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*Medicine: Cellular Pathology > GI pathology: Colorectal cancer > Flashcards

GI pathology: Colorectal cancer Flashcards

1
Q

What are the 5 histological concentric layers of the GI tract?

A
  • Mucosa (structure varies, where others stay relatively constant)
  • Submucosa
  • Muscularis propria
  • Subserosa
  • Serosa
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2
Q

What is the mucosal structure in the colorectum and why is this?

A
  • glandular w/ crypts
  • to facilitate water reabsorption

nb: in the rectum, the serosa is largely absent and so the subserosal connective tissue is called the mesorectum

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3
Q

How common is colon cancer?

A
  • 3rd commonest malignant tumour in UK (after lung + breast)
  • ~ 1/20 in UK will develop bowel cancer during lifetime
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4
Q

What are risk factors for colorectal cancer?

A
  • increasing age
  • diet - low fibre, high animal fat/meat/refined carbs
  • adenomatous polyps
  • hereditary cancer syndromes (nb. most CRCs are sporadic + occur in individuals without these syndromes)
    • familial adenomatous polyposis (FAP)
    • Lynch syndrome
  • long standing (>10yrs) active UC or Crohn’s affecting colorectum also increases risk
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5
Q

The clinical presentation of colon cancer depends to a degree on the site of the tumour. How do right-sided colon (5%) + caecal (15%) tumours present?

A
  • anaemia (bleeding)*
  • weight loss
  • right iliac fossa mass (rarely small bowel obstruction)

*right-sided colon cancers often present clinically w/ non-specific features due to iron-deficiency anaemia (eg. fatigue, weakness). This is a major reason why iron def anaemia in an older man or post-menopausal woman is GI cancer until proven otherwise.

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6
Q

How do left-sided (10%) and sigmoid colon (20%) cancers present?

A
  • altered bowel habit
  • altered blood per rectum
  • 1/3 large bowel obstruction
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7
Q

How do rectal cancers (50%) present clinically?

A
  • altered bowel habit
  • fresh blood per rectum
  • mucus per rectum
  • tenesmus
  • mass per rectum
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8
Q

What are adenomatous polyps?

A
  • colorectal adenomas dervied from epithelial cells lining in mucosa
  • v common, incidence increases w age
  • at 60 years they are found in approx 20% of population
  • adenomas may be sporadic or familial
  • familal adenomas occur in syndromes such as FAP
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9
Q

What can you gather from the term ‘polyp’?

A
  • naked-eye appearance: mass projecting from mucosal surface
  • term ‘polyp’ tells us nothing about its biological behaviour
  • may be benign, premalignant or malignant
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10
Q

How can you be sure of a polyp’s biological behaviour?

A
  • remove it
  • send it to pathology lab
  • for microscopic examination
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11
Q

What is meant by the following terms to describe a polyp?

  • pedunculated
  • sessile
  • tubular
  • villous
  • tubulovillous
A
  • pedunculated - attached to the normal mucosa by a stalk
  • sessile - atttached to normal mucosa by broad base
  • tubular - composed of tubular structures when looked at down microscope
  • villous - composed of finger-like projections when looked at down microscope
  • tubulovillous - contains mixture of tubular + villous architectures
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12
Q

Are colorectal adenomas cancerous?

A
  • no - they are dysplastic by definition
  • pre-malignant, so left untreated may progress to adenocarcinoma
  • in the GI tract, dyplasia is graded as low or high
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13
Q

Majority of adenomas will not progress to adenocarcinoma during a person’s lifetime. What are features associatd with a greater risk of progression?

A
  • high grade dysplasia (rather than low grade)
  • increasing size
  • histological type (villous is higher risk than tubular)
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14
Q

Why is the term ‘adenoma’ in the GI tract confusing?

A
  • in most contexts, an adenoma is a benign tumour of glandular epithelium which does not have the potential to become cancer (ie. adenomas are not premalignant)
  • however in GI tract, term ‘adenoma’ is used for premalignant lesions
  • by definition adenomas in GI tract are dysplastic (premalignant)
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15
Q

What are the two pathways for developing colorectal cancers?

A
  • 70%: chromosomal instability pathway (=adenoma-carcinoma pathway)
  • 30%: microsatellite instability (MSI) pathway (= serrated pathway)
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16
Q

About 70% of colorectal cancers arise as a result of a (3) stepwise progression. What is this progression?

A

normal mucosa -> adenoma -> invasive adenocarcinoma

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17
Q

What is the progession to invasive adenocarcinoma due to?

