Basal cell carcinoma (overview) C44.-

Author: Prof. Dr. med. Peter Altmeyer

Co-Autors: Jeton Luzha, Hadrian Tran

All authors of this article

Last updated on: 21.02.2021

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Synonym(s)

basal cell carcinoma; Basal cell carcinoma; Basal cell carcinoma ulcerative; basal cell epithelioma; Basal cell epithelioma; Basalioma; basocellular epithelioma; BCC; Epithelioma metatypical of the "type mixte; Epithelioma metatypical "type intermediare; Krompecher carcinoma

History
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Krompecher, 1900

Definition
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Heterogeneous group of fibroepithelial malignant tumors of the skin, which grow locally infiltrating and destructive, metastasize extremely rarely and often show morphological analogies to adnexal structures (evidence of stem cell formations in basal cell carcinomas as well as in embryonic hair germs). Basal cell carcinoma is the most common (semi-)malignant skin tumor in humans, and its incidence and prevalence have been increasing worldwide in recent years. For Caucasians, the current lifetime risk of developing basal cell carcinoma is estimated at 30%. In Germany, between 1.0 and 2.0 million new diagnoses are made each year.

Classification
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I. Clinical Classification:

  1. Nodular basal cell carcinoma (>50% of cases)
  2. Superficial basal cell carcinoma (15% of cases)
  3. Sclerodermiform basal cell carcinoma (about 25% of cases)
  4. Pigmented basal cell carcinoma
  5. Ulcerated basal cell carcinoma

Special forms:

  1. Basal cell carcinomatosis / basaliomatosis: Genodermatoses with basal cell carcinomas
  2. Non-syndromal multiple basal cell carcinomas (also linear form); see below Gorlin-Goltz Syndrome

II. Histological classification:

  1. Keratotic Basal Cell Carcinoma
  2. Solid basal cell carcinoma
  3. Dimorphic basal cell carcinoma
  4. Superficial basal cell carcinoma
  5. Sclerodermiform basal cell carcinoma.

Special forms:

  1. Fibroepithelial basal cell carcinoma
  2. Metatypical basal cell carcinoma (metatypical epithelioma of the "mixed or intermediaire" type
  3. Cystic basal cell carcinoma.

Occurrence/Epidemiology
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The most frequent carcinoma of the skin among the Caucasian population group whose predisposition is determined by individual patient characteristics such as light skin type, advanced age, immune competence and genetic syndromes (e.g. Gorlin-Goltz syndrome, Xeroderma pigmentosum, Rombo syndrome).

Incidence rates are missing for most European countries. In Germany the incidence is about 70-200/100,000 inhabitants/year. Well-known European data indicate the highest incidence in Wales (112/100,000 inhabitants/year) and the lowest in Finland (49/100,000 inhabitants/year). For Australia the incidence is estimated at 800/100,000.

Men and women are equally affected.

People with actinic cheilitis and solar lentigines have a higher risk of developing basal cell carcinoma.

Only very rarely does metastasis occur (less frequently than 1:1000). In North America, the incidence in the population is < 40 years, higher in women than in men.

Etiopathogenesis
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According to current knowledge, basal cell carcinoma originates from epidermal stem cells from the hair follicle bulge or from undifferentiated cells of the outer root sheath, see also figures.

UV radiation: causative multiplicative factors (e.g., history of sunburns, cumulative sun exposure, intermittent high exposure peaks) play a role in its development.

Genetic factors: somatic mutations of the p53 tumor suppressor gene, various mutations in the so-called hedge gene. Mutations in the so-called hedgehog signalling pathway - PTCH1; SMO - see Gorlin-Goltz syndrome; furthermore frequent occurrence in xeroderma pigmentosum and albinism.

Other triggering factors in the development of basal cell carcinoma:

  • Fair-skinnedness
  • Carcinogenic substances, especially arsenic
  • Long-term immunosuppressive therapy

Chronic skin damage e.g. by infections or by physical stimuli, trichotillobasal cell carcinoma), radiodermatitis chronica.

Prostaglandins: Animal experiments have shown a massive increase in prostaglandin synthesis in UV-induced murine skin tumours. Selective inhibitors of prostaglandin synthesis reduce the development of basal cell carcinomas.

Manifestation
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Preferably occurring in fair-skinned people (skin types I and II), very rarely in dark-skinned people. Up to 80% in the head and neck area. Peak age 6th to 8th decade of life. A tendency towards younger age of manifestation is recognizable. Men and women are equally affected. In addition, occurrence in the context of hereditary syndromes (then also possible in young patients), especially in:

Localization
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Basically: Localization only on skin areas with formation of hair follicles. No primary manifestation on mucous membranes and semi-mucous membranes.

