Colorectal Cancer Flashcards
Colorectal cancer is a/an ______genous disease classified into different subtypes that have specific morphological and molecular characteristics
Studies have shown _____asing incidence with _______ prognosis
hetero
incre; dismal
Colorectal cancer is the _____ most common cancer accounting for ____% of all cancers and _____ most common
cause of (9.4%) of all cancer deaths. Globocan, 2020
4th; 10
2nd
Increasing Incidence of CRC
• It’s projected that global incidence will increase by ___% in 2035 with significant rise in the _______ and ______ countries
80
young and underdeveloped
Increasing Incidence of CRC
• Review of CRC in Nigeria have also indicated ______asing incidence in with greater proportion in (younger or older?) patients
incre
Younger
Age and Gender Prevalence
• The mean ages in most studies in
Nigeria ranged from _____ to ______ years
(average of _____years).
39 to 50.7
46.2
Age and Gender Prevalence
• M:F ratio = ——- to _____
• Patients <40years =______ %
1.3 to 1.
32.2
Aetiology/Predisposing factors
• CRC is a/an _____genous and _____-factorial disease
hetero
multi
Aetiology/Predisposing factors of CRC
• Multiple factors predispose to the disease:
•________ and ______
• host __________ disorders
•__________
Environmental & dietary
inflammatory GI
Genetic
Predisposing factors to CRC
Environmental and Dietary factors
• High content of ______ and ______
• Low content of _______________ in
diet
• Low overall __________ and ______ intake
• Low intake _____ micronutrients
• _______ and ______ consumption
• Obesity
•_______ habits
red meat and animal fat
un-absorbable fiber
fruits and vegetable
protective
Alcohol and tobacco
Sedentary
Protective factors against CRC
• Use of ______ (_____ ————)
• Vegetables
•______ activity
• _____________________ therapy
•_______ intake
NSAIDs; COX 2 inhibitors
Physical
Hormone replacement
calcium
Host inflammatory disorders that predispose to CRC
Inflammatory bowel diseases such as
•________________
•_______ disease
• The risk increases with ______ of the IBD and the ________ of ____________
Ulcerative colitis
Crohn’s; duration
extent of colonic involvement
Risk factors- Genetic (Major Familial
syndromes)
2 conditions
Mention them
Hereditary non-polyposis coli (HNPCC) syndrome
Familial adenomatous polyposis (FAP) syndrome
Risk factors- Genetic
Hereditary non-polyposis coli (HNPCC) syndrome
Abnormal Genes:
Lifetime cancer risks:
Features:
DNA mismatch repair gene MLH1, MLSH2, MSH6, PMS2
50-80%
No polyps, microsatellite instability
Risk factors- Genetic
Familial adenomatous polyposis (FAP) syndrome
Abnormal Genes:
Lifetime cancer risks:
Features:
APC gene mutation in on chromosome 5q21.
100% by age , 40yrs
multiple adenomatous polyps throughout the GIT (50-500 polyps)
Classification of CRC Pathology
• CRC is a single disease
T/F
F
• CRC is not a single disease but a collection of multiple diseases
Classification of CRC Pathology
• It is highly ______genous and dynamic with multiple ______ and ______ alterations underlying its
pathogenesis.
