Pathology of Serrated Colon Adenomas

Serrated polyps of the large intestine consist of those that display a lumen with a serrated or stellate architecture. Until recently, serrated polyps were thought to consist only of reputedly benign and innocuous hyperplastic polyps (see the first image below). Recent discoveries have unveiled that, in addition to hyperplastic polyps, there exist other serrated lesions, for which the natural history is not as benign. ^[1] The current classification of serrated lesions of the large intestine includes: hyperplastic polyps, traditional serrated adenomas (see the second image below), and sessile serrated adenomas or polyps with or without cytologic dysplasia (see the last image below). ^{[2, 3]} The terms "sessile serrated adenoma" and "sessile serrated polyp" are considered synonomous.

Epidemiologic data are still evolving, given the recently updated classification of serrated polyps. Hyperplastic polyps are believed to represent 80-90% of all serrated polyps. ^{[4, 5, 6]} Serrated adenomas were found to represent 15.9% of colorectal polyps in one Finnish study. ^[7] Other studies have shown that traditional serrated adenomas comprise 7% of large intestine polyps, ^{[4, 8]} whereas sessile serrated adenomas made up 9% of all colorectal polyps and 22% of serrated polyps. ^[9]

The etiology of serrated adenomas of the colon is largely unknown, but much recent work has shed light on associated genetic alterations (see Molecular/Genetics, below).

Hyperplastic polyps are most frequently found in the left colon and rectum. ^[10] About 54% of traditional serrated adenomas are found in the left colon, ^{[4, 8]} whereas sessile serrated adenomas are more common in the right colon. ^[10]

Most patients with serrated adenomas of the colon are asymptomatic, unless the polyp is greater than 1 cm in its largest diameter, or unless it is cancerous. Symptoms can include blood-streaked stools, rectal bleeding, or a positive fecal occult blood test (FOBT). Once cancer develops, additional symptoms can consist of changes in bowel habits and significant weight loss.

Hyperplastic polyps are usually small, less than 0.5 cm in size, and sessile or slightly raised.

Traditional serrated adenomas are usually pedunculated or have a broad-based polypoid pattern of growth. ^[11] Endoscopically, these lesions can have a cerebriform appearance; however, smaller polyps of this type are indistinguishable endoscopically and grossly from hyperplastic polyps. ^{[8, 12]}

Serrated lesions are more difficult to detect endoscopically than conventional adenomatous polyps but do have a distinct endoscopic appearance. They have been described to have a "mucous cap" and are similar in color to normal mucosa, with indistinct edges. The adherent mucus and residue contributes to the difficulty in discriminating the polyp from the surrounding normal colonic mucosa with white light endoscopy. Sessile serrated adenomas are typically greater than 1 cm in size, flat, and located along the crests of haustral folds, at times mimicking enlarged folds. ^[1]

Hyperplastic polyps

Hyperplastic polyps have a hypermature appearance with a serrated or stellate-shaped lumen, as seen in the following image. Serration is limited to the upper half to upper third of the crypts in most cases, but some hyperplastic polyps show more serration. They display normal proliferation; that is, the proliferation zone occupies the basal third to lower half of the crypt and that the proliferation zone is symmetrical. Importantly, the bottom part of the crypts remains narrow, straight, and tubular, and no horizontal or irregular branching is seen. Minimal cytologic atypia is present. The nuclei are small, oval to slightly elongated, without stratification. Evaluation of the architecture is most important because atypia can be seen in inflamed polyps with regenerative changes.

The following table compares the characteristics among serrated polyps of the large intestine.

Table 1. Comparison of Characteristics Seen in Serrated Polyps of the Large Intestine. (Open Table in a new window)

 

There are 3 subtypes of hyperplastic polyps: microvesicular serrated polyps (MVSPs), goblet cell-rich serrated polyps (GCSPs), and mucin-poor serrated polyps (MPSPs). ^[5] The degree of lumen serration can vary among these subtypes. For practical purposes, distinguishing these types of polyps from each other does not have clinical or prognostic significance for patient care; however, these subclassifications have been used in research studies. In addition, awareness of these morphologic subtypes may aid in diagnosis of hyperplastic polyps.

MVSPs are the most common type and correlate with the traditionally known hyperplastic polyps found in the distal colon. These are characterized by decreased content of goblet cells, or abnormal (vesicularlike) goblet cells, which contain small droplet mucin within the cytoplasm. Nuclear atypia and stratification may be seen. These polyps occur primarily in the left colon, often in multiples. ^[5]

GCSPs have less prominent serration and the almost exclulsive presence of large-appearing goblet cells without fine vesiculation of the cytoplasm. Minimal nuclear atypia or stratification is seen. Goblet cell rich serrated polyps are also most common in the left side of the colon and are usually less than 0.5 cm. ^[5]

MPSPs are rare, show uniform and prominent serration, and have almost no evidence of mucin, and with large round hyperchromatic nuclei without pseudostratification. They can be associated with hyperplasia of clear neuroendocrine cells These features have led some to hypothesize these polyps are in reality MVSPs with reactive changes. ^[5]

Traditional serrated adenomas

Traditional serrated adenomas consist of a uniform population of abnormal columnar cells with eosinophilic cytoplasm (see the following image) and centrally placed elongated nuclei, which are somewhat hyperchromatic and display mild pseudostratification (but not to the degree seen in tubular adenomas or villous adenomas). Cell proliferation is mainly within the crypt base, and occasional mitoses may be seen in the upper crypt zone. Overall, there is a definite transition from a basal proliferative zone to a more superficial zone of maturing cells.

