Melanocytic naevi and Melanoma Flashcards
T/F
Freckling inherited as autosomal dominant trait
T
onset age 5 ish
MC1R gene mutation may lead to freckling
T/F
freckles, CALMs and vulval/penile/oral melanosis all have increased melanin production but no increase in number or distribution of melanocytes
T
In vulval melanosis may be slight increase in number of melanocytes esp in larger, darker lesions.
T/F
Lentigines have increased melanin production but no increase in number or distribution of melanocytes
F
In lentigines the number of melanocytes is often increased
melanocytes remain limited to basal layer
Solar lentigo may or may not have increased melanocyte numbers
Melnaocytes are usually normal in appearance but PUVA lentigines have large melanocytes with mild cytological atypia
T/F
Freckles are independent risk factor form melanoma
T
people with many freckles are more than twice as likely to get a melanoma
T/F
freckles and lentigines fade with time out fo the sun
F
freckles do lentigines may fade a little but tend to persist
CALMs do not change
T/F
Freckled people have more naevi
T
What are Rx for freckles?
Sun protect
IPL first line about 3 treatments
QS 532nm (freq doubled Nd:YAG) laser - end point is even frosting
Can use ablative or fractionated laser – fractionated probably better esp erbium
35% TCA peel
2-4% hydroquinone in morning and retinoic acid in evening and high SPF (UVA blocking) sunscreen
Gentle cryotherapy
What syndromes are associated with freckles?
XP NF (trunk, axilla, groin - Crowe's sign) Progeria LEOPARD Moynihan’s syndrome (HOCM + LEOPARD)
T/F
Regarding CALMs
10-20% of normal population have one
1% of normal population have up to 3
T
Rare to have more than 3 unless part of a syndrome
T/F
CALMs are rare in afro-caribbeans
F
more common
T/F
In CALM there are usually fewer melanocytes than in surrounding normal skin
T
but increased melanin production
What syndromes are assoc w/ CALMs?
Cheer leader with CALMs spins the BATANS
Bloom’s syndrome
Albright (McCune-Albright) syndrome (coast of Maine)
Tuberous sclerosis
Ataxia telangiectasia
NF1
Silver-Russell (Russell-Silver) syndrome
Also; Idiopathic NF1-like syndrome (Legius syndrome) NF2 Watson syndrome (Allelic to NF1) Noonans syndrome LEOPARD syndrome (cafe noir), Moynihan's Carney complex (cafe noir) Fanconis anaemia Gorlin’s Cowdens (sometimes) MEN1 (sometimes) Mafuccis Gaucher Chediak-Higashi Hunter syndrome Multiple mucosal neuroma syndrome
What syndromes are assoc w/ Cafe noir macules?
LEOPARD syndrome
Carney complex
T/F
NF1 typically has several CALMs >15cm diameter
T
but only size >15mm in adult required for diagnostic criteria
T/F
topical skin lighteners help CALMs
F
no effect
generally Rx resistant
Can try pulsed dye, QS Ruby or freq doubled Nd:YAG lasers
ablative erbium laser has also been used
variable response, high risk of recurrence
What is lentiginosis?
Lentiginosis means either many lentigines or lentigines in a specific distribution in keeping with a clinical syndrome
NB lentiginosis syndromes often also have ephelides and/or CALMs
What are the types of lentigo?
Simple lentigo (lentigo simplex) Solar lentigo (=senile lentigo) + variants; - Ink spot lentigo - PUVA lentigo Scar lentigo
T/F
Solar lentigo can evolve into lichenoid keratosis or reticulated seb K
T
T/F
Xeroderma pigmentosum is associated with many CALMs
F
Many ephelides and solar lentigines
What are treatments for solar lentigo?
simialr to freckles but topical whiteners rarely effective
Sun protect
QS 532nm (freq doubled Nd:YAG) laser - end point is even frosting - 1st line treatment
IPL – may need up to 5 Rx at monthly intervals
35% TCA peel
Gentle cryotherapy - C tip spray; 3-5secs from 2cm
Can use ablative or fractionated laser – fractionated probably better esp Erbium
PUVA lentigo occurs in 90% of pts treated with PUVA
False
50%
More develop if – receive more treatments, older age, male sex
Fewer develop in darker skin phototypes
T/F
PUVA lentigines can occur on any skin exposed to PUVA regardless if normally sun exposed or not
T
T/F
PUVA lentigines occcur early during PUVA Rx
F
usually after 5-7 yrs of Rx
Persist for years after PUVA stopped
T/F
PUVA lentigines are a marker for increased risk for PUVA-related malignancy
T
T/F
PUVA lentigines are darker and more stellate appearance than solar lentigines
T
look more like simple lentigo than solar lentigo
T/F
lentifo simplex is more common in darker skin types
T
M=F
simple lentigo may be present at birth or appear shortly after birth
T/F
simple lentigo of the nail matrix are a common cause of longitudinal melanonychia
T
T/F
simple lentigo is a brown-black homogenous pigmented macule. usually
T
T/F
Acral pigmented lesions are most often lentigo simplex histologically
T
What is Generalized lentiginosis (syndrome)?
Multiple lentigines appearing singularly in small crops from infancy onwards
No known cause or association
What is Eruptive lentiginosis (syndrome)?
Rare, widespread development of numerous lentigines over months-years
Adolescents and young adults
No systemic illness/associations
What is Unilateral (zosteriform/segmental) lentiginosis (syndrome)?
Lentigines appearing on one side of the body during childhood
May be zosteriform appearing in dermatome like distribution – often naevoid
May be associated neurological abnormalities – usually not in zosteriform cases
2-10mm lentigines clustered without background hyper pigmentation as seen in naevus spillus
What is Centrofacial lentiginosis?
