Path Notes: Neoplastic Polyps******:)

Question 1

What is an adenoma?

Answer 1

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

Question 2

What is the epidemiological picture of adenomas?

Answer 2

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

Question 3

What is the macroscopic appearance of adenomas?

Answer 3

Either pedunculated or sessile

Question 4

What are the subtypes of adenomas, based on their architecture? (Just name them, no details)

Answer 4

1. Tubular Adenomas
2. Tubulovillous Adenomas
3. Villous Adenomas
4. Serrated Adenomas

Question 5

What are the features of Tubular Adenomas?

Answer 5

They are the most common type of adenomas

Macroscopically: small and pedunculated

Microscopically: >75% tubular glands

Question 6

What are the features of tubulovillous adenomas?

Answer 6

Account for 5-10% of all adenomas

Microscopically: Comprised of mixed villous and tubular gland architecture. Usually 25-50% villous architecture

Question 7

What are the features of villous adenomas?

Answer 7

Account for 1% of adenomas

Macroscopically: Large and Sessile

Microscopically: Comprised >50% villous projections

Question 8

What are the features of serrated adenomas?

Answer 8

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

Question 9

What are the clinical concerns associated with adenomas?

Answer 9

1. Progression to malignant lesion
2. Can cause anaemia if bleeding
3. Can have ‘mass effect’ - cause symptoms via compression
4. Occasionally, villous adenomas can secrete mucoid material*

Question 10

What are the familial syndromes associated with adenomatous polyps?

Answer 10

1. Familial Adenomatous Polyposis (FAP) Syndrome

2. Hereditary Non-Polyposis Colorectal Cancer (Lynch Syndrome) (HNPCC)

Question 11

What is Familial Adenomatous Polyposis (FAP) Syndrome? What are the subtypes/clinical presentations? (just name the subtypes)

Answer 11

FAP syndrome involves presence of adenomatious polyps throughout the bowel that will progress to adenocarcinomas.

Subtypes/clinical presentation:

1. Classic
2. Attenuated

Question 12

What is the aetiology of Familial Adenomatous polyposis (FAP) syndrome?

Answer 12

Mutation of the Adenomatous Polyposis Coli (APC) gene on chromosome 5q2.

Question 13

Describe the features of ‘Classic’ type Familial Adenomatous Polyposis (FAP) Syndrome

Answer 13

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.

Question 14

Describe the features of ‘Attenuated’ type Familial Adenomatous Polyposis (FAP) syndrome

Answer 14

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)

Question 15

What is Gardner’s Syndrome?

Answer 15

Has similar appearance to ‘Classic’ type FAP, but includes other pathologies:

1. Osteomas of mandible, long bones, skull bones
2. Epidermal Cysts
3. Fibromatosis
4. Abnormal dentition
5. Higher frequency of duodenal and thyroid cancer

*obviously also predisposes to colorectal adenocarcinomas

Question 16

What is Turcot Syndrome?

Answer 16

Similar to FAP syndrome.
Very rare.
Also typically includes adenomas of CNS

(medulloblastomas, glioblastomas, depending on the genes affected)

Question 17

What is Hereditary Non-Polyposis Colorectal Cancer (HNPCC) (Lynch Syndrome)?
Describe epidemiology

Answer 17

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.

Question 18

What is the aetiology of Hereditary Non-Polyposis Colorectal Cancer?

Answer 18

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

Question 19

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?

Answer 19

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*

Question 20

What is Sporadic Colorectal Andeonocarcinoma?

Answer 20

Occurrence of colorectal adenocarcinoma without FAP or HNPCC.

Most colorectal cancers are sporadic.

Question 21

What percentage of colorectal cancers are due to sporadic, FAP, IBD and HNPCC?

Answer 21

Most are sporadic colorectal adenocarcinomas

1-3% are caused by FAP, HNPCC and IBD

Question 22

What is the epidemiology of Sporadic Colorectal Adenocarcinomas?

Answer 22

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

Question 23

What are the key risk factors associated with colorectal adenocarcinomas?

Answer 23

Genetic: FAP and HNPCC, other family history not consistent with an inherited syndrome

Environment:

1. Increased calorific intake
2. Low fibre diets (decreased stool bulk, increased transit time)
3. High content of refined carbohydrates (release toxic products of bacterial digestion in LI)
4. High red meat intake (increased release of bile acids)
5. Decreased intake of protective micronutrients (A, C, & E vits)

Note, NSAIDS/aspirin / COX2 inhibitor use seems protective

Question 24

What is the pathogenesis of colorectal adenocarcinoma? (Don’t describe in detail, but what is involved?)

Answer 24

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)

Question 25

Describe the APC gene-mutation pathway

Answer 25

APC pathway occurs in more than 80% of sporadic colon tumours

1. As APC (at 5q21) is a tumour suppressing gene, APC gene mutations / silence leads to adenomatous formation.
2. Loss of APC functioning leads to increased leels of B-catenin, which is involved int he WNT signalling pathway
3. Increased B-catenin levels causes it to translocate to the nucleus, where is activates genes that promote uncontrolled cell proliferation - leading to adenomatous lesions
4. Other additional mutations then occur, and the accumulation of mutations is associated with increased proliferation, dysplasia and eventual malignancy
5. Mutations in KRAS = enhances proliferation, prevents apoptosis
6. Loss of SMADs = Involved in TGF-B signalling
7. Loss of P53 = another tumour suppressor gene, plays a role in cell cycling
8. Activation of telemorase, which ensures cell immortality

Question 26

Describe the Microsatellite Instability Pathway:

Answer 26

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.

Question 27

What percentages of colon cancers are in each section of the colon? (Describe the distribution of CRCs)

Answer 27

22% in caecum and ascending colon.

11% in transverse

6% in descending colon

55% are rectosigmoidal

6% - other

99% are single tumours***

Question 28

What is the typical macroscopic morphology of adenocarcinomas of the proximal colon?

Answer 28

Polypoid. Obstruction is uncommon

Af faeces not so dehydrated at this point

Question 29

What is the typical macroscopic morphology of adenocarcinomas of the distal colon?

Answer 29

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.

Question 30

Microscopic morphology of colon adenocarcinomas?

Answer 30

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

Question 31

What are the clinical features of CRC?

Answer 31

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

Question 32

Where do CRCs typically spread?

Answer 32

Tend to have direct, infiltrative spread

Metastases to lymph nodes, liver, lungs, bones.

*25-30% of patients diagnosed have spread beyond curable surgery