Lecture 31 - Cancer Case History Flashcards by Eleanor Nicklason

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

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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

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Describe techniques that were previously used for cancer investigation, but have been superseded

Electron microscopy
Histochemical stains
• Perls Prussian Blue
• PAS (Periodic acid Schiffs)

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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

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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

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What are sarcomas?

Malignant tumours

Of the following tissues:
 • Bone
 • Cartilage
 • Soft tissues:
- fat
- fibrous tissue
- smooth muscle
- skeletal muscle

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Compare Rhabdomyoma with Rhabdomyosarcoma

Both tumours showing skeletal muscle differentiation, however:

Rhabdomyoma: benign

Rhabdomyosarcoma: malignant

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What is the name for tumours of smooth muscle?

Leiomyoma

Leiomyosarcoma

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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

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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

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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

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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

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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

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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

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What was the ‘cause’ of this girl’s neoplasm?

None identified

As in, no inheritance or exposure to environmental carcinogen

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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

1. H&E tissue stain • Pink and purple 2. Immunohistochemistry • Brown & blue 3. 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.