Information for Health Professionals, Polyposis

Serrated Polyposis Syndrome


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.

Intermediate magnification micrograph of a SSA.

Intermediate magnification micrograph of a SSA. (Photo credit: Wikipedia)

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

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Endoscopic appearance of a flat sessile serrated adenoma with white light

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).

This is a mixed histology polyp from an affected individual in a large hyperplastic polyposis family. It contains both villous, serrated portions, the latter contains a zone of high grade dysplasia with BRAF mutations, the villous section was BRAF wild type.

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).

The Galway Family: A large Irish family affected with Hyperplastic Polyposis Syndrome

Screening

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.

 

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About kjmonahan

Service lead for Family History of Bowel Cancer Clinic

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