Gi polyps

PG seminar discussion

1. Gastrointestinal polyps
Presenter –Madhumitha U
Moderator –Dr.DS Chauhan

2. •Is a clinical term or gross description
of any circumscribed growth that
projects above the surrounding
mucosa
Polyps

3. Sessile–base directly attached to the GIT
wall.
Pedunculated –mucosal stalk interposed
b/w polyp & the wall (<5mm rarely )
Flat–height less than one half the diameter
of the lesion.
Depressed–likely to harbourhigh grade
dysplasia or malignancy even if small.
Endoscopic classification of polyps

5. •Highly prevalent in the older
population.
•If there is a family history of polyp or
colon cancer.
•Smoker/ alcoholic
•Overweight/ fatty food intake.
Risk factors

6. •Mostly asymptomatic, until they grow
to 2 cm in diam.
•They can lead to bleeding, frank
blood or microscopic bleeding.
•Rarely present with a change in
bowel habit.
Clinical presentation

7. •Large polyp in the rectum can present
with tenesmus.
•Large amount of mucus can also be
passed.
•Rarely a polyp will prolapse through the
anus or act as an apex for an
intussusception.

8. Polypoidallesions
Hyperplasia/ heterotropia
Benign epithelial lesions
Inflammatory lesions
NEC tumors
Mesenchymal tumors
Lymphoid lesions
Metastasis

9. Inflammatory Polyps
•Etiology –ulcerative colitis, crohn’sdisease,
ischemia, infections, adjacent to ulcers, at
surgical anastomotic sites.
•Full thickness ulceration of mucosa,
followed by inflammation & regeneration
of the non-ulcerated epithelium.
•Gross –solitary or numerous, <2 cm (giant
inflmpolyp) , sessile or pedunculated.

10. Classic microscopic features
1)Variable degree of fibromuscular
hyperplasia of the lamina propria
2)Thickening, splaying, and vertical extension
of the muscularismucosae into the lamina
propria
3)Crypt abnormalities (e.g., elongation,
hyperplasia, architectural distortion, and
serration)
4)Inflammation, ulceration, and reactive
epithelial change

11. Giant filiform
inflammatory poyp
Diffuse inflammatory polyposis in ulcerative colitis

12. Surface erosion
Distorted and dilated crypts with
crypt abscess and cryptitis
Mixed inflammatory
infiltrate in lamina
propria

13. 1.Bizarre enlarged stromal
cells(pseudosarcomatous
cells)
2.Often seen underneath
areas of ulceration and
granulation tissue

14. Inflammatory polyps 2˚ to mucosal
prolapse
different spectra/stages of mucosal polyps
•Inflammatory cap polyposis
•inflammatory myoglandularpolyp
•diverticular polyps

15. Inflammatory cap polyposis
•Limited to rectosigmoidand distal
colon
•Usually sessile and can be solitary to
numerous
•Histologically -eroded surface with a
fibrinosuppurativeinflammatory cap

16. Body of polyp –acute and chronic
inflammation
Proliferation of muscularismucosae
Fibromuscular obliteration of lamina
propria
Epithelial changes –goblet cell
hyperplasia and tortuosity of glands

19. Inflammatory myoglandularpolyp
•Mainly located in distal colon, rarely
seen in ileum
•Solitary and usually pedunculated
Histologically
1.Branching and dilated glands

20. 2.background of radially proliferating
smooth muscle
3.Surface is often eroded with a
fibrinopurulent cap
Treatment–directed at the underlying
inflammatory condition / rarely,surgical
excision when large or numerous polyps
causing symptoms (bleeding or
obstruction).

21. Inflammatory myoglandularpolyp

22. Inflammatory fibroid polyp
Occuringin small intestine, stomach and
less commonly large intestine
Gross –ranges from 1.5 to 13 cm in size
Most often limited to submucosa, but can
infiltrate the mucosa

23. Microscopically
•Vascularized, fibromyxoidstroma
•Abundant inflmmatorycells (eosinophils,
lymphocytes, plasma cells, macrophages
and mast cells )
•Spindle or stellate shaped stromal cells
(fibroblasts ) arranged in an onion skin
fashion around blood vessels.

