Gastrointestinal Tumours Flashcards
what is associated with squamous cell carcinoma of oesophagus?
- diet (trace material and vitamin deficient)
- fungal contamination of food
- nitrites/nitrosamines
- alcohol/smoking
risk factors for squamous cell carcinoma of the oesophagus
- GORD
- lye stricture
- irradiation
from which condition do most of the adenocarcinomas of the oesophagus arise?
Barrett’s, prolonged GORD
what is the precursor of adenocarcinoma?
high grade dysplasia
what other tumours can occur in the oesophagus?
- smooth muscle (leiomyoma)
- GIST
- melanoma
- lymphoma
- small cell carcinoma
- metastasis
causes of gastric carcinoma
- environmental (smoking, low B12, hypochlorohydria)
- gastric polyp
- menetrier’s disease
- gastric stump
- h. pylori
- EBV-related
- gastric peptic ulcer
- genetic (HNPCC, APC, Li Fraumeni, HDGC)
gastric carcinoma and h.pylori
- nitrate reduction generates mutagenic niroso
- polymorph activation generates ROM and NO which results in DNA damage. repair is enhanced by ascorbic acid, the secretion of which into gastric juice is decreased by h pylori
- increased cell turnover, important for carcinogenesis
why is Her2 staining important in gastric tumours?
they can test positive for the receptor, which indicates that they can respond to trastuzumab
other types of tumours that can occur in the stomach
- smooth muscle tumours
- lymphoma
- carcinoid
- GIST
associations to GI lymphomas
- H.pylori gastritis
- mediterranean region
- refractory sprue
- congenital immunodeficiencies
- HIV
associations to sprue
- EATCL in long standing sprue
- younger age group
- poor prognosis
features of mediterranean lymphoma
- IPSID
- Plasma cell diff. with synthesis of IgA heavy chain
- Malabsorption often precedes lymphoma
- May regress after antibiotic therapy (Campylobacter
jejuni?)
where is it most common to have SI adenoma?
- ampulla
- jejunum
- ileum
risk factors for SI adenoma
- FAP
- cystic fibrosis
- Crohn’s
- coeliac
- PJ syndrome and juvenile polyposis
- long standing ileostomies
where, in the GIT, can carcinoid tumours happen?
- appendix
- SI
- rectum
- stomach
- colon
what are colonic polyps?
an abnormal growth of tissue projecting from the colonic mucosa
what is the most common precursor of colon cancer?
adenomas
types of epithelial colonic polyps
- neoplastic: serrated, adenomatous
- hamartomatous: juvenile, peutz-jeghers (both cause polyposis)
- polyposis syndromes: FAP, Gardner’s, serrated polyposis
what are pedunculated polyps?
polyps with stalks
how do pedunculated polyps arise?
as the sessile polyp enlarges, the adjacent cells proliferate and there is traction on the luminal protrusion, creating the stalk
causes of hamartomatous polyps
- sporadic
- components of various genetically determined or acquired syndromes
- can be associated with pre-malignant or neoplastic lesions
what are juvenile polyps?
focal malformations of the epithelium and lamina propria
types of juvenile polyps
- sporadic
- syndromic
presentation of juvenile polyps
rectal bleeding
what can these juvenile polyps cause?
- intussusception
- intestinal obstruction
- polyp prolapse through the anal sphincter
what is another name for retention polyps?
sporadic juvenile polyps
extraintestinal manifestation of juvenile polyposis
- pulmonary arteriovenous malformation
- congenital manifestations
what is Peutz-Jeghers syndrome?
rare autosomal dominant syndrome presents at a median age of 11 years with multiple GI hamartomatous polyps and mucocutaneous hyperpigmentation (dark blue to brown)
what can lesions of Peutz-Jeghers syndrome cause?
intersussception
clinical features of Peutz-Jeghers syndrome
- multiple polyps in th SI
- mucocutaneous hyperpigmentation
- positive family history
how do inflammatory polyps present?
solitary rectal ulcer syndrome
clinical features of inflammatory polyps
- rectal bleeding
- mucus discharge
- inflammatory lesion of the anterior rectal wall
underlying cause of inflammatory polyps
impaired relaxation of the anorectal
sphincter that creates a sharp angle at the anterior rectal shelf and leads to recurrent abrasion
and ulceration of the overlying rectal mucosa
how can the mucosa prolapse in scenarios of inflammatory polpys
the polyps can get trapped in the faecal stream leading to mucosal prolapse
histological features of inflammatory polyps
- mixed infiltratory infiltrates
- erosion
- epithelial hyperplasia
- lamina propria fibromuscular hyperplasia
what are adenomatous polyps?
True neoplastic polyps formed by excessive growth of the colorectal epithelium; divided by
the morphology of the glandular tissue into tubular, tubulovillous, and villous types.
causes of adenomatous polyps
- sporadic (mainly)
- hereditary syndromes
risk factors of adenomatous polyps
- family history of colorectal adenocarcinoma
management of high risk patients
- frequent colonoscopic screening
True or False: colorectal adenomas are characterised by the presence of epithelial dysplasia
false - most adenomas do not progress to become adenocarcinomas; most adenomas are clinically silent, with the exception of large polyps that produce occult bleeding and anaemia
what do rare villous adenomas secrete?
