1B skin cancer Flashcards
What do these photos show?
Melanoma
What cells does melanoma arise from?
Melanocytes
How deadly are melanomas?
Causes >75% of skin cancer deaths
Where on the body can melanocytes arise?
- Mucosal surfaces (e.g. oral, conjunctival, vaginal)
- Within uveal tract of eye
What genetic factors are there for melanoma?
- Lightly pigmented skin
- Red hair
- Family history (CDKN2A mutations), MC1R variants
- DNA repair defects (e.g. xeroderma pigmentosum)
What environmental factors are there for melanoma?
- Intense intermittent/chronic sun exposure
- Sunbeds
- Immunosuppression
What phenotypic risk factors are there for melanoma?
- > 100 melanocytic nevi (moles)
- Atypical melanocytic nevi (moles)
What does the mitogen-activated protein kinase (MAPK) [RAS-RAF-MEK-ERK] pathway regulate?
- Cellular proliferation
- Growth
- Migration
What is a KIT mutation and what melanomas is it present in?
- A mutation along the MAPK pathway
- Is in 30-40% of acral and mucosal melanomas
- Activating mutations or copy number amplifications of KIT gene found in melanomas from chronically sun-exposed skin
What 2 other common genes are activation mutations present in in a lot of melanomas?
- NRAS gene (15-20% of melanomas)
- BRAF gene (50-60%)
What type of melanomas is BRAF gene low in?
Low in melanomas of skin with high cumulative UV exposure
Explain how CDKN2A mutations can cause MAPK pathway activation leading to melanoma
- CDKN2A codes for tumour suppressor P16
- P16 binds to CDK4/6 and prevents formation of cyclin D1-CDK4/6 complex
- This complex phosphorylates Rb, inactivating it, leading to E2F release
- once released, E2F promotes cell cycle progression
- Therefore a mutation will mean that P16 can’t stop the complex forming which goes on to release E2F and progress the cell cycle
What is CTLA-4?
Cytotoxic T-lymphocyte-associated antigen-4
It is a natural inhibitor of T cell activation by removing the costimulatory signal (B7 on APC and CD28 on T cell)
How does CTLA-4 influence immunotherapy for melanoma?
It’s based on a CTLA-4 blockade e.g. ipilimumab
What other type of immunotherapy other than CTLA-4 blockade do we have?
- There are also checkpoint inhibitors (PD-1, PDL1)
- PD1 is a signal to our immune system to not kill a certain cell (usually to prevent autoimmunity)
What are the subtypes of melanoma?
- Superficial spreading
- Nodular
- Lentigo maligna
- Acral lentiginous
How common is superficial spreading in melanomas?
60-70% of melanomas
Most common in fair skinned people
Where is superficial spreading seen on the body most frequently?
Trunk of men and legs of women
How can superficial spreading arise?
de novo or in pre-existing nevus
How is regression seen and why does it happen?
- In 2/3 of tumours, regression is visible as grey or hypopigmentation
- Shows interaction of host immune system with tumour
Describe the growth pattern of superficial spreading melanoma
- Initially there’s horizontal (or radial) growth where you see the 4 characteristic features
- Then you have vertical growth phase
- Clinically shows the appearance of a nodule or bump
What are the four characteristic features of superficial spreading?
- Asymmetry
- Border irregularity
- Colour variation
- Increased diameter
How common is nodular in melanomas?
15-30% of all melanomas
Which group of people are nodular melanomas common ni?
- 2nd most common type of melanoma in fair skinned individuals
- More common in men than women
Which body parts are nodular melanomas most common in?
Trunk, head and neck
How do nodular melanomas present?
- Usually as blue to black, sometimes pink to red nodule (so a pigmented nodule)
- May be ulcerated, bleeding
- Develops rapidly
What does amelanotic mean?
When a nodule has no pigment
Describe the growth of nodular melanomas
- There is no radial (horizontal growth phase)
- Only vertical growth phase
What does lack of horizontal and only vertical growth phase for nodular melanomas mean clinically?
