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Treatment of Facial Basal Cell Carcinoma: A Review

Treatment of Facial Basal Cell Carcinoma: A Review Hindawi Publishing Corporation Journal of Skin Cancer Volume 2011, Article ID 380371, 7 pages doi:10.1155/2011/380371 Review Article Vanessa Smith and Shernaz Walton Department of Dermatology, Hull Royal Infirmary, Hull and Hull York Medical School (HYMS), Hull HU2 3JZ, UK Correspondence should be addressed to Vanessa Smith, vanessasmith@doctors.org.uk Received 13 December 2010; Revised 23 January 2011; Accepted 27 January 2011 Academic Editor: Arash Kimyai-Asadi Copyright © 2011 V. Smith and S. Walton. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Basal cell carcinomas (BCCs) are locally destructive malignancies of the skin. They are the most common type of cancer in the western world. The lifetime incidence may be up to 39%. UV exposure is the most common risk factor. The majority of these tumours occur on the head and neck. Despite BCCs being relatively indolent the high incidence means that their treatment now contributes a significant and increasing workload for the health service. A good understanding of the options available is important. Management decisions may be influenced by various factors including the patient’s age and comorbidities and the lesion subtype and location. Due to the importance of a good cosmetic and curative outcome for facial BCCs treatment decisions may differ significantly to those that would be made for BCCs arising elsewhere. There is little good randomized controlled data available comparing treatment modalities. Although traditionally standard excision has been the treatment of choice various other options are available including: Mohs micrographic surgery, curettage and cautery, cryosurgery, radiotherapy, topical imiquimod, photodynamic therapy and topical 5-fluorouracil. We discuss and review the literature and evidence base for the treatment options that are currently available for facial BCCs. 1. Introduction bidities and the type of tumour involved. The location of the lesion is important, as tumours that arise in cosmetically Basal cell carcinomas (BCCs) are locally destructive malig- or functionally important areas are best managed with nancies of the skin. They are the most common type of treatments that minimise the amount of tissue removed whilst ensuring a high chance of complete cure. In the cancer in Europe, Australia [1] and the U.S.A [2]. A Cana- dian study found the lifetime incidence in the Caucasian elderly population, the slow growing nature of BCCs means population to be between 15%–28% in women and 17%– that less invasive treatments may be favoured despite the fact that some of these methods have higher recurrence 39% in men [3]. In the U.K. the true incidence is not known due to inconsistencies in cancer registration [4]. However, rates. Cystic and nodular BCCs (nBCC) have relatively well estimates suggest that 53,000 new cases are diagnosed in the defined borders, while morphoeic, micronodular, trabecular, UK each year [5]. Despite BCCs being relatively indolent the infiltrative and basosquamous BCCs are often less well high incidence means that the treatment of these tumours defined and are also more aggressive [9]. Superficial BCCs contributes a significant and ever growing workload for the (sBCC) may be amenable to topical treatments as a result of NHS. their minimal depth of invasion. The most significant aetiological factors appear to be Over recent years, various treatments beside traditional excision have been tried inaneffort to provide better results, exposure to ultraviolet radiation and genetic predisposition [6]. BCCs tend to occur in areas of chronic sun exposure and in terms of reduction of recurrence, better patient accept- therefore a large proportion, around 74%, occurs on the head ability, and improved cosmesis. Although many treatments and neck [3]. Although BCCs are usually slow growing and are now used for BCCs, there is little research that accurately rarely metastasize [7], local destruction, and disfigurement compares these different treatment modalities against each may occur if left untreated or if incompletely removed [8]. other for different types of tumours in different locations. As Management is dependent upon a variety of factors, a result of the importance of a good cosmetic outcome when including the location of the lesion, the patient’s age, comor- tumours arise on the face treatment decisions may differ 2 Journal of Skin Cancer significantly to those that would be made for BCCs arising et al. [17] of 140 patients, that reports a recurrence rate of elsewhere. We discuss and review the literature and evidence 21% also reports that 31% of the cohort died of other causes base for the treatment options that are currently available for during