hetero
genetic and epigenetic
Classification of CRC Pathology
• The different subtypes have distinct clinical, morphological, and molecular characteristics which explains the differences in disease outcomes and
response to therapy
T/F
T
Classification of CRC : Hereditary or acquired
Hereditary-____-___%
•____ syndrome
•____________ syndrome
• others
Sporadic -____-____%
• Complication of ________________
20-30 ; Lynch; Familial Polyposis
70-80; Inflammatory bowel syndrome
Classification of CRC: Anatomic
based on location of the tumour
___________ and _________ colon cancer
Right sided
Left sided
Classification of CRC: Molecular
based on the _________________
underlying genetic abnormality
Molecular classification
• In CRC, the transformation of colonic mucosa into invasive cancer occurs through __________ or __________ changes
within the genome and epigenome
• -so-called _______ and ________ hypothesis
an accumulated somatic or inherited
multi-hit and multi-step
Tumour Cancer Genome Atlas, TCGA,
____________(___%)
____________(___%)
____________(___%)
Hyper mutated; 13
Ultramutated; 3
Chromosomal instability;84
Consensus Molecular Subtype
___________(_____%)
___________(_____%)
___________(_____%)
___________(_____%)
___________(_____%)
MSI: immune; 14
Canonical; 37
Metabolic ;13
Mesenchymal ;23
Mixed features;13
Tumour Cancer Genome Atlas, TCGA : Consensus Molecular Subtype
__________ = _________
__________ = ___________
Hypermutated; CMS1 : MSI immune
Chromosomal instability; canonical, metabolic, and mesenchymal
Anatomical location of:
MSI immune
Canonical
Metabolic
Mesenchymal
Right sided colon
Left sided colon and rectum
No predominance
Typically diagnosed at more advanced stages
Prognosis and survival of:
MSI immune
Canonical
Metabolic
Mesenchymal
Good prognosis but poor survival after relapse
Good survival after relapse
Intermediate survival
Worst overall and relapse-free survival
Treatment plan for :
MSI immune
Canonical
Metabolic
Mesenchymal
Likely benefit from immune checkpoint blockade
Anti-EGFR therapies likely effective , may respond to oxali-platin based regimens
Likely resistant to anti-EGFR therapies
Maybe responsive to antiangiogenic therapies and perhaps more sensitive to irinotecan-based regimens
Colorectal carcinogenesis
• The mechanisms that underlie
development of CRC have been
described as a “multi-hit, multi-stage”
phenomenon in which
•__________ mutations (alterations or changes) occur in ______ genes, after exposure to ___________ of
environmental and dietary risk factors.
several
multiple
multiple hits
Colorectal carcinogenesis
These mutations occur at (same or different?) stages and result in increasing _______________ from normal _____proliferative epithelium,
to _________,__________ and then finally _________
As the tumour grows, it is prone to _________ that confer on it, _________________ potential
Different
phenotypic abnormality; hyper
small adenoma, large adenoma
invasive cancer; more mutations
metastatic potential
3 Major Pathogenetic Pathways in CRC
Pathology
___________
_______________
______________
Chromosomal instability
Hypermutated (microsatellite instability)
Serrated pathways
Chromosomal instability
Hypermutated (microsatellite instability)
Serrated pathways
Sporadic:
Hereditary:
80%; FAP 1%
15%; Lynch syndrome 3-4%
10-20%
Chromosomal instability
_______ activation
__________ inactivation
(Early or Late?) abnormalities of _____ pathway
Oncogen
Tumor surpressor gene
Early abnormalities of WNT
Hypermutated (microsatellite instability)
Defective ___________________
DNA mismatch repair
Serrated pathways
Overlapping with ________________
Mutation in _______ or _______ leading to ________ of ______ pathway
CIN and MSI
KRAS or BRAF
hyper activation of
MAPkinase
Chromosomal instability
_____________________ sequence
•________ ————
Adenoma→Carcinoma
Classical adenocarcinoma
Hypermutated (microsatellite instability)
_______ differentiated tumour
•_____________ lymphocytes
Poorly
Tumour infiltrating
Serrated pathways
Premalignant lesions-
• Traditional _________ (TSA) and
•_____________ adenomas/______
serrated adenomas
Sessile serrated
polyps
The adenoma-carcinoma mode of
mechanism of pathogenesis
• This implies that ———————————————————————-
some carcinoma of the colon arise
from adenoma
The adenoma-carcinoma mode of
mechanism of pathogenesis
There is cumulative alteration in the genome which results in→ increasing _____,______ of _______ & ______ potential
of the tumour→carcinoma
size, level of dysplasia
invasive
Microsatellite instability pathway
• characterized by genetic abnormalities in the _________________ genes
• It is responsible for ____-____% of sporadic colorectal cancers
DNA mismatch repair
10-15
_____________ is the main pathway in Hereditary non-polyposis coli cancer syndrome (HNPCC syndrome).
Microsatellite instability pathway
Microsatellite instability pathway
Cancer occurs in ______ colon, tends to be _________ and in (younger or older?) age.
