Cutaneous malignancy is the most common type of cancer.1 As a result, dermatologists spend a large amount of time identifying, treating and educating patients with skin cancer, particularly non-melanoma skin cancer (NMSC). While cancer registries do not require reporting of NMSC, the American Cancer Society and dermatologists recognize the yearly incidence of NMSC far outnumbers all other cancer types combined.1,2 Thus, prevention and treatment of NMSC is critical.
The 2 most common types of NMSC are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This article will focus on the main treatment modalities for these 2 types of NMSC. New treatments are continually emerging, and we discuss 5 of therapies for BCC and SCC.
Treatment Options For BCC And SCC
Various treatment options must be considered based on the lesion location, size, immunosuppression, perineural invasion, chronic inflammation, previous radiation, growth rate, primary versus recurrent disease, histology subtype and differentiation and borders.
Mohs Surgery
Mohs surgery allows for the excision of a primary tumor with histological confirmation of clear margins, which would not otherwise be ascertained in a typical excision. In areas such as the face, the Mohs procedure also offers the best cosmetic outcome as the least amount of tissue is excised to achieve clear margins. Cost, provider availability, contraindications, length of the procedure and risk versus benefit analysis are considered in this treatment option.
A 2012 report published in the Journal of the American Academy of Dermatology detailed the appropriate use criteria for the Mohs surgical technique. This report offers guidelines for the first time, agreed upon by several dermatological associations, determining which skin cancers should be treated with Mohs surgery. The guidelines are based on location, subtype and size of the lesion.3
• The use of the Mohs technique is indicated in previously radiated skin, traumatic scars, in areas of osteomyelitis, areas of chronic inflammation or ulceration or in patients with genetic syndromes regardless of location, depth or subtype.
• Mohs surgery is the preferred treatment option for all high-risk SCC cases which are listed as sclerosing, basosquamous, poorly or undifferentiated, perineural or perivascular, spindle cell, pagetoid, infiltrating, keratoacanthoma type: central facial, single cell, clear cell, lymphoepithelial, sarcomatoid, breslow depth of 2 mm or greater or Clark level IV or greater.
• Mohs was not suggested for treatment of actinic keratosis (AK) with focus SCC in situ, Bowenoid AK or SCC in situ of AK subtype. Also, Mohs may not be beneficial for treatment of primary SCC in areas of the trunk and extremities when it is not an aggressive subtype, <2 mm in depth and <2 cm in size in healthy patients and <1 cm in size in immunocompromised patients.
• Mohs is appropriate for use in all forms of BCC including recurrent, primary aggressive, primary nodular and primary superficial on the face, genitalia, hands, feet, nail units, ankles, nipples/areola, cheeks, forehead, scalp, neck, jawline and pretibial surfaces regardless of size or patient type.
•
Exceptions to the use of Mohs for BCC include primary superficial BCC 0.5 cm or smaller on the cheeks, forehead, scalp, neck, jawline and pretibial surfaces for healthy patients. As for other areas on the trunk and extremities, appropriate use of Mohs surgery depends considerably on the type and size of BCC.
Surgical Excision
Although Mohs surgery is considered the gold standard for NMSC removal, it is not always appropriate or available as treatment. Surgical excision is also an option in which both the lesion and a margin of healthy tissue are removed. Surgical excision relies on gross tumor inspection and histology. The amount of a margin to remove has been a topic of consideration. Primary low-risk SCC lesions <2 cm should be removed with at least a 5-mm margin with 95% confidence of removing the tumor. Higher risk lesions may require as much as a 13.25-mm margin, which may be unreasonable on areas such as the face, and referral for Mohs is indicated. For both low- and high-risk BCC lesions, excisions should be made with 4.75-mm and 8-mm margins, respectively.4
Cryotherapy
Cryotherapy involves the application of liquid nitrogen (-195.6o C) causing intracellular and extracellular ice formation, which destroys tissue by cell dehydration.5 Cryotherapy is used in the treatment of BCC6, SCC in situ7, and is considered the treatment of choice for AKs.8
The advantages of cryotherapy led to a systematic review in 2003 to determine if it was effective in the treatment of BCC.6 The review found that treatment of BCC with cryotherapy yielded low recurrence rates based on clinical diagnosis with acceptable cosmetic results.6 Cryotherapy has also been proven effective in treating Bowen’s disease, though healing may be prolonged and discomfort may limit treatment of multiple lesions.9
The major drawback of using cryotherapy treatment is the inability to provide histological evidence of tumor removal post-treatment. However, physicians have been combining cryotherapy treatment of superficial BCC with reflectance confocal microscopy (RCM). This allows visualization of cell necrosis in the tissue and thus ablation of tumor tissue.10
Electrodesiccation And Curettage
With electrodesiccation and curettage (ED&C), the more friable cancerous tissue is debulked with a curette first. The stroma and surrounding dermis are then electrodesiccated. This process is often performed a total of 3 times.5 Primary small and low-risk BCCs, such as the non-morpheaform BCC types, are frequently treated with ED&C. In research cases where tissue is taken after treatment with ED&C, 25% of cases showed persistent BCC.11
ED&C can also be an effective treatment for low-risk or SCC in situ. However, when compared to other treatment modalities, ED&C showed no significant difference in recurrence of tumors that demonstrated low-risk histology or in tumors of the face.12 Tumors that fall within the vast spectrum of AKs to invasive SCC pose some controversy as to the appropriate treatment modality. Additionally, ED&C does not allow for a histologic evaluation to ensure clear margins after treatment, thus leading to clinical uncertainty regarding complete excision. American Academy of Dermatology guidelines suggest using ED&C only for small, primary SCCs on sun-exposed skin that do not invade into the subcutaneous tissues or fat.13
Radiation
Radiation can be an effective alternative treatment when cosmetic considerations, size and/or location limit surgical options. It can also be used as an adjuvant therapy that can reduce the size of the tumor to increase the chances of successful surgical resection. Proper technique considers the extension of the tumor microscopically or grossly to ensure adequate volume of radiotherapy within appropriate margins. Margins into healthy tissue can increase morbidity, therefore appropriate volume of radiotherapy is essential. Available evidence to guide planning is limited. One study attempted to provide some guidelines for treatment.14 In order to achieve a 95% or greater chance of covering microscopic extent of disease, they recommend for clinical target volume margins 10 mm for BCC <2 cm, 13 mm for BCC >2 cm, 11 mm for SCC <2 cm and 14 mm for SCC >2 cm.14 Radiotherapy is not recommended in young patients or those with impaired DNA repair mechanisms.14
Radiotherapy has an additional role in treating perineural invasion (PNI) by skin cancers, as resection would lead to disruption of vital structures. The spread into such structures is considered an aggressive characteristic of NMSC and most cases occur in SCCs. PNI is associated with poorer outcomes and adjuvant radiotherapy is recommended when extensive, even if the tumor is resected and margins are clear.
