Recent advances in Pathology. Important topic!!

1. SERRATED LESIONS
OF COLON AND RECTUM
PRESENTER- Dr. Snehal Kosale (Junior Resident)

2. Contents
 Normal anatomy and histology of colon and rectum
 Precancerous lesions
 Adenomas-
 Clinical features,
 Colonoscopy findings,
 Histopathology
 Adenoma Carcinoma sequence
 Classic
 Serrated neoplastic pathways
 Serrated polyps
 Classification
 Types
 Description
 Clinical implications

3. ANATOMY

4. ANATOMY
 The large bowel comprises the terminal 1–1.5 m of the
gastrointestinal tract and is divided into the following regions:
 Cecum,
 Ascending (right) colon,
 Transverse colon,
 Descending (left) colon,
 Sigmoid colon, and
 Rectum
 The rectum forms the distal 8–15 cm
 Extraperitoneal
 Lies within the pelvis
 Ends at the anal canal

5. Histology
 The large bowel wall is composed of four layers:
 Mucosa,
 Submucosa,
 Muscularis propria, and
 Serosa (or, in the rectum, perimuscular tissues).
 The mucosa has three components:
 Epithelium,
 Lamina propria, and
 Muscularis mucosae.
 The mucosal surface is covered by a single layer of cuboidal
to low columnar epithelium.

6. HISTOLOGY OF COLONIC MUCOSA
The mucosa consists of cells of two types: absorptive cells and mucus
secreting goblet cells arranged in closely packed straight tubular glands
or crypts, which extend down to sit on to the muscularis mucosae.

7. PRECANCEROUS LESIONS
BACKGROUND

8. Colon polyps
 A polyp is any lesion that is elevated above the
mucosal surface of the bowel.
 Polyps are most common in the colon
 But may occur in
 Esophagus,
 Stomach, or
 Small intestine.
 Polyps without stalks are referred to as sessile while
those with stalks are termed pedunculated.
 Proliferation of cells adjacent to the polyp and the effects of
traction on the luminal protrusion, may combine to create a
stalk.

9. Colon polyps
 In general, intestinal polyps can be classified
 Nonneoplastic
 Neoplastic.
 Non-neoplastic colonic polyps can be further classified
as
 Inflammatory,
 Hamartomatous, or
 Hyperplastic.
 The most common neoplastic polyp is the adenoma
 Potential to progress to carcinoma

10. Adenomas
 The most common and clinically important
neoplastic polyps are colonic adenomas
 Majority of colorectal adenocarcinomas arise
from adenomas.
 Colorectal adenomas are characterized by the
presence of epithelial dysplasia

11. Adenomas- Colonoscopy
 Typical adenomas range from 0.3 to 10 cm in diameter
having a texture resembling velvet or a raspberry, due to
the abnormal epithelial growth pattern.

12. Adenomas- Histopathology
 The hallmark of epithelial dysplasia is
 Nuclear Hyperchromasia,
 Nuclear Stratification
 Nuclear Elongation.

13. Adenomas- Histopathology
 Adenomas can be classified as (on the basis of
their architecture)
 Tubular,
 Tubulovillous, or
 Villous
 Villous adenomas have more malignant potential than
the other types.

14. Adenomas- Histopathology
 Tubular adenoma
 Closely packed tubular
crypts
 <20% villous component
 Tubulo-villous adenoma
 Both tubular and villous
components
 Villous component 20-80%
Hiromi Shinya., William 1. Wolff, Morphology, Anatomic Distribution and Cancer Potential of Colonic Polyps. ANNALS OF SURGERY 1979; Vol 190:6

15. Adenomas - Screening
 As precursors to colorectal cancer (CRC),
 All adults should undergo screening colonoscopy
starting at age 50 years
 Persons with a family history increased risk for
CRC earlier in life
 If family history is present, then screening
colonoscopy should be started at least 10 years
before the youngest age at which a relative was
diagnosed.
Vinay Kumar, Abul K. Abbas, Jon C. Aster. Oral cavity and Gastrointestinal tract, 9 ed. Canada: Elsevier; 2013.

