2. ⢠Is a clinical term or gross description
of any circumscribed growth that
projects above the surrounding
mucosa
Polyps
3. ďź Sessile â base directly attached to the GIT
wall.
ďź Pedunculated â mucosal stalk interposed
b/w polyp & the wall (<5mm rarely )
ďź Flat â height less than one half the diameter
of the lesion.
ďź Depressed â likely to harbour high grade
dysplasia or malignancy even if small.
Endoscopic classification of polyps
4.
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.
9. Inflammatory Polyps
⢠Etiology â ulcerative colitis, crohnâs disease,
ischemia, infections, adjacent to ulcers, at
surgical anastomotic sites.
⢠Full thickness ulceration of mucosa,
followed by inflammation & regeneration
of the non-ulcerated epithelium.
⢠Gross â solitary or numerous, <2 cm (giant
inflm polyp) , 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 muscularis mucosae into the lamina
propria
3) Crypt abnormalities (e.g., elongation,
hyperplasia, architectural distortion, and
serration)
4) Inflammation, ulceration, and reactive
epithelial change
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 2Ë to mucosal
prolapse
different spectra/stages of mucosal polyps
⢠Inflammatory cap polyposis
⢠inflammatory myoglandular polyp
⢠diverticular polyps
15. Inflammatory cap polyposis
⢠Limited to rectosigmoid and distal
colon
⢠Usually sessile and can be solitary to
numerous
⢠Histologically - eroded surface with a
fibrinosuppurative inflammatory cap
16. ďBody of polyp â acute and chronic
inflammation
ďProliferation of muscularis mucosae
ďFibromuscular obliteration of lamina
propria
ďEpithelial changes â goblet cell
hyperplasia and tortuosity of glands
17.
18.
19. Inflammatory myoglandular polyp
⢠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 â directed at the underlying
inflammatory condition / rarely,surgical
excision when large or numerous polyps
causing symptoms (bleeding or
obstruction).
22. Inflammatory fibroid polyp
ďOccuring in small intestine, stomach and
less commonly large intestine
ďGross â ranges from 1.5 to 13 cm in size
ďMost often limited to submucosa, but can
infiltrate the mucosa
23. Microscopically
⢠Vascularized, fibromyxoid stroma
⢠Abundant inflmmatory cells (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 â 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
26. Hamartomatous polyps
⢠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
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. Association Diagnostic Criteria Inheritance Genetics Risk 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)
âĽ3 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
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
ďType A classical JP - found most frequently
in isolated cases
ďType B atypical JP â seen mostly in patients
with jps
35. Microscopically
ďCystically dilated and tortuous glands in an
inflamed stroma
ďGlands â well formed mucus secreting cells
that may be flattened and attenuated
ďStroma â a/c and c/h inflammation &
granulation tissue
36. Smooth surface with
cystically dilated glands
Numerous cystically
dilated glands with
expanded laminpropria
Irreguraly dilated 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,
ďcompared with typical cases, they
contain less abundant lamina propria
and greater epithelial overgrowth
ďwith many elongated, tortuous, and
irregularly shaped crypts
39. ď nonneoplastic
ďHowever , dysplasia - observed in 15 to 30 %
of syndromic and rarely in non syndromic
cases
ďFoci of dysplasia - more frequently in
atypical jp than in typical jp
41. ď evaluation by polyp
type revealed a
distinct pattern of
dysplasia in polyps
with
a SMAD4 or BMPR1A
ď Focal dysplasia in
a SMAD4 setting was
found only in type B
polyps,
ď BMPR1A setting focal
dysplasia was seen in
both type B and
type A polyps
ď All sporadic polyps
were negative for
dysplasia.
42. Treatment
ď Upper and lower endoscopy - usually
recommended by age 15 and repeated
annually.
ď Endoscopic polypectomies and histologic
examination until the patient is free of
polyps
ď Prophylactic gastrectomy or colectomy if
diffuse polyposis not be controlled by
endoscopic polypectomy or a family
history of GI carcinoma.
43. Peutz-Jeghers syndrome
ď§ Rare autosomal dominant inherited
disorder (1:8300-200000 live births)
associated with a lifetime hazard for
cancer up to 93%
ď§ Germline mutation in the STK11 gene (Chr
19p13.3)
44. ď§ 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
mucocutaneous pigmentation
45. ď C/F â Age â second to third
decade
ď SI â obstruction & abd pain
ď LI â 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
48. Microscopically
⢠Glandular epithelium resting on a
branching smooth muscle derived
from the muscularis mucosae.
