Nowotwory i stany przednowotworowe skóry
Stany przedrakowe
1) związane z działaniem UV
rogowacenie słoneczne i róg skórny
skóra pergaminowata i barwnikowa
uszkodzenie rentgenowskie skóry
2) rogowacenie chemiczne
3) rogowacenie białe
Actinic (solar) keratosis:
Występuje w miejscach przewlekłej ekspozycji na UV
Żółtobrunatne nawarstwienia rogowe o suchej, nierównej powierzchni
przebieg choroby wieloletni
Rogowacenie słoneczne
pogrubienie zmarszczek i pobruzdowanie skóry
szarożółty kolor z przbarwieniami i odbarwieniami
Zgrubienie skóry
suchość i złuszczanie
Róg skórny
Twór rogowy rozmaitego kształtu
nacieczenie podstawy
starczy - odmiana rogowacenia posłonecznego lub starczego
u dzieci - na bazie zmian zapalnych
Skóra barwnikowa i pergaminowata
Choroba dziedziczna, związana z defektem endonukleazy, odpowiedzialnej za naprawę uszkodzeń posłonecznych
zmiany chorobowe typu plam soczewicowatych pojawiaja się po pierwszej ekspozycji na UV w miejscach odsłoniętych
rozwój nowotworów Scc, Bcc, czerniaki już w dzieciństwie
Przewlekłe uszkodzenie porentgenowskie skóry
Nierównomierne stwardnienie z odbarwieniami i przebarwieniami, teleangiektazjami i zanikami skóry
obecne ogniska nadmiernego rogowacenia
Why is skin cancer important?
most common malignant tumors in humans ( over 2/3)
estimated life-time risk as 1:5
incidence is rising more quickly than any other tumor
…. and it is largely preventable
Skin malignancies: The „Big Three”
Cutaneous Melanoma (CM)
Non-melanoma skin cancers (NMSC):
Basal cell carcinoma (BCC)
Squamous cell carcinoma (SCC)
Incidence and Epidemiology
NMSC - 2.75 mln new cases worldwide per year
(true incidence diffcult to determine !!!)
CM - app. 150 000/ per year worldwide
6th cancer in males
7th cancer in females
NMSC and CM worldwide
Incidence rates (per 100,000)
Risk factors: UVR exposure
80 % of NMSC and CM in sun-exposed skin
both UVB (290-320nm) and UVA (320-400nm) play a role:
damage to cell DNA (mutations)
impair the ability to control cell proliferation
(mutations in suppressor genes:p53, PTCH)
induce immunosuppression (Langerhans cells depletion)
total dose of UVR necessary to induce skin cancer is not clearly defined
role of type, quantity and timing of sun exposure
intensive sun-exposure and
severe sunburns (5 or more) in childhood and adolescence
recreational sun-exposure
less important total life-time exposure
Exposure to UVR (natural or sun beds)
is one of the most important risk factors for NMSCs and CM,
BUT the major one
is skin color (melanin)
!!!
the incidence rates in non-white populations are less than 2% of the rates among fair-skined individuals
Fitzpatric's skin phototypes
Skin Cancer Risk Factors
exposure to chemical carcinogens (arsenic, hydrocarbons)
exposure to ionizing radiation
HPV infection (in SCC)
family or personal history of skin cancer:
sporadic molecular alterations (tumor suppressor genes mutations; p53, p16/CDKN2)
inherited syndromes (increased susceptibility to UVR or impaired DNA-repair mechanisms) : albinizm, xeroderma pigmentosum, atypical mole syndrome
chronic immunodeficiency
Immunosuppression & Skin Cancer
organ transplants recipients are at greater risk for cutaneous malignancy:
10-fold increased risk of BCC
40-150-fold increased risk of SCC
> 50% of renal transplant recipients develop NMSC
often multiple tumors
more aggressive, increased metastatic potential
app. 4 times higher risk of melanoma
Cells of origin:
SCC originates from keratinocytes of spinous layer of the epidermis/epithelium
BCC - pluripotent epidermal cells of outer root sheath of the hair follicle or intrafollicular basal layer
CM - melanocytes or nevoid cells
embryologically come from the neural crest
located in the basal layer of the epidermis
Basal Cell Carcinoma
no well-defined histological precursors !!! (arises de novo)
50 % H&N, 27% trunk, 21% limbs
slow-growing tumor
local invasion - destruction of local tissue and difigurement
rarely metastasizes (0.028%-0.55%)
generally favourable prognosis
relatively high recurrence rate
BCC: Subtypes
nodular or micronodular (60%)
superficial (20%)
morpheaform (2%)
solid
cystic
adenoid
keratotic (basosquamous)
BCC: Nodular type
asymptomatic
„pearly”, translucent
papule or nodule
telangiectases
central ulceration and crusting
Histologically:
nests of basaloid cells
palisaded nuclei at the periphery
well-defined contours (easy to treat)
BCC: Superficial type
more frequently involves the trunk or extremities
non-healing sore, bleeding with mild trauma
erythemateous patch or plaque
often raised, irregular pearly border
increase in size by spreading peripherally
crusted, ulcerated