Radiation therapy may also provide a benefit for recurrent or high-risk SCC with diameters >2 cm, with ill-defined margins, depths >4 mm, poorly differentiated or rapid growth.15
Chemotherapy
In 2010, Kirby et al published a review of the literature on the use of intralesional chemotherapy for NMSC.16 BCC tumors represented a large portion of the NMSC treated with intralesional chemotherapies such as interferon alpha 2a, interferon alpha 2b, interferon gamma, interferon beta, bleomycin and 5-FU. Results showed simple excision and Mohs surgery provided superior complete response rates when compared to the interferon therapies. Complete response rates for bleomycin and 5-FU were comparable to treatment with Mohs, however small sample size indicates a need for further study.16
In more recent years, researchers have enhanced the delivery of chemotherapy through electrochemotherapy (ECT). This method utilizes electric pulsations to temporarily increase the permeability of cells to the drug. A case series of 25 patients documented the results of using ECT with bleomycin to treat cutaneous or subcutaneous NMSC of the head or neck. There was a 72% complete response rate with no recurrence during 18 months of follow-up. Of the 72%, 100% of the patients with BCC had a complete response and 65% of patients with SCC had a complete response.17
Topical Photodynamic Therapy
Photodynamic therapy (PDT) uses light to activate topical photosensitizers and create cytotoxic reactive oxygen species. Photosensitizers are localized on the diseased tissue and include chemicals such as methyl aminolevulinate and 5-aminolevulinic acid. According to a systematic literature review, PDT is extremely effective for the treatment of AK and Bowen’s disease.18 The review also demonstrated topical PDT is effective, reliable and offers good cosmetic results for superficial and thin nodular BCC. More recently, PDT has been used in conjunction with imaging techniques such as in vivo RCM, which has the ability to diagnose BCC, as well as monitor the efficacy of PDT.19
At the time of the Braathen et al systematic review in 2007, the authors could not recommend the use of PDT for SCC due to high recurrence rates coupled with the potential for SCC to metastasize.18 More recent research has suggested that PDT may be effective for SCC in situ and for patients with multiple AKs, however its use continues to be discouraged for SCC.20
New and Emerging Treatments
New treatments will provide clinicians with more options to help improve outcomes for patients with NMSC. Here, we highlight 5 new and emerging treatments for BCC and SCC.
Cryoimmunotherapy
In recent years, cryoimmunotherapy has been implemented as treatment for BCC resulting in a recurrence rate of only 2%. This treatment combines cryotherapy with imiquimod cream. Researchers speculate that cryotherapy mediated damage to the stratum corneum facilitates penetration of imiquimod. This modality was also used for SCC in situ, with no recurrences after the treatment of 31 lesions.21
Ingenol Mebutate
Ingenol mebutate is a purified compound from the sap of Euphorbia peplus, also known as radium weed.22 It is being developed as a short course topical treatment for superficial BCC and AK.22,23 Ingenol mebutate causes primary necrosis followed by an inflammatory response targeting residual tumor cells. Rather than 6 to 12 weeks of treatment with imiquimod or 5-FU, patients may be able to treat their lesions with only a 2 to 3 day course of ingenol mebutate.22,23 Results for treatment of AK lesions show statistically significant partial and complete clearance rates when compared to vehicle treatment as well as a median percentage reduction in baseline AK lesions ranging from 75%-100% compared with 0% for vehicle gel.22
Dermato-Oncology for BCC
A new class of drugs, known as the hedgehog inhibitors, is emerging as a valuable treatment option for BCC not treatable by surgical means or radiotherapy. The FDA approved vismodegib (Erivedge) in 2012 for oral treatment of metastatic and locally invasive BCC.24 It works by antagonizing the smoothened homologue in the hedgehog pathway.24 Recent clinical studies demonstrate a partial or complete response to treatment, however adverse effects such as myalgia and alopecia have led to discontinuation of treatment in some instances.25 Additional hedgehog inhibitors are being studied for use as neoadjuvant therapy to surgical treatment.
Dz13
A recent Phase I trial assessed the safety and tolerability of deoxyribozyme, Dz13.26 Dz13 was injected into nodular basal cell carcinomas in 9 patients. The treatment was well tolerated with no serious drug-related side effects. In addition, the tumors showed decreased expression of c-Jun, the molecular target of Dz13, as well as decreased histological tumor depth in more than half of the patients.
Superficial X-ray Therapy
The use of superficial X-ray therapy declined after the introduction of Mohs surgery. Researchers are now trying to reintroduce the therapy as a non-surgical option for patients with primary non-aggressive BCC and SCC, particularly for patients who decline surgery or are poor surgical candidates.27
Conclusion
The increasing incidence of NMSC requires further investigation of new treatment methods, including non-invasive options. Severity of disease, location and patient comorbidities guide treatment selection. While Mohs surgery continues to be the mainstay, some circumstances require use of other treatment modalities. Knowledge of available and emerging therapies will be helpful in improving patient outcomes. In addition, prevention strategies such as reduced sun exposure are of equal importance. n
Ms. Watkins, BS, is a medical student at Texas Tech University Health Sciences Center in Lubbock, TX.
Ms. Roberts, BS, is a medical student at Texas Tech University Health Sciences Center in Lubbock, TX.
Ms. Nies, BS, is a medical student at Texas Tech University Health Sciences Center in Lubbock, TX.
Dr. West is a first-year dermatology resident at Texas Tech University Health Sciences Center in Lubbock, TX.
Disclosures: The authors have no conflicts of interest to report.
References
1. American Cancer Society. Don’t fry: Preventing skin cancer. American Cancer Society Website. https://www.cancer.org/research/infographicgallery/skin-cancer-prevention?gclid=CMTN7NOP1bgCFRFp7AodBX4AVg. Accessed October 19, 2013.
2. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146(3):283-287.
3. Connolly SM, Baker DR, Coldiron BM, et al. AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol. 2012;67(4):531-550.
4. Schell AE, Russell MA, Park SS. Suggested excisional margins for cutaneous malignant lesions based on Mohs micrographic surgery. JAMA Facial Plast Surg. 2013;15(5):337-343.
