Melanoma Flashcards
What is melanoma?
Malignancy of melanocytes
Epidemiology of melanoma
sex, age, survival rate, ethnicity
M>F (1.3 to 1)
Median age: late 50s
survival rate: 93% overall, 18% w/ mets
White non hispanics
Risk factors for melanoma
Unprotected sun exposure sunburn in childhood fair skin, light eye colour/hair, tendency to burn. multiple benign/dysplastic naevi FHx of melanoma Immunosuppression
Prognosticating factors for melanoma
- Tumour thickness - 1st predictor
(higher chance of microscopic involvement of LN) - Mitotic rate (2nd predictor)
- Ulceration
- Primary tumour location (arm/leg not as bad as scalp, hand, mucosal membrane)
- Lymph node involvement
CLassification
determined by microscopic evaluation of melanoma skin lesion as well as clinical and radiological assessment.
Genes associated with melanoma
BRAF (most common)
MEK
Other mutation in wildtype BRAF: c-KIT NRAS NF1 CTNNB1
BRAF mutation:
- characteristic
- position of mutation
- MOA
- most common mutation (40-60% mutation)
- less frequent in chronic sun damage
- common in younger patient
- 80-90%: mutation in V600E, 20% in V600K
- causes down stream activation of MEK/ERK pathway causing cell to proliferate
- useful for direct therapy
Stage 0 melanoma:
- definition
- treatment
melanoma in situ, located on top layer of skin, not invading dermis.
Tx: resection
Stage 1 melanoma:
- definition
- treatment
Definition:
<2mm + no ulceration
<1mm + ulceration
Tx:
Surgical resection
+/- sentinel node biopsy if >1mm or if >0.75mm+high risk features
Stage 2 melanoma
Definition:
>1mm + ulceration
>2mm + no ulceration
Tx:
Surgical resection
Sentinel node biopsy
Adjuvant RT +/- systemic Tx
Stage 3
Definition: LN involvement
Tx:
Surgical resection
Nodal dissection
+ adjuvant therapy and chemotherapy
What is sentinel node biopsy?
inject blue dye and radioisotope around primary site.
Sentinel node is then identified by inspection for blue stain and high uptake or radioisotope Node is then removed for analysis.
Principles of treatment of: Stage 4 (metastatic melanoma)
- Surgery (metastasectomy for a number of lesions)
- Immunotherapy
- IL2
- immune check point blockade (anti CTLA4, antiPD1, combination of both treatment)
- experimental: antiPDL1 - Targeted therapy:
- BRAF inhibitor
- MEK inhibitor - Oncolytic virus
- Chemotherapy
BRAF inhibitor:
- example
- MOA
- side effect
- clinical evidence
e.g. vemurafenib + dabrafenib
MOA: stop downstream activation of MEK /ERK thus cease uncontrolled cell proliferation+survival.
Evidence:
Vemurafenib has better outcomes compared to chemotherapy alone.
Combination BRAF/MEK inhibitor:
- example
- MOA
- side effect
- clinical evidence
- side effect
e.g.
vemurafenib +cobimetinib OR
dabrafenib + trametinib
MOA:
- Resistance to BRAF inhibitors occurs in almost all patient. By inhibiting BRAF+MEK, can prolong PFS and OS.
-decrease side effect from BRAF inhibitors due to a decrease in the paradoxical activation of the MAPK pathway.
Principle of immunotherapy:
- immune response to tumours
cancer relies on T cell activation in cancer surveillence.
in cancer, immune tolerance occurs because foreign molecules expressed by tumour cell are viewed as self.
Elimination:
Equilibrium: immune cell can eliminate all cell and prevent mets. This is a static phase
Escape: overtime this can escape, then cause detectable tumour
Principle of immunotherapy:
- mechanism of tumour evasion of the immune system
- Loss of antigenicity (loss of protein on cell surface to create peptide-MHC)
- Gain of immunosuppressive properties
- Creating an immunosuppresive environment.
Effect of immunotoxicity on endocrine
Thyroiditis (hypo/hyper)
Hypophysitis:
- visual change, headache, lethargy, imbalance, libido
Adrenalitis
Effect of immunotoxicity on endocrine
- presentation
- can this be recovered?
- management
Thyroiditis (hypo/hyper)
Hypophysitis:
- visual change, headache, lethargy, imbalance, libido
Adrenalitis:
- lethargy, weight loss, anorexia, nausea/fatigue, hypotension.
Mgmt:
- regular thyroid and cortisol level.
- replace hormone
- endocrine function will not recover with immunosuppression
- continue immunotherapy
Effect of immunotoxicity on respiratory system:
- presentation
- management
Pneumonitis:
- imaging changes
- dry cough
- dyspnoea
- tachypnoea
Mgmt:
- exclude RT changes, infection
- mild: monitor, r/v frequently
- moderate: admit, O2 support+ventilation, methylpred
Effect of immunotoxicity on liver:
- presentation
- management
Hepatitis
- deranged LFT
- lethargy
Mgmt:
- mild: observation
- severe: stop immunotherapy, steroid, mycophenolate
Rare presentation of immunotoxicity
Neurological:
GBS, encephalitis, MG, Peripheral sensory motor neuropathy.
Blood: haemolytic anaemia, neutropenia, CLL
Renal: nephritis
Cardiac: myositis
Endocrine: pancreatic failure - diabetes
What is pseudoprogression in immunotherapy
(10% across tumour types) - basically tumour appears to get bigger, patient is systemically well and then after that it shrinks in 4-6 weeks time.
Immunotoxicity: cutaneous
- Presentation: common, less common
Macular/papular rash over trunk and chest
Less common:
Stephen Johnson syndrome
Sweet syndrome
Bullous pemphigoid
Can worsen psoriasis + lupus
Mgmt:
symptomatic, steroids if bad