- Features resulting from radial growth phase (e.g. asymmetry, border irregularity, colour variation) aren’t present or not v obvious
- It invades earlier and tends to present at a more advanced stage with a worse prognosis
What do these photos show?
Nodular melanomas
How common are lentigo malignas?
Minority of cutaneous melanomas (around 10%)
Which group of people are lentigo malignas seen most commonly in?
- > 60 year olds
- Occurs in chronically sun-damaged skin, most commonly on the face
What does the term ‘lentigo maligna’ refer to?
Pre-invasive slow growing, asymmetric brown to black macule with colour variation and an irregular indented border
When do we call lentigo maligna ‘lentigo maligna melanoma’?
- When lentigo maligna becomes invasive
- Around 5% of lentigo maligna lesions progress to invasive melanoma
What do these photos show?
Lentigo maligna
How common is acral lentiginous?
5% of all melanomas
Which group is acral lentiginous diagnosed most frequently in?
People in their 60s
Where in the body does acral lentiginous occur?
Typically occurs on palms and soles or in and around the nail apparatus
What is the incidence of acral lentiginous in different racial groups?
- Similar across all racial and ethnic groups
- As more darkly pigmented Africans and Asians do not typically develop sun-related melanomas
- ALM represents disproportionate % of melanomas diagnosed in Afro-Caribbean (up to 70%) or Asians (up to 45%)
What are these photos of?
Acral lentiginous
What are these photos of?
Melanonychia
How are patients instructed to detect melanomas early?
Look for history of change in colour, shape or size of a pigmented skin lesion
What is the ABCDE public awareness campaign?
- Asymmetry- one half does not match
- Border- uneven borders
- Colour- variety of colours
- Diameter- larger than a pencil eraser
- Evolution- change in size, shape, colour → most important one
What is Garbe’s rule?
If a patient is worried about a single skin lesion, don’t ignore their suspicion and have a low threshold for performing a biopsy
How do we diagnose melanoma?
Skin biopsy
What are the differential diagnoses for melanoma?
- Basal cell carcinoma- can be pigmented
- Seborrheic keratosis- harmless skin lesions that increase in number with age
- Dermatofibroma- harmless benign skin tumour
What are poor prognostic features for melanoma?
- Increased Breslow thickness >1mm
- Ulceration
- Age
- Male gender
- Anatomical site- head, neck, trunks
- Lymph node involvement
How is Breslow thickness measured?
Measured histologically from stratum granulosum downwards
What are the survival rates of melanoma?
- Stage 1A melanoma has 10 year survival rate of >95%
- Thick melanoma >4mm and ulceration pT4b has 10 year survival rate of 50%
What technique do we use to investigate melanoma?
Dermoscopy- can improve correct diagnosis of melanoma by nearly 50%
What do we do if in doubt for diagnosing melanoma?
Excise the lesion for histological assessment because clinical features aren’t specific for us not to have a low threshold for excision
What are the stages of excision of a melanoma?
- Primary excision → down to subcutaneous fat and 2mm peripheral margin
- If there’s melanoma, then a wide excision is done
- Margin determined by Breslow depth
- 5mm for in situ
- 10mm for ≤1mm
- Prevents local recurrence or persistent disease
What does excision prevent?
Local recurrence or persistent disease
How do we stage melanoma?
- Pathological staging occurs then clinical exam
- TNM staging happens in some instances
What is a sentinel lymph node?
- The first node within a nodal basin that lymphatic drainage goes to
- These are the nodes most likely to contain metastatic disease
What types of TNM tumours is sentinel lymphoma node biopsy available for?
Currently offered for pT1b and more advanced
What would extracapsular spread on lymph node biopsy require?
Lymph node dissection
What 2 types of imaging are available for melanoma?
- PET-CT
- MRI Brain
What stages of melanoma are PET-CT/MRI brain available for?
- Stage IIc without SLNB (sentinel lymph node biopsy)
- Stage III
- Stage IV
What is a major prognostic factor in metastatic melanoma?
LDH
What are 2 ways we can treat unresectable or metastatic melanomas?
- Immunotherapy
- Mutated oncogene targeted therapy
How does immunotherapy work?
