polyps of the colon and rectum. Estimates of the population prevalence of Juvenile Polyposis syndrome suggest a frequency of around 1:100 000. It accounts for less than 0.1% of all colorectal cancer cases.(JPS) is defined by the presence of multiple hamartomatous
Histological differences and topographical distribution within the gastrointestinal tract serve to distinguish between this disorder and (PJS). Juvenile hamartomatous polyps have an apparently normal epithelium with a dense stroma, an inflammatory infiltrate, and a smooth surface with dilated, mucus-filled cystic glands in the lamina propria with smooth muscle fibres, which distinguishes these from PJS polyps. The glandular proliferative characteristics of adenomas are typically absent.
The term ‘juvenile’ refers to the polyp type rather than to the age of onset, although most individuals with juvenile polyposis have some polyps by 20 years of age. Most individuals with JPS have some polyps by age 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than a hundred. Juvenile polyposis usually manifests during childhood, but diagnosis of the condition is confounded by the occurrence of isolated juvenile-type polyps in children. These solitary polyps are noteworthy because their identification in childhood does not necessarily indicate a heritable cancer predisposition syndrome, and they do not appear to be associated with excess cancer risk. In contrast, juvenile polyposis is associated with a colorectal cancer risk of around 10-38% and a gastric cancer risk of 21%.
If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk of GI cancers in families with JPS ranges from 9% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have been reported.
Around 20% of cases are due to mutations in the SMAD4 gene, while a further 20% are due to mutations in another gene in the same TGF-beta molecular signaling pathway, BMPR1A, indicative of genetic heterogeneity. Mutations in BMPR1A have been particularly implicated in European populations and SMAD4 mutations may have a more aggressive clinical phenotype. A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) (termed JPS/HHT) may be present in 15%-22% of individuals with an SMAD4 mutation.
JPS is clinically diagnosed if any one of the three following findings is present:
Testing relatives at risk: When the family-specific mutation is known, it is appropriate to perform molecular genetic testing on at-risk family members in the first to second decade of life to identify those who will benefit from early surveillance and intervention.
UK BSG Screening Guidelines
< Large bowel surveillance for at-risk individuals and mutation carriers every 1-2 years is recommended from age 15-18 years, or even earlier if the patient has presented with symptoms. Screening intervals could be extended at age 35 years in at-risk individuals. However, documented gene carriers or affected cases should be kept under surveillance until age 70 years and prophylactic surgery discussed. The intervention should visualise the whole colon and so colonoscopy is the preferred modality. Although isolated juvenile polyps are relatively common, juvenile polyposis is rare and consequently experience is limited. There are few large descriptive studies, and no comparative study to demonstrate potential benefit. Nonetheless, there is a substantial risk of colorectal cancer amounting to 10-38%. Many polyps are located in the right colon, and so the whole colon should be visualised. There is particular risk of malignancy in cases where there is adenomatous change, or where there is a dysplastic element to the polyps.
Upper gastrointestinal surveillance
< Upper gastrointestinal surveillance every 1-2 years is recommended from age 25 years, contemporaneously with lower gastrointestinal surveillance. The risk of gastric and duodenal cancer in juvenile polyposis is round 15-21%.
Disease characteristics. Peutz-Jeghers syndrome(PJS (OMIM 175200)) is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation. Gastrointestinal cancer risks include gastro-oesophageal, small bowel, pancreatic and colorectal cancers with a cumulative risk of 57% by the age of 70. here is a 50% lifetime risk of breast cancer, and clinicians managing PJS patients should ensure breast screening arrangements are in place. In 20–63% of cases, inactivating mutations can be identified in the gene STK11 (LKB1). There is evidence for genetic heterogeneity with a possible further locus on chromosome 19q. Estimates of the population prevalence of Peutz–Jeghers syndrome suggest a frequency of around 1:50 000.
Peutz-Jeghers-type hamartomatous polyps are most common in the small intestine (in order of prevalence: in the jejunum, ileum, and duodenum) but can also occur in the stomach, large bowel, and nasal passages. Gastrointestinal polyps can result in chronic bleeding and anemia and cause recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection.
Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa. Hyperpigmented macules on the fingers are common. The macules may fade in puberty and adulthood. Individuals with Peutz-Jeghers syndrome are at increased risk for a wide variety of epithelial malignancies (colorectal, gastric, pancreatic, breast, and ovarian cancers). Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer. Males occasionally develop calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia.
Diagnosis/testing. The diagnosis of Peutz-Jeghers syndrome is based on clinical findings. In individuals with a clinical diagnosis of PJS, molecular genetic testing of STK11 (LKB1) reveals disease-causing mutations in nearly all individuals who have a positive family history and approximately 90% of individuals who have no family history of PJS. Such testing is available clinically.
Large bowel surveillance is recommended 2-yearly from age 25 years. The intervention should visualise the whole colon and so colonoscopy is the preferred mode of surveillance. PJS is rare and so evidence on effectiveness of surveillance is limited to case series and anecdote. The risk of colorectal cancer increases with age being 3%, 5%, 15%, and 39% at ages 40, 50, 60, and 70 years, respectively. Males may be at greater risk. There is also an excess risk of small bowel, pancreatic and oesophago-gastric cancer. The risk for all gastrointestinal cancers combined is 1%, 9%, 15%, 33%, and 57% up to ages 30, 40, 50, 60 and 70 years, respectively.154
Treatment of other manifestations:
Upper gastrointestinal surveillance is recommended 2-yearly from age 25 years, comprising gastro-duodenoscopy. Intermittent MRI enteroclysis or small bowel contrast radiography is recommended.
There is an elevated risk of gastric malignancy in Peutz–Jeghers syndrome amounting to around 5–10%. Although evidence from pooled case series indicates that small intestinal cancer is rare, the risk is sufficient to merit intermittent imaging. MRI enteroclysis appears appropriate for surveillance because it avoids repeated radiation exposure in young individuals and has very good sensitivity and overall accuracy for small bowel polyps in PJS as well as for patients with small bowel tumours who do not have PJS. However, video capsule endoscopy is also an option, with evidence of better sensitivity than MRI enteroclysis for smaller lesions in small bowel polyposis syndromes in one small comparative study.
Testing of relatives at risk: If the family mutation is known, offer molecular genetic testing to at-risk relatives so that morbidity and mortality can be reduced in those with the family-specific mutation by early diagnosis and treatment and appropriate surveillance; if the family mutation is not known, offer clinical diagnostic evaluations to identify those family members who will benefit from early treatment and appropriate surveillance.
Other: Although not studied in individuals with PJS, the following could be considered: prophylactic mastectomy to manage high risk for breast cancer and prophylactic hysterectomy and bilateral salpingo-oophorectomy after age 35 years or after child-bearing has been completed to prevent gynecologic malignancy.
Genetic counseling. Peutz-Jeghers syndrome is inherited in an autosomal dominant manner. About 50% of affected individuals have an affected parent and about 50% have no family history of PJS; the proportion of cases caused by de novo gene mutations is unknown as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient. The risk to the offspring of an individual with a pathogenic STK11 mutation is 50%. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known
September 5, 2012 — People with a relatively low socioeconomic status account for a disproportionate number of colorectal cancers in the United States. Now, for the first time, a large prospective, observational study has shed light on the degree to which behavior and body mass contribute to this disparity.
Over one third of the excess risk…could be explained by differences in…behavioral risk factors.
“This study showed that over one third of the excess risk of invasive adenocarcinoma of the colon and rectum resulting from low [socioeconomic status] could be explained by differences in…behavioral risk factors, particularly in an unhealthy diet,” conclude the authors, led by Chyke A. Doubeni, MD, MPH, from the Department of Family Medicine and Community Health at the University of Pennsylvania Perelman School of Medicine in Philadelphia.
In addition to diet, Dr. Doubeni and colleagues found that physical inactivity, smoking, and being overweight are likely contributors to this risk.
In their study, published online September 5 in the Journal of the National Cancer Institute, the authors looked at health behaviors, obesity, and colorectal cancer risk among Americans of all socioeconomic statuses.
