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GI cancers Flashcards

1
Q

Colorectal cancer - epidemiology

A

Disease of westernised societies

2nd Commonest cause of cancer death


Survival improved but still only 55% chance of being alive in 5 years

15% of all male cancers, 12% of all female cancers


  • 3rd commonest incident male cancer (after lung & prostate)
  • 3rd commonest incident female cancer (after breast & lung)

Colon F>M
Rectum M>F
 (BUT rectum more common than colon)

Distribution – Most common rectum -> sigmoid -> colon -> caecum

Peak age 75-79 yrs (age-specific mortality increases exponentially with age)

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2
Q

Colorectal cancer - aetiology

A

Age

Western diet

  • Diet high in fat, red meat
  • Low in fibre, fruit and green vegetables (brassica vegetables protect)
  • High stool pH


Lifestyle factors - Smoking, lack of exercise, beer (rectal cancer)

Inflammatory bowel disease

  • Pan-Ulcerative colitis 30% risk at 30 yrs, 40% risk if <15yrs at dx
  • Crohn’s disease RR 2.5

Genetic predisposition

  • Overall genetic contribution 35%
  • Dominant gene disorders 2 - 5% (HNPCC, FAP, Others - PJS, JPS)

FH
Defined syndromes: HNPCC 2-5% or FAP 0.07%

Lifetime risk - 5.1

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3
Q

Colorectal cancer presentation

  • emergency
  • elective
A

Emergency

  • Obstruction or Perforation
  • > May lead to peritonitis, localized abscess or fistula formation
  • Bleeding
  • Localized pain

Elective

  • Altered bowel habit
  • Rectal bleeding
  • Colicky pain
  • Unexplained anaemia
  • Anorexia/ weight loss/ malaise
  • Flatulence
Symptoms 
- Change in bowel habits
Frequency &amp; consistency 
Diarrhoea more likely to be cancer than constipation
- Abdominal pain
= Generally not present unless big
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4
Q

Left colon cancer symptoms

A 
Fresh rectal bleeding, mucus
Altered bowel habit
Tenesmus
Mass
Obstruction occurs early
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5
Q

Right colon cancer symptoms

A

Present with anaemia from occult bleeding or with altered bowel habit
Weight loss
Abdominal pain
Obstruction = late feature

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6
Q

Colorectal cancer diagnosis

A

Bloods - FBC, CRP , UandEs

Digital rectal exam

1st line = colonoscopy

  • biopsy any polyps
  • if high risk of complications - consider CT colonoscopy

Emergency operation (20-25%)

Surveillance
- HNPCC, FAP, Inflammatory bowel disease, prior cancer

Population FOBT screening

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7
Q

Colonic polyp

A

Excrescence of colonic mucose

Does not indicate nature of lesion

  • Neoplastic
  • Non-neoplastic (Hamartomas; Metaplastic (hyperplastic); Inflammatory)

70% of people aged 65-75 will have a polyp

Bigger polyps more likely to become cancerous

Dysplasia -> higher chance of adenocariconoma in future

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8
Q

Most common type of rectal cancer

- metastasis site

A

mostly adenocarcinoma

Mets to liver and lung

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9
Q

FAP

A

1.8 new patients per million

Uncommon - 1% of all colorectal cancers

Autosomal dominant with ~100% penetrance

Inactivating mutations of the tumour suppressor APC (5q21) gene
Germline mutation - > 1400 mutations reported; most = loss-of-function mutations resulting in truncated APC protein

APC normally binds to and sequesters beta-catenin. Cant do this when mutated – allowing beta-catenin to translocate to nucleus -> upregulates expression of many genes

20% - new mutations, no FH

100s polyps develop in 80% of patients by age 15, symptoms e.g. rectal bleeding begin few years later

Cancer will develop within 10-15 years of appearance of adenomas, 90% develop colorectal cancer by 50 years

Extra-intestinal manifestations: CHRPE – congenital hypertrophy of retinal pigment epithelium, epidermoid cysts (extremities, face, scalp – 50%), benign osteomas – esp. skull and angle of mandible, dental abnormalities, desmoid tumours (mesentery, abdominal wall, benign but may cause compression of organs. Difficult to remove, may respond to tamoxifen)

