125 - Dysplasia and Carcinoma Sequence Flashcards
Biological factors that define malignancy
1
2
3
– Cells with dysregulated growth (loss of cell cycle control)
– Invasive and metastatic potential
– Morbidity and mortality
Morphological features that define malignancy
1
2
– Demonstration of invasion or metastasis
– Aberrant cytomorphology and disordered architecture
Molecular/genetic features that define malignancy 1 2 3 4
– 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
Example of a tumour suppressor gene involved in some breast cancers
BRCA1
Example of an anti-cancer therapy targeted to cells avoiding immune destruction
Immune-activating anti-CTLA4 mAb
Threat of pre-malignancies
Could become invasive
Intraepithelial neoplasia
Pre-malignant epithelium that hasn’t become invasive
Transformation
Change from a pre-malignant neoplasm into an invasive cancer
Cancer of epithelium
Carcinoma
Cancer of connective tissue
Sarcoma
When is a dysplasia classed as a carcinoma?
When it breaches basement membrane to invade underlying stroma
A cellular response to microenvironment
Metaplasia
Normal metaplasia
Cervical epithelial mucosa changes with hormonal cycle
Examples of pathological metaplasias
1
2
3
1) Barret oesophagus
2) Chronic atrophic gastritis leads to intestinal metaplasia
3) Chronic inflammation or smoking leads to squamous
metaplasia in lung bronchial epithelium
HPV viral oncogenes
E6, E7
Low-risk HPVs
– Low risk types (e.g. types 6 and 11)
• major cause of genital warts
• mild squamous dysplasia (CIN1)
High-risk HPVs
– High risk types (e.g. types 16 and 18)
• moderate to severe squamous dysplasia (CIN 2-3)
• major cause of squamous cell carcinoma
Aspect of HPV that can lead to invasive tumour
Genome integration into host genome
HPV genome integration 1 2 3 4 5
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
Name for characteristic appearance of HPV-infected histology
Koilocytosis
Way to differentiate dysplasia in cervix
Can have low-level replication with inflammation.
Without inflammation, replication could be dysplasia.
CIN grading
Used for squamous epithelial lines (CIN1, 2, 3 -> squamous cell carcinoma)
CIN 2
Cell proliferaiton, mild dysplasia (squamous)
CIN 3
Severe dysplasia.
E6 effect
Binds p53.
Confers resistance to apoptosis.
Loss of G1/S, G2.M phase cel cycle check points.
Genome instabolity
E7 effect
- E7 binds Rb
- Disrupts G1/S phase cell cycle checkpoint
- Compensatory upregulation of P16 expression (G1/S function) due to loss of Rb function
Cytological features of dysplasia on a pap smear 1 2 3 4 5
1) Increased nuclear:cytoplasmic ratio
2) More marked nuclear hyperchromasia
3) Enlargement and irregularity
4) Mitoses
5) Loss of cytoplasmic differentiation
CIN, AIN, VAIN
Cervical intraepithelial neoplasia, anal intraepithelial neoplasia, vaginal intraepithelial neoplasia, etc
What do CIN, AIN, VAIN measure?
Classifications of dysplasias (1 is least severe, 3 is close to becoming a carcinoma)
Proportion of those with longstanding reflux oesophagitis that develop Barrett’s oesophagus
5-8%
How is Barrett’s oesophagus diagnosed (American College of Gastroenterology)?
1
2
3
– 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
Metaplasia in Barrett’s oesophagus
Re-epithelialisation of simple squamous epithelium with columnar epithelium
What can Barrett’s oesophagus lead to?
Adenocarcinoma
Increase in adenocarcinoma risk with Barrett’s oesophagus
30-60x increase
Annual rate of malignant transformation of Barrett’s oesophagus
0.5% progress to adenocarcinoma
Most reliable way to ID cancers
Microscopically. Molecular techniques can be unreliable
Aspect of low-grade dysplasia in Barrett’s oesophagus versus Barrett’s oesophagus without dysplasia
Dysplasic epithelium becomes pseudostratified
Carcinoma in situ
Pre-invasive term for severe dysplasia at certain sites
Name for carcinoma in situ of skin
Bowen’s disease
Names of carcinoma in situ of breast
Ductal carcinoma in situ
Lobular carcinoma in situ
Are there metaplastic precursors to breast cancers?
Not really
Ductal carcinoma in situ
Carcinoma in situ of breast, with ducts present under microscope
Features of progression from carcinoma in situ to invasive carcinoma
1 a
1) Breach of mucosal/anatomical boundary
a) Access to lymphatics, blood vessels, now has metastatic potential
Modes of carcinoma spread 1 2 3 4
1) Direct invasion
2) Lymphatic invasion
3) Vascular invasion
4) Perineural invasion
Direct invasion
1
2
– Transcoelomic spread in body cavities
– Pleura (lung), peritoneum (ovary, GI tract)
Lymphatic invasion 1 2 3 4
– Nodal metastases
– Sentinel lymph nodes
– Regional and distal lymph nodes
– Virchow’s node / Troisier’s sign: Left supraclavicular node
Vascular invasion
1
2
– Direct invasion of blood vessels (renal cell carcinoma)
– Lymphatic drainage -> thoracic duct -> L subclavian vein
