Nevoid basal cell carcinoma syndrome

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162

Nevoid basal cell carcinoma syndrome

Patricia Reutemann and Gary L. Peck

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

Multiple basal cell carcinomas arising after radiation therapy of a solitary BCC in a patient with NBCCS.

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin–Goltz syndrome or basal cell nevus syndrome (BCNS), is characterized by a variety of neoplasms and skeletal anomalies with the universal finding being multiple basal cell carcinomas (BCCs). In addition, more than 50% of patients exhibit palmar and plantar pits, odontogenic keratocysts, rib abnormalities, and ectopic bilamellar calcification of the falx cerebri. Associated neoplasms include medulloblastomas and ovarian fibromas. The chromosomal defect in this autosomal dominant disease is mapped to chromosome 9q22.3-q31, resulting in a mutation of the patched gene (PTCH), which functions as a tumor suppressor gene. The PTCH protein operates in the hedgehog signal transduction pathway and inhibits the activity of smoothened protein. Dysregulation of this transmembrane protein favors subsequent tumor formation.

Management strategy

Affected individuals usually present with multiple primary BCCs that pose a therapeutic challenge because of their number, size, and location. The goal of therapy is to achieve adequate cancer control while minimizing cosmetic disfigurement. Therapy should also include emotional support and genetic counseling. The treatment of BCCs in NBCCS is similar to that of sporadic BCCs and includes multiple modalities such as surgery, lasers, and topical, injectable or systemic therapy; it also highlights the role of chemoprophylaxis, sun protection, and radiation avoidance. Furthermore, in the last several years, research has focused on the hedgehog signaling pathway with the development of smoothened protein inhibitors for metastatic or locally advanced BCCs.

Specific investigations

Radiologic studies

Genetic studies

Dermatoscopy

Radiologic images in dermatology: nevoid basal cell carcinoma syndrome.

Mirowski GW, Liu AA, Parks ET, Caldemeyer KS. J Am Acad Dermatol 2000; 43: 1092–3.

Radiologic studies detect the various skeletal and soft tissue anomalies associated with NBCCS including odontogenic keratocysts, lamellar calcification of the falx cerebri, macrocephaly, cleft lip and/or palate, rib and vertebral anomalies, and short fourth metacarpal (Albright sign).

Nevoid basal cell carcinoma syndrome (Gorlin syndrome).

Lo Muzio L. Orphanet J Rare Dis 2008; 25: 32.

PTCH1 gene mutation analysis is the definitive diagnostic test to demonstrate NBCCS, although it is labor-intensive as there are 24 exons. Newly designed high-resolution oligonucleotide microarrays with a much smaller median distance between the probes have been used to detect gene deletions that could not have been detected by conventional chromosomal analysis.

A novel polymorphism in the PTC gene allows easy identification of allelic loss in basal cell nevus syndrome lesions.

Zedan W, Robinson PA, High AS. Diagn Mol Pathol 2001; 10: 41–5.

How to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part II. Nonmelanocytic skin tumors.

Zalaudek I, Kreusch J, Giacomel J, Ferrara G, Catricalà C, Argenziano G. J Am Acad Dermatol 2010; 63: 377–86.

Under dermoscopy, branched arborizing vessels are a specific finding of nodular, cystic or sclerodermiform BCC, while fine arborizing vessels of a smaller diameter, either alone or associated with dotted vessels and whitish streaks are characteristic of fibroepithelioma of Pinkus, an unusual variant of BCC. Superficial BCC frequently has the presence of fine ‘microarborizing’ vessels, shiny red-white structureless areas, and multiple small erosions.

First-line therapies

Surgical management	B
Mohs micrographic surgery	B
Protection against radiation exposure	C
Chemoprevention:
–Oral retinoids (isotretinoin, acitretin)	A
–Difluoromethylornithine	A
–Celecoxib	A
–Others	B–E

Assessment and surgical treatment of basal cell skin cancer.

Goldberg DP. Clin Plast Surg 1997; 24: 673–86.

Surgical excision, with a 2–5 mm margin of normal skin depending on tumor size, has a cure rate as high as 95–99% for primary tumors. Low-risk sporadic BCCs located on the neck, trunk, and extremities are associated with recurrence rates of 1–10%, while BCCs on the ear, nasolabial groove, scalp, or forehead exhibit higher recurrence rates.