Head and neck area (about 80%: nose, inner corner of the eye, zygomatic bone, forehead, rarely lower third of the face, followed by capillitium and ears - also retroauricular).

Stem (15-20%) and extremities(superficial basal cell carcinoma) are rarer localizations.

Genital and perianal localisations are possible, but very rare.

Clinical features
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Mostly skin-coloured or red or red-brown nodules, plaques, nodules or ulcers. The clinical aspect depends on the age of the lesions (size, surface, colour), the localisation and the type of basal cell carcinoma present (see different clinical variants).

Marginal accentuation: Typical for basal cell carcinomas is the accentuation of the edges of the foci in the form of glassy, skin-coloured or white-grey, often "pearl-like" nodules, the atrophic shiny surface of the plaques or nodules (absence of follicular structures due to the destructive growth of the tumour). This phenomenon can be highlighted by tightening the surrounding skin.

Bizarre tumor vessels: The occurrence of atypical, mostly bizarrely configured tumor vessels, which can be visualized particularly well with the reflected light microscope, is also of diagostic value.

Imaging
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Imaging is usually not required for basal cell carcinoma.

Further imaging is recommended in the following cases:

  1. Locally advanced basal cell carcinoma (lfBCC): If bone infiltration is suspected, computed tomography and/or contrast-enhanced magnetic resonance imaging should be performed.
  2. Periorbital basal cell carcinoma: If orbital infiltration is suspected, computed tomography of the orbit and contrast-enhanced magnetic resonance imaging should be performed.
  3. Perineural growth: If perineural growth is suspected, MRI with fat-saturated high-resolution contrast-enhanced T1w sequences should be performed.
  4. Metastasis: Ifmetastasis is suspected, further diagnostic imaging should be performed. For this purpose, 18F-FDG PET/CT and/or CT may be considered.
  5. Basal cell carcinoma syndrome: If basal cell carcinoma syndrome is suspected, further imaging diagnostics should be performed to exclude other associated malignancies and malformations. For this purpose, according to the current guidelines, a dermatological whole-body examination, MRI of the skull, echocardiography, X-ray of the spine and dental panoramic radiography should be performed. In female patients, a gynaecological pelvic ultrasound should also be performed.

Histology
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  • Mostly solid epithelial strands of cells with little cytoplasm and roundish to oval dark nuclei, which form palisade-like at the edges. Cystic, adenoid or trichoid forms are possible without these histological varieties being clinically specific among the individual basal cell carcinoma types. A cell-rich tumor stroma is characteristic.
  • The tumor cell clusters show positive results when stained with the antibody against BerEp4, the "epithelial cell adhesion molecule" EpCAM. This antibody is not expressed by squamous cell carcinomas and thus represents an important differentiation possibility between the two tumor entities.
  • In contrast to trichoepithelioma, basal cell carcinomas show PHLDA1 (pleckstrin homology-like domain family A member 1) negativity (see also premalignant fibroepithelioma).
  • Laser scanning microscopy: elongated, monomorphic cell nuclei, polarization of these cells along an axis, pronounced inflammatory infiltrate, proliferated as well as dilated vessels and loss of the epidermal honeycomb structure, islets of tumor cells with peripheral palisade position in the dermis delimited by a dark slit = optical slit, see figure.

Diagnosis
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The diagnosis is normally made by biopsy and conventional histology in case of clinical suspicion. The safety of clinical diagnostics is routinely supplemented by non-invasive dermatoscopy. Furthermore, non-invasive laser scanning microscopy or non-invasive optical coherence tomography (OCT) can extend clinical diagnostics.

External therapy
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For the topical therapy of basal cell carcinoma, 3 therapeutic procedures are approved:

  • 5-fluorouracil (only for superficial basal cell carcinoma): Local chemotherapeutic treatment. 5-fluorouracil ointment (e.g. Efudix ointment) is applied to the basal cell carcinoma twice a day for about 6 weeks. Due to strong external irritation reactions as well as the long duration of treatment (sometimes up to 3 months, Cave! patient compliance), other procedures are usually preferable. For multiple basal cell carcinoma of the trunk skin, local chemotherapy in combination with curettage may be a sensible method.
  • Imiquimod: After histological confirmation local therapy with Imiquimod (Aldara 5%). Treatment is given once a day for 5 days a week for a total of 6 weeks. Numerous studies prove the good healing (80%). Imiquimod is approved for superficial basal cell carcinomas under 7.25 cm². The topical treatment is a suitable alternative to surgical resection in superficial basal cell carcinoma, especially in multiple trunk skin basal cell carcinoma and induces an acute inflammatory reaction in the affected area by activating the Toll-like receptors 7 and 8. This inflammatory reaction, which is induced by the immune system, leads to an activation of the body's own defence and consequently to a healing of the original skin change. Pronounced irritation of the treated areas is an expected side effect.
  • Photodynamic therapy (PDT): Therapeutic procedure which causes a sensitization of basal cell carcinoma cells by means of the affinity of externally or internally applied photosensitizers (ALA = 5-aminolevulinic acid, or the ester MAL = methyl-aminolevulinic acid). Subsequent irradiation leads to the destruction of the tumour without affecting the surrounding tissue. A larger comparative study (n=601 Pat) between MAL-PDT and Imiquimod showed a therapeutic benefit for the Imiquimod group (Roozeboom 2016).

