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Year 2 Derm > Skin Cancers > Flashcards

Skin Cancers Flashcards

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1
Q

What is melanoma?

A

Malignant tumour arising from melanocytes
Leads to >75% of skin cancer deaths
Rising incidence rates observed worldwide

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2
Q

Where can melanoma arise?

A

Can arise on mucosal surfaces (e.g. oral, conjunctival, vaginal) and within uveal tract of eye

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3
Q

What are the genetic risk factors for skin cancer?

A

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

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4
Q

What are the environmental risk factors for melanoma?

A 
Intense intermittent sun exposure
Chronic sun exposure 
Residence in equatorial latitudes 
Sunbeds 
Immunosuppression
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5
Q

What are the phenotypic risk factors for melanoma?

A

> 100 Melanocytic nevi

Atypical melanocytic nevi

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6
Q

What is the molecular pathogenesis for melanoma?

A

MAPK (RAS-RAF-MEK-ERK) pathway regulates cellular proliferation, growth and migration

KIT mutations - 30-40% of acral and mucosal melanomas

melanomas from chronically sun-exposed skin harbour activating mutations or copy number amplifications of KIT gene

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7
Q

What are some genes that link to melanoma?

A
  • NRAS gene (15-20% of melanomas)

- BRAF gene (50-60%) – high in melanomas of skin with intermittent UV exposure

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8
Q

What does BRAF substitution result in?

A

BRAF mutations substitution leads to activation of mitogen-activated protein kinase (MAPK) pathway

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9
Q

What other gene can cause MAPK pathway dysfunction?

A

Inherited CDKN2A mutations also cause MAPK pathway activation
P16 - tumour suppressor encoded by CDKN2A

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10
Q

How does CDKN2A cause melanoma?

A
  • 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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11
Q

What is the host 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-Cel

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12
Q

What is immunotherapy for melanoma based on?

A

Immunotherapy based on CTLA-4 blockade – ipilimumab

- Also checkpoint inhibitors (PD-1, PDL1)

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13
Q

What are the subtypes of melanoma?

A 
Superficial spreading 
Nodular
Lentigo maligna 
Acral lentiginous
Unclassifiabl
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14
Q

What are the features of superficial spreading melanoma?

A

60-70% of all melanomas

Most frequently seen on trunk of men and legs of women

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15
Q

What are the features of superficial spreading melanoma tumours?

A

In up to 2/3 of tumours, regression (visible as grey, hypo-or depigmentation), reflecting the interaction of host immune system with tumour.

After a slow horizontal (radial) growth phase, limited to epidermis, a more rapid vertically oriented growth phase, which presents clinically with development of nodule

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16
Q

What are the main features of 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

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17
Q

What are the main features of nodular melanoma tumours?

A

Usually present as blue to black, but sometimes pink to red, nodule – may be ulcerated, bleeding

Develops rapidly

Nodular melanoma is believed to arise as a de novo vertical growth phase without the pre-existing horizontal growth phase

Tend to present more advanced stage, with poorer prognosis.

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18
Q

What are the features of lentigo maligna?

A

Minority of cutaneous melanomas (around 10%) and is
>60 years old
- Occurs in chronically sun-damaged skin, most commonly on the face

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19
Q

What are the features of lentigo maligna tumours?

A

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).

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20
Q

What is the disease course for maligna tumors?

A

It has been estimated that 5% of lentigo maligna lesions progress to invasive melanoma

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21
Q

What are the features of acral lentiginous?

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

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22
Q

Why are a large percentage of acral lentiginous melanomes diagnosed in BAME groups?

A
  • 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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23
Q

What is important re early detection?

A

History of change in colour, shape or size of a pigmented skin lesion

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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24
Q

What were the steps in the public awareness campaign for early detection?