They used the National Institutes of Health-AARP Diet and Health Study as their data source. Specifically, they looked at middle-aged and elderly people from 6 states (California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania) and 2 metropolitan areas (Atlanta, Georgia and Detroit, Michigan). All of the participants enrolled in the study in 1995/96 and were followed through 2006. Health behaviors of the participants were determined using questionnaires.
Of the 506,488 study participants, 7676 developed colorectal cancer during the 10-year follow-up period.
How Class and Behavior/Body Mass Are Related
The authors evaluated the socioeconomic status of the participants in 2 ways: by census-tract data, which revealed “neighborhood socioeconomic status,” and by self-reported educational level (less than high school vs high school and more than high school).
On the basis of data from other studies on colorectal cancer and behavior, Dr. Doubeni and his team used statistical modeling to estimate the likely percentage of colorectal cancers mediated by behavioral risk factors.
They found that differences in socioeconomic status in the reported levels of physical inactivity, unhealthy diet, smoking, and unhealthy weight each explained between 11.3% and 21.6% of the association between education and risk for colorectal cancer, and between 8.6% and 15.3% of the association between neighborhood status and risk for colorectal cancer. Diet was found to have the biggest impact of all the health behaviors.
Overall, the combination of health behaviors and body mass index (BMI) explained approximately 43.9% (95% confidence interval [CI], 35.1% to 57.9%) of the association between risk for colorectal cancer and education and 36.2% (95% CI, 28.0% to 51.2%) of the association between the risk and neighborhood socioeconomic status.
In short, somewhere between one third and nearly one half of colorectal cancers among either low-income or less-than-high-school-educated Americans might be attributable to obesity and unhealthy behaviors.
However, a pair of experts not involved with the study do not find these results to be a cause for despair.
Instead, the study “demonstrates the intricate interplay” of socioeconomic and behavioral factors affecting colorectal cancer risk, write John Z. Ayanian, MD, and John M. Carethers, MD, in an accompanying editorial. Dr. Ayanian is from the Department of Health Care Policy at Harvard Medical School in Boston, Massachusetts, and Dr. Carethers is from the Department of Internal Medicine at the University of Michigan in Ann Arbor.
Public health practitioners can learn from these results, they believe. The study “underscores the need for more effective public health strategies to improve nutrition and physical activity in the United States and thereby curb the rising tide of obesity, particularly for those with less education and in disadvantaged communities,” the editorialists write.
Colon Cancer by Location
The study accounted for the anatomic location of the participants’ cancers (proximal colon, distal colon, or rectum), which resulted in one of the study’s “key findings,” according to the editorialists.
The health behaviors and BMI explained 95% of the association between education and the incidence of proximal colon cancer, but only 38% of the association between education and distal cancer and 24% of that between education and rectal cancer, Dr. Ayanian and Dr. Carethers point out.
That is a dramatic difference, they note. However, the editorialists think that these contrasting results for proximal and more distal cancers might “reflect the impact of an important omitted variable — colorectal cancer screening by socioeconomic status.”
Colorectal cancer screening has been shown to be more effective in reducing cancer incidence and mortality in the distal colon and rectum than in the proximal colon, the editorialists explain. Thus, this finding might have an easy explanation, they note.
“Because adults who are less educated and from less affluent communities are less likely to be screened, the greater effectiveness of screening for distal colorectal cancer may explain why socioeconomic gradients were much steeper for these anatomic sites than for proximal cancer,” they write.
The study was funded in part by the National Cancer Institute. The study authors and editorialists have disclosed no relevant financial relationships.
The hyperplastic polyp and serrated adenoma pathway
The first series of mixed hyperplastic-adenomatous polyps were described in 1990 (Longacre and Fenoglio-Preiser 1990), and have been an increasingly recognised phenomenon. Most hyperplastic polyps have no malignant potential, although there is now some have malignant potential, especially those with serrated architecture (sessile serrated adenomas – SSAs), large hyperplastic polyps, mixed polyps and polyps on the right side of the colon (Torlakovic et al. 2003).