BCC: Morpheaform (Infiltrative) type
sclerosing or fibrosing BCC
most common on face (nose or cheeks)
shiny, whitish, atrophic, indurated plaque (confused with scar)
eventually few telangiectases
histologically extends beyond clinical margins (complete excision difficult)
BCC: Pigmented variant
usually nodular BCC
contains areas of pigment (melanin deposits; no proliferation of melanocytes)
mostly in darker-skined individuals
easly misdiagnosed as melanocytic nevus or melanoma
Squamous cell carcinoma
only few cases arises de novo
mostly evolve from precursor lesions
actinic keratosis (AK)
Bowen's disease (BD)
chronic ulcers and thermal burns
mostly on chronically sun-exposed skin (app.2/3 involve the lower lip - „sun terrace”)
grow more rapidly than BCC
frequency of metastases 1%-12.5%
depending on: histological features,size, location and precursor lesion
Bowen's disease
usually single
asymptomatic
well-demarcated
erythematous, scaly patch
SCC in situ
(keratinocytes atypia
histologically confined
to the epidermis)
Invasive SCC:
erythematous, hard nodule
often inflamed, indurated surrounding area
become ulcerated, crusted and necrotic
Cutaneous Melanoma
50-60% arises de novo within normally-looking skin
or from precursor lesions (premelanoma states)
lentigo maligna
congenital melanocytic nevi
acquired common melanocytic nevi
dysplastic (atypical) nevi
Precursors of melanoma:
Lentigo maligna
elderly faces
very slow growing
large irregularly pigmented macule
melanoma in situ
up to 50% evolve into
invasive melanoma within 15-20 years
Precursors of melanoma:
congenital melanocytic nevi
present at birth or within the first few months
small (<1.5 cm) or medium (<20 cm)
1% life-time risk of CM
can be followed clinically
large (> 20.0 cm)
up to 10% risk of CM
complete surgical excision usually recommended (if possible)
Precursors of melanoma:
common melanocytic nevi:
proliferation of normal melanocytes
appear after 6 -12 months of age
enlarge and increase in number in early childhood and puberty
remain less than 5 mm
Acquired melanocytic nevi:
Risk markers or precursors of CM?
spatial association of nevi and melanoma observed both clinically and histologically
a history of preexisting nevus at the site of melanoma is recorded between 19% and 85% of cases
on histologic examination, nevus cells in association with a melanoma have been reported in 46% to 72% of cases
the risk of CM is strongly related to the number of dysplastic nevi
Familial Atypical Multiple Mole and Melanoma (FAMMM) Syndrome
very high rates of melanoma development (184-fold )
occurrence of melanoma in one or more first- or second-degree relatives
presence of > 50 melanocytic nevi, some of which are atypical clinically and histologically
autosomal dominant
mutattions in the tumor suppressor gene p16/CDKN2a
in 20-50% of families
Melanoma: Histogenetic classification
Amelanotic Melanoma
it lacks a pigmentation
redish macule or nodule
less differentiated
Skin Cancer Clinical Diagnosis:
Algorithm of Differentiation
The ABCDE rule
Benign Nevus vs. Melanoma:
Benign Nevus vs. Melanoma:
The ABCDE rule
The ABCDE rule
Benign Nevus vs. Melanoma:
The ABCDE rule
Benign Nevus vs. Melanoma:
The ABCDE rule
Benign Nevus vs. Melanoma:
Benign Nevus vs. Melanoma: Misdiagnosis
app. 40% of melanomas less or equal to 6 mm
melanomas measuring 3 mm or less constitutes up to 3 %
nodular melanomas usually failed ABCDE rule
by solely following ABCDE rule up to 25% of melanomas will be missed
Early detection of melanoma: Dermoscopy
skin surface microscopy (magnification up to 20x)
surface and subsurface structures of lesion
essential in differentiation between melanocytic and nonmelanocytic lesions
additional sensitive features for identifying melanoma
several complicated diagnostic algorithms that recquire an experience
Three-point checklist of Dermoscopy
[Consensus Net Meeting on Dermoscopy]
quick, screening approach for primary physician as well as for experienced dermatologist
assessment of 3 features:
asymmetry
atypical pigment network
blue-whitish veil
Asymmetry
in shape and/or color in 1 or 2 perpendicular axes
Atypical Pigment Network
dark brown or black network with irregular, broadened holes and thick lines
Blue-whitish veil
transparent, blue-whitish, structurless area that may extend over much of the lesion
occurs from heavily pigmented melanocytes in the upper dermis.
when present at least one of these features
diagnostic excision is highly recommended
sensitivity > 90%
Histological evaluation
is a „gold standard”
in diagnosing skin cancers
and in determining appropriate treatment
!!!!