the (minimum 5-year) followup period and therefore facial BCCs. the incidence may have been higher. When incomplete excision occurs on the face there is good evidence to support the need for re-excision. Boulinguez et al. [19] report a 24% chance of incompletely 2. Surgical Management excised BCCs becoming more aggressive when they recur, with the likelihood being higher for perinasal, periocular and 2.1. Standard Excision of Primary BCC with Predetermined Margins. Standard surgical excision is a highly effective periauricular lesions. Although treatment should therefore treatment for primary BCC and historically has been the be with early re-excision, there is a role for radiotherapy mostly common treatment option. BCCs are generally in special circumstances [20]. Recurrent tumours, especially removed with a predetermined excision margin of 3-4 mm on the face, are at high risk of further recurrence following of normal skin. Especially on the face, grafts and flaps may surgical excision and require wider surgical margins. be necessary to close the wound, rather than direct closure. Generally standard surgical excision is considered a good A study of 2016 BCCs byBreuninger and Dietz [10], using treatment option for all BCCs arising on the face with 5-year recurrence rates of anything up to 10% providing horizontal sections to accurately detect BCC at any part of the surgical margin, found that excision of small (<10 mm adequate margins are taken. We would therefore recommend diameter) lesions with a 2-mm peripheral surgical margin at least a 3-mm margin for standard surgical excision. While cleared 70%, margins of 3-mm cleared 84% and margins it would seem sensible to take larger margins at the sites of 5-mm cleared 95% of all tumours. Morphoeic and large where subclinical spread is known to be more extensive, these BCCs required wider surgical margins in order to maximize sites are all of great cosmetic and functional importance thechance ofcompleteexcision. For primary morphoeic and therefore striking the correct balance is necessary while lesions, the rate of complete excision was 66% for a 3-mm considering the option of Mohs’ micrographic surgery as an alternative. margin, 82% for 5-mm and >95% for 13–15 mm. Although little data exists on the correct deep surgical margin, excision through to the subcutaneous fat is generally 2.2. Mohs Micrographic Surgery. Mohs micrographic surgery advisable. Overall the 5-year recurrence rate after a simple (MMS) was first reported by an American physician and excision of a BCC is reported as being between 4.1% [11]and general surgeon, Dr. Mohs, in 1941 [21]. Excised tissue is 10.1% [12]. If the excision has been reported as histologically frozen and sectioned horizontally. The entire margin can complete therecurrence rateisreportedtobe <2% [13]. This then be intraoperatively histologically examined. Further is due to sampling errors that occur as histological specimens excision can then be performed if necessary from the are examined in a vertical plane. specifically involved margin. MMS allows greater histological Basalcellcarcinoma on the facemay have ahigher degree accuracy and increased tissue conservation. of subclincal spread than tumours arising elsewhere.Batra Studies and reviews have found 5-year cure rates of and Kelley [14] retrospectively analysed 1131 cases of Mohs’ between 93.5% [22] and 100% [23] for primary tumours and micrographic surgery on the face and found there to be 90% [22] to 96% [24] for recurrent disease. higher rates of extensive subclinical spread on the nose, A prospective randomised Dutch trial [11, 25]compar- ear, eyelid, temple, and neck than the cheek. The nasal ala, ing MMS with standard surgical excision found recurrence nasal bridge, nasal tip, ear helix, and lower eyelid were all rates to be comparatively lower after MMS for the treatment found to be locations of particularly high extensive spread. of both primary (pBCC) and recurrent BCCs (rBCC). For In addition, morpheaform BCCs were 2.3 times (P< .001), pBCCs rates were 2% and 3%, respectively, at 30 months recurrent BCCs were 3.2 times (P< .001), and recurrent and 2.5% and 4.1%, respectively, at 5 years. These differences SCCs were 4.2 times (P = .01) more likely than nodular were not statistically significant. In addition there was BCCs to exhibit extensive subclinical spread. no significant difference in patient perception of cosmetic Generally the cosmetic outcome for standard surgical appearance following the procedure. For rBCCs, the rates excision is felt to be good [15]. However, having to remove were 0% and 3%, respectively, at 18 months and 2.4% and large lesions with adequate excision margins can be disfig- 12.1%, respectively, at 5 years. These differences were only uring as a result of loss of tissue, grafting, and subsequent statistically significant (P = .015) at 5 years. In addition, scarring. Special attention must be paid to the location of the in the standard surgical group 30% of rBCCs were initially BCC on the face as there are many areas of functional and incompletely excised and required further surgery. This cosmetic importance for example the periocular, perioral, suggests that MMS should be the treatment of choice for and perinasal areas. facial rBCC on the basis of fewer recurrences. However, it Various studies of incompletely excised BCCs suggest is worth noting that in this study some patients who were that not all recur and in a series of 74 patients Griffiths randomised to standard surgical excision were moved to reports residual tumour in just 54% of re-excised tissue [16]. the MMS treatment group. Recurrent lesions retreated with Studies with a 5 year followup have reported recurrence thesamemodalityhavea greater risk of recurrenceand in rates ranging from 21%–41% for patients following previous such cases MMS will offer the best chance of complete cure incomplete excisions [17, 18]. However, the study by Wilson [26]. Journal of Skin Cancer 3 Even primary lesions need to be appropriately stratified 2.4. Cryosurgery. Cryosurgery involves the destruction of to determine the optimal course of treatment [12, 27]. tissue using liquid nitrogen. Again, it is advisable to biopsy Histological subtype, location, size of the lesion, age and first to confirm the diagnosis and determine the histological patient comorbidities are all important factors to consider. subtype, especially for facial lesions. It is very operator Guidelines suggest the following as being specific indica- dependant, and there are huge variations in practice. Data tions: Tumour site (especially central face, around the eyes, is therefore very inconsistent. Cryosurgery tends to be most nose, lips, and ears), tumour size (any size, but especially useful in the treatment of low risk BCCs although good >2 cm), histological subtype (especially morphoeic, infil- results have been reported following treatment of high risk trative, micronodular, and basosquamous subtypes), poor lesions, either as sole treatment or in combination with clinical definition of tumour margins, recurrent lesions, and curettage. perineural or perivascular involvement [28]. Recurrence rates are very variable, but when the lesion MMS is more labour intensive and the cost of each is carefully selected and in expert hands recurrence rates procedure is significantly higher than for standard excision. may be as low as 1% [36]. However, a nonrandomised study However, in view of the reduced recurrence rate, MMS is cost comparing cryosurgery (60 seconds freeze, 90 second thaw 2 effective treatment for appropriately selected cases. A recent × cycles) to radiotherapy found the 2-year recurrence rates study comparing Mohs’ surgery to standard excision for to be 39% and 4%, respectively [37]. facial and auricular nonmelanoma skin cancer found MMS Cryosurgery wounds generally heal with minimal tissue to be more cost effective than standard surgical excision [29]. contraction, resulting in good cosmetic results. However, a Mohs surgery provides the best chance of cure for study comparing cryosurgery (20 seconds freeze, 60 seconds all BCCs arising on the face with 5-year recurrence rates thaw 2 × cycles) to standard surgical excision for head and of anything up to 6.5%. However, due to time and cost neck sBCC and small nBCCs found no significant difference limitations, it should be reserved for the treatment of high- in recurrence rates at 1-year but significantly worse cosmetic risk primary or recurrent BCCs on the face. outcomes for those who had received cryosurgery [38]. Cryosurgery should not be first line in the management of facial BCCs due to the high risk or recurrence and 2.3. Curettage with and without Cautery. Curettage is widely potentially poorer cosmetic outcome. used in management of BCC. The tumour is scraped off with a curette and then the base and wound margin is often 2.5. Laser Ablation. Carbon dioxide laser ablation has been treated with electrocautery to control bleeding and destroy used in the treatment of BCCs. There are reports of use in any residual tumour. This may be repeated. As excision combination with curettage for treatment of low-risk BCCs, margins are being destroyed it is advisable to confirm the but supportive data is generally lacking. diagnosis and determine the histological subtype with a preoperative biopsy, especially for facial lesions, unless a very confident clinical diagnosis can been made. 3. Non Surgical Management For standard curettage and electrocautery recurrence rates have been reported to be between 7.7% [12] and 19% 3.1. Radiotherapy. Radiotherapy can be used to treat pri- [30] at 5 years. Recurrence rates have been found to be much mary, recurrent