Melanoma + Skin Flashcards
What are the types of melanoma?
Radial Growth Phase
- Superficial Spreading
- Lentigo Maligna
- Acral Lentiginous
Vertical Growth Phase
- Nodular
Superficial Spreading
- Most common (70%)
- Intermittent exposure - sunburns
- Trunk and limb location
Lentigo Maligna:
- 10-15% of melanoa
- Cumulative UV exposure
- Commonly found on the face+ neck
Acral Lentignous Melanoma (soles/palms)
- Do not arise from moles
- Not caused by UV light
- Palms, soles, under nails
- Accounts for most melanoma in Asian people and almost all black people
Nodular Melanoma
- Vertical growth from outset
- Grow rapidly
- Worse prognosis as they tend to metastasize and they have growth in depth while others have horizontal growth.
- Not associated with high mole count
- Invasive melanoma
What are risk factors for melanoma?
- Unprotected sun exposure where episodic/intense sunburn in childhood is particularly harmful - blistering sunburns as child
- Light skin
- > 10 dysplastic naevi
- Immunosuppression
- Family history of melanoma
- DNA repair abnormalities (xeroderma pigmentosum) - autosomal recessive,
inherited condition characterized by an extreme sensitivity to ultraviolet (UV) rays from sunlight - Previous melanoma
- Multiple (>20) naevi
- Genetics: BRAF especially V600E and CDKN2A (p16) and CDK4 gene mutations.
- Physical interaction between CDKN2A/p16 and CDK4 proteins regulates the cell cycle progression through the G1 phase and dysfunction of these proteins by gene mutation is implicated in genetic predisposition to melanoma.
What characteristics would cause you to think it is a malignant skin lesion?
- A = Asymmetry
- B = Border (irregular border with indistinct
- C = Color (new changes in pigmentation or variations in pigmentation within the same lesion)
- D = Diameter > 6 mm
- E = Evolving (new lesion or a lesion that changes in size, shape, or color over time)
Where does melanoma metastasise to?
LN Liver Lung Brain Bone
What is the main prognostic factor for melanoma?
Tumour thickness (Breslow thickness) Others include: mitotic rate, ulceration, primary tumour location, LN older age/gender
Layers of the epidermis
Corn lovers give special bread Stratum corneum Stratum lucidum Stratum granulosum Stratum spinosum Stratum basale
Staging of melanoma
- Stage 0: melanoma in situ, not invading the dermis - surgical resection
- Stage 1: <1mm + ulceration or <2mm with no ulceration - surgical resection, sentinel LN biopsy
- Stage 2: >1mm+ ulceration and >2mm + no ulceration - surgical resection, sentinel LN biopsy, adjuvant RT +/- systemic therapy
- Stage 3: LN involved - surgical resection, nodal dissection, consider adjuvant RT +/- systemic tx
- Stage 4: mets
Stage 0-III: Surgery
Stage III-IV: systemic or RT
Surgical treatment for melanoma
Full thickness excision with 1-2cm safety margin.
If tumour thickness >1mm, requires sentinel LN biopsy.
Medical treatment for melanoma.
- Low response rates for chemotherapy
Systemic
- Immunotherapy: (normally use this first then targeted)
○ Anti-PD1: Pembrolizumab, Nivolumab
○ Anti-CTLA4: Ipilimumab
○ Combination Anti-PD1 + Anti-CTLA4: Ipilimumab and Nivolumab
○ PD-L1: Atezolizumab, Avelumab, Durvalumab
- Targeted Therapy:
○ BRAF Inhibitors “fenib” for patients with BRAF mutations: vemurafenib - selective V600E*, dabrafenib - all V600 + CNS activity *, encorafenib - all V600 + CNS - specific to metastatic or unresectable melanomas that have the BRAF V600E mutation
○ MEK Inhibitors “metinib”: trametinib, cobimetinib, binimetinib
○ To reduce/prevent resistance, BRAF + MEK inhibitors are used
Vemurafenib + Cobimetinib (Zelboraf + Cotellic)
Dabrafenib + Trametinib (Tafinlar +Mekinist) as 80% of patients on BRAF inhibitors develop RESISTANCE via the MAPK reactivation through MEK. BRAF + MEK are first line treatment for BRAF mutated melanoma. - Chemo: dacarbazine
- cKIT inhibitors: imatinib
Note: BRAF mutations in 50% cases, V600E (80%)< V600K (5%)
- BRAF more common in younger patients with minimal chronic sun induced damage
Usually do dual blockade for 3 months and then 2 years of anti-PD1 activity.