- hypoproteinemmic
- hypokalaemia
histological features of epithelial dysplasia
- nuclear hypochromasia
- elongation
- stratification
- prominent nucleoli
- eosinophilic cytoplasm
- reduction in the goblet cell population
histological features of pedunculated polyps
- slender fibromuscular stalks
- prominent blood vessels
types of adenoma
- tubular
- tubulovillous
- villous
which type is more likely to have foci of invasion?
villous (but this mainly depends on its size)
characteristics of sessile serrated adenomas
- hyperplastic polyps
- commonly found in the right colon
- have histological features of dysplasia present in adenomas
histological criteria of sessile serrated adenomas
- cryst base
- crypt dilation
- lateral growth
classification of colon adenocarcinoma
Haggitt’s classification
Level 0: mucosal invasion superficial to muscularis mucosae
Level 1: submucosal invasion, limited to the head of the polyp
Level 2: submucosal invasion of the neck
Level 3: submucosal invasion anywhere in the stem
Level 4: submucosal invasion below the stem without reaching muscularis propria
characteristics of familial adenomatous polyposis
- AD defect in APC gene
- early colon cancer diagnosis
- SI involvement
- fibromatosis
clinical features of FAP
- thousands of polyps in the colorectum
- increased risk of polyp formation in the stomach and duodenum
what is associated to FAP?
- Desmoid formation, particularly in the abdominal tissues.
- Multiple osteomata, fibromata, and thyroid inflammation (called Gardner’s syndrome).
management of FAP
- prophylactic colectomy
- ileorectal anastomosis (lifelong surveillance of the rectal stump)
- restorative proctolectomy
- pouch procedure with removal of rectal mucosa
what other conditions can be associated with FAP?
- congenital hypertrophy of the retinal pigment epithelium
- thyroid cancer
- pancreatic cancer
- hepatoblastoma
what is attenuated familial adenomatous polyposis?
An inherited predisposition to colorectal cancer characterized by fewer than 100 adenomatous polyps in the colon and rectum
characteristics of attenuated familial adenomatous polyposis
- later onset adenocarcinoma (50 vs 30)
- fewer extra GI manifestations
- mutations at the extremes of the APC gene
which type of tumours are people with Turcot’s syndrome at risk of?
- polyposis
- colorectal cancer
- CNS tumours
how is MUTYH-associated polyposis inherited?
autosomal resistant
what type of conditions are associated with MUTYH-associated polyposis
- adenomatosis (10-100)
- later development of adeno CA
- adenomas and serrated polyps
what does the MUTYH gene code for?
a base-excision repair protein which corrects reaction oxygen species-induced DNA damage; induces a mutation in APC and Kras
when are hyperplastic polyps usually discovered?
60s or 70s
pathogenesis of hyperplastic polyps
from decreased epithelial
cell turnover and delayed shedding of surface epithelial cells, leading to a “piling up” of
goblet cells and absorptive cells
why are they important?
they are histologically similar to sessile serrated adenoma, the latter has malignant potential when hyperplastic polyps are BENIGN
histological features of hyperplastic polyps
- distal colon
- serrated polyps
- microvesicular
- globet cell rich
- mucin poor
features of a serrated adenoma
- pedunculated or villous
- serration, dysplasia, leaf life, eosinophilic
how many types of serrated adenoma are there?
3;
- Type 1
- Type 2
- filiform serrated adenoma
characteristics of sessile serrated adenoma
- right colon
- multiple
- normally, no dysplasia
- BRAF mutations
- associated with MSI-high colorectal CA
features of mesenchymal polyps
- asymptomatic
- symptoms start as this increases in size and with proximity to the anus
- bleeding (fresh bleeding, dark red)
- mucus discharge (white, clear or watery)
- prolapse
diagnosis and investigations of mesenchymal polyps
- Dx: colonoscopy
- follow up to monitor the situation
- hereditary polyposis syndromes can be investigated by genetic mutation analysis
medical treatment of mesenchymal polyps
- colonoscopic polypectomy
- if the patient has FAP, you can check for more premalignant polyps using a gastroscopy
surgical treatment of polyps
- surgical excision (if the polyps are too large to take out in colonoscopy)
- transanal microsurgery
- FAP: protocolectomy (prophylactic colectomy)
increased risk factors for colorectal cancer
- increasing age
- animal fat and red meat consumption
- sugar consumption
- colorectal polyps
- family history
- chronic IBD
- obesity
- smoking
- acromegaly
- abdominal radiotherapy
- ureterosigmoidostomy
decreased risk factors for colorectal cancer
- vegetable, garlic, milk, Ca consumption
- exercise (for colon)
- aspirin and other NSAIDs
clinical features of colorectal cancer
- PR bleeding (deep red)
- change in bowel habits (difficulty, tenesmus and sensation of incomplete defaecation)
- Fe deficiency anaemia
emergency presentations of colorectal cancer
- large bowel obstruction
- perforation with peritonitis
- acute PR bleeding
investigation of colorectal cancer
- colonoscopy
- double-contrast barium enema
- endoanal ultrasound and pelvic MRI
- chest, abdomen and pelvic CT
- PET scanning
- MR
- serum CEA (used for monitoring and follow up)
- faecal occult blood tests
how can fibre reduce the risk of developing colon cancer?