24. •IHC –vimentin, CD34 (82-100%),
SMA (25%).
•Associated with activating
PDGFRA mutaions
1.Exon 12 predominate in small
intestinal lesions
2.Exon 18 in gastric lesions

25. Polypoidalmass expanding the
sub mucosa
Bland, spindled cells
arranged in onion skin
fashion

26. Hamartomatouspolyps
•defined as overgrowths of cells and tissues
native to the anatomic location in which
they occur.
•In the GI tract, hamartomas typically
incorporate both stromal and epithelial
components.
•Hamartomas are most often solitary but
may occur as part of a hamartomatous
polyposis syndrome

27. •PeutzJeghers
•Juvenile polyp
•Cowden syndrome
•BannayanRiley-Ruvalcaba
syndrome
•CronkhiteCanada
PTEN
hamartoma
tumor
syndromes
Types of Hamartomatouspolyps

28. Juvenile Polyps & Juvenile Polyposis
•Juvenile polyps occur in four distinct
settings
•Sporadic or isolated juvenile polyps are
the most common type of colon polyp
among patients in the first decade of
life

29. AssociationDiagnostic CriteriaInheritanceGeneticsRisk of
malignancy
Sporadic <3 polyps; no family
history of juvenile
polyposis
None Essentially none
Juvenile
polyposis of
infancy
Diarrhea, protein-losing
enteropathy, bleeding,
rectal prolapse, polyps
from stomach through
rectum (resembles adult
Cronkhite-Canada
syndrome)
None De novo
germline
deletion of
10q
encompassin
g PTEN and
BMPR1A
Usually fatal
before age 2 years
from non-
neoplastic
complications

30. Juvenile
polyposis
coli
(1) Any number of
polyps in a patient with
family history, or (2)
≥3 polyps
[*]
without
family history. Polyps
are predominantly
colonic; small bowel
polyps, if present, are
few
Autosomal
dominant, but
family history in
only 20% to
50%
BMPR1A
mutation or
SMAD4 mutation
30% to 68% risk
of colorectal
carcinoma
Generalized
juvenile
polyposis
Polyps throughout
stomach, small bowel,
and colorectum,
usually numbering
from 50 to 200
Autosomal
dominant, but
family history in
only 20% to
50%
SMAD4 mutation
> BMPR1A
mutation
At least 55% risk
of gastrointestinal
carcinomas,
including 20%
upper tract
(stomach,
duodenum)
carcinomas

31. BMPR1A
and
TGF beta
Signalling
pathway

32. 1.5 or more juvenile polyps in the
colorectum
2.1 juvenile polyp in the upper and one
in the lower GI tract
3.any number of juvenile polyps and a
family history of juvenile polyposis .
Diagnostic criteria (any one)

33. Types of JP
Type A classical JP -found most frequently
in isolated cases
Type B atypical JP –seen mostly in patients
with jps

34. Classical JP
Pathological features
Gross –mainly pedunculated, rarely
sessile
< 3cm in diameter
Smooth glistening surface
c/s cystic fluid filled spaces

35. Microscopically
Cysticallydilated and tortuous glands in an
inflamed stroma
Glands –well formed mucus secreting cells
that may be flattened and attenuated
Stroma –a/c and c/h inflammation &
granulation tissue

36. Smooth surface with
cysticallydilated glands
Numerous cystically
dilated glands with
expanded laminpropria
Irreguralydilated gland
lined by benign
epithelium

37. larger, multilobulated, and villiform, often
giving the gross appearance of several
polyps attached to a single stalk.
Atypical JP
Histologically,
compared with typical cases, they
contain less abundant lamina propria
and greater epithelial overgrowth
with many elongated, tortuous, and
irregularly shaped crypts

38. Polyps with villiform
architecture
Epithelial overgrowth
and less abundant
stroma
Crypt architectural
distortion with
crypt branching
and dilatation

39. nonneoplastic
However , dysplasia -observed in 15 to 30 %
of syndromic and rarely in non syndromic
cases
Foci of dysplasia -more frequently in
atypical jpthan in typical jp

40. Foci of dysplasia

41. evaluation by polyp
type revealed a
distinct pattern of
dysplasia in polyps
with
aSMAD4orBMPR1A
Focal dysplasia in
aSMAD4setting was
found only in type B
polyps,
BMPR1Asetting focal
dysplasia was seen in
both type B and
type A polyps
All sporadic polyps
were negative for
dysplasia.