or incompletely excised BCCs. It encom- higher for facial lesions and recurrent disease [30, 31]. A passes superficial X-ray and electron beam. Brachytherapy prospective study of 69 re-excised BCC wounds immediately is used for contoured surfaces. The cure rates are over 90% after curettage and electrocautery found residual tumour in for most skin lesions [12]. It may be used on tumours that 47% of head and neck wounds and 8.3% of trunk and limb occur in areas where surgery would either be technically wounds [32]. Curettage is very operator dependant; however, difficult or would result in unacceptable amounts of tissue a retrospective study of curettage alone reported a 5-year cure destruction. Radiotherapy therefore plays an important role rate of 96% for nonaggressive BCC, and tumours involving in the management of head and neck BCCs. Tumours of more than 50% of the deep edge of the specimen were found the lower eyelid, inner canthus, lip, nose, and ear may be to have an increased risk of recurrence [33]. amenable to radiotherapy [39]. However, the upper eyelid is A randomised controlled trial comparing a double freeze not an appropriate site for radiotherapy due to keratinization thaw cycle of cryosurgery after curettage with standard of the conjunctiva, lesions on the ear must be treated with excision for nonaggressive BCC of the head and neck caution due to the risk of damage to the underlying cartilage reports recurrence rates of 17.6% and 8.2%, respectively and the bridge of the nose is particularly susceptible to [34]. However, there are other studies that report much radionecrosis. Radiotherapy may be a good option for elderly lower recurrence rates than this. Lindemalm-Lundstam and patients with very large BCCs of the scalp. Radiotherapy is Dalenback ¨ report a 1.5% recurrence rate following curettage not appropriate for recurrent BCCs or patients with Gorlin’s and cryosurgery for head and neck BCCs after a median syndrome or with connective tissue disease. It tends not followup of 34-months [35]. to be used in younger patients as skin cancers can arise Given the disproportionate amount of residual tumour from radiotherapy field scars and long term cosmetic results on head and neck wounds and higher recurrence rates are poor. Side effects include radionecrosis, atrophy, and curettage and electrocautery is not considered first line telangiectasia. Treatment in fractions over several visits may treatment for BCCs on the face. produce better cosmetic outcomes than a single fraction 4 Journal of Skin Cancer treatment. However, a daily regimen for a period of weeks on the eyelid, this time treated with 5% imiquimod once may be a significant inconvenience to the patient as opposed daily, 5 days/week for 6 weeks, reports that all tumors showed to a single surgical treatment. histopathological remission within 3 months of starting A randomised trial by Avril et al. [40]comparing treatment, and sustained clinical remission was documented radiotherapy to surgical excision for facial BCC of less than in each patient after 24–28 months’ followup. The authors 4 cm found 4 year recurrence rates to be 7.3% and 0.7%, acknowledge that treatment tolerability was difficult in 7 respectively. Cosmetic outcome also significantly favoured patients with local effects being most problematic, but all surgical excision at 4 years with 87% of patients assessing the symptoms disappeared when treatment ended and final surgical scar as good, compared to 69% after radiotherapy aesthetic results were rated as excellent. They conclude that (P< .01) [41]. 5% imiquimod is a useful alternative to surgery in patients with periocular BCCs when other therapies have failed or are In addition, radiotherapy tends to be more expensive not possible. than any other form of treatment. A recent prospective study Studies have also been done investigating the combi- by Lear et al. in Canada [42] looked at the cost of MMS nation of curettage of nBCC prior to the use of topical and radiotherapy for 49 BCCs. The authors found the cost of imiquimod. Results have been variable with recurrence rates radiotherapy to be significantly greater and state direct costs ranging from 6% [50] to 10% [51]. of a “5-year cure” to be $952 (range $644–1,647) for MMS Effective treatment with imiquimod is dependent upon and $3,758 (range $3,564–4,675) for radiotherapy. tissue penetration. sBCC may be more amenable to topical We believe radiotherapy is a good treatment option for treatments as a result of their minimal depth of invasion. The facial BCCs located at difficult sites in patients who are not increased depth of nodular tumours results in incomplete able to tolerate surgery. tumour penetration with the drug and hence lower clearance rates. 