- CTLA-4 inhibition e.g. ipilimumab
- PD-L1 (programmed cell death ligand) inhibitors e.g. nivolumab
- Combination immunotherapy leads to 60% response vs 20% monotherapy alone
What is mutated oncogene targeted therapy?
Combination of a BRAF inhibitor (e.g. encorafenib, vemurafenib, dabrafenib) and MEK inhibitor (e.g. trametinib)
What groups of people do keratinocyte dysplasia or carcinoma affect mostly and how?
Predominantly pale skin types via solar induced UV damage
What are the stages of development of keratinocyte dysplasia?
- Actinic keratoses
- Bowen’s disease
- Squamous cell carcinoma
- Basal cell carcinoma
What is actinic keratoses?
Atypical dysplastic keratinocytes that are confined to the epidermis
Where do actinic keratoses develop?
- On sun-damaged skin
- Usually head, neck, upper trunk and extremities
How do actinic keratoses present?
- Macules or papules
- Red or pink
- Usually some scale - may be thick
When would a biopsy be needed for actinic keratoses?
The distinction of an actinic keratosis from SCC is sometimes difficult so a biopsy would be needed
What is there a risk of in actinic keratoses?
Progression to SCC- 0.025-16% per year for any single lesion
What is Bowen’s disease?
Squamous cell carcinoma in situ
How does Bowen’s disease present?
Erythematous scaly patch or slightly elevated plaque
How may Bowen’s disease arise?
De novo or from pre-existing AK
What may Bowen’s disease resemble?
- Actinic keratoses
- Psoriasis
- Chronic eczema
What is the treatment for actinic keratoses and Bowen’s disease?
- 5-fluorouracil cream
- Cryotherapy
- Imiquimod cream
- Photodynamic therapy
- Curettage and cautery
- Excision
What is squamous cell carcinoma?
- Invasive atypical keratinocytes
- potential for metastasis/death
What skin do SCC arise in?
Background of sun-damaged skin
What different ways can SCC look?
- Erythematous (red) to skin coloured
- Papule or bump
- Plaque-like- raised area
- Exophytic- like a mushroom
- Hyperkeratotic- scaly
- Ulceration
What type of keratinocyte carcinoma is there that doesn’t metastasise?
Basal cell carcinoma
What is a significant risk factor for BCC?
UV radiation
What is BCC dependent on?
Stroma produced by dermal fibroblasts
What happens between tumour cells and mesenchymal cells of stroma?
- Cross talk occurs, including with platelet derived growth factor (PDGF)
- Receptors for PDGF are upregulated in stroma but PDGF is upregulated in tumour cells
What kind of activity does BCC have and how does that help it?
- Proteolytic activity e.g. metalloproteinases and collagenases
- Degrade pre-existing dermal tissue and facilitate spread of tumour cells
What signalling pathway is important for BCC progression and something we can target for treatment?
- Loss of function in chromosome 8q (PTCH gene) is important here
What other type of mutation is important in BCC pathogenesis and why?
p53 mutations- majority are missense mutations that carry a UV signature
How does the epidemiology of BCC compare with SCC?
- BCC is most common skin cancer
- BCC to SCC is 4:1
- Both commoner in pale skin types
- Both more common in men vs women (2 or 3:1)
- Median age of diagnosis of BCC is 68
What are the main 6 subtypes of BCC?
- Nodular
- Micronodular
- Superficial
- Morphoeic
- Basisquamous
- Infiltrative
How does nodular BCC present?
- Typically presents as shiny, pearly papule or nodule
- On dermoscopy you can see arborizing (branching) blood vessels
How common is nodular BCC?
- Most common subtype
- Accounts for approx 50% of BCC
What other subtype does micronodular BCC resemble and how is it different?
- Resembles nodular BCC clinically
- More destructive behaviour though- high rates of recurrence and subclinical spread
How does superficial BCC present?
Well-circumscribed, erythematous macule/patch
or thin papule/plaque
How does morphoeic BCC present?
- Slightly elevated or depressed area of induration
- Usually light-pink to white in colour
- Aggressive behaviour- can cause extensive local tissue destruction
What are the histological features of basisquamous carcinoma
Histological and clinical behaviour is a mix of both BCC and SCC
Can metastasise
How can we investigate BCC?