5. Marks JG Jr, Miller JJ. Lookingbill and Marks’ Principles of Dermatology. 5th ed. New York, NY: Saunders Elsevier; 2013.
6. Kokoszka A, Scheinfeld N. Evidence-based review of the use of cryotherapy in treatment of basal cell carcinoma. Dermatol Surg. 2003;29(6):566-570.
7. Shimizu I, Cruz A, Chang KH, Dufresne RG. Treatment of squamous cell carcinoma in situ: a review. Dermatol Surgery. 2011;37(10):1394-1411.
8. Ibrahim SF, Brown MD. Actinic keratoses: a comprehensive update. J Clin Aesthet Dermatol. 2009;2(7):43-48.
9. Cox NH, Eedy DJ, Morton CA. Guidelines for management of Bowen’s disease: 2006 update. Br J Dermatol. 2006;156:(1)11-21.
10. Ahlgrimm-Siess V, Horn M, Koller S, Ludwig R, Gerger A, Hofmann-Wallenhof R. Monitoring efficacy of cryotherapy for superficial basal cell carcinoma with in vivo reflectance confocal microscopy: a preliminary study. J Dermatol Sciences. 2009;53(1):60-64.
11. Filho LL, de Oliveira de Avelar Alchorne A, Pereira GC, Lopes LR, de Carvalho TC. Histological and immunohistochemical evaluation of basal cell carcinoma following curettage and electrodessication. Int J Dermatol. 2008;47(6):610-614.
12. Chren MM, Linos E, Torres JS, Stuart SE, Parvataneni R, Boscardin WJ. Tumor recurrence 5 years after treatment of cutaneaous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol. 2013;133(5):1188-1196.
13. Drake LA, Ceilley RI, Cornelison Rl, et al. Guidelines of care for cutaneous squamous cell carcinoma. J Am Acad Dermatol. 1993;28(4):628-631.
14. Khan L, Choo R, Breen D, et al. Recommendations for CTV margins in radiotherapy planning for non melanoma skin cancer. Radiother Oncol. 2012;104(2):263-266.
15. Hulyalkar R, Rakkhit T, Garcia-Zuazaga J. The role of radiation therapy in the management of skin cancers. Dermatol Clin. 2011;29(2):287-296.
16. Kirby JS, Miller CJ. Intralesional chemotherapy for nonmelanoma skin cancer: a practical review.
J Am Acad Dermatol. 2010;63(4):689-702.
17. Gargiulo M, Papa A, Capasso P, Molo M, Cubicciotti E, Parascandolo S. Electrochemotherapy for non-melanoma head and neck cancer: Clinical outcomes in 25 patients. Ann Surg. 2012;255(6):1158-1164.
18. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. J Am Acad Dermatol. 2007;56(1):125-143.
19. Longo C, Casari A, Pepe P, et al. Confocal microscopy insights into the treatment and cellular immune response of basal cell carcinoma to photodynamic therapy. Dermatology. 2012;225(3):264-270.
20. Calin MA, Diaconeasa A, Savastru D, Tautan M. Photosensitizers and light sources for photodynamic therapy of the Bowen’s disease. Arch Dermatol Res. 2011;303(3):145-151.
21. MacFarlane DF, El Tal AK. Cryoimmunotherapy: superficial basal cell cancer and squamous cell carcinoma in situ treated with liquid nitrogen followed by imiquimod. Arch Dermatol. 2011;147(11):1326-1327.
22. Anderson L, Schmieder GJ, Werschler WP, et al. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dematol. 2009;60(6):934-943.
23. Gross K. Safety and efficacy of ingeol mebutate (PEP005) gel for topical treatment of superficial basal cell carcinoma. J Am Acad Dermatol. 2009;60(3):AB141.
24. The Medical Letter, Inc. Vismodegib (Erivedge) for basal cell carcinoma. Med Lett Drugs Ther. 2012;54(1394):53-55.
25. Ali FR, Lear JT. Systemic treatments for basal cell carcinoma (BCC): The advent of dermato-oncology in BCC. British J Dermatol. 2013;169(1):53-57.
26. Cho EA, Moloney FJ, Cai H, et al. Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER). Lancet. 2013;381(9880):1835-1843.
27. Cognetta AB, Howard BM, Heaton HP, Stoddard ER, Hong HG, Green WH. Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients. J Am Acad Dermatol. 2012;67(6):1235-1241.
Cutaneous malignancy is the most common type of cancer.1 As a result, dermatologists spend a large amount of time identifying, treating and educating patients with skin cancer, particularly non-melanoma skin cancer (NMSC). While cancer registries do not require reporting of NMSC, the American Cancer Society and dermatologists recognize the yearly incidence of NMSC far outnumbers all other cancer types combined.1,2 Thus, prevention and treatment of NMSC is critical.
The 2 most common types of NMSC are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This article will focus on the main treatment modalities for these 2 types of NMSC. New treatments are continually emerging, and we discuss 5 of therapies for BCC and SCC.
Treatment Options For BCC And SCC
Various treatment options must be considered based on the lesion location, size, immunosuppression, perineural invasion, chronic inflammation, previous radiation, growth rate, primary versus recurrent disease, histology subtype and differentiation and borders.
Mohs Surgery
Mohs surgery allows for the excision of a primary tumor with histological confirmation of clear margins, which would not otherwise be ascertained in a typical excision. In areas such as the face, the Mohs procedure also offers the best cosmetic outcome as the least amount of tissue is excised to achieve clear margins. Cost, provider availability, contraindications, length of the procedure and risk versus benefit analysis are considered in this treatment option.
A 2012 report published in the Journal of the American Academy of Dermatology detailed the appropriate use criteria for the Mohs surgical technique. This report offers guidelines for the first time, agreed upon by several dermatological associations, determining which skin cancers should be treated with Mohs surgery. The guidelines are based on location, subtype and size of the lesion.3
• The use of the Mohs technique is indicated in previously radiated skin, traumatic scars, in areas of osteomyelitis, areas of chronic inflammation or ulceration or in patients with genetic syndromes regardless of location, depth or subtype.
• Mohs surgery is the preferred treatment option for all high-risk SCC cases which are listed as sclerosing, basosquamous, poorly or undifferentiated, perineural or perivascular, spindle cell, pagetoid, infiltrating, keratoacanthoma type: central facial, single cell, clear cell, lymphoepithelial, sarcomatoid, breslow depth of 2 mm or greater or Clark level IV or greater.
