.BMJ. 2008; 336: 995-998Crossref PubMed Google Scholar In brief, the GRADE process categorizes the quality of the evidence as high, moderate, low, or very low on the basis of the strength of underlying studies, and that categorization can be adjusted on the basis of study limitations. For example, randomized trials begin as high-quality evidence and observational studies as low-quality evidence, but their quality may be adjusted up or down on the basis of specific study factors. Although the GRADE process entails a formal meta-analysis to assess the quality of evidence for each recommendation, the USMSTF employs a modified, qualitative approach for this assessment. The GRADE process separates evaluation of the quality of the evidence to support a recommendation from the strength of that recommendation. This is done in recognition of the fact that, although the quality of the evidence can influence the strength of the recommendation, other factors can influence a recommendation, such as adverse effects, patient preferences, values, and cost. Generally, strong recommendations mean that most informed patients would choose the recommended management. Weak recommendations mean that patients’ choices will vary according to their values and preferences, and clinicians should ensure that patient care is in keeping with their values and preferences. When the quality of the evidence to support a recommendation is low or very low, or if there is a close balance between desirable and undesirable consequences, then usually only a weak recommendation would be warranted. Weaker recommendations are indicated by phrases such as “we suggest,” and stronger recommendations are typically stated as “we recommend.” However, the relative infrequency of, and absence of controlled prospective trials of the interventions (eg, to prevent cancer) in, these syndromes leave all of the recommendations without a robust basis of underlying evidence. Thus, all of the interventional recommendations fall (at best) into the “low quality of evidence” GRADE category, indicating that the true effect of the interventions may be markedly different than estimated at this time, and that further research is likely to impact or change our confidence in the effects. As such, this review is intended to establish a starting point for future research into the care of patients with the hamartomatous polyposis syndromes. Question: Which individuals with hamartomatous polyps should be referred for genetic evaluation?Recommendation: We recommend patients with any of the following undergo a genetic evaluation: 2 or more lifetime hamartomatous polyps, a family history of hamartomatous polyps, or a cancer associated with a hamartomatous polyposis syndrome in first- or second-degree relatives. Genetic testing (if indicated) should be performed using a multigene panel test. (Strong recommendation, low quality of evidence) Question: Which individuals with hamartomatous polyps should be referred for genetic evaluation? Recommendation: We recommend patients with any of the following undergo a genetic evaluation: 2 or more lifetime hamartomatous polyps, a family history of hamartomatous polyps, or a cancer associated with a hamartomatous polyposis syndrome in first- or second-degree relatives. Genetic testing (if indicated) should be performed using a multigene panel test. (Strong recommendation, low quality of evidence) Hereditary cancer syndromes account for approximately 5%–10% of new cancer diagnoses and many of the cancers that arise in families with undiagnosed hereditary cancer syndromes are preventable. The identification of individuals with a hereditary gastrointestinal cancer syndrome requires a thorough evaluation of the patient’s personal and family history of cancer. The collection and assessment of family cancer history is a valuable tool for cancer interception and prevention and can be critical in the identification of genetic susceptibility. An accurate family history is one that collects the following information: 1) type of cancer, 2) age at diagnosis of each primary cancer, 3) lineage (maternal or paternal), 4) ethnicity (people of some ethnicities, such as those with Ashkenazi Jewish ancestry, are at greater risk for certain cancers), and 5) results of any previous cancer-related genetic testing.2Lu K.H. Wood M.E. Daniels M. et al.American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.J Clin Oncol. 