Skin and subcut tissue

Question 1

Pathophys of melanoma

Answer 1

proliferation of the melanocytes within the basal layer of the epidermis
- UV exposure leads to thymine dimers and reactive oxygen species which cause damage to DNA
- Mutation of tumour suppressor genes or proto-oncogenes lead to unchecked proliferation and melanoma

Clarkes model
benign nevus -BRAF-> atypical or dysplastic nevus -CDKN2a-> Radial growth - E cadherin loss leads to -> vertical growth phase -> Metastatic melanoma

Question 2

Features of melanoma on histo report important for prognosis

Answer 2

Histological subtype
T stage
- Breslow
- Ulceration
Mitoses
LVI
Margins
TILS, regression

Question 3

MSLT 1

Answer 3

SLNB study

Phase 3 multicentre RCT published in 2014, looking at the role of SLNB
- 2001 patients with intermediate or thick melanoma, followed up for 10 years
- randomised to either WLE + SLNB vs WLE + observation of LN basins

Those with SLNB
- No difference in 10yr melanoma specific survival
- Improved 10yr DFS in those with positive nodes and mid-thickness primary

SNB+ve patients did worse than SLNB-ve patients therefore, strongest predictors of recurrence or death from melanoma
Conclusion is that the combination of SLNB and/or earlier LN dissection for node positive patients has improved disease-free survival, though need deCOG and MSLTII to establish whether the LN dissection is worthwhile or not.

Question 4

MSLT2 and DeCOG-SLT

Answer 4

Lymph node dissection trial

Trials that looked at the outcome of LN clearance vs clinical observation after postitive SLNB

• LND did not affect melanoma specific survival
• Rate of locoregional recurrence was lower in those with LND, but no difference in overall survival and higher rate of complications.
• Only included small volume disease < 0.5mm in small number of nodes (excluded high risk patients such as ENE, multiple positive nodes, immunosuppressed patients)

Question 5

Pembroluzimab

Answer 5

Monoclonal antibody

PD1 inhibitor - Binds to the PD-L1 ligand on tumour cells to allow them to be recogenised by the patient’s T cells

Funded in non-resectable stage III melanoma and stage IV melanoma in NZ

Side effects (10% of ppl): Rash, colitis, hepatitis, hypothyroid, hypophysitis (permanent pituitary dysfunction)

Question 6

Dabrafenib
Trametenib

Answer 6

30% of patients with melanoma are BRAF positive

Dabrafenib is a BRAF kinase inhibitor, and tranetenib is a MEK inhibitor which inhibit the MAPK pathway leading to proliferation of cells in melanoma

Question 7

Merkel Cell cancer pathology

Answer 7

neuroendocrine tumour of unknown origin

2 pathological pathway
- Polyomavirus infects cells, causes production of oncogenes leading to tumourgenesis and inhibition of tumour suppressor genes

• UVB pathway - sun damage causes a large number of mutations leading to malingnacy

Question 8

Pathophys of nec fasc

Answer 8

Infection with organism due to hematogenous spread or direct innoculation
-Release of toxins, cytokines and enzymes breaks down hyaluronic acid and allows horizontal and vertical spread along tissue planes
- Activation of thrombotic cascare causes Microthrombi of vessels adds to ischaemic environment and necrosis of tissue. Consumption of factors.
Facultative anaerobes facilitated in acid and ischaemic environment
- Destruction of cells leads to oedema, swelling, and impaired perfusion of tissues
-Tissue death and toxin release leads to SIRS, septic shock, MODS and death