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
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
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
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
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.
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
7
Q
How do rectal cancers (50%) present clinically?
A
- altered bowel habit
- fresh blood per rectum
- mucus per rectum
- tenesmus
- mass per rectum
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
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
10
Q
How can you be sure of a polyp’s biological behaviour?
A
- remove it
- send it to pathology lab
- for microscopic examination
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
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
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)
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)
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)
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
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
18
Q
Hence, use examples of genes to describe the process occurring from normal colon to carcinoma
A
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
Fairly recently it has been recognised that ~30% cancers arise from an alternative pathway. What is this pathway?
* Microsatellite instability pathway (=serrated pathway)
* cancers arise from **serrated** polyps (also termed serrated "lesions")
* called serrated as they have a serrated appearance _microscopically_
26
These serrated polyps may acquire sporadic mutations in a number of key genes, such as?
* 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
What is Lynch syndrome?
* 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
**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?
* 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
What cancers are patients with Lynch syndrome at risk of developing?
* **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
Lynch syndrome is thought to account for what proportion of colorectal cancers?
* ~3%
* commonest familial syndrome associated w colorectal cancer
31
How are colorectcal cancers in Lynch syndrome different from sporadic cases?
* tend to arise in right-side of colon
* more commonly poorly differentiated
32
What is the liftetime risk of developing colorectal cancer in Lynch syndrome?
* 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
What is the average age of CRC diagnosis in LS mutation carriers?
* 45-50 years compared to 70 in sporadic cases
34
What investigations are important for suspected colorectal cancer?
* 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
Surgery has a dominant role in the management of colorectal cancer. Name the 4 commonly performed operations
* **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
What is the pathology of colorectal cancer?
* vast majority are adenocarcinomas
* arise from mucosa which is glandular in type
* they are graded: well/moderately/poorly differentiated
37
How is colorectal carcinoma staged?
* Duke's
* TNM
Both systems assess the depth of invasion by the tumour through the bowel wall, but TNM considers nodal involvement separately.
38
Describe the TNM staging system
39
Describe Dukes' staging system
40
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?
* **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
What is the circumferential (mesorectal) margin and why is it important?
* 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
Bowel cancer screening aims to reduce the morbidity and mortality of bowel cancer. In what 2 ways does it do this?
* 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
Who is the NHS bowel cancer screening programme offered to?
* every 2 years to all men + women aged 60-75
* older patients can request a screening kit
44
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?
* 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
How does FOBT work?
* 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
What is bowel scope screening and who is being offered to?
* 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
What are the most common type of polyp in the large bowel?
_small hyperplastic polyps_ in the _left colon + rectum_