16. 1. CLASSIC PATHWAY
2. MICROSATELLITE INSTABILITY
3. SERRATED NEOPLASTIC PATHWAY
ADENOMA CARCINOMA
SEQUENCE

17. Adenoma Carcinoma
Sequence - Classic
 The classic adenoma-carcinoma sequence,
 Accounts for as much as 80% of sporadic colon
tumors
 Involves mutation of the APC tumor
suppressor on chromosome 5q early in the
neoplastic process.
 For adenoma to develop,
 Both copies of the APC gene must be functionally
inactivated.

18. Adenoma Carcinoma Sequence -
Classic
 APC is a key negative regulator of β-catenin, a
component of the WNT signaling pathway.
 β-catenin accumulates and translocates to the
nucleus, where it activates the transcription of
genes which promote proliferation.
 This is followed by additional mutations, including
activating mutations in KRAS, SMAD2, and
SMAD4, and the tumor suppressor gene TP53
which also promote growth and prevent apoptosis.

21. Microsatellite Instability
Pathway
 Occurs in patients with DNA mismatch repair
deficiency.
 Mutations in microsatellite sequences in
coding/promoter regions
 Type II TGF-β receptor- uncontrolled cell proliferation
(inhibits epithelial proliferation)
 Pro-apoptotic protein BAX- inhibits survival.
 Mutations in the oncogene BRAF along with
hypermethylation of CpG islands within gene
promoters- CpG island methylator phenotype
(CIMP) also occur.

22. Microsatellite Instability
Pathway
Thus, signature of this pathway of
carcinogenesis is the combination of
 Microsatellite instability,
 BRAF mutation, and
 Methylation of specific targets (MLH1)

23. The pathways for left sided and right sided colon differ and are
now cumulatively called
‘THE SERRATED NEOPLASTIC PATHWAY’

24. Left colon
Traditional SNP
Distal Hyperplastic Polyps
Traditional serrated
adenoma
Silencing of tumor suppressor
genes MSS (CIMP-L)
Serrated adenocarcinoma
The Serrated Neoplastic
Pathway
Right colon
Sessile SNP
Proximal Hyperplastic
Polyps
Sessile serrated Lesion
leading to Serrated
Adenoma
MLH1 hypermethylation
MSI (CIMP-H)
Serrated adenocarcinoma
K-ras mutation BRAF mutation

25. SERRATED POLYPS

26. Serrated Polyps
 Serrated polyp is a general term for any polyp
that shows a serrated (sawtooth or stellate)
architecture of the epithelial compartment.
 It is a heterogeneous group of lesions that
mainly include
 Hyperplastic polyp,
 Sessile serrated lesions
 Traditional serrated adenoma

27. Serrated
Polyps -
Why so
important?
High frequency in
proximal colon:
Missed in
colonoscopy
Flat/Sessile
Morphology:
Easily Overlooked
Ill-defined
Borders:
Incomplete
Resection
Putative rapid
growth of MSI
cancers
Aggressive
biological behavior
and poorer
outcomes of
BRAF, MSS
cancer

28. SERRATED LESIONS

29. WHO Classification of Serrated
Lesions (2010)
 Hyperplastic polyp (HP)
 Microvesicular HP (MVHP)
 Goblet cell rich HP (GCHP)
 Mucin poor HP (MPHP)
 Sessile serrated adenoma/polyp (SSA/P)
 SSA/P with atypia
 Adenomatous
 Serrated
 SSA/P without atypia
 Traditional serrated adenoma (TSA)
Snover D et al. WHO classification of tumours. Pathology and genetics. Tumours of the digestive system. 4th edition. Berlin: Springer-Verlag. 2010.

