pathology of bowel cancer Flashcards
variation
colon and rectum have similar diseases but different treatment
small bowel has similar spectrum of disease but adenocarcinoma is less common
low grade neuroendocrine tumours are more common in the appendix
lymphoma is the bowel
almost always non-hodgkin
B and T cell lymphomas
adenocarcinoma
malignant epithelial tumour forming glands
types of bowel cancer
carcinoma lymphoma neuroendocrine disorders GIST sarcomas metastases from other organs
risk factors for bowel cancer
obesity
diet high in processed meat, red meat and alcohol
sedentary lifestyle
inflammatory bowel disease
risk of smoking is unclear
some benefit with longterm NSAIDS eg. low dose aspirin
four classes of regulatory genes
- growth promoting proto-oncogenes - gain of function
- growth inhibiting tumour suppressor genes - loss of function
- genes that regulate cell death - pro apoptotic
- genes involved in DNA repair
mucosa at risk
macroscopically norma
histologically mild, hard to identify abnormalities
adenoma
macroscopically small polyp
histologically low grade dysplasia
acquisition of additional mutations
benign
advanced adenoma
high grade dysplasia
larger irregular polyps
acquisition of additional mutation and overexpression of various growth factors
carcinoma
acquires ability to invade bowel wall and lymph vascular spaces
becomes less well differentiated
serrated adenomas
macroscopically small polyp
histologically serrated architecture
parallel pathway toward bowel cancer
progress directly to carcinoma
mechanisms of genetic instability in colon cancers
- chromosomal instability
- micro satellite instability
- defective DNA polymerase proofreading
chromosomal instability
results In high levels of somatic copy number alterations and DNA gains/amplifications or losses/deletions
micro satellite instability
due to defective DNA mismatch repair
leads to high mutation rate
most of these tumours show CpG island hypermethylation
defective DNA polymerase proofreading
very high mutation rate affecting large numbers of genes
most of these are silent passenger mutations, with some mutations occurring in driver genes
dysplasia
cellular atipica in absence of invasion
can occur in squamous or glandular epithelium
reflects underlying cellular and molecular changes
increase the risk of subsequent development of cancer
adenoma in the tubular GIT
have pre malignant potential
show dysplasia and/or molecular changes in key cancer genes
serrated polyps
colorectal neoplasms that have serrated/saw tooth glands
historically thought to be benign, we know know that a proportion of these lesions progress to cancer via the MSI/serrated pathway
types of serrated polyps
hyperplastic polyp
sessile serrated lesion
traditional serrated adenoma
hyperplastic polyp
small, sessile (done like_ or flat lesion, serrated glands in superficial portion of crypt, often rich in goblet cells
more common in the left colon
sessile serrated lesion
ill-defined, dome-like, small, often have a mucus cap imparting a cloud like appearance on endoscopy, serrations involve full depth of crypt, usually don’t have conventional dysplastic nuclei, but sometimes can
traditional serrated adenoma
larger
exophytic polyp
serrated epithelium with conventional cytological featured of dysplasia
adenomatous polyps
colorectal neoplasms that have dysplastic glands
macroscopically, polypoid, flat or depressed
larger = higher risk
small ones can be removed endoscopically
are benign
types of adenomatous polyps
tubular
tubulovillous
villous
advanced
villous
forms fingers
slightly higher risk of malignancy, usually larger
advanced type adenomatous polyps
are usually large, can’t be removed endoscopically, always show areas of high grade dysplasia, often have higher mutation burden and foci of early invasive carcinoma
adenomatous polyps mutations
usually mutates through WNT pathway
may also acquire mutations in Pi3k pathway, TP53, KRAS, SMAD4 and SMAD2
WNT pathway
mutations in the APC genes - increases ability to grow
KRAS
important to progression to carcinoma
KRAS mutations are present in larger invasive adenomas
is a porto-oncogene and up regulates growth factors
P53 alterations
also significant in the development into cancer
APC gene
tumour suppressor gene
helps to down regulate B-catenin and E-cadherin (WNT signalling pathway)
B-catenin
is a porto-oncogene and up-regulates multiple growth pathways
KRAS gene function
is a proto-oncogene and up regulates growth factors
P53 gene function
is a major TSG, regulates cell cycle and initiates senescence
telomerase
prevents telomere shortening and loss of multiple DNA signals
initial mutations in serrated/microsatellite instability pathway
mutation in mismatch repair proteins - MLH1 or MSH2 etc.
