Coll. Antropol. 34 (2010) Suppl. 2: 85–88 Original scientific paper

Senile – Cosmetic or Medical Issue of the Elderly Population

Mirna [itum1, Vedrana Bulat1, Marija Buljan1, Zvonimir Puljiz2, V. [itum3 and @eljana Bolan~a1

1 Department of and Venereology, University Hospital »Sestre Milosrdnice«, Zagreb, Croatia 2 Department of General Surgery, University Hospital »Sestre milosrdnice«, Zagreb, Croatia 3 Department of General Practice, Split, Croatia

ABSTRACT

Senile lentigo or age spots are hyperpigmented macules of skin that occur in irregular shapes, appearing most com- monly in the - exposed areas of the skin such as on the face and back of the hands. Senile lentigo is a common compo- nent of photoaged skin and is seen most commonly after the age of 50. There are many disscusions on whether senile lentigo represents a melanoma precursor, namely melanoma and, if there is a need for a regular follow up in cases of multiple lesions. Clinical opservations sometimes report that in the location of the newly diagnosed mela- noma, such lesion preexsisted. On contrary, some authors believe that senile lentigo represents a precursor of , which does not require a serious medical treatment. However, the opservation of the possible association of se- nile lentigo with the melanoma development makes us cautious in the assessment of this lesion. Histologically, there are elongated rete ridges with increased at the tips, and the number of is not increased. The dermato- scopic features are also distinctive. If the lesion becomes inflammed it may evolve into benign lichenoid keratosis. Cryo- therapy and laser treatment are common therapeutic approaches. Sun protection creams may be useful in early lesions.

Key words: senile lentigo, UV radiation, photoimmunology, oncogene

Introduction

Lentigo senilis (synonyms: lentigo solaris, spot, are considered benign lesions and not routinely added old age spot, senile ) is well-circumscribed, round, into National Register4. oval or irregularly shaped macule that vary in color from The most significant environmental factor for the de- light brown to dark brown or black which usually devel- velopment of senile lentigo is cumulative UV radiation, ops on chronically photoexposed areas in the elderly peo- particularly solar UVB radiation5. During the past cen- ple, predominantly on the face, the dorsal aspects of tury, changes in clothing styles, recreational activities, hands, extensor forearms, the upper chest and back1. chronic occupational solar exposure, longevity, and other More than one half of all patients over age 64 will have at aspects of lifestyle have resulted in increased exposure to least one senile lentigo, and most patients have more sunlight. Although most UV radiation comes from the than one. Senile lentigines are found in 90% of the Cau- sun, the use of sunbeds as arteficial sunlight has resulted casian poplulation older than 60 years, and according to in a rising incidence of UV-induced lentigines. The most published epidemiological data their incidence increase important defense mechanisms in the protection of hu- with advancing age and cumulative (UV) light man skin against UV radiation involve melanin synthe- exposure 2,3. With respect to increased incidence of this sis and active repair mechanisms. Low pigmentation ca- common skin lesion, senile lentigo has become a signifi- pacity in Caucasians and rare genodermatosis Xeroderma cant cosmetic and medical issue. The incidence rates of pigmentosum lead to multiple senile lentigines associ- lentigines have increased worldwide over the past sev- ated with multiple skin cancers. Inherited patterned len- eral decades. The similar trend has been observed in tiginosis favors more lightly pigmented African-Ame- Croatia. The exact incidence rate is unknown since they ricans6.

