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

• 6^th cancer in males

• 7^th 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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