Guidelines for the management of BCC.

Telfer NR, Colver GB, Bowers PW. Br J Dermatol 1999; 141: 415–23.

Mohs micrographic surgery has an overall 5-year cure rate of 99%, and is the treatment of choice for high-risk BCCs, such as those tumors located on the eyelids, nose, lips, and ears, and those malignancies exhibiting infiltrative, morpheic, and micronodular growth patterns.

The nevoid basal cell carcinoma syndrome: sensitivity to the ultraviolet and x-ray irradiation.

Frentz G, Munch-Petersen B, Wulf HC, Niebuhr E, da Cunha Bang F. J Am Acad Dermatol 1987; 17: 637–43.

Radiation therapy should be avoided in patients with NBCCS since these patients develop BCC as a consequence of radiotherapy within 6 months to 3 years, in contrast to the usual 20- to 30-year lag period for radiation-induced tumors seen in patients with sporadic BCC.

Chemoprevention of basal cell carcinoma with isotretinoin.

Peck GL, Gross EG, Butkus D, DiGiovanna JJ. J Am Acad Dermatol 1982; 6(Suppl 2): 815–23.

Effectiveness of isotretinoin in preventing the appearance of basal cell carcinomas in basal cell nevus syndrome.

Goldberg LH, Hsu SH, Alcalay J. J Am Acad Dermatol 1989; 21: 144–5.

Skin cancer chemoprevention with systemic retinoids: an adjunct in the management of selected high-risk patients.

Campbell RM, DiGiovanna JJ. Dermatol Ther 2006; 19: 306–14.

Systemic retinoids in chemoprevention of non-melanoma skin cancer.

Lens M, Medenica L. Expert Opin Pharmacother 2008; 9: 1363–74.

A randomized, double-blind, placebo-controlled phase 3 skin cancer prevention study of α-difluoromethylornithine in subjects with previous history of skin cancer.

Bailey HH, Kim K, Verma AK, Sielaff K, Larson PO, Snow S, et al. Cancer Prev Res (Phila) 2010; 3: 35–47.

Inhibition of ornithine decarboxylase by α-DFMO decreases tissue concentrations of polyamines and prevents neoplastic developments in many tissue types. Patients (n=291) with a history of prior NMSC were randomized to oral DFMO (500 mg/m²/day) or placebo for 4 to 5 years. While there was only a very little difference in the development of new SCCs between groups, there was a significant difference in development of new BCCs in the DFMO group. Compliance with DFMO was >90% and was well tolerated with evidence of only mild ototoxicity.

Basal cell carcinoma chemoprevention with nonsteroidal anti-inflammatory drugs in genetically predisposed PTCH1+/− humans and mice.

Tang JY, Aszterbaum M, Athar M, Barsanti F, Cappola C, Estevez N, et al. Cancer Prev Res (Phila) 2010; 3: 25–34.

In vitro and epidemiologic studies favor the efficacy of NSAIDs in preventing skin squamous photocarcinogenesis. A 3-year double-blinded randomized clinical trial in 60 (PTCH1 +/−) patients with BCNS assessed the effects of oral celecoxib on the development of BCCs. A trend for reducing BCC burden was detected in all subjects (p=0.069). The placebo group had a 50% increase in BCCs per year, whereas the celecoxib group had only a 20% increase (p=0.024). The study was discontinued because of concern of enhanced cardiovascular risks. However, no subjects had a serious adverse event related to the drug.

Nonsurgical innovations in the treatment of nonmelanoma skin cancer.

Amini S, Viera MH, Valins W, Berman B. J Clin Aesthet Dermatol 2010; 3: 20–34.

While primary prevention of NMSC includes strict sun-protective behaviors, several topical agents can serve as secondary prevention. Topical retinoids have demonstrated efficacy in decreasing the risk of developing NMSCs, and other topical agents such as perilly alcohol, T-4 endonuclease, DL-α-tocopheral, DFMO and COX-2 inhibitors have shown positive results. Furthermore, a recent study showed that short-term (<5 years) non-aspirin NSAID use had significant protective effects against BCC.