Received for publication January 10, 2010

85 M. [itum et al.: Senile lentigo, Coll. Antropol. 34 (2010) Suppl. 2: 85–88

Despite their benign nature, lentigines can cause sub- detected in 7% of senile lentigines, suggesting that FGFR3 stantial cosmetic issue, with strong impact on health and PIK3CA mutations are involved in their pathoge- care budgets due to their extraordinary high incidence. nesis and further substantiating previous speculations that UV exposure may be a causative factor for FGFR3 and PIK3CA mutations in human skin11. UV Radiation and Senile Lentigo Furthermore, UV radiation induces the release of UV radiation is well-known, potent, environmental prostaglandins and cytokines by the keratinocytes. agent closly associated with the development of senile Among the mediators released by keratinocytes in re- lentigo in fair-skinned, elderly individuals. The concept sponse to UV radiation, there is a small peptide en- of UV radiation as the significant etiologic factor in the dothelin-1 (ET-1), a ligand for the endothelin-B (ETB)re- pathogenesis of senile lentigo originates from the begin- ceptor expressed on melanocytes, which can lead to an ning of the twentieth century followed by astute observa- increase in activity followed by an increase in tions of clinicians who noted that senile lentigo fre- melanin production. A recent report (Kadono et al.) dem- quently appeared on the sun-damaged skin of fair-ski- onstrates focal epidermal ET-1 hypersecretion and en- nned individuals who pursued outdoor occupations. dothelin-B (ETB) overexpression in human skin samples Within the UV radiation spectrum, the UVA (wave- from lentigo senilis12. lengths between 320 and 400 nm), and particularly UVB (wavelengths between 290 and 320 nm) are the most sig- The activation of the ET-1/ETB pathway downregu- nificant. Besides occupational UV exposure, UV photo- lates E-cadherin and associated catenin proteins in hu- therapy has been associated with senile lentigo. man melanocytes and melanoma cells. E-cadherin is an PUVA (psoralen+ UVA) lentigo is a well- circum- established suppressor of melanoma cell invasion in vitro scribed hyperpigmented macule that commonly develops and in vivo. Downregulation of E-cadherin, cellular ad- in individuals undergoing long-term PUVA chemother- hesion molecule, by ET-1/ETB receptor involves the down- apy. About 50% of PUVA-treated patients develop PUVA stream activation of caspase-8 but not of distal, execu- 13 lentigines after average of 5 to 7 years of photochemo- tioner caspases, and does not lead to apoptosis . therapy. The frequency and severity of the lesions are Interactions between keratinocytes and melanocytes positively correlated with greater number of treatments, including ET-1 and ETB receptor as well as stem cell fac- age of starting therapy, and male sex. There is a negative tor (SCF) and c-KIT receptor expressed on melanocytes association wih skin phototypes V and VI. In contrast to are responsible cytokine networks for senile lentigo and typical senile lentigines, PUVA lentigines usually exhibit UVB-melanosis14. Disturbed keratinocytes-melanocytes darker pigmentation and more of a stellate appearance. interactions during transfer and skin me- Histologically, the PUVA-induced lesions display lenti- lanosome distribution patterns could be related to senile ginous hyperplasia of larger melanocytes that often ex- lentigo formation. Melanocytes located in the basal layer hibit mild cytologic atypia. Patients treated with PUVA of epidermis produce melanin-loaded , which should also be monitored for the development of mela- are distributed to neighboring keratinocytes. Chronic 2,7 noma . UV radiation lead to an accumulation of melanosomes in Numerous studies have supported the notion that UV melanocytes and also increase the phagocytose of mela- radiation causes significant damage to keratinocytes and nosomes by keratinocytes15. melanocytes8. A case-controlled study in France found that multiple senile lentigines on the upper back and Affymetrix gene-expression analysis (Goyarts et al.) shoulders of adults may serve as clinical markers of past was performed on mRNAs from involved and uninvolved severe sunburn and may be used to identify a population skin biopsies from volunteers with lentigo senilis. In this at higher risk of developing cutaneous melanoma9. The study serine peptidase gene was downregulated in keep- researchers suggested that senile lentigo may be induced ing with the suggestion that lentigo senilis is associated by the mutagenic effect of repeated past UV light expo- with impaired melanin degradation. The antiapoptotic sures, leading to characteristic enhancement of melanin genes were downregulated, and six genes associated with production10. transmembrane transport of melanosomes were upre- 16 Little is known about the genetic basis of human se- gulated . nile lentigines, which were analyzed for potential fibro- Production of the growth factors, can also lead to an blast growth factor receptor 3 (FGFR3) and phospha- increase in the pigment content within melanocytes in tidylinositol 3 CA-kinases (PIK3CA) mutations. A recent senile lentigo. There is also increasing evidence that UV study (Hafner et al.) investigated environmental and ge- radiation can affect receptors, kinases, phosphatases and netic risk factors for senile lentigo. FGFR3 and PIK3CA transcription factors. regulate several important cellular processes, including regulation of cell growth and division. The FGFR3 gene The most important defense mechanisms in the pho- is located on the short (p) arm of at position 16.3 and toprotection involve melanin synthesis and active repair PIK3CA gene is located on the long (q) arm of at position mechanisms. Low pigmentation capacity in Caucasians 26.3. The FGFR3 gene mutations were detected in 17% and rare genodermatosis Xeroderma pigmentosum are of senile lentigines, and PIK3CA gene mutations were mainly responsible for protection failures.

