Pathophys/Path 2 Flashcards
Melanoma Epidemeology
est. 138,000 new cases in 2013
Highest risk: caucasian men >50
Most common cancer in: 25-29y/o
2nd most common: 15-29y/o
1 American dies every hour from melanoma
Rising: young women with tanning
older menHow do melanomas develop?
80% is denovo
20% from nevi
Must be in dermis to metastasize
What are the three types of nevi?
1) Junctional - epidermis
2) Compound - epidermis/dermis
3) Intradermal Melanocytic
What defines nevi?
Well circumscribed
Small
Symmetric
Uniformly pigmented
Nevi and Melanoma Relationship?
- compromised by melanocytes
- share some mutations (BRAF)
- more nevi (>50) increase chance of melanoma
- melanoma can develop from pre-exisiting nevi
Why get melanoma?
Multifactorial: Genetic (CDNK2, BRAF)
Environment (UV)
Underlying immune status
Melanoma risk factors?`
- Large # of nevi (>50)
- giant congenital nevi
- atypical nevi
- history of blistering sunburns
- family history of melanoma
- light complexing
- tanning bed use
- underlying immune dysfunction
Screening for melanoma?
A asymmetry B borders-irregular, scalloped C color-mottled, variegated D diameter >6mm E elevation "change" "ugly duckling"
Melanoma Metastasis
Often lymphatics
#1 site is skin
most common cause of death: CNS involvement
Most important prognostic factor: lymph node involvement
Most important histologic prognostic: Breslow thickness and ulceration
Melanoma Treatment
Early, cut it out
Metastatic: no proof that anything increases survival (late 2011)
Vemurafenib
attacks MAPK kinase signaling pathway
-Small molecular inhibitor of BRAF (V600E mut.)
-good for unresectable/metastatic melanoma
survival benefit for 50% of patients with mutation
-modest in duration (6 month survival)
Sunlight and Cancer
UVB forms dimers b/w neighboring thymine pairs in DNA, repaired by endonucleases and other repair
- Squamous: cumulative
- Basal: not relate to cumulative?
- Melanoma: role with genetic and immune
Xeroderma Pigmentosum
Autosomal recessive 1 in 1 million
deficient repair of UV-induced DNA damage (nucleotide excision repair of thymine dimers)
-freckles, wrinkling, skin atrophy
first cancer at 8, at 20 risk is 10,000 higher (2,000 for melanoma)
eyes, CNS, death 32y/o
Solar Radiation
5% is between 100-400nm, lots of diseases
UVC
200-290nm don’t penetrate ozone layer, most potent, when artificially produced it’s absorbed by DNA, RNA, proteins and can be lethal to epidermal cells
UVB
290-320nm, window glass filters out <320nm, sunburn/photochemical rxns in skin
SPF against this one
2-5% of what reaches earth surface
UVA
320-400nm then its visible
least potent, penetrates glass and deeper than UVB-cause of wrinkles
98% of what reaches us from sun
what modifies UVR?
atmosphere, latitude, altitude (1000ft is 4% increase), reflection (water-7%, sand-25%, snow-80%), clouds (scatter not absorb), time of day, season
When sunlight hits skin…
reflected, absorbed by epidermis, dermis, DNA, proteins
Action spectrum is determined by?
UV absorbing properties of molecule that initiates response: chromophore
Major UVB chromophores in skin?