Very rare poorly defined triad;
Lentigines limited to medial face
Neuropsychiatric problems
Dysraphic anomalies
AD inheritence
Small black/brown macules appear in infancy in horizontal band across central face
Also; coalescence of eyebrows, high-arched palate, absent upper median incisors, spina bifida, sacral hypertrichosis & scoliosis
Frequent learning difficulties and epilepsy
What is Laugier-Hunziker syndrome?
Rare acquired lentiginosis syndrome onset in adulthood, benign cause unknown
Macular pigmentation of lips and buccal mucosa, palms and soles
Longitudinal black melanonychia
No systemic associations, good prognosis
DD for Peutz-Jeghers
Which lentiginosis syndromes have pigment change only with no systemic features?
Generalized lentiginosis
Unilateral (zosteriform/segmental) lentiginosis
Eruptive lentiginosis
Inherited patterned lentiginosis in black people
Laugier-Hunziker syndrome
NB Dowling-Degos and variants can look like lentigines but often look more reticulate and may be hypopigmented/erythematous
Which lentiginosis syndromes have pigment change with systemic features?
Centrofacial lentiginosis Cronkhite-Canada syndrome Carney complex Peutz-Jeghers syndrome LEOPARD syndrome all AD except Cronkite-Canada (acquired, cause unknown)
Mucosal melanotic macules, mucosal melanosis or mucosal lentiginosis are all the same thing
T
T/F
Mucosal melanosis is common and usually benign
T
but vulval melanosis is seen in middle aged women (esp early 40s)
- if occurs in older women think of melanoma even if multifocal
- if occurs in children think of lentiginosis or similar syndromes;
Peutz-Jeghers
Carney complex
LEOPARD
Bannayan-Riley-Ruvalcaba
Dowling-Degos
T/F
smoking, trauma and inflammatory demratoses can trigger mucosal melanosis
T
T/F
mucosal melanosis is pre-malignant
F
also No proof that melanosis is a risk factor for melanoma
T/F
Labial melanotic macules are most common on the lateral parts of the lip
F
Most commonly central 1/3 of lower lip, ?due to UV
T/F
Vulvar melanoma is the most common vulval cancer
F
2nd most common after SCC
10% of vulval cancers
T/F
Vulval bleeding, pruritus, discharge, irritation or lymphadenopathy can ll be due to vulval melanoma
T
take these serious;y and examine carefully
T/F
Molecular typing of vulval melanoma is more like acral melanomas than cutaneous ones
T
KIT gene is most common mutation – up to 35% of cases
T/F
radical vulvectomy is performed for vulval melanoma
False
treat simialrly to skin melanoma
WLE is best if possible
vulvectomy rarely indicated
T/F
Vulvar naevi arise in younger women than melanosis or melanoma
T
naevus - late 20s, early 30s
melanosis - 40-44yrs
melanoma - 40-70 or older
T/F
Vulvar naevi occur in 20% of adult women
F
2%
account for 23% of all pigmented vulvar lesions
arise on lab maj, lab min or clitoral hood
T/F
Atypical Melanocytic Naevi of Genital Type (AMNGT) are generally seen in slightly younger women
T
can be children and teens
more often on lab min and on mucosal parts esp in girls under 10
T/F
Atypical Melanocytic Naevi of Genital Type (AMNGT) account for 5% of vulval naevi
T
may be large, irregular, darkly pigmented. May have personal or FHx of dysplastic naevi or melanoma
T/F
Atypical Melanocytic Naevi of Genital Type (AMNGT) ae pre-malignant lesions
F
Both vulval naevi and AMNGT appear to have benign behaviour
AMNGT is a special site naevus - may have focal pagetoid, cytological atypia and rare mitoses
T/F
most vulval melanomas arise from a naevus
F
Vulval melanomas on mucosal and border of mucosal and hairy skin rarely have a benign naevus associated (2%)
35% of melanomas on hairy vulva may arise from a naevus
T/F
Both vulval melanosis and AMNGT can arise on a background of vulval lichen sclerosus
T
but LS not a risk factor for vulval melanoma
T/F
In first 1-2 years of life infants may develop acquired naevi which clinically and histologically resemble congenital naevi
T
‘congenital naevus tardive’
T/F
Congenital melanocytic naevi (CMN) are present in up to 12% of newborns esp Asian and black skin
F
2%
and 2% of adults have lesions resembling congenital naevi which may or may not be truly congenital
T/F
Congenital melanocytic naevi are due to a postzygotic mutations in BRAF gene
F
NRAS gene
type of mosaic RASopathy
T/F
There is a higher risk of melanoma in congenital naevi >10cm diameter when an adult
T
What is the calssification of CMN?
Small less than 1.5cm medium/large 1.5-19.9cm large/giant 20cm and over - based on adult diameter attained some call naevi >40cm diameter ‘garment naevi’
T/F
Naevi >9cm on scalp in adults are considered giant
T
Also naevi >6cm on the body in neonates
size grows in proportion with child
T/F
Giant/garment naevi in lumbosacral region often called ‘bathing trunk’ naevi
T
Bathing trunk naevi usually cover lower back, buttocks and extend to thighs
75% also have many satellite naevi and develop more with time esp in first 2 years. These can be at distant sites to the main naevus
T/F
Most congenital naevi are in small category
T
T/F
Congenital melanocytic naevi dont change in appearance with age, only in size
F
Many become more pale in first 2 years
can become thicker in childhood
Surface often becomes thick/rugose or warty - esp on scalp; simulates cutis verticis gyrata
Often also develop nodules within larger naevi
Can be increased terminal hair in naevus skin esp on scalp – hair often dark, thick and wiry
What are the associations of CMN on the skin?
