Lecture 31 - Cancer Case History Flashcards
Describe the sequence of investigations that would be taken with a suspected cancer case
- History
• History of the problem
• Past history of the patient (social, hobbies, travel )
• Medical history of the family - Examination
• Masses anywhere
• Other signs: anaemia etc.
3. Biopsy • Excisional biopsy • Incisional biopsy • Needle biopsy • Fine needly aspiration
- Light microscopy
• Histology
• Cytology
5. Immuno-histochemistry Tells us about: • Cell lineage • Which treatments may be appropriate e.g. Herceptin
• Fluorescent mAbs against antigens:
- membrane
- cytoplasmic
- nuclear
• Panel ordered, covering various tumours appropriate to history
→ Diagnosis
6. Molecular and genetic studies • Prognosis • Management • Diagnosis • Molecular mechanisms of carcinogenesis
• Chromosome translocation tests
- Management
Compare the different biopsy techniques
How is it decided which is used?
Excisional:
• Cutting out
• Attempt to completely remove
• Therapeutic and diagnostic
Incisional:
• Cut out a small portion
• Only diagnostic
Needle:
• Preservation of architecture
Fine needle aspiration:
• Suck out cells
• No preservation of architecture
Describe techniques that were previously used for cancer investigation, but have been superseded
- Electron microscopy
- Histochemical stains
• Perls Prussian Blue
• PAS (Periodic acid Schiffs)
Which tumours were tested for in the IHC panel in this case?
• Lymphoid neoplasms
Soft tissue tumours: • Rhabdomyosarcoma • Ewing family tumours • Primitive neural tumours • Rhabdoid tumour
What was the girl’s diagnosis?
Describe this kind of cancer
Alveolar Rhabdomyosarcoma
‘Myo-‘: showing muscle differentiation
‘Rhabdo-‘: showing specifically skeletal muscle differentiation
‘Sarcoma’: malignant, non-epithelial tumour
Alveolar:
• More aggressive subtype of rhabdomyosarcoma
• Specific microscopic appearances
What are sarcomas?
Malignant tumours
Of the following tissues: • Bone • Cartilage • Soft tissues: - fat - fibrous tissue - smooth muscle - skeletal muscle
Compare Rhabdomyoma with Rhabdomyosarcoma
Both tumours showing skeletal muscle differentiation, however:
Rhabdomyoma: benign
Rhabdomyosarcoma: malignant
What is the name for tumours of smooth muscle?
Leiomyoma
Leiomyosarcoma
Describe the molecular and genetic studies that are carried out
Chromosome translocation tests
This is a very new field
This allows specific identification of translocation events that are driving the malignant transformation
Process:
1. RT-PCR
- Protein products run on a gel
- Identification of fusion protein products through comparison with normal and a known positive
Different translocations associated with different tumours
Helps guide the therapy
Which chromosomal translocations are seen in Alveolar Rhabdomyosarcoma?
What is the result of these translocations?
- PAX3-FKHR
• Paired box homeodomain of PAX3
• Forkhead domain gene
• t ( 2 ; 13 ) - PAX7-FKHR
• Paired box homeodomain of PAX7
• Forkhead domain gene
• t ( 1 ; 13 )
These translocations result in a chimeric fusion protein
Chimeric protein contributes to the initiation or progression of the neoplastic state
NB translocations won’t be examined
Pathological diagnosis of many cancers is a combined…
… morphologic and molecular / genetic exercise
Parameters: 1. Demographics • Infant • Child • Adult
- Clinical features
• Histology
• Metastasis
• Prognosis - Genetics
- Gene expression
What is the importance of classical prognostic and management information?
Despite all the new technologies, this is still important
- Grading
• How aggressive the tumour appears to be on microscopy
• The more closely a tumour resembles normal tissue, the lower grade it is
• Performed with light microscopy + H&E stain
e.g. Bowel tissue that closely resembles normal tissue → low grade
Bowel tissue that is an undifferentiated mass of cells with mitoses etc → high grade - Staging
• Assessment of how far the cancer has spread at the time of diagnosis
• Early stage: small, not invaded deeply
• Later stage: large, invaded deeply, metastasised
• There are varying degrees of metastasis as well
What would be the histological features of a high grade tumour?
- An almost undifferentiated sheet of malignant cells
- Very atypical nuclei
- High mitotic activity • Maybe some necrosis
Describe the management of the case in question
- Chemotherapy
2. Two weeks later re-admitted with evidence of chemotherapy toxicity • Nausea • Vomiting • Diarrhoea • Abdominal pain • Gut toxicity (dilated bowel loops)
- Improvement
- Likely death
• Due to the aggressive nature of this particular cancer and late stage diagnosis
What was the ‘cause’ of this girl’s neoplasm?
None identified
As in, no inheritance or exposure to environmental carcinogen
Are childhood cancers curable?