• There is Increase incidence of ______ and ________ cancer
proximal; mucinous
Younger
endometrial and ovarian
In Microsatellite instability pathway
Presence of preceding polyps.
T/F
F
No preceding polyps.
Microsatellite instability pathway
abnormality may be inherited or sporadic
T/F
T
microsatellites
Are ______ (small or large?) ( DNA or RNA?) sequences scattered in the genome and are (fixed or variable?) in
number for an individual
They are _____________ during DNA
replication
repetitive; small; DNA
Fixed
prone to errors
microsatellites
are located in the _____ or _______ region of genes involved in ______ of _______
coding or promoter
regulation of
cell growth
microsatellites
The mutations occur within hMLH1,
hMSH2, hMSH6, hPMS1 or hPMS2. hMLH1 & hMSH2 are the most common
T/F
T
Diagnosis of CRC
_________ is taken to obtain ___________ for _______ diagnosis
Biopsy; tumour tissue; histological
_________ and ________ are the commonest site of CRC in Nigeria
Rectum and sigmoid colon
Morphology -MACROSCOPY
Site:
_________ and _________ colon
_______ and _________ colon
_________ colon
caecum and ascending
Rectum and sigmoid
Descending
Macroscopy: Right sided, Caecal
tumour- ___________
Macroscopy: Left sided colon cancer __________________
fungating
annular constricting
Morphology: Right sided, Caecal
tumour-fungating
In (proximal or distal?) colon (right sided tumour), they grow as:
• ______________ mass along ______ of the _______ and ______ colon
• Obstruction is ( common or rare?)
• (Acute or Chronic?) blood loss
Proximal
Polypoid fungating
one wall; caecum & ascending
Rare; chronic
Left sided colon cancer: annular constricting
In (proximal or distal?) colon (lt. sided tumour) are:
•________,_________ lesion that produces a _______-_____ constriction of the bowel
• Obstruction and bleeding per ______ are (common or rare?)
Distal
annular, encircling
napkin-ring
rectum; common
Microscopy: WHO Histologic classification of CRC
___________
___________(_____) adenocarcinoma
_____________ carcinoma
Adenocarcinoma
Mucinous (colloid)
Signet-ring cell
Microscopy: WHO Histologic
classification of CRC
Adenocarcinoma –most _________ , (poorly or well?) formed glands
Mucinous adenocarcinoma (> ____ % ________)
Signet-ring cell carcinoma (> ____ % __________)
common; well
50; mucinous
50; signet-ring cells
Microscopy of CRC
_________ carcinoma
__________ carcinoma
________ carcinoma
________ carcinoma
___________ carcinoma
Others
Squamous cell
Adenosquamous
Medullary; Small cell
Undifferentiated
Small cell carcinoma
Aka
_____ grade ___________ carcinoma
high
neuroendocrine
Microscopy of CRC
__________ is the most common, with significant proportion of (poor or good?) prognostic types
Adenocarcinoma
Poor
Colonic adenocarcinoma
(poorly or well?) differentiated
_____ gland formation
T__
Poorly
no
3
Histologic grading of CRC
Grade 1- _____ differentiated
Grade 2 - _______ differentiated
Grade 3 - ________ differentiated
Well
Moderately
Poorly
Size of primary tumor
Tis- carcinoma insitu
T1-tumour invades _________
T2-tumour extends to ___________
but ____________
T3-tumor is ________________ into ________