DNA, urocanic acid, aromatic amino acids
Photodamage
UVB majority of effects on skin
acute/chronic response depends on phototype
Types I-VI burning, tanning, cancer
Acute effects of UVR
inflammation immunomodulation tanning epidermal hyperplasia (skin thickening) Vit D photosynthesis DNA damage -apoptosis, cell cycle arrest to repair
Sunburn
mostly UVB erythema-vasodilation heat-increased blood flow pain/pruritus - cytokine release intracellular edema/perivascular edema hyperkeratosis, acenthosis >72hrs
Suntan
UVA/visible: immediate, fades in hour, oxidation/redistribution of existing melanin, no protection
-Delayed is UVB, >72hrs, increased melanin synthesis and transfer, some protection
Chronic Effects of UVR
photoaging
BCC, SCC, melanoma
chronologic aging
smooth, pale, finely wrinkled skin, benign growths
photoaging
UVA(penetrate deeper)/UVB(more efficient)
dry, deep wrinkles, inelastic, leathery, atrophic, telangiectasias, irrugular pigmentation, comedone/cyst formation, actinic keratoses, malinancies, benign
DNA damage
direct: UVB-obsorption of photons by bases of DNA
indirect: absorption of photons by other chromophores
DNA photoproducts
dimers formed by covalent binding of 2 adjacent pyrimidines in the same polynucleotide chain
- cyclobutane
- 6,4 photoproducts
- **signature mutations C to T or CC to TT
Skin defense against UVR
stratum-reflection melanin-absorption tumor suppressor genes-patched, p53,016 DNA repair apoptosis
Immunosuppression and sun
langerhans cells disapear with sunburn
those and lymohocytes are sensitive to DNA damage
Light used to treat?
Eczema, Psoriasis, Cutaneous lymphoma
Tanning Beds
Mostly UVA, 5X normal amount, no protection, melanoma associated
>75% increase in those that use before 30s
carcinogenic by WHO
Acral Lentiginous Melanoma
hands and feet
Lentigo Maligna Melanoma
face
nodular
nodular
sun exposed
“no preceding radical growth”
15%MM 2x more in men
Superficial Spreading
not as aggressive
“red, white, blue”`
Breslow’s thickness
distance of involvement from the stratum granulosum (top) to the deepest tumor cell (bottom) 4mm bad
Nonmelanoma risk?
1 in 5 lifetime
rising in young females
Basal Cell Carcinoma
-germinative keratinocytes “picket fence” blue
-most common invasive neoplasm in US
2million/year
PTCH mutation in 30% (tumor suppressor of basal epidermal cell proliferation)
RIsk of BCC
UV fair complexion sunburns (blistering) family history of BCC immunosuppression
Pathology of BCC
- basophilic hyperchormatic cells that form nodules, extending from surface of epidermis
- peripheral cells form palisade
- tumor nodule set in mucinous stroma with retraction from that stroma (clefting)
BCC Subtypes
nodular (most common) superficial pigmented morpheoform (cutaneous) micronodular cystic infiltrative
BS nevus syndrome (Gorlin Syndrome)
auto dominant 1 in 56,000 mutation of PTCH1 BCC in 20's MSK defects/jay cysts increase other cancer risk (fibrosarcoma, medulloblastoma)
BCC metastasis/treatment
rare 0.0028%-0.55%
surgery, radiation, topical (targated Vismodegib)-SMO inhibitor
Squamous Cell C
- epidermal keratinocytes (resembles spinous layer)
- 2nd most common skin cancer
- progress like cervical cancer, minimal atypia, full thickness epidermal atypia above BM, incasive
Actinic Keratoses
thin non-indurated lesion
superficial
in epidermis
SSC Pathology
- hyperchromatic pleomorphic nuclei, disorganized growth, mitoses and invasion throughout basal layer
- pink, keratinizing cells like stratum spinosum
SSC Risks
no mutation only p53 UV HPV Immunosuppression -scars,inflammation,chemical,radiation,leukoplakia
Cutaneous SCC metastasis risk?
size, depth, site, host immune status
1) larger than 2cm
2) greater than 4mm depth
3) on lips or ears
SCC metastasis
<5%, mets to lymph nodes and lung
Keratoacanthoma
SCC related, neoplasm of keratinocytes rapidly grows over 2-6 weeks painful involute spontaneously
Marjolin’s Ulcer
ulcerative incasive SCC
chronic inflammation, scarring, radiation, trauma
SCC Treatment
excision
actinic keratosis: topical/cryotherapy
topical
