Serrated Lesions of Colorectum: A New pathway in Colorectal Carcinogenesis

Colorectal polyps were traditionally classified as hyperplastic or adenomatous polyps. Adenomatous polyps were thought to be the precursor lesions of most of the colorectal cancers, but later serrated lesions were recognized as precursors of nearly one-third of colorectal cancers. Serrated lesions are a distinct group of polyps with special morphologic and histologic properties and a different carcinogenesis pathway to colorectal cancers. They are pale, flat or depressed lesions which may result in failure of detection on colonoscopy. So the endoscopist should be aware of these lesions and should follow the patients according to the surveillance guidelines. DOI : 10.14302/issn.2471-7061.jcrc-13-375 Corresponding author: Nurten Savas, e-mail: nakyurek2000@yahoo.com, Phone: 0090 216 5541500 Fax:0090 216 474 95 96 Running Title: Serrated adenoma Received : Dec 13, 2013 Accepted : Jan 01, 2015 Published : Jan 20, 2015 Freely Available Online www.openaccesspub.org | JCRC CC-license DOI : 10.14302/issn.2471-7061.jcrc-13-375 Vol-1 Issue 1 Pg. no.2 Introduction Traditionally colorectal polyps were classified as either hyperplastic or adenomatous polyps and adenomatous polyps were thought to be the precursor of most of the colorectal cancers (CRC). Later serrated adenoma was described by Longacre and Fenoglio-Preiser in 1990 [1] for a subset of polyps that had both a serrated hyperplastic-like architecture and adenomatous changes or dysplasia, thereafter Torlakovic and Snover characterized a group of patients with serrated adenomatous polyposis, which showed similar features to hyperplastic polyps but with a sessile pattern of growth. [2]. Serrated lesions of colorectum are currently classified into three general categories [3]; hyperplastic polyp (HP), sessile serrated adenoma / polyp (SSA/P) with or without cytological dysplasia, and traditional serrated adenoma (TSA). The terms SSA and SSP are considered synonyms and both are acceptable (Table1). In general the subtypes of serrated lesions are identified by cytological and architectural features also by location and extent of proliferative zone. Hyperplastic Polyp (HP) True HP compromise 80-90% of all serrated lesions, and likely have no neoplastic risk. They are typically small (<5mm), appear slightly raised and occur more frequently in the rectosigmoid region. It is difficult to differentiate hyperplastic polyps from other polyps by conventional light endoscopy and histology is needed for diagnosis [3,4]. HP occur most fresquently in the fifth and sixth decades of life. HP’s are characterized by variably prominent serrations occuring in the upper one-third to one half of crypts that are generally straight and demonstrate more or less normal localization of the proliferative zone to the base of the crypts. The superficial saw-tooth outline feature is a consequence of simultaneous increase of proliferation as well as inhibition of programmed cellular apoptosis. The degree of serration is more pronounced in the upper half and surface of the polyps than at the base. According to the morphological growth pattern, lack of proliferative abnormalities and the mucin content of the epithelial cells, 3 subtypes of HP are described [4,5,6]. The most frequent subtype of HP is the one with microvesicular mucinous cells named mivrovesicular hyperplastic polyp (MVHP) this type is characterized with the presence of small droplet mucin in cytoplasm of the Table 1. Classification of serrated lesions of colorectum Prevalence Shape Distribution Malignant potential Hyperplastic polyp Very common Sessile/flat Mostly distal Very low Sessile serrated adenoma/polyp Common Sessile/flat 80% proximal


Introduction
Traditionally colorectal polyps were classified as either hyperplastic or adenomatous polyps and adenomatous polyps were thought to be the precursor of most of the colorectal cancers (CRC). Later serrated adenoma was described by Longacre and Fenoglio-Preiser in 1990 [1] for a subset of polyps that had both a serrated hyperplastic-like architecture and adenomatous changes or dysplasia, thereafter Torlakovic and Snover characterized a group of patients with serrated adenomatous polyposis, which showed similar features to hyperplastic polyps but with a sessile pattern of growth. [2].
Serrated lesions of colorectum are currently classified into three general categories [3]; hyperplastic polyp (HP), sessile serrated adenoma / polyp (SSA/P) with or without cytological dysplasia, and traditional serrated adenoma (TSA). The terms SSA and SSP are considered synonyms and both are acceptable (Table1).
In general the subtypes of serrated lesions are identified by cytological and architectural features also by location and extent of proliferative zone.

