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GIT > Cancer > Flashcards

Cancer Flashcards

1
Q

Biological behaviours that define malignancy?

A

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

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2
Q

When are inflmmatory cells around a tumour a negative thing?

A

They can digest the stroma and allow invasion

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3
Q

Morphology/appearance that define malignancy?

A

Demonstration of invasion or metastasis
Aberrant cytomorphology and disordered architecture
Nuclear abnormality → nuclear atypia,

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4
Q

Molecular/genetic basis that define malignancy?

A

(mutations accumulate to cause dysplasia)

i. Inherited or acquired mutations (usually multiple hit)
ii. Oncogenes (tumor driving), tumour suppressor genes, DNA repair genes
iii. Chromosomal gains/losses, translocations -> aneuploidy [genomic complexity]
iv. Epigenetics (hypermethylation, hypomethylation, miRNA); regulate expression of genes

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5
Q

What are proto-onco genes?

A

Code for proteins regulating cell growth and differentiation;

Activation by either genetic damage (mutation) or increased expression results in the development of oncogenes.

Their activation will result in proliferation (ie it’s like their ‘accelerator is stuck ‘on’)

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6
Q

How many mutations are required to cause loss of function for proto-onco genes?

A

Only one copy needs to be mutated to confer growth advantage ‘1 hit hypothesis’

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7
Q

What are some genes which would be considered proto-onco?

A

Growth factor
receptors (HER2, EGFR)
kinases (Kras, Braf)
Transcription factors

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8
Q

What are the tumour driving mutations? (proto-onco genes)

A

Gene amplification =-ie same oncogen is made over and over again
Sequence mutation
Translocation

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9
Q

What are tumour suppressor genes?

A
  • Code for proteins involved in regulating the cell cycle:
  • Repairing damaged DNA
  • or, if the DNA is damaged beyond repair, inducing apoptosis
  • Limit cell proliferation.
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10
Q

How many mutations are required for a loss of function?

A

Both copies need to be mutated to cause loss of function ‘2 hit hypothesis’

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11
Q

When is a person at risk of loss of function of tumour suppressor genes?

A

1 copy can be inherited (higher disposition to cancer) but still normal.
An example is BRACA

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12
Q

What are the tumour driving mutations? (Tumour suppressor genes)

A

Missense, nonsense, frameshift mutations (thus can happen in a series of locations, thus need to sequence the whole exome sequence of BRACA for example)
Large deletions
Loss of hetrozygosity
Promoter hypermethylation (this could also be considered the second hit)

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13
Q

What are pre-malignant neoplasias?

A

Dyslplasia (intra-epithelial neoplasia)

Carcinoma in situ

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14
Q

What are the characteristics of dysplasia?

A

Disordered growth -> occurs due to the accumulation of clonal mutations (begins with a single cell)

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15
Q

What is a cancer of the epithelium called?

A

Carcinoma

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16
Q

What is a cancer of the stroma called?

A

Sarcoma

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17
Q

What is a haematopoietic cancer called?

A

Lymphoma/Leukaemia

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18
Q

What is the progression from dysplasia to carcinoma?

A
  1. Dysplasia -> Carcinoma in situ -> Carcinoma
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19
Q

What is the defintion of a carcinoma?

A

Epithelial cancer, defined by invasion: Malignant cells breach the basement membrane to invade underlying stroma

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20
Q

What are some features of dysplastic cells?

A

Dysplastic cells exhibit

1) pleomorphism
2) large hyperchromatic nuclei
3) high nuclear to-cytoplasmic ratio.

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21
Q

How is the depth of the dysplasia considered?

A

Lower 1/3 abnormality = mild,
2/3 abnormality = moderate,
3/3 abnormality = severe

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22
Q

What does the progression from dysplasia to carcinoma involve?

A

Mutations allow invasion
Evasion of apoptosis (eg. p53)
Immortalization
Angiogenesis (ef. VEGF)

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23
Q

What is carcinoma in situ?

A

When dysplastic changes are marked and involve the entire thickness of the epithelium but the lesion remains confined by the BM, it is considered a preinvasive neoplasm and is referred to as carcinoma in situ

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24
Q

What is metaplasia?

A

Replacement of one type of cell with another type (the other cell type is more suited to environment)

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25
Q

What is metaplasia associated with?