It is theorized that reduced fiber content leads to decreased stool bulk and altered composition
of the intestinal microbiota. This change may increase synthesis of potentially toxic oxidative
by-products of bacterial metabolism, which would be expected to remain in contact with the
colonic mucosa for longer periods of time as a result of reduced stool bulk.
what is pharmacologic chemoprevention?
when taking drugs actually prevents you from getting cancer
pathogenesis of colon cancer
these are the APC/β-
catenin pathway, which is activated in the classic adenoma-carcinoma sequence; and the microsatellite instability pathway, which is associated with defects in DNA mismatch repair
and accumulation of mutations in microsatellite repeat regions of the genome.
Both pathways involve the stepwise accumulation of multiple mutations, but differ in the
genes involved and the mechanisms by which mutations accumulate. Epigenetic events, the
most common of which is methylation-induced gene silencing, may enhance progression
along either pathway.
describe the APC/B-catenin pathway
The classic adenoma-carcinoma sequence, accounts for up to 80% of sporadic colon
tumors and typically includes mutation of APC early in the neoplastic process. Both copies of the APC gene must be functionally inactivated, either by mutation or epigenetic events, for adenomas to develop. APC is a key negative regulator of β-catenin, a component
of the Wnt signalling pathway. The APC protein normally binds to and promotes degradation
of β-catenin. With loss of APC function, β-catenin accumulates and translocates to the
nucleus, where it forms a complex with the DNA-binding factor TCF and activates the
transcription of genes, including MYC and cyclin D1, that promote proliferation.
what is microsatellite instability?
Some microsatellite sequences are
located in the coding or promoter regions of genes involved in regulation of cell growth, such
as those encoding the type II TGF-β receptor and the pro-apoptotic protein BAX. Because
TGF-β inhibits colonic epithelial cell proliferation, mutation of type II TGF-β receptor can
contribute to uncontrolled cell growth, while loss of BAX may enhance the survival of
genetically abnormal clones.
what is MSI associated to?
- HPNCC
what are microsatellites?
Microsatellites are nucleotide repeat sequences that are prone to formation of
insertion/deletion loops during DNA replication
what is Lynch syndrome?
A range of abnormalities of the mismatch repair (MMR) genes that predispose adenomas to
acquire multiple genetic defects and so progress more rapidly than normal to cancer, although
the overall rate of adenoma formation is similar to that in normals. AD
another name for Lynch syndrome
hereditary non-polyposis colorectal cancer
pathogenesis of lynch syndrome
The disease is caused by a mutation in one of the DNA mismatch repair genes, usually hMSH2 or hMLH1 but others (hMSH6, PMS1 and PMS) have been reported. Mismatch repair genes are responsible for maintaining the stability of DNA during replication. Inheritance is
autosomal dominant.
The defect in function of the mismatch repair mechanism causes naturally occurring highly
repeated short DNA sequences known as microsatellites to be shorter or longer than normal,
a phenomenon called microsatellite instability (MSI).
what other cancers are common in people with HNPCC?
- stomach
- small intestine
- bladder
- skin
- brain
- hepatobiliary system
- endometrial
- ovarian
molecular features of chromosomal instability colorectal cancers
- widespread loss of heterozygosity
- aneuploidy or polyploidy
- predominantly left-sided location in colon
- highly differentiated histological features
- little lymphocytic infiltration
- rarely mucinous
- worse prognosis
features of microsatellite instability colorectal cancer
- widespread microsatellite instability
- diploidy
- predominantly right-sided location in colon
- poorly differentiated histologic features
- lymphocytic infiltration
- often mucinous
- better prognosis
what determines the prognosis of colorectal cancer?
- stage
- grade
- age
- sex
- site
- type of tumour
- margins
- vascular invasion
how do you stage colorectal tumours?
- Duke’s
- TNM
what is budding?
single cancer cells or clusters comprising less than 5 cancer cells
subtypes of colorectal cancer
- mucinous
- medullary
what does PTEN hamartoma-tumour syndrome include?
- Cowden’s syndrome
- Bannayan-Riley-Ruvalcaba syndrome
what does PTEN stand for?
phosphatase and tensin homolog mutations
which tumours, apart from colon, are patients with PHTS at risk of?
- thyroid
- beast
- uterine
- ovarian
how do you screeen for colorectal cancer?
- faecal occult blood test
- flexi-sigmoidoscopy
- colonoscopy
- CT colonography