Radiation therapy
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Basal cell carcinomas are very sensitive to radiation. Radiation therapy has approximately comparable healing prospects to surgical treatment, but is rarely used because of the often better cosmetic results of microsurgical procedures. The indication for radiation treatment exists mainly in cases of primary inoperability, postoperative microscopic (R1-resection) or macroscopic residual tumor (R2-resection). A further indication exists if there is a recurrence postoperatively and a sano resection is unlikely. The surrounding tissue as well as risk organs, especially eyes, including eyelashes and tear glands or ear cartilage are protected by lead masks. Soft X-rays or fast electrons are used.

  • Soft X-rays: Fractionated irradiation with ED of 3-5 Gy at GD of 50-60 Gy 3-6 times/week. The GHWT (tissue half depth) should correspond to the depth invasion of the tumor, generally 6-12 mm. The radiation field should be 0.5-0.7 cm larger than the tumor. If after reaching the GD no complete tumor regression or erosion is visible over the entire radiation field, the radiation is continued in intervals of several days. At least an erosion extending over the entire tumour (erosive reaction) is to be aimed at in order to complete the treatment.

Internal therapy
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It could be shown that the hedgehog signalling pathway is of crucial importance for the pathogenesis of basal cell carcinomas. Most sporadic basal cell carcinomas have mutations in this signalling pathway. Systemic approaches in the therapy of basal cell carcinoma are inhibitors of the Hedghog signalling pathway that bind to SMO and thus prevent signal transduction.

With Vismodegib and Sonidegib, two specific inhibitors of SMO are available for the treatment of inoperable or metastasized basal cell carcinoma. The results are encouraging.

Experimental: It could be shown that the azole antifungal drug itraconazole has an inhibitory effect on the SHH signaling pathway. The mechanism of action via SMO binding sites is different from the mode of action of vismodegib and sonidegib. A first phase II study (n=19 pat.) showed some efficacy (200mg 2x/day).

Operative therapie
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Remark: In the different entities of basal cell carcinoma different local infiltration patterns are usually to be expected. Especially in sclerodermiform basal cell carcinoma an asymmetric distributed growth is to be expected, often subclinical narrow spindle-like extensions are found in the surrounding tissue. This growth pattern has to be considered when planning a surgical intervention.

Excision: The most frequent therapy for uncomplicated basal cell carcinoma. This usually requires (depending on the findings) a two-stage operation with temporary covering of the defect (e.g. Syspuderm or Epigard). The safety margin is usually 0.5 cm, in primary nodular basal cell carcinoma 0.1-0.6 cm are sufficient, in recurrences as well as in cases of unclear clinical demarcation, e.g. in sclerodermifom basal cell carcinoma, complete visualization of the three-dimensional incision margins is required.

Since basal cell carcinomas are frequently localized in the head and neck region (e.g. nose), the safety distance must be adapted to the given circumstances. Attention must be paid to optimal reconstruction. For small, favorably localized basal cell carcinomas, oval or spindle excision in the "relaxed-skin-tension-lines" is recommended. Histological margin control is obligatory, a post excision according to the histological findings and the anatomical conditions. The intraoperative frozen section is often insufficient as a margin control, as it only allows a punctual statement.

Micrographically controlled surgery: Micrographically controlled surgery is the safest and most gentle surgical procedure. The serial histological 3D preparation and evaluation in the so-called bread loaf technique allows a safe and comprehensive statement about the spread of the tumor to the side and depth. With this technique, the local recurrence rate is reported to be < 2%.

Flat ablation: For basal cell carcinomas of the cheek and nose, flat ablation with 3D-histology confirmed R0 resection and secondary wound healing is a cosmetically good alternative to large (sliding) plastic surgery.