Diagnosis

  • Early identification of affected individuals before symptoms develop
  • Can be excluded if sigmoidoscopy normal
  • In new cases – genetic testing should be carried out to confirm diagnosis & identify causal mutation
  • All 1st degree relatives should undergo testing
  • Known FAP – offered mutation testing at 13-14, if have mutation offered colectomy at 18

Operation of choice = total proctocolectomy with ileal pouch-anal anastomosis (prophylactically done)

Periodic upper GI endoscopy every 1-3 years to detect and monitor duodenal and periampullary adenomas – large may be removed

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10
Q

What does APC do in cell?

A

APC normally binds to and sequesters beta-catenin. Cant do this when mutated – allowing beta-catenin to translocate to nucleus -> upregulates expression of many genes

Cells unaware that joined together so divide uncontrollably

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11
Q

Extra-intestinal manifestation of FAP

A

CHRPE – congenital hypertrophy of retinal pigment epithelium

epidermoid cysts (extremities, face, scalp – 50%)

benign osteomas – esp. skull and angle of mandible

dental abnormalities

desmoid tumours (mesentery, abdominal wall, benign but may cause compression of organs. Difficult to remove, may respond to tamoxifen)

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12
Q

Peutz-Jeghers syndrome

A

AD – most commonly from truncating mutations in serine-threonine kinase gene on chromosome 19

Multiple hamartomatous polyps occur in small intestine & colon

Melanin pigmentation of lips, mouth and digits

Most asymptomatic BUT may have chronic bleeding, anaemia or intussusceptino

Risk of small bowel or colonc adenocarcinoma and cancer of lung, pancreas, testis, ovary, breast and endometrium

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13
Q

HNPCC

- definition criteria

A

HNPCC
Definition criteria:
(1) >3 family member with histologically proven colorectal cancer
(2)One relative a first degree relative of the other two

(3) >2 generations affected

(4) Age at onset <50yrs in at least one family member

Uterine cancer in one or more relatives acceptable as part of a 3 member family

Not as many polyps

Mutations in DNA mismatch repair genes
MSH2 40%; MLH1 40%; MSH6 20%

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14
Q

Colorectal cancer surgery

A

Only treatment modality offering potential cure

Emergency (obstructed, perforated - unprepared bowel)

  • Segmental excision and on-table colonic lavage
  • Colectomy and ileorectal anastomosis
  • Hartmann’s procedure -> Bowel obstruction, perforation or palliation

Elective (low rectal cancer require mechanical bowel preparation)

  • Segmental resection (eg R-hemicolectomy, ant. resection etc)
  • Restorative rectal excision +/- colonic pouch
  • Transanal excision of rectal cancer

  • Colonoscopic polypectomy

Endoscopic removal
- Small/moderate adenomas

Sigmoid + rectum = anterior resection

Right hemicolectomy = caecal, ascending or proximal transverse colon tumours

Left hemicolectomy = distal transverse or descending colon

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15
Q

Left hemicolectomy

A

distal transverse or descending colon

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16
Q

Right hemicolectomy

A

caecal, ascending or proximal transverse colon tumours

17
Q

Colorectal cancer - adjuvant chemotherapy

A

Locally advanced rectal cancer

  • Neoadjuvant radiotherapy or chemoradiotherapy to increase chance of complete surgical resection
  • Continuity should be restored with direct anastomosis

5-fluorouracil based regimens – now capecitabine (TS inhibitor)

  • 30% reduction in mortality for Dukes’ C

  • 5% overall increase in absolute survival for Dukes’ C
  • 3% overall increased survival Dukes B

Combination therapy (CAPOX)


Capecitabine (thymidylate synthase inhibitor) + oxaliplatin

2nd line agents


  • Cetuximab –mab to epidermal growth factor receptor
  • Bevacizumab - mab to vascular endothelial growth factor
  • Temozolomide
18
Q