Second-line therapies

Electrodesiccation and curettage

Combined curettage and excision: a treatment method for primary basal cell carcinoma.

Johnson TM, Tromovitch TA, Swanson NA. J Am Acad Dermatol 1991; 24: 613–17.

Electrodesiccation and curettage (ED&C) is appropriate for non-aggressive smaller primary BCCs that are located in low-risk recurrence areas such as the neck, trunk, and extremities, with the 5-year cure rate approaching 97%. However ED&C should be avoided on tumors that are recurrent, large, infiltrative, invade fat, soft tissues or adnexal structures, or are located in high-risk areas of the face.

Third-line therapies

Photodynamic therapy	A
Imiquimod	A
Cryosurgery	B
5-Fluorouracil	B
CO₂ laser	B
Neodymium lasers	B
Interferon	B
Bleomycin	B
Retinoids	C
Pulsed-dye laser	C
Interleukin-2	C
Chemical peel	E
Dermabrasion	E
Paclitaxel	E
Alexandrite laser	E
Capecitabine	E

Treatment of Gorlin syndrome (nevoid basal cell carcinoma syndrome) with methylaminolevulinate photodynamic therapy in seven patients, including two children: interest of tumescent anesthesia for pain control in children.

Girard C, Debu A, Bessis D, Blatière V, Dereure O, Guillot B. J Eur Acad Dermatol Venereol 2013; 27:e171–5.

Seven Gorlin patients with 41 BCCs had prior superficial curettage for superficial BCCs or debulking for nodular BCCs, then had methylaminolevulinic acid applied topically to lesions 3 hours before illumination with 635 nm red light for 10 minutes. Overall clearance in patients was 60% after one session and 78% after three sessions. There were excellent cosmetic outcomes in all patients. Treatments were well tolerated in adults with moderate pain sensation during illumination. Ropivacaine–lidocaine tumescent anesthesia was used on the youngest patient to assure excellent pain tolerance.

δ-Aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with nevoid basal cell carcinoma syndrome.

Itkin A, Gilchrest B. Dermatol Surg 2004; 30: 1054–61.

Two patients underwent two courses of photodynamic therapy (PDT) with 20% δ-aminolevulinic acid solution and a 417 nm blue light source. A complete clinical response was observed in eight of nine superficial BCCs and five of 16 nodular BCCs located on the face and in 18 of 27 superficial BCCs located on the lower extremities. The remaining lesions demonstrated partial clinical resolution and no new BCCs in areas that were treated were observed during the 8-month follow-up period.

Treatment of diffuse basal cell carcinomas and basaloid follicular hamartomas in nevoid basal cell carcinoma syndrome by wide-area 5-aminolevulinic acid photodynamic therapy.

Oseroff AR, Shieh S, Frawley NP, Cheney R, Blumenson LE, Pivnick EK. Arch Dermatol 2005; 141: 60–7.

5-Aminolevulinic acid 20% was applied to three children with BCCs and basaloid follicular hamartomas involving 12–25% of their body surface areas for 24 hours under occlusion followed by dye laser and lamp illumination. The responses varied from 85% to 98% overall clearance with excellent cosmetic outcomes and were durable up to 6 years.

Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus.

Braathen LR, Szeimies R, Basset-Seguin N, Bissonnette R, Foley P, Pariser D. J Am Acad Dermatol 2007; 56: 125–43.

Efficacy of photodynamic therapy as a treatment for Gorlin syndrome-related basal cell carcinomas.

Loncaster J, Swindell R, Slevin F, Sheridan L, Allan D, Allan E. Clin Oncol (R Coll Radiol) 2009; 21: 502–8.

Gorlin patients (n=33; 138 lesions) were treated with PDT, and lesion thicknesses were assessed using ultrasound, both prior to treatment and during follow-up. Topical PDT was used to treat superficial lesions (<2 mm thick) and a systemic photosensitizer ± light delivered by interstitially placed optical fibers, which extended the remit of PDT, allowed for thicker lesions (>2 mm) to be treated. Local control rates of 56.3% at 12 months were achieved overall.

Imiquimod 5% cream for the treatment of superficial basal cell carcinomas: results from two phase III, randomized, vehicle-controlled studies.

Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. J Am Acad Dermatol 2004; 50: 722–33.

Two identical, randomized, vehicle-controlled 6-week studies using imiquimod to treat superficial BCCs demonstrated histologic clearance rates of 79% for the seven times a week dosing and 82% for the five times a week dosing. The difference in response between these two groups was not significant.

Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review.

Love WE, Bernhard JD, Bordeaux JS. Arch Dermatol 2009; 145: 1431–8.

A review of imiquimod therapy of non-melanoma skin cancer (NMSC) revealed varying clearance rates of 43–100% for superficial BCC, 42–100% for nodular BCC, and 56–63% for infiltrative BCC, while fluorouracil produced clearance rates of 90% for superficial BCC.

The use of imiquimod 5% cream for the treatment of basal cell carcinoma as observed in Gorlin’s syndrome.

Micali G, Lacarrubba F, Nasca MR, De Pasquale R. Clin Exp Dermatol 2003; 28(Suppl 1): 19–23.

Four patients with Gorlin syndrome had multiple facial and trunk BCCs treated with imiquimod 5% cream, topically applied to the lesions three to five times a week for 8 to 14 weeks. Thirteen of 17 BCCs were successfully treated, with no patients suffering a relapse at the follow-up visit.

Cryosurgery for cutaneous malignancy: an update.

Kuflik EG. Dermatol Surg 1997; 23: 1081–7.

Cryosurgery is best suited for superficial non-infiltrating tumors with well-defined borders. Cryosurgery is not effective for morpheaform or infiltrating histologic subtypes, recurrent lesions, or deeply penetrating or very aggressive tumors.

Cryosurgery and topical fluorouracil: a treatment method for widespread basal cell epithelioma in basal cell nevus syndrome.

Tsuji T, Otake N, Nishimura M. J Dermatol 1993; 20: 507–13.

Nonsurgical innovations in the treatment of nonmelanoma skin cancer.

Amini S, Viera MH, Valins W, Berman B. J Clin Aesthet Dermatol 2010; 3: 20–34.

Several studies have shown efficacy in topical 5-fluorouracil (5-FU) 5% ointment for the treatment of superficial BCCs, in situ SCC and AKs. However, due to limited percutaneous absorption making complete responses unlikely, 5-FU ointment is not recommended for invasive BCCs or SCCs.

Nonsurgical treatment of basal cell carcinomas with intralesional 5-fluorouracil/epinephrine injectable gel.

Miller BH, Shavin JS, Cognetta A, Taylor RJ, Salasche S, Korey A, et al. J Am Acad Dermatol 1997; 36: 72–7.

A total of 122 patients with biopsy-proven nodular or superficial BCC were assigned to varying intralesional treatment regimens using a proprietary gel containing 5-FU (30 mg/mL). Excision and histologic examination 3 months after treatment demonstrated a complete response rate of 91%. Optimal dosage was reported with 0.5 mL of the gel instilled three times per week for 2 consecutive weeks. Side effects were mild, localized to the injection site, and resolved with follow-up.

Gorlin syndrome: the role of the carbon dioxide laser in patient management.

Grobbelaar AO, Horlock N, Gault DT. Ann Plast Surg 1997; 39: 366–73.

Microscopically controlled surgical excision combined with ultrapulse CO₂ vaporization in the management of a patient with the nevoid basal cell carcinoma syndrome.

Krunic AL, Viehman E, Madani S, Clark RE. J Dermatol 1998; 25: 10–2.

Can the carbon dioxide laser completely ablate basal cell carcinomas? A histological study.

Horlock N, Grobbelaar AO, Gault DT. Br J Plast Surg 2000; 53: 286–93.

Full-face carbon dioxide laser resurfacing in the management of a patient with the nevoid basal cell carcinoma syndrome.

Doctoroff A, Oberlender SA, Purcell SM. Dermatol Surg 2003; 29: 1236–40.

Ultrapulse CO₂ used for the successful treatment of basal cell carcinomas found in patients with basal cell nevus syndrome.

Nouri K, Chang A, Trent JT, Jiménez GP. Dermatol Surg 2002; 28: 287–90.

