Sessile Serrated Polyp / Adenoma

Definition

• Cytologically bland lesion of the large intestine composed of serrated glands with architectural disturbances of the deep crypts

Alternate/Historical Names

• Serrated adenoma
• Serrated adenoma type I
• Serrated polyp with abnormal proliferation

Covered separately

• Traditional serrated adenoma

Background

• Sessile serrated adenoma (SSA) and sessile serrated polyp (SSP) are equivalent terms
  • SSP appeals to those who note that the lesion lacks neoplastic cytologic features
  • SSA appeals to those who note the genetic abnormalities and association with carcinoma
• Although not generally used as diagnostic criteria, characteristic location and genotypic abnormalities linking SSA/P to sporadic MSI high colorectal carcinoma (serrated carcinoma pathway) are the main justifications for defining this as a separate lesion from usual hyperplastic polyp

Diagnostic Criteria

• Serration is variably present throughout gland length
  • Usually exaggerated serration
  • Apical cytoplasm typically filled with microvesicular mucin
    • Goblet cells not conspicuous
• Bases of crypts show architectural disturbances
  • Dilation of crypts with flattened bases
  • Horizontal glands at base
    • “L, inverted T, hockey stick or boot” shaped
  • Mature mucinous cells at base of crypts
    • May form serrations at base
  • How many abnormal crypts are required for the diagnosis is currently in a state of flux
    • The WHO requires at least three adjacent abnormal crypts to make the diagnosis
  • A recent consensus conference recommends that a single abnormal crypt be sufficient for the diagnosis of SSA (Rex 2012)
• Lacks significant architectural complexity
• Most crypts extend from lumen to muscularis mucosae
• Aberrant proliferation
  • Proliferative zone frequently displaced from base
    • Patchy proliferative zones can be seen at all levels
  • Crypt compartmentalization aberration (CCA) (Torlakovic 2008)
    • Abnormalities of location of proliferative and mature compartments within the length of the crypt
      • Encompasses most of the above criteria
    • May be visualized with Ki67 and CK20 stains
• Significant nuclear dysplasia is not a feature of pure sessile serrated adenoma
  • Nuclear stratification and loss of polarity are not seen
  • Nuclei may be mildly atypical with open chromatin and distinct nucleoli
  • Presence of dysplasia in a lesion with hyperplastic features suggests either
    • Traditional serrated adenoma if present throughout (see Differential Diagnosis at left)
    • Sessile serrated adenoma with dysplasia if focal (see below)
• Usually large (≥1 cm) sessile right sided lesions
  • Using strictly the histologic criteria above (and even genetic studies), many small left sided lesions could be considered sessile serrated adenoma
    • As sporadic MSI high colorectal carcinomas are unusual in the left colon, this has led to the suggestion that SSA/P should only be diagnosed on right sided lesions ≥1 cm in size (Chung)
    • We suggest that lesions that are left sided and <1cm should be designated hyperplastic polyp unless they unequivocally and fully fulfill the criteria above for SSA/P
  • Left sided lesions should raise the possibility of hyperplastic polyp or traditional serrated adenoma
• In our experience, nearly all serrated lesions >0.5 cm proximal to the splenic flexure are SSA
• Sessile serrated adenoma may be associated with dysplasia or carcinoma
  • Discrete foci of dysplasia or carcinoma may develop
    • Dysplastic foci resemble classic tubular adenomas
      • Many were historically called mixed hyperplastic-adenomatous polyps
        • Polyps representing a true "collision" of a hyperplastic and an adenomatous polyp, especially in the right colon, must be rare
      • May show usual low grade dysplasia or high grade dysplasia
      • Carcinomas are frequently invasive into submucosa even when small
  • Dysplastic and carcinomatous foci may be MSI high
    • About half of studied cases show loss of MLH1 and PMS2
  • Adjacent SSA lacks both cytologic dysplasia and MSI
  • Clinical and morphologic evidence suggests that the development of dysplasia may herald rapid development of carcinoma (Sheridan 2006)
• There is poor interobserver agreement in the recognition and diagnosis of SSA by both endoscopists and pathologists (Hetzel 2010)
  • The criteria for the recognition of SSP/A can be expected to be refined in the future
• Serrated polyposis (hyperplastic polyposis) (covered separately)
  • Any of the following:
    • ≥20 serrated polyps, any kind or size, anywhere in colorectum
      • Some investigators prefer ≥30
    • ≥5 serrated polyps proximal to sigmoid
      • ≥2 of which are ≥1 cm
    • Any serrated polyp proximal to sigmoid in a first degree relative of a patient with serrated polyposis
  • It is now apparent that many of the polyps of this entity are SSA
• SSP/A and hyperplastic polyps may be associated with perineurioma
  • No clinical significance