What are signs of more aggressive disease in melanoma?
- High LDH, brain mets, symptomatic systemic mets
What percentage of melanoma harbour a BRAF mutation?
40%
Most common are V600E (80%) and V600K (5%) mutations.
They are more common in melanomas arising in skin with little chronic sun-induced damage, less frequent in chronic sun damage and more common in younger patients.
What cancers are associated with BRAF mutation?
Melanoma 70%
Thyroid 50%
Colon 10%
B- CMT
What cancers are associated with RAS mutations?
Pancreatic cancer 90%
Colon cancer 50%
NSCLC 30%
PCRN
Side effects/toxicity of
- BRAF inhibitors
- MEK inhibitors
BRAF Inhibitors
- Fever: frequent, drenching sweats, tachycardia (much higher with dabrafenib)
- Rash, pruritus
- Photosensitivity - higher with vemurafenib, cobimetinib
- Arthrlagia
- Squamous cell carcinoma in patients who have cells with RAS mutations
- Skin toxicities improved if given MEK inhibitor
- Vemurafenib (selective V600E mutation): diarrhoea, arthralgia, rash, photosensitive ++, no CNS activity
- Dabrafenib (all V600 mutations + activity in CNS): fevers, vomiting, HTN, pruritus
MEK Inhibitors
- Rash
- Fatigue
- Arthralgia
- Diarrhoea
- Peripheral oedema
- Retinopathy
- No increased incidence of squamous cell carcinoma as inhibits the downstream MEK
What is the treatment for BRAF positive and BRAF WT melanoma.
BRAF positive: BRAF +MEK, eg: dabrafenib + trametinib
BRAF WT (other mutations like NRAS, CKIT, NF1, CTNNB1 or no know mutation): immunotherapy with anti-PD1 + anti-CTLA4. Nivolumab + Ipilimumab.
What is the function of CTLA4 and PD1 and where are they located.
PD-1 sits on T cells
PD-L1 sits on APC
- PDL1/PD1 binding inhibits T cell killing of tumour cell
- Blocking PDL1 or PD-1 allows T cell killing of tumour cell
- The PD-1 (programmed cell death-1) receptor is expressed on the surface of activated T cells.
- Its ligands, PD-L1 and PD-L2, are expressed on the surface of dendritic cells or macrophages
- PD-L1 is overexpressed on tumor cells
- PD-L1 expressed on the tumor cells binds to PD-1 receptors on the activated T cells, which leads to the inhibition of the cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment.
PD-1 inhibitors:
Nivolumab
Pembrolizumab
PD-L1 inhibitors:
Atezolizumab
Durvalumab
CTLA-4 is expressed on T cells and binds to B7 co-stimulatory receptors on APC preventing T cell activation.
CTLA-4 inhibitors e.g. Ipililumab block the binding of CTLA-4 to B7 resulting in T cell activation and immune clearance of tumour cell
What other cancers can PD1 inhibitors be used in?
Lung, renal, bladder, hodgkins
How does anti-PD1 and anti-CTLA4 compare?
anti-PD1 > anti-CTLA4 but combination best and shows synergistic effect.
Usually do dual blockade for 3 months and then 2 years of anti-PD1 activity.
Side effects of immunotherapy = immunotoxicity (anti-PD1 and anti-CTLA4)
- Normal role is to retain balance between activity and quiescence in the immune system.
- Anti-PD1 and anti-CTLA4 can cause unopposed immune activation and T cell dysregulation results in inflammation and tissue damage and can occur in any tissue
- most commonly in the skin, GI tract, liver, endocrine(thyroid, , adrenal, pituitary), lung. Normally peak in first 3 months but can occur anytime and after months therapy.
- Rash/pruritus, diarrhoea/colitis (>4 diarrhoea above baseline), hypophysitis, liver toxicity
CTLA4
- Diarrhoea and colitis more common
- Skin rash
- Pruritus
- Hepatitis
- Hypophysitis
- Thyroiditis
PD1
- Thyroid dysfunction especially hypothyroidism
What are the rates of toxicity for anti-PD1 and anti-CTLA4.
- Ipi+Nivo > Ipi > Nivo
- Ipilimumab + Nivolumab: higher rate of liver and lung
- Ipi: higher rates of GI involvement
- Nivo: high rates of endocrine involvement.
Treat like autoimmune with steroids and if worse with TNFi/mycophenolate, ivig/plasmapheresis etc