• Mohs was not suggested for treatment of actinic keratosis (AK) with focus SCC in situ, Bowenoid AK or SCC in situ of AK subtype. Also, Mohs may not be beneficial for treatment of primary SCC in areas of the trunk and extremities when it is not an aggressive subtype, <2 mm in depth and <2 cm in size in healthy patients and <1 cm in size in immunocompromised patients.
• Mohs is appropriate for use in all forms of BCC including recurrent, primary aggressive, primary nodular and primary superficial on the face, genitalia, hands, feet, nail units, ankles, nipples/areola, cheeks, forehead, scalp, neck, jawline and pretibial surfaces regardless of size or patient type.
•
Exceptions to the use of Mohs for BCC include primary superficial BCC 0.5 cm or smaller on the cheeks, forehead, scalp, neck, jawline and pretibial surfaces for healthy patients. As for other areas on the trunk and extremities, appropriate use of Mohs surgery depends considerably on the type and size of BCC.
Surgical Excision
Although Mohs surgery is considered the gold standard for NMSC removal, it is not always appropriate or available as treatment. Surgical excision is also an option in which both the lesion and a margin of healthy tissue are removed. Surgical excision relies on gross tumor inspection and histology. The amount of a margin to remove has been a topic of consideration. Primary low-risk SCC lesions <2 cm should be removed with at least a 5-mm margin with 95% confidence of removing the tumor. Higher risk lesions may require as much as a 13.25-mm margin, which may be unreasonable on areas such as the face, and referral for Mohs is indicated. For both low- and high-risk BCC lesions, excisions should be made with 4.75-mm and 8-mm margins, respectively.4
Cryotherapy
Cryotherapy involves the application of liquid nitrogen (-195.6o C) causing intracellular and extracellular ice formation, which destroys tissue by cell dehydration.5 Cryotherapy is used in the treatment of BCC6, SCC in situ7, and is considered the treatment of choice for AKs.8
The advantages of cryotherapy led to a systematic review in 2003 to determine if it was effective in the treatment of BCC.6 The review found that treatment of BCC with cryotherapy yielded low recurrence rates based on clinical diagnosis with acceptable cosmetic results.6 Cryotherapy has also been proven effective in treating Bowen’s disease, though healing may be prolonged and discomfort may limit treatment of multiple lesions.9
The major drawback of using cryotherapy treatment is the inability to provide histological evidence of tumor removal post-treatment. However, physicians have been combining cryotherapy treatment of superficial BCC with reflectance confocal microscopy (RCM). This allows visualization of cell necrosis in the tissue and thus ablation of tumor tissue.10
Electrodesiccation And Curettage
With electrodesiccation and curettage (ED&C), the more friable cancerous tissue is debulked with a curette first. The stroma and surrounding dermis are then electrodesiccated. This process is often performed a total of 3 times.5 Primary small and low-risk BCCs, such as the non-morpheaform BCC types, are frequently treated with ED&C. In research cases where tissue is taken after treatment with ED&C, 25% of cases showed persistent BCC.11
ED&C can also be an effective treatment for low-risk or SCC in situ. However, when compared to other treatment modalities, ED&C showed no significant difference in recurrence of tumors that demonstrated low-risk histology or in tumors of the face.12 Tumors that fall within the vast spectrum of AKs to invasive SCC pose some controversy as to the appropriate treatment modality. Additionally, ED&C does not allow for a histologic evaluation to ensure clear margins after treatment, thus leading to clinical uncertainty regarding complete excision. American Academy of Dermatology guidelines suggest using ED&C only for small, primary SCCs on sun-exposed skin that do not invade into the subcutaneous tissues or fat.13
Radiation
Radiation can be an effective alternative treatment when cosmetic considerations, size and/or location limit surgical options. It can also be used as an adjuvant therapy that can reduce the size of the tumor to increase the chances of successful surgical resection. Proper technique considers the extension of the tumor microscopically or grossly to ensure adequate volume of radiotherapy within appropriate margins. Margins into healthy tissue can increase morbidity, therefore appropriate volume of radiotherapy is essential. Available evidence to guide planning is limited. One study attempted to provide some guidelines for treatment.14 In order to achieve a 95% or greater chance of covering microscopic extent of disease, they recommend for clinical target volume margins 10 mm for BCC <2 cm, 13 mm for BCC >2 cm, 11 mm for SCC <2 cm and 14 mm for SCC >2 cm.14 Radiotherapy is not recommended in young patients or those with impaired DNA repair mechanisms.14
Radiotherapy has an additional role in treating perineural invasion (PNI) by skin cancers, as resection would lead to disruption of vital structures. The spread into such structures is considered an aggressive characteristic of NMSC and most cases occur in SCCs. PNI is associated with poorer outcomes and adjuvant radiotherapy is recommended when extensive, even if the tumor is resected and margins are clear.
Radiation therapy may also provide a benefit for recurrent or high-risk SCC with diameters >2 cm, with ill-defined margins, depths >4 mm, poorly differentiated or rapid growth.15
Chemotherapy
In 2010, Kirby et al published a review of the literature on the use of intralesional chemotherapy for NMSC.16 BCC tumors represented a large portion of the NMSC treated with intralesional chemotherapies such as interferon alpha 2a, interferon alpha 2b, interferon gamma, interferon beta, bleomycin and 5-FU. Results showed simple excision and Mohs surgery provided superior complete response rates when compared to the interferon therapies. Complete response rates for bleomycin and 5-FU were comparable to treatment with Mohs, however small sample size indicates a need for further study.16
In more recent years, researchers have enhanced the delivery of chemotherapy through electrochemotherapy (ECT). This method utilizes electric pulsations to temporarily increase the permeability of cells to the drug. A case series of 25 patients documented the results of using ECT with bleomycin to treat cutaneous or subcutaneous NMSC of the head or neck. There was a 72% complete response rate with no recurrence during 18 months of follow-up. Of the 72%, 100% of the patients with BCC had a complete response and 65% of patients with SCC had a complete response.17
Topical Photodynamic Therapy
Photodynamic therapy (PDT) uses light to activate topical photosensitizers and create cytotoxic reactive oxygen species. Photosensitizers are localized on the diseased tissue and include chemicals such as methyl aminolevulinate and 5-aminolevulinic acid. According to a systematic literature review, PDT is extremely effective for the treatment of AK and Bowen’s disease.18 The review also demonstrated topical PDT is effective, reliable and offers good cosmetic results for superficial and thin nodular BCC. More recently, PDT has been used in conjunction with imaging techniques such as in vivo RCM, which has the ability to diagnose BCC, as well as monitor the efficacy of PDT.19
At the time of the Braathen et al systematic review in 2007, the authors could not recommend the use of PDT for SCC due to high recurrence rates coupled with the potential for SCC to metastasize.18 More recent research has suggested that PDT may be effective for SCC in situ and for patients with multiple AKs, however its use continues to be discouraged for SCC.20
New and Emerging Treatments
New treatments will provide clinicians with more options to help improve outcomes for patients with NMSC. Here, we highlight 5 new and emerging treatments for BCC and SCC.
