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2.2 Cellular Pathology > Immunohistochemistry - Prognosis > Flashcards

Immunohistochemistry - Prognosis Flashcards

1
Q

What is the main proliferation marker

A

Ki67

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2
Q

What is Ki67
(4)

A

Proliferation marker
Much easier than counting mitotic figures
High proliferation vs low proliferation
High proliferation = aggressive tumour

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3
Q

What are therapy markers
(3)

A

Expression of these antigens/proteins in the tumour cells is predictive of response to therapy, and/or more aggressive tumours

They look for changes in protein expression to indicate therapy

Change is the result of a mutation

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4
Q

Write about breast cancer therapy
(3)

A

Oestrogen and progesterone receptors - responsive to oestrogen blocking with Tamoxifen in 70-80% of breast tumours

Human epidermal growth factor receptor 3, Her-2-over-expression - found in 20% of cancers, may be responsive to HER2 blocking therapy (Trastuzumab immunotherapy)

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5
Q

What are the main breast cancer markers

A

Oestrogen and progesterone receptors
Her-2 over expression

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6
Q

How are oestrogen and progesterone receptor positive breast cancers treated

A

Oestrogen blocking with Tamoxifen

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7
Q

How are Her-2 over expression breast tumours treated

A

May be responsive to Her2 blocking therapy such as Trastuzumab immunotherapy

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8
Q

Write about colon cancer therapy markers
(3)

A

DNA repair proteins - loss of expression indicates genetic mutation
EGFR - high expression - may be responsive to antibody therapy
Her2 in gastric adenocarcinoma

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9
Q

How can EGFR positive colon cancer be treated

A

Antibody therapy

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10
Q

Write about lung cancer therapy markers

A

PDL1 in lung adenocarcinoma

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11
Q

Write about estrogen positive breast cancer

A

If overexpressed this means estrogen is driving the tumour

Tamoxifen can be given

Works for 70-80% of tumours

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12
Q

Write about Her-2 expression

A

Over expressed in 20% of breast cancers
Usually look for estrogen receptor first then look for Her-2 -> if you have neither than you are triple negative
Trastuzumab used to treat - majority of Her-2 can be treated with this some cannot

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13
Q

Write about colon therapy markers

A

Wide range of tumour types

Look for DNA repair proteins

These proteins are there to fix errors in DNA replication -> these take out the incorrect nucleotide and replace it

If you have a mutation in your DNA repair protein gene you will get more tumours over all but they are often found in colon but also in gynae in women (Lynch syndrome)

DNA mismatch repair proteins have been mutated -> don’t work -> they are weak points in DNA that are prone to error e.g. prone to tumours

EGFR – high expression

HER2 also seen in gastric adenocarcinomas -> only really learned this in the past 8 years – treated with Herceptin

Tend to see same mutations in different tumours -> e.g Her 2 -> could be weak points in our human DNA etc
- Lung Cancer

PDL1

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14
Q

What are the three types of immunohistochemistry markers for breast cancer

A

Diagnostic markers
Markers of myoepithelial cells - BM invasion
Prognostic and therapeutic markers

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15
Q

Write about breast cancer Diagnostic markers

A
  • Cytokeratin [CAM5.2] , Epithelial Membrane antigen, Human Milk Fat globule
    1 and 2 [HMFG1,2]
  • E-cadherin – lost or reduced in invasive lobular carcinoma
  • EGFR, Cytokeratin5/6 - certain basal subtypes
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16
Q

Write about markers of myoepithelial cells- BM invasion of Breast Cancer

A

Smooth muscle actin
Calponin
p53

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17
Q

Write about prognostic markers of breast cancers

A
  • Hormone receptors (oestrogen and progesterone receptors), HER 2 – human
    epidermal growth factor 2,
  • Ki67, p53 – proliferation, prognostic
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18
Q

Write about p53

A

o P53 is the most mutated gene you will find in every tumour that exists
o P53 mutation is not good
 First found as an inherited syndrome
 But now this mutation has been found in many tumours outside of the inherited syndrome

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19
Q

How does tamoxifen work

A

Blocks tumour growth
Hormone therapy
Blocks eostrogen in tumour cells
Other methods of treatment not as popular

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20
Q

What are some other treatment regimes for breast cancer?