Cryosurgery: Multiple freezing with intermediate thawing phases at temperatures of -30 °C at the tumor base (temperature measurements with temperature probe). Alternative: 15 seconds at -180 °C, two cycles. A few days after application of cold, necrosis with blister formation occurs in the treated area. The patient should be made aware of the regular occurrence of oedema. Sterile wound dressing (e.g. Oleo-Tuell or Varihesive extra thin). Tumours in the area of the nasolabial fold are unsuitable for cryosurgical procedures because of the particularly high risk of recurrence in these areas. Basal cell carcinoma of the eyelid should only be treated in exceptional cases and by a surgeon experienced in cryosurgery.

Laser: In defocused application for superficial vaporization with single pulse lengths of 0.1-0.2 sec, spot size 0.2-0.4 cm, 5-10 watts. In focused application, theCO2 laser is used as a "light scalpel". The use of the laser offers no reliable advantage over conventional procedures. As a so-called blind procedure, a high recurrence rate is to be expected.

Suggestions for the primary cutting depth and the safety distance for primary excision (n. Breuninger)

Depth of cut shallow ablation, epidermis, dermis, subcutis (depending on size)
Safety distance 0.1 - 0.6 cm

Prophylaxis
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Retinoid therapy: Acitretin (neotigason) can be used as a preventive long-term therapy for basal cell carcinomatosis, basal cell nevus syndrome or xeroderma pigmentosum (0.5 to max. 1 mg/kg bw/day). In order to prevent the occurrence of basal cell carcinoma, higher doses are required than for other long-term applications.

Caution! Women of childbearing age! Children (bone growth)!

Naturopathy
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Order therapy: Avoid UV

Phytotherapy: betulin, green tea, garden spurge

Vitamin B3: For nicotinamide (Vit B3), a phase III study in 386 patients has been completed to investigate its preventive effect on basal cell carcinoma (2x500mg Vit B3). The rate of new cases could be reduced by 20%. The chemopreventive effect lasted only as long as the preparation was administered.

Tables
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Therapeutic methods and their indication

Procedure

Indication

Advantage

Disadvantage

Excision

Solid basal cell carcinomas in unproblematic localization, clear clinical limitability.

Simple and fast procedure, histological edge control, relatively low recurrence rate

Difficult in basal cell carcinomas with unclear boundaries and a large depth extension. Compared to MKC higher risk of recurrence.

MKC - Micrographically Controlled Surgery

Recurrence of basal cell carcinoma, extensive basal cell carcinoma of the face, unclear clinical delimitation, scleroderma basal cell carcinoma, basal cell carcinoma in special localisation (corner of the eye, nasal bridge, auricle).

Reliable marginal incision control, lowest recurrence rate

Elaborate, multi-stage procedure.

Curettage and electrodesiccation1

Superficial basal cell carcinomas of the trunk and extremities, basaliomatoses (e.g. basal cell nevus syndrome), toxic induced basal cell carcinomas (e.g. arsenic intoxications), especially in older patients.

Quick

Edge cut control not possible. Relatively poor cosmetic results, especially after electrodesiccation, tendency to hypertrophic scarring.

Cryosurgery1

Flat, small basal cell carcinomas whose tumor parenchyma does not exceed the middle corium.

Non-invasive, relatively good cosmetic result

Edge cut control not possible. Extensive experience with the method is important. Relatively high recurrence rate, frequent depigmentation.

CO2 laser focused (light scalpel)

Superficial basal cell carcinomas

Low risk of bleeding, clear operating field

Tendency to scar and keloid formation.

CO2- Laser1 defocused

Superficial basal cell carcinomas

Non-invasive

Edge cut control not possible. The depth effect of the therapy is difficult to measure.

Radiotherapy1

Only in patients of advanced age, medium-sized nodular basal cell carcinomas, pigmented basal cell carcinomas, trunk skin basal cell carcinomas. Suitable are localisations in the face, also on eyelids, eye corners, nose, nasolabial fold, auricle and lips. Not over ear cartilage, bony base, back of the hand.

Non-invasive, recurrence rate depends on basal cell carcinoma type (solid approx. 5%, sclerodermiform > 30%)

Edge cut control not possible. Induction of new tumours, X-ray dermis, danger of poorly healing necroses, especially over cartilage and bony base.

Interferons1

Superficial and small nodular basal cell carcinomas

Non-invasive

Edge cut control not possible. Application is not recommended because it is expensive and unsafe.

5-fluorouracil1

Superficial basal cell carcinomas

Non-invasive

Edge cut control not possible. Considerable local side effects with inflammations, pigment shifts, scarring are possible.

Prophylaxis: Retinoid therapy

Absolute indication: Xeroderma pigmentosum, basal cell nevus syndrome, condition after prolonged use of arsenic.