Absence of subcut fat and muscle mass under the naevus is most common and can cause discomfort in naevi over the sacrum etc Atopic dermatitis Perineavic leukoderma Neurofibromatosis – up to 5% of NF pts have a CMN CALMs Mucosal naevi (30%) Infantile haemangioma can be part of epidermal naevus syndrome Benign nodules Plexiform-like overgrowths Fascicular schwannoma Lipoma Lymphangioma Fibroepithelial polyp Ectopic Mongolian spot Neurilemmoma Cartilaginous hamartoma
What are the non-skin asociations of CMN?
Limb hypertrophy (22.5%) club foot, atrophy or hypertrophy of musculoskeletal structures esp under naevi on limbs
EEG abnormalities (20%)
CNS symptoms due to neuro melanosis
Rasopathy induced hormonal disturbances;
- Higher BMI compared to normal due to increased adiposity
- Premature thelarche (breast development) 3%
- Cryptorchidism 6%
What is neurocutaneous melanosis?
Neurocutaneous melanosis = neuromelanosis associated with a CMN
Usually giant CMN or multiple smaller lesions
Involvement of nervous system by melanocytic proliferation – can be amygdala, cerebrum, cerebellum, midbrain, pons, medulla, meninges or spinal cord
Present before age 3 in most cases; often before or around age 2;
2nd peak in teens-20s
Complications rare but can cause raised ICP, hydrocephalus, spinal space-occupying lesions
Risk if CMN overlying spin – meningeal involvement, spina bifida, meningocele, tethered spinal cord, pits, lipoma
Can develop melanoma in skin lesions or in neuromelanosis but not in both
What are the histo features of CMN?
Dermal or compound type melanocytic naevi with naevus cells extending more deeply into dermis
Often naevus cells involve appendages and can extend into fat and muscle
Naevus cells may be arranged in ‘splaying’ pattern AKA single file or ‘Indian filing’
T/F
In CMN Naevus cells start higher up and go deep in first months of life
F
so no benefit from early dermabrasion or similar
What investigations should be performed for CMN?
T1 weighted MRI of brain if want to look for neuromelanosis – some advocate screening if giant CMN; some advocate only investigating if symptoms as there is no curative Rx
MRI may be more accurate if performed before 4 months
Cannot predict which neuromelanosis cases will cause symptoms and which will be assymptomatic
MRI all pts if CMN overlies spine – can treat tethered cord with surgery but cannot sure after it becomes symptomatic
T/F
nodular melanoma is most common type to arise from CMN
F
superficial spreading
but arise from dermal portion making diagnosis difficult
Higher risk of presenting with mets and unknown primary
What are the complications of CMN?
Melanoma - 5-7% of giant CMN pts get melanoma by age 60
Nodular proliferative neurocristic hamartoma – tumour derived from neural crest, may be present at birth, often on scalp, benign but can turn into melanoma
Nodularities caused by proliferation of epiphelioid melanocytes – simulate melanoma
Pts w/ giant naevi can develop extracutaneous melanoma – CNS, retroperitoneum etc
Other malignant tumours (rare) – malignant blue naevus, neurogenic sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, neurosarcoma, osteogenic sarcoma, liposarcoma
Psychological – behavioural and emotional problems, bullying
T/F
In CMN there is No clear evidence that removal of the naevus has any effect on melanoma risk
T
T/F
symptomatic neurocutaneous melanosis has a poor prognosis
T
dont excise their naevi as unnecessary morbidity
What are the treatment options for CMN?
Monitoring only - photos and FSE every 6-12 months lifelong
complete excision if small
staged excison with graft/flap repair
Partial thickness treatment options – remove some naevus cells but often not satisfactory;
- Dermabrasion– done in 1st 6 months of life when cleavage plane exists between naevus and underlying tissue
- Dermatome shaving
- Chemical peel
- Curettage – done in 1st 6 months of life when cleavage plane exists between naevus and underlying tissue
- Cryotherapy
- Electosurgery
- Pigment laser – QS; Ruby, Alexandrite, Nd:YAG
- Ablative laser – CO2 or Erbium:YAG
- XRT – described but least useful option and high risk AEs
which syndromes are associated w/ naevus spillus?
phakomatosis pigmentovascularis (type 3+4)
phakomatosis pigmentokeratotica
Rare speckled lentiginous naevus syndrome – naevus + ipsilateral dysaesthesia, muscle weakness and hyperhidrosis
T/F
Speckled and lentiginous naevus has a small increased risk of melanoma
T
T/F
Unlike the individual lentigines and junctional naevi within a naevus spillus, the background hyperpigmentation has normal melanosyte numbers
F
subtle increase in melanocytes in background lesion in lentiginous arrangement
T/F
90% of naevi are junctional in childhood
T
T/F
get some new naevi up until around mid 40s then begin to involute
T
T/F
Number of naevi is mainly genetically determined
T
small effect of sun exposure esp if intermittent
What things can trigger development of new naevi?