Duke’s staging

A 
A  Limited to bowel wall 

B  Through full thickness bowel wall 

C1 Regional lymph nodes involved 
C2 Apical lymph node involved 
D – cancer spread to another part of body
19
Q

APC/Beta-catenin pathway

A

Inactivation of APC (Adenomatous Polyposis Coli) tumour suppressor gene seen in about 80% of colorectal carcinomas

Genetic basis of the inherited condition FAP

Early event in the adenoma-carcinoma sequence

Subsequent accumulation of multiple mutations and chromosomal instability

20
Q

Microsatellite instability pathway

A

10-15% of sporadic colorectal carcinomas (R>L) 


Inactivation of DNA mismatch repair genes

MSH2, MLH1 (90% of cases involve one of these)

Others - MSH6, PMS1, PMS2 


Inherited mutation in one of these genes is the basis of Hereditary Non-Polyposis Colorectal Carcinoma (HNPCC) syndrome (Lynch syndrome) 


Loss of one of these genes increases mutation rate by up to 1000-fold 


Not associated with typical adenoma-carcinoma sequence 


21
Q

Colorectal cancer Screening

A

Scotland

  • FIT test – keyring swab poo
  • Age 50-74 – every 2 years
  • 50-60% sensitivity so lots of false positives

20% survival benefit in 50-75 years old

England → 60-74 year olds

22
Q

Anal carcinoma

  • incidence
  • aetiology
  • pathology
  • clinical presentation
  • treatment
A

UK incidence: 300 cases annually
(1.5% of all malignant colorectal disease)

Aetiology

  • Human papilloma virus type 6, 11 and 16
  • Anoreceptive intercourse
  • Immunosuppression (HIV, pharmacological, haematological)

Pathology

  • AIN (anal intra-epithelial neoplasia)
  • Squamous
  • Adenocarcinoma
  • Basiloid
  • Small cell carcinoma
  • Malignant melanoma

Clinical presentation:
Ulcer, warty lesion, pruritis, pain, bleeding

Treatment
- AIN1&2 - Observe, often settles

- AIN3 - Surveillance with magnifying anoscopy and biopsy
- Local excision for invasive carcinoma T1/T2 tumours
- Combined chemo-radiation for invasive carcinoma
5FU
- Enters reactions in place of uracil
- Inhibits thymidylate synthetase and interferes with DNA & RNA synthesis
- SE: nausea, diarrhea, stomatitis, myelosuppresion
Mitomycin C and radiotherapy

Abdomino-perineal excision - salvage procedure

Outcome: 65-80% 5yr survival

23
Q

Most common type of gastric cancer

A

adenocarcinoma

  • incidence falling
  • arises from mucus secreting cells in base of gastric crypts
  • most develop on background of chronic atrophic gastritis with intestinal metaplasia and dysplasia
24
Q

GISTs

A

Gastro-intestinal stromal tumours

  • Arise from interstitial cells of Cajal
  • Express c-kit proto-oncogene – encodes tyrosine kinase receptor
  • Mostly benign leiomyomas but can bleed

Histology – “spindle-cell” or “epitheliod “pattern

IHC – C-kit

Treatment
Metastatic – imatinib (Glivec) → bonds to C-kit (CD117), a tyrosine kinase, where adenosine phosphate normally binds preventing phosphorylation and c-kit activated signalling is abolished

25
Q

Gastric carcinoma

  • incidence
  • RF
A

Increased Incidence with age, increase in >50 years old

3rd leading cause of cancer death worldwide

Often presents late 


China, Japan, Korea, Eastern Europe, Parts of S. America
- Japanese migrants to USA –increased incidence → environmental factors

Poor prognosis - <30% survive 5 years

Males > females

Familial link in about 10% 

- Small % have germline mutations e.g. TP53, CDH1 genes 


Aetiology multifactorial: diet, H. pylori, bile reflux 


26
Q

Early gastric cancer

A

Confined to mucosa and submucosa

27
Q

Two main histological patterns of gastric carcinoma

A

Intestinal

Diffuse

28
Q

Intestinal carcinoma

A

Majority of cases in high incidence areas; More common

Arises against a background of chronic mucosal injury

Increased risk with FAP

Histology – obvious gland formation

Arise from intestinal metaplasia with histological features reminiscent of intestinal epithelium or ‘diffuse’ arising from normal gastric mucosa