Cryoimmunotherapy
In recent years, cryoimmunotherapy has been implemented as treatment for BCC resulting in a recurrence rate of only 2%. This treatment combines cryotherapy with imiquimod cream. Researchers speculate that cryotherapy mediated damage to the stratum corneum facilitates penetration of imiquimod. This modality was also used for SCC in situ, with no recurrences after the treatment of 31 lesions.21
Ingenol Mebutate
Ingenol mebutate is a purified compound from the sap of Euphorbia peplus, also known as radium weed.22 It is being developed as a short course topical treatment for superficial BCC and AK.22,23 Ingenol mebutate causes primary necrosis followed by an inflammatory response targeting residual tumor cells. Rather than 6 to 12 weeks of treatment with imiquimod or 5-FU, patients may be able to treat their lesions with only a 2 to 3 day course of ingenol mebutate.22,23 Results for treatment of AK lesions show statistically significant partial and complete clearance rates when compared to vehicle treatment as well as a median percentage reduction in baseline AK lesions ranging from 75%-100% compared with 0% for vehicle gel.22
Dermato-Oncology for BCC
A new class of drugs, known as the hedgehog inhibitors, is emerging as a valuable treatment option for BCC not treatable by surgical means or radiotherapy. The FDA approved vismodegib (Erivedge) in 2012 for oral treatment of metastatic and locally invasive BCC.24 It works by antagonizing the smoothened homologue in the hedgehog pathway.24 Recent clinical studies demonstrate a partial or complete response to treatment, however adverse effects such as myalgia and alopecia have led to discontinuation of treatment in some instances.25 Additional hedgehog inhibitors are being studied for use as neoadjuvant therapy to surgical treatment.
Dz13
A recent Phase I trial assessed the safety and tolerability of deoxyribozyme, Dz13.26 Dz13 was injected into nodular basal cell carcinomas in 9 patients. The treatment was well tolerated with no serious drug-related side effects. In addition, the tumors showed decreased expression of c-Jun, the molecular target of Dz13, as well as decreased histological tumor depth in more than half of the patients.
Superficial X-ray Therapy
The use of superficial X-ray therapy declined after the introduction of Mohs surgery. Researchers are now trying to reintroduce the therapy as a non-surgical option for patients with primary non-aggressive BCC and SCC, particularly for patients who decline surgery or are poor surgical candidates.27
Conclusion
The increasing incidence of NMSC requires further investigation of new treatment methods, including non-invasive options. Severity of disease, location and patient comorbidities guide treatment selection. While Mohs surgery continues to be the mainstay, some circumstances require use of other treatment modalities. Knowledge of available and emerging therapies will be helpful in improving patient outcomes. In addition, prevention strategies such as reduced sun exposure are of equal importance. n
Ms. Watkins, BS, is a medical student at Texas Tech University Health Sciences Center in Lubbock, TX.
Ms. Roberts, BS, is a medical student at Texas Tech University Health Sciences Center in Lubbock, TX.
Ms. Nies, BS, is a medical student at Texas Tech University Health Sciences Center in Lubbock, TX.
Dr. West is a first-year dermatology resident at Texas Tech University Health Sciences Center in Lubbock, TX.
Disclosures: The authors have no conflicts of interest to report.
References
1. American Cancer Society. Don’t fry: Preventing skin cancer. American Cancer Society Website. https://www.cancer.org/research/infographicgallery/skin-cancer-prevention?gclid=CMTN7NOP1bgCFRFp7AodBX4AVg. Accessed October 19, 2013.
2. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146(3):283-287.
3. Connolly SM, Baker DR, Coldiron BM, et al. AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol. 2012;67(4):531-550.
4. Schell AE, Russell MA, Park SS. Suggested excisional margins for cutaneous malignant lesions based on Mohs micrographic surgery. JAMA Facial Plast Surg. 2013;15(5):337-343.
5. Marks JG Jr, Miller JJ. Lookingbill and Marks’ Principles of Dermatology. 5th ed. New York, NY: Saunders Elsevier; 2013.
6. Kokoszka A, Scheinfeld N. Evidence-based review of the use of cryotherapy in treatment of basal cell carcinoma. Dermatol Surg. 2003;29(6):566-570.
7. Shimizu I, Cruz A, Chang KH, Dufresne RG. Treatment of squamous cell carcinoma in situ: a review. Dermatol Surgery. 2011;37(10):1394-1411.
8. Ibrahim SF, Brown MD. Actinic keratoses: a comprehensive update. J Clin Aesthet Dermatol. 2009;2(7):43-48.
9. Cox NH, Eedy DJ, Morton CA. Guidelines for management of Bowen’s disease: 2006 update. Br J Dermatol. 2006;156:(1)11-21.
10. Ahlgrimm-Siess V, Horn M, Koller S, Ludwig R, Gerger A, Hofmann-Wallenhof R. Monitoring efficacy of cryotherapy for superficial basal cell carcinoma with in vivo reflectance confocal microscopy: a preliminary study. J Dermatol Sciences. 2009;53(1):60-64.
11. Filho LL, de Oliveira de Avelar Alchorne A, Pereira GC, Lopes LR, de Carvalho TC. Histological and immunohistochemical evaluation of basal cell carcinoma following curettage and electrodessication. Int J Dermatol. 2008;47(6):610-614.
12. Chren MM, Linos E, Torres JS, Stuart SE, Parvataneni R, Boscardin WJ. Tumor recurrence 5 years after treatment of cutaneaous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol. 2013;133(5):1188-1196.
13. Drake LA, Ceilley RI, Cornelison Rl, et al. Guidelines of care for cutaneous squamous cell carcinoma. J Am Acad Dermatol. 1993;28(4):628-631.
14. Khan L, Choo R, Breen D, et al. Recommendations for CTV margins in radiotherapy planning for non melanoma skin cancer. Radiother Oncol. 2012;104(2):263-266.
15. Hulyalkar R, Rakkhit T, Garcia-Zuazaga J. The role of radiation therapy in the management of skin cancers. Dermatol Clin. 2011;29(2):287-296.
