Determining Best Management for Serrated Adenomas

Q: The Pathologists Keep Sending me Reports About Serrated Adenomas. What is a Serrated Adenoma and What do I Tell my Patients in Terms of Follow-up?

Issue: August 2016

ByFrancis A. Farraye, MD, MSc

ByChristopher S. Huang, MD

ByMichael J. O'Brien, MD, MPH

A: Serrated adenomas are polyps that simultaneously demonstrate the serrated architecture typical of hyperplastic polyps and the epithelial dysplasia of conventional adenomas. They are a subset of a larger group of polyps collectively known as serrated polyps, which are characterized by the histologic feature of “saw-toothed” (serrated) infolding of the crypt epithelium. Hyperplastic polyps (HPs) are the most common type of serrated polyp and have long been regarded as completely innocuous lesions with no malignant potential. While this viewpoint is valid for the majority of small HPs, particularly in the distal colon, we now recognize that some HPs represent precursor lesions in an alternative pathway to colon cancer, termed the serrated pathway. Although its actual contribution to the overall burden of colon cancer is not precisely known, it has been estimated that the serrated pathway accounts for up to 10% to 15% of all colon cancers, and represents the primary pathway to sporadic cancers with microsatellite instability (MSI). Thus, serrated adenomas and other serrated polyps have recently received a great deal of attention.

There are several types of serrated polyps, which can be classified based on the presence or absence of dysplasia (Table). Non-dysplastic serrated polyps include the lesions commonly known as HPs (of which there are actually several subtypes) and an atypical HP variant known as the sessile serrated adenoma (SSA), sessile serrated polyp (SSP), or serrated polyp with abnormal proliferation (SPAP). Unfortunately, this nomenclature is confusing and, it must be emphasized, despite its “adenoma” designation, the SSA is non-dysplastic and is a distinct entity from the serrated adenoma, a dysplastic serrated polyp. The relationships between the various serrated polyps are still being defined, but molecular genetic studies have linked a HP subtype known as the microvesicular serrated polyp with SSAs, serrated adenomas, and serrated cancers, based on their high concordance of BRAF mutations and CpG island methylation status. The progression of nondysplastic serrated polyps to dysplastic serrated polyps and ultimately to serrated cancers is associated with increasing levels of CpG island methylation, which results in inactivation of important tumor-suppressor and mutator genes (eg, hMLH1, a DNA mismatch repair gene). High levels of MSI frequently characterize the cancers that arise as an endpoint of this pathway. A second, less well-defined arm of the serrated pathway is associated with KRAS (as opposed to BRAF) mutation, low levels of CpG island methylation, and endpoint cancers that are microsatellite stable, sharing features similar to those of APC-mutated cancers of the conventional adenoma-carcinoma sequence. The postulated pathways are illustrated in Figure 1.

Figure 1. Schematic illustration of the postulated serrated pathways to colon cancer. ACF-H = aberrant crypt foci-hyperplastic type; HP = hyperplastic polyp; MVSP = microvesicular serrated polyp; SA/HGD = serrated adenoma with high-grade dysplasia.

Figure 2. Endoscopic appearance and histology of serrated adenoma. (A) A serrated adenoma of the proximal colon that shows smooth and cerebriform surface patterns with a sessile shape. (B) Histology of Figure A, showing a dysplastic serrated polyp (serrated adenoma) at right, contiguous with non-dysplastic serrated polyp precursor classified as sessile serrated adenoma. (C) A pedunculated serrated adenoma of the descending colon. (D) Histology of Figure C showing a polyp with serration and dysplasia. (Reprinted with permission from Huang CS, O’Brien MJ, Yang S, Farraye FA. Hyperplastic polyps, serrated adenomas, and the serrated polyp neoplasia pathway. Am J Gastroenterol. 2004;99[11]:2242-2255.)

Serrated adenomas (Figure 2) are actually quite uncommon, compared to conventional adenomas, SSAs, and HPs. In the original report describing this entity, serrated adenomas represented only 101 of more than 18,000 polyps reviewed (<0.6%). In contrast to SSAs, which occur predominantly in the proximal colon, serrated adenomas are more prevalent distally. They may be flat, sessile, or polypoid and may show a tubular, tubulovillous, or villous architecture. In one study of 357 serrated adenomas, 240 (67%) were polypoid and 127 (33%) were superficial (sessile or flat). The superficial serrated adenomas had a significantly larger diameter than polypoid serrated adenomas (mean 10.1 mm vs 6.3 mm) and were more commonly located in the proximal colon, reflecting their likely origin in SSAs. A tubulovillous growth pattern was common in polypoid serrated adenomas (31.5%).

Figure 3. Sessile serrated adenoma. (A) Mucus-covered sessile polyp on the crest of a mucosal fold. (B) Histological section shows a sessile serrated adenoma (atypical hyperplastic polyp). This serrated polyp overall resembles a hyperplastic polyp (microvesicular variant) but an area of the polyp (C inset) shows disordered growth patterns in the crypt bases represented by irregular branching (green arrow), long axes parallel to the surface, and goblet cells in the crypt base (white arrow).

Despite their rarity, serrated adenomas are nonetheless important because of their malignant potential. The magnitude of cancer risk in patients with serrated adenomas is not known. Studies have reported a prevalence rate of high-grade dysplasia and intramucosal carcinoma within serrated adenomas ranging from 5% to 37% and 4% to 11%, respectively. It is likely that the risk of malignant progression varies significantly with the size and location of the serrated adenoma, as suggested by one study in which 1.5% of serrated adenomas smaller than 10 mm demonstrated concomitant carcinoma, compared to 10% of those 10 mm or larger. Serrated adenomas that arise from precursor SSAs may share the aggressive nature of adenomas in patients with hereditary nonpolyposis colon cancer syndrome (HNPCC), related to defective DNA mismatch repair and high levels of MSI (MSI-H). Several studies have indicated, however, that MSI-H develops late in serrated adenomas and is concordant with the appearance of high-grade dysplasia or carcinoma. It is clear that serrated adenomas are premalignant lesions that should be treated with at least the same degree of diligence as that afforded conventional advanced adenomas in terms of resection and postpolypectomy surveillance. Therefore, we currently recommend surveillance colonoscopy in 3 to 5 years after complete resection of a serrated adenoma.

A greater dilemma revolves around the management of SSAs. The first challenge is to recognize the lesion (Figure 3) — SSAs are typically subtle, smooth lesions, frequently covered with mucus, show poor endoscopic circumscription (often having the appearance of a prominent fold of mucosa), and are encountered mainly in the proximal colon. These endoscopic features should prompt the endoscopist to attempt complete resection whenever possible and to specifically ask the pathologist whether the lesion represents an SSA. In contrast to serrated adenomas, SSAs are quite common, representing 9% of all polyps in a recent study of consecutive patients in whom high-resolution chromoendoscopy was performed in the proximal colon. Unfortunately, there are limited data to guide the clinical management of these growth-disordered but non-dysplastic lesions. Until more is known, we feel it is prudent to assign a single SSA the same status of a small tubular adenoma and recommend complete resection followed by surveillance colonoscopy 5 years after resection.

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Finally, although evidence is accumulating to support the potential for neoplastic progression of some HPs, we acknowledge that it is impractical and unnecessary to advocate removal of every single minute HP, especially those located in the distal colon and rectum. However, certain clinical and endoscopic features may identify HPs that warrant special consideration, such as multiplicity (>20), large size (>10 mm), proximal location, and positive family history of colon cancer. These features may point to underlying hyperplastic polyposis syndrome or identify patients at risk for developing cancer via the serrated pathway.

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