3.2. Topical 5% Imiquimod Cream (Aldara). Imiquimod is Imiquimod may be an alternative to surgery for patients an immune response modifier. It acts by binding to toll-like with primary facial superficial BCCs, but long-term clear- receptor. This induces proinflammatory cytokine production ance is not as good as some of the other treatment modalities. and subsequent cytotoxic T cell mediated cell death. It is It is not recommended for recurrent disease but is a good licensed for use in the treatment of sBCCs. treatment option for elderly frail patients and patients who Vehicle-controlled studies in the treatment of small sBCC are not keen on surgical treatment. by Geisse et al. [43] have reported reasonable results. Twelve weeks following the 6 week treatment course the clearance 3.3. Photodynamic Therapy (PDT). Photodynamic therapy rates were 82% (5x/week), 79% (7x/week) and 3% (vehicle (PDT) involves the destruction of sensitised cells by an only). Moderate to severe local site reactions occurred in 87% irradiating light source. A prodrug, either 5-aminolaevulinic with erosions and ulceration in 36% and 22%, respectively. acid (ALA) or methyl aminolaevulinic (MAL), is applied However, it is worth noting that facial BCCs were not to the skin. This is converted intracellularly into protopor- included in this study. Schulze et al. [44] found similar phyrin IX by the tumour cells. In the presence of intense clearance rates following a 6 weeks course of 7x/week topical red or blue light, a cytotoxic reaction occurs with reactive imiquimod, with a 80% histological clearance compared oxygen in the cell-membranes of tumour cells containing to 6% for vehicle alone. However, long term clearance protoporphyrin IX and so the tumour cells are destroyed rates are lower. A prospective study of 182 patients who with sparing of uninvolved skin. received topical imiquimod applied 5x/week for 6 weeks gave Superficial BCCs have been shown to achieve 87% clearance rates of 69% at 5-years [45]. clearance [52]. A prospective randomized study comparing There is some data to suggest that imiquimod may PDT and standard surgical excision for the treatment of be used in the treatment of nBCCs. A randomized dose- nBCCs found 5 years recurrence rates to be 14% and response study reported that 6 weeks after treatment with 4%, respectively; however, cosmesis was better for PDT either a 6- or 12-week course of 7x/week imiquimod histo- with 87% of patients rating the cosmetic outcome as good logical clearance rates were 71% and 76%, respectively [46]. compared to 54% for surgery [53]. PDT has also been A further randomized trial on nBCCs reported complete compared with cryosurgery in the treatment of both sBCC clinical clearance in 78% following 3x/week imiquimod. and nBCC. Clinical recurrence rates at 12 months of 5% However, 8 weeks later excision revealed residual BCC in (PDT) and 13% (cryosurgery) were underestimates, as 13% of the patients considered to have shown complete histology demonstrated residual BCC in 25% and 15% of clinical clearance [47]. cases, respectively [54]. In terms of studies specifically focusing on the treatment Vinciullo et al. [55] reported 102 patients with sBCCs of facial BCCs with 5% imiquimod Vun and Siller [48]report and nBCCs regarded as “difficult to treat” (defined as large a retrospective study of 19 lesions involving 12 patients. A and/or central facial lesions, or patients at increased risk of once-daily treatment regimen for up to 9 weeks was used surgical complications) who received MAL-PDT treatment. to treat both superficial and nodular basal cell carcinomas Histologically confirmed clearance rates at 3 months were on the face. The authors report a clearance rate of 89.5% at 93% (sBCC) and 82% (nBCC). The authors used a time-to- an average of 39 months of followup. Another more recent event approach to estimate sustained lesion clearance rates of study from 2010 [49] of fifteen patients with nodular BCCs 82% (sBCC) and 67% (nBCC) at 24 months. Journal of Skin Cancer 5 Due to the clearance rates being lower than for surgical [7] P.T.Ting, R. Kasper,and J. P. 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Journal of Dermatology, vol. 15, no. 5, pp. 374–381, 2005. Levenstein, “Recurrence rates of treated basal cell carcinomas: [46] S. Shumack, J. Robinson, S. Kossard et al., “Efficacy of topical part 2: curettage-electrodesiccation,” Journal of Dermatologic 5% imiquimod cream for the treatment of nodular basal Surgery and Oncology, vol. 17, no. 9, pp. 720–726, 1991. cell carcinoma: comparison of dosing regimens,” Archives of [32] P. C. Suhge d’Aubermont and R. G. Bennett, “Failure of Dermatology, vol. 138, no. 9, pp. 1165–1171, 2002. curettage and electrodesiccation for removal of basal cell [47] T. K. Eigentler, A. Kamin, B. M. Weide et al., “A phase carcinoma,” Archives of Dermatology, vol. 120, no. 11, pp. III, randomized, open label study to evaluate the safety and 1456–1460, 1984. efficacy of imiquimod 5% cream applied thrice weekly for 8 [33] J. O. Barlow,M. J.Zalla,A. Kyle, D. J. DiCaudo, K. K. and 12 weeks in the treatment of low-risk nodular basal cell Lim, and J. A. 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Treatment of Facial Basal Cell Carcinoma: A Review