30. HYPERPLASTIC POLYPS
(HP)

31. Hyperplastic Polyps-
Introduction
 Formerly called
metaplastic polyps
 More common on left
side of colon and in
males
 Characteristics
 Small <10mm
 Sessile
 K-ras mutation more
common
Otori K, Yoda Y, Sugiyama K et al. High frequency of K-ras mutations in human colorectal hyperplastic polyps. Gut 1997; 40:6660-663

32. Hyperplastic Polyps-
Progression
Inhibition of
Apoptosis
Epithelial Cell
Accumulation
Luminal
Inbudding
Serrated or
saw tooth
Appearance
NO genuine nuclear dysplasia. Only minor nuclear enlargement with reactive

33. Immunohistochemistry
 Immunohistochemistry shows regularly
expanded proliferative and luminal
compartments with Ki67 observed in the crypt
bases

34. Hyperplastic Polyps-
Subtypes
 Microvesicular Hyperplastic Polyp (MVHP)
 Have microvesicular mucin
 Goblet Cell rich Hyperplastic Polyp (GCHP)
 Mostly have goblet cells and less serrations
 Small in size
 Mucin poor hyperplastic polyp
 Although pathological and molecular differences,
NO clinical implication.

35. Microvesicular HP
 Mostly right colon
 Cells have
microvesicular mucin
droplets that impart a
hazy, basophilic
quality to the
cytoplasm
 Minimal nuclear
atypia and mild
nuclear stratification
occurs in crypts and
surface
H/E stained sections showing hypermucinous
surface cells with few goblet cells and papillary
tufting
Hamilton S, Aoltonen L. Pathology and genetics of tumours of the digestive system (WHO classification of tumours). Internayional agency for research on

36. HYPERPLASTIC POLYP –MICROVESICULAR SUBTYPE
Serration and goblet cells are generally limited to the
superficial half of the crypt

37. Goblet Cell Rich HP
 Found in the left colon
 Crowded crypts containing a
disproportionately high number of mature
goblet cells
 Minimal serrations
Hamilton S, Aoltonen L. Pathology and genetics of tumours of the digestive system (WHO classification of tumours). Internayional agency for research on

38. HYPERPLASTIC POLYP –GOBLET CELL RICH SUBTYPE

39. Mucin Poor HP
 Rare Hyperplastic polyp
 Show a relative lack of goblet
cells and microvesicular
mucin
 Epithelial cells are smaller
with less cytoplasm
 Uniform and prominent
serrations with a
micropapillary pattern may be
seen
 Nuclear hyperchromasia and
anisocytosis may be
prominent

40. Hyperplastic Polyposis
Syndrome (HPS)
 Familial clustering of multiple/ large (>3 cm)
hyperplastic polyps
 Predominantly distal location in colon
 Usually asymptomatic
 Associated with an increased risk (approx.
25%) of CRC with MSI.
Williams GT et al. Metaplastic polyps and polyposis of the colorectum. Histopathology 1980;40:155-170.
Legett BA et al, Hyperplastic polyposis: association with colorectal cancer. Am J Surg Pathol 2001;25:177-184.

41. Definition of HPS
 Greater than five hyperplastic polyps proximal
to the sigmoid of which two are >10 mm.
 Greater than 30 hyperplastic polyps of any
size, proximal to the sigmoid colon.
 Any number of hyperplastic polyps with a first
degree relative with known HPS.

42. SESSILE SERRATED LESIONS
(SSL)

43. Sessile Serrated Lesions
(SSL)
 According to European
guidelines of 2011, SSL
 More common in the right
side of colon and in
females
 Endoscopically-
 Large
 Sessile
 Yellow in color
 May have a mucus cap
which when present may
be missed
Quirke P et al. Quality assurance in pathology in colorectal cancer screening and diagnosis-European recommendations. Virchow Arch 2011;
4581:1-19

44. SSL - Progression
Inhibition of
Apoptosis
Epithelial Cell
Accumulation
Luminal
Inbudding
Serrated or
saw tooth
Appearance

