Published on 19/03/2015 by admin
Filed under Dermatology
Last modified 22/04/2025
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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
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.
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.
Radiologic studies
Genetic studies
Dermatoscopy
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).
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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.
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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.
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.
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.
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.
Peck GL, Gross EG, Butkus D, DiGiovanna JJ. J Am Acad Dermatol 1982; 6(Suppl 2): 815–23.
Goldberg LH, Hsu SH, Alcalay J. J Am Acad Dermatol 1989; 21: 144–5.
Campbell RM, DiGiovanna JJ. Dermatol Ther 2006; 19: 306–14.
Lens M, Medenica L. Expert Opin Pharmacother 2008; 9: 1363–74.
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.
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.
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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.
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.
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.
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.
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.
Braathen LR, Szeimies R, Basset-Seguin N, Bissonnette R, Foley P, Pariser D. J Am Acad Dermatol 2007; 56: 125–43.
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.
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.
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.
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.
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.
Tsuji T, Otake N, Nishimura M. J Dermatol 1993; 20: 507–13.
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.
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.
Grobbelaar AO, Horlock N, Gault DT. Ann Plast Surg 1997; 39: 366–73.
Krunic AL, Viehman E, Madani S, Clark RE. J Dermatol 1998; 25: 10–2.
Horlock N, Grobbelaar AO, Gault DT. Br J Plast Surg 2000; 53: 286–93.
Doctoroff A, Oberlender SA, Purcell SM. Dermatol Surg 2003; 29: 1236–40.
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.
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.
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.
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%.
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.
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-β1α are the most widely used intralesional regimens for BCC.
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.
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.
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.
Kaminaka C, Yamamoto Y, Furukawa F. J Dermatol 2007; 34: 841–3.
Melandri D, Carruthers A. J Am Acad Dermatol 1992; 26: 270–1.
El Sobky RA, Kallab AM, Dainer PM, Jillella AP, Lesher JL Jr. Arch Dermatol 2001; 137: 827–8.
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.
Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, et al. N Engl J Med 2009; 361: 1164–72.
A phase I trial tested oral GDC-0449 at one of three doses (150 mg/day in 17 patients, 270 mg/day in 15 patients, and 540 mg/day in one patient) in patients with metastatic (n=18) or locally advanced (n=15) BCC. Eighteen patients had either a complete (2/33) or partial (16/33) response, while 11 patients had stable disease and four patients progressed. Overall the treatment was very well tolerated, with adverse effects including fatigue, muscle spasm, weight loss, and hyponatremia. No dose-limiting toxicities were seen.
Tang JY, Marghoob AA. Semin Cutan Med Surg 2011; 30(Suppl 4): S14–18.
A phase II trial of GDC-0449 was conducted to determine the efficacy in preventing BCCs in patients with BCNS. Forty-one patients were randomized to receive either 150 mg/day of oral GCD-0449 or placebo. The placebo arm was ended early because of statistically significant differences between the groups seen at the interim analysis. Twenty-four patients in the treatment group developed 0.07 new BCCs per month compared to 1.74 new BCCs per month in the placebo group (p<0.001). In the treatment group, the aggregate size of existing BCCs decreased by 24 cm, compared to 3 cm in the placebo group (p=0.006). Near complete remission was seen in some patients in the treatment group and histological clearance was seen in 7/11 biopsied lesions taken after 3 months, and no BCC lesions developed resistance. The most common side effects from GDC-0449 were taste loss, muscle cramps, and weight loss.
Five other smoothened pathway inhibitors have been developed (BMS-833923, LDE225, LEQ506, IPI926, and TAK-441), several of which are currently undergoing phase I or phase II clinical trials in patients with advanced or metastatic BCC, Gorlin syndrome, and other cancers.
Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. N Engl J Med 2012; 366: 2171–9.
In a phase II pivotal study (ERIVANCE BCC), 104 patients with advanced BCC (71 locally advanced, 33 metastatic) received 150 mg of oral vismodegib (GDC-0449) daily. The response rate was 30% in patients with metastatic BCC and 43% in patients with locally advanced BCC, with complete responses in 21% of these patients. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia, weight loss, and fatigue. Serious adverse events were thought to be related to treatment with vismodegib in 4% of patients.
Kudchadkar R, Lewis K, Gonzalez R. Semin Oncol 2012; 39: 139–44.
Based on results of ERIVANCE study, the US FDA approved vismodegib (marketed under the trade name Erivedge) in January 2012 for the treatment of locally advanced or metastatic BCCs that recur or cannot be treated with radiation or surgery.
Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, et al. N Engl J Med 2012; 366: 2180–8.
In a randomized, double-blind, placebo-controlled trial in patients with BCNS vismodegib was found to reduce BCC tumor burden and block growth of tumors. However, the adverse events associated with treatment led to discontinuation in over half of treated patients.
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.
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.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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Surgical management
Mohs micrographic surgery
Protection against radiation exposure
Chemoprevention:
Electrodesiccation and curettage
Photodynamic therapy
Imiquimod
Cryosurgery
5-Fluorouracil
CO2 laser
Neodymium lasers
Interferon
Bleomycin
Retinoids
Pulsed-dye laser
Interleukin-2
Chemical peel
Dermabrasion
Paclitaxel
Alexandrite laser
Capecitabine
GDC-0449 (vismodegib, Erivedge)
Other hedgehog inhibitors
