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Skin Cancer Flashcards

1
Q

What are Melanomas?

A

Malignant tumour arising from melanocytes
Leads to >75% of skin cancer deaths
Can arise on mucosal surfaces (e.g. oral, conjunctival, vaginal) and within uveal tract of eye
Rising incidence rates observed worldwide

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2
Q

What are the risk factors for Melanoma?

A

Genetic factors
Family history (CNKN2A mutations), MC1R variants
Lightly pigmented skin
Red hair
DNA repair defects (e.g. xeroderma pigmentosum)

Environmental factors
Intense intermittent sun exposure
Chronic sun exposure 
Residence in equatorial latitudes 
Sunbeds 
Immunosuppression

Phenotypic
>100 Melanocytic nevi
Atypical melanocytic nevi

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3
Q

What is the Pathogenesis of Melanoma?

A

Mitogen-activated protein kinase (MAPK) [RAS-RAF-MEK-ERK] pathway regulates cellular proliferation, growth and migration
KIT mutations - 30-40% of acral and mucosal melanomas – also melanomas from chronically sun-exposed skin harbour activating mutations or copy number amplifications of KIT gene.

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4
Q

What are the Activate mutations in Melanoma?

A 
NRAS gene (15-20% of melanomas) 
 BRAF gene (50-60%) – high in 	melanomas of skin with intermittent 	UV exposure, yet low in melanomas of 	skin with high cumulative UV exposure
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5
Q

What happens in CDKN2A mutations?

A

Inherited CDKN2A mutations also cause MAPK pathway activation
P16 - tumour suppressor encoded by CDKN2A
- Binds to CDK4/6, p16 prevents formation of cyclin D1-CDK4/6 complex
- Cyclin D1-CDK4/6 complex phosphorylates Rb, inactivating it, leading to E2F release (once released, E2F promotes cell cycle progression)

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6
Q

What is the hosts response to Melanoma?

A

CD8+ T-cell recognise melanoma-specific antigens and if activated appropriately, are able to kill tumour cells.

CD4+ helper T-cells and antibodies also play a critical role

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is natural inhibitor of T-cell activation by removing the costimulatory signal (B7 on APC to CD28 on T-Cell)
Immunotherapy based on CTLA-4 blockade – ipilimumab
- Also checkpoint inhibitors (PD-1, PDL1)

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7
Q

What is the epidemiology of Melanoma?

A

Increasing worldwide
Develops predominantly in Caucasian populations
Incidence low amongst darkly pigmented populations
10-19/100,000 per year in Europe
60/100,000 per year in Australia / NZ

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8
Q

What are the subtypes of Melanoma?

A 
Superficial spreading 
Nodular
Lentigo maligna 
Acral lentiginous
Unclassifiable
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9
Q

What happens in superficial spreading melanoma?

A

60-70% of all melanomas
- Most common type in fair-skinned individuals
Most frequently seen on trunk of men and legs of women
Can arise de novo or in pre-existing nevus
In up to 2/3 of tumours, regression (visible as grey, hypo-or depigmentation), reflecting the interaction of host immune system with tumour.

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10
Q

How do superficial spreading melanomas grow?

A

Horizontal and then vertical

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11
Q

What happens in Nodular melanoma?

A

2nd most common type of melanoma in fair skinned individuals
15-30% of all melanomas
Most commonly trunk, head and neck
M>F
Usually present as blue to black, but sometimes pink to red, nodule – may be ulcerated, bleeding
Develops rapidly

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12
Q

How do nodular melanomas grow?

A

only vertically

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13
Q

What happens in Lentigno maligna melanoma?

A

Minority of cutaneous melanomas (around 10%) and is
>60 years old
- Occurs in chronically sun-damaged skin, most commonly on the face
Slow growing, asymmetric brown to black macule with colour variation and an irregular indented border.
Invasive Lentigo Maligna Melanoma arises in a precursor lesion termed lentigo maligna (in situ melanoma) in sun damaged skin).
It has been estimated that 5% of lentigo maligna lesions progress to invasive melanoma

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14
Q

What happens in Acral Lentiginous Melanoma?

A

Relatively uncommon: ~5% of all melanomas
Diagnosed most frequently in 7th decade of life
Typically occurs on palms and soles or in and around the nail apparatus
Incidence similar across all racial and ethnic groups
- As more darkly pigmented Africans and Asians do not typically develop sun-related melanomas, ALM represents disproportionate percentage of melanomas diagnosed in Afro- Caribbean (up to 70%) or Asians (up to 45%)

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15
Q

What is the public awareness campaign for Melanoma suspicion?