45. SSL without atypia
 Distorted architecture due
to altered proliferative zone
 Proliferative zone often
displaced from base to
side
 Crypts may herniate
through muscularis
mucosae k/a inverted
growth pattern
 Pronounced serration
reaching upto the bases

46. SSL without atypia
 Crypts are dilated
and branched with L
or inverted T shaped
 Crypts are irregular,
branched
 Dilatation of crypt
bases

47. SSL with atypia-
adenomatous
 More commonly found in the
cecum and ascending colon
 Similar to conventional
adenomatous polyps
 An abrupt transition to
dysplastic crypts resembling
adenomatous crypts
 Showing relatively small
rounded and fairly uniform
nuclei
 Suggestion of residual
serration

48. SSL with atypia- serrated
 Glands retain a
serrated architecture
 Have ample
eosinophilic
cytoplasm
 Nuclei are typically
 Vesicular
 Basally located

49. Criteria
For
Serrated
Lesions
Serrated
appearance at the
base of the crypts
Horizontalisation
of crypts with
branching
Dilatation of the
crypts
Increase in
epithelium-
stroma ratio
> 50%
Mitoses on the
surface of the crypts
Cellular atypia:
Enlarged nucleus,
overproduction of
mucin
2 of 6 criteria must be present for diagnosing sessile serrated
lesions

50. TRADITIONAL SERRATED
ADENOMAS

51. Traditional Serrated Adenoma-
TSA
 Rare subtype (<6% of
serrated polyps)
 Occur in older adults
particularly females
 Located in the left colon
 Endosopically-
 Polypoidal lesions: Reddish
discoloration and granulo-
lobular appearance
 Sessile lesions: Larger,
proximally located, white
mucosa
Torkalovic EE, Gomez DK et al. Sessile serrated adenoma (SSA) vs traidtional serrated adenoma (TSA). Am JSUrg Pathol 2008; 32:21-29

52. Traditional Serrated Adenoma-
Progression
Fully developed TSA with multiple
ectopic crypts lining villi.
Early TSA- an outward
growth creates ectopic
growth

53. Traditional Serrated Adenoma-
TSA
 Prominent serration
 Diffuse low grade dysplasia
(10% high grade dysplasia)
 Luminal infoldings
perpendicular to the main
axis of the crypts called
‘ectopic crypt foci’

54. Traditional Serrated Adenoma-
TSA
 Abundant
eosinophilic
cytoplasm
 Centrally placed,
pencillate nuclei
 Nuclear
stratification
 Nuclear
hyperchromasia

55. Features of Serrated Adenomas
WHO
Classification
Prevalence Shape Distribution Malignant
Potential
Hyperplastic polyp Very
common
Sessile/ flat Mostly distal Very low
Sessile serrated
adenoma/polyp
Common Sessile/ flat 80% proximal Significant
Traditional serrated
adenoma
Rare Sessile/
Pedunculated
Mostly distal Significant

56. SERRATED
ADENOCARCINOMA

57. Serrated Adenocarcinoma
 End point of the serrated pathway
 Reported to account for 7.5% of all colorectal
carcinomas
 More common in right colon
 Left sided occur from microsatellite stable (MSS) or
show low microsatellite instability (MSI) and arise from
TSA
 Right sided occur from high frequency of microsatellite
instability (MSI) and arise from SSL

58. SERRATED ADENOCARCINOMA

59. Serrated Adenocarcinoma
 Cells are cuboidal to
short columnar
 Moderate
eosinophilic
cytoplasm
 Very large nuclei
 Open chromatin
 Prominent nucleoli.