⢠In low power gives a âChristmas treeâ
or âarborescent like appearanceâ
49. ⢠The overlying mucosa is typically
nondysplastic and maintains its
normal architecture.
⢠Unlike juvenile polyps, the mucosa
has a normal ratio of lamina propria
to epithelium and the crypts are not
cystically dilated.
51. ⢠Peutz-Jeghers polyps show foci of
epithelial misplacement, pseudoinvasion,
or herniation of benign epithelium into
the intestinal wall â enteritis cystica
profunda
52. Histologic
features
pseudoinvasion carcinoma
1) Cellular atypia absent present
2) Hemosiderin
depositon
present absent
3) Deep
mucinous cysts
present absent
4) Desmoplastic
response
absent present
Discriminators of pseudoinvasion and carcinoma
53. Somatic loss of the 19p13.3 allele
Nondysplastic polyps and hamartoma
formation
Additional genetic alterations at loci such as
TP53 and β-catenin
Dysplasia and carcinoma
Molecular alterations
55. At 18 years onwards â
1. Colonoscopy & Upper endoscopy with
either push enteroscopy or double contrast
radiology of the entire small intestine every
2-3 years
2. Monthly breast self examination
At 25 years onwards â
1. Semiannual clinical breast examination &
annual mammography
ď§ Pelvic examination & PAP smears / annual
testicular examination.
ď§ Pancreatic USG every 1-2 years
S
U
R
V
E
I
L
A
N
C
E
I
N
P
J
S
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. ⢠Mucocutaneous lesions â 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
ď GI hamartomas - only 35% to 40% of patients
ď most common esophageal manifestation is
glycogenic acanthosis
ď Most polyps resemble juvenile polyps and
consist of cystically dilated, mucin-filled
crypts set within an abundant lamina propria
ď Colonic lipomas, fibrolipomas, fibromas,
ganglioneuromas, and adenomas also
reported in Cowden syndrome.
59.
60. Cronkite â Canada Syndrome
ď§ Nonhereditary GI polyposis associated with
alopecia, nail atrophy, hyperpigmentation of
the skin.80% - 50 years old or more
ď§ C/F â diarrhea, wt loss, anorexia, nausea,
vomiting, weakness.
ď§ Polyps all over GIT except esophagus.
ď§ Histologically resemble JP, cystically dilated
tortuous crypts filled with inspissated mucin
embedded in an edematous & inflammed
lamina propria.
61. Polypoidal structure with cystically dilated glands
Dilated gland
from the flat
non-polypoidal
mucosa
62. Treatment
ďThe mortality rate is high (50% to 60%).
ďDeath usually results from malnutrition, GI
bleeding, or infection.
ďaggressive nutritional support, antibiotics,
corticosteroids, and/or surgical resection of
symptomatic segments of the GI tract.
64. ďEpithelial polyps
⢠Hyperplastic/serrated
⢠Conventional adenoma
⢠Adenomatous polyposis syndrome
⢠Adenomas and adenoma-like
dysplasia-associated lesions or
masses in inflammatory bowel
disease
65. ďHyperplastic / 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
ďConventional adenoma pathway accounts for
approximately 70 to 80% of CRC
ďSerrated pathway â 20 to 30% of all CRC.
67.
68. ďThe âserrated neoplastic pathwayâ describes
the progression of serrated polyps, (most
commonly SSAs and TSAs) to colorectal
cancer.
ďTheir 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
69.
70.
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 tumors are MLH1-negative
and mismatch repair-deficient.
74. KRAS proto-oncogene
⢠RAS family genes
⢠Point mutations of RAS family genes
constitute the most common type of
abnormality of proto oncogenes in
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 factors leads to exchange of GDP for
GTP and subsequent conformational
changes that generate active RAS
76. ď 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.
ď Normally : Activation of RAS is transient
because RAS has an intrinsic GTPase activity
that binds to active RAS and terminates
signal transduction.
77.
78.
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 glutamatic acid (E)
81. A single, activating, point mutation in BRAF (V600E)
Constitutive signaling of 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 tumors with 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
⢠Microvesicular hyperplastic polyp
⢠Goblet cell hyperplastic polyp
⢠Mucin poor hyperplastic polyp
2) Abnormal architecture,abnormal proliferation
⢠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
Microvesicular hyperplastic polyp
Grossly measure < 0.5 cm
Histology â
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 â limited
to the lower half of the
crypts
86. Serrations
only at
surface
Abundant mucin
Goblet cells +++
No dysplasia
Goblet cell hyperplastic polyp
Grossly measure < 0.5 cm,
sessile lesion, mc â in left
colon
Histology â
1) Elongated crypts rich
in goblet cells.