86 M. [itum et al.: Senile lentigo, Coll. Antropol. 34 (2010) Suppl. 2: 85–88

Clinical, Histological and Dermatoscopic tion. There is no evidence of basaloid cell proliferation or Features of Senile Lentigo budding and no resemblance to lentigo senilis19. The development of cytologic atypia in se- Clinical appearance and histologic features of lentigo nile lentigines on occasion suggests a relationship of so- senilis have been well documented. Senile lentigines are lar lentigines to lentigo maligna, but clear progression to well-circumscribed, round or oval macules that vary in lentigo maligna has not been established20. Senile len- color from yellow, light brown to dark brown or black. tigines have been shown to be an independent risk factor More lightly pigmented lesions are usually homoge- for the development of melanoma.Senile lentigines are neous, whereas darker ones tend to have a mottled ap- phenotypic manifestation of sun exposure. They are as- pearance. The lesions increase in number and in size sociated with a two-to threefold relative risk for the de- gradually. They usually vary from about 3 mm to 2 cm in velopment of melanoma4,20. In a study of 513 melanoma diameter and demonstrate a tendency towards conflu- patients these lesions were identified with increasing ence. Larger and older lesions are often irregular in age21. shape and are often dark brown or brownish-black in color. Senile lentigines occur on sun-exposed areas, pre- A biopsy is mandatory for any lesion that develops an dominantly the dorsal aspects of hands, extensor fore- irregular border and color, particularly very dark brown arms, the face, the upper chest and back of fair-skinned, or black hues. The biopsy findings in solar lentigo are elderly individuals1. characterized by proliferation of basaloid cells forming buds and strands that contain increased amounts of mel- Differential diagnosis of senile lentigo includes a wide anin. In some cases, the melanocytes are increased in range of benign and malignant lesions, such as early number at the dermoepidermal junction. There is no stage of seborrheic keratosis and lentigo maligna. Der- junctional activity. Melanocytes in dopa-stained sections matoscopy as new, noninvasive diagnostic technique may of solar lentigines exhibit increased melanogenesis, and be helpful in diagnosis of senile lentigo, since senile these cells have more numerous as well as longer and lentigo may mimic early stage of seborrheic keratosis, thicker dendritic processes than the melanocytes of nor- solitary -like keratosis (SLPLK) or lentigo mal skin. In the superficial dermis there is the constant maligna. finding of actinic elastosis and dermis often contains Major dermatoscopic features of senile lentigo are: a melanophages and occasionally a mild perivascular infil- diffuse light brown structureless area, sharply demar- trate of lymphocytes. Electron microscopic studies reveal cated and/or moth-eaten borders, fingerprinting, and a abbundant melanosome complexes in keratinocytes which reticular pattern with thin lines that are occasionally appear to be larger than in normal surrounding skin2,22. short and interrupted17. According to Nouveau et al. dermatoscopic pictures of senile lentigo have shown that the observed structures can be vary different within a given lesion, suggesting Treatment of Senile Lentigo that different areas of a senile lentigo could be in differ- ent grades of severity, which proves the heterogeneity of senile lentigo architecture18. There is clinical and histolo- and laser surgery have been shown to be gic evidence of close relationship between lentigo senilis, equally effective, but caution must be used to prevent SLPLK, and reticulated form of seborrheic keratosis. In post-treatment dyspigmentation. Senile lentigines may the histologic study performed by Mehregan histologic be removed with various types of chemical peels, 2% transformation was found from lentigo senilis into cen- /0,01% tretinoin, or special lasers23. They may tral SLPLK. also be temporarily bleached with 3-4% concentration creams which are used as cytotoxic effects It was concluded that SLPLK is an inflammatory to melanocytes and tyrosinase inhibitors. Another de- variant of lentigo senilis with irritation, trauma, or other pigmenting agent kojic acid interrupts intermediates in yet unknown factors leading to basal cell damage, lique- melanin synthesis24. faction degeneration, and incontinentia of pigment fol- lowed by induction of an inflammatory cell reaction in a Primary prevention of senile lentigo is appropriately fashion similar to that which recently has been postu- focused on the avoidance of excessive sun exposure of the lated to occur in lichen planus. The same study also has skin. Photoprotection is one of the fundamental preven- shown histologic transformation from lentigo senilis into tion of BCC. Dermatologists should educate their pa- reticulated seborrheic keratosis. Fully developed reticu- tients in the use of sunscreen. The use of a highly effec- lated seborrheic keratosis shows a more complicated net- tive broad-spectrum UVA and UVB sunscreen have been work pattern of pigmented basaloid cell and areas of ker- shown to influence the development of nevi in children, atin cyst formation. Intention of the study performed by suggesting that they should play a role in preventing se- Mehregan was to evaluate the possibility of relationship nile lentigines if used correctly and consistently. Combi- between lentigo senilis and lentigo maligna. The light- nation of UVA and UVB filters may offer a powerful pro- -brown area of lentigo maligna exhibits diffuse prolifera- tection against UV-induced effects in the use of suncare tion of anaplastic clear cells at the dermoepidermal junc- products25.