Classification of hyperplastic polyps
A new understanding of the clinical relevance of hyperplastic polyps has emerged over the past decade (Young and Jass 2010). The simple hyperplastic polyp has itself been subclassified into a goblet cell variant and a microvesicular variant, the latter appear to be the precursors for serrated adenomas and thus colorectal cancer. Serrated adenomas usually have serrations low in the crypts which help differentiate them from hyperplastic polyps.
However, serrated polyps also include a broader spectrum of polyp subtypes ranging from these small common lesions to the recently described sessile serrated adenoma (SS
A), which is often large and proximal with abundant mucin secretion, exaggerated serration, and atypical architecture. Rarer serrated polyp subtypes with unequivocal dysplasia include traditional serrated adenoma (SA), which combines the dysplastic features of an adenoma with the architectural features of a hyperplastic polyp and the mixed polyp (MP) in which separate hyperplastic and dysplastic elements are combined within a single polyp (see figure). SSA, SA, and MP are described as “advanced serrated polyps” and comprise ∼5% of all serrated polyps retrieved in colonscopy patients. Importantly, these advanced serrated lesions show frequent BRAF mutation and widespread DNA methylation.
Endoscopic appearances of serrated adenomas
Serrated and hyperplastic polyps present endoscopic features that could help to differentiate them from adenomatous polyps. HPs appear flat and pale and are often covered by a thin film of mucus. They exhibit Kudo type 2 pit pattern typically. As they are not highly vascular they will appear pale compared to surrounding mucosa using narrow-band imaging (NBI). In addition, chromoendoscopy may be helpful in the endoscopic characterisation of these lesions.
Inherited Colorectal Cancer Syndrome?
An inherited hyperplastic polyposis syndrome (HPS) has also been increasingly recognised (Cohen et al. 1981; Sumner et al. 1981). It is now more commonly known as serrated polyposis syndrome. There is no sex predominance and the mean age at diagnosis is around 55 years. HPS has largely been considered a genetic disease, but the pattern of inheritance remains unknown: both autosomal recessive and autosomal dominant patterns have been suggested. Environmental factors could be partially responsible for the phenotypic differences and model the unknown pattern of inheritance. Smoking, being overweight and some drugs have been postulated as potential risk factors of HPs.
In HPS, multiple serrated polyps develop in the colorectum, and approximately 50% of cases present with at least one CRC (Ferrandez et al. 2004; Young and Jass 2006). Boparai et al (2011) have recently described an increased risk of CRC [relative risk (RR) = 5.4] and HPS (RR = 39) in first-degree relatives of probands diagnosed with HPS compared to the general population. Estimates for CRC risk associated with serrated polyposis may range from 7% to 50% and vary with phenotype.
Classification of the Syndrome
In the WHO criteria, Burt and Jass defined HPS as at least five HPs proximal to the sigmoid colon, two of which are > 1 cm diameter, or more than 30 HPs at any site in the large bowel (Burt 2000). Rashid et al, however, used a different classification system, in which HPS was defined as any person with more than 20 HPs, and separate classes were used for patients with large (>1 cm diameter) or multiple (5-10) HPs (Rashid et al. 2000). These differing classification systems reflect a syndrome which may be both genetically and phenotypically heterogeneous, but one which is becoming increasingly recognised.
The serrated pathway to colorectal cancer
Some evidence suggests that some but not all of these tumours develop along a ‘serrated pathway’ separate from the classical adenoma-carcinoma sequence (Sawyer et al. 2002; Spring, Zhao et al. 2006). This serrated pathway involves one group who accumulate BRAF V600E mutations and another separate pathway which involves KRAS mutations(Carvajal-Carmona et al. 2007). In addition the tumours often have methylation of the MLH1 promoter with subsequent microsatellite instability, and other genes such as P16, MGMT, or IGFBP7 may also be epigenetically inactivated. The CIMP phenotype identified by increased levels of methylation in the CpG island marker MINT31(Jass 2005).