2014; 32: 833-840Crossref PubMed Scopus (162) Google Scholar Features of a patient’s personal history and clinical characteristics may suggest an inherited susceptibility to cancer. Although it is not rare to identify individuals with an isolated hamartomatous polyp (particularly an isolated juvenile polyp), other features may prompt further evaluation for an underlying hereditary syndrome. Features associated with the hamartomatous polyposis syndromes are outlined in detail in this document and include early age at cancer onset, multiple cancers in close relatives, unusual numbers of hamartomatous polyps, or associated dermatologic findings. Genetic evaluation may include genetic counseling and/or genetic testing. Genetic counseling is a key component to hereditary cancer risk assessment. The purpose of genetic counseling is to educate individuals about the genetic and biologic factors that are related to a patient’s cancer diagnosis or risk of disease. Counseling helps an individual understand the relevant genetic, medical, and psychosocial information to make informed decisions about their health care. This includes reviewing and expanding the following: family history information, elements of genetic testing, tailored cancer risks associated with a pathogenic variant, impact on medical management, reproductive issues and options, confidentiality of results, risks with genetic discrimination, potential significance of test results for other family members, and other pertinent topics. Practice guidelines from the American College of Medical Genetics and Genomics and National Society of Genetic Counselors are available for details regarding the elements and process of genetic counseling.3Hampel H. Bennett R.L. Buchanan A. et al.A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Genet Med. 2015; 17: 70-87Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar Although traditional models of genetic evaluation and testing included a certified genetic counselor, alternative models exist and are emerging that include provisions for pretest counseling to be provided by physicians and other health care providers in order to deal with the increasing demand for genetic testing. If a patient is found to be a carrier of a germline pathogenic variant, or the results are ambiguous due to the finding of a variant of uncertain significance, the help of a genetics provider for post-test counseling and education is recommended. In the current era, the vast majority of genetic testing for inherited cancer risk predisposition is performed using a multigene panel testing approach.4Heald B. Hampel H. Church J. et al.Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis.Fam Cancer. 2020; 19: 223-239Crossref PubMed Scopus (0) Google Scholar Some patients or families may elect to decline genetic testing due to concerns about risk to confidentiality and insurance; in these cases, surveillance may still be indicated in the presence of a concerning clinical and/or family history. If a germline pathogenic variant is identified, other family members should be offered testing for clarification of their own risk. This testing may facilitate initiation of screening for associated cancers before symptomatic manifestations occur and reduce the morbidity and mortality associated with the syndrome. For example, early small bowel surveillance may find a polyp that could be removed from a child with a pathogenic variant in STK11 before leading to intussusception. It is important to recognize that genetic testing may not identify pathogenic variants in every family suspected of a hereditary syndrome. However, there may be clinical features in the family history that suggest a familial predisposition to cancer and suggest more intensive surveillance recommendations. Referral to Centers of Excellence might be particularly helpful when genetic testing results are ambiguous in the setting of suspicious features and prophylactic surgery is being considered. Lastly, in the era of multigene panel testing, there may be a scenario in which a germline variant is found incidentally associated with an unsuspected syndrome. In these cases, patients may be eligible for cancer screening and surveillance as outlined. However, phenotype and cancer risk compared with patients with classic familial features are not established and are areas of active research. Enlisting the assistance of a genetic specialist may be particularly helpful in interpreting ambiguous results and providing management recommendations in these cases. When children are identified with a hamartomatous polyposis syndrome, their transition of care to adulthood for cancer surveillance is a unique aspect that bears consideration. It is imperative to transition adolescents with life-long medical conditions from child-centered to adult-centered care. Preparation for this transition takes place throughout childhood and adolescence to achieve independent health management in adulthood. Steps required are individualized based on the developmental needs of the patient. Inherited conditions involve generational factors, as multiple family members may be affected. Health care providers can assist in the transition of care by coordinating screening and surveillance to ensure patients receive recommended care.5Attard T.M. Burke C.A. Hyer W. et al.ACG clinical report and recommendations on transition of care in children and adolescents with hereditary polyposis syndromes.Am J Gastroenterol. 