Sun exposure esp multiple or severe sunburns
Skin injury – SJS/TEN, EB, LS
Immunosuppression inc drugs and AIDS, BMT
Hormones - Pregnancy, growth hormone, addisons Dx, thyroid hormone, afamelanotide (αMSH analogue)
Sorafenib (kinase inhibitor)
EB naevi which develop at blister sites maybe up to 3cm diameter - Should observe but no reports of melanoma developing
T/F
A persons overall number of naevi is single biggest risk factor for melanoma
T
T/F
Renal transplant pts have fewer naevi
F
more
Childhood leukaemia survivors also have more than ave naevi and inc risk of melanoma
T/F
Eczema pts often have fewer naevi than average
T
T/F
Balloon cell melanoma does NOT arise from balloon cell naevi
T
T/F
In acral melanocytic naevi some degree of architectural atypia (including Pagetoid spread) and cytological atypia is normal
T
What are the dermoscopic patterns of naevi on feet?
Fibrillar – in friction prone, wt bearing parts
Classical groove pattern – seen in peri-wt bearing areas
Lattice pattern – seen on the arch
T/F
conjunctival naevi are more risky than skin naevi
F
behave the same
T/F
Nail matrix naevi present as longitudinal melanonychia
T
T/F
It is common for melanocytes in IDNs to become spindle shaped (neuroid)
T
What is Sutton’s naevus
Halo naevus
T/F
In older adults a sudden onset of multiple halo naevi can indicate a melanoma of the skin, eye or elsewhere
T
What are the stages of change in halo naevus?
4 stages; 1 – central brown naevus 2 – central pink naevus 3 – depigmented macule only remains 4 – repigmentation of macule
What is the management of a new halo naevus?
Ensure naevus appears benign clinically, perform FSE
Ask about personal/Fam Hx of MM, atypical naevi and vitiligo (may be associations)
Reassure in young person usually best
If older but under 40 r/w in 3/12 (?w/ photo?) and then 6 monthly
If over 40; FSE and ensure examination of scalp, perianal, genital tract etc and send to ophthal
Advise sun protection as risk of burning depigmented area
Higher degree of suspicion in older pts as can get same phenomenon in melanoma esp superficial spreading or can indicate MM elsewhere
If any doubt remove for excision biopsy
What is a Meyerson’s naevus?
Melanocytic naevus with associated eczematous inflammatory reaction
Treat with mod TCS then review after a few weeks to properly examine naevus
What is a Cockade naevus?
Rare phenomenon Means rosette-shaped naevus Occurs in young people Usually have multiple Central junctional naevus surrounded by concentric rings of increased pigmentation in a target-like arrangement No significance
T/F
75% of Spitz naevi occur under age 30 and 50% under age 14
T
up to 7% congenital
T/F
Spitz navei look red due to vascularity
T
diascopy or dermoscopy can compress vessels and often pigment is seen
can look more pigmented esp in adults
DDs esp in kids are vasc lesions, pyogenic granuloma also histiocytoma, JXG, granulomas
T/F
a period of rapid growth ove rmonths then long term stability is normal history of Spitz naevus
T
T/F
Reed naevus most commonly seen in young females (mean age 25) esp on thighs
T
T/F
indeterminate Spitzoid lesions are often reported as Atypical spitzoid tumour of unknown malignant potential (STUMP)
T
These should be managed as melanoma but the pt informed that the diagnosis is uncertain and it may in fact be a benign lesion
T/F
In pts over 12 best to completely excise all spitzoid lesions
T
As per JAAD 2015 study
In pt of any age if there are atypical features lesion should be excised – asymmetry, irregular colour etc
Child w/ typical Spitz is low risk and should not be excised but should be monitored. Take a photo and r/w in 2-3 months to ensure no evolution of atypical features
T/F
Pigmented spindle cell naevus of Reed should be excised routinely as hard to r/o MM clinically – ensure complete excision
T
If any atypical features perform WLE w/ 5-10mm margins and follow up regularly
Which features are more c/w benign Spitz neavus than spitzoid melanoma?
Symmetry
Uniformity of cell nests or sheets of cells
Kamino bodies
Which features are more c/w spitzoid melanoma than Spitz naevus?
Mitoses >2 per mm2 >10mm diameter Atypical mitoses Deep mitoses (in base of lesion) Sheets of atypical melanocytes in dermis Ulceration extends into fat
What is Mx of suspicious Spitz or STUMP
Excision biopsy followed by WLE depending on Breslow thickness
1cm if 2mm deep
consider SNB for lesions >1mm deep if atypical/high risk Spitz or STUMP or melanoma
T/F
Spitzoid melanoma has very poor prognosis
False
trick with Spitz is not missing the MM
Spitzoid melanoma may have a better prognosis than other types
T/F
FISH or CGH may help distinguish benign and malignant spitzoid lesions
T
Spitz naevi have gains in chromosome 11p not seen in MM
Some Spitz naevi have isochromasome 5p, rarely seen in melanoma
What is a Deep penetrating naevus?
JAAD rw 2014
Rare tumour
Some consider as distinct entity, some as blue naevus variant, some as spindle cell naevus variant
F>M
more common in pts under 30 but can be congenital or any age
head + neck region then trunk then arms; rare elsewhre
Deep blue-black dome shaped papule
Often sudden onset, changing and suspicious appearance
non-specific dermoscopy
What are histo features of Deep penetrating naevus?
Pleomorphic spindle-shaped and epithelioid naevus cells extend into deep reticular dermis in wedge shape
Clusters of widely separated deep naevus cells esp around appendages
rare mitoses; cells have abundant pale cytoplasm, small nucleoli + large nuclear pseudoinclusions
Often (2/3) combined with combined (true & blue) naevus and Spitz naevus or congenital naevus with the other naevus occupying the superficial portion - papillary dermis
Lymphocytic infiltrate in 75%
More epithelioid cells than in blue naevus
distinguished from MM by H&E alone, usual IHC stains not that useful but is HMB45 positive
CGH or FISH may help
What is the Mx of Deep penetrating naevus?