A 
Asymmetry
Border irregularity
Colour variegation
Diameter greater than 5mm 
E evolving

Garbe’s rule: If a patient is worried about a single skin lesion, do not ignore their suspicion and have a low threshold for performing a biopsy

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16
Q

What gives a poor prognosis following Melanoma Diagnosis?

A 
Poor Prognostic features
Increased Breslow thickness >1mm
Ulceration
Age
Male gender
Anatomical site – trunk, nhead, neck
Lymph node involvement

Stage 1A melanoma have 10 year survival of >95% whereas thick melanomas >4mm and ulceration pT4b have a 10 year survival rate of 50%

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17
Q

What is Breslow thickness?

A

Measurement from granular layer to the bottom of the tumour.

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18
Q

What do you look for in a Dermoscopy of Melanoma?

A

Dermoscopy –can improve correct diagnosis of melanoma by nearly 50%

Global features: 
Asymmetry
Presence of multiple colours
Reticular, globular, reticular-globular, homogenous
Starburst

Atypical network, streaks, atypical dots or globules, irregular blood vessels, regression structures, blue-white veil

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19
Q

What is important with Melanoma investigations?

A

Dermoscopic findings should not be considered n isolation

History and risk factor status are important

Excise lesion for histological assessment if in any doubt

“If in doubt, take it out”

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20
Q

What is the management for Melanomas?

A

Primary excision down to subcutaneous fat
- 2mm peripheral margin

Wide excision
	- Margin determined by 	Breslow depth
	- 5mm for in situ	
	- 10mm for =1mm
Prevents local recurrence or persistent disease
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21
Q

How do you stage melanomas?

A

Pathological

TNM

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22
Q

What is Sentinal lymphoma node biopsy?

A

Sentinel lymphoma node biopsy
Lymphatic drainage of finite regions of skin drain specifically to an initial node within a given nodal basin - the ‘sentinel node’
Represent most likely nodes to contain metastatic disease
Currently offered for pT1b+
Extracapsular spread on lymph node biopsy – needs lymph node dissection

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23
Q

What is the imaging for melanoma?

A

Stage III, IV
And Stage IIc without SLNB

PET-CT
MRI Brain

LDH is MAJOR prognostic factor in metastatic melanoma

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24
Q

What is the treatment for unresectable/metastatic melanoma?

A

Immunotherapy
CTLA-4 inhibition – unresectable or metastatic BRAF negative melanoma (Ipilimumab)
PD-L1 (Programmed cell death ligand) inhibitors (Nivolumab)Combination immunotherapy not much better than ingle agent in
- Combination immunotherapy leads to 60% response vs 20% monotherapy alone

Mutated oncogene targeted therapy
- Combination of aBRAFinhibitor (e.g. encorafenib, vemurafenib, dabrafenib) andMEK inhibitor (e.g. trametinib)