2) Serrations are of far
lesser degree and
limited to uppermost
portions of crypts.
87. Mucin poor hyperplastic polyp
Serrations
prominent at
surface and crypts
Absent mucin
Goblet cells nil
No dysplasia
Least common type and
usually sessile.
Histology â
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
exagerrated at deep
parts of crypts
Crypt disarray
Inverted T/L
Lateral growth
No dysplasia
Serrated sessile polyp (SSA)
Histology â
1) Characterised by
architectural changes
such as
a) Crypt branching and
dilatation,
b) Peculiar growth pattern
â 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 â 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
92. Traditional Serrated adenoma
Prominent
Serrations
Dysplas
ia
Nuclear stratification
Hypereosinophilic
cytoplasm
Filiform growth 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
Mucin depletion1) 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
ď Distinction of HP from SSA/P and TSA is
based mainly on architectural criteria
ď Not all serrated lesions are easily
classified, often because of sampling
issues or poor orientation of the
specimen.
ď "serrated polyp, unclassified with/without
dysplasiaâ may be used
95. Serrated polyposis syndrome
ď Rarely described entity with rapidly evolving
diagnostic and molecular criteria due to
increased risk of CRC.
ď Diagnostic criteria of SPS were first defined
by Burt and Jass in 2000 for the WHO. These
criteria have been recently redefined this
entity.
96. Diagnostic criteria
(1) at least 5 histologically confirmed serrated polyps located
proximal to the sigmoid colon, of which atleast two 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. ď Approximately, 1/3rd of SPS cases are
associated with CRC
ď SPS with BRAF mutations â cancer risk high
ď SPS with KRAS mutation â little or no cancer risk
99. The clinical importance of serrated lesions of the colorectum Rev. gastroenterol.
PerĂş v.33 n.2 Lima abr./jun. 2013
99
100. Conventional adenoma
ď Morphologically defined as dysplastic
clonal proliferation of epithelium.
ď Grossly, classified as sessile or
pedunculated.
ď 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 â
3%
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,Atypical mitoses,
significant loss of
polarity, and
pleomorphism minimal
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 â back to
back gland
configuration and
cribriforming
105. Intramucosal adenocrcinoma
ďInvasion of mucosa or muscularis mucosae
ďDifferentiation of high grade dysplasia is
based on presence of definite invasion of the
lamina propria.
ďRecommended 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 â
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 âĽ1 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 yr after resection, then
repeat in 3 yr
Guidelines for adenoma surveilance
108. 2. Moderate risk (first-degree relative with
colon cancer at <60 yr or âĽ2 first-degree
relatives with colon cancer)
ďColonoscopy at age 40 yr, or 10 yr before
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
112. Flat adenomas
ď defined as dysplastic, non-invasive lesions
without a polypoidal component.
ďTypically have a central depression.
ďConstellation of molecular abnormalities
different from conventional adenomas
Gastrointest Endosc 2002 Nov;56(5):663-71.
Molecular analysis of diminutive, flat, depressed colorectal lesions: are they
precursors of polypoid adenoma or early stage carcinoma?
Morita T, Tomita N, Ohue M
113.
114. FAMILIAL ADENOMATOUS POLYPOSIS
ď1% of all large intestinal tumour diagnosIs
ďAutosomal dominant condition caused
by inheritance of a mutated APC gene
(Chr 5q)
ďCharacterized by 100-1000s
adenomatous polyps in large bowel
115. ďFAP symptoms occur earlier and
generally start to appear in the 2nd and
3rd decade of life with most patients
developing adenomas by age 35.
116.
117. Signs and Symptoms
ďBright red blood in the stool
ďDiarrhea and/or constipation
ďAbdominal pain, cramping, or bloating
ďContinued weight loss
ďAnemia
118. Genetics - APC gene
ďTumor suppressor gene
ďLocation: 5q21
ďDual function
1) Inhibition of signal transduction
2) Gatekeeper Gene â regulates levels
of Ă-catenin ( a member of cadherin
based cell adhesive complex)
119. ďRegulates the WNT/Ă-catenin signaling
pathway
ďLoss of APC function: Ă-catenin
accumulates and activates the
transcription of MYC and cyclin D1 -
proliferation of cells
ďHalf of tumors without APC mutations
have Ă-catenin mutations
120.
121.