T4-(directly or indirectly?) _______________________
submucosa
muscularis propria
not penetrating through
penetrating through muscularis propria
into subserosa
Directly invades surrounding
structures/organs
TNM- Nodal metastasis (N)
Nx— regional nodes _______________
N0—_____ regional node metastasis
N1-metastasis in _____ nodes
N2-metastasis in ________ nodes
cannot be assessed
no
1-3
4 or more
Staging- distant metastasis (M)
• Mx- metastasis __________
• M0- _____distant metastasis
• M1-distant metastasis_______
cannot be assessed
No
present
Screening for CRC
• ___________________ test (FOBT)
• _______________________ test (FIT)
• ______________________________ (DCBE),
•_______________
Faecal occult blood
Faecal Immunochemical
Double contrast barium enema
Colonoscopy
Clinically majority show no
symptoms for several years. Later,
Left sided tumour–(distal)
•______/______ bleeding
•Change in _______
• _______ left lower abdominal discomfort
•______,______,______
Occult/frank
bowel habit
Crampy
Malena, diarrhoea,
constipation
Right side tumour-Proximal
fatigue,weakness,
____________ anemia,
__________ if bulky
iron deficiency
bleeding
Colon Polyps
Are _________ of tissue into lumen
May be __________
Raised outgrowth
pre-cancerous
Removal of colon polyps can prevent colon cancer
T/F
T
Hyperplastic Polyp
• (Benign or malignant?)
• Common in ________ colon
• (Normal or Abnormal?) cellular structure, ____ dysplasia
Benign
rectosigmoid; normal
no
Most common type of polyp is ???
Hyperplastic Polyp
Hyperplastic Polyp
Classically have a “________” or _______ pattern
Usually ________ screening is required after biopsy
saw tooth; serrated
no special
Adenomatous Polyp
Dysplastic with ________ potential
malignant
Adenomatous polyp
By shape:
______ and ______
Sessile
Pedunculated
Adenomatous polyp
By histology:
______ and ______
Tubular
Villous
Sessile vs. Pedunculated
Sessile: (broad or narrow?) base attached to _____
Pedunculated: attached via _______
Broad ; colon
stalk
Tubular vs. Villous
Tubular
• (Most or least?) common subtype (___%+)
•________ epithelium forming ______
Most; 80
Adenomatous; tubules
Tubular vs. Villous
Villous
• (more or less?) common type
• Often (sessile or pedunculated?)
• (Short or Long?) projections extending from surface
• (Low or High?) risk of development into colon cancer
Less; sessile
Long; High
Polyp Symptoms
Almost always (asymptomatic or symptomatic?)
Screening ________ done for detection
asymptomatic
colonoscopy
Polyp Symptoms
Large polyps may cause bleeding
• Usually (visible or not visible?) in stool (“______”)
• Basis for screening with _______________ testing
Not visible ; occult
fecal occult blood
High Risk Polyps
Likely to develop into _____
• _______ histology
•Dysplasia grade
• Determined by pathologist
• “______ grade dysplasia” = ↑ risk
cancer; Villous
High
Patient likely to develop more polyps
• Metachronous adenoma: new lesion ~ _________ after prior
• >___ cm in diameter = ↑ risk
•_______ of polyps = ↑ risk
six months
1
Number
Juvenile Polyps
(Benign or Malignant?) tumors ( _________ ) that occur in (children or adults?)
• Usually in _______
• Usually (sessile or pedunculated?)
