125 - Dysplasia and Carcinoma Sequence

Question 1

Biological factors that define malignancy
1
2
3

Answer 1

– Cells with dysregulated growth (loss of cell cycle control)
– Invasive and metastatic potential
– Morbidity and mortality

Question 2

Morphological features that define malignancy
1
2

Answer 2

– Demonstration of invasion or metastasis

– Aberrant cytomorphology and disordered architecture

Question 3

Molecular/genetic features that define malignancy 
1
2
3
4

Answer 3

– Inherited or acquired mutations
– Oncogenes, tumour suppressor genes, DNA repair genes
– Chromosomal gains/losses, translocations and aneuploidy
– Epigenetic changes (hyper/hypomethylation, miRNA) and altered gene expression

Question 4

Example of a tumour suppressor gene involved in some breast cancers

Answer 4

BRCA1

Question 5

Example of an anti-cancer therapy targeted to cells avoiding immune destruction

Answer 5

Immune-activating anti-CTLA4 mAb

Question 6

Threat of pre-malignancies

Answer 6

Could become invasive

Question 7

Intraepithelial neoplasia

Answer 7

Pre-malignant epithelium that hasn’t become invasive

Question 8

Transformation

Answer 8

Change from a pre-malignant neoplasm into an invasive cancer

Question 9

Cancer of epithelium

Answer 9

Carcinoma

Question 10

Cancer of connective tissue

Answer 10

Sarcoma

Question 11

When is a dysplasia classed as a carcinoma?

Answer 11

When it breaches basement membrane to invade underlying stroma

Question 12

A cellular response to microenvironment

Answer 12

Metaplasia

Question 13

Normal metaplasia

Answer 13

Cervical epithelial mucosa changes with hormonal cycle

Question 14

Examples of pathological metaplasias
1
2
3

Answer 14

1) Barret oesophagus
2) Chronic atrophic gastritis leads to intestinal metaplasia
3) Chronic inflammation or smoking leads to squamous
metaplasia in lung bronchial epithelium

Question 15

HPV viral oncogenes

Answer 15

E6, E7

Question 16

Low-risk HPVs

Answer 16

– Low risk types (e.g. types 6 and 11)
• major cause of genital warts
• mild squamous dysplasia (CIN1)

Question 17

High-risk HPVs

Answer 17

– High risk types (e.g. types 16 and 18)
• moderate to severe squamous dysplasia (CIN 2-3)
• major cause of squamous cell carcinoma

Question 18

Aspect of HPV that can lead to invasive tumour

Answer 18

Genome integration into host genome

Question 19

HPV genome integration
1
2
3
4
5

Answer 19

1) E2 gene disruption during viral genome integration
2) Overexpression of E6 and E7 oncoproteins
3) Loss of p53 and Rb tumour suppressor function
4) Cell cycle can proceed despite DNA damage
5) Loss of p53 apoptosis function

Question 20

Name for characteristic appearance of HPV-infected histology

Answer 20

Koilocytosis

Question 21

Way to differentiate dysplasia in cervix

Answer 21

Can have low-level replication with inflammation.

Without inflammation, replication could be dysplasia.

Question 22

CIN grading

Answer 22

Used for squamous epithelial lines (CIN1, 2, 3 -> squamous cell carcinoma)

Question 23

CIN 2

Answer 23

Cell proliferaiton, mild dysplasia (squamous)

Question 24

CIN 3

Answer 24

Severe dysplasia.

Question 25

E6 effect

Answer 25

Binds p53. Confers resistance to apoptosis. Loss of G1/S, G2.M phase cel cycle check points. Genome instabolity

Question 26

E7 effect

Answer 26

- E7 binds Rb - Disrupts G1/S phase cell cycle checkpoint - Compensatory upregulation of P16 expression (G1/S function) due to loss of Rb function

Question 27

``` Cytological features of dysplasia on a pap smear 1 2 3 4 5 ```

Answer 27

1) Increased nuclear:cytoplasmic ratio 2) More marked nuclear hyperchromasia 3) Enlargement and irregularity 4) Mitoses 5) Loss of cytoplasmic differentiation

Question 28

CIN, AIN, VAIN

Answer 28

Cervical intraepithelial neoplasia, anal intraepithelial neoplasia, vaginal intraepithelial neoplasia, etc

Question 29

What do CIN, AIN, VAIN measure?

Answer 29

Classifications of dysplasias (1 is least severe, 3 is close to becoming a carcinoma)

Question 30

Proportion of those with longstanding reflux oesophagitis that develop Barrett's oesophagus

Answer 30

5-8%

Question 31

How is Barrett's oesophagus diagnosed (American College of Gastroenterology)? 1 2 3

Answer 31

– Endoscopic evidence of columnar lining in oesophagus above gastroeosophageal junction, AND – Histological evidence of intestinal metaplasia (goblet cells) in biopsies from the columnar epithelium – N.B. Presence of goblet cells not required for diagnosis of Barrett’s oesophagus in Japan or UK

Question 32

Metaplasia in Barrett's oesophagus

Answer 32

Re-epithelialisation of simple squamous epithelium with columnar epithelium

Question 33

What can Barrett's oesophagus lead to?

Answer 33

Adenocarcinoma

Question 34

Increase in adenocarcinoma risk with Barrett's oesophagus

Answer 34

30-60x increase

Question 35

Annual rate of malignant transformation of Barrett's oesophagus

Answer 35

0.5% progress to adenocarcinoma

Question 36

Most reliable way to ID cancers

Answer 36

Microscopically. Molecular techniques can be unreliable

Question 37

Aspect of low-grade dysplasia in Barrett's oesophagus versus Barrett's oesophagus without dysplasia

Answer 37

Dysplasic epithelium becomes pseudostratified

Question 38

Carcinoma in situ

Answer 38

Pre-invasive term for severe dysplasia at certain sites

Question 39

Name for carcinoma in situ of skin

Answer 39

Bowen's disease

Question 40

Names of carcinoma in situ of breast

Answer 40

Ductal carcinoma in situ | Lobular carcinoma in situ

Question 41

Are there metaplastic precursors to breast cancers?

Answer 41

Not really

Question 42

Ductal carcinoma in situ

Answer 42

Carcinoma in situ of breast, with ducts present under microscope

Question 43

Features of progression from carcinoma in situ to invasive carcinoma 1 a

Answer 43

1) Breach of mucosal/anatomical boundary | a) Access to lymphatics, blood vessels, now has metastatic potential

Question 44

``` Modes of carcinoma spread 1 2 3 4 ```

Answer 44

1) Direct invasion 2) Lymphatic invasion 3) Vascular invasion 4) Perineural invasion

Question 45

Direct invasion 1 2

Answer 45

– Transcoelomic spread in body cavities | – Pleura (lung), peritoneum (ovary, GI tract)

Question 46

``` Lymphatic invasion 1 2 3 4 ```

Answer 46

– Nodal metastases – Sentinel lymph nodes – Regional and distal lymph nodes – Virchow’s node / Troisier’s sign: Left supraclavicular node

Question 47

Vascular invasion 1 2

Answer 47

– Direct invasion of blood vessels (renal cell carcinoma) | – Lymphatic drainage -> thoracic duct -> L subclavian vein