Excision is curative
If margins involved clinicians decision as to re-excision or not but sometimes can recur
If any atypical features re-excise with 5-10mm margin and palpate LNs
No follow up recommendations exist
What is the Tyndall effect?
red light (longer wavelength) diffused by dermis but blue light (shorter wavelength) reflected by deep pigment makes melanin in dermis look blue - eg blue naevus, deep penetrating naevus and all the cerulodermas
T/F
50% of blue naevi occur on dorsal hands and feet
T
face and scalp also common sites
T/F
Cellular blue naevus is o 5x more common than common type
F
5x less common
Which genes are often mutated in blue naevi?
GNA11 and GNAQ
same as in >80% of uveal melanomas
What is histo of blue naevus?
wedge-shaped outline
spindle shaped (dendritic) melanocytes in dermis alone or in groups
Long axis of melanocytes mostly parallel to DEJ
Most profuse in deep dermis, can extend into fat
concentrate around appendages, vessels and nerves
Melanocytes have fine melanin granules and are deeply pigmented
Desmoplastic stroma with sclerotic increased collagen
macrophages containing coarse melanin
Overlying epi is normal unless it’s a true and blue
No mitoses – if any present may be a malignant blue naevus
3% amelanotic
Cellula rblue is similar but has also has islands of larger cells arranged in a neuroid or sarcomatoid arrangement
These have abundant pale eosinophilic cytoplasm and little pigment
T/F
malignant blue naevi always arise from a blue naevus
F
some do and some just resemble blue naevus
T/F
malignant blue naevi are best thought of as melanomas whoch resemble blue naevi
T
Often more aggressive than other melanomas
Scalp is most common site
Often >1cm diameter at presentation
T/F
A clonal neavus has a homogenous clinical appearance
F
Typically tan macule and a darker central papule
Histo shows localized proliferation of pigmented epithelioid dermal melanocytes within an otherwise ordinary nevus
When do naevi recur if incompletley removed e.g. by hsave biopsy?
50% recur in first 6 months post procedure
should excise if late recurrence >6 months or any other suspicious features
T/F
recurrent naevi may show atypia
T
may be low grade cytological atypia and some pagetoid spread not extending beyond the scar edges. Often residual dermal naevus cells below the scar
T/F
recurrent naevi have increased risk of melanoma
F
T/F
Dysplastic naevus may be precursor lesions of melanoma
T
but currently No evidence that dysplastic naevi turn into melanomas
What is Clark’s naevus?
means Dysplastic naevus
Clinically atypical naevi are >8mm diameter
F
>5mm
T/F
Dysplastic naevi are markers of risk of melanoma
T
Relative risk for melanoma is 6.36 if you have 5 atypical naevi versus zero
What is atypical naevus syndrome?
Familial tendency to have multiple atypical naevi and higher incidence of melanomas
Relative risk for melanoma is 6-10 that of pts with few naevi
What are the histo features of dysplastic naevi?
Atypical architectural features;
- Lentiginous proliferation of melanocytes (melanocyte hyperplasia)
- Fusion of nests of melanocytes
- Elongation of epidermal rete ridges
Atypical cytological features;
- Inc nuclear:cytoplasm ration
- Increased nuclear staining (darker)
- Occasional normal mitoses
- Sometimes other features: random slight-moderate atypia, occasional macronuclei, scattered epithelioid naevus cells, scattered cells w/ dusky pigment
Features of atypical host response;
- Lymphocytic infiltrate
- A degree of fibroplasia of collagen of papillary dermis
- Relative increase vascularity of dermis
How should dysplastic naevi be mananged?
a single atypical naevus is best removed (ugly duckling!)
Syndrome need regular checks etc -f/u scheduled epends on individual pt risk factors
Controversial!
Mild or Mod dysplastic naevi completely excised don’t need WLE
5mm WLE if severely dysplastic reported
Mild atypia and excision incomplete – no need to re-excise if clinically complete (no residual pigmentation seen) – re excise if pigment seen
Moderate atypia incompletely excised – judgement call but latest paper suggests no need to re-excise if no pigment seen clinically can just monitor but often re-excised esp if pigment seen
What is a Kossard naevus?
= lentiginous junctional dysplastic naevus of the elderly
Now considered melanoma in situ
Age over 60; earlier in women than men
Esp on back in men and legs in women
B/g solar damage
Histo
Atypical lentiginous proliferation of melanocytes
No nests in dermis
Cellular atypia
Sometimes pagetoid spread
Most often go on to give rise to superficial spreading MM
What is the incidence of melanoma in Aus?
40-60 per 100,000
T/F
Melanoma is responsible for 75% of skin cancer deaths
T
T/F
Women have better prognosis for melanoma
T
almost half the relative risk of dying from their melanoma when all other factors are identical. Same if preg or non-preg and pre or post menopause
T/F
The elderly have higher mortality from melanoma
T
T/F
Intermittent sun exposure is the most important environmental risk factor for melanoma
T
sunny holidays with sunburn and minimal sun exposure the rest of the time is the highest risk behaviour
Painful sunburns are an important risk factor in Hx
T/F
regular drinking causes 50% increased risk of melanoma
F
20%
but may be due to higher risk of severe sunburn
T/F
Using sunbeds more than 10x in your life increases melanoma risk
F
Use of sunbeds for any amount of time increases risk of melanoma
esp if first sunbed use was under the age of 35
(at least 20% increased risk if ever used sunbed under age 35 – rel risk 1.2)
T/F
Melanoma risk with sunbed use increases in dose-dependent way
T
T/F
Type 1 skin is the biggest phenotypic risk factor for melanoma
F
many melanocytic naevi is the biggest phenotypic risk factor for melanoma
>100 naevi – 7x increased risk
>6x increased risk if 5 or more atypical naevi
What are phenotypic risk factors for melanoma?