Architecturally, traditional serrated adenomas have a somewhat villiform configuration and appear protuberant rather than sessile. ^[1] Additionally, "ectopic crypts" may be seen; that is, the crypts appear shortened and do not contact the muscularis mucosae, which is in contrast to normal colonic crypts. ^[10] These polyps can also show areas of high-grade dysplasia or intramucosal carcinoma ^[4] (see Sessile Serrated Adenomas/Polyps with cytologic dysplasia, below, for more details).

Sessile serrated adenomas/polyps

The terms "sessile serrated adenomas" and "sessile serrated polyps" are used interchangeably and are synonymous. The diagnostic feature of sessile serrated adenomas include branching crypts, crypts that are dilated at the base, and crypt bases that grow parallel to the muscularis mucosae, creating the distinctive L-shaped, boot-shaped, or inverted T-shaped crypt (see the image below). These architectural findings often permit the diagnosis of sessile serrated adenoma under low-power examination of a well-oriented specimen. This growth pattern is accompanied by the presence of mature cells with a goblet cell or gastric foveolar cell phenotype at the base of the crypt, replacing the proliferative zone of normal mucosa (as shown in the image below). They often produce excessive mucin and fill the crypts, thus imparting the grossly seen "mucin cap."

Additionally, the proliferation zone is abnormal and has often migrated upward within the crypt in an asymmetrical fashion. ^[1] Unlike hyperplastic polyps, serration can be seen at the base of the crypts (see the image above). The surface epithelium can look just like that of a hyperplastic polyp, especially with small or poorly oriented biopsies, hence the importance of obtaining deeper sections for a poorly oriented specimen.

Other less common but helpful features include small foci of pseudostratification of nuclei and eosinophilic cytoplasmic change (identical to that seen in traditional serrated adenomas) in the surface epithelium (see the image above). Subtle nuclear alterations, including small prominent nucleoli, open chromatin, and irregular nuclear contours, might also be present, along with mitoses in the upper one third of the crypts or on the surface itself. However, note that sessile serrated adenomas do not require overt cytologic dysplasia for the diagnosis but require only the "architectural dysplasia." ^[1]

Although definitive minimal criteria for sessile serrated adenomas or polyps has not yet been defined, a single, unequivocal architecturally distorted, dilated, and/or horizontally branched crypt is sufficient for a diagnosis of sessile serrated adenoma/polyp, especially if associated with inverted maturation. ^[13] Diagnosing them as such places the patient within a more frequent follow-up bracket; provide appropriate follow-up for any patient who potentially has a sessile serrated polyp. The term "mixed serrated polyp" is discouraged, and this suggested minimal criteria thus nullifies the need for that category.

Sessile serrated adenomas/polyps with cytologic dysplasia

Histologically, one may see a sessile serrated polyp with a portion that transitions to conventional adenomalike areas, consisting of cells with elongated and pseudostratified nuclei and increased mitoses. Sessile serrated adenomas that display conventional cytologic dysplasia are more advanced in progression to cancer than those without cytologic changes. Any sessile serrated adenoma with any conventional cytologic dysplasia should be considered an "advanced" polyp, with clinical significance similar to high-grade dysplasia in conventional adenomas. ^[13] The term "conventional adenoma (tubular, tubulovillous, or villous) with serrated growth pattern" is reserved for those polyps that show conventional adenomatous change with a serrated pattern of growth but no areas diagnostic of sessile serrated adenomas or traditional serrated adenomas. ^[13]

There has been some discussion of the use of immunohistochemical stains in the evaluation of serrated adenomas of the colon. Sessile serrated adenomas often focally lose expression of hMLH1. ^{[5, 14]} However, the practicality of this stain is low, given the focality of staining loss and the specimen volume. Similarly, although proliferation markers (Ki-67) demonstrate some differences among types of polyps (see the previous table) and might emphasize the abnormal proliferation in sessile serrated adenomas, Ki-67 staining is not likely to be very useful. ^[15] Therefore, the diagnosis will most likely remain in the realm of routine histopathologic examination.

Cytokeratin 20 (CK20) staining was shown to have different distribution in the different types of serrated polyps (see the following table). ^[16] Whereas CK20 stains the surface epithelium and upper crypts in hyperplastic polyps, similar to the pattern seen in the normal colon, CK20 staining is limited to the surface epithelium in traditional serrated adenoma. In sessile serrated adenomas, the staining is irregular in intensity and distribution, and it can be seen in the dilated crypt bases.