A

Metaplasia is nearly always found in association with tissue damage, repair, and regeneration.
Adaptive change in epithelial cell differentiation in response to the microenvironment

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26
Q

What is the cervical transformation zone?

A

Area whereby there is transformation (or metaplasia) of columnar/glandular epithelium of the of the cervical canal to squamous epithelium of the vagina -> squamous metaplasia

Glandular epithelium changes with menstrual cycle (hence it is actually a physiological process)

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27
Q

What is HPV?

A

Human papillomavirus

It is a ubiquitous STI with >150 serotypes

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28
Q

What does tropism mean?

A

Tissue tropism is the cells and tissues of a host which support growth of a particular virus or bacteria.

29
Q

What is the tropism of HPV?

A

Tropism for basal keratinocytes, such as basal cells of the transformation zone

30
Q

What are the low risk serotypes of HPV?

A

6 and 11

31
Q

What are the high risk serotypes of HPV?

A

16 and 18

32
Q

What is CIN and how is it classified?

A

Cervical intraepithelial neoplasia

CIN is classified in grades (1-3)
1 = least risky mild squamous dysplasia
2-3 = Moderate to severe dysplasia that spans more than 2/3 of the epithelium

33
Q

What distinguishes the low risk HPV from high risk?

A

Low risk type =
Major cause of genital warts
CIN1

High risk
CIN2-3
Major cause of squamous cell carcinoma

34
Q

What are the two major outcomes of an HPV infection?

A

Episomal viral replication

Integration with cellular genome

35
Q

What happens when an HPV infection results in episomal viral replication?

A

Latent infection with low level viral replication
Majority of infections transient, with viral clearance

Does not progress to tumour

36
Q

What happens when the HPV becomes integrated within the cellular genome?

A

There is an E2 gene disruption during viral genome integration

  • > overexpression of E6 and E7 oncoproteins
  • > prevents function of tumour suppressors p53 and Rb
  • > Cell cycle progresses despite DNA damage
  • > Loss of p53 apoptosis function
37
Q

What does HPV E6 bind to?

A

E6 binds p53 = confers apoptosis resistance, loss of G1/S and G2/M phase ell cycle checkpoints and genomic instability

38
Q

Which types of HPV are most likely to become integrated within the cellular genome?

A

16 and 18

39
Q

What does HPV E7 bind to?

A

E7 binds Rb = disrupts G1/s phase cell cycle checkpoint, S phase gene expression can proceed and cell cycle proceeds despite DNA damage

40
Q

What is seen on a nomral histological slide of the cervic?

A

Small, dark glands at the base, orderly maturation towards surface

41
Q

What effect does HPV have on the histological slide of the cervix?

A

Koilocytosis

Apical cells towards surface (binucleate, perinuclear halo)

42
Q

What happens when CIN 3 cells are stained for P16?

A

Strong expression of P16 seen in dysplastic cells infected with HPV (not in normal)

43
Q

What happens when CIN 3 cells are stained for Ki67?

A

Ki67 is a marker of cell proliferation so can be seen in tumour cells. However inflammatory processes and regeneration also cause a similar pattern

44
Q

What is a pap smear?

A

Screening cytology for squamous dysplasia

45
Q

What are the two classifications of lesions found in a pap smear?

A

Low grade squamous intraepithelial lesion (LSIL): HPV-CIN1

High grade squamous intraepithelial lesion (HSIL): at least CIN2-CIN3

46
Q

What are the features of a LSIL?

A
  1. Majority of squamous cells have lots of cytoplasm, small nuclei
  2. Some are enlarged, binucleate and have a halo (HPV effect)
47
Q

What are the features of a HSIL?

A

Grossly abnormal
Very increased nuclear: cytoplasmic ratio (hyperchromatic)
Disorderly
Crowed architecture

48
Q

What are the CIN grading levels?

A

CIN1
CIN2
CIN3

49
Q

What causes Barrett’s oesophagus?

What is the prevalence?

A

Gastroesophageal reflux damages the stratified squamous ep. of the esophagus, leading to its replacement by glandular (gastric or intestinal) epithelium, more suited to the acidic environment [occurs in 5-8% with GERD]

50
Q

What are the diagnostic criteria of Barrett’s oesophagus?

A

i. Endoscopic evidence of columnar lining in esophagus above gastroesophageal junction

AND

ii. Histological evidence of intestinal metaplasia (goblet cells) in biopsies from the columnar epithelium

51
Q

What is the dispute with regard to the classification of Barrett’s oesophagus?

