Skin Flashcards
What is the outermost layer of the epidermis
The stratum corneum.
What cell types are found in the epidermis that are relevant to cutaneous malignancies
Melanocytes
Dendritic cells (langerhans cells)
Squamous epithelial cells
Merkel cells
What is the full name for a mole. What type of mutations are common
Melanocytic nevus
RAS and BRAF mutations are common. They usually don’t go on to become malignant because they induce senescence via p16/INK4.
What type of lesion can be a direct precursor to melanoma. What are frequent mutations these contain
Dysplastic nevi.
NRAS and BRAF mutations (ie similar to melanocytic nevi), but they often also have mutations of the CDKN2A gene, so senescence is not induced
What are macroscopic and microscopic features that distinguish a melanocytic nevi from dysplastic nevi
Macroscopic: larger size, variability in pigmentation, irregular borders
Microscopic: cytological and architectural atypia
What is the most important predisposing factor for risk of melanoma
UV exposure
What are the most common driver mutations in melanoma
CDKN2A: affecting p16 and ARF production
Growth signalling pathways; BRAF (non V600E), NRAS, PTEN, KIT
NF1
Mutations activating telomerase
What receptor tyrosine kinase has frequent activating mutations in melanoma
KIT, particularly mucosal melanoma
What are the two growth phases of melanoma
Horizontal growth phase: epidermis/ superficial dermis spreading of the melanoma, with less malignant potential. This phase is the earlier phase
Vertical growth phase: deeper invasion into the deep dermis with increased malignant potential
What are the microscopic features of melanoma
Larger than normal melanocytes, enlarged nuclei with red (eosinophilic) nuclei, and chromatin clumped at periphery of nuclei.
What pathological features are used to predict probability of metastatic spread of an excised melanoma
1- depth of invasion/breslow thickness
2- number of mitosis
3- evidence of tumour regression
4- ulceration of overlying skin
5- presence and number of tumour invading lymphocytes
6- location
What is the relevance of sentinel lymph node micrometastases in melanoma
A worse prognosis. Degree of involvement prognosticates for overall survival
What are the clinical warning signs for melanoma
ABCDE
A- asymmetry
B- irregular Borders
C- variegated Colour
D- diameter
E- evolution, ie change over time
What does pembrolizumab inhibit
PD-1
What is mutated in Cowden syndrome, what is its normal role
PTEN, a suppressor of the PI3K pathway
What pre-malignant lesson of the skin is often a precursor to SqCC
Actinic keratosis
What are some microscopic features of actinic keratosis
Thinning of epidermis or hyperplasia of basal cells
Thickened elastic fibres
Thickened stratum corneum with retained nuclei (parakeratosis)
What are risk factors for developing skin SqCC
1: UV exposure/ lifetime exposure to sun
2: immunosuppression; possibly due to ability of HPV viruses to cause infection.
What mutations are common in cutaneous SqCC
P53
Also RAS and Notch signalling
What signalling pathway is mutated in most cutaneous basal cell carcinomas
The hedgehog pathway.
It becomes constitutively activated, no longer needing signalling from the sonic hedgehog (SHH) signalling molecule. This causes upregulation of growth promoting gene signalling.
What pathway is mutated in Gorlin’s syndrome. What malignancies are associated with it
Also known as nevoid basal cell carcinoma syndrome
Hedgehog pathway: mutation of PTCH1 gene which is inhibitor for pathway. Therefore pathway becomes more active
Hedgehog pathway important for normal development of cerebellum
Associated with early onset BCCs, medulloblastoma, ovarian fibromas
What are the two main neoplasms of the dermis (from primary dermis cells) benign or malignant
Benign fibrous histiocytoma (dermatofibroma)
Dermatofibrosarcoma protruberans: a low grade sarcoma that doesn’t tend to metastasise.
What is mycosis fungoides. Ie, what sort of cells are involved. What syndrome is associated with systemic spread
It is a cutaneous t-cell lymphoma involving CD4+ helper T cells that home to the skin due to expression of cutaneous lymphocyte antigen.
Sezary syndrome.
What are some of the clinical presentations of mycosis fungoides
Early:
Psoriasis like lesions
Eczema like lesions
Patches or plaques
Later:
Nodule formation
Patches or nodules can ulcerate
What IHC marker is most useful in distinguishing malignant melanoma from a intradermal nevus
HMB45
Positive from superficial to deep in melanoma. Positive only of superficial immature cells in a nevus
What is the typical IHC profile of Merkel cell carcinoma
Neuroendocrine markers positive
AE1AE3, cam-5.2 positive
TTF1 negative
CK20 dot positivity
Rb retained
What virus is associated with kapai sarcoma
HHV8- the cause of all subtypes
What is the gross appearance of kaposi sarcoma
3 stages:
-patch
-plaque
-nodule
Red/purple in colour. Bleed if surface cut
What is the key differential diagnosis of kaposi sarcoma
Angiosarcoma
What are the epidemiological subtypes of kaposi sarcoma
Classical: older men on lower extremities. Indolent
Endemic/African: not hiv associated. Lower limbs, may be aggressive if node spread
Iatrogenic: related to immunosuppressive drugs. May regress of immunosuppressive drugs stopped
HIV associated: most aggressive. May regress if antiretroviral drugs successfully treat AIDS
What IHC tests distinguish kaposi sarcoma from angiosarcoma
HHV8 nuclear staining: 100% of kaposi sarcoma, negative angiosarcoma
Also for kaposi sarcoma: ERG, CD34, D2-40 positive
Melanoma markers negative
What is the microscopic appearance of kaposi sarcoma
Spindle cells with slit-like channels containing red blood cells
What are the microscopic features of basal cell carcinoma
Basaloid cells
Arranged in nests with pallisading at edges of nests
Fibromyxoid stroma
Mild pleomorphism
What are common unfavourable variants of basal cell carcinoma
Micro nodular
Infiltrative
Sclerosing
Basosquamous
What IHC stain can distinguish BCC from SqCC skin
BerEP4 positive in BCC.
