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CancerGen > Molecular Pathology of Lung Cancer > Flashcards

Molecular Pathology of Lung Cancer Flashcards

1
Q

Lung cancer is how common and how deadly compared to other cancers?

A

The third most common cancer, but the cause of most cancer deaths (21%)

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2
Q

What is Stage I lung cancer?

A

1 nodule in one place, <3cm

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3
Q

What is Stage II lung cancer?

A

3-5cm tumour. Some affected lymph nodes from metastatic cells

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4
Q

What is Stage III lung cancer?

A

More metastasis, both sides of lung affected. Tumour >5cm.

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5
Q

What is Stage IV lung cancer?

A

Tumour metastasis to distant site. Tumour >7cm.

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6
Q

Most lung cancer is diagnosed when?

A

At stage IV

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7
Q

What is the 1 year survival of Stage IV cancer when detected?

A

20%

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8
Q

How do you sample lung cancers?

A

Resections in early stages.
Core biopsy or cytology for stage 3 and 4 diagnosis and staging…

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9
Q

What do we want to maximise in lung cancer patients?

A

The use of their tissue/cores/blocks.

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10
Q

What is the most common type of lung cancer?

A

NSCLC 80%

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11
Q

What is the less common type of lung cancer?

A

Small Cell carcinomas 20%

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12
Q

What are the histo features of small cell LC?

A

Big nuclei, staining blue from the DNA replicating

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13
Q

How is SCLC treated typically?

A

chemotherapy

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14
Q

What are the main two types of NSCLC?

A

50% Adenocarcinoma.
30% Squamous cell carcinoma (appears pinker, produces keratin).

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15
Q

How is NSCLC treated typically?

A

Lobectmy surgery if early enough. Otherwise chemo or radiotherapy.

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16
Q

In 2004 a subset of lung adenocarcinomas were found to have what type of mutation where?

A

Activating mutations in the TK domain of EGFR transmembrane receptor.

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17
Q

What do EGFR mutations in lung cancers typically do?

A

Causes abnormal dimerisation so they don’t need EGFR

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18
Q

What makes EGFR mutations able to be targeted?

A

Mutant EGFR can have increased binding affinity for TKIs over ATP when compared to WT protein. Treatment increases progression free survival.

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19
Q

What mutations are very high in an Asian never smoker population?

A

EGFR

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20
Q

Which mutations seems particularly associated with smoking?

A

KRAS mutations

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21
Q

EGFR mutations tend to occur in which type of adenocarcinomas?

A

Well differentiated adenocarcinomas with a lepidic pattern of growth (on surfaces, not penetrating deeper)

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22
Q

How does ALK typically get affected in LC?

A

Get’s rearranged forming a chimeric protein. The TK domain of ALK is given an N terminal partner, often EML4. It leads to an activated TK with transforming abilities that drives carcinogenesis

23
Q

What is the TKI that treats ALK fusion LC with a response rate of 65%?

A

Crizotinib

24
Q

Who do we test for ALK fusions?

A

All advanced adenocarcinomas and any not otherwise specified

25
Q

Who usually has ALK fusions?

A

Young never smokers

26
Q

What can normally be seen by Histo for ALK fusion LC?

A

Signet ring/goblet mucin cells. Mucin fills cells, pushes nucleus to the side

27
Q

What’s the ALK fusion rate between UK and Asia?

A

2% for UK, 11% for Asia

28
Q

How do you normally detect the EML4 inversion on chr2 that fuses in the middle of ALK?

A

FISH with breakapart probes

29
Q

What used to be the first screen for ALK fusions?

A

ALK IHC with a sensitivity of 99%. Any weak staining would be checked with FISH or NGS. If negative results on IHC, normally confident it would be true.

30
Q

What’s on the pansolid NGS panel at Manchester?

A

ALK, BRAF, EGFR, KRAS, MET

31
Q

EGFR variants, and ALK and ROS1 rearrangements tend to be in…?

A

Adenocarcinomas

32
Q

How do you test for ROS1?

A

NGS, FISH, or IHC strongly positive

33
Q

BRAF mutations are in lung cancer but are mainly in what other cancer?

A

Melanoma

34
Q

Which BRAF mutation is most common in LC and why is it a good thing?

A

V600E, it is treatable.

35
Q

What is V600E associated with morphologically and survival wise in Lung cancer?

A

Micropapillary features in 80% of patients.
Shortest disease free and lowest survival rates.

36
Q

KRAS mutations are associated with smoking. Which is the most common in NSCLC which can be treated with sotorasib?

A

G12C in 13% of NSCLC.

37
Q

Which histology pattern has the best prognosis?

A

Lepidic, just on surface (tends to be well differentiated)

38
Q

Which histology pattern has an intermediate prognosis?

A

Acinar

39
Q

What are the 5 listed histology patterns?

A

Lepidic, Acinar, Solid, Papillary and Micropapillary

40
Q

TRK receptors A, B and C (NTRK) signal to cause what?

A

Proliferation, survival, invasion and angiogenesis

41
Q

What drugs are used against NTRK fusions?

A

Larotrectinib and Antrectinib

42
Q

NTRK fusion rates are rare. But they are more common in rare cancers. name which rare cancers.

A

Infantile fibrosarcoma, secretory breast cancer, congenital mesoblastic nephroma

43
Q

IHC staining is good for detecting NTRK fusions, yes or not?

A

Good at 1 and 2, not good at 3 so much.

44
Q

MET is mutated in what percentage of squamous LC and adenocarcinomas?

A

3% of squamous LC.
8% of adenocarcinomas

45
Q

What changes are relevant in MET in LC?

A

Exon 14 splicing alterations that lead to skipping. Or gene amplification.

46
Q

So NSCLC is gradually classified based on:

A

Histology then molecular pathology.

47
Q

What are the two ways a tumour might become drug resistant?

A

Small subclone with an alteration already hangs around and grows once other cells are killed (can be mono or polyclonal).
Gain of new mutations over time.

48
Q

How can ALK positive lung cancers sometimes be mechanically resistant?

A

Drugs unable to reach brain metastases

49
Q

How do LCs get EGFR treatment resistance?

A

After a year many get resistance that can be from MET, HER2, BRAF or PIK3CA mutations. OR T790M in EGFR itself half the time.

50
Q

Which EGFR mutations have the best treatment response?

A

Exon 19 deletion and L858R in exon 21

51
Q

What does the EGFR T790M variant do?

A

Reduces the binding affinity of TKIs so EGFR binds ATP more, leading to more proliferation

52
Q

We’re now on 3rd and 4th gene EGFRi. Which one works well against T790M?

A

Osimertinib.

53
Q

What does C797S in TK domain of EGFR fo?

A

Prevents Osimertinib and other TKIs from working

54
Q

How is PD-L1 testing also important?

A

Might need to use a drug in combination with one targeting PD-L1 if highly expressed.

CancerGen (18 decks)

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