Robert V Rouse MD
Amirkaveh Mojtahed MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/last update : 1/31/10, 7/15/11, 11/11/11, 6/11/12, 3/20/13

Supplemental studies

Immunohistology

• We do not use stains for the identification of SSA/P
• B- Catenin (nuclear staining)
  • 41%  of SSA, 0% in HP
• CDX2
  • Labels crypt bases in SSAs, and extends to crypt surface in HPs
• MUC6 positive
  • At least focal staining of basal crypts in 100% of cases
  • Most staining seen in straight, regular crypts
  • Occasional staining in horizontal or dilated bases of crypts
  • Only rare staining in branched or basally serrated crypts
  • (Based on one report so far by Owens 2008, but Gibson 2011 finds considerable overlap with hyperplastic polyps)
    
    

  	Ki67	CK20
  Normal mucosa	Limited to basal ¼	Limited to surface
  Hyperplastic polyp	Expanded to basal 1/3-1/2	Expanded to luminal 1/2-2/3
  SSA	Patches of staining at all levels	Patches of staining at all levels
  TSA	Mainly localized to ectopic crypts	Irregular staining of luminal surface
  Usual adenoma	High overall	Random

  (based on Torlakovic 2008)

• Clear cell variant reported to be positive for hepatocyte nuclear factor-1Beta but sensitivity and specificity do not appear to be useful for diagnosis

Genetic analysis

• Genotype  is not useful for diagnosis but supportive of separate pathways for TSA and SSA

  	Traditional Serrated Adenoma	Sessile Serrated Polyp / Adenoma
  KRAS	Majority (~80%)	Minority (~0-10%)
  BRAF	Minority (~20%)	Majority (~75%)
  p53	Infrequent	Infrequent
  APC	Infrequent	Infrequent
  MSI	Can lead to MSI-L or MSS Serrated adenocarcinoma (SAca)	Can lead to MSI-H or L SAca
  CpG island methylator phenotype (CIMP)	Primarily MGMT involvement in SAca	Primarily MLH1 involvement in SAca

  (based on Makinen 2007 and O’Brien 2006)
• Genotype suggests SSA may be a precursor of sporadic MSI high colorectal carcinomas (serrated carcinoma pathway)
  • BRAF mutations and DNA hypermethylation in both
  • Large (≥1 cm) SSA share marked predominance of right colon location with sporadic MSI high carcinomas
  • Same genotype is frequent in small left sided lesions demonstrating some but not all of the histologic features of SSA
    • This suggests that size ≥1 cm and right side location should be required for the diagnosis to maintain its relevance to the serrated carcinoma pathway

Differential Diagnosis

• Hyperplastic polyp
• Traditional serrated adenoma
• Usual adenoma

Clinical

• Primarily occur in adults
• Age range of patients with SSA and foci of dysplasia or carcinoma 54-87 years
• May be the principal source of sporadic MSI high adenocarcinomas
• They share DNA hypermethylation and BRAF mutations
• Complete removal is recommended if possible, especially for:
• Lesions >1 cm
• Lesions with focal dysplasia
• Following resection, patients are typically followed up in a similar manner as those with a usual type tubular adenoma (Huang 2011, Snover 2011)

  Number and Size	Surveillance Interval
  <3 polyps, all <1 cm	5 years
  ≥3 polyps or any one ≥1 cm	3 years

  • If dysplasia is present, polyp must be completely removed
    • May require both colonoscopic and pathologic evaluation
    • May require immediate repeat endoscopy to assess adequacy
    • Surveillance colonoscopy in 1 to 3 years
  • Above intervals may be shortened in cases with family history or arising < age 50
• See serrated adenomatous polyposis if numerous

Bibliography

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