25
What happens in Keratinocyte Dysplasia/Carcinoma?
``` Predominantly pale skin types Solar induced UV damage Actinic keratoses - Dysplastic keratinocytes Bowen’s disease (Squamous cell carcinoma in situ) Squamous cell carcinoma - Potential for metastasis/ death Basal cell carcinoma - (Virtually) never metastasises - Locally invasive ```
26
What is the pathogenesis of Basal cell carcinoma?
UV radiation is significant risk factor Dependent on stroma produced by dermal fibroblasts Cross talk between tumour cells and mesenchymal cells of stroma - Receptors for PDGF are upregulated in Stroma but PDGF is upregulated in tumour cells BCC has proteolytic activity e.g. metalloproteinases and collagenases – degrade pre-existing dermal tissue and facilitate spread of tumour cells Loss of function in chromosome 8q (PTCH gene) - Sonic Hedgehog-Patched signalling pathway / SHH signalling is required for growth of established BCCs p53 mutations are also important – majority are missense mutations that carry a UV signature
27
What is the pathogenesis of Squamous Cell Carcinoma?
UV radiation is significant risk factor Develops through addition of genetic alterations – alterations in p53 are most common - CDKN2A also NOTCH1 or NOTCH2 (Wnt / β-catenin signalling) also plays role
28
What is the epidemiology of Keratinocyte Carcinomas?
Basal cell carcinoma is most common skin cancer BCC:SCC 4:1 Both commoner in pale skin types Both more common in men vs women (2-3:1) Median age at diagnosis of BCC is 68
29
What are the risk factors for Keratinocyte Carcinomas?
``` UV exposure - PUVA Fair skin Genetic syndromes - Xeroderma pigmentosum - Oculocutaneous albinism - Muir Torre syndrome - Nevoid basal cell carcinoma syndrome* Nevus sebaceous Porokeratosis Organ transplantation (immunosuppressive drugs) Chronic non-healing wounds Ionising radiation - Airline pilots Occupational chemical exposures - Tar, polycyclic aromatic hydrocarbons ```
30
What happens in Actinic Keratoses?
Atypical keratinocytes confined to epidermis Develop on sun-damaged skin - usually head, neck, upper trunk and extremities Erythematous macule or scale or both-> thick papules or hyperkeratosis or both - Sometimes cutaneous horn Distinction from squamous cell carcinoma sometimes difficult – requiring biopsy Risk of progression to squamous cell carcinoma: 0.025–16% per year for any single lesion
31
What happens in Bowen's disease?
Squamous cell carcinoma in situ Erythematous scaly patch or slightly elevated plaque May arise de novo or from pre-existing AK May resemble actinic keratoses, psoriasis, chronic eczema
32
What is the treatment forActinic Keratoses & Bowen’s Disease?
``` 5-fluorouracil cream Cryotherapy Imiquimod cream Photodynamic therapy Curettage and cautery Excision ```
33
Why does Squamous cell carcinoma develop?
``` Arises within background of sun-damaged skin May be: - Erythematous to skin coloured - Papule - Plaque-like - Exophytic - Hyperkeratotic - Ulceration ```
34
What are the risk factors for Squamous cell carcinoma?
Localisation: Trunk and limbs > 2cm; Head / neck > 1cm; Periorificial zones Margins: Ill-defined Rapidly growing Immunosuppressed patients Previous radiotherapy or  site of chronic inflammation Histology: - Grade of differentiation: poorly differentiated - Acantholytic, adenosquamous, demosplastic subtypes - Tumour thickness - Clark level: >6mm, Clark IV, V - Invasion beyond subcutaneous fat - Perineural, lymphatic or vascular invasion
35
What is a Keratoacanthoma?
Controversial entity - Pseudo-malignancy vs variant of SCC Rapidly enlarging papule that evolves into a sharply circumscribed, crateriform nodule with keratotic core Resolves slowly over months to leave atrophic scar Most occur on head or neck / sun exposed areas Difficult to distinguish clinically and histologically from squamous cell carcinoma
36
What are the investigations for squamous cell carcinoma's?
Often clinical diagnosis sufficient Diagnostic biopsy may be taken if diagnostic uncertainty Ultrasound of regional lymph nodes ± FNA if concerns regarding regional lymph node metastasis
37
What is the treatment for squamous cell carcinoma?
``` Examination of rest of skin and regional lymph nodes Excision Radiotherapy - Unresectable - High risk features e.g. perineural invasion Cemiplimab for metastatic SCC Secondary prevention - Skin monitoring advice - Sun protection advice ```
38
What are the subtypes of Basal cell carcinoma?
``` Nodular Superficial Morpheic Infiltrative Basisquamous Micronodular ```
39
How common is nodular BCC?
Most common subtype Accounts for approximately 50% of all Basal cell carcinomas Typically presents as shiny, pearly papule or nodule
40
What is Superficial BCC?
Well-circumscribed, erythematous, macule / patch or thin papule /plaque
41
What is Morphoeic BCC?
``` Less common Slightly elevated or depressed area of induration Usually light-pink to white in colour More aggressive behaviour - Extensive local destruction ```
42
What is Basisquamous BCC?
Histological features of both basal cell carcinoma and squamous cell carcinoma
43
What is Micronodular BCC?
