Path Notes: Neoplastic Polyps******:) Flashcards
What is an adenoma?
Benign neoplasm of glandular origin, that results from epithelial proliferation and dysplasia.
The dysplasia ranges from low-high grade, to carcinoma in situ
Adenomas are benign, but there is much evidence to suggest they are a precursor to malignant and invasive colorectal adenocarcinomas
What is the epidemiological picture of adenomas?
Adenomas are common, affecting nearly 50% of adults aged 50 and over.
M:F
Familial disposition to adenomas gives a 4x increase for 1st degree relations, with a 4 fold increase in colorectal cancer
What is the macroscopic appearance of adenomas?
Either pedunculated or sessile
What are the subtypes of adenomas, based on their architecture? (Just name them, no details)
- Tubular Adenomas
- Tubulovillous Adenomas
- Villous Adenomas
- Serrated Adenomas
What are the features of Tubular Adenomas?
They are the most common type of adenomas
Macroscopically: small and pedunculated
Microscopically: >75% tubular glands
What are the features of tubulovillous adenomas?
Account for 5-10% of all adenomas
Microscopically: Comprised of mixed villous and tubular gland architecture. Usually 25-50% villous architecture
What are the features of villous adenomas?
Account for 1% of adenomas
Macroscopically: Large and Sessile
Microscopically: Comprised >50% villous projections
What are the features of serrated adenomas?
Most commonly occur in the Right Colon
Have a serrated architecture that extends through the whole length of the glands.
Lack the typical dysplasia associated with most other adenomas, but still has potential to progress to malignancy
What are the clinical concerns associated with adenomas?
- Progression to malignant lesion
- Can cause anaemia if bleeding
- Can have ‘mass effect’ - cause symptoms via compression
- Occasionally, villous adenomas can secrete mucoid material*
What are the familial syndromes associated with adenomatous polyps?
- Familial Adenomatous Polyposis (FAP) Syndrome
2. Hereditary Non-Polyposis Colorectal Cancer (Lynch Syndrome) (HNPCC)
What is Familial Adenomatous Polyposis (FAP) Syndrome? What are the subtypes/clinical presentations? (just name the subtypes)
FAP syndrome involves presence of adenomatious polyps throughout the bowel that will progress to adenocarcinomas.
Subtypes/clinical presentation:
- Classic
- Attenuated
What is the aetiology of Familial Adenomatous polyposis (FAP) syndrome?
Mutation of the Adenomatous Polyposis Coli (APC) gene on chromosome 5q2.
Describe the features of ‘Classic’ type Familial Adenomatous Polyposis (FAP) Syndrome
500+ adenomatous polyps carpet the mucosal surface (at least 100)
Mostly tubular, some villous.
100% will develop into adenocarcinoma often by age 30 if untreated.
Describe the features of ‘Attenuated’ type Familial Adenomatous Polyposis (FAP) syndrome
Fewer polyps are present (~30)
Tends to be in proximal colon
Tend to develop adenocarcinoma later in life (compared to by 30s in ‘Classic’ type FAP)
What is Gardner’s Syndrome?
Has similar appearance to ‘Classic’ type FAP, but includes other pathologies:
- Osteomas of mandible, long bones, skull bones
- Epidermal Cysts
- Fibromatosis
- Abnormal dentition
- Higher frequency of duodenal and thyroid cancer
*obviously also predisposes to colorectal adenocarcinomas
What is Turcot Syndrome?
Similar to FAP syndrome.
Very rare.
Also typically includes adenomas of CNS
(medulloblastomas, glioblastomas, depending on the genes affected)
What is Hereditary Non-Polyposis Colorectal Cancer (HNPCC) (Lynch Syndrome)?
Describe epidemiology
More common than Familial Adenomatous Polyposis Syndrome.
HNPCC is an autosomal dominant condition (‘cancer syndrome’) that carries high risk of colorectal cancer.
Colon cancers in HNPCC tend to occur at younger ages than sporadic types. Also tend to be located in right-side of colon.
Adenomas occur in lower numbers, but tend to form earlier than in the general adult population.
Also carries high risk for other cancers: endometrial carcinoma, stomach, ovary, small intestine, hepatobiliary, ureter, renal pelvis and brain carcinomas.
What is the aetiology of Hereditary Non-Polyposis Colorectal Cancer?
Germline mutation in DNA mismatch repair.
This leads to microsatellite cell instability.
90% of such mutations involve MSH2 and MSH1
Some microsatellite sequences are involved in promotion / coding of genes involved in cell growth:
TGF-II receptors, which leads to cell growth
and BAX, which leads to enhanced survival
What kinds of tumours tend to be associated with Hereditary Non-Polyposis Colorectal Cancer? What is the importance of recognising these particular features in a cancer patient?
Tend to occur in the right-side of the colon, in proximal regions.