Many naevi Dysplastic naevi Type 1 skin/poor tanning ability Many freckles Blue eyes Red hair or fair hair colour
T/F
dysplstic naevus syndrome pts are the pts at highest risk for melanoma
F
The pts at overall highest risk are those who have multiple family members with melanoma - must take FHx
More than double risk if one parent or sib has a melanoma
9x increased risk if a parent and a sibling had melanoma
Highest risk if a parent has had multiple melanomas
T/F
the risk of melanoma in Parkinsons disease is the same as the risk if you have >100 naevi
T
both 7x risk
What are the melanoma risk genes in families?
CDKN2A gene which codes for the tumour suppressor p16
CDK4 is a rarer melanoma gene in some families
BAP1 mutations found in some kindreds with uveal or skin melanomas
T/F
MC1R gene mutations directly cause increased melanoma risk
F
MC1R mutations which cause red hair phenotype resulting in 2.44x increased melanoma risk due to phenotype alone (not due to cellular level changes predisposing to cancers)
MC1R is G-protein coupled receptor which binds αMSH
What habits or medicines may protect from melanoma?
smoking
NSAIDs
T/F
Men >60 years are most likely to benefit from screening FSE
T
Which pts are classified as high risk for primary melanoma?
High risk = any of;
1st degree relative with melanoma
Increased number of naevi (not specified but >50 in Canadian guideline)
one or more clinically atypical naevi (2-15x increased rsik)
Fitzpatrick type 1 or 2 skin
Hx of non-melanoma skin cancers
Which pts are classified as very high risk for primary melanoma?
Very high risk = any of;
Familial CDKN2A mutation
>100 total naevi
>5 atypical naevi
T/F
Radial growth phase melanomas are unlikely to metastasize
T
What are the ABCDE of suspicious lesions?
A – assymetry
B – border irregularity
C – colour variation
D – diameter > 5/6mm (originally reported as 6, some use 5 or simply ‘increasing’)
E - Evolution
Some like to try to incorporate nodular MMs by adding;
E – elevated
F – firm
G -growing
Some groups recommend biopsy if any of the ABCDE criteria are met
What is the Glasgow 7 point checklist?
3 Major criteria - change in size - change in shape - change in colour 4 Minor criteria - diameter >5mm - inflammation - oozing or bleeding - mild itch or altered sensation should consider for excision any lesion with one or more major criterion or a combination of minor criteria
What is the little red riding hood sign?
Melanomas may be erythematous or inflamed
what are the key things in the concerning mole consultation?
Should ask about - Duration of lesion - Change in size, shape or colour - Symptoms e.g. itch or bleeding - Risk factors – sunburns, immunosuppression, skin phototype, personal/FHx - Ask if any other concerning naevi and if a female has cheked her vulva for pigmented spots Should document - Size – max diameter - Whether any elevation/nodularity - Other descriptive features – irreg margins, irreg pigmentation, ulceration etc Should always do FSE and document; - Any other concerning lesions - Estimate of total number of naevi - Estimate of number of atypical naevi if any - Presence of any congenital naevi - Examination of LNs
What do smartphone apps for moles offer?
functions include; information education classification risk assessment monitoring change Reminders to self examine in some cases automated or remote dermatological diagnosis
What are drawbacks of smartphone apps for moles?
Mostly not evidence based
May not be reliable – mostly low sensitivity and specificity esp if automated
cannot perform comparative analysis or grade naevus atypia
only assesses the lesions which have already been designated as the lesions of concern
cost to patient
What are drawbacks of teledermatology for mole chacking?
only assesses the lesions which have already been designated as the lesions of concern (Pts often overlook lesions in areas they cannot see or genital areas)
Non melanoma skin cancers may be detected by dermo at FSE but missed by telederm
Does not allow the identification of the ‘ugly duckling’ or familiarity w/ a pts ‘signature naevi’
Photo factors may affect assessment
What new technologies are available for melanoma detection?
Dermatoscopy
Total body photography
Confocal microscopy
Multispectral imaging/SIAscopy – SIAscope, Molemate, Melafind
Electrical impedance spectroscopy device e.g. Nevisense
Smartphone Apps/ telemedicine
T/F
combination IHC stains may help differentiate melanoma from benign naevus
T
What is a triple negative melanoma?
BRAF/NRAS/KIT wild type
T/F
BRAF mutations seen in up to 50% of melanomas
T
T/F
BRAF mutations dont occur in benign naevi
F
common
T/F
Comparative genomic hybridization may help differentiate melanoma from benign naevus
T
80-90% sensitive for melanoma and 80-90% specific
T/F
FISH is highly sensitive in detecting melanoma but not very specific
F
sensitivity in order of 80-100%
specificity of approx 95% for distinguishing MM from naevi
T/F The standard 4 probe FISH assay for MM Vs naevus looks at the following locations and associated genes; 6p25 – RREB1 6q23 - MYB 11q13 – CCND1 Centromere 6 – CEP6
T
T/F
Sunscreen use can prevent melanoma
T
T/F
Pts with sun sensitive skin phenotypes are most likely to use sun protection measures
T
What are margins for melanoma?
