Derm Skin cancer Flashcards
genetic risk factors for melanoma (4)
- family Hx (CDKN2A), MC1R (melanocortin 1 receptor) variants
- lightly pigmented skin
- red hair
- DNA defects (e.g. xeroderma pigmentosum)
Environmental risk factors melanoma (5)
Intense intermittent sun exposure Chronic sun exposure Residence in equatorial latitudes Sunbeds Immunosuppression
What pathway regulates cellular proliferation, growth and migration of melanocytes
(Mitogen- activated protein kinase) MAPK (RAS-RAF-MEK-ERK)
Where are KIT mutations present and how does it occur?
30-40% of acral and mucosal melanomas
also melanomas from chronically sun-exposed skin harbour activating mutations or copy number amplifications of KIT gene.
ACTIVATION MUTATIONS PRESENT IN MELANOMA? (2)
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.
what does BRAF mutations substitution lead to?
activation of mitogen-activated protein kinase (MAPK) pathway
Inherited CDKN2A mutations also cause MAPK pathway activation
How does P16 - tumour suppressor encoded by CDKN2A - work?
- 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)
Host response to melanoma
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
Melanoma: Subtypes (5)
Superficial spreading Nodular Lentigo maligna Acral lentiginous Unclassifiable
What is the - Most common type of melanoma in fair-skinned individuals
How common is this melanoma?
Superficial Spreading
60-70% of all melanomas
Where is superficial melanoma most frequently seen (different for M and F)
Most frequently seen on trunk of men and legs of women
appearance of superficial spreading melanoma
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
incidence M:F of nodular melanoma?
M>F
physical appearance of nodular melanoma?
Usually present as blue to black, but sometimes pink to red, nodule – may be ulcerated, bleeding
Develops rapidly
Mostly affects trunk, head and neck
how does nodular melanoma develop (growth pattern)?
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.
Melanoma: Lentigo Maligna age group?
> 60 y/o
- Occurs in chronically sun-damaged skin, most commonly on the face
features of growth and appearance of lentigo malina?
Slow growing, asymmetric brown to black macule with colour variation and an irregular indented border.
Melanoma: Acral Lentiginous, commonest age of diagnosis? How common is it?
Diagnosed most frequently in 7th decade of life
Relatively uncommon: ~5% of all melanomas
site of Melanoma: Acral Lentiginous
Typically occurs on palms and soles or in and around the nail apparatus
racial/ethnic incidence of Acral Lentiginous
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%)
public awareness campaign for melanoma
Asymmetry Border irregularity Colour variegation Diameter greater than 5mm 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
Melanoma: Prognostic Factors
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%
Melanoma: Investigation
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
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
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
Melanoma: Staging
pathological
TNM
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
Melanoma: Management, imaging
Stage III, IV
And Stage IIc without SLNB
PET-CT
MRI Brain
what biomarker is a major prognostic factor in metastatic melanoma?
LDH
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 aBRAFinhibitor (e.g. encorafenib, vemurafenib, dabrafenib) andMEK inhibitor (e.g. trametinib)
Keratinocyte Dysplasia / Carcinoma: skin colour incidence
Predominantly pale skin types
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
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
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
what properties do the metalloproteinases and collagenases give basal cell carcinomas?
proteolytic- can degrade pre-existing dermal tissue and facilitate spread of tumour cells
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
Squamous Cell Carcinoma and sun light?
UV radiation is significant risk factor
how does Squamous Cell Carcinoma develop?
through addition of genetic alterations – alterations in p53 are most common (CDKN2A important too):
- 1st p53 mutation: Resistance to UV induced apoptosis and colonial expansion (epidermal p53 clone)
- 2nd p53 mutation: Additional mutation- selection for growth advantage (SC dysplasia)
- Additional genetic mutation: progression of neoplastic clone and genomic instability (SCC in situ)
- Tumour progression: Additional genetic alteration and acquisition if invasive properties (Invasive SCC)
- Tumour progression: Additional genetic mutation and acquisition of metastatic capacity (Metastasis of SCC)
NOTCH1 or NOTCH2 (Wnt / β-catenin signalling) also plays role
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
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
Actinic Keratoses features and presence
Atypical keratinocytes confined to epidermis
where does actinic keratoses usually develop
Develop on sun-damaged skin - usually head, neck, upper trunk and extremities
Actinic Keratoses physical appearance
Erythematous macule or scale or both-> thick papules or hyperkeratosis or both
-> can progress to SCC
actinic keratoses: when is biopsy used?