Tend to be poorly differentiated
Typically have mucinous histology, with lymphocyte infiltration
**Important to recognise such features as potentially related to HNPCC. These people will require genetic testing and counselling*
What is Sporadic Colorectal Andeonocarcinoma?
Occurrence of colorectal adenocarcinoma without FAP or HNPCC.
Most colorectal cancers are sporadic.
What percentage of colorectal cancers are due to sporadic, FAP, IBD and HNPCC?
Most are sporadic colorectal adenocarcinomas
1-3% are caused by FAP, HNPCC and IBD
What is the epidemiology of Sporadic Colorectal Adenocarcinomas?
98% of cancers in the large intestine are adenocarcinomas.
Lifetime risk is greater for men (1 in 17) than women (1 in 26)
Peak incidence is 60s-70s, with 20% occurring before 50yo
*Must suspect a pre-existing / hereditary condition is found in younger persons
Rectal adenocarcinomas = M:F ratio 1.2:1
Other areas 1:1 M:F
What are the key risk factors associated with colorectal adenocarcinomas?
Genetic: FAP and HNPCC, other family history not consistent with an inherited syndrome
Environment:
- Increased calorific intake
- Low fibre diets (decreased stool bulk, increased transit time)
- High content of refined carbohydrates (release toxic products of bacterial digestion in LI)
- High red meat intake (increased release of bile acids)
- Decreased intake of protective micronutrients (A, C, & E vits)
Note, NSAIDS/aspirin / COX2 inhibitor use seems protective
What is the pathogenesis of colorectal adenocarcinoma? (Don’t describe in detail, but what is involved?)
The molecular carcinogenesis associated with colorectal adenocarcinoma includes an accumulation of multiple mutations.
The ‘First Pathway’ is through APC gene mutations
(accounts for 80% of sporadic adenocarcinomas)
The ‘Second Pathway’ is through Microsatellite Instability (seen in only 10-15% of sporadic CR adenocarcinomas, but in 90% of people with HNPCC)
Describe the APC gene-mutation pathway
APC pathway occurs in more than 80% of sporadic colon tumours
- As APC (at 5q21) is a tumour suppressing gene, APC gene mutations / silence leads to adenomatous formation.
- Loss of APC functioning leads to increased leels of B-catenin, which is involved int he WNT signalling pathway
- Increased B-catenin levels causes it to translocate to the nucleus, where is activates genes that promote uncontrolled cell proliferation - leading to adenomatous lesions
- Other additional mutations then occur, and the accumulation of mutations is associated with increased proliferation, dysplasia and eventual malignancy
- Mutations in KRAS = enhances proliferation, prevents apoptosis
- Loss of SMADs = Involved in TGF-B signalling
- Loss of P53 = another tumour suppressor gene, plays a role in cell cycling
- Activation of telemorase, which ensures cell immortality
Describe the Microsatellite Instability Pathway:
MSI pathway is seen in 90% of individuals with Hereditary Non-Polyposis Colorectal Cancer, and 10-15% of individuals with sporadic colon cancer.
MSI involves mutations in the DNA mismatch repair genes that proof-read the DNA during replication.
Eventually there is an accumulation of mutations in genes that regulate growth, differentiation and apoptosis.
What percentages of colon cancers are in each section of the colon? (Describe the distribution of CRCs)
22% in caecum and ascending colon.
11% in transverse
6% in descending colon
55% are rectosigmoidal
6% - other
99% are single tumours***
What is the typical macroscopic morphology of adenocarcinomas of the proximal colon?
Polypoid. Obstruction is uncommon
Af faeces not so dehydrated at this point
What is the typical macroscopic morphology of adenocarcinomas of the distal colon?
Ring-shaped, tend to encircle the lumen causing ‘napkin-ring’ constrictions.
Classically have a ‘heaped’ appearance with central ulceration.
Proximal bowel tends to be dilated.
Microscopic morphology of colon adenocarcinomas?
Tall, columnar cells forming glands
Invades the submucosa and muscularis propria
Many tumours produce mucin (especially if highly villous architecture)
Tends to be a foci of endocrine differentiation (10%), signet-ring-like cells, and undifferentiated small-cell proliferation
What are the clinical features of CRC?
Often asymptomatic.
Caecal/R-side = *Fe-deficiency anaemia, weakness, fatigue
Left side = Changes in bowel habits (diarrhoea and constipation is sign of more infiltrative lesion with poorer prognosis), occult bleeding
Highly suspect CRC if find Fe-deficiency anaemia in older men. Although there are more causes for Fe-deficiency anaemia in women, you should always suspect / keep in mind
Where do CRCs typically spread?
Tend to have direct, infiltrative spread
Metastases to lymph nodes, liver, lungs, bones.
*25-30% of patients diagnosed have spread beyond curable surgery