A

accumulation of mutations in a number of critical growth-regulating genes:

  • inappropriate activation of proto-oncogenes (eg. K-ras, c-myc)
  • inactivation of tumour suppressor genes (eg. APC, TP53) - remember that both copies of tumour suppressor genes must be inactivated (‘two-hit’ hypothesis) since if only one allele for the gene is damaged, the second can still produce the correct protein

the exact order in which these mutations are acquired may very; it is the accumulation of mutations rather than their occurrence in a specific order which is most critical

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18
Q

Hence, use examples of genes to describe the process occurring from normal colon to carcinoma

A
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19
Q

The large majority of pts who develop colorectal cancer through the adenoma-carcinoma pathway do so by acquiring sporadic mutations during life. These pts do not have a familial syndrome.

A small minority of pts who develop colorectal cancer through the adenoma-carcinoma pathway have a germline mutation in what gene?

A
  • APC gene
  • these pts have familial adenomatous polyposis
20
Q

What is familial adenomatous polyposis?

A
  • have germline mutation in one allele of APC gene
  • other allele is normal
  • FAP is a familial syndrome, inherited (autosomal dominant)
  • although de novo germline mutations may account for up to 25% of cases
  • affects 1 in 10,000
21
Q

How/why do patients with FAP develop cancer?

A
  • by following adenoma-carcinoma pathway sequence
  • however, bc they have a germline mutation in the APC gene, every single cell in the body has the mutation (ie. every cell is already one step further along the pathway than in non-FAP patients)
  • they develop hundreds of adenomatous polyps throughout the large intestine during their teens + 20s - t_he risk of development of an adenocarcinoma in one of these polyps is almost 100%_ by the age of about 40
  • prophylactic panproctocolectomy is usually advised in these pts
22
Q

FAP is thought to account for less than 1% of colorectal cancers (it is less common than Lynch syndrome). What is the mean age of developing colorectal cancer in FAP patients?

A
  • 39 - compared to 70 in sporadic cases
23
Q

FAP confers an increased risk of developing small intestinal adenomas/carcinomas - where, in particular?

A
  • ampulla of Vater
24
Q

What extra-intestinal manifestations is FAP associated with?

A
  • desmoid tumours (locally aggressive tumor that does not metastasize)
  • thyroid carcinomas
  • osteomas (non-cancerous bony growths)
  • congenital hypertrophy of the retinal pigmented epithelium
25
Q

Fairly recently it has been recognised that ~30% cancers arise from an alternative pathway. What is this pathway?

A
  • Microsatellite instability pathway (=serrated pathway)
  • cancers arise from serrated polyps (also termed serrated “lesions”)
  • called serrated as they have a serrated appearance microscopically
26
Q

These serrated polyps may acquire sporadic mutations in a number of key genes, such as?

A
  • activation of BRAF (an oncogene)
  • silencing of mismatch repair genes (eg. MLH1, MSH2) due to hypermethylation of promotors. This results in microsatellite instability (MSI) - insertion or deletion of nucleotides within repeated sequences of DNA.

the accumulation of these mutations may lead to development of carcinoma

27
Q

What is Lynch syndrome?

A
  • familial syndrome, inherited (autosomal dominant)
  • up to 5% of cases may be due to de novo mutations
  • have germline mutation in one allele of a DNA mismatch repair gene
  • other allele is normal
  • a ‘second hit’ (eg. promotor methylation, second mutation) is present in the genome of tumours in patients with LS
28
Q

Lynch syndrome: The order of frequency for germline mutation in the DNA mismatch repair gene is: MSH6 (most common), MSH2, MLH1, PMS2. What are the mismatch repair genes responsible for?

A
  • recognising + repairing mistakes in DNA transcription
  • which occur particualrly in areas of repeat DNA sequences (microsatellites) where DNA polymerases have a tendency to ‘slip’, either inserting extra or removing repeats.
  • in the case of mononucleotide and dinucleotide repeat sequences this often leads to a frameshift mutation, resulting in a shortened non-functional protein
29
Q

What cancers are patients with Lynch syndrome at risk of developing?

A
  • Colorectal
  • Endometrial - in women with LS, this is more common than colorectal cancer + it is more often the first (sentinel) cancer they develop
  • Stomach
  • Pancreatic
  • Small bowel
  • Ureter
  • Renal pelvic
  • Ovarian
30
Q

Lynch syndrome is thought to account for what proportion of colorectal cancers?

A
  • ~3%
  • commonest familial syndrome associated w colorectal cancer
31
Q

How are colorectcal cancers in Lynch syndrome different from sporadic cases?

A
  • tend to arise in right-side of colon
  • more commonly poorly differentiated
32
Q

What is the liftetime risk of developing colorectal cancer in Lynch syndrome?

A
  • approx 70%
  • but varies depending on which mismatch repair gene is mutated (the risk of developing CRC is highest in MLH1 or MSH2 mutation carriers)
33
Q

What is the average age of CRC diagnosis in LS mutation carriers?

A
  • 45-50 years compared to 70 in sporadic cases
34
Q

What investigations are important for suspected colorectal cancer?