42. Treatment
Upper and lower endoscopy -usually
recommended by age 15 and repeated
annually.
Endoscopic polypectomies and histologic
examination until the patient is free of
polyps
Prophylactic gastrectomy or colectomy if
diffuse polyposis not be controlled by
endoscopic polypectomy or a family
history of GI carcinoma.

43. Peutz-Jegherssyndrome
Rare autosomal dominant inherited
disorder (1:8300-200000 live births)
associated with a lifetime hazard for
cancer up to 93%
GermlinemutationintheSTK11gene(Chr
19p13.3)

44. Diagnostic criteria
a) =>2 histologically confirmed P-J
polyps
b) Any number of P-J polyps with a
family history
c) Prominent mucocutaneous
pigmentation with a family history
d) Any number of P-j polyps and
mucocutaneouspigmentation

45. C/F –Age –second to third
decade
SI –obstruction & abdpain
LI –bloody stools & prolapse

46. •occur throughout the GI tract, small
bowel (65% to 95%) > colon (60%) >
stomach (20% to 50%).
•Involved bowel segments -1 to 20 polyps
•size varies from 0.5 to 3 cm in diameter
•Well developed polyps in the small
intestine and colon -pedunculated.
Pathological features

47. Lobuar, pedunculated polyp in
the deuodenalmucosa

48. Microscopically
•Glandular epithelium resting on a
branching smooth muscle derived
from the muscularismucosae.
•In low power gives a “Christmas tree”
or “arborescent like appearance”

49. •The overlying mucosa is typically
nondysplasticand maintains its
normal architecture.
•Unlike juvenile polyps, the mucosa
has a normal ratio of lamina propria
to epithelium and the crypts are not
cysticallydilated.

50. Branching smooth muscle core
Over growth of
epithelium with
arborizing pattern

51. •Peutz-Jegherspolyps show foci of
epithelial misplacement, pseudoinvasion,
or herniation of benign epithelium into
the intestinal wall –enteritis cystica
profunda

52. Histologic
features
pseudoinvasioncarcinoma
1) Cellular atypiaabsent present
2) Hemosiderin
depositon
present absent
3) Deep
mucinous cysts
present absent
4) Desmoplastic
response
absent present
Discriminators of pseudoinvasionand carcinoma

53. Somatic loss of the 19p13.3 allele
Nondysplasticpolyps and hamartoma
formation
Additional genetic alterations at loci such as
TP53and β-catenin
Dysplasia and carcinoma
Molecular alterations

54. Cancer risk in P-J syndrome

55. At 18 years onwards –
1.Colonoscopy & Upper endoscopy with
either push enteroscopyor double contrast
radiologyof the entire small intestine every
2-3 years
2.Monthly breast self examination
At 25 years onwards –
1.Semiannual clinical breast examination &
annual mammography
Pelvic examination & PAP smears / annual
testicular examination.
Pancreatic USG every 1-2 years
S
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56. Cowden syndrome
•Autosomal dominant hamartoma /
neoplasia syndrome
•Mutations in PTEN gene on chromosome
10q23 reported in 80-85% families with
this syndrome
•Hamartomas in all 3 germ layers

57. •Mucocutaneouslesions –acral
keratoses,Trichilemmoma
•Fibroadenoma, breast CA
•Thyroid-goitre, CA
•Macrocephaly, cerebellar
gangliocytoma, and genitourinary
malformations
•Recently, increased risks for endometrial
carcinoma and renal cell carcinoma

58. Pathological features
GI hamartomas -only 35% to 40% of patients
most common esophagealmanifestation is
glycogenic acanthosis
Most polyps resemble juvenile polyps and
consist of cysticallydilated, mucin-filled
crypts set within an abundant lamina propria
Colonic lipomas, fibrolipomas, fibromas,
ganglioneuromas, and adenomas also
reported in Cowden syndrome.