HPS (sometimes known as the ‘serrated pathway syndrome’ or ‘serrated pathway syndrome’ (SPS) and sometimes ‘Jass Syndrome’) may, in fact, be a heterogeneous group of conditions leading to sporadic and inherited cases of colorectal neoplasia. There are two alternative clinical criteria for the diagnosis of HPS families (Burt 2000; Rashid, Houlihan et al. 2000). This syndrome is usually associated with somatic mutations in either BRAF or KRAS, but not both together (Carvajal-Carmona, Howarth et al. 2007), providing further evidence of molecular as well as phenotypic heterogeneity. BRAF mutations are associated with low-grade microsatellite instability due to methylation in CpG islands (CIMP)(Young, Jenkins et al. 2007). This may result in loss of expression of DNA repair genes MLH1 and MGMT (O(6)-methylguanine-DNA methyltransferase) in dysplastic mixed polyps from HPS patients, possibly as a result of promoter methylation (Oh et al. 2005).
Linkage analysis in a large family affected with hyperplastic polyposis syndrome demonstrated a maximum parametric LOD score of 2.71 on the short arm of chromosome 8 (8p.21; Monahan et al 2007). Another group have identified genetic linkage to chromosome 2q32.2-q33.3 with a LOD score of 2.07 (Roberts et al 2011 Fam Cancer).
As of this time however, there is no known causative germline mutation responsible for this condition, therefore genetic testing for predisposition is not possible. Because the natural history of HPS is poorly understood, colonoscopic screening guidelines have not been developed. Empirically we recommend 5 yearly colonoscopic screening from the age of the earliest known affected relative, or from 45 years of age.
Dedicated Clinics: Referrals on the basis of family history are best coordinated through centres with a specialist interest, such as regional genetics services or medical/surgical gastroenterology centres. Such centralisation enables audit of family history ascertainment, assigned level of risk, collection of outcome data and research.
Screening Procedure: Total colonoscopy is the preferred mode of surveillance for the moderate risk categories defined here, owing to the propensity for proximal colonic lesions and the opportunity for snare polypectomy. Incomplete colonoscopy should initiate an alternative imaging modality on the same day, such as double-contrast barium enema or CT colonography. A repeat colonoscopy soon after an incomplete examination is acceptable, but success must be assured. However, radiation exposure should be minimised and regular radiological surveillance is not recommended.
High moderate risk group inclusion criteria comprise familial aggregations where affected relatives are first-degree relatives of each other (first-degree kinship) with at least one being a first-degree relative of the consultand. If both parents are affected, these count as being within first-degree kinship:
– Three affected relatives any age in a first-degree kinship (eg, a parent and a blood-related aunt/uncle and/or grandparent), at least one of whom is a first-degree relative of the consultand, or two siblings/one parent or two siblings/one offspring combinations, or both parents and one sibling. However, there should be no affected relative <50 years old, as otherwise the family would fulfil high risk criteria.
– Two affected relatives aged <60 years in a first-degree kinship or mean age of two affected relatives <60 years. At least one relative must be a first-degree relative of the consultand and so this category includes a parent and grandparent, >2 siblings, >2 children or child+sibling. The risk is sufficiently increased to merit low-intensity surveillance comprising 5-yearly colonoscopy between age 50 and age 75 years. Polyps should be snared; adenoma surveillance applies thereafter if a benign neoplasm is confirmed.
Low-moderate risk group. Inclusion criteria are:
– One affected first-degree relative under 50 years old or
– Two affected first-degree relatives, aged 60 or older.
In both high-moderate and low-moderate categories, pathology tumour material from an affected relative may be available to test for Lynch syndrome gene involvement.
Excluding such instances, there is a modest excess risk meriting a single colonoscopy at age 55 (if older at presentation then instigate forthwith), in the low–moderate group to identify polyp formers. Polyps should be snared; adenoma surveillance applies thereafter if a benign neoplasm is confirmed. If colonoscopy is clear, reassure and discharge with recommendations relevant to population risk (uptake of faecal occult blood test screening in the UK).