A 
Asymmetry
Border irregularity
Colour variegation
Diameter greater than 5mm 
Evolving
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25
What are some poor prognosis features?
``` Increased Breslow thickness >1mm Ulceration Age Male gender Anatomical site – trunk, nhead, neck Lymph node involvement ```
26
What are the prognosis for thin vs. thick melanomas?
Stage 1A melanoma have 10 year survival of >95% whereas thick melanomas >4mm and ulceration pT4b have a 10 year survival rate of 50%
27
How is breslow thickness measured?
From granular layer to bottom of tumor
28
What is dermoscopy?
Investigation that can improve correct diagnosis of melanoma by nearly 50%
29
What are global features of melanomas?
Asymmetry Presence of multiple colours Reticular, globular, reticular-globular, homogenous Starburst
30
What is key regarding dermoscopic findings?
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”
31
How are melanomas removed?
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
32
How are melanomas staged?
Thickness Ulceration TNM
33
How is TNM staging done in melanomas?
Imaging Stage III, IV And Stage IIc without SLNB PET-CT MRI Brain LDH is MAJOR prognostic factor in metastatic melanoma 
34
How are unresectable or metastatic melanomas managed?
Immunotherapy | Mutated oncogene targeted therapy
35
What immunotherapy is used in melanoma?
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
36
What mutated oncogene targeted therapy is used in melanoma?
Combination of a BRAF inhibitor (e.g. encorafenib, vemurafenib, dabrafenib) and MEK inhibitor (e.g. trametinib
37
What are the features of keratinocyte dysplasia (carcinoma)?
Predominantly pale skin types | Solar induced UV damage
38
What are the different types of carcinoma?
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
39
Describe the pathogenesis of basal cell carcinoma?
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
40
Why does UV radiation play such an important role in squamous cell carcinoma?
Develops through addition of genetic alterations – alterations in p53 are most common - CDKN2A also NOTCH1 or NOTCH2 (Wnt / β-catenin signalling) also plays role
41
What are the main features of keratinocyte carcinoma?
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
42
What are risk factors for keratinocyte carcinomas?
``` UV exposure 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 ```
43
What is 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
44
What is 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
45
What is the treatment for Actinic Keratoses and Bowen's treatment?
``` 5-fluorouracil cream Cryotherapy Imiquimod cream Photodynamic therapy Curettage and cautery Excision ```
46
What are the main features of squamous cell carcinoma tumours?
``` Arises within background of sun-damaged skin May be: - Erythematous to skin coloured - Papule - Plaque-like - Exophytic - Hyperkeratotic - Ulceration ```
47
What are some high risk features of 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
48
What features in the histology of SCC is worrying?
- 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
49
What is keratoacanthoma?
Controversial entity - Pseudo-malignancy vs variant of SCC 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
50
How is SCC diagnosed?
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
51
How is SCC treated?
Examination of rest of skin and regional lymph nodes Excision Radiotherapy - Unresectable - High risk features e.g. perineural invasion Cemiplimab for metastatic SCC
52
What secondary prevention is advised in those with SCC?
- Skin monitoring advice | - Sun protection advice
53
What are the main types of basal cell carcinoma?
``` Nodular Superficial Morpheic Infiltrative Basisquamous Micronodular ```
54
What is the most common subtype of BCC?
Nodular | Accounts for approximately 50% of all Basal cell carcinomas
55
How does nodular BCC typically present?
Typically presents as shiny, pearly papule or nodule
56
How does superficial BCC typically present?
Well-circumscribed, erythematous, macule / patch or thin papule /plaque
57
How does morphoeic BCC typically present?
``` Less common Slightly elevated or depressed area of induration Usually light-pink to white in colour More aggressive behaviour - Extensive local destruction ```
58
How does basisquamous BCC typically present?
Histological features of both basal cell carcinoma and squamous cell carcinoma
59
What are the features of micronodular basal cell carcinoma?
Resembles nodular basal cell carcinoma clinically | More destructive behaviour – high rates of recurrence and subclinical spread
60
How is BCC diagnosed?
Often clinical diagnosis sufficient Diagnostic biopsy may be taken
61
What is the treatment for BCC?
Standard surgical excision Mohs micrographic surgery Other options
62
When is Mohs micrographic surgery used?
- Recurrent basal cell carcinoma - Aggressive subtype (morpheic / infiltrative / micronodular) - Critical site
63
What are the other features of BCC?
Topical therapy e.g. 5-Fluorouracil, Imiquimod Photodynamic therapy Curettage Radiotherapy Vismodegib - selectively inhibits abnormal signalling in Hedgehog (Hh) pathway
64
What is Mohs micrographic surgery?
Remove visible path of lesion | Take secessional onion layer and examine it before taking more tissue
65
What are the features of cutaneous T-cell lymphomas?
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
66
What are the most common subtypes of cutaneous T-cell Lymphoma?
Sézary syndrome and mycosis fungoides are most common subtypes
67
What is the pathogenesis of CTCL?
Underlying molecular pathogenesis of CTCL is unknown | - Inactivation of genes controlling cell cycle and apoptosis has been identified
68
What is mycosis fungoides?
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 Patches or plaques
69
What is the progression of myocsis fungoides?
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
70
What is the avergae time from onset to diagnosis in MF?
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
71
What is the early patch stage of MF characterised by?
Early patch stage is characterised by variably sized erythematous, finely scaling lesions which may be mildly pruritic
72
What is the pathogenesis of MF?
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, but no constitute pattern 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
73
How is MF evaluated?
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
74
What is the treatment for MF?
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-30) - for advanced disease
75
What is the prognosis for MF?
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
76
What is Sezary syndrome?
Triad of: Erythroderma Generalised lymphadenopathy Presence of neoplastic T-cells (Sézary cells) in the skin, lymph nodes and peripheral blood
77
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
78
What are the main features of Kaposi Sarcoma?
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
79
What are the main features of Merkel cell carcinoma?
Malignant proliferation of highly anaplastic cells which share structural and immunohistochemical features with various neuroectodermally derived cells, including Merkel cells
80
What are risk factors for Merkel Cell Carcinoma?
80% are associated with polyomavirus UV exposure is also an aetiological factor Predilection for the head and neck region of older adults
81
What are the features of MCC tumours?
Solitary, rapidly growing nodule- pink-red to violaceous, firm, dome shaped, - Ulceration can occur
82
What is the behaviour and treatment of Merkel Cell Carcinoma?
Aggressive, malignant behaviour >40% develop advanced disease Treated with surgery, radiation therapy anti-PD1 (Pembrolizumab) / anti-PDL1 (Avelumab)

Year 2 Derm (3 decks)

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