16. Kirby JS, Miller CJ. Intralesional chemotherapy for nonmelanoma skin cancer: a practical review.
J Am Acad Dermatol. 2010;63(4):689-702.
17. Gargiulo M, Papa A, Capasso P, Molo M, Cubicciotti E, Parascandolo S. Electrochemotherapy for non-melanoma head and neck cancer: Clinical outcomes in 25 patients. Ann Surg. 2012;255(6):1158-1164.
18. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. J Am Acad Dermatol. 2007;56(1):125-143.
19. Longo C, Casari A, Pepe P, et al. Confocal microscopy insights into the treatment and cellular immune response of basal cell carcinoma to photodynamic therapy. Dermatology. 2012;225(3):264-270.
20. Calin MA, Diaconeasa A, Savastru D, Tautan M. Photosensitizers and light sources for photodynamic therapy of the Bowen’s disease. Arch Dermatol Res. 2011;303(3):145-151.
21. MacFarlane DF, El Tal AK. Cryoimmunotherapy: superficial basal cell cancer and squamous cell carcinoma in situ treated with liquid nitrogen followed by imiquimod. Arch Dermatol. 2011;147(11):1326-1327.
22. Anderson L, Schmieder GJ, Werschler WP, et al. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dematol. 2009;60(6):934-943.
23. Gross K. Safety and efficacy of ingeol mebutate (PEP005) gel for topical treatment of superficial basal cell carcinoma. J Am Acad Dermatol. 2009;60(3):AB141.
24. The Medical Letter, Inc. Vismodegib (Erivedge) for basal cell carcinoma. Med Lett Drugs Ther. 2012;54(1394):53-55.
25. Ali FR, Lear JT. Systemic treatments for basal cell carcinoma (BCC): The advent of dermato-oncology in BCC. British J Dermatol. 2013;169(1):53-57.
26. Cho EA, Moloney FJ, Cai H, et al. Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER). Lancet. 2013;381(9880):1835-1843.
27. Cognetta AB, Howard BM, Heaton HP, Stoddard ER, Hong HG, Green WH. Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients. J Am Acad Dermatol. 2012;67(6):1235-1241.
Cutaneous malignancy is the most common type of cancer.1 As a result, dermatologists spend a large amount of time identifying, treating and educating patients with skin cancer, particularly non-melanoma skin cancer (NMSC). While cancer registries do not require reporting of NMSC, the American Cancer Society and dermatologists recognize the yearly incidence of NMSC far outnumbers all other cancer types combined.1,2 Thus, prevention and treatment of NMSC is critical.
The 2 most common types of NMSC are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This article will focus on the main treatment modalities for these 2 types of NMSC. New treatments are continually emerging, and we discuss 5 of therapies for BCC and SCC.
Treatment Options For BCC And SCC
Various treatment options must be considered based on the lesion location, size, immunosuppression, perineural invasion, chronic inflammation, previous radiation, growth rate, primary versus recurrent disease, histology subtype and differentiation and borders.
Mohs Surgery
Mohs surgery allows for the excision of a primary tumor with histological confirmation of clear margins, which would not otherwise be ascertained in a typical excision. In areas such as the face, the Mohs procedure also offers the best cosmetic outcome as the least amount of tissue is excised to achieve clear margins. Cost, provider availability, contraindications, length of the procedure and risk versus benefit analysis are considered in this treatment option.
A 2012 report published in the Journal of the American Academy of Dermatology detailed the appropriate use criteria for the Mohs surgical technique. This report offers guidelines for the first time, agreed upon by several dermatological associations, determining which skin cancers should be treated with Mohs surgery. The guidelines are based on location, subtype and size of the lesion.3
• The use of the Mohs technique is indicated in previously radiated skin, traumatic scars, in areas of osteomyelitis, areas of chronic inflammation or ulceration or in patients with genetic syndromes regardless of location, depth or subtype.
• Mohs surgery is the preferred treatment option for all high-risk SCC cases which are listed as sclerosing, basosquamous, poorly or undifferentiated, perineural or perivascular, spindle cell, pagetoid, infiltrating, keratoacanthoma type: central facial, single cell, clear cell, lymphoepithelial, sarcomatoid, breslow depth of 2 mm or greater or Clark level IV or greater.
• Mohs was not suggested for treatment of actinic keratosis (AK) with focus SCC in situ, Bowenoid AK or SCC in situ of AK subtype. Also, Mohs may not be beneficial for treatment of primary SCC in areas of the trunk and extremities when it is not an aggressive subtype, <2 mm in depth and <2 cm in size in healthy patients and <1 cm in size in immunocompromised patients.
• Mohs is appropriate for use in all forms of BCC including recurrent, primary aggressive, primary nodular and primary superficial on the face, genitalia, hands, feet, nail units, ankles, nipples/areola, cheeks, forehead, scalp, neck, jawline and pretibial surfaces regardless of size or patient type.
•
Exceptions to the use of Mohs for BCC include primary superficial BCC 0.5 cm or smaller on the cheeks, forehead, scalp, neck, jawline and pretibial surfaces for healthy patients. As for other areas on the trunk and extremities, appropriate use of Mohs surgery depends considerably on the type and size of BCC.