A
  • a full history + examination is important
  • sigmoidoscopy + colonoscopy allow visualisation of bowel mucosa w/ biopsy of any lesion
  • staging investigations are important eg. CT, MRI, LFTs
  • all cases are discussed in the cancer MDT where a treatment plan for each patient is decided
35
Q

Surgery has a dominant role in the management of colorectal cancer. Name the 4 commonly performed operations

A
  • Hartmann’s procedure - emergency op, for perforated/obstructed left colon cancer or for diverticular disease. Sigmoid + part of rectum are resected, temporary end colostomy formed
  • Anterior resection - for upper/mid/low rectal tumours, surgical resection of all or part of the rectum w/ primary anastomosis
  • Abdomino-perineal (AP) resection + colostomy - for v low rectal tumours in which primary anastomosis not feasible. Excision of rectum + anus leaving a permanent colostomy. Pt has 2 wounds (perineal + laparotomy) and a colostomy
  • Total mesorectal excision (TME) - for rectal cancers (in combo w/ AP resection or anterior resection), involves precise dissection + removal of all mesentery around rectum (mesorectum) as a single intact unit, includes lymph nodes.
36
Q

What is the pathology of colorectal cancer?

A
  • vast majority are adenocarcinomas
  • arise from mucosa which is glandular in type
  • they are graded: well/moderately/poorly differentiated
37
Q

How is colorectal carcinoma staged?

A
  • Duke’s
  • TNM

Both systems assess the depth of invasion by the tumour through the bowel wall, but TNM considers nodal involvement separately.

38
Q

Describe the TNM staging system

A
39
Q

Describe Dukes’ staging system

A
40
Q

Prognostic factors are factors which help predict the probable course and outcome of a disease. What are some important pathological prognostic factors in colorectal cancer?

A
  • stage (most important) - higher Duke’s stage, the lower 5 yr survival
  • grade - aggressiveness of behaviour, most CRCs are moderately differentiated ie. intermediate aggressiveness
  • presence or absence of extramural vascular invasion - extramural invasion refers to presence of tumour in blood vessels outside the muscularis propria ie. blood vessels in the subserosal or mesorectal tissue
  • status of surgical margins - in rectal cancer, the circumferential margin is v important
41
Q

What is the circumferential (mesorectal) margin and why is it important?

A
  • in rectal cancer surgery, the circumferential resection margin (= radial margin) is the surgically-created plane of dissection produced during the TME procedure which removes the rectum and mesorectum from its surrounding tissue
  • the pathologist assesses this margin by slicing the resection specimen in the axial plane and then examines the cut surfaces with the naked eye and microscopically
  • distance of the tumour to the closest CRM is assessed microscopically by the pathologist and measured in mm:
    • a clear (negative) CRM is defined as tumour situated 1mm or further from the closest CRM
    • an involved (positive) CRM is defined as tumour less than 1mm from the CRM
      ​
  • a positive CRM correlates strongly with increased risk of local recurrence, distant mets and poor survival ie. it is an important prognostic factor!
42
Q

Bowel cancer screening aims to reduce the morbidity and mortality of bowel cancer. In what 2 ways does it do this?

A
  • it can detect bowel cancer at an early stage (in ppl with no symptoms), when treatment is more likely to be effective
  • it can also detect adenomatous (premalignant) polyps, which are easily removed, thus eliminating the risk of the polyps progressing to cancer
43
Q

Who is the NHS bowel cancer screening programme offered to?

A
  • every 2 years to all men + women aged 60-75
  • older patients can request a screening kit
44
Q

For the screening programme, eligible men/women are sent a faecal occult blood (FOB) testing kit. They complete the test at home and send the samples to a hub laboratory. What are the statistics with this results of this test?

A
  • 98% of people receive a normal result + will be returned to routine screening
  • 2% of people will receive an abnormal result + will be referred for further investigation + usually offered a colonoscopy
  • 4% of people will receive an unclear result which requires the FOB test to be repeated
45
Q

How does FOBT work?

A
  • polyps and bowel cancers sometimes bleed
  • and FOBt works by detecting tiny amounts of blood
  • which cannot normally be seen in bowel motions
  • patient uses cardboard stick to apply a smear of bowel motion into the box labelled I
  • they repeat the procedure with a fresh stick taken from a different area of the bowel motion and smear it in box II
46
Q

What is bowel scope screening and who is being offered to?

A
  • 55-60yr age group
  • people aged over 55 years will be able to request flexible sigmoidoscopy up to their 60th bday
  • at 60years, people will be offered FOB testing whether or not they have had screening with flexi-sig
47
Q

What are the most common type of polyp in the large bowel?

A

small hyperplastic polyps in the left colon + rectum

*Medicine: Cellular Pathology (16 decks)

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