Certain variants are:
• Early stage neuroblastoma
• Retinoblastoma
• some types of Lymphoma
Alveolar Rhabdomyosarcoma is particularly aggressive and cure is unlikely
Describe why cancer is a genetic disease
What about in this particular case?
Cancer cell exhibits abnormalities of gene sequence or expression
To be clear: this does not mean it is inherited
Just means that the basic abnormality is in the genes
Due to: • Exposure to environmental carcinogens • Inherited abnormalities (germ line mutations) (small % of cases) • Random events • or interactions of the above
In this particular case:
• Characteristic chromosomal translocation
Specifically, abnormalities in which sorts of genes will cause malignant transformation?
What is the result of these abnormalities?
Genes encoding critical components that regulate:
• Cell growth
• Differentiation
• Cell death
Result:
• Population of cells that have a growth advantage
• Uncontrolled proliferation
What can molecular and genetic studies tell us?
- Prognosis
- Management
- Diagnosis
- Molecular mechanisms of carcinogenesis
What does management depend on?
- Tumour type
- Aggressiveness (grade)
- Progression (stage)
Describe the Grade and Stage in the case of the young girl
Grade: high
Stage: advanced
Which age groups are most commonly affected by cancer?
Adults
In this way, the story of the young girl is unusual
Which sorts of cancer are most common?
Carcinomas (epithelial)
- Lung
- Breast
- Colon
Cause:
• Environmental agent such as cigarette smoke
Describe the multi-step theory of carcinogenesis
To which types of cancer does it apply well? To which doesn’t it?
Abnormal cells progressively acquire mutations that alter their appearance and their capabilities
This is often the case in adult carcinomas
Not yet shown to have convincing evidence of being the case in soft tissue tumours
More often the case:
• One or two well defined mutations or genetic abnormalities (e.g. chromosomal translocations)
List some clearly defined, avoidable or modifiable risk factors for malignancies
For which sort of malignancies are these risk factors, and which not?
• Cigarette smoking
• UV light
• Dietary factors
etc.
These are common risk factors for adult malignancies
Paediatric cancers are not associated with such environmental risks (as far as we know)
What are some questions for the future of cancer research?
Why are sarcomas arising in adolesencts and young adults often more aggressive than those arising in very young children?
Why do some late stage apparently aggressive neuroblastomas suddenly regress?
What event or events cause the genetic abnormality in a tumour such as rhabdomyosarcoma?
What are some questions for the future of diagnosis and treatment?
Will tissue still need to be taken for a final diagnosis?
How can malignant neoplasms be more effectively treated with less toxicity?
In the bulk of cancer diagnoses in Australia today, what is the technique used to deliver the initial diagnosis?
Light microscopy of tissue
+ H & E stain
When performing an excisional biopsy, where is the tissue taken from?
Inguinal lymph nodes
Fairly superficial, so easy to access
What is great about immunohistochemistry?
It can tell us about cell lineage: e.g. • Epithelial • Soft tissue etc.
What does the ‘leio-‘ prefix mean?
Smooth
Summarise diagnostic images obtained over the whole process
- H&E tissue stain
• Pink and purple - Immunohistochemistry
• Brown & blue - Molecular analysis (on a gel)
• Identification of fusion
protein product
Why would we do molecular and genetic analyses?
This pigeon-holes the underlying genetic changes
This provides:
• Definitive diagnosis
• A strong target for therapy
What is the role of PAX3-FKHR in Alveolar rhabdomyosarcoma?
Fusion protein that partly drives the tumour
Describe molecular subgroups of Medulloblastoma
What is the take home message for the lecture?
2 years ago, there would have been some H&E staining and immunohistochemistry, then that would be it
Now, there is a new step: tumour identified as either • Wnt pathway • Sonic hedgehog • Group 3 • Group 4 (in the case of medulloblastoma)
These classifications are based on the underlying genetic abnormality and FISH for amplification of crucial oncogenes
Molecular signature (i.e. Wnt pathway, Sonic Hedgehog etc) may come to define groups of cancer
At the moment, it is grouped the other way around:
Medulloblastoma grouped into various groups based on the aberrant molecular pathways
There is metastasis to lymph nodes. Does this indicate an early or late stage tumour?
Late stage
What does chemotherapy target?
What is bad about this?
Not specific
Targets rapidly proliferating cells
Very hard to target cancer rapidly proliferating cells, without targeting non-tumour cells
Gut epithelium targeted → GIT complaints
Red cells targeted → anaemia
Hair follicle cells targeted → baldness
Where did the cancer come from in this case?
We don’t know
It has differentiated towards skeletal muscle, but this doesn’t tell us about where it came from
What is often the trigger or cause for paediatric cancers?
It is quite unclear
It’s not like adult cancers, which are triggered by risk factors such as cigarette smoke, diet etc.