In situ – 5mm margin (Bolognia recommends 1cm margins for LM of face if >1.5cm diameter due to increased risk of local recurrence)
Up to 1mm thick – at least 1cm margin
1.01-2mm thick – 1-2cm margin (2 preferred)
2.01-4mm thick – >2cm margin
>4mm thick – >2cm (some still say >3cm)
What is a field effect in melanoma?
scattered atypical melanocytes away from the maintumour bulk
often occurs in LMM but can be any type of MM
T/F
30% of LM progress to invasive melanoma LMM
False
5%
T/F
desmoplastic melanoma may arise in a LM
True
most nodules will be just invasive MM but should query desmoplastic on path form
LM is more likely to give rise to radial growth phase MM than nodular
T/F
In LM atypical melanocytes may involve hair follicle epithelium (outer root sheath)
T
T/F
LM has high recurrence rate
T
8-20%
take wider margin if possible
T/F
second line treatemnt for LM which cannot be excised is always XRT
F
not clear XRT used so is immiquimod
cryo can be used if palliative
T/F
Grenz rays are suitable for LM
F
do not penetrate deep enough to get follicular extension
use superficial XRT
How is LM terated with immiquimod?
Need at least 6 days per week for at least 10 weeks (60 treatments minimum) – 12 weeks suggested
Go at least 1-2cm beyond clinical edge of lesion if possible
adding Tazarotene may give better results
Must take multiple post Rx biopsies and follow up very closely
BAD guidance is to use only within a clinical trial
T/F
immiquimod is useful for any melanoma in situ
False
only for LM
How does desmoplastic melanoma behave differently to other types?
Local recurrence risk higher than other types of MM
Lower nodal recurrence rate than other MMs
Similar risk of mets to other MMs but seem to metastasize less than expected given depth at diagnosis
Why is desmoplastic MM hard to diagnose?
Often amelanotic pink/red scar-like nodule clinically
On Histo Stromal change is more obvious and may only be a few malignant melanocytes
but often has associated lymphoid aggregates – important clue!
If any suspicion get pathologist to do S100 to show up the atypical spindle shaped melanocytes
T/F
PREVALENCE of Acral lentiginous melanoma similar across all ethnic groups
True
but accounts for 50% of MM in dark skin types and only 10% of MM in caucasians
T/F
Hutchinson’s sign is commonly seen in nail matrix melanomas
False
classical presentation is uncommon! Many subungual MMs are hypopigmented or amelanotic – often present as progressive destruction of a nail beginning proximally – MUST BIOPSY matrix
T/F
Mucosal melanomas are often amelanotic
T
35%
T/F
Mucosal melanomas are often cKIT mutation +ve
T
40%
T/F
Mucosal melanomas often present at a late stage
T
Where should you look if a melanoma presents with liver mets?
must assess eyes as ocular MM metastasize to liver first in most cases
T/F
Advanced stage melanomas from an unknown primary may have a better prognosis than those from a known primary
T
What is the approach to melanoma mets from unknown primary?
Try to locate primary – FSE, genital, perianal/proctoscopy, ophthalmology review
Most pts can recall a pigmented lesion which has resolved or have a depigmented macule somewhere in skin draining to the affected LN basin
Assess for disease extent – examine LNs and for hepatosplenomegaly, CT chest, abdo, pelvis and head
Treat as per stage – usually by surgeons and oncologists eg if only one LN basin involved should stage as stage III and perform LN dissection
T/F
melanoma in pregnancy has poor outcomes
F
No evidence of worse outcome of pregnancy or melanoma for mother or baby directly from MM
How is Breslow thickness emasured?
Measure from granular layer to deepest invasive malignant melanocytes using an ocular micrometer
T/F
At diagnosis lesions within 2 cm of the primary melanoma are termed satellite lesions – lesions occurring >2cm from the primary are in transit mets
T
T/F
A recurrence within 2cm of the primary is called a local recurrence but usually it is in fact an in transit metastasis rather than direct extension of the primary tumour – lesions occurring >2cm from the primary are in transit mets
T
When and how is melanoma staging investigation indicated?
SLNB for stage 1B if tumour 0.76mm or more (some say alos 1A if this deep)
For stage 3 and above (nodes involved)
CT with contrast of chest and abdo and CXR (as baseline) and LFTs and LDH
If stage 4 disease suspected or diagnosed or any new neurology should CT the brain as well
T/F
High serum LDH confers worse prognosis in stage 4 melanoma (metastatic)
T
Not of proven use in earlier disease
T/F
Stage 1A melanoma corresponds to a T1a tumour with no spread
T
T/F
Stage 1B melanoma corresponds to a T1b tumour with no spread
T
T1b is 1.0mm deep or less + one of ulceration, >1 mitoses per mm2 or Clark level 4 or 5
but can also be a T2a tumour - 1.01-2mm thick without ulceration
What are the tumour stages of melanoma TNM staging?
Tx = primary cannot be assessed e.g. severely regressed or curetted T0 = primary tumour not identified Tis = melanoma in situ T1 = melanoma 1mm thick or less T2 = melanoma 1.01-2mm thick T3 = melanoma 2.01-4mm thick T4= melanoma >4mm thick a if not ulcerated, b if ulcerated
T/F
In transit mets form part of LN staging for melanoma
T
N2c = in transit mets w/out local node involvement.
corresponds with at least stage IIIb disease
40-70% 5 year survival depending on primary depth, ulceration etc
What are tumour stages and 5 year survival figures for stage I and II melanoma?
0 Tis 100% IA T1a 97% IB T1b or T2a 93% IIA T2b or T3a 80% IIB T3b or T4a 70% IIC T4b 53%
T/F
high expression of FOXP3 is an independent (of Breslow thickness) marker of increased risk of disease progression of melanoma
T
T/F
BRAF mutations in early melanomas (I-III) are associated with better melanoma specific survival esp the V600E mutation
False
poorer survival
When should SLNB be offered?