60. CLINICAL IMPLICATIONS

61. Clinical Implications
 Irrespective of size SSLs may progress
rapidly to MSI carcinomas
Polyp size >2 cm
Thorough examination of
resection margins
Polyp morphology-
Serrated Polyps
Comment on margins as
free/involved

62. Clinical Implications
 Distal serrated adenocarcinomas have a
worse prognosis compared with non-serrated
and proximal cancers.
 Therefore, important to distinguish SSLs and
TSAs
 Associated malignancies may have a different
prognosis and treatment.
Mäkinen MJ. Colorectal serrated adenocarcinoma. Histopathology 50, 131–150 (2007)
Laiho P, Kokko A, Vanharanta S et al. Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis. Oncogene 26, 312–
320 (2007).
Garcia-Solano J, Perez-Guillermo M, Conesa-Zamora P et al. Clinicopathologic study of 85 colorectal serrated adenocarcinomas: further insights

63. Clinical Implications
 The presence of large, serrated polyps (>1
cm) are an independent risk factor for the
presence of CRC
 The data by Goldstein et al suggest that
surveillance colonoscopy intervals for SSAs
should be at least as frequent as those
recommended for conventional adenomas.
Hiroaka S, Kato J, Fujiki S et al. The presence of large serrated polyps increases the risk of colorectal cancer.Gastroenterology 139,
1503–1510 (2010)
Schriener MA, Weiss DG, Lieberman DA et al. Proximal and large hyperplastic and nondysplastic serrated polyps detected by
colonoscopy are associated with neoplasia. Gastroenterology 139, 1497–1502 (2010).

64. Guidelines for endoscopic
surveillance
Serrated Lesion Lesion Size Recommended
Surveillance
(years)
Hyperplastic Polyp <10 mm 10
Sessile Serrated Lesion <10 mm 5
Sessile Serrated Lesion >10 mm 3
Mixed Hyperplastic/
Adenomatous Polyp
Mixed serrated/ adenoma
Any size 1
Traditional Serrated Adenoma Any size 1
Hyperplastic/ Serrated Polyposis Any size 1

65. References
 Snover D et al. WHO classification of tumours. Pathology and genetics. Tumours of the digestive
system. 4th edition. Berlin: Springer-Verlag. 2010.
 Vinay Kumar, Abul K. Abbas, Jon C. Aster. Oral cavity and Gastrointestinal tract, 9 ed. Canada: Elsevier;
2013.
 Hiromi Shinya., William 1. Wolff, Morphology, Anatomic Distribution and Cancer Potential of Colonic
Polyps. ANNALS OF SURGERY 1979; Vol 190:6
 Hamilton S, Aoltonen L. Pathology and genetics of tumours of the digestive system (WHO classification
of tumours). Internayional agency for research on cancer, 2000:314
 Hamilton S, Aoltonen L. Pathology and genetics of tumours of the digestive system (WHO classification
of tumours). Internayional agency for research on cancer, 2000:314
 Torkalovic EE, Gomez DK et al. Sessile serrated adenoma (SSA) vs traidtional serrated adenoma
(TSA). Am JSUrg Pathol 2008; 32:21-29
 Torkalovic EE, Gomez DK et al. Sessile serrated adenoma (SSA) vs traidtional serrated adenoma
(TSA). Am JSUrg Pathol 2008; 32:21-29
 Mäkinen MJ. Colorectal serrated adenocarcinoma. Histopathology 50, 131–150 (2007)
 Laiho P, Kokko A, Vanharanta S et al. Serrated carcinomas form a subclass of colorectal cancer with
distinct molecular basis. Oncogene 26, 312–320 (2007).
 Garcia-Solano J, Perez-Guillermo M, Conesa-Zamora P et al. Clinicopathologic study of 85 colorectal
serrated adenocarcinomas: further insights into the full recognition of a new subset of colorectal
carcinoma. Hum. Pathol.41, 1359–1368 (2010).
 Hiroaka S, Kato J, Fujiki S et al. The presence of large serrated polyps increases the risk of colorectal
cancer.Gastroenterology 139, 1503–1510 (2010)
 Schriener MA, Weiss DG, Lieberman DA et al. Proximal and large hyperplastic and nondysplastic
serrated polyps detected by colonoscopy are associated with neoplasia. Gastroenterology 139, 1497–
1502 (2010).
 Torlakovic E, Snover DC. Serrated adenomatous polyposis in humans. Gastroenterology 110, 748–755