Case 5 -

Serrated Lesions of the Colon Lisa Yerian, John Hart and Amy Noffsinger

Introduction Traditionally, two forms of colorectal epithelial polyp have been recognized, adenomatous and hyperplastic. Adenomatous polyps have for many years been known to represent neoplastic, premalignant lesions, and indeed the molecular basis of the now famous adenoma-carcinoma sequence has been clearly established [1]. This pathway applies predominantly to sporadic colorectal cancers but also characterizes familial adenomatous polyposis and is thus called the "adenomatous polyposis coli" or "APC" pathway. Subsequently, another molecular pathway to colorectal cancer, the DNA mismatch repair pathway, was also described [2]. The mismatch repair pathway accounts for approximately 15% of sporadic colorectal adenocarcinomas, and is the pathway involved in colorectal cancers arising in association with the inherited condition "hereditary non-polyposis colon cancer" (HNPCC). The key elements of this pathway are dysfunctional DNA mismatch repair enzymes [3] the loss of which leads to the accumulation of mutations, most commonly in repetitive microsatellite regions of the genome. The result is the development of microsatellite instability in the tumors derived through this genetic pathway. Serrated Adenoma In 1990, Longacre and Fenoglio-Preiser [4] described a type of colonic polyp in which the glands demonstrated a serrated architecture, but the cells lining the glands resembled those of an adenoma. This initial description was based on a survey of over 18,000 polyps of which only 110 (0.6%) were considered to show features of serrated adenoma. In this study serrated adenomas were more likely to occur in the proximal colon (35.4%) than either adenomas (23.3%) or hyperplastic polyps (7.5%). Approximately two-thirds of the lesions were initially diagnosed as either hyperplastic polyp or adenoma. Eleven percent of serrated adenomas showed high grade dysplastic changes or intramucosal carcinoma. On this basis, serrated adenomas were considered by the authors (and others) to represent a variant of adenoma. "Hyperplastic Polyps" and Cancer Hyperplastic polyps were traditionally viewed as benign, non-neoplastic lesions with no potential for neoplastic transformation. However, i n recent years hyperplastic polyps have been recognized as clonal epithelial growths with underlying genetic alterations, most notably in the oncogenes KRAS [5, 6] and BRAF [7]. In addition, it has been suggested that the normal loss of surface epithelial cells through a form of apoptosis referred to as anoikis, is inhibited in hyperplastic polyps and serrated adenomas. This process may be mediated by activated Ras or Raf [8, 9]. The characteristic serrated contour of the crypts in hyperplastic polyps and serrated adenomas may thereby be explained by the need to accommodate increased numbers of retained cells as a result of inhibition of apoptosis [10]. In addition, scattered reports and small series of adenocarcinomas being associated with "giant" or "large" hyperplastic polyps (usually defined as >1cm) suggested that some hyperplastic polyps may have malignant potential [11, 12]. The presence of multiple "hyperplastic polyps" in the form of hyperplastic polyposis [13, 14, 15] was clearly associated with the development of colorectal adenocarcinoma. In some non-polyposis patients with microsatellite unstable (MSI+) colorectal cancers an increased incidence of both hyperplastic polyps and serrated adenomas was observed [16, 17]. A large series of more than 90 MSI+ colorectal cancers in which hyperplastic polyps had been diagnosed near the site of the colorectal cancer at earlier examination further implicated hyperplastic polyps in at least a subset of colorectal carcinomas [18]. Morphologic Features and Classification of Serrated Colon Polyps The WHO recognizes three types of serrated polyp: 1) hyperplastic, 2) mixed and 3) serrated adenoma. However, as described above, data suggests that some polyps recognized previously as "hyperplastic polyps" appear to have malignant potential. How does one differentiate that inconsequential true hyperplastic polyp from the "hyperplastic polyp" that carries a cancer risk? Some of these observations came from study of patients with multiple serrated polyps, a condition variably referred to as hyperplastic polyposis, serrated adenomatous polyposis, metaplastic polyposis and hyperplastic-adenomatous polyposis. Serrated Adenoma As previously described, the term "serrated adenoma" was applied in 1990 to a subset of polyps that had both a serrated hyperplastic-like architecture and adenomatous changes or dysplasia [4]. As a result of this study, through the 1990's serrated polyps were classified as hyperplastic polyps, serrated adenomas, or mixed hyperplastic polyps/adenomas. In most clinical practices, serrated adenomas were diagnosed only rarely, reflecting the incidence of <1% noted in the original article [19, 20]. Additionally, it is likely that in many daily practices, serrated adenomas may have been called villous adenomas since the absence of a known significance for the serrated morphology would lead one to perhaps not spend too much time worrying about whether a dysplastic polyp demonstrated serrations or not. True serrated adenomas, as defined by Longacre and Fenoglio-Preiser demonstrate unequivocal dysplastic (adenomatous) cytologic features. In the original article, serrated adenomas were distinguished