Hyperplastic Polyp (HP)
True HP compromise 80-90% of all serrated lesions, and likely have no neoplastic risk. They are typically small (<5mm), appear slightly raised and occur more frequently in the rectosigmoid region. It is difficult to differentiate hyperplastic polyps from other polyps by conventional light endoscopy and histology is needed for diagnosis [3,4]. HP occur most fresquently in the fifth and sixth decades of life.
HP's are characterized by variably prominent serrations occuring in the upper one-third to one half of crypts that are generally straight and demonstrate more or less normal localization of the proliferative zone to the base of the crypts. The superficial saw-tooth outline feature is a consequence of simultaneous increase of proliferation as well as inhibition of programmed cellular apoptosis.
The degree of serration is more pronounced in the upper half and surface of the polyps than at the base.
According to the morphological growth pattern, lack of proliferative abnormalities and the mucin content of the epithelial cells, 3 subtypes of HP are described [4,5,6].
The most frequent subtype of HP is the one with microvesicular mucinous cells named mivrovesicular hyperplastic polyp (MVHP) this type is characterized with the presence of small droplet mucin in cytoplasm of the HP's involving right colon and those seen in the context of serrated polyposis syndrome is more likely to harbor malignancy [7][8][9].
They are more likely to be sessile than pedunculated and more often located in proximal to splenic flexura.
Endoscopically they are slightly elevated lesions with irregular borders and may be covered with mucus [7].
The histological diagnosis of SSA/P is based mainly on the architectural features of the lesion, which include branched crypts, dilatation of the bases of the crypts and formation of inverted L-or T shaped crypts [6]. The basal half of the crypts often contain serration and mature goblet cells and mucinoud cells. The proliferative zone is often not located in the base of the crypts but rather asymmetrical and abnormal proliferation in the middle and upper crypts. Also various degrees of nuclear atypia and excessive production of extracellular mucin are the other characteristic findings of SSA/P [6,7].  [10][11].
SSA/P is the presursor lesion for many sporadic CRC with microsatellite instability (MSI) and for some other CRC's that are associated with hypermethylation. In many SSAs with dysplasia, the dysplastic component has hypermethylated MLH1 and is therefore defective in terms of DNA mismatch repair. There is at least theoretical evidence that such foci progress to malignancy more rapidly than usual adenoma.

Traditional Serrated Adenoma (TSA)
Traditional serrated adenomas (TSA) are uncommon and account for less than 1% of colorectal cancers, TSA are distinguisable from sessile serrated adenomas in that they contain a uniform population of abnormal epithelial cells. TSA are usually pedunculated and often have a tubulovillous or villous configuration. In many cases the villi are elongated with bulbous tips and have been termed filliform TSA, but they may also be flat or slightly raised. The most characteristic feature is ectopic crypt formation, in which the crypts have lost their anchoring to the underlying mucosa [9,10,12]. This ectopic crypt formation does not occur in SSA/P which will allow better distinction of the types of serrated polyps and indicates that they have different molecular defects. [13]. TSA typically occur in the distal colon and rectum and tend to be pedunculated or broad based polypoid growth pattern compared with SSA/P. Although uncommon they are probably precursor lesions to some CRCs, even to some author 11% of TSA contain intramucosal carcinoma [3].

Carcinogenesis Pathway
Among asymptomatic, average-risk patients, the prevalence of conventional adenoma is approximately 10 -20% in sigmoidoscopy studies and over 25% in colonoscopy studies, whereas the prevalence of CRC among these patients is less than 1%. Regional differences in adenoma prevalence rates demonstrate a clear, positive correlation with increasing age and with increasing incidence of cancer in the population under study: with 4-6% of those under <50 years having adenomas, and up to 50-60% of those over 75 years having an adenoma. [14,15].
In the colorectal carcinogenesis according to the type of the genomic instability; two different types of molecular pathways are described.
The first pathwas is chromosomal instability (CIS) pathway and the second one is microsatellite pathway [16,17]). In the first pathway; CIS develops after the accumulations of several mutations at the oncogens and tumor suppressor genes. The earliest lesion is localised epithelial proliferation [18] and following this is the adenoma and invasive carcinoma [19], this pathway is known as adenoma -carcinoma pathway. According to this pathway, mutations at the APC tumor suppressor gene occurs at the earlier stage of adenoma, later K-ras mutations occur, which is followed by p53 and 18 q deletions [20][21][22]. The APC gene is considered the ''gatekeeper'' for the process of colon carcinogenesis.
Mutation or loss of this gene is believed to be crucial first step that confers susceptibility to colonic adenomas in patients with familial adenomatous polyposis as well as in people with sporadic adenomas. The APC somatic  [38,39].

Risk Factors for Serrated Polys
Risk factors for serrated adenoma are both genetic and enviromental factors. Acoording to some reports patients with serrated polyposis syndrome present syncronous adenocarcinoma of cancer in 50% [40]. There are families with high incidences of colorectal cancer and serrated polyps with CIMP and BRAF mutations and also although very rare, there are families with multiple members affected by HPS [41]. Cigarette smoking is strongly associated with SSA [42][43][44], especially cigarette smoking >20 pack-years is related with an increased risk of having SSA (42). Diabetes mellitus and obesity is also associated with SSA [42][43][44] Fiber intake, calcium intake, alcohol intake, nonsteroidal antiinflammatory drug use, familiy CRC history, high body mass index have inconsistent associations with distal serrated lesions [10]. Dietary fat, total energy intake, and red meat intake are associated with an increased risk for distal serrated polyps. Although aspirin treatment is associated with a reduced risk of proximal serrated polyps, folate treatment is found to be associated with an increased risk for proximal serrated polyps [44].

Serrated Polyposis Syndrome
According to WHO, serrated polyposis syndrome is described as [45];