Table 2. Comparison of 2 Proliferation Markers Among Serrated Polyps (Open Table in a new window)

Studies indicate the presence of at least 2 molecular serrated polyp pathways to colon cancer, with both sharing an underlying abnormality with CPG island methylation (CIMP). ^[15]

The first pathway (the serrated polyp-carcinoma sequence) involves tumors arising from sessile serrated adenomas predominantly in the right colon, which then progress to sessile serrated adenomas with cytologic dysplasia and then finally to cancer. These cancers show BRAF mutations, particularly V600E mutation, and a high-level CpG island methylation (CIMP-H). This leads to inactivation of MLH1 and MGMT, which leads to low and high levels of microsatellite instability. These observations suggest that the sessile serrated adenoma is the most likely precursor to sporadic high-level microsatellite instability (MSI-H) colorectal cancer, and may account for as much as one third of all colorectal cancers. Interestingly, some hyperplastic polyps also show BRAF mutations and are CIMP-high and may be a part of this sequence ^{[17, 13]}

The second pathway involves tumors arising from traditional serrated adenomas, leading to low-level microsatellite instability (MSI-L) or microsatellite stable (MSS) serrated colorectal adenocarcinomas. They can also be CIMP-H but more frequently contain KRAS mutations rather than BRAF mutations. ^[17]

Traditional hyperplastic polyps usually represent innocuous lesions, if diagnosed correctly. ^[5] Sessile serrated adenoma and traditional serrated adenomas, however, are premalignant lesions and can progress to adenocarcinoma; adenocarcinoma developing at sites of preexisting serrated polyps has been reported. ^{[14, 18, 19, 20]} Sessile serrated adenomas are the principle serrated precursor for colorectal cancer. ^[13]

A study that explored the coexistent presence of hyperplastic polyps (HPs), sessile serrated adenomas (SSAs) and adenomatous polyps within a large cohort of traditional serrated adenoma (TSAs) found that more than 50% of TSAs are associated with a precursor lesion or adjacent tubular/tubulovillous adenomas (TA/TVA). ^[21]

Serrated polyps with cytologic dysplasia are believed to be more aggressive lesions and are regarded as more advanced in progression to cancer. Direct transition of mixed polyps into invasive carcinoma has been observed. ^{[4, 5, 22, 23, 24, 25, 26, 27, 28]} One report noted evolution of a sessile serrated adenoma into invasive adenocarcinoma in as little as 8 months. ^[29] In addition, Lu et al reported that 15% of patients with sessile serrated adenoma developed colorectal adenocarcinoma or advanced polyp with high-grade dysplasia on follow-up. ^[30] New recommendations suggest that all serrated lesions proximal to the sigmoid colon and all serrated lesions greater than 5 mm be completely removed. ^[13]

Serrated polyposis syndrome

Serrated polyposis syndrome has had many names, including "hyperplastic polyposis syndrome," "hereditary mixed polyposis syndrome," "hyperplastic-adenomatous polyposis," "metaplastic polyposis," and the more recent term "serrated adenomatous polyposis." The World Health Organization (WHO) criteria for Serrated polyposis syndrome consist of the following: ^[31]

• At least 5 "serrated polyps" proximal to the sigmoid colon, of which 2 are greater than 1 cm in diameter, or

• Any number of serrated polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis syndrome, or

• Greater than 20 serrated polyps of any size, distributed throughout the colon

Hyperplastic polyposis patients can have polyps of varying histology, including hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, or classical tubular or villous adenomas. These patients have an increased risk for colorectal cancer, which may be as high as 50%, and they can have multiple synchronous or metachronous cancers. ^[32]

Hyperplastic polyposis is the only remaining polyposis condition for which no germline mutation predisposing to the condition has been identified. It can overlap with attenuated familial adenomatous polyposis (FAP). Although the natural history of hyperplastic polyposis syndrome remains unclear, careful surveillance is recommended, with colonoscopies every 1-2 years. ^[33] Screening colonoscopies should be recommended for first-degree relatives of affected individuals, beginning at age 40 years, or 10 years earlier than the earliest age at diagnosis in the family.

Differential Diagnosis

The differential diagnosis of a serrated polyp includes traditional hyperplastic polyp, traditional serrated adenoma, and sessile serrated adenoma. With clearly outlined morphologic differences (see Gross Findings and Microscopic Findings), one would assume that distinguishing among the different types of serrated polyps should be straightforward. Unfortunately, 2 recent studies show poor to moderate interobserver agreement, especially for the distinction between hyperplastic polyps and sessile serrated adenomas. ^{[34, 35]}

It should be noted that in one of the studies, polyps smaller than 5 mm and those with suboptimal orientation were excluded. ^[34] In daily practice, in which small polyps, superficial sampling, suboptimal orientation, and cautery artifacts are common, interobserver agreement is likely to be very poor. It is currently unknown whether including any of the immunohistochemical markers would improve interobserver agreement.