from mixed polyps, which were considered to be a chance collision of two independent polyps, one hyperplastic and the other adenomatous. It is important to note, however, that serrated adenomas may themselves be "mixed", and can include components resembling either classical hyperplastic polyp or adenoma. Some serrated adenomas show high grade dysplastic changes or intramucosal carcinoma. On this basis, serrated adenomas were initially considered to represent a variant of adenoma. Our current thinking, however, suggests that this is not true, and that serrated adenoma may follow a different pathway to cancer than the traditional adenoma-carcinoma pathway (see below). Hyperplastic Polyposis Diagnostic Criteria for Hyperplastic Polyposis 1. At least five histologically confirmed hyperplastic (serrated) polyps proximal to the sigmoid colon, of which two are greater than 1 cm in diameter 2. Any number of hyperplastic (serrated) polyps proximal to the sigmoid colon in a subject with a first-degree relative with hyperplastic polyposis 3. More than 30 hyperplastic (serrated) polyps of any size distributed evenly throughout the colon. Most patients with hyperplastic polyposis, in particular those who also develop colorectal cancer, have polyps of varying histology with some representing typical hyperplastic polyps, others are serrated adenomas or traditional adenomas. Still others resemble sessile serrated polyps (see below). Sessile Serrated Polyps Torlakovic and Snover recognized in 1996 that the "hyperplastic polyps" seen in association with hyperplastic polyposis differed morphologically from traditional hyperplastic polyps [36]. In addition, Goldstein et al [37] found similar features among serrated polyps preceding the development of MSI positive colon cancers. The morphologic criteria for these so-called sessile serrated polyps are summarized in Table 2. Major Histologic Features of Sessile Serrated Polyps Abnormal proliferation/dysmaturation Nuclear atypia in mid/upper crypts Oval nuclei in middle crypts Prominent nucleoli in middle/superficial crypts Dystrophic goblet cells Irregular distribution of goblet cells Mitoses in mid/upper crypts Architectural Abnormalities Basal crypt dilation Horizontal orientation of deep crypts Prominent serrations Serration to base of crypt Inverted crypts Other features Lack of thickened basement membrane Focal loss of hMLH1 positivity These polyps have a tendency to be right sided, large, sessile, and endoscopically poorly circumscribed, sometimes mimicking enlarged folds. It is important to note, however, that similar polyps may be found on the left side of the colon, and should be still be diagnosed as "sessile serrated polyps". At the University of Chicago, we prefer the term "sessile serrated polyp" over the other terms commonly used in the literature (sessile serrated adenoma, giant hyperplastic polyp, etc) because the term reflects the fact that these lesions lack the traditional-type dysplasia that we see in other "adenomas" of the colon. Hyperplastic Polyps True hyperplastic polyps are found most frequently in the left colon, and are usually less than 5mm in size. They too show glandular serration, but this change is limited to the superficial one half of the crypt. The deeper crypts often show expansion of the proliferative zone, but do not appear dilated. They remain straight and tubular in shape. The collagen table underlying the surface epithelium of hyperplastic polyps is commonly thickened. Molecular Evidence for the "Serrated Pathway" of Colorectal Cancer Triggered by the morphologic observations, molecular studies now provide convincing evidence that a pathway from serrated polyps (sessile serrated polyp and serrated adenoma) to colorectal carcinoma exists. Studies looking at molecular alterations in serrated adenomas demonstrated different genetic alterations than those traditionally seen in the adenoma-carcinoma sequence [6, 38, 39, 40]. For example, APC, KRAS and TP53 mutation and loss of heterozygosity were uncommon, DNA microsatellite instability and chromosomal instability were absent, and immunostaining for the WNT pathway transcriptional activator beta-catenin showed a normal membranous distribution consistent with the presence of wild-type APC and CTNNB1 genes. Eventually, studies began to demonstrate a set of changes in serrated adenomas that were also present in hyperplastic polyps and a subset of colorectal cancers. These changes included: mutations of BRAF or KRAS (inversely related) [7, 41, 42], microsatellite instability [43, 44, 45] mutation of TGFβ RII [44], loss of expression of the DNA repair genes MGMT (O-6-methylguanine-DNA methyltransferase) [46, 47] and MLH1 [48], and widespread DNA methylation abnormalities [44, 49]. The reasons for the variations in genetic signatures are that serrated adenomas are not homogeneous lesions, pathologists have different diagnostic thresholds for serrated adenoma/sessile serrated polyp, and types of serrated adenoma may differ according to anatomic region in the colon or the population under study. Natural History of Serrated Polyps and Clinical Implications Knowledge of the true frequency of hyperplastic polyps, serrated adenomas and sessile serrated polyps is important because it will allow estimation of the true rate of malignant conversion of these lesions. In one study, residual serrated polyp was observed adjacent to 5.8% of CRCs [17]. 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