•Cause (painful or painless?) rectal bleeding
• Often “____________”
Benign; hamartomas
children; rectum
pedunculated; painless
auto-amputate
Juvenile polyposis syndrome
•(Single or Multiple?) (usually >___) polyps
• ____eased risk of cancer
• Surveillance ______
Multiple
10
Incr
colonoscopy
Cyclooxygenase-2 expression is ____eased in colon cancer
Incr
Chromosomal Instability Pathway
“Adenoma-Carcinoma sequence”
•Sequence of genetic events seen in colon cancer. Leads to colon cancer over many years
• Progression probably takes ____-____ years
• “_______” mutations occurs with aging
•More common in _____ sided tumors
•Descending colon, sigmoid, rectum
10-40
Somatic
left
APC (____________________) protein/gene
Is a __________ gene
It Prevents ________ of ________ that activates __________
Adenomatous polyposis coli
Tumor suppressor
accumulation of β-catenin
oncogenes
Chromosomal Instability Pathway
Step 1: APC mutation
• Loss of APC → ↑_______ → _______ activation
• Leads to increased risk for ______
β-catenin; oncogene
polyps
Chromosomal Instability Pathway
Step 2: K-RAS mutation
• Aberrant _________ Leads to ___________ formation
cell signaling
adenoma polyp
K-RAS mutation is a ____________
Proto-oncogene
Chromosomal Instability Pathway
Step 3: p53
• Loss of p53 _________ gene leading go Tumor ________
•
tumor suppressor
cell growth
Chromosomal Instability Pathway
Step 1:__________ causes a ______
Step 2:____________ leads to ______
Step 3: ________ ends in _____
APC mutation; high risk colon
KRAS mutation; polyps formation
Loss of P53; colon cancer
FAP
Familial Adenomatous Polyposis
(Autosomal or X-linked?) (dominant or recessive ?) disorder
_______ mutation of ____ gene (chromosome ____)
(Always or sometimes?) (_____%) progresses to colon cancer
Autosomal dominant
Germline; APC; 5q
Always ; 100
FAP
Familial Adenomatous Polyposis
Treatment: _________(____)
Colon removal (colectomy)
Microsatellite Instability pathway can arise without polyps
T/F
T
Microsatellite Instability can arise “de novo” without polyp
microsatellite?
•usually (coding or non-coding?)
• (Same or Different?) density as/from other DNA
• (Same as or Separate from?) other genetic material in testing (“satellites”)
Non coding
Different
Seperate from
a stable microsatellite
•Successive cellular divisions:
_____________ microsatellites
•Each person has unique, ___________ of microsatellites
• Different person-to-person; same for each individual
same length
“stable” length
_________ enzymes resolve base errors
Mismatch repair
Examples of Mismatch repair enzymes
E.g: _____,_______,_______,_______ etc
MLH1, MSH2, MSH6, PMS2
Microsatellite Instability
__________ can lead to accumulation of errors . This can occur in ________ in cancer cells
Result is ______________
Gene mutations
microsatellites
microsatellite instability
Microsatellite Instability
•_____ testing
• Different _____ of microsatellites in tumor cells vs other cells
• Indicates ______________ dysfunction
PCR
length
mismatch repair enzyme
Colon Cancer Screening
CEA (______________)
Tumor marker
(Elevated or depressed?) in colon CA and other tumors (pancreas)
(Poor or excellent?) sensitivity/specificity for screening
Carcinoembryonic Antigen
Elevated
Poor
Colon Cancer Screening
CEA
Patients with established disease
• CEA level correlates with ________
• Elevated levels should return to baseline after ________
• Can be monitored to ________
disease burden
surgery
detect relapse
HNPCC
_____________ Cancer/ _____ Syndrome
Inherited mutation of ___________
Leads to colon cancer via __________
• About ____% lifetime risk
Hereditary Non-Polyposis Colorectal ; Lynch
DNA mismatch repair enzymes
microsatellite instability ; 80
Colon Cancer Screening
HNPCC
• Arise with pre-existing adenoma
T/F
F
Arise with out pre-existing adenoma
HNPCC
Usually ______-sided tumors
Also increased risk of:
•_________ cancer , Other cancers (ovary, stomach, others)
right
Endometrial
HNPCC
Classic case
• Patient with ______ sided colon CA
• (Single or Multiple?) ___________ members also with cancer
right
Multiple
1st family
__________ cancer is most common non-colon malignancy
Endometrial