A

Aromatase inhibitors - block synthesis of oestrogen

Taxol - tree-derived antagonists of oestrogen

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21
Q

Write about Her2

A

Its an oncogene
Member of epidermal growth factor receptor (EGFR) family
Involved in cell growth and proliferation
Block with Trastuzumab monoclonal antibody therapy (Herceptin)
Found in 15-20% of invasive breast cancers and gastric adenocarcinomas

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22
Q

Write about Her2 amplification or overexpression in breast cancer

A

Its associated with increased disease recurrence and worse prognosis

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23
Q

How is Her2 breast cancer treated

A

Herceptin - monoclonal antibody activity

24
Q

Write about Her-2-analysis
(3)

A

Laboratory investigation on FNA or biopsy

IHC - Score: 0, 1+, 2+ and 3+ for Her2 staining

ISH - detection of Her2 gene amplification (FISH or CISH)

25
Q

Write about IHC Her-2 analysis

A
  • 0 and 1+ - non-amplified, no HER2 therapy
  • 3+ is considered true amplification, only 25% of IHC 2+ are amplified
  • If 2+, then proceed for FISH HER2 test to check for amplification
26
Q

Write about ISH detection of Her2 using FISH or CISH

A
  • Ratio of normal chromosome to HER2 gene expression
  • 1:1 ratio = normal, >2.2 HER2/Chromosome 17 = amplified
  • If amplified then recommend Herceptin antibody therapy
  • Can also test by chromogenic ISH [CISH or DISH]
27
Q

Write about Her2 amplification

A
  • FISH is the gold standard
  • Pink = Her2
  • Need to count 50 to 100 cells for ratio
  • Ratio is over 2;2
    o Patient will respond
  • Medical scientist signs this and recommends treatment -> not passed on to the pathologist
  • Fluorescence fades so pictures are taken of the slide
  • Colorimetric = black
28
Q

How is triple negative treated

A

o Total mastectomy
o Local radiation
o Chemotherapy
o Worst prognosis
o Further markers – basal vs non basal

29
Q

Write about triple-negative breast cancer

A
  • Tumour does not express the receptors - OR, PR and HER2- negative
    [by IHC]
  • Two types – Basal [CK5/6 + and EGFR +] and non-basal type
  • Chemotherapy main form of therapy
  • Worse prognosis that other breast cancers, as less treatment options
30
Q

What are the prognostic factors for breast cancer

A
  • Lymph node status – how many positive
  • Size of tumour
  • Histologic type (lobular, ductal, mucinous)
  • Lymphovascular invasion – tumour cells in vessels
  • Hormone receptor status –
  • Ostrogen and progesterone receptor positive [good prognosis]
  • Oncogene expression
  • Her2/Neu amplification positive [worse prognosis]
  • Proliferative rate [immunostain for Ki67]
31
Q

Write about breast cancer staging

A

 TNM (Tumour, lymph Node, Metastases)
 Tis Carcinoma in situ
 T1 - Limited to breast, <2cm
 T2 and T3 Limited to breast, larger tumours
 T4 Evidence of metastatic sprea

32
Q

How is breast cancer spread

A

Local spread: skin, nipple, chest wall

Lymphatic -> lymph nodes (sentinel and axillary)

Blood - lungs, liver, bones, serous cavities

33
Q

Write about the progression of breast cancer

A

Long term survival is improving due to improved therapies and patient management

34
Q

What are the side effects of cancer immunotherapies

A

Herceptin causes heart disease
Herceptin patients often cant tolerate it due to heart problems
Increased risk of endometrial cancer with all immunotherapies
Affects calcium metabolism (Tamoxifen)

35
Q

Write about breast cancer therapy

A

Selected based on age, hormone receptor, Her3, Lymph node status

36
Q

What therapies are used for breast cancer

A
  • Combined hormonal and chemotherapy
  • Chemotherapy and HER2 antibody therapy
  • Adjuvant radiotherapy
37
Q

Write about gastric tumours

A

Majority are gastric adenocarcinomas
* Differentiation biomarkers -Immunopositive -
Cytokeratin 7-, 20+, Carcinoembryonic antigen
* Therapy Biomarkers –erbB2/HER2 amplification
[20%]
* If HER2 positive – receive monoclonal antibody therapy
* Trastuzumab (Herceptin

38
Q

What are the therapeutic markers for adenocarcinoma

A

Only Her-2 amplification (worst prognosis then not having it)
Patients are given Herceptin but they won;t respond near as well as in breast cancer

39
Q

Write about gastric lymphoma

A

3% of tumours
Immunostain for CD45 (all lymphomas), CD20 (B lymphocyte) or CD3+ (T lymphocyte)

40
Q

Write about gastric sarcomas

A

2% of tumours
Immunostain for Vimentin, Ckit (CD117), DOG1

41
Q

Write about targeted therapy biomarkers for gastric tumours

A
  • Gastric adenocarcinoma: EGFR/HER2, 20% positive
  • GIST – CD117 (ckit) + - treat with Gleevec (anti c-kit)
  • Lymphoma - CD20 +, block with monoclonal antibody anti-CD20 targeted therapy
42
Q