Three patients with BCNS with multiple small BCCs were effectively treated with ultrapulse CO₂ laser, with complete histologic clearance and minimal scarring noted at follow-up. While superficial BCCs can be ablated to the mid-dermis or deeper with 100% clearance, large nodular BCCs, with diameters greater than 10 mm, cannot reliably be removed with this method.

The efficacy of facial skin cancer treatment with high-energy pulsed neodymium and Nd : YAG lasers.

Moskalik K, Kozlov A, Demin E, Boiko E. Photomed Laser Surg 2009; 27: 345.

A total of 3461 patients with facial skin cancers (3534 BCCs, 90 SCCs) were treated with pulsed Nd and Nd : YAG lasers then followed for 3 months to 5 years. Recurrences were seen in 1.8% of BCCs treated with pulsed Nd laser, in 2.5% of BCCs treated with Nd : YAG laser, and in 4.4% of SCCs treated with pulsed Nd laser.

Pulsed dye laser as a novel non-surgical treatment for basal cell carcinomas: response and follow up 12–21 months after treatment.

Konnikov N, Avram M, Jarell A, Tannous Z. Lasers Surg Med 2011; 43: 72–8.

Multiple treatments with PDL have been shown to be effective for the treatment of superficial and nodular BCCs as they have supporting vasculature that serves as a target for this laser. Fourteen patients with 20 biopsy-proven BCCs were treated with four consecutive PDL treatments at 3- to 4-week intervals. Overall, 90% of treated BCCs showed no clinical or histologic recurrence more than 12 months after treatment.

Single treatment of non-melanoma skin cancers using a pulsed-dye laser with stacked pulses.

Tran HT, Lee RA, Oganesyan G, Jiang SB. Lasers Surg Med 2012; 44: 459–67.

Twenty patients with 23 biopsy-proven BCCs and SCC in situ were randomized to receive either no treatment, or 595 nM PDL either without or with double-stacked pulses. The non-stacked treatment group had a clearance rate of 25% (similar to the non-treated group), while the double-stacked group had a clearance rate of 71%. The lesions with residual tumors were noted to be beyond the central treatment zone by histopathology, and, if excluded, resulted in a clearance rate of 100%.

755nm alexandrite laser for the reduction of tumor burden in basal cell nevus syndrome.

Ibrahimi OA, Sakamoto FH, Tannous Z, Anderson RR. Lasers Surg Med 2011; 43: 68–71.

A patient with BCNS and a history of radiation presented with over 250 BCCs, and several lesions were treated with a single treatment of the long-pulsed 755 nm alexandrite laser. At 2-month and 7-month clinical follow-up, 15 of 18 treated lesions showed a complete clinical response and histopathological analysis of one treated lesion at 7-month clinical follow-up showed no evidence of residual tumor.

Intralesional agents in the management of cutaneous malignancy: a review.

Good LM, Miller MD, High WA. J Am Acad Dermatol 2011; 64: 413–22.

Intralesional treatment of skin cancer is a consideration when surgical intervention is not a viable option and for cases where cosmetic outcome may be superior. IFN-α (1.5 M IU, three times weekly for 3 weeks) and IFN-β_1α are the most widely used intralesional regimens for BCC.

Intralesional bleomycin-mediated electrochemotherapy in 20 patients with basal cell carcinoma.

Glass LF, Jaroszeski M, Gilbert R, Reintgen DS, Heller R. J Am Acad Dermatol 1997; 37: 596–9.

Electrochemotherapy (ECT) reportedly increases cellular penetration of bleomycin, as it involves sending high-intensity electrical pulses into the tumor via electrodes 10 minutes after bleomycin administration. ECT with bleomycin was used on 20 patients with BCC and observed a complete response in 98%. The dose of bleomycin was dependent on tumor size and ranged from 0.5 to 1 U, with only a single treatment needed in 51 cases, and no recurrences at the mean follow-up of 18 months. This treatment was well tolerated and side effects included uncomfortable muscle contractions from the electrical pulses, painless erythema, edema, ulcers or erosions at the treatment sites, and one case of skin infection treated with antibiotics.

Treatment and prevention of basal cell carcinoma with oral isotretinoin.

Peck GL, DiGiovanna JJ, Sarnoff DS, Gross EG, Butkus D, Olsen TG, et al. J Am Acad Dermatol 1988; 19: 176–85.