Surgical Excision
Although Mohs surgery is considered the gold standard for NMSC removal, it is not always appropriate or available as treatment. Surgical excision is also an option in which both the lesion and a margin of healthy tissue are removed. Surgical excision relies on gross tumor inspection and histology. The amount of a margin to remove has been a topic of consideration. Primary low-risk SCC lesions <2 cm should be removed with at least a 5-mm margin with 95% confidence of removing the tumor. Higher risk lesions may require as much as a 13.25-mm margin, which may be unreasonable on areas such as the face, and referral for Mohs is indicated. For both low- and high-risk BCC lesions, excisions should be made with 4.75-mm and 8-mm margins, respectively.4
Cryotherapy
Cryotherapy involves the application of liquid nitrogen (-195.6o C) causing intracellular and extracellular ice formation, which destroys tissue by cell dehydration.5 Cryotherapy is used in the treatment of BCC6, SCC in situ7, and is considered the treatment of choice for AKs.8
The advantages of cryotherapy led to a systematic review in 2003 to determine if it was effective in the treatment of BCC.6 The review found that treatment of BCC with cryotherapy yielded low recurrence rates based on clinical diagnosis with acceptable cosmetic results.6 Cryotherapy has also been proven effective in treating Bowen’s disease, though healing may be prolonged and discomfort may limit treatment of multiple lesions.9
The major drawback of using cryotherapy treatment is the inability to provide histological evidence of tumor removal post-treatment. However, physicians have been combining cryotherapy treatment of superficial BCC with reflectance confocal microscopy (RCM). This allows visualization of cell necrosis in the tissue and thus ablation of tumor tissue.10
Electrodesiccation And Curettage
With electrodesiccation and curettage (ED&C), the more friable cancerous tissue is debulked with a curette first. The stroma and surrounding dermis are then electrodesiccated. This process is often performed a total of 3 times.5 Primary small and low-risk BCCs, such as the non-morpheaform BCC types, are frequently treated with ED&C. In research cases where tissue is taken after treatment with ED&C, 25% of cases showed persistent BCC.11
ED&C can also be an effective treatment for low-risk or SCC in situ. However, when compared to other treatment modalities, ED&C showed no significant difference in recurrence of tumors that demonstrated low-risk histology or in tumors of the face.12 Tumors that fall within the vast spectrum of AKs to invasive SCC pose some controversy as to the appropriate treatment modality. Additionally, ED&C does not allow for a histologic evaluation to ensure clear margins after treatment, thus leading to clinical uncertainty regarding complete excision. American Academy of Dermatology guidelines suggest using ED&C only for small, primary SCCs on sun-exposed skin that do not invade into the subcutaneous tissues or fat.13
Radiation
Radiation can be an effective alternative treatment when cosmetic considerations, size and/or location limit surgical options. It can also be used as an adjuvant therapy that can reduce the size of the tumor to increase the chances of successful surgical resection. Proper technique considers the extension of the tumor microscopically or grossly to ensure adequate volume of radiotherapy within appropriate margins. Margins into healthy tissue can increase morbidity, therefore appropriate volume of radiotherapy is essential. Available evidence to guide planning is limited. One study attempted to provide some guidelines for treatment.14 In order to achieve a 95% or greater chance of covering microscopic extent of disease, they recommend for clinical target volume margins 10 mm for BCC <2 cm, 13 mm for BCC >2 cm, 11 mm for SCC <2 cm and 14 mm for SCC >2 cm.14 Radiotherapy is not recommended in young patients or those with impaired DNA repair mechanisms.14
Radiotherapy has an additional role in treating perineural invasion (PNI) by skin cancers, as resection would lead to disruption of vital structures. The spread into such structures is considered an aggressive characteristic of NMSC and most cases occur in SCCs. PNI is associated with poorer outcomes and adjuvant radiotherapy is recommended when extensive, even if the tumor is resected and margins are clear.
Radiation therapy may also provide a benefit for recurrent or high-risk SCC with diameters >2 cm, with ill-defined margins, depths >4 mm, poorly differentiated or rapid growth.15
Chemotherapy
In 2010, Kirby et al published a review of the literature on the use of intralesional chemotherapy for NMSC.16 BCC tumors represented a large portion of the NMSC treated with intralesional chemotherapies such as interferon alpha 2a, interferon alpha 2b, interferon gamma, interferon beta, bleomycin and 5-FU. Results showed simple excision and Mohs surgery provided superior complete response rates when compared to the interferon therapies. Complete response rates for bleomycin and 5-FU were comparable to treatment with Mohs, however small sample size indicates a need for further study.16
In more recent years, researchers have enhanced the delivery of chemotherapy through electrochemotherapy (ECT). This method utilizes electric pulsations to temporarily increase the permeability of cells to the drug. A case series of 25 patients documented the results of using ECT with bleomycin to treat cutaneous or subcutaneous NMSC of the head or neck. There was a 72% complete response rate with no recurrence during 18 months of follow-up. Of the 72%, 100% of the patients with BCC had a complete response and 65% of patients with SCC had a complete response.17
Topical Photodynamic Therapy
Photodynamic therapy (PDT) uses light to activate topical photosensitizers and create cytotoxic reactive oxygen species. Photosensitizers are localized on the diseased tissue and include chemicals such as methyl aminolevulinate and 5-aminolevulinic acid. According to a systematic literature review, PDT is extremely effective for the treatment of AK and Bowen’s disease.18 The review also demonstrated topical PDT is effective, reliable and offers good cosmetic results for superficial and thin nodular BCC. More recently, PDT has been used in conjunction with imaging techniques such as in vivo RCM, which has the ability to diagnose BCC, as well as monitor the efficacy of PDT.19
At the time of the Braathen et al systematic review in 2007, the authors could not recommend the use of PDT for SCC due to high recurrence rates coupled with the potential for SCC to metastasize.18 More recent research has suggested that PDT may be effective for SCC in situ and for patients with multiple AKs, however its use continues to be discouraged for SCC.20
New and Emerging Treatments
New treatments will provide clinicians with more options to help improve outcomes for patients with NMSC. Here, we highlight 5 new and emerging treatments for BCC and SCC.
Cryoimmunotherapy
In recent years, cryoimmunotherapy has been implemented as treatment for BCC resulting in a recurrence rate of only 2%. This treatment combines cryotherapy with imiquimod cream. Researchers speculate that cryotherapy mediated damage to the stratum corneum facilitates penetration of imiquimod. This modality was also used for SCC in situ, with no recurrences after the treatment of 31 lesions.21
Ingenol Mebutate
Ingenol mebutate is a purified compound from the sap of Euphorbia peplus, also known as radium weed.22 It is being developed as a short course topical treatment for superficial BCC and AK.22,23 Ingenol mebutate causes primary necrosis followed by an inflammatory response targeting residual tumor cells. Rather than 6 to 12 weeks of treatment with imiquimod or 5-FU, patients may be able to treat their lesions with only a 2 to 3 day course of ingenol mebutate.22,23 Results for treatment of AK lesions show statistically significant partial and complete clearance rates when compared to vehicle treatment as well as a median percentage reduction in baseline AK lesions ranging from 75%-100% compared with 0% for vehicle gel.22
Dermato-Oncology for BCC
A new class of drugs, known as the hedgehog inhibitors, is emerging as a valuable treatment option for BCC not treatable by surgical means or radiotherapy. The FDA approved vismodegib (Erivedge) in 2012 for oral treatment of metastatic and locally invasive BCC.24 It works by antagonizing the smoothened homologue in the hedgehog pathway.24 Recent clinical studies demonstrate a partial or complete response to treatment, however adverse effects such as myalgia and alopecia have led to discontinuation of treatment in some instances.25 Additional hedgehog inhibitors are being studied for use as neoadjuvant therapy to surgical treatment.
