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PATH30001 - Mechanisms of Disease > Lecture 31 - Cancer Case History > Flashcards

Lecture 31 - Cancer Case History Flashcards

1
Q

Describe the sequence of investigations that would be taken with a suspected cancer case

A
  1. History
    • History of the problem
    • Past history of the patient (social, hobbies, travel )
    • Medical history of the family
  2. Examination
    • Masses anywhere
    • Other signs: anaemia etc.
3. Biopsy
 • Excisional biopsy
 • Incisional biopsy
 • Needle biopsy
 • Fine needly aspiration
  1. 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

  1. Management
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2
Q

Compare the different biopsy techniques

How is it decided which is used?

A

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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3
Q

Describe techniques that were previously used for cancer investigation, but have been superseded

A
  1. Electron microscopy
  2. Histochemical stains
    • Perls Prussian Blue
    • PAS (Periodic acid Schiffs)
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4
Q

Which tumours were tested for in the IHC panel in this case?

A

• Lymphoid neoplasms

Soft tissue tumours:
 • Rhabdomyosarcoma
 • Ewing family tumours
 • Primitive neural tumours
 • Rhabdoid tumour
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5
Q

What was the girl’s diagnosis?

Describe this kind of cancer

A

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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6
Q

What are sarcomas?

A

Malignant tumours

Of the following tissues:
 • Bone
 • Cartilage
 • Soft tissues:
- fat
- fibrous tissue
- smooth muscle
- skeletal muscle
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7
Q

Compare Rhabdomyoma with Rhabdomyosarcoma

A

Both tumours showing skeletal muscle differentiation, however:

Rhabdomyoma: benign

Rhabdomyosarcoma: malignant

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8
Q

What is the name for tumours of smooth muscle?

A

Leiomyoma

Leiomyosarcoma

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9
Q

Describe the molecular and genetic studies that are carried out

A

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

  1. Protein products run on a gel
  2. 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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10
Q

Which chromosomal translocations are seen in Alveolar Rhabdomyosarcoma?

What is the result of these translocations?

A
  1. PAX3-FKHR
    • Paired box homeodomain of PAX3
    • Forkhead domain gene
    • t ( 2 ; 13 )
  2. 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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11
Q

Pathological diagnosis of many cancers is a combined…

A

… morphologic and molecular / genetic exercise

Parameters:
1. Demographics
 • Infant
 • Child
 • Adult
  1. Clinical features
    • Histology
    • Metastasis
    • Prognosis
  2. Genetics
  3. Gene expression
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12
Q

What is the importance of classical prognostic and management information?

A

Despite all the new technologies, this is still important

  1. 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
  2. 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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13
Q

What would be the histological features of a high grade tumour?

A
  • An almost undifferentiated sheet of malignant cells
  • Very atypical nuclei
  • High mitotic activity • Maybe some necrosis
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14
Q

Describe the management of the case in question

A
  1. Chemotherapy
2. Two weeks later re-admitted with evidence of chemotherapy toxicity
 • Nausea
 • Vomiting
 • Diarrhoea
 • Abdominal pain
 • Gut toxicity (dilated bowel loops)
  1. Improvement
  2. Likely death
    • Due to the aggressive nature of this particular cancer and late stage diagnosis
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15
Q

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

A

None identified

As in, no inheritance or exposure to environmental carcinogen

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16
Q

Are childhood cancers curable?

A

Certain variants are:
• Early stage neuroblastoma
• Retinoblastoma
• some types of Lymphoma

Alveolar Rhabdomyosarcoma is particularly aggressive and cure is unlikely

17
Q

Describe why cancer is a genetic disease

What about in this particular case?

A

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

18
Q

Specifically, abnormalities in which sorts of genes will cause malignant transformation?

What is the result of these abnormalities?

A

Genes encoding critical components that regulate:
• Cell growth
• Differentiation
• Cell death

Result:
• Population of cells that have a growth advantage
• Uncontrolled proliferation

19
Q

What can molecular and genetic studies tell us?

A
  • Prognosis
  • Management
  • Diagnosis
  • Molecular mechanisms of carcinogenesis
20
Q

What does management depend on?

A
  • Tumour type
  • Aggressiveness (grade)
  • Progression (stage)
21
Q

Describe the Grade and Stage in the case of the young girl

A

Grade: high

Stage: advanced

22
Q

Which age groups are most commonly affected by cancer?

A

Adults

In this way, the story of the young girl is unusual

23
Q

Which sorts of cancer are most common?

A

Carcinomas (epithelial)

  • Lung
  • Breast
  • Colon

Cause:
• Environmental agent such as cigarette smoke

24
Q

Describe the multi-step theory of carcinogenesis

To which types of cancer does it apply well? To which doesn’t it?

A

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)

25
Q

List some clearly defined, avoidable or modifiable risk factors for malignancies

For which sort of malignancies are these risk factors, and which not?

A

• 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)

26
Q

What are some questions for the future of cancer research?

A

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?

27
Q

What are some questions for the future of diagnosis and treatment?

A

Will tissue still need to be taken for a final diagnosis?

How can malignant neoplasms be more effectively treated with less toxicity?

28
Q

In the bulk of cancer diagnoses in Australia today, what is the technique used to deliver the initial diagnosis?

A

Light microscopy of tissue

+ H & E stain

29
Q

When performing an excisional biopsy, where is the tissue taken from?

A

Inguinal lymph nodes

Fairly superficial, so easy to access

30
Q

What is great about immunohistochemistry?

A 
It can tell us about cell lineage:
e.g.
 • Epithelial
 • Soft tissue
etc.
31
Q

What does the ‘leio-‘ prefix mean?

A

Smooth

32
Q

Summarise diagnostic images obtained over the whole process

A
  1. H&E tissue stain
    • Pink and purple
  2. Immunohistochemistry
    • Brown & blue
  3. Molecular analysis (on a gel)
    • Identification of fusion
    protein product
33
Q

Why would we do molecular and genetic analyses?

A

This pigeon-holes the underlying genetic changes

This provides:
• Definitive diagnosis
• A strong target for therapy

34
Q

What is the role of PAX3-FKHR in Alveolar rhabdomyosarcoma?

A

Fusion protein that partly drives the tumour

35
Q

Describe molecular subgroups of Medulloblastoma

What is the take home message for the lecture?

A

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

36
Q

There is metastasis to lymph nodes. Does this indicate an early or late stage tumour?

A

Late stage

37
Q

What does chemotherapy target?

What is bad about this?

A

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

38
Q

Where did the cancer come from in this case?

A

We don’t know

It has differentiated towards skeletal muscle, but this doesn’t tell us about where it came from

39
Q

What is often the trigger or cause for paediatric cancers?

A

It is quite unclear

It’s not like adult cancers, which are triggered by risk factors such as cigarette smoke, diet etc.

PATH30001 - Mechanisms of Disease (34 decks)

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