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Derm Skin cancer Flashcards

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1
Q

genetic risk factors for melanoma (4)

A
  1. family Hx (CDKN2A), MC1R (melanocortin 1 receptor) variants
  2. lightly pigmented skin
  3. red hair
  4. DNA defects (e.g. xeroderma pigmentosum)
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2
Q

Environmental risk factors melanoma (5)

A 
Intense intermittent sun exposure
Chronic sun exposure 
Residence in equatorial latitudes 
Sunbeds 
Immunosuppression
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3
Q

What pathway regulates cellular proliferation, growth and migration of melanocytes

A

(Mitogen- activated protein kinase) MAPK (RAS-RAF-MEK-ERK)

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4
Q

Where are KIT mutations present and how does it occur?

A

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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5
Q

ACTIVATION MUTATIONS PRESENT IN MELANOMA? (2)

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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6
Q

what does BRAF mutations substitution lead to?

A

activation of mitogen-activated protein kinase (MAPK) pathway

Inherited CDKN2A mutations also cause MAPK pathway activation

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7
Q

How does P16 - tumour suppressor encoded by CDKN2A - work?

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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8
Q

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-Cell)
Immunotherapy based on CTLA-4 blockade – ipilimumab**
- Also checkpoint inhibitors (PD-1, PDL1)- normally prevent autoimmunity so removing it allows immune system to kill melanoma cells

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9
Q

Melanoma: Subtypes (5)

A 
Superficial spreading 
Nodular
Lentigo maligna 
Acral lentiginous
Unclassifiable
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10
Q

What is the - Most common type of melanoma in fair-skinned individuals
How common is this melanoma?

A

Superficial Spreading

60-70% of all melanomas

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11
Q

Where is superficial melanoma most frequently seen (different for M and F)

A

Most frequently seen on trunk of men and legs of women

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12
Q

appearance of superficial spreading melanoma

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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13
Q

incidence M:F of nodular melanoma?

A

M>F

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14
Q

physical appearance of nodular melanoma?

A

Usually present as blue to black, but sometimes pink to red, nodule – may be ulcerated, bleeding
Develops rapidly
Mostly affects trunk, head and neck

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15
Q

how does nodular melanoma develop (growth pattern)?

A

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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16
Q

Melanoma: Lentigo Maligna age group?

A

> 60 y/o

- Occurs in chronically sun-damaged skin, most commonly on the face

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17
Q

features of growth and appearance of lentigo malina?

A

Slow growing, asymmetric brown to black macule with colour variation and an irregular indented border.

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18
Q

Melanoma: Acral Lentiginous, commonest age of diagnosis? How common is it?

A

Diagnosed most frequently in 7th decade of life

Relatively uncommon: ~5% of all melanomas

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19
Q

site of Melanoma: Acral Lentiginous

A

Typically occurs on palms and soles or in and around the nail apparatus

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20
Q

racial/ethnic incidence of Acral Lentiginous

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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21
Q

public awareness campaign for melanoma

A 
Asymmetry
Border irregularity
Colour variegation
Diameter greater than 5mm 
Evolving
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22
Q

Garbe’s rule:

A

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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23
Q

Melanoma: Prognostic Factors

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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24
Q