Prophylaxis

Side effects of retinoid therapy: teratogenicity (up to 24 months after discontinuation), dryness of the mucous membranes, cheilitis, hair loss. Monitor bone growth in children!

Relative indication: multiple basal cell carcinomas in immunocompromised patients (condition after organ transplantation), multiple basal cell carcinomas after severe light damage to the skin or arsenic intoxication.

Aftercare
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Close-meshed follow-up care for at least 5 years, as the basal cell carcinoma risk due to recurrences or new tumours in basal cell carcinoma anamnesis is 25%. In the first year every 3 months, thereafter every half year. After 5 years an annual check is recommended. Patients with basal cell carcinomatosis, nevoid basal cell carcinoma syndrome (Goltz-Gorlin syndrome) or xeroderma pigmentosum should be checked every 3 months in the long term.

Note(s)
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Metatypical basal cell carcinoma (metatypical epithelioma of the "mixed or intermediaire" type): This is a rare variant which histologically reveals both morphological aspects of a basal cell carcinoma and a squamous cell carcinoma. Such peculiarities are particularly present in elderly people with long-term lesions. This type shows faster and more aggressive growth.

Literature
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  1. Alter M et al (2015) Current diagnosis and treatment of basal cell carcinoma. JDDG 13: 862-876
  2. Bivens MM et al (2006) Nonmelanoma skin cancer: is the incidence really increasing among patients younger than 40? A reexamination using 25 years of U.S. outpatient data. Dermatol Surgery 32: 1473-1479
  3. Breuninger H et al (1992) Quantitative analysis of the recurrence or spontaneous regression of basal cell carcinoma parts left in situ. Dermatologist 43: 561-56
  4. Breuninger H (2015) Safety distances for malignant skin tumours. Derm 21: 203-211
  5. Chen AC et al.(2015) A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. N Engl J Med 373:1618-1626.
  6. Dummer R et al(2016) The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): A phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol 75:113-125.
  7. Geisse J et al (2004) Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 50: 722-733
  8. Gold Vulture M et al (2003) Noninvasive imaging, treatment, and microscopic confirmation of clearance of basal cell carcinoma. Dermatol Surgery 29: 205-210
  9. Heppt M et al (2016) What is the latest news on basal cell carcinoma? Dermatologist 67: 876-883
  10. Herzinger T et al (2003) Basal cell carcinoma of the toenail unit. J Am Acad Dermatol 48: 277-278
  11. Joshi A et al (2000) Basal cell carcinoma arising in a localized linear verrucous epidermal naevus. Acta Derm Venereol 80: 227-228
  12. Kim DJ et al (2014) Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol 32:745-751.
  13. Krompecher E (1900) The glandular surface cancer (Ca epithelial adenoides). Path Anat 28: 1-41
  14. Kumar P (2002) Incomplete excision of basal cell carcinoma: a prospective multicentre audit. Br J Plast Surgery 55: 616-622
  15. Lobeck A et al (2017) Consideration of the dermatosurgical patient collective at a skin tumor center in Germany. Dermatologist 68: 377-384
  16. Mieczko A et al (2011) BerEP4-negative basal cell carcinoma of the palm: Case report and literature review. JDDG 9:140-143
  17. Oster-Schmidt C, Altmeyer P, Stucker M (2002) Basal cell carcinoma of the foot. Is the pedoscope a risk factor? dermatologist 53: 819-821
  18. Roozeboom MH et al (2016) Three-Year Follow-Up Results of Photodynamic Therapy vs. Imiquimod vs. Fluorouracil for Treatment of Superficial Basal Cell Carcinoma: A Single-Blind, Noninferiority, Randomized Controlled Trial. J Invest Dermatol 136:1568-1574.
  19. Sterry W et al (2002) Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: randomized studies comparing low-frequency dosing with and without occlusion. Br J Dermatol 147: 1227-1236
  20. Stücker M et al (2002) In vivo differentiation of pigmented skin tumors with laser Doppler perfusion imaging. dermatologist 53: 244-249
  21. Van Hoff et al (2009) Inhibition of the hedgehog pathway in advanced basal cell carcinoma. N Engl J Med 361: 1164-1172
  22. Walther U et al (2004) Risk and protective factors for sporadic basal cell carcinoma: results of a two-center case-control study in southern germany. Clinical actinic elastosis may be a potective factor. Br J Dermatol 151: 170-178
  23. Wang LE et al (2005) In vitro sensitivity to ultraviolet B light and skin cancer risk: a case-control analysis. J Natl Cancer Inst 97: 1822-1831

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