Where are melanomas and nevi derived from?
melanocytes (neural crest cells that migrate to hair follicles on the skin primarily, as well as pigment in eye, the retina/iris, inner ear and medulla). So anywhere melanocytes are, you can get melanoma
Ulceration and depth of dermal involvement (the anatomic site itself doesnt make it worse BUT having it on the feet tend to be diagnosed later)
Note: About 50% of melanomas habor a BRAF mutation BUT the presence doesnt contribute as much to prognosis
What is the relationship between nevi and melanomas?
Both are proliferations of melanocytes (nevi=benign), both share BRAF mutations commonly
High numbers of nevi (esp over 50) can increase risk of melanoma and melanomas develop from nevi about 20% of the time (80% are de novo)
What are the types of Nevi?
-acquired melanocytic nevi (junctional, compound, intradermal)
-atypical ('dysplastic') nevi
-Other (spitz, blue nevi)
Junctional (top left): Nests of proliferating melanocytes that are connected to the epidermis
Compound (top right): in both
Intradermal (bottom): purely in the dermis
Symmetric, rounded= benign
Describe junctional nevi
2-3mm in diameter, deeply pigmented and macular, arising at the dermal-epidermal junction above the basement membrane zone
Because they dont have a dermal component they tend to be more flat
Describe compound nevi
Tend to be raised because they have a dermal component (whereas dermal nevi are rasied but dont have a epidermal component so may not even be pigmented and can present as skin tags)
What is this?
Intradermal nevi- can tell because it is raised (suggesting dermis involvement) and lacks pigment (suggests no epidermal involvement)
Classified according to size (can be up to 20cm) with pigment ranging from brown to black, grossly irregular surfaces and larger nevi put you at risk for melanoma (highest risk in the first 5 yrs of life)
What is this?
Atypical (dysplastic) nevi- not melanoma (biopsied often); large number of these increases risk of melanoma (but not thought to be a stepwise progression to melanoma- but can!!)
One dysplastic nevus DOES NOT increase a patient's risk of melanoma
What gene may be associated with atypical nevi?
CDNK2 (p16INK4A) tumor suppressor gene (common in melanoma)
These are BENIGN but definitely concerning
What patients have the highest risks of melanoma?
caucasion men over 50 (although its the most common cancer type in 25-29 yo)
Look for the ABCDEs!
Maturation of melanocytes means they get smaller with descent (in melanoma they are just as big as the ones above them)
melanomas can grow radially and vertically
Melanoma is thought to have a multifactorial etiology. What are some contributors?
-Genetic predisposition (familial, BRAF, CDNK2)
-Underlying immune status
What are some risk factors for melanoma?
-large number of common nevi (50+)
-presence of giant congenital nevi
-many atypical nevi (or familial Hx)
-History of blistering sunburns
-Fam history (not a huge driver)
-light complexion, tanning bed use
-underlying immune dysfunction
ABCDEs of Melanoma
Color: mottled, not uniform
Diameter over 6mm
changing moles and 'ugly duckling sign'
What are the subtypes of melanoma?
-acral lentiginous (usually not driven by sunlight- found in protective sites, cit mutations common)
-lentigo maligna melanoma
-amelonotic (doesnt make much melanon so appears pink)
What kind of melanoma is this?
acral lentiginous melanoma- defined by anatomic location on palmar, plantar, and subungal skin. (The most common type of melanoma in darker skin patients)
Common on sun-damaged skin of the face of elderly pts.
Nodular MM are almost all vertical growth (nodular)
These start to grow down very quickly and dont radiate out much
Superficial spreading melanoma common on sun-exposed skin (a lot of these have BRAF mutations)
What is this?
Where does Melanoma like to MET?
Often via lymphatics (but not exclusively) and the #1 organ site to go to is SKIN but it can go anywhere
What is the single most important prognostic factor for melanoma progression?
lymph node involvement
What is the most important histological factor for melanoma progression?
Breslow thickness and ulceration
What is Breslow's thickness?
Distance of involvement from the stratum granulosum to the deepest tumor cell
thickness: less than 1mm= 83-88% 10 yr survival
How can metastatic melanoma be treated?
Targeted therapy for BRAF mutations (Vemurafenib) - provides modest survival benefit- ~6 months (good initially but melanoma adapts and can bypass the BRAF pathway)
-new drugs can bind MEK as well
How does immunotherapy work for melanoma?
-Ipilimumab (binds CTLA4 to promote T-cell immune response in advanced melanoma)
-PD-1 inhibitors (Pembroizumab and Nivolumab)-same mechanism
Role of sunlight in Squamous cell CA?
chronic CUMULATIVE lifelong exposure clearly related to development
Role of sunlight in Basal cell CA?
UV important but not clearly related to cumulative doses. Intermediate?
Role of sunlight in Melanoma?
Involved, but clearly driven by more than just sunlight
AR disease casued by defects in nucleotide excision repair of thymine dimers that leads to increased risk of all skin cancers
What are the first symptoms of XP?
acute sun sensitivity, pigmented macules, and dry skin in infancy