Dz13
A recent Phase I trial assessed the safety and tolerability of deoxyribozyme, Dz13.26 Dz13 was injected into nodular basal cell carcinomas in 9 patients. The treatment was well tolerated with no serious drug-related side effects. In addition, the tumors showed decreased expression of c-Jun, the molecular target of Dz13, as well as decreased histological tumor depth in more than half of the patients.
Superficial X-ray Therapy
The use of superficial X-ray therapy declined after the introduction of Mohs surgery. Researchers are now trying to reintroduce the therapy as a non-surgical option for patients with primary non-aggressive BCC and SCC, particularly for patients who decline surgery or are poor surgical candidates.27
Conclusion
The increasing incidence of NMSC requires further investigation of new treatment methods, including non-invasive options. Severity of disease, location and patient comorbidities guide treatment selection. While Mohs surgery continues to be the mainstay, some circumstances require use of other treatment modalities. Knowledge of available and emerging therapies will be helpful in improving patient outcomes. In addition, prevention strategies such as reduced sun exposure are of equal importance. n
Ms. Watkins, BS, is a medical student at Texas Tech University Health Sciences Center in Lubbock, TX.
Ms. Roberts, BS, is a medical student at Texas Tech University Health Sciences Center in Lubbock, TX.
Ms. Nies, BS, is a medical student at Texas Tech University Health Sciences Center in Lubbock, TX.
Dr. West is a first-year dermatology resident at Texas Tech University Health Sciences Center in Lubbock, TX.
Disclosures: The authors have no conflicts of interest to report.
References
1. American Cancer Society. Don’t fry: Preventing skin cancer. American Cancer Society Website. https://www.cancer.org/research/infographicgallery/skin-cancer-prevention?gclid=CMTN7NOP1bgCFRFp7AodBX4AVg. Accessed October 19, 2013.
2. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146(3):283-287.
3. Connolly SM, Baker DR, Coldiron BM, et al. AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol. 2012;67(4):531-550.
4. Schell AE, Russell MA, Park SS. Suggested excisional margins for cutaneous malignant lesions based on Mohs micrographic surgery. JAMA Facial Plast Surg. 2013;15(5):337-343.
5. Marks JG Jr, Miller JJ. Lookingbill and Marks’ Principles of Dermatology. 5th ed. New York, NY: Saunders Elsevier; 2013.
6. Kokoszka A, Scheinfeld N. Evidence-based review of the use of cryotherapy in treatment of basal cell carcinoma. Dermatol Surg. 2003;29(6):566-570.
7. Shimizu I, Cruz A, Chang KH, Dufresne RG. Treatment of squamous cell carcinoma in situ: a review. Dermatol Surgery. 2011;37(10):1394-1411.
8. Ibrahim SF, Brown MD. Actinic keratoses: a comprehensive update. J Clin Aesthet Dermatol. 2009;2(7):43-48.
9. Cox NH, Eedy DJ, Morton CA. Guidelines for management of Bowen’s disease: 2006 update. Br J Dermatol. 2006;156:(1)11-21.
10. Ahlgrimm-Siess V, Horn M, Koller S, Ludwig R, Gerger A, Hofmann-Wallenhof R. Monitoring efficacy of cryotherapy for superficial basal cell carcinoma with in vivo reflectance confocal microscopy: a preliminary study. J Dermatol Sciences. 2009;53(1):60-64.
11. Filho LL, de Oliveira de Avelar Alchorne A, Pereira GC, Lopes LR, de Carvalho TC. Histological and immunohistochemical evaluation of basal cell carcinoma following curettage and electrodessication. Int J Dermatol. 2008;47(6):610-614.
12. Chren MM, Linos E, Torres JS, Stuart SE, Parvataneni R, Boscardin WJ. Tumor recurrence 5 years after treatment of cutaneaous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol. 2013;133(5):1188-1196.
13. Drake LA, Ceilley RI, Cornelison Rl, et al. Guidelines of care for cutaneous squamous cell carcinoma. J Am Acad Dermatol. 1993;28(4):628-631.
14. Khan L, Choo R, Breen D, et al. Recommendations for CTV margins in radiotherapy planning for non melanoma skin cancer. Radiother Oncol. 2012;104(2):263-266.
15. Hulyalkar R, Rakkhit T, Garcia-Zuazaga J. The role of radiation therapy in the management of skin cancers. Dermatol Clin. 2011;29(2):287-296.
16. Kirby JS, Miller CJ. Intralesional chemotherapy for nonmelanoma skin cancer: a practical review.
J Am Acad Dermatol. 2010;63(4):689-702.
17. Gargiulo M, Papa A, Capasso P, Molo M, Cubicciotti E, Parascandolo S. Electrochemotherapy for non-melanoma head and neck cancer: Clinical outcomes in 25 patients. Ann Surg. 2012;255(6):1158-1164.
18. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. J Am Acad Dermatol. 2007;56(1):125-143.
19. Longo C, Casari A, Pepe P, et al. Confocal microscopy insights into the treatment and cellular immune response of basal cell carcinoma to photodynamic therapy. Dermatology. 2012;225(3):264-270.
20. Calin MA, Diaconeasa A, Savastru D, Tautan M. Photosensitizers and light sources for photodynamic therapy of the Bowen’s disease. Arch Dermatol Res. 2011;303(3):145-151.
21. MacFarlane DF, El Tal AK. Cryoimmunotherapy: superficial basal cell cancer and squamous cell carcinoma in situ treated with liquid nitrogen followed by imiquimod. Arch Dermatol. 2011;147(11):1326-1327.
22. Anderson L, Schmieder GJ, Werschler WP, et al. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dematol. 2009;60(6):934-943.
23. Gross K. Safety and efficacy of ingeol mebutate (PEP005) gel for topical treatment of superficial basal cell carcinoma. J Am Acad Dermatol. 2009;60(3):AB141.
24. The Medical Letter, Inc. Vismodegib (Erivedge) for basal cell carcinoma. Med Lett Drugs Ther. 2012;54(1394):53-55.
25. Ali FR, Lear JT. Systemic treatments for basal cell carcinoma (BCC): The advent of dermato-oncology in BCC. British J Dermatol. 2013;169(1):53-57.
26. Cho EA, Moloney FJ, Cai H, et al. Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER). Lancet. 2013;381(9880):1835-1843.
27. Cognetta AB, Howard BM, Heaton HP, Stoddard ER, Hong HG, Green WH. Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients. J Am Acad Dermatol. 2012;67(6):1235-1241.