Melanoma: Investigation

A

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

Dermoscopic findings should not be considered n isolation

History and risk factor status are important

Excise lesion for histological assessment if in any doubt

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25
global features of melanoma
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
26
Melanoma: Management
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 ```
27
Melanoma: Staging
pathological | TNM
28
Melanoma: Management
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
29
Melanoma: Management, imaging
Stage III, IV And Stage IIc without SLNB PET-CT MRI Brain
30
what biomarker is a major prognostic factor in metastatic melanoma?
LDH
31
Melanoma: Management, Unresectable or metastatic
Immunotherapy CTLA-4 inhibition – unresectable or metastatic BRAF negative melanoma (Ipilimumab) PD-L1 (Programmed cell death ligand) inhibitors (Nivolumab) - Combination immunotherapy leads to 60% response vs 20% monotherapy alone Mutated oncogene targeted therapy - Combination of a BRAF inhibitor (e.g. encorafenib, vemurafenib, dabrafenib) and MEK inhibitor (e.g. trametinib)
32
Keratinocyte Dysplasia / Carcinoma: skin colour incidence
Predominantly pale skin types
33
Keratinocyte Dysplasia / Carcinoma types (3)
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
34
Basal Cell Carcinoma: sunlight impact?
UV radiation is significant risk factor | p53 mutations are also important – majority are missense mutations that carry a UV signature
35
how do cells interact in basal cell carcinoma (involves PDGF/r)?
Cross talk between tumour cells and mesenchymal cells of stroma - Receptors for PDGF are upregulated in Stroma but PDGF is upregulated in tumour cells
36
what properties do the metalloproteinases and collagenases give basal cell carcinomas?
proteolytic- can degrade pre-existing dermal tissue and facilitate spread of tumour cells
37
What chromosome loses function in basal cell carcinoma?
``` chromosome 8q (PTCH gene) (tumor suppressor gene) Receptor for Sonic Hedgehog ``` - Sonic Hedgehog-Patched signalling pathway / SHH signalling is required for growth of established BCCs
38
Squamous Cell Carcinoma and sun light?
UV radiation is significant risk factor
39
how does Squamous Cell Carcinoma develop?
through addition of genetic alterations – alterations in p53 are most common (CDKN2A important too): 1. 1st p53 mutation: Resistance to UV induced apoptosis and colonial expansion (epidermal p53 clone) 2. 2nd p53 mutation: Additional mutation- selection for growth advantage (SC dysplasia) 3. Additional genetic mutation: progression of neoplastic clone and genomic instability (SCC in situ) 4. Tumour progression: Additional genetic alteration and acquisition if invasive properties (Invasive SCC) 5. Tumour progression: Additional genetic mutation and acquisition of metastatic capacity (Metastasis of SCC) NOTCH1 or NOTCH2 (Wnt / β-catenin signalling) also plays role
40
what is the most common skin cancer?
Basal cell carcinoma 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
41
keratinocyte carcinomas RFs
``` UV exposure - PUVA Fair skin Genetic syndromes Nevus sebaceous Porokeratosis Organ transplantation (immunosuppressive drugs) Chronic non-healing wounds Ionising radiation Occupational chemical exposures ```
42
Actinic Keratoses features and presence
Atypical keratinocytes confined to epidermis
43
where does actinic keratoses usually develop
Develop on sun-damaged skin - usually head, neck, upper trunk and extremities
44
Actinic Keratoses physical appearance
Erythematous macule or scale or both-> thick papules or hyperkeratosis or both -> can progress to SCC
45
actinic keratoses: when is biopsy used?
Distinction from squamous cell carcinoma sometimes difficult – requiring biopsy
46
what is Bowen’s Disease
Squamous cell carcinoma in situ
47
appearance of bowen's disease?
Erythematous scaly patch or slightly elevated plaque May resemble actinic keratoses, psoriasis, chronic eczema
48
how can Bowen's disease arise?
May arise de novo or from pre-existing AK
49
Actinic Keratoses & Bowen’s Disease: Treatment
``` 5-fluorouracil cream Cryotherapy Imiquimod cream Photodynamic therapy Curettage and cautery Excision ```
50
squamous cell carcinoma appearance
May be: - Erythematous to skin coloured - Papule - Plaque-like - Exophytic - Hyperkeratotic - Ulceration Arises within background of sun-damaged skin
51
who is at risk of squamous cell carcinoma?
Immunosuppressed patients
52
SCC 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
53
appearance of Keratoacanthoma
Rapidly enlarging papule that evolves into a sharply circumscribed, crateriform nodule with keratotic core Resolves slowly over months to leave atrophic scar -> ?Pseudo-malignancy
54
what does Keratoacanthoma look like?
SCC - hard to differentiate | ?variant of SCC
55
SCC investigation
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
56
Squamous Cell Carcinoma: Treatment
``` 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 ```
57
Basal Cell Carcinoma Main subtypes | 6
``` Nodular Superficial Morpheic Infiltrative Basisquamous Micronodular ```
58
Basal Cell Carcinoma: Nodular. Frequency and appearance
Most common subtype Accounts for approximately 50% of all Basal cell carcinomas Typically presents as shiny, pearly papule or nodule
59
Basal Cell Carcinoma: Superficial appearance
Well-circumscribed, erythematous, macule / patch or thin papule /plaque
60
Basal Cell Carcinoma: Morphoeic | frequency, appearance, aggression
``` Less common Slightly elevated or depressed area of induration Usually light-pink to white in colour More aggressive behaviour - Extensive local destruction ```
61
Basal Cell Carcinoma: Basisquamous | what defines this type of carcinoma?
Histological features of both basal cell carcinoma and squamous cell carcinoma
62
Basal Cell Carcinoma: Subtypes (1) | appearance, behaviour