60. Cronkite –Canada Syndrome
Nonhereditary GI polyposis associated with
alopecia, nail atrophy, hyperpigmentation of
the skin.80% -50 years old or more
C/F –diarrhea, wtloss, anorexia, nausea,
vomiting, weakness.
Polyps all over GIT except esophagus.
Histologically resemble JP, cysticallydilated
tortuous cryptsfilled with inspissatedmucin
embedded in an edematous & inflammed
lamina propria.

61. Polypoidalstructure with cysticallydilated glands
Dilated gland
from the flat
non-polypoidal
mucosa

62. Treatment
The mortality rate is high (50% to 60%).
Death usually results from malnutrition, GI
bleeding, or infection.
aggressive nutritional support, antibiotics,
corticosteroids, and/or surgical resection of
symptomatic segments of the GI tract.

63. Overview of Hamartomatouspolyposis syndromes

64. Epithelial polyps
• Hyperplastic/serrated
• Conventional adenoma
• Adenomatous polyposis syndrome
• Adenomas and adenoma-like
dysplasia-associated lesions or
masses in inflammatory bowel
disease

65. Hyperplastic / serrated polyps
Traditionally considered as non-neoplastic but
some hyperplastic may show abnormal
proliferation and maturation and may be sessile
(SSA/Polyp). Recognised to have potential
neoplastic nature Serrated pathway of
carcinogenesis

66. Progression of adenoma to carcinoma
Conventional adenoma pathway accounts for
approximately 70 to 80% of CRC
Serrated pathway –20 to 30% of all CRC.

68. The “serrated neoplastic pathway” describes
the progression of serrated polyps, (most
commonly SSAs and TSAs) to colorectal
cancer.
Their development can be divided into two
distinct pathways,
◦One that occurs on the right side of the colon
◦One that occurs on the left side or distal
bowel

71. Two examples of BRAF V600E
mutant colon carcinomas with
strong VE1 immunoreactivity.
The upper row shows a
mucinous carcinoma and lower
row a poorly differentiated
gland-forming adenocarcinoma.
Both tumorsare MLH1-negative
and mismatch repair-deficient.

73. Adenoma-carcinoma
sequence
Serrated pathways
APC BRAF
KRAS KRAS
p53 h-MLH-I
SMAD4 p16
MGMT
Genetic Alterations

74. KRAS proto-oncogene
•RAS family genes
•Point mutations of RAS family genes
constitute the most common type of
abnormality of proto oncogenesin
human cancers
•90% of pancreatic adenocarcinomas
and cholangiocarcinomas
•50% of colon, endometrial, and thyroid
cancers

75. •RAS proteins are members of a family of
membrane-associated small G proteins that
can bind GTP and GDP
•normally flip back and forth between an
excited signal-transmitting state in which
they are bound to GTP and a quiescent
state in which they are bound to GDP.
•Stimulation of receptor tyrosine kinases by
growth factorsleads to exchange of GDP for
GTP and subsequent conformational
changes that generate active RAS

76. downstream kinases phosphorylate and
activate a number of cytoplasmic effectors
as well as several transcription factors that
turn on genes that support rapid cell
growth.
Normally : Activation of RAS is transient
because RAS has an intrinsic GTPaseactivity
that binds to active RAS and terminates
signal transduction.

79. BRAF (member of RAF kinase family
•A serine/threonine protein kinase
•Top of cascade of kinases belonging to
MAPK family
•Involved by gain-of-function mutations in
various cancers
•100% of hairy cell leukemia,60% of melanoma

80. ◦Like activating RAS mutations, activating
mutations in BRAF stimulate each of the
downstream kinases and ultimately activate
transcription factors.
◦> 30 mutations recognised in the BRAF gene.
◦V600E mutation = most common (90% of BRAF
mutations).
valine (V) to glutamaticacid (E)

81. A single, activating, point mutation in BRAF (V600E)
Constitutive signalingof the mitogen-activated protein
kinase or (MAPK) pathway
Cell proliferation, survival, inhibition of apoptosis

82. When compared to CRCs arising from classical adenoma-
carcinoma pathway tumorswith CIMP-H/non MSI-H and
non MSI-H CRCs with BRAF or KRAS mutations (arising from
the serrated neoplasia pathway) show
•Reduced survival
•More aggressive
•More resistant to adjuvant therapy

