Colorectal Cancer Flashcards by Iseoluwa Ojo

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

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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

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Increasing Incidence of CRC
• It’s projected that global incidence will increase by ___% in 2035 with significant rise in the _______ and ______ countries

young and underdeveloped

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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

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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

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Age and Gender Prevalence

• M:F ratio = ——- to _____

• Patients <40years =______ %

1.3 to 1.

32.2

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Aetiology/Predisposing factors
• CRC is a/an _____genous and _____-factorial disease

hetero

multi

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Aetiology/Predisposing factors of CRC

• Multiple factors predispose to the disease:
•________ and ______
• host __________ disorders
•__________

Environmental & dietary

inflammatory GI

Genetic

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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

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Protective factors against CRC

• Use of ______ (_____ ————)
• Vegetables
•______ activity
• _____________________ therapy
•_______ intake

NSAIDs; COX 2 inhibitors

Physical

Hormone replacement

calcium

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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

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Risk factors- Genetic (Major Familial
syndromes)

2 conditions
Mention them

Hereditary non-polyposis coli (HNPCC) syndrome

Familial adenomatous polyposis (FAP) syndrome

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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

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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)

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Classification of CRC Pathology
• CRC is a single disease

T/F

• CRC is not a single disease but a collection of multiple diseases

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Classification of CRC Pathology

• It is highly ______genous and dynamic with multiple ______ and ______ alterations underlying its
pathogenesis.

hetero

genetic and epigenetic

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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

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Classification of CRC : Hereditary or acquired

Hereditary-____-___%
•____ syndrome
•____________ syndrome
• others

Sporadic -____-____%
• Complication of ________________

20-30 ; Lynch; Familial Polyposis

70-80; Inflammatory bowel syndrome

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Classification of CRC: Anatomic

based on location of the tumour
___________ and _________ colon cancer

Right sided

Left sided

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Classification of CRC: Molecular

based on the _________________

underlying genetic abnormality

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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

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Tumour Cancer Genome Atlas, TCGA,

____________(___%)

Hyper mutated; 13

Ultramutated; 3

Chromosomal instability;84

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Consensus Molecular Subtype

___________(_____%)

MSI: immune; 14

Canonical; 37

Metabolic ;13

Mesenchymal ;23

Mixed features;13

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Tumour Cancer Genome Atlas, TCGA : Consensus Molecular Subtype

__________ = _________

__________ = ___________

Hypermutated; CMS1 : MSI immune

Chromosomal instability; canonical, metabolic, and mesenchymal

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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

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

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

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