Treatment options
CM
simple excision (reexcision) surgery - the only currently recommended treatment option
NMSC
surgery - is the prime treatment
non-surgical modalities
NMSC treatment: Non-surgical
accepted for:
precancerous lesions (AK, actinic cheilitis)
SCC in situ (Bowen's Disease)
low-risk well-defined primary BCCs:
superficial or thin nodular
small in size (< 2 cm) and depth (<2 mm)
histologically well-differentiated
!!! Should be combined with initial curettage or shave biopsy
to provide a specimen for histological evaluation:
to confirm invasive tumors
NMSC treatment: Non-surgical
radiotherapy
cryotherapy
laser therapy
photodynamic therapy (PDT)
Use of topical agents:
5-Fluorouracil (5-FU)
Imiquimod
Diclofenac
Photodynamic therapy (PDT)
oxygen-dependent destruction of tumor cells after photosensitization
and subsequent irradiation with light
non-invasive
highly-selective
most commonly used topical sensitizers:
5-Aminolevulinic acid (ALA) [Levulan®]
Methyl aminolevulinate (MAL) [Metvix®]
PDT: Mechanism of action
topical application of photosensitizer
it is preferentially absorbed by the tumor cells
conversion to protoporphyrin IX
exposure to laser or cold red light (634 nm)
generation of reactive oxygen species (ROS)
highly-selective destruction of tumor cells (necrosis and apoptosis)
Status of PDT in Skin Cancers: 2007
PDT has been registered for treatment of:
thin (non-hyperkeratotic) AK
BD
superficial BCC
thin nodular BCC
PDT: Actinic keratosis
1 session of PDT
85%-90% complete responce rate
(phase III randomized controlled studies)
superior efficacy to cryothrapy (68%)
favourable cosmetic outcome
PDT: Bowen's Disease
1 or 2 sessions of PDT
>95 % complete clinical response
acceptable long-term efficacy (17% recurrence rate within 64-month vs. 34% for cryotherapy)
PDT: Basal cell carcinoma
2 sessions with interval of 1 week
85%-97% clearance rates (equally to cryotherapy or surgery)
long-term efficacy within 4-year follow-up [recurrence rates comparable with cryotherapy (22% vs. 19%)]
PDT in Skin Cancer: Pros & Coins
high (90%) responce rates
long-term efficacy
recurrence rates within range of standard treatments (cryptherapy and surgery)
excellent cosmetic results
multiple lesions can be treated at one time
do not complicate future surgery if required
time delay between application and cure
limited depth of tissue penetration (thicker treatment may require repeat treatments)
„On the basis of this evidence,
PDT can be recommended as a
first-line treatment for
AK, BD, and sBCC.
PDT can also be recommended for nBCC lesions”.
5% Imiquimod (Aldara®)
first in a new class of drugs - Immune Responce Modifiers (IRM)
Toll-like receptor agonist
registered for treatment of:
Actinic Keratoses
superfical BCC
Antitumoral action of Imiquimod
binding to TLR-7 and TLR-8 on DC
secrection of proinflammatory cytokines
induction of tumor-directed cellular immune response
direct proapoptotic activity against tumor cells
Imiquimod in AK
recommended dosing:
once daily, 3 x per week for 4 weeks (+/- 4 weeks)
reported complete clearance rates : 84%*-100%**
lower incidence of new AK lesions in treatment area
8% clinically diagnosed at 1 year*
Imiquimod in AK
Imiquimod in sBCC:
recommended dosing:
once daily,5 x per week for 6 weeks
clearance assessment 12 weeks post treatment
reported clearance rates: 82%-94%
app. 9.0% recurrance rate after 24-month follow-up
Imiquimod in sBCC:
Imiquimod in BD
Imiquimod in LM - a pilot study
Imiquimod in Skin Cancer:
Pros & Coins
can treat large surface or multiple lesions
excellent cosmetic outcomes
patients can self-treat
long duration of inflammation and pain at site of aplication
long treatment period
Topical Diclofenac
3% Diclofenac in 2.5% hialuronian gel [Solaraze®]
nonsteroidal anti-inflammatory drug (NSAID)
potent inhibitor of inducible cyclo-oxygenase (reduction of PG synthesis)
approved for treatment of AK (US, Canada, countries of EU)
sun-induced skin damage
and AK are associated
with increase PG synthesis
in the skin
Topical Diclofenac in AK
Topical Diclofenac in AK:
Studies review
NMSC and CM: a growing problem
CM - accounts for 80% of all skin cancer deaths
NMSCs - exact numbers of deaths not available (not
consistently reported)
dramatic increase in incidence
among white populations
3%-8% per year for NMSC
app. 10 % for CM (greater than any other cancer !!!)
due to:
aging populations
life-style changes with increased sun-exposure (UVR)
Skin Cancer: can it be PREVENTED?
Avoid exposure to solar UVR
especially between 11 a.m. and 3 p.m. (the highest UV index)
wear protective clothing and sunglasses
Use SUNSCREENS
sun protective factor (SPF) of 30 or higher
users of sunscreen have 40% reduction in skin cancer over non-users (4-year randomized trial)*
intensive sun protection before age 18 reduce nonmelanoma skin cancer by 78%
Sunscreens
should not be used to extend
the duration
of sun-exposure
!!!!!
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