83. Classification of serrated colonic polyps
Non dysplastic serrated polyps
1) Normal architecture with normal proliferation
•Microvesicularhyperplastic polyp
•Goblet cell hyperplastic polyp
•Mucin poor hyperplastic polyp
2) Abnormal architecture,abnormalproliferation
•Sessile Serrated polyp (SSA)

84. Dysplastic serrated polyps
•Traditional serrated adenoma
•Serrated sessile polyp with dysplasia
•Conventional adenoma with serrated
architecture

85. Serrated
Abundant mucin
Columnar mucin
secreting cells
Goblet cells few
No dysplasia
Microvesicularhyperplasticpolyp
Grossly measure < 0.5 cm
Histology –
1)irregular saw tooth or
luminal serrated
surface,pronounced
in the upper portion of
crypts.
2)Simple tubular
architecture
3)Presence of abundant
(microvesicular) mucin
4)Ki67 staining –limited
to the lower half of the
crypts

86. Serrations
only at
surface
Abundant mucin
Goblet cells +++
No dysplasia
Goblet cell hyperplasticpolyp
Grossly measure < 0.5 cm,
sessile lesion, mc –in left
colon
Histology –
1)Elongated crypts rich
in goblet cells.
2)Serrations are of far
lesser degree and
limited to uppermost
portions of crypts.

87. Mucinpoor hyperplasticpolyp
Serrations
prominent at
surface and crypts
Absent mucin
Goblet cells nil
No dysplasia
Least common type and
usually sessile.
Histology –
1)Prominent serrations,
often runs entire
length of the crypts.
2)Lack of mucin and
absence of goblet
cells.
3)Exhibit small cells with
less cytoplasm,
hyperchromatic nuclei
and micropapillary
architecture

88. •Sessile Serrated Polyp/adenoma are often
larger than 0.5 cm and commonly seen in right
side.
•Endoscopically, smooth surface contour and
often covered with mucus.
•Other commonly used terminologies
1) Atypical hyperplastic polyp
2) Large hyperplastic polyp with
architectural abnormalities.
3) Hyperplastic polyp with abnormal
proliferation

89. Serrations
exagerratedat deep
parts of crypts
Crypt disarray
Inverted T/L
Lateral growth
No dysplasia
Serrated sessile polyp (SSA)
Histology –
1)Characterised by
architectural changes
such as
a) Crypt branching and
dilatation,
b) Peculiar growth pattern
–crypts grow parallel to
muscular mucosa,
creating an inverted T or L
shape.
2) Prominent serrations at
the base or throughout
the crypt.
3) Ki 67 staining –irregular
asymmetric and highly
variable expressions

90. Dysplasia++
Serrated sessile polyp with dysplasia
Prominent
Serrations
Crypt disarray
Dysplasia
1)These lesions referred
as mixed hyperplastic/
adenomatous polyps
2)Morphologically,these
lesions may show
discrete areas of
hyperplastic change
typical of MVP, show
features of SSP
combined with
dysplasia

91. Prominent
Serrations
Dysplasia
Dysplasia ++
Serrated sessile polyp with dysplasia
Sharp Junction

92. Traditional Serrated adenoma
Prominent
Serrations
Dysplas
ia
Nuclear stratification
Hypereosinophilic
cytoplasm
Filiformgrowth pattern seen in
rectum
1)Grossly, tends to be
pedunculated
2)Histology: prominent
serrations, villiform
growth pattern and
hypereosinophilic
epithelium
with/without
phenotypic evidence
of dysplasia(either low
or high grade).

93. Conventional adenoma with Serrated architecture
Prominent
Serrations
Dysplasia
Cigar shaped
nucleus
Nuclear stratification
Mucindepletion1)Rarely,conventional
adenoma show areas
of architectural
serrations but should
be distinguished from
TSA by nucleai
features,
2)Develop through APC
+ KRAS fusion
molecular pathway.

94. Serrated polyp, unclassified
Distinction of HP from SSA/P and TSA is
based mainly on architectural criteria
Not all serrated lesions are easily
classified, often because of sampling
issues orpoor orientationof the
specimen.
"serrated polyp, unclassified with/without
dysplasia“ may be used

95. Serrated polyposis syndrome
Rarely described entity with rapidly evolving
diagnostic and molecular criteria due to
increased risk of CRC.
Diagnostic criteria of SPS were first defined
by Burt and Jassin 2000 for the WHO. These
criteria have been recently redefined this
entity.