2021; 116: 638-646Crossref PubMed Scopus (2) Google Scholar The hamartomatous polyposis syndromes are rare entities with an estimated prevalence of 1/100,000–200,000,6van Lier M.G. Wagner A. Mathus-Vliegen E.M. et al.High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations.Am J Gastroenterol. 2010; 105 (author reply 1265): 1258-1264Crossref PubMed Scopus (336) Google Scholar,7Latchford A.R. Phillips R.K. Gastrointestinal polyps and cancer in Peutz-Jeghers syndrome: clinical aspects.Fam Cancer. 2011; 10: 455-461Crossref PubMed Google Scholar but this has not been measured directly in any population. The term hamartoma implies a non-neoplastic tumor with a markedly distorted architecture composed of an abnormal mixture of cells and tissue normally present in that particular area. The diagnosis is based on the presence of a pathogenic germline variant or meeting clinical criteria for the syndrome. The hamartomatous polyposis syndromes are distinct from Lynch syndrome and the adenomatous polyposis syndromes, based on the presence of hamartomas (Figures 1 and 2). Certain hamartomatous polyps of the gut have a unique histopathological appearance, such as those associated with PJS, PHTS, JPS, and HMPS.8Shaco-Levy R. Jasperson K.W. Martin K. et al.Morphologic characterization of hamartomatous gastrointestinal polyps in Cowden syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome.Hum Pathol. 2016; 49: 39-48Crossref PubMed Google Scholar Hamartomas are not typically characterized by dysplasia, but some evidence suggests the existence of a hamartoma–carcinoma pathway in some of these polyps.Figure 2Endoscopic images of hamartomatous polyposis syndromes. Endoscopic photos provided courtesy of Swati Patel, MD, Gregory Idos, MD, and Carol Burke, MD. (A) Peutz-Jeghers small bowel polyps. (B) Peutz-Jeghers gastric polyps. (C) Peutz-Jeghers colon polyps. (D) Juvenile polyposis gastric polyps. (E) Juvenile polyposis colon polyp. (F) Cowden syndrome associated–esophageal glycogenic acanthosis. (G) Cowden syndrome small bowel polyps. (H) Cowden syndrome colon polyps. (I) Cowden syndrome gastric polyps.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Question: Who should undergo a genetic evaluation for Peutz-Jeghers syndrome?Recommendation: We recommend genetic evaluation for any individual with the following: 1) 2 or more histologically confirmed Peutz-Jeghers polyps, 2) any number of Peutz-Jeghers polyps in an individual who has a family history of Peutz-Jeghers syndrome in a first-degree relative, 3) characteristic mucocutaneous pigmentation in a person with a family history of Peutz-Jeghers syndrome, and 4) any number of Peutz-Jeghers polyps in a person with the characteristic mucocutaneous pigmentation of Peutz-Jeghers syndrome. (Strong recommendation, low quality of evidence) Question: Who should undergo a genetic evaluation for Peutz-Jeghers syndrome? Recommendation: We recommend genetic evaluation for any individual with the following: 1) 2 or more histologically confirmed Peutz-Jeghers polyps, 2) any number of Peutz-Jeghers polyps in an individual who has a family history of Peutz-Jeghers syndrome in a first-degree relative, 3) characteristic mucocutaneous pigmentation in a person with a family history of Peutz-Jeghers syndrome, and 4) any number of Peutz-Jeghers polyps in a person with the characteristic mucocutaneous pigmentation of Peutz-Jeghers syndrome. (Strong recommendation, low quality of evidence) PJS was the first hamartomatous polyposis syndrome described, by Peutz in Holland in 1921 and by Jeghers, McKusick, and Katz in the United States in 1949.9Menko F.H. LKB1/ STK11, Peutz-Jeghers syndrome and cancer.Fam Cancer. 2011; 10: 413-414Crossref PubMed Scopus (5) Google Scholar The clinical recognition of PJS was facilitated by the characteristic mucocutaneous freckling around the mouth and multiple cerebriform-appearing polyps due to smooth muscle bands coursing through the polyp (Figures 1A and 2A–C, and Table 2). Hamartomatous polyps vary in size and may have a characteristic histologic structure, which makes it possible to distinguish the PJ polyp. PJ polyps are typically composed of branching bands of smooth muscle covered by hyperplastic glandular mucosa.10Jass J.R. Colorectal polyposes