Resembles nodular basal cell carcinoma clinically | More destructive behaviour – high rates of recurrence and subclinical spread
44
What are the investigations for BCC?
Often clinical diagnosis sufficient Diagnostic biopsy may be taken
45
What is the treatment for BCC?
Standard surgical excision Mohs micrographic surgery - Recurrent basal cell carcinoma - Aggressive subtype (morpheic / infiltrative / micronodular) - Critical site Other options: Topical therapy e.g. 5-Fluorouracil, Imiquimod Photodynamic therapy Curettage Radiotherapy Vismodegib - selectively inhibits abnormal signalling in Hedgehog (Hh) pathway
46
What happens in Cutaneous T cell lymphoma?
75% of cutaneous lymphomas are T-cell Heterogenous group of neoplasms of skin-homing T-cells that show considerable variation in clinical presentation, histological appearance, immunophenotype and prognosis Sézary syndrome and mycosis fungoides are most common subtypes Underlying molecular pathogenesis of CTCL is unknown - Inactivation of genes controlling cell cycle and apoptosis has been identified
47
What is the epidemiology of Cutaneous T-cell lymphoma?
Mycosis fungoides 0.4/100,000 Typically older adults (median age of diagnosis 55-60) Sézary syndrome is rare - <5% of all CTCL
48
What is Mycosis Fungoides CTCL?
Common variant of primary CTCL and accounts for 50% of all primary cutaneous lymphoma Indolent clinical course Diagnosis requires skin biopsy Diagnosis may take years as skin lesions may be present that are neither clinically nor histologically diagnostic for many years Atypical T-cell infiltrates may also be found in lymphomatoid drug eruptions
49
What is the process of Mycosis Fungoides CTCL?
Patients progress from patch stage → plaque stage → (finally) tumour stage disease Protracted clinical course over years → decades Generally many years of nonspecific eczematous or psoriasiform skin lesions Median duration of onset of skin lesions to diagnosis of MF is 4-6 years, but may vary from several months to more than 5 decades Early patch stage is characterised by variably sized erythematous, finely scaling lesions which may be mildly pruritic
50
What is the pathogenesis of Mycosis Fungoides?
Considered to be a stepwise accumulation of genetic abnormalities → clonal proliferation → malignant transformation → progressive and widely disseminated disease Molecular events remain unidentified Genetic abnormalities described – not constituting a patter P53, CDKN2A, PTEN, STAT3 identified in advanced MF, but not early e.g. likely secondary genetic events Persistent antigenic stimulation plays a crucial role in various lymphomas but no antigens known in MF
51
What are the investigations for Mycosis Fungoides?
Evaluation requires examination with attention to: Type and extent of skin lesions Presence of palpable lymph nodes Skin biopsies Complete blood counts and serum chemistries
52
What is the treatment for Mycosis Fungoides?
Plaque / patch stage treatments include topical corticosteroids, phototherapy and radiotherapy Systemic chemotherapy is only indicated in advanced stage when there is nodal or visceral involvement or in patients with rapidly progressive tumours unresponsive to less aggressive therapies Brentuximab vedotin (anti-CD30)
53
What is the prognosis for Mycosis Fungoides?
Depends on stage 10 year survival rates are: >95% in limited patch / plaque disease 85% in generalised patch / plaque disease 42% in tumour stage disease 20% in those with histological lymph node involvement
54
What characterises Sezary syndrome?
Erythroderma Generalised lymphadenopathy Presence of neoplastic T-cells (Sézary cells) in the skin, lymph nodes and peripheral blood
55
What is the criteria for Sezary syndrome diagnosis?
Demonstration of a T-cell clone in peripheral blood by molecular or cytogenetic methods Demonstration of immunophenotypical abnormalities an expanded CD4+ T-cell population – resulting in a CD4/ CD8 ratio of greater than 10 and / or aberrant expression of pan-T-cell antigens) An absolute Sézary cell count of at least 1000 cells per microlitre
56
What is the treatment for Sezary syndrome?
Systemic treatment is required Extracorporeal photophoresis Skin-directed therapies like PUVA or potent topical corticosteroids may be used as adjuvant therapy
57
What happens in Capos sarcoma?
HHV8 Multifocal systemic disease May be endemic or related to immunosuppression Cutaneous lesions can vary from pink patches to dark violet plaques, nodules or polyps Treatment with chemotherapy (vincristine, doxorubicin, etoposide, bleomycin) and / or radiation is favoured over surgery
58
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 80% are associated with polyomavirus UV exposure is also an aetiological factor Predilection for the head and neck region of older adults Solitary, rapidly growing nodule- pink-red to violaceous, firm, dome shaped, - Ulceration can occur
59
What is the treatment for Merkel cell carcinoma?
Aggressive, malignant behaviour >40% develop advanced disease Treated with surgery, radiation therapy anti-PD1 (Pembrolizumab) / anti-PDL1 (Avelumab)

BRS Phase 1b (80 decks)

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