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
What is currently used for stage III melanoma?
- Inteferon
What therapy is used for BRAF + patients.
BRAF + MEK are first line treatment for BRAF mutated melanoma.
Dabrafenib + Trametinib shows improved OS in BRAF + patients.
Which medication has shown improvement in recurrence free survival between nivolumab and ipilimumab?
Nivolumab has shown improvement in recurrence free survival compared to impilimumab.
What’s more damaging? UVA or UVB?
UVB
Clinical features + characteristics of BCC.
- Most common skin cancer (75%)
- Least lethal
- 80-85% arise in sun-exposed areas on head and neck
- More common >40yo
- Dysregulation of PTCH gene (tumour suppressor) - dysfunction in Hedgehog signalling pathway
- Typically a ‘pearly’ nodule with superficial telangiectasia
- Non-healing ulcer with a central depression and rolled, non-tender borders (rodent ulcer) - often ulcerates and erodes
- Scaling plaque (superficial basal cell carcinoma)
- Typically painless
- Slow growing over months-years - never metastasise but are very locally invasive
DDx: seborrhoeic keratosis.
Clinical features + characteristics of SCC.
- 20% of skin cancers
- 90% arise in sun-exposed areas
- More common >50yo, males > females
- Red, scaling nodule, may ulcerate and bleed, may be tender
- Atypical proliferating cells resemble keratinocytes, may produce keratin
- Slow to metastasise (<2%), higher risk from lip or ear (10-15%)
- Histologically - nests of keratinocytes, keratin whorls, lymphocyte infiltrate
- Has intercellular bridges (desmosomes)
- Elastosis - degeneration of dermal elastin fibres due to UV
- Pyrimidine dimers in DNA is a UV signature
- UV-B locally impairs immune response (T-cells)
- The classic clinical presentation of cSCC is a painless, nonhealing, bleeding ulcer
- All forms eventually ulcerate
- Ulcers are typically red with everted edges
- The floor of the ulcer resembles ulceration tissue and bleeds easily
- The skin around the ulcer is inflamed and indurated
- Location: most commonly on the face and neck
Typical locations include lower lip, ears, hands
What are premalignant lesions for SCC?
- Bowen’s disease (SCC in situ): atypical keratinocytes are confined to the epidermis. Pre-cancerous skin lesion that presents as an erythematous and scaly plaque with irregularly shaped and sharply defined borders.
- Actinic (solar) keratosis (exhibits atypia of the basal layer of the epidermis, dyskeratosis, hyperkeratosis, parakeratosis)
What looks very similar to SCC?
Keratoacanthoma
- A cutaneous low-grade tumour
- More common in middle-aged and elderly individuals
- Associated with Muir Torre syndrome
Phenotypic variant of hereditary nonpolyposis colorectal carcinoma syndrome (Lynch syndrome) caused by mutations in MLH1, MSH2 or MSH6 that are inherited in an autosomal dominant pattern. Causes the formation of several cutaneous tumours (eg: sebaceous adenomas and carcinomas, keratocanthomas) and visceral malignancies (eg: colorectal, endometrial, ovarian, urothelial)
- Rapidly developing neoplasm that may resemble SCC clinically and histologically
- Dome-shaped nodule with central keratin plug
The difference between keratoacanthoma between SCC is that keratoacanthoma have rapid growth and develop within a few weeks.
Characteristics of dysplastic naevi.
- Occur in 2-10% of people
- Usually >6 mm diameter; often multiple; show variation in pigmentation
- Compound naevi with cytological and architectural atypia
- If no family history of melanoma, approximately 6% lifetime risk of malignancy
- If positive family history of melanoma, may be associated with dysplastic naevus syndrome (autosomal dominant, caused by mutations in tumour suppressor genes such as CDKN2A) →60% lifetime risk of melanoma (90% in Australian studies)
Treatment for metastatic squamous cell carcinoma
- Combination of surgery, RT, chemo, targeted therapy + immunotherapy
- Platinum based chemo with fluorouracil + cetuximab (EGFRi) is standard of care for distant mets
- Cemiplimab (novel PD1 inhibitor) does who some efficacy for metastatic SCC
What is actinic keratosis a precursor to?