122. Pathological features
ďMACRO
ďFlexible endoscopy is the gold standard -
screening
ďMild â 100-1000
ďSevere - >1000
ďClassic - small raised lesion with a rounded
contour
ďAFAP - flat in appearance, showing only
minimal mucosal elevation (<1cm)
127. Screening of FAP
ďGenetic screening of family members for APC
mutations
ďAnnual flexible sigmoidoscopy beginning at age
10-12 until age 40,then every 3-5 years.
ďIf polyposis is present, colectomy should be
considered
ďUGIE every 1-3 years is also recommended to
evaluate for upper GI adenomas
128. Attenuated FAP
ď 8% of patients
ďFewer polyps ,<100 (median 25)
ďAverage age of onset of 41 years
ďLifetime risk of malignancy â 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 mutY homolog (MUTYH) gene(Chr 1)
⢠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
ďaccounts for 6-15% of CRC and caused by
inactivation of DNA mismatch repair (MMR)
genes
ďIf a mismatch or small loop is found,
endonuclease cuts the strand bearing the
mutation and exonuclease (MLH1 and
PMS2) then digests this strand.
ďMMR corrects errors that spontaneously occur
during DNA replication, such as single base
mismatches or short insertions and deletions.
132. ďMSI refers to altered lengths (âinstabilityâ) of
short nucleotide repeat sequences
(âmicrosatellitesâ) in tumor DNA compared
with normal DNA
ďMutations of coding mononucleotide repeats
in
ďtumor suppressor genes
Tansforming growth factor (TGF)- receptor
type 2 (TGFBR2)
ďBAX (proapoptotic gene) have been shown
to be important in carcinogenesis
133. ď microsatellites are short, sequences of 1
to 6 nucleotide base pairs which are
repeated dozens to hundred times
throughout the genome.
ď are a ubiquitous component of the
genome of higher organisms.
ď 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. ď 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.
ď frameshift mutations â affecting
critical areas of cell growth regulation
genes â promotion of tumorigenesis
135. ⢠Mutation of both alleles of mismatch
repair (MMR) system
â DNA strand might be displaced, and
realigns creating small loop of unpaired
DNA â unable to remove the loops â
microsatellite increases or decrease in
size due to either insertion or deletion of
repeating units when compared to the
normal cellâs
136. Hereditary nonpolyposis colon cancer
syndrome (HNPCC/Lynch syndrome)
ďAD disorder characterised by familial CRCs
ďIndividuals inherit one abnormal copy of DNA
mismatch repair gene. When loss of function
mutation occurs in the 2nd allele their
âproofreadingâ function is lost.
ďErrors accumulate and these may activate
proto-oncogenes or inactivate tumor
suppressor genes.
137. ďOne of the hallmarks of patients with mismatch
repair defects is microsatellite instablitity
ďOf various mismatch repair genes two most
commonly involved are:
⌠MLH1
⌠MSH2
ďEach of these account for 30% cases of
HNPCC.
ďOther 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,diagnosis is based on family history of
CRC only
1. One member less than 50 years of age
2. Two involved generations
3. Three family members affected, one of
whom is a first degree relative of the other
two
141. MSI testing
ďMOLECULAR TESTING
⌠Evaluation of certain loci within human
genome that are known to harbour
microsatellites
⌠DNA extracted from both normal tissue &
tumor tissue
⌠After PCR amplification of selected
microsatellites , size of PCR products obtained
from normal & tumor tissue are compared.
ďMSI 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
analyzing five 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
instability of its microsatellite DNA & so may
have chromosomal instability instead)
143.
144.
145. ďMSI-H is present as a distinct phenotype in
approximately 15% of CRCs
ďTumors with microsatellite instability can
also be recognized by the absence of
immunohistochemical staining 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
ďColonoscopy every 2 years starting at ages 20-25
or 5 years younger than the earliest diagnosis of
CRCwhichever is earlier until 40yr , and then
annually
ďFlexible sigmoidoscopy is not acceptable, due to
the proximal location of tumours
ďTransvaginal US and endometrial aspiration
annually starting at ages 25-35 years are also
recommended
148. Treatment
ďTotal colectomy with ileorectal anastomosis
ďRestorative proctocolectomy with ileal pouch-
anal anastomosis
ďSegmental colectomy not recommended
because of high rate of metachronous CRC
ďTAHBSO for endometrial cancer
149. Adenoma and adenoma like dysplasia
Dysplasia in IBD
FLAT RAISED
No endoscopic lesion Visible endoscopic lesion
150.
151. Malignant epithelial polyps
ď Defined as adenoma that contains invasive
adenocarcinoma ( cancer extends beyond
muscularis mucosa into the submucosal polyp
stalk)