Journal of Skin Cancer , Volume 2011 – Apr 27, 2011

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Hindawi Publishing Corporation
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Copyright © 2011 Vanessa Smith and Shernaz Walton. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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2090-2905
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2090-2913
DOI
10.1155/2011/380371
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Abstract

Hindawi Publishing Corporation Journal of Skin Cancer Volume 2011, Article ID 380371, 7 pages doi:10.1155/2011/380371 Review Article Vanessa Smith and Shernaz Walton Department of Dermatology, Hull Royal Infirmary, Hull and Hull York Medical School (HYMS), Hull HU2 3JZ, UK Correspondence should be addressed to Vanessa Smith, vanessasmith@doctors.org.uk Received 13 December 2010; Revised 23 January 2011; Accepted 27 January 2011 Academic Editor: Arash Kimyai-Asadi Copyright © 2011 V. Smith and S. Walton. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Basal cell carcinomas (BCCs) are locally destructive malignancies of the skin. They are the most common type of cancer in the western world. The lifetime incidence may be up to 39%. UV exposure is the most common risk factor. The majority of these tumours occur on the head and neck. Despite BCCs being relatively indolent the high incidence means that their treatment now contributes a significant and increasing workload for the health service. A good understanding of the options available is important. Management decisions may be influenced by various factors including the patient’s age and comorbidities and the lesion subtype and location. Due to the importance of a good cosmetic and curative outcome for facial BCCs treatment decisions may differ significantly to those that would be made for BCCs arising elsewhere. There is little good randomized controlled data available comparing treatment modalities. Although traditionally standard excision has been the treatment of choice various other options are available including: Mohs micrographic surgery, curettage and cautery, cryosurgery, radiotherapy, topical imiquimod, photodynamic therapy and topical 5-fluorouracil. We discuss and review the literature and evidence base for the treatment options that are currently available for facial BCCs. 1. Introduction bidities and the type of tumour involved. The location of the lesion is important, as tumours that arise in cosmetically Basal cell carcinomas (BCCs) are locally destructive malig- or functionally important areas are best managed with nancies of the skin. They are the most common type of treatments that minimise the amount of tissue removed whilst ensuring a high chance of complete cure. In the cancer in Europe, Australia [1] and the U.S.A [2]. A Cana- dian study found the lifetime incidence in the Caucasian elderly population, the slow growing nature of BCCs means population to be between 15%–28% in women and 17%– that less invasive treatments may be favoured despite the fact that some of these methods have higher recurrence 39% in men [3]. In the U.K. the true incidence is not known due to inconsistencies in cancer registration [4]. However, rates. Cystic and nodular BCCs (nBCC) have relatively well estimates suggest that 53,000 new cases are diagnosed in the defined borders, while morphoeic, micronodular, trabecular, UK each year [5]. Despite BCCs being relatively indolent the infiltrative and basosquamous BCCs are often less well high incidence means that the treatment of these tumours defined and are also more aggressive [9]. Superficial BCCs contributes a significant and ever growing workload for the (sBCC) may be amenable to topical treatments as a result of NHS. their minimal depth of invasion. The most significant aetiological factors appear to be Over recent years, various treatments beside traditional excision have been tried inaneffort to provide better results, exposure to ultraviolet radiation and genetic predisposition [6]. BCCs tend to occur in areas of chronic sun exposure and in terms of reduction of recurrence, better patient accept- therefore a large proportion, around 74%, occurs on the head ability, and improved cosmesis. Although many treatments and neck [3]. Although BCCs are usually slow growing and are now used for BCCs, there is little research that accurately rarely metastasize [7], local destruction, and disfigurement compares these different treatment modalities against each may occur if left untreated or if incompletely