this leads to micro satellite instability, which accelerated accumulation of mutations in numerous genes
familial adenomatous polyposis
autosomal dominant
100% risk of colon by age 40
mutation in APC gene at 5q21
carpet of >100 adenomas increases the probability of second, third hits
prophylactic total colectomy at age 25, screening of relatives
HNPCC - Lynch syndrome
autosomal dominant
fewer adenomatous polyps, more than people who develop sporadic cancers
mutations in mismatch repair genes
results in inherited microsatellite instability
Lynch syndrome increases risk of developing
bowel, endometrial, bladder, gastric, and skin cancers
microsatelite instability
DNA can’t be repaired as well which icreases likelihood of further mutations
2 strategies for genetic testing for Lynch syndrome is Called
Amsterdam criteria or Bethesda criteria
people with Lynch syndrome require
full colonoscopy every 1-2 years from age 25, plus endometrial screening for women age 25-35, bladder surveillance, gastroscopy
role of chronic inflammation in colorectal cancer
- driver of dysplasia
inflammatory bowel disease increases risk of bowel cancer due to repeated cycles of inflammation, ulceration and epithelial damage leasing to increased turnover of epithelium and higher chance of mutations occurring
chronic inflammation as a response to cancer
CRC triggers a host immune response
more inflammation within a tumour means the body has recognised cancer as non-self and is attacking the tumour cells
implication for prognosis and potential for immunotherapy
early symptoms of colon cancer
bowel obstruction with seminal symptoms
Melaena
fecal occult blood
advanced colon cancer symptoms
local effects - bowel obstruction - perforation - severe haemorrhage systemic effects - spread to other organs - cachexia - paraneoplastic symptoms
perforation sequelae of colon cancer
tumour bursts a hole in the colon
causes tumour seeding throughout the peritoneum
peritonitis - fecal material throughout the peritoneum
sever haemorrhage and anaemia as a sequelae of colon cancer
due to erosion of the large vessels
cachexia
loss of body mass
nausea, viminting, loss of appetite, loss of weight
metabolic and systemic proinflammatory changes resulting in muscle and adipose tissue atrophy, loss of appetite, insulin resistance etc.
paraneoplastic symptoms
hormone secretion
uncommon in colon cancer except in rare variants
eg. nueroendocrone tumours
- history and examination at diagnosis of colon cancer
- personal and family history
- clinical symptoms
- clinical signs
clinical symptoms for suspicion of colon cancer
- mostly asymptomatic
- altered blood in stool - melaena
- pain/weight loss/bowel obstruction only when advanced
clinical signs for suspicion of colon cancer
- often nothing except in lower rectum
palpable mass at advanced stage
investigations for colon cancer
- faecal occult blood testing
- imaging
- endoscopy
- pathology
imaging for colon cancer
barium studies, ultrasound, CT scan, virtual colonoscopy
if faecal occult blood testing is positive
referral for colonoscopy
if patient is symptomatic or has frank bleeding
screening FOBT is not indicated - needs diagnostic colonoscopy and biopsy
if small polyp is found (adenoma)
can be removed via endoscopic resection
if large mass is found
needs to be biopsied for histopathological diagnosis
- is it an adenoma with low grade dysplasia, high grade dyslalia or carcinoma
if cancer or large adenomatous polyp is found
colectomy - removal of part of the bowel - plus lymph nodes
clinical and pathological assessment of bowel cancer
- how advanced
- has it or is it likely to spread to other sites
- does the patient need further treatment
- what is th e likely prognosis
TNM staging
T - tumour size
N - lymph nodes
M - metastasis
low stage cancer
resection means high chance of cure
locally advanced cancer
cure is possible but there is a risk of distant spread
chemotherapy/radiotherapy/targetted therapy may be indicated
high stage colon cancer
systemic disease at prevention
liver/bone/brain/lung metastasis
cure unlikely
resection improves morbidity and survival
chemotherapy restricts tumour growth and increases survival
ways that tumour spread
- blood
- lymph
- direct invasion
- transcoelomic (via body cavities)
transcoelomic spread
when cancer spread to body cavities/peritoneum and spreads to other organs
pathological examination of specimen (resected tumour)
diagnosis of tumour type grading TNM staging assessing margins provide prognostic information
for a screening program to be worthwhile
- disease must have serious consequence
- disease must have a detectable preclinical period before it becomes clinically apparent and during which is can be detected by a screening test
- the test must be sensitive and specific - not too many false positives or false nagative results
- the test must be safe
- effective treatment exists
- treatment is more effective when started earlier
national bowel cancer screening program
- offered to the general population - normal risk level
- looking for faecal occult blood which is present due to microscopic haemorrhage from cancer or precancerous lesions
- patient puts sample in container and sends it back to be tested
- immunochemical test for globin from blood
bowel cancer screening is offered to
> 50 year olds
2 yearly