Distinction from squamous cell carcinoma sometimes difficult – requiring biopsy
what is Bowen’s Disease
Squamous cell carcinoma in situ
appearance of bowen’s disease?
Erythematous scaly patch or slightly elevated plaque
May resemble actinic keratoses, psoriasis, chronic eczema
how can Bowen’s disease arise?
May arise de novo or from pre-existing AK
Actinic Keratoses & Bowen’s Disease: Treatment
5-fluorouracil cream Cryotherapy Imiquimod cream Photodynamic therapy Curettage and cautery Excision
squamous cell carcinoma appearance
May be:
- Erythematous to skin coloured - Papule - Plaque-like - Exophytic - Hyperkeratotic - Ulceration
Arises within background of sun-damaged skin
who is at risk of squamous cell carcinoma?
Immunosuppressed patients
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
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
what does Keratoacanthoma look like?
SCC - hard to differentiate
?variant of SCC
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
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
Basal Cell Carcinoma Main subtypes
6
Nodular Superficial Morpheic Infiltrative Basisquamous Micronodular
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
Basal Cell Carcinoma: Superficial
appearance
Well-circumscribed, erythematous, macule / patch or thin papule /plaque
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
Basal Cell Carcinoma: Basisquamous
what defines this type of carcinoma?
Histological features of both basal cell carcinoma and squamous cell carcinoma
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
Basal Cell Carcinoma: Investigations
Often clinical diagnosis sufficient
Diagnostic biopsy may be taken
Basal Cell Carcinoma: Differential Diagnosis
- Squamous cell carcinoma
- Adnexal (Sebaceous) carcinoma
- Merkel cell carcinoma
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
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)
Cutaneous T-cell Lymphoma: what % of cutaneous lymphomas are T cell?
75
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
Commonest subtypes of cutaneous T cell lymphoma
Sézary syndrome and mycosis fungoides are most common subtypes
Sézary syndrome is rare - <5% of all CTCL
molecular pathogenesis of cuteaneous T cell lymphoma
unknown
- inactivation of genes controlling cell cycle and apoptosis has to be identified
What is required for diagnosis of Cutaneous T-cell Lymphoma: Mycosis Fungoides
skin biopsy
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
Cutaneous T-cell Lymphoma: Mycosis Fungoides t cell infiltration pattern
T cells also found in in lymphomatoid drug eruptions
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
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
Role of antigens in cutaneous T cell lymphoma
Persistent antigenic stimulation plays a crucial role in various lymphomas but no antigens known in MF
Genetic abnormalities and cutaneous T cell lymphoma?
P53, CDKN2A, PTEN, STAT3 identified in advanced MF, but not early
e.g. likely secondary genetic events
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
Cutaneous T-cell Lymphoma: Mycosis Fungoides - Treatment of patches
Plaque / patch stage treatments include topical corticosteroids, phototherapy and radiotherapy
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)
Mycosis Fungoides: Differential Diagnosis
Psoriasis
Eczema (discoid)
Parapsoriasis
Cutaneous T-cell Lymphoma: triad of Sézary syndrome
- Erythroderma
- Generalised lymphadenopathy
- Presence of neoplastic T-cells (Sézary cells) in the skin, lymph nodes and peripheral blood
Cutaneous T-cell Lymphoma: Sézary syndrome - Investigations (criteria for diagnosis) (3)
- 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
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
Kaposi Sarcoma - what might be responsible for it?
- might be endemic
could be due to immunosuppression
treatment of kaposi sarcoma
Treatment with chemotherapy (vincristine, doxorubicin, etoposide, bleomycin) and / or radiation is favoured over surgery
Merkel Cell Carcinoma summary
Malignant proliferation of highly anaplastic cells which share structural and immunohistochemical features with various neuroectodermally derived cells, including Merkel cells
what virus is associated with 80% of merkel cell carcinoma cases
polyomavirus
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
behaviour and development: merkel cell carcinoma
Aggressive, malignant behaviour
>40% develop advanced disease
treatment for merkel cell carcinoma
surgery, radiation therapy
anti-PD1 (Pembrolizumab) / anti-PDL1 (Avelumab)
What are phenotypic risk factors of melanomas?
> 100 melanocytic nevi (moles)
Atypical melanocytic nevi
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
Where can a melanoma arise?
Mucosal surfaces (e.g. oral, conjunctival, vaginal) Within uveal tract of eye
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
How does a superficial spreading melanoma arise?
De novo or in pre-existing nevus
How common is nodular melanoma?
2nd most common type
20-30% of all melanomas
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