96. Diagnostic criteria
(1) at least 5histologically confirmed serrated polyps located
proximal to the sigmoid colon, of which atleasttwo are larger
than 10 mm in diameter;
(2) any number of serrated polyps located proximal to the
sigmoid colon in a subject with a first-degree relative with SPS; or
(3) More than 30 serrated polyps of any size distributed evenly
throughout the colon.

97. Approximately, 1/3
rd
of SPS cases are
associated with CRC
SPS with BRAF mutations –cancer risk high
SPS with KRAS mutation –little or no cancer risk

98. 98

99. The clinical importance of serrated lesions of the colorectumRev. gastroenterol.
Perúv.33n.2Limaabr./jun.2013
99

100. Conventional adenoma
Morphologically defined as dysplastic
clonal proliferation of epithelium.
Grossly, classified as sessile or
pedunculated.
Microscopically, categorised as
1) tubular
2) tubulo-villous and
3) villous

101. Tubular adenoma
1)> 75% of
tubular
architect
ure
2)Low
malignan
cy risk
ranging
from 2 –
3%

102. Tubulovillousadenoma Villous adenoma > 75% villous
1)Villous –35 to
40%
malignant
transformation
2)TubuloVillous–
20 to 35%
malignant
transformation

103. 1.Architecturally, non-
complex crypts
containing nuclei that
are pseudostratified.
2.Cell nuclei reach only
the lower half of the cell
cytoplasm
3.Mitotic activity
brisk,Atypicalmitoses,
significant loss of
polarity, and
pleomorphismminimal
4.Crypts are arranged in
a parallel configuration
Low grade dysplasia

104. High grade dysplasia
1)Marked
pseudostratification
/stratification,
2)Increased mitotic
activity/atypical
mitoses
3)Marked loss of
polarity
4)Architectural
changes –back to
back gland
configuration and
cribriforming

105. Intramucosaladenocrcinoma
Invasion of mucosa or muscularismucosae
Differentiation of high grade dysplasia is
based on presence of definite invasion of the
lamina propria.
Recommended that documentation of this
entity should always include the statement
regarding absence of invasive cancer in the
polyp stalk and status of resection margin.

106. Composite adenoma -microcarcinoid
1)Adenomas
associated with
minute proliferation
of well
differentiated
neuroendocrine
cells underlying
dysplastic crypts.
2)When these nests
are confined to
lamina propria–
considered benign

107. 1.Average risk (no first-degree relative with colon cancer)
Colonoscopy at age 50 yr:
•If no adenoma or carcinoma, repeat in 10 yr
•If 1-2 small (<1 cm) tubular adenomas with low-grade
dysplasia, repeat in 5-10 yr.
•If 3-10 adenomas, or any adenoma ≥1 cm, with villous
features, or with high-grade dysplasia, repeat in 3 yr
•If >10 adenomas, repeat in <3 yr; consider possibility of
underlying familial syndrome
•If carcinoma, colonoscopy 1 yrafter resection, then
repeat in 3 yr
Guidelines for adenoma surveilance

108. 2. Moderate risk (first-degree relative with
colon cancer at <60 yror ≥2 first-degree
relatives with colon cancer)
Colonoscopy at age 40 yr, or 10 yrbefore
age of occurrence in relative, whichever
comes first: follow guidelines as above
Guidelines for adenoma surveilance

109. Adenoma with epithelial misplacement
(pseudocarcinoma)
1.Foci of misplaced
epithelium or
extravasated
mucin within the
submucosa of an
adenoma
2.Occurs in 2-4% of
adenomatous
polyp
3.More common -
left sided polyps
and pedunculated
polyps.
Lobule of misplaced glands in
submucosa

110. Misplaced
epithelium
Vs
Invasive
adenocarcinoma

111. Invasive
adenocarcinoma

112. Flat adenomas
defined as dysplastic, non-invasive lesions
without a polypoidalcomponent.
Typically have a central depression.
Constellation of molecular abnormalities
different from conventional adenomas
GastrointestEndosc2002 Nov;56(5):663-71.
Molecularanalysis of diminutive, flat, depressedcolorectallesions: are they
precursors of polypoid adenoma or early stage carcinoma?
Morita T,Tomita N,OhueM

114. FAMILIAL ADENOMATOUS POLYPOSIS
1% of all large intestinal tumour diagnosIs
Autosomal dominant condition caused
by inheritance of a mutated APC gene
(Chr5q)
Characterized by 100-1000s
adenomatous polyps in large bowel

115. FAP symptoms occur earlier and
generally start to appear in the 2nd and
3rd decade of life with most patients
developing adenomas by age 35.