CK20 neg (vs Merkel)
Melanoma markers negative
What are the microscopic features of cutaneous SqCC
Keratinocytes
Keratinisation/keratin pearls (but lost in poorly differentiated)
Marked nuclear atypia in poorly differentiated
Many variants
What are the IHC features of cutaneous SqCC
P40, p63 positive
Negative:
-CK20 (Merkel)
-BerEP4 (basal cell)
-melanoma markers
What is the difference between a melanocytic nevus and a dysplastic nevus
A dysplastic nevus is a melanocytic nevus that is showing atypical characteristics histologically.
-architectural disorder
-cytological atypia
What are the architectural changes found in dysplastic nevi
Larger size >4mm
Lateral extension of junctional component beyond dermal component
Lentiginous hyperplasia of melanocytes
Bridging of rete ridges by horizontal nests
Fibroblasts
Patchy lymphocyte infiltrate
What are the features of cytological atypia in dysplastic nevi
Nuclear enlargement (compared to resting basal keratinocyte)
Hyperchromasia
Prominent nucleoli
Abundant cytoplasm with dusty melanin
How is melanoma defined cytologically
Atypical melanocytes
Large nuclei
Prominent nucleoli
Irregular clumped or dense chromatin
Eosinophilic or lightly pigmented cytoplasm
What are the architectural abnormalities in melanoma
Asymmetry
Poorly defined borders
Lack of maturation with dermal descent
Deep mitosis
Pagetoid spread
Sheets of cells rather than dermal nesting
Epidermal consumption
What are the two growth phases of melanoma
Radial growth phase: tumour spreads horizontally in epidermis and superficial dermis (superficial spreading melanoma and lentigo malignant: better prognosis)
Vertical growth phase: deeper/thicker expansile invasion of dermis (nodular melanoma)
What is lentiginous growth pattern in melanoma
Growth along the DEJ (dermal epidermal junction) without pagetoid scatter
What are the key prognostic features of melanoma histology
Depth of invasion (breslow thickness)
Ulceration
Mitoses
LVI
What defines invasive melanoma vs melanoma in situ
Extension into the dermis
What are the microscopic features of superficial spreading melanoma versus lentigo maligna melanoma
Both: radial growth phase, lentiginous or pagetoid spread
Superficial spreading: underlying skin has low cumulative sun damage. Pagetoid or lentiginous spread of atypical melanocytes in the epidermis. Frequent BRAF V600E mutation. Commonly associated with benign nevus
Lentigo maligna: background cumulative sun damage: severe solar elastosis. Mostly lentiginous spread rather than pagetoid. Spread is along base of dermis. Epidermis often thin/atrophic. High mutation burden. Initially radial growth phase/in situ latency before developing invasion and Mets.
What is the name of a melanoma with an accelerated vertical growth phase
Nodular melanoma
What type of melanoma is most common in people with darker skin types. What is prognosis in comparison to other melanoma types
Acral melanoma
No UV mediated. Low tumour mutation burden.
Worse prognosis for stage
What is the microscopic appearance of desmoplastic melanoma
Spindled melanocytes (resemble fibroblasts)
Collagen fibres
Often appears very bland
Cannon ball lymphcytes or plasma cells.
Often adjacent solar elastosis, lentigo maligna.
Neurotrophism
What is the typical IHC profile of desmoplastic melanoma
Positive: S100, SOX10
Negative: Melan A, HMB45
What would support a diagnosis of a mucosal melanoma rather than metastasis from a cutaneous melanoma
An in situ component or lentiginous component
What is the natural history of mucosal melanoma
Very aggressive
What is the most common presentation of spread of a melanoma to skin nearby. What are they termed dependent of distance from primary
Usually a solitary dermal nodule.
Can involve epidermis, resembling a primary
Satellite metastasis: within 2cm of primary
In-transit metastasis: beyond 2cm
What is the difference in sun exposure as a risk factor for BCC and SqCC
BCC: intermittent exposure
SqCC: chronic sun exposure
What are common molecular abnormalities in melanoma
BRAF V600E
NRAS
HRAS
cKIT (mucosal)
NF1
BAP1 (cutaneous and uveal)