- Often clinical diagnosis sufficient
- Diagnostic biopsy can be taken if doubt
What differentials are there for BCC?
- SCC
- Adnexal (sebaceous) carcinoma
- Merkel cell carcinoma
What treatments for BCC are there?
- Standard surgical excision
- Mohs micrographic surgery
- Topical therapy e.g. 5-fluorouracil, imiquimod for superficial BCC only
- Photodynamic therapy for superficial BCC only
- Curettage for superficial BCC
- Radiotherapy- only above age of 70 though because it can cause SCC
- Vismodegib- selectively inhibits abnormal signalling in Hedgehog (Hh) pathway
What is Mohs micrographic surgery used for?
- Recurrent BCC
- Aggressive subtype e.g. morphoeic/infiltrative/micronodular
- Critical site
What is bread loafing?
When you send a histological specimen for analysis, it’s sectioned using bread loafing technique
Sometimes after an excision when you’re checking to see if there’s any carcinoma left, the section doesn’t analyse a specific part of skin where there is some left so you get a falsely reassuring report
How does Mohs micrographic surgery avoid false negative problems in bread loafing?
- You remove the tumour
- Then you take thin onion skin layers from the margin and examine them repeatedly until you see there’s healthy tissue there
Why can’t Mohs micrographic surgery be used for everyone?
Because it takes hours for a single lesion to be removed
What is a significant risk factor for SCC?
UV radiation
What causes SCC to develop?
- Develops through a series of genetic alterations
- Alterations in p53 are most common
- CDKN2A alterations also common
What other signalling pathway other than p53 plays a role in SCC pathogenesis?
NOTCH1 or NOTCH2 (Wnt/β-catenin signalling)
What high risk features for SCC are there?
- Localisation:
- trunk and limbs >2cm
- Head/neck >1cm
- Periorificial zones
- Ill defined margins
- Rapidly growing
- Immunosuppressed patients
- Previous radiotherapy or site of chronic inflammation
- Histological features
What histological features are a high risk feature for SCC?
- Poorly differentiated
- Acantholytic, adenosquamous, demosplastic subtypes
- Tumour thickness → Clark level >6mm, Clark IV, V
- Invasion beyond subcutaneous fat
- Perineural, lymphatic or vascular invasion
How do we investigate SCC?
- Often clinical diagnosis is sufficient
- Diagnostic biopsy may be taken if diagnosis is uncertain
- Ultrasound of regional lymph nodes, maybe with fine needle aspiration, if there’s concerns of regional lymph node metastasis
What differentials are there for SCC?
- BCC
- Viral wart
- Merkel cell carcinoma
What is the treatment for SCC?
- Examination of rest of skin and regional lymph nodes
- Excision (4-6mm margin)
- Radiotherapy if unresectable or high risk features e.g. perineural invasion
- Cemiplimab (PD1 inhibitor) for metastatic SCC
- Secondary prevention e.g. skin monitoring and sun protection advice, because they are at high risk of developing another SCC
What is a keratoacanthoma?
A rapidly enlarging papule that evolves into a sharply circumscribed, crateriform nodule with a keratotic core
Why is keratoacanthoma so difficult to classify?
Difficult to distinguish clinically and histologically from SCC
Can only really tell it was keratoacanthoma if/when it resolves
How is keratoacanthoma treated?
It resolves slowly over months to leave atrophic scar
Where does keratoacanthoma occur on the body?
Most occur on head or neck or sun-exposed areas
What is merkel cell carcinoma?
Malignant proliferation of highly anaplastic cells which share structural and immunohistochemical features with various neuroectodermally derived cells, including Merkel cells
What are aetiological factors for MCC?
- 80% are associated with polyomavirus
- UV exposure
How does merkel cell carcinoma present?
- Solitary, rapidly growing nodule
- Pink-red to violaceous, firm, dome shaped
- Ulceration can occur
How does merkel cell carcinoma behave?
- Aggressive, malignant behaviour
- > 40% develop advanced disease