117. Signs and Symptoms
Bright red blood in the stool
Diarrheaand/or constipation
Abdominal pain, cramping, or bloating
Continued weight loss
Anemia

118. Genetics -APC gene
Tumorsuppressor gene
Location: 5q21
Dual function
1) Inhibition of signal transduction
2) Gatekeeper Gene –regulates levels
of ß-catenin ( a member of cadherin
based cell adhesive complex)

119. Regulates the WNT/ß-catenin signaling
pathway
Loss of APC function: ß-catenin
accumulates and activates the
transcription of MYC and cyclin D1 -
proliferation of cells
Half of tumorswithout APC mutations
have ß-catenin mutations

122. Pathological features
MACRO
Flexible endoscopy is the gold standard -
screening
Mild –100-1000
Severe ->1000
Classic -small raised lesion with a rounded
contour
AFAP -flat in appearance, showing only
minimal mucosal elevation (<1cm)

123. Resected specimen of colon showing diffuse polyposis

125. Extracolonicmanifestations
• Congenital hypertrophy of retinal pigment
epithelium (CHRPE)
• Osteomas, desmoidtumours,
epidermoidcysts(Gardner’s syndrome)
• CNS malignancies including
medulloblastomaand glioblastoma (Turcot’s
syndrome)
• Duodenal, hepatobiliary-pancreatic, thyroid
tumours

127. Screening of FAP
Genetic screening of family members for APC
mutations
Annual flexible sigmoidoscopy beginning at age
10-12 until age 40,then every 3-5 years.
If polyposis is present, colectomy should be
considered
UGIE every 1-3 years is also recommended to
evaluate for upper GI adenomas

128. Attenuated FAP
8% of patients
Fewer polyps ,<100 (median 25)
Average age of onset of 41 years
Lifetime risk of malignancy –80%

129. Diagnostic criteria
1.2 patients in a family are diagnosed
with 10-99 adenomas at age >30 years
or
2.1 patient diagnosed with 10-99
adenomas at age >30 and a first-
degree relative is diagnosed with
colorectal cancer

130. MUTYH -associated polyposis
•Autosomal recessive syndrome -mutations of
the mutYhomolog (MUTYH) gene(Chr1)
•Penetrance for colon polyps is close to 100%
and bi-allelic MUTYH mutation carriers
generally develop 10-100 adenomatous
polyps/ adenomas of the colon and rectum.
•60-70% of MAP CRC patients -first diagnosed
at a mean age of 47 years.

131. Microsatellite instability
accounts for 6-15% of CRC and caused by
inactivation of DNA mismatch repair (MMR)
genes
If a mismatch or small loop is found,
endonuclease cuts the strand bearing the
mutation and exonuclease (MLH1 and
PMS2)then digests this strand.
MMR corrects errors that spontaneously occur
during DNA replication, such as single base
mismatches or short insertions and deletions.

132. MSI refers to altered lengths (“instability”) of
short nucleotide repeat sequences
(“microsatellites”) in tumorDNA compared
with normal DNA
Mutations of coding mononucleotide repeats
in
tumorsuppressor genes
Tansforminggrowth factor (TGF)-receptor
type 2 (TGFBR2)
BAX (proapoptoticgene) have been shown
to be important in carcinogenesis

133. microsatellitesare short, sequences of 1
to 6 nucleotide base pairs which are
repeated dozens to hundred times
throughout the genome.
are a ubiquitous component of the
genome of higher organisms.
The most common microsatellite in
humans is a dinucleotide repeat of the
nucleotides C and A, which occurs tens
of thousands of times across the genome.