29
Q

Diffuse carcinoma

A

Poorly differentiated

Relatively more common in low incidence areas – UK

Often younger patients; Female > male

Mutation or inactivation of CDH1 gene

Histology – sheets of ‘signet ring’

30
Q

Gastric carcinoma clinical features

A

Early – usually asymptomatic
-> May be found on endoscopy for investigation of dyspepsia

Anorexia, nausea, early satiety, haematemesis, melaena, dyspepsia

Advanced – weight loss, ulcer-like pain

Dysphagia – tumours of gastric cardia, obstruct gastro-oesophageal junction

Anaemia – from bleeding

Examination normal or have weight loss, anaemia, epigastric mass

Advanced cases:

  • Left supraclavicular node – Virchow’s node
  • Periumbilical nodule (Sister Mary Joseph’s nodule)
  • Left axillary node (Irish node)
31
Q

Gastric carcinoma investigations

A

Upper GI endoscopy

  • Perform if dyspeptic & alarm symptoms
  • Biopsies from edge and base of gastric ulcer

CT – intra-abdominal spread, liver metastases, staging

Laparoscopy with peritoneal washings – detect spread to peritoneum & decide if resectable

32
Q

Gastric carcinoma management

A

Chemo

  • Peri-operative chemo with epirubicin, cisplatin and fluorouracil (ECF) improves survival rates
  • Inoperable disease

Surgery

  • Resection – only hope of cure
  • Locally advanced disease – total gastrectomy with lymphadenopathy
  • Proximal tumours involving oesophageal junction – also requires distal oesophagectomy
  • Small distally sited tumours – partial gastrectomy with lymphadenopathy
33
Q

Gastric carcinoma palliative treatment

A

May require surgery if bleeding or gastric flow obstruction

Chemotherapy

Trastuzumab – if tumours over-express HER2

Dysphagia/ recurrent bleeding – endoscopic laser ablation

Endoscopic for palliation – APC, laser, stents

34
Q

RF for gastric carcinoma

A

Smoking

Helicobacter pylori

  • Contributes to 70% of cases
  • Class 1 carcinogen
  • Most have normal or increased acid secretion, few become hypo or achlorhydric (don’t produce any acid) → greatest risk
  • Associated with chronic atrophic gastritis, gastric mucosal atrophy and gastric cancer
  • Induces chronic inflammation, reactive oxygen species and depletion of normally abundant antioxidant ascorbic acid

Alcohol

FAP syndromes / adenomatous gastric polyps

Pernicious anaemia/ autoimmune gastritis

Diet rich in nitrosamines (natural carcinogens)

  • Salted, smoked, pickled foods, nitrites/nitrates
  • Lack fresh fruit and vegetables, Vit C and A

Link with blood group A

FH - Mutations of E-cadherin (CHD1) gene

35
Q

Zollinger – Ellison Syndrome

A

Gastrinoma – non-beta cell islet tumour of pancreas
-> Gastric acid hyper-secretion causing peptic ulceration

  • 2/3 are malignant but slow growing
  • 20-60% have co-existing adenomas of parathyroid and pituitary (MEN1)
  • 0.1% of ulcer cases

Pancreatic enzymes get inactivated due to low pH & bile salts precipitate causing diarrhoea and steatorrhoea

Clinical features

  • Multiple ulcers often unusual sites
  • Poor response to standard therapy
  • Complications common – GI bleed from peptic ulcers
  • Diarrhoea can be presenting feature

Investigations

  • Serum gastrin levels grossly elevated
  • Secretin stimulation further increases levels

Tumour localisation difficult
CT / EUS and sampling / Selective angiography for bleeding complication

Management

  • Surgical resection if tumour localised
  • PPI’s high doses
  • Octreotide injections to reduce gastrin levels -> Mimics somatostatin – inhibits GH, glucagon, insulin

5 year survival – 60-75%

GI (7 decks)

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