removed [8]. other for different types of tumours in different locations. As Management is dependent upon a variety of factors, a result of the importance of a good cosmetic outcome when including the location of the lesion, the patient’s age, comor- tumours arise on the face treatment decisions may differ 2 Journal of Skin Cancer significantly to those that would be made for BCCs arising et al. [17] of 140 patients, that reports a recurrence rate of elsewhere. We discuss and review the literature and evidence 21% also reports that 31% of the cohort died of other causes base for the treatment options that are currently available for during the (minimum 5-year) followup period and therefore facial BCCs. the incidence may have been higher. When incomplete excision occurs on the face there is good evidence to support the need for re-excision. Boulinguez et al. [19] report a 24% chance of incompletely 2. Surgical Management excised BCCs becoming more aggressive when they recur, with the likelihood being higher for perinasal, periocular and 2.1. Standard Excision of Primary BCC with Predetermined Margins. Standard surgical excision is a highly effective periauricular lesions. Although treatment should therefore treatment for primary BCC and historically has been the be with early re-excision, there is a role for radiotherapy mostly common treatment option. BCCs are generally in special circumstances [20]. Recurrent tumours, especially removed with a predetermined excision margin of 3-4 mm on the face, are at high risk of further recurrence following of normal skin. Especially on the face, grafts and flaps may surgical excision and require wider surgical margins. be necessary to close the wound, rather than direct closure. Generally standard surgical excision is considered a good A study of 2016 BCCs byBreuninger and Dietz [10], using treatment option for all BCCs arising on the face with 5-year recurrence rates of anything up to 10% providing horizontal sections to accurately detect BCC at any part of the surgical margin, found that excision of small (<10 mm adequate margins are taken. We would therefore recommend diameter) lesions with a 2-mm peripheral surgical margin at least a 3-mm margin for standard surgical excision. While cleared 70%, margins of 3-mm cleared 84% and margins it would seem sensible to take larger margins at the sites of 5-mm cleared 95% of all tumours. Morphoeic and large where subclinical spread is known to be more extensive, these BCCs required wider surgical margins in order to maximize sites are all of great cosmetic and functional importance thechance ofcompleteexcision. For primary morphoeic and therefore striking the correct balance is necessary while lesions, the rate of complete excision was 66% for a 3-mm considering the option of Mohs’ micrographic surgery as an alternative. margin, 82% for 5-mm and >95% for 13–15 mm. Although little data exists on the correct deep surgical margin, excision through to the subcutaneous fat is generally 2.2. Mohs Micrographic Surgery. Mohs micrographic surgery advisable. Overall the 5-year recurrence rate after a simple (MMS) was first reported by an American physician and excision of a BCC is reported as being between 4.1% [11]and general surgeon, Dr. Mohs, in 1941 [21]. Excised tissue is 10.1% [12]. If the excision has been reported as histologically frozen and sectioned horizontally. The entire margin can complete therecurrence rateisreportedtobe <2% [13]. This then be intraoperatively histologically examined. Further is due to sampling errors that occur as histological specimens excision can then be performed if necessary from the are examined in a vertical plane. specifically involved margin. MMS allows greater histological Basalcellcarcinoma on the facemay have ahigher degree accuracy and increased tissue conservation. of subclincal spread than tumours arising elsewhere.Batra Studies and reviews have found 5-year cure rates of and Kelley [14] retrospectively analysed 1131 cases of Mohs’ between 93.5% [22] and 100% [23] for primary tumours and micrographic surgery on the face and found there to be 90% [22] to 96% [24] for recurrent disease. higher rates of extensive subclinical spread on the nose, A prospective randomised Dutch trial [11, 25]compar- ear, eyelid, temple, and neck than the cheek. The nasal ala, ing MMS with standard surgical excision found recurrence nasal bridge, nasal tip, ear helix, and lower eyelid were all rates to be comparatively lower after MMS for the treatment found to be locations of particularly high extensive spread. of both primary (pBCC) and recurrent BCCs (rBCC). For In addition, morpheaform BCCs were 2.3 times (P< .001), pBCCs rates were 2% and 3%, respectively, at 30 months recurrent BCCs were 3.2 times (P< .001), and recurrent and 2.5% and 4.1%, respectively, at 5 years. These differences