A

Goblet cells not required for diagnosis of Barrett’s esophagus in Japan or UK

52
Q

What is the pathogenesis to Barrett’s oesophagus?

A

i. Repetitive mucosal injury by gastric acid and duodenal content (bile, pancreatic enzymes)
ii. Cellular proliferation
iii. Likely exposure to carcinogens (eg. nitrosamines)
iv. Re-epithelialization by columnar epithelium

53
Q

What can Barrett’s oesopagus cause, what is risk?

A

Key precursor for esophageal adenocarcinoma (30 to 60 fold relative risk)

0.5% annual rate for malignant transformation; 10% lifetime risk; short segment (

54
Q

The progression from dysplasia to carcinoma is a multiple step process which involves a series of molecular events. What some of these?

A 
P16 mutation,
P53 mutation, 
EGFR over-expression, 
HER2 amplification, 
Abnormal WNT signalling
55
Q

Who does one identify dysplasia?

A

a. Surface maturation of glandular mucosa - comparison with underlying glands
b. Architecture of glands - crowding, change in shape and complexity; gland fusion a feature of malignancy
c. Cytology of proliferating cells - nuclear atypia, loss of polarity
d. Response to inflammation and erosions/ulcers - reactive/regenerative changes vs. dysplasia

56
Q

What is seen when staining a section of oesophagus with Barrett’s which is negative for dysplasia?

A

Intestinal metaplasia = goblet cells present, basal nuclei

57
Q

What is seen when staining a section of oesophagus with Barrett’s with low grade dysplasia?

A

Glands abnormal
Crowded
Enlarged atypical nuclei which are hyperchromatic
Pseudostratified

58
Q

What is seen when staining a section of oesophagus with Barrett’s with high grade dysplasia?

A

Severe nuclear atypia,
Big/irregular clumped chromatin,
Still forming discrete glands and not an invasive tumour

59
Q

What is seen when staining a section of oesophagus with Barrett’s with Intramucosal carcinoma?

A

Glands invade into LP where the tumour cells gain access to lymphatics and have metastatic potential (hence becomes a carcinoma); still background of dysplasia

  1. Characterized by fused, cribriform structure
  2. Can invade through the muscularis propria
60
Q

What is carcinoma in situ?

A

Pre-invasive term for severe dysplasia at certain sites eg. skin, glans penis, breast, bladder, endocervix

61
Q

What anatomical boundary is breached allowing a carcinoma access to lymphatics and blood vessels (and hence invasion and metastasis) in the cervix?

A

Basement membrane

62
Q

What anatomical boundary is breached allowing a carcinoma access to lymphatics and blood vessels (and hence invasion and metastasis) in the` oesophagus?

A

Basement membrane

63
Q

What anatomical boundary is breached allowing a carcinoma access to lymphatics and blood vessels (and hence invasion and metastasis) in the Colon?

A

Muscularis mucosae [into LP STILL regarded as carcinoma in situ]

64
Q

What anatomical boundary is breached allowing a carcinoma access to lymphatics and blood vessels (and hence invasion and metastasis) in the Breast?

A

Myoepithelial cell layer loss

65
Q

What anatomical boundary is breached allowing a carcinoma access to lymphatics and blood vessels (and hence invasion and metastasis) in the prostate/

A

Basal cell layer loss

66
Q

What is DCIS?

A

Ductal carcinoma in situ (DCIS) = non-invasive, high or low grade
Shows expansion of ducts but still orderly and not infiltrative

67
Q

What is DCIS with mircoinvasion?

A

Irregular infiltrative glands, invasive ductal carcinoma from DICS

68
Q

What are the modes of carcinoma spread?

A

a. Direct invasion = transcoelomic spread in body cavities
b. Lymphatic invasion = common for carcinomas, RARE for sarcomas i. Nodal metastases ii. Sentinel lymph nodes = first/first group of lymph nodes draining a tumour cell 1. Surgery often removes primary disease and sentinel lymph nodes iii. Regional and distal lymph nodes
c. Vascular invasion (eg. renal cell carcinoma) i. Via left supraclavicular lymph node to subclavian vein then to the circulation
d. Perineural invasion i. Common in some tumours, more a feature for local recurrence than for distant spread

GIT (15 decks)

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