Micronodular basal cell carcincoma Resembles nodular basal cell carcinoma clinically More destructive behaviour – high rates of recurrence and subclinical spread
63
Basal Cell Carcinoma: Investigations
Often clinical diagnosis sufficient Diagnostic biopsy may be taken
64
Basal Cell Carcinoma: Differential Diagnosis
- Squamous cell carcinoma - Adnexal (Sebaceous) carcinoma - Merkel cell carcinoma
65
Basal Cell Carcinoma: Treatment (non-surgical)
Topical therapy e.g. 5-Fluorouracil, Imiquimod Photodynamic therapy Curettage Radiotherapy Vismodegib - selectively inhibits abnormal signalling in Hedgehog (Hh) pathway
66
Basal Cell Carcinoma: Treatment
Standard surgical excision Mohs micrographic surgery (recurrent basal cell carcinoma, aggressive subtypes, critical site): - Removing layers of skin until all layers of cancer removed - takes hours but only takes skin that's needed - This is better than breadloafing which shows false -ve tumour resection margin (takes skin samples without tumour and report says they're -ve for tumour when they're not)
67
Cutaneous T-cell Lymphoma: what % of cutaneous lymphomas are T cell?
75
68
physical appearance of cutaneous T cell lymphoma
Heterogenous group of neoplasms of skin-homing T-cells that show considerable variation in clinical presentation, histological appearance, immunophenotype and prognosis
69
Commonest subtypes of cutaneous T cell lymphoma
Sézary syndrome and mycosis fungoides are most common subtypes Sézary syndrome is rare - <5% of all CTCL
70
molecular pathogenesis of cuteaneous T cell lymphoma
unknown | - inactivation of genes controlling cell cycle and apoptosis has to be identified
71
What is required for diagnosis of Cutaneous T-cell Lymphoma: Mycosis Fungoides
skin biopsy
72
Why can diagnosis of Cutaneous T-cell Lymphoma: Mycosis Fungoides take long?
skin lesions may be present that are neither clinically nor histologically diagnostic for many years 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 Lesions appear like Patches or plaques
73
Cutaneous T-cell Lymphoma: Mycosis Fungoides t cell infiltration pattern
T cells also found in in lymphomatoid drug eruptions
74
Cutaneous T-cell Lymphoma: Mycosis Fungoides plaque history
Generally many years of nonspecific eczematous or psoriasiform skin lesions variably sized erythematous, finely scaling lesions which may be mildly pruritic
75
Cutaneous T-cell Lymphoma: Mycosis Fungoides: Pathogenesis
Considered to be a stepwise accumulation of genetic abnormalities → clonal proliferation → malignant transformation → progressive and widely disseminated disease
76
Role of antigens in cutaneous T cell lymphoma
Persistent antigenic stimulation plays a crucial role in various lymphomas but no antigens known in MF
77
Genetic abnormalities and cutaneous T cell lymphoma?
P53, CDKN2A, PTEN, STAT3 identified in advanced MF, but not early e.g. likely secondary genetic events
78
Cutaneous T-cell Lymphoma: Mycosis Fungoides: Evaluation / Investigation
``` Examination which pays attention to: Type and extent of skin lesions Presence of palpable lymph nodes Skin biopsies Complete blood counts and serum chemistries ```
79
Cutaneous T-cell Lymphoma: Mycosis Fungoides - Treatment of patches
Plaque / patch stage treatments include topical corticosteroids, phototherapy and radiotherapy
80
Cutaneous T-cell Lymphoma: Mycosis Fungoides - Treatment
``` 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) ```
81
Mycosis Fungoides: Differential Diagnosis
Psoriasis Eczema (discoid) Parapsoriasis
82
Cutaneous T-cell Lymphoma: triad of Sézary syndrome
1. Erythroderma 2. Generalised lymphadenopathy 3. Presence of neoplastic T-cells (Sézary cells) in the skin, lymph nodes and peripheral blood
83
Cutaneous T-cell Lymphoma: Sézary syndrome - Investigations (criteria for diagnosis) (3)
1. Demonstration of a T-cell clone in peripheral blood by molecular or cytogenetic methods 2. 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) 3. An absolute Sézary cell count of at least 1000 cells per microlitre
84
Cutaneous T-cell Lymphoma: Sézary syndrome - Treatment (3)
Systemic treatment is required Extracorporeal photophoresis Skin-directed therapies like PUVA or potent topical corticosteroids may be used as adjuvant therapy
85
Kaposi Sarcoma - what might be responsible for it?
1. might be endemic | could be due to immunosuppression
86
treatment of kaposi sarcoma
Treatment with chemotherapy (vincristine, doxorubicin, etoposide, bleomycin) and / or radiation is favoured over surgery
87
Merkel Cell Carcinoma summary
Malignant proliferation of highly anaplastic cells which share structural and immunohistochemical features with various neuroectodermally derived cells, including Merkel cells
88
what virus is associated with 80% of merkel cell carcinoma cases
polyomavirus
89
appearance of merkel cell carcinoma
Predilection for the head and neck region of older adults Solitary, rapidly growing nodule- pink-red to violaceous, firm, dome shaped, - Ulceration can occur
90
behaviour and development: merkel cell carcinoma
Aggressive, malignant behaviour | >40% develop advanced disease
91
treatment for merkel cell carcinoma
surgery, radiation therapy anti-PD1 (Pembrolizumab) / anti-PDL1 (Avelumab)
92
What are phenotypic risk factors of melanomas?
>100 melanocytic nevi (moles) | Atypical melanocytic nevi
93
What is a melanoma? How does it affect the population?
Malignant tumour arising from melanocytes Leads to >75% of skin cancer deaths Rising incident rates worldwide
94
Where can a melanoma arise?
``` Mucosal surfaces (e.g. oral, conjunctival, vaginal) Within uveal tract of eye ```
95
What is the epidemiology of melanomas?
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
96
How does a superficial spreading melanoma arise?
De novo or in pre-existing nevus
97
How common is nodular melanoma?
2nd most common type | 20-30% of all melanomas
98
Can lentigo maligna become invasive?
Yes 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

BRS Year 2 (110 decks)

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