134. Frameshift mutations occur when the
number of bases added or deleted is
not a multiple of three. The reading
frame is shifted so that completely
different sets of codons are read
beyond the point of mutation.
frameshift mutations → affecting
critical areas of cell growth regulation
genes → promotion of tumorigenesis

135. •Mutation of both alleles of mismatch
repair (MMR) system
→ DNA strand might be displaced, and
realigns creating small loop of unpaired
DNA → unable to remove the loops →
microsatellite increasesor decrease in
size due to either insertion or deletion of
repeating units when compared to the
normal cell’s

136. Hereditary nonpolyposis colon cancer
syndrome (HNPCC/Lynch syndrome)
AD disorder characterised by familial CRCs
Individuals inherit one abnormal copy of DNA
mismatch repair gene. When loss of function
mutation occurs in the 2
nd
allele their
“proofreading” function is lost.
Errors accumulate and these may activate
proto-oncogenes or inactivate tumor
suppressor genes.

137. One of the hallmarks of patients with mismatch
repair defects is microsatellite instablitity
Of various mismatch repair genes two most
commonly involved are:
◦MLH1
◦MSH2
Each of these account for 30% cases of
HNPCC.
Other mutated genes: TGF-receptor II, BAX
and TCF component of beta-catenin pathway

138. Diagnosis Amsterdam criteria 1
Due to lack of phenotypic markers like
polyps,diagnosisis based on family history of
CRC only
1. Onemember less than 50 years of age
2. Twoinvolved generations
3. Threefamily members affected, one of
whom is a first degree relative of the other
two

139. Amsterdam criteria 2

141. MSI testing
MOLECULAR TESTING
◦Evaluation of certain loci within human
genome that are known to harbour
microsatellites
◦DNA extracted from both normal tissue &
tumortissue
◦After PCR amplification of selected
microsatellites , size of PCR products obtained
from normal & tumortissue are compared.
MSI is defined as change of any length due to
either insertion or deletion of repeating units in
a microsatellite within a tumor.

142. Bethesda panel -MSI is typically assessed by
analyzingfive microsatellite markers:
A) 2 mononucleotide repeat (BAT 25 & BAT
26)
B) 3 dinucleotide repeats (D2S123, D5S346 &
D17S250 )
• MSI-H : >2/5
• MSI-L : 1/5
• MSS : None (Genome does not have
instabilityof its microsatellite DNA & so may
have chromosomal instability instead)

145. MSI-H is present as a distinct phenotype in
approximately 15% of CRCs
Tumorswith microsatellite instability can
also be recognized by the absence of
immunohistochemicalstaining for
mismatch repair proteins.

146. MMR protein IHC + for all 4 proteins; does not rule out MSI:
Missense mutation -5%
Epigenetic changes at promoter site
Mutation of lesser known MMR enzymes

147. Screening
Colonoscopy every 2 years starting at ages 20-25
or 5 years younger than the earliest diagnosis of
CRCwhicheveris earlier until 40yr , and then
annually
Flexible sigmoidoscopy is not acceptable, due to
the proximal location of tumours
Transvaginal US and endometrial aspiration
annually starting at ages 25-35 years are also
recommended

148. Treatment
Total colectomy with ileorectalanastomosis
Restorative proctocolectomywith ilealpouch-
anal anastomosis
Segmental colectomy not recommended
because of high rate of metachronousCRC
TAHBSO for endometrial cancer

149. Adenoma and adenoma like dysplasia
Dysplasia in IBD
FLAT RAISED
No endoscopic lesion Visible endoscopic lesion

151. Malignant epithelial polyps
Defined as adenoma that contains invasive
adenocarcinoma ( cancer extends beyond
muscularismucosa into the submucosal polyp
stalk)

153. Mesenchymal Polyp

154. Mesenchymal polyp

156. Esoophagealpolyp

157. Esophagus
Epithelial
Benign
Inflammatory polyp
Hyperplastic polyp
Gastric heterotopia
Adenoma
Glycogenic acanthosis
Malignant
Polypoid dysplasia
Spindle cell carcinoma
Squamous cell carcinoma
Adenocarcinoma
Melanoma
Mesenchymal
Granular cell tumour
Leimyoma
Fibrovascularpolyp
GIST
Leimyosarcoma

161. Contents from

162. Next activity 24/07/17 Dr Seema (journal club)