87 M. [itum et al.: Senile lentigo, Coll. Antropol. 34 (2010) Suppl. 2: 85–88

Conclusion epidermal disorder rather than a disease of the me- lanocytic system. There is no histologic evidence to in- Senile lentigo is an entity with distinct histologic fea- criminate lentigo senilis as an early or precursor stage of tures characterized by proliferation and downward bud- the precancerous . However, It is crucial to rec- ding of basaloid cells accumulating melanin pigment. ognize its role as an indication of chronic UV damage There is no significant degree of proliferation of melano- which dictates monitoring of the patient for non-mela- cytes and in this respect lentigo senilis is a proliferative noma and melanoma.

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M. [itum

Department of Dermatology and Venereology, University Hospital »Sestre milosrdnice«, Vinogradska cesta 29, 10000 Zagreb, Croatia e-mail: [email protected]

LENTIGO SENILIS- KOZMETSKI ILI MEDICINSKI PROBLEM TRE]E DOBI

SA@ETAK

Lentigo senilis (senilne pjege) podrazumijeva promjene na ko`i koje se klini~ki o~ituju kao hiperpigmentirane ma- kule koje se naj~e{}e pojavljuju na fotoeksponiranim podru~jima kao {to su lice i dorzumi {aka. Senilni lentigo spada u uobi~ajene komponente tzv. fotostarenja ko`e i naj~e{}e se vidi u osoba starijih od 50 godina. ^esto se vode rasprave je li lentigo senilis prete~a melanoma, i to lentigo maligna melanoma te treba li osobe koje imaju multiple promjene redovito kontrolirati. U klini~kim iskustvima ponekad se dobije podatak da je melanomu prethodila upravo takva lezija. Ta- ko|er, neki autori smatraju, suprotno prethodnome, da je lentigo senilis prete~a seboreji~ke keratoze, a koja ne zahtjeva ozbiljan medicinski tretman. No, ipak nas opservacije o poveznici senilnog lentiga s mogu}im nastankom melanoma ~ine opreznijim u opserviranju ove lezije. Histolo{ki, kod senilnog lentiga vide se produljene epidermalne pre~ke s pove- }anom koli~inom melanina u vr{cima, dok broj melanocita nije pove}an. Dermatoskopska slika je tako|er karakte- risti~na. Uslijed inflamatornog procesa solarni lentigo mo`e prije}i u dobro}udnu lihenoidnu keratozu. Krioterapija i laserski tretman danas su naj~e{}e primjenjivane metode u uklanjanju senilnih pjega, a kod po~etnih promjena pri- mjena krema s UV filtrima mo`e biti u~inkovita.

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