Of 270 tumors due to NBCCS, arsenic exposure, or sunlight exposure in 12 patients treated with a mean dose of 3.1 mg/kg/day for 8 months, 8% underwent complete clinical and histologic regression. Lower doses given to three patients for 3 to 8 years were effective for chemoprevention of new BCCs.

Effect of perilesional injections of PEG-interleukin-2 on basal cell carcinoma.

Kaplan B, Moy RL. Dermatol Surg 2001; 26: 1037–40.

Twelve BCCs in eight patients were treated with intralesional pegylated IL-2, with a 66% (8/12) clinical and histologic cure rate. Erythema, swelling, and pain occurred in 10 of 12 injection sites, but resolved in a week’s time, and only one patient experienced systemic flu-like symptoms.

Nevoid basal cell carcinoma syndrome successfully treated with trichloroacetic acid and phenol peeling.

Kaminaka C, Yamamoto Y, Furukawa F. J Dermatol 2007; 34: 841–3.

Widespread basal cell carcinoma of the scalp treated by dermabrasion.

Melandri D, Carruthers A. J Am Acad Dermatol 1992; 26: 270–1.

Successful treatment of an intractable case of hereditary basal cell carcinoma syndrome with paclitaxel.

El Sobky RA, Kallab AM, Dainer PM, Jillella AP, Lesher JL Jr. Arch Dermatol 2001; 137: 827–8.

Novel approach to Gorlin syndrome: a patient treated with oral capecitabine.

Beach DF, Somer R. J Clin Oncol 2011; 29: e397–e401.

Capecitabine, a systemic prodrug of FU, is metabolized in the liver, and then converted to the active form of FU by cytidine deaminase, an enzyme found in tumor cells. A trial of oral capecitabine (1500 mg twice a day for 14 days, every 3 weeks) was used on a NBCCS patient with extensive disease. On follow-up, he had dramatic improvement of skin lesions and tolerated the medication well. After 2 years on therapy, many lesions had complete clinical resolution and no new lesions developed.

Treatment for locally advanced or metastatic disease

GDC-0449 (vismodegib, Erivedge)	A
Other hedgehog inhibitors	B, C

Resolution of odontogenic keratocysts of the jaw in basal cell nevus syndrome with GDC-0449.

Goldberg LH, Landau JM, Moody MN, Kazakevich N, Holzer AM, Myers A. Arch Dermatol 2011; 147: 839–41.

A patient with BCNS with multiple large BCCs and odontogenic keratocysts in the mandible was started on GDC-0449. He had complete resolution of all BCCs at 12-week follow-up and nearly complete resolution of three odontogenic keratocysts as documented by serial dental radiographs after 2 years of therapy.

Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449.

Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, et al. N Engl J Med 2009; 361: 1173–8.

A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with the hedgehog pathway inhibitor GDC-0449. Treatment resulted in rapid (although transient) regression of the tumor and reduction of symptoms.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

162

Nevoid basal cell carcinoma syndrome

Patricia Reutemann and Gary L. Peck

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

Management strategy

Specific investigations

Radiologic studies

Genetic studies

Dermatoscopy

Radiologic images in dermatology: nevoid basal cell carcinoma syndrome.

Mirowski GW, Liu AA, Parks ET, Caldemeyer KS. J Am Acad Dermatol 2000; 43: 1092–3.

Nevoid basal cell carcinoma syndrome (Gorlin syndrome).

Lo Muzio L. Orphanet J Rare Dis 2008; 25: 32.

A novel polymorphism in the PTC gene allows easy identification of allelic loss in basal cell nevus syndrome lesions.

Zedan W, Robinson PA, High AS. Diagn Mol Pathol 2001; 10: 41–5.

How to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part II. Nonmelanocytic skin tumors.

Zalaudek I, Kreusch J, Giacomel J, Ferrara G, Catricalà C, Argenziano G. J Am Acad Dermatol 2010; 63: 377–86.

First-line therapies

Surgical management	B
Mohs micrographic surgery	B
Protection against radiation exposure	C
Chemoprevention:
–Oral retinoids (isotretinoin, acitretin)	A
–Difluoromethylornithine	A
–Celecoxib	A
–Others	B–E