Early-onset colorectal cancer (<50 years). The elevation of risk in relatives of an early-onset case is modest. However, the heightened anxiety and emotive nature of cancer in this age group merit special mention because this frequently initiates requests for surveillance. Such cases are covered by the above risk categorisation, but algorithms can also be used to predict whether the affected relative is a carrier of a mutation in a Lynch syndrome gene. These approaches identify affected individuals where tumour immunohistochemistry and/or microsatellite instability analysis could lead to identification of a DNA mismatch repair gene mutation. Bethesda criteria are not discriminatory within this group because all patients fulfil these criteria due to age alone.
Low Risk Group: People with only one affected relative and who do not fulfil any of the above criteria, and do not fulfil high risk criteria, should be reassured and encouraged to avail themselves of population-based screening measures. The low level residual risk over that of the general population should be explained.
Outcome of screening in Moderate Risk Groups (Dove-Edwin et al BMJ 2005)
Colonoscopic surveillance is effective in preventing colorectal cancer in individuals from families with hereditary non-polyposis colorectal cancer (group 4) and in individuals with a family history of colorectal cancer that does not meet the Amsterdam criteria. However, colonoscopic surveillance in the families at moderate risk seems not indicated until age 45 (or even 50), and this is true even for the relatives of young patients. Furthermore, surveillance intervals of more than five years may be appropriate in individuals with a moderate risk family history (groups 1-3) in whom no advanced pathology is found.
Colonoscopic polypectomy has been shown to decrease the incidence of colorectal cancer in a large cohort study as well as in clinical practice and to decrease both the incidence and mortality of colorectal cancer in individuals with a family history of hereditary non-polyposis colorectal cancer. It is also considered by some to be a safe tool for population screening. Clear guidelines exist for colorectal surveillance in hereditary non-polyposis colorectal cancer families, but guidelines and practices for individuals at moderate risk on the basis of their family history are heterogeneou.
Concerns exist about colonoscopic surveillance in individuals with a moderate risk family history, as some will not be at increased risk. Dunlop et al calculated that if surveillance were offered to individuals aged 30-70 who have two direct relatives affected or one under age 45 then 235 000 individuals would be eligible in the United Kingdom. Even if the age of initiating surveillance is raised, the potential burden on resources is immense. Colonoscopy is associated with a small risk of serious complications, and this may substantially outweigh any benefits in people at low risk.
In this study, only one incident cancer was detected on surveillance in an individual with a moderate risk family history during 9281 person years of follow-up. In families at moderate risk, advanced neoplasia is very rare below the age of 45 and, if not seen initially, it remains uncommon (under age 65) if follow-up colonoscopy is carried out within six years. These findings are important because individuals with a moderate risk family history who are under age 65 with no advanced neoplasia can be considered to be at low risk and extended surveillance intervals may be sufficient. Individuals with a moderate risk family history in whom advanced neoplasia is seen on initial colonoscopy should continue with colonoscopy every three years. The low yield of advanced neoplasia under the age of 45 is true also of those with a first degree relative affected under age 45. Only 4% of 139 individuals in group 1—families with one case of colorectal cancer diagnosed under age 45, and no other cases—screened under age 45 (mean age 33) had an adenoma of any description. Despite the increased risk of colorectal cancer in this group individuals’ absolute risk therefore remains small and the benefit of screening seems minimal below the age of 45.
The world’s original polyposis registry is based at St Mark’s Hospital, Harrow. FAP (Familial Adenomatous Polyposis) is an inherited condition which mainly affects the large intestine (also known as the large bowel or colon and rectum). People with FAP develop many polyps (which are like small cherries on stalks) inside their large bowel. There are many different types of polyps but these particular polyps are called adenomas (the “adenomatous” in FAP). An adenoma can in time turn into a cancer which is why it is so important to make sure anyone at risk of inheriting FAP is examined.
FAP is a serious condition unless detected early when it can be treated.
(Familial Adenomatous Polyposis) FAP is an inherited condition which mainly affects the large intestine (also known as the large bowel or colon and rectum). People with FAP develop many polyps (which are like small cherries on stalks) inside their large bowel. There are many different types of polyps but these particular polyps are called adenomas (the “adenomatous” in FAP). An adenoma can in time turn into a cancer which is why it is so important to make sure anyone at risk of inheriting FAP is examined.
FAP is a serious condition unless detected early when it can be treated.