What are the three markers for colorectal cancer

A
  1. Diagnostic markers
  2. Therapeutic markers
  3. Monitoring biomarkers (blood assay)
43
Q

Write about diagnostic biomarkers for colorectal cancer

A

Adenocarcinoma tumours express:
- Cytokeratin - epithelial
- Cytokeratin 20+, Cytokeratin 7-
- Carcinoembryonic antigen Ca19.9

44
Q

Write about therapeutic markers for colorectal cancer

A
  • Immunotherapy is given to block EGFR and VEGFR
  • K-RAS, N-RAS, BRAF, mutation status to see if targeted therapy will work, IF K-RAS or N-RAS positive
    then EGFR immunotherapy will not work.
  • HER2 – small percentage are amplified
45
Q

What monitoring biomarkers are there for Colorectal cancer

A

CEA
Ca19.9

46
Q

Write about melanoma

A

Skin, Eye, Acral <400 cases p.a
- Legs - female, Trunk - male

Mostly due to sun exposure
- Sunbeds also associated with raised risk

Commonly from pre-existing moles

Removal by excision – sample for histology
* Cytology – FNA of organs invaded by melanoma cells

Various types:
* Superficial spreading, Nodular, Amelanotic
* Vascular spread to brain, lungs, LN

47
Q

How are melanomas prevented

A

Sunscreen
Cover moles
Childhood protection (no burning)
Cover up - hats
Avoid sunbeds, UV light
Check moles for:
- change in size or shape
- change in colour, texture
- sore, reddening around edges, bleeding

48
Q

Write about Melanoma biomarkers

A

Mel-A, S100 and HMB45 (malignant melanomaa)

SOX 10 positive in malignant melanoma’s

PPRAME for melanoma

BRAF - for therapeutic treatment e.g. Vemurafenib

49
Q

Write about BRAF treatment for melanoma

A

Only extends life for about 6 months max
Some people get 2 months while other get 2 years

50
Q

Write about V600E for melanoma

A

Most common mutation
The only mutation therapy will respond to
Very specific therapy for codon 600 of the BRAF gene

51
Q

Write about gene mutation analysis of BRAF

A

Molecular test: BRAF gene mutation analysis
* 50 -60% melanomas have this gene mutation

Most common mutation is V600E

Predicts targeted therapy responders

Positive for BRAF mutation - given anti-braf inhibitor therapy - vemurafenib

52
Q

Write about V600E mutation of BRAF

A
  • Codon 600; Thymine instead of adenine in DNA/mRNA
  • Leads to enzyme produced with glutamate (E) instead of
    valine (V) - V600E
53
Q

Who responds to therapy

A
  • Not all patients will respond to therapy
  • Many mechanisms of resistance
  • When resistant cells dominate the population of the tumour, the
    disease doesn’t/ceases to react to medications
54
Q

Write about lung adenocarcinoma

A

2 main histological subtypes (NSCLC and SCLC)

NSCLC can be further defined at a molecular level according to the oncogenes it contains

Rarely concurrent - with non smokers having the highest rates of actionable mutations

55
Q

What lung mutations respond to therapy

A
  • Activating mutations of EGFR in NSCLC are a favourable predictive facor for
    EGFR tyrosine kinase inhibitors (TKI’s)
  • Patients with primary EGFR exon 19 deletions and mutation in exon 21
    (L858R) get standard first line treatment – gefitinib or erlotinib but also
    second generation TKI’s Afatinib
  • EGFR TKI’s improve response rates, time to progression and over all survival
  • Patients will develop disease progression after a median of 10 to 14
    months
  • Optimal treatment regimes are not clearly defined except for the T790M
    mechanism of resistance
56
Q

Write about T790M mutation in lung cancer

A
  • 30-50% of resistance is caused be mutation T790M in lung cancer
  • Usually late stage disease
  • Primary treatment has failed
  • Repeat tissue biopsy id important to explore resistance mechanisms
  • Difficult to get a biopsy sample
  • Liquid biopsy is ideal in this situation
57
Q

Write about the treatment of NSC lung cancer

A
  • Third generation TKI’s- osimertinib has been approved for NSCLC with
    acquired EGFR resistance
  • Other mechanisms may require combination therapy
  • Discover of resistance mutation to T790M treatments- emergence of
    mutation L718V and C797S mutation
  • Mechanisms still being identified

2.2 Cellular Pathology (29 decks)

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