- Precursor to invasive squamous cell carcinoma
- Typically treated with cryosurgery
- Can trial topical fluorouracil or imiquimod
- Topic tribanibulin novel agent binding to tubulin
Diagnosis of nodular melanoma
EFG - Elevated, Firm, Growing Progressively
- ELEVATION: is the key feature of vertical growth phase
- FIRMNESS: is the key examination finding that helps distinguish NM from an inflammatory lesion
- Progressive GROWTH distinguishes aggressive malignancy from a stable benign tumour such as dermatofibromas
Melanoma ulceration
Indicates high risk for metastatic disease
Imaging in melanoma in regards to stage
- Stage I: Nil
- Stage II/III:
MRI brain, CTCAP
PET: locoregional vs metastatic disease (curable vs incurable) - Stage IV
MRI brain, CTCAP
PET - resectable vs nonresctable disease (curable vs incurable)
PBS Available Stage 3B/3C/3D or Resected Stage 4
PBS Available Stage 3B/3C/3D or Resected Stage 4
- Targeted therapy for BRAF mutated - Dabrafenib + Trametinib for 12 months
- Immunotherapy for all patients - nivolumab or pembrolizumab for 12 months
Stage III Melanoma Treatment
Surgery
- Clinical/radiological LN: lymphadenectomy
- Sentinel LN Biopsy +: observation with strict imaging protocol
Stage 3A: observation
Stage 3B/C/D/Resected Stage 4: Adjuvant therapies
- Dabrafenib + Trametinib for BRAF mutant for 12 months
- Anti- D1 for all patients
Nivolumab q4w/Pembrolizumab a3w or q6w for 12 months
Stage IV melanoma treatment
- Only curative option is surgical resection of metastasis if feasible - considered in the absence of locoregional disease and when mets confined to a single site amenable to complete resection
- Pulmonary mets: most common initial visceral site of metastatic disease
- Adrenal mets: benefit for surgical excision
- Brain mets:
single lesion - surgical excision = survival advantage
Stereotactic radiosurgery for <3 lesions which are <3cm in diameter
Multiple brain mets: whole brain radiotherapy
Stage IV melanoma treatment
- Only curative option is surgical resection of metastasis if feasible - considered in the absence of locoregional disease and when mets confined to a single site amenable to complete resection
- Pulmonary mets: most common initial visceral site of metastatic disease
- Adrenal mets: benefit for surgical excision
- Brain mets:
single lesion - surgical excision = survival advantage
Stereotactic radiosurgery for <3 lesions which are <3cm in diameter
Multiple brain mets: whole brain radiotherapy
Novel approaches in Melanoma mangement
Target Therapy
- BRAF inhibition
VEMURAFENIB: selective V600E mutations, no activity CNS
DABRAFENIB: inhibits all V600 mutations, CNS activity
- MEK inhibition
TRAMETINIB
BINIMETINIB - cKIT inhibition: acral and mucosal subtypes treat with IMATINIB
Immunotherapy
- CTLA4 monoclonal ab
- Anti-PD1 ab
Which gene is most commonly mutated in melanoma?
Activating BRAF mutations are most common mutated gene in melanoma
What are the features of CTLA4?
- CTLA-4 is a T cell receptor and a naturally occurring negative regulator of the immune system
- Has a role in preventing autoimmune disease and an important role in immunosuppression in tumourigenesis
Features of CTLA-4
- Receptor expressed on activated helper T cells and cytotoxic T lymphocytes
- Inhibits T cell activation and proliferation
Binds to the B7 molecule on the APC surface with higher affinity than CD28 (which is found on the T cell)
Puts a break on T cell proliferation
Blocking the CTLA4 receptor essentially allows for T cell activation and thus improve T cells to destroy tumour cells
- Tumour cells have foreign antigens on their surface
- They are surveyed by antigen presenting cells (APC)
- APC presents the antigen as a MHC/Antigen complex which bind with the T cell receptor.
- Signals from the TCR are then amplified by costimulatory molecules (CD28/B7)
- This results in T cell proliferation and differentiation allow for destruction of the tumour cells via lysis.