Should be offered to clinically node negative pts Tumour stage T1b or above; i.e.
tumour >1mm thick (especially this group)
Tumour 1mm or less (0.76mm or more) but has ulceration Or >1 mitoses per mm2 Or if not ulcerated and mitotic rate cannot be determined tumour is Clarks level 4 or 5
Note - some recommend offering SLNB even for 1A tumours of 0.76mm or more
T/F
SLNB has no effect on disease specific survival proven from trials so far
T
but it can offer some prognostic information
For intermediate thickness melanomas (1.2-3.5mm) 5 year survival if node positive on SNB is 75% but is 90% if node negative
T/F
The presence or absence of micromets as determined by SNB (in clinically node negative pts) is required for accurate Node staging
T
T/F
SNB followed by urgent completion lymphadenectomy may have a survival benefit in some patients
T
What is the complication rate of SLNB?
5-10% of pts get complications
mostly minor; seroma, infection most common
lymphoedema v rare
T/F
lymphadenectomy for +ve SLNB has fewer complications than LN dissection performed when there is clinically evident LN involvement
T
T/F
Small sentinel LN deposits
T
T/F
SLNB is +ve in up to 5% of melanomas
T
T/F
pts with histologic regression are more likely to have positive SLNB
F
less likely
T/F
USS +/- FNA can be offered as an alternative to SLNB
T
T/F
most melanoma recurrence is found by pts in between f/u
T
75% of recurrences in Aus are pt detected
T/F
1st year after diagnosis is highest risk period for another melanoma
T
Young pts under 40 are at highest risk of another melanoma
T/F
Most second melanomas occurs at same body site as first
T
T/F
In the case of positive LNs should stage prior to LN dissection to exclude widely metastatic disease
T
Also do biomarker testing for V600 BRAF mutations
T/F
Melanoma lung and soft tissue mets are more responsive to chemo than CNS or liver mets
T
T/F
Desmoplastic melanomas should have adjuvant XRT after WLE
T
T/F
XRT in melanoma used for locoregional disease not amenable to surgery
T
also used for palliation e.g. bone mets
T/F
Adjuvant XRT to LNs after excision results in reduced morbidity and reduced LN relapse but no improvement in overall survival demonstrated so far
T
is recommended in some countries guidelines now
T/F
Dacarbazine is standard of care chemo for melanoma
F No longer first line about 10% response rate - usually partial Median response duration 8 months Has not been shown to prolong survival
Which drugs are BRAF inhibitors?
Vemurafenib (Zelboraf)
Dabrafenib (Tafinlar)
Both have ‘raf’ and ‘nib’ in the name
Which drugs are MEK inhibitors?
Trametinib (Mekinist)
Cobimetanib
Both have ‘met’ and ‘nib’ in the name
What kind of drug is Ipalimumab (Yervoy)?
Fully humanized mAb against the T-cell antigen CTLA-4 (cytotoxic T-lymphocyte associated antigen 4)
name contains ‘lim’ for lymphocyte and ‘umab’ for human monoclonal antibody
Which drugs are antibodies against programmed death 1 receptor PD1?
Pembrolizumab (Keytruda)
Nivolumab
Lambrolizumab
all have ‘ol’ and ‘umab’ in the name
What is the first line treatment for unresectable BRAF mutation +ve metastatic melanoma?
Dabrafenib + Trametinib Combi Rx improves progression-free survival and alters adverse effect profile of dabrafenib w/ higher risk of fever (Mx w/ low dose steroids and dose reduction) and lower incidence of skin AEs; Much lower SCC risk Much lower verrucal keratosis risk Much lower Grover’s disease disease risk Increased folliculitis Other AEs at similar rates
What is the first line treatment for unresectable BRAF wild type metastatic melanoma?
Ipalimumab
What is the second line treatment for unresectable BRAF mutation +ve metastatic melanoma?
Pembrolizumab (Keytruda)
In Aus available on PBS as 2nd line for unresectable stage 3 or 4 melanoma which has progressed following Rx with a BRAF inhibitor w/ or w/out a MEK inhibitor (pts must have V600 mutation)
What are the skin side effects of BRAF inhibitors?
Grover’s disease, Acneiform eruptions, AKs, SCC, Photosensitvity, keratosis pilaris, cysts, folliculitis, alopecia, plantar hyperkeratosis, verrucal keratosis, verruca vulgaris, vitiligo, panniculitis, Cymotrichous (wavy hair)
T/F
4-14% of melanoma pts get in transit mets
T
T/F
Local melanoma recurrence often still has a good prognosis
F
is strongly predictive of development of in transit, regional or distant mets
Pts usually get local LN involvement either concurrently or eventually
Rarely pts get in transit Dx for years w/out LN spread
T/F
In transit mets on a limb can be distal to the site of the original tumour
T
although usuallly proximal
anywhere >2cm from tumour site designated in transit mets
What are the Rx options for in transit mets?
Excision if small and small number; aim for clear margins with curative intent and perform SLNB
Isolated limb perfusion if limb recurrences cannot be surgically controlled – usually Melphalan +/- TNF which may increase efficacy. Sometimes use dacarbazine or fotemustine
Isolated limb Infusion - less invasive procedure; Uses Melphalan and Actinomycin D
CO2 laser if numerous small mets
XRT can be used for disease not controlled by other methods
Intralesional BCG
Intralesional IFNalpha
Topical immiquimod
DPCP topical immunotherapy
What is the risk of missing an invasive melanoma if only a partial biopsy of lentigo maligna is taken?
about 20%
best to take one or multiple shaves