- Following activation of the T cell, CTLA4 is upregulated in the T cell
- CTLA4 has much higher affinity for B7 compared to CD28
- Approximately 48 hours post T cell activation, CTLA4 begins to bind with the B7 molecule on the APC surface to provide inhibitory signals to the T cells to discrease activity
IPILIMUMAB: binds to CTLA4 expressed on the surface of T cells
- CTLA-4 bound to Ipilimumab is then not able to bind with B7, leaving B7 (APC) free to continue to bind to CD28 (T cell) and provide ongoing stimulation of the T cell
Note: B7 = CD80/86
Essentially B7/C28 co- stimulation = T cells!
CTLA4 normally binds to B7 preferentially on APC but when you block CTLA4, you get B7/CD28 costimulation = T CELLS
What is involved in T cell activation
Signal 1: ANTIGEN RECOGNITION
- The TCR recognises and binds to the antigen peptide-MHC complex on APC
- This initial signal (signal 1) is insufficient for full T cell activation
Signal 2: COSTIMULATION
- The co-stimulatory receptor CD28 on the T cell surface interacts with the B7 molecule on the APC’s surface
- This costimulation results in activation of the T cell
Side effects of immunotherapy - immune related adverse events
Most common IRAEs
- Rash
- Colitis
- Arthritis
- Hepatitis
- Hypo/hyperthyroidism
- Pneumonitis
- Immunosuppression with mycophenolate may be required
- Grade IV colitis may require prolonged steroid taper + TNF blockade with infliximab or prolonged bowel rest with TPN
MOA of nivolumab + ipilimumab
Nivolumab: PD1 inhibitor
Restores anti-tumour T cell function
Ipilimumab: CTLA4 inhibitor
Induces de novo anti tumour T cell responses
45 yo M with metastatic melanoma presents for 18th cycle of Pembrolizumab with 5 day hx of headache + fatigue.
• TSH <0.01, T3 6T4
• Cortisol6
What is the most appropriate next Ix: • A. Testosterone • B.ACTH • C.MRI pituitary • D. Thyroid Scan
• C.MRI pituitary
CTLA4 and colitis
Grade 1
Diarrhoea: <4 stools/day, asymptomatic colitis = continue tx
Grade 2
Diarrhoea 4-6 stool/day
Colitis - abdominal pain, mucous/blood in stool
WH treatment, start oral pred
Grade 3 -4
Diarrhoea >7 stools
Grade 3 colitis - severe abdo pain
Grade 4 - life threatening diarrhoea, colitis or perforation
WH treatment
IV methylpred
If no improvement in 72 hours or worsening = infliximab
Immune related toxicities - thyroid
Hypothyroid > Hyperthyroid
HYPOTHYROID
- Low T4 with elevated TSH or TSH >10 with normal T4
- Treatment: thyroxine
- Continue checkpoint inhibitor
HYPERTHYROID/THYROTOXICOSIS
- Anti TSH receptor Ab, TPO, thyroid uptake scan
- Tx: propranolol or atenolol for symptoms
TSH receptor positive - carbimazole
- If unwell, consider WH immunotherapy and restart when well
PAINFUL THYROIDITIS
- Pred
When do you consider hypopituitarism?
If TSH normal and low T4 - check 9am cortisol
If TSH low and low T4 - check 9am cortisol
May indicate hypopituitarism
Treatment of hypophysitis
- Hypophysitis is an inflammation of the pituitary gland and is a rare cause of hypopituitarism.
Mild Hypophysitis
- Vague symptoms: fatigue, anorexia, headache or asymptomatic
- Can continue treatment
- Replace cortisol/thryoxine accordingly
Moderate:
- Headache but no visual disturbance
- WH immunotherapy
- Oral pred
Severe:
- mass effect, severe headache, visual disturbance or hypoadrenalism (hypotension, electrolyte disturabnce
- IV methyl pred
- WH immunotherapy
Immune related hepatotoxicity
Grade 1: ALT/AST >ULN - 3x ULN
Continue treatment
Grade 2: ALT/AST 3-5x ULN
WH treatment
If rising, PO Pred
Grade 3: ALT/AST 5-20x ULN
- Cease treatment
- ALT/AST < 400: oral pred
- ALT/AST >400: IV methyl pred
Grade 4: ALT/AST >20x ULN
IV methyl pred
Cease treatment permanently
Typical management of SE of immunotherapy
Grade 1: monitor closely, continue immunotherapy
Grade 2: PO steroids, WH immunotherapy
Grade 3: PO or maybe IV steroids, WH immunotherapy
Grade 4: Normally IV methylpred and may require infliximab