SCCs were 4.2 times (P = .01) more likely than nodular were not statistically significant. In addition there was BCCs to exhibit extensive subclinical spread. no significant difference in patient perception of cosmetic Generally the cosmetic outcome for standard surgical appearance following the procedure. For rBCCs, the rates excision is felt to be good [15]. However, having to remove were 0% and 3%, respectively, at 18 months and 2.4% and large lesions with adequate excision margins can be disfig- 12.1%, respectively, at 5 years. These differences were only uring as a result of loss of tissue, grafting, and subsequent statistically significant (P = .015) at 5 years. In addition, scarring. Special attention must be paid to the location of the in the standard surgical group 30% of rBCCs were initially BCC on the face as there are many areas of functional and incompletely excised and required further surgery. This cosmetic importance for example the periocular, perioral, suggests that MMS should be the treatment of choice for and perinasal areas. facial rBCC on the basis of fewer recurrences. However, it Various studies of incompletely excised BCCs suggest is worth noting that in this study some patients who were that not all recur and in a series of 74 patients Griffiths randomised to standard surgical excision were moved to reports residual tumour in just 54% of re-excised tissue [16]. the MMS treatment group. Recurrent lesions retreated with Studies with a 5 year followup have reported recurrence thesamemodalityhavea greater risk of recurrenceand in rates ranging from 21%–41% for patients following previous such cases MMS will offer the best chance of complete cure incomplete excisions [17, 18]. However, the study by Wilson [26]. Journal of Skin Cancer 3 Even primary lesions need to be appropriately stratified 2.4. Cryosurgery. Cryosurgery involves the destruction of to determine the optimal course of treatment [12, 27]. tissue using liquid nitrogen. Again, it is advisable to biopsy Histological subtype, location, size of the lesion, age and first to confirm the diagnosis and determine the histological patient comorbidities are all important factors to consider. subtype, especially for facial lesions. It is very operator Guidelines suggest the following as being specific indica- dependant, and there are huge variations in practice. Data tions: Tumour site (especially central face, around the eyes, is therefore very inconsistent. Cryosurgery tends to be most nose, lips, and ears), tumour size (any size, but especially useful in the treatment of low risk BCCs although good >2 cm), histological subtype (especially morphoeic, infil- results have been reported following treatment of high risk trative, micronodular, and basosquamous subtypes), poor lesions, either as sole treatment or in combination with clinical definition of tumour margins, recurrent lesions, and curettage. perineural or perivascular involvement [28]. Recurrence rates are very variable, but when the lesion MMS is more labour intensive and the cost of each is carefully selected and in expert hands recurrence rates procedure is significantly higher than for standard excision. may be as low as 1% [36]. However, a nonrandomised study However, in view of the reduced recurrence rate, MMS is cost comparing cryosurgery (60 seconds freeze, 90 second thaw 2 effective treatment for appropriately selected cases. A recent × cycles) to radiotherapy found the 2-year recurrence rates study comparing Mohs’ surgery to standard excision for to be 39% and 4%, respectively [37]. facial and auricular nonmelanoma skin cancer found MMS Cryosurgery wounds generally heal with minimal tissue to be more cost effective than standard surgical excision [29]. contraction, resulting in good cosmetic results. However, a Mohs surgery provides the best chance of cure for study comparing cryosurgery (20 seconds freeze, 60 seconds all BCCs arising on the face with 5-year recurrence rates thaw 2 × cycles) to standard surgical excision for head and of anything up to 6.5%. However, due to time and cost neck sBCC and small nBCCs found no significant difference limitations, it should be reserved for the treatment of high- in recurrence rates at 1-year but significantly worse cosmetic risk primary or recurrent BCCs on the face. outcomes for those who had received cryosurgery [38]. Cryosurgery should not be first line in the management of facial BCCs due to the high risk or recurrence and 2.3. Curettage with and without Cautery. Curettage is widely potentially poorer cosmetic outcome. used in management of BCC. The tumour is scraped off with a curette and then the base and wound margin is often 2.5. Laser Ablation. Carbon dioxide laser ablation has been treated with electrocautery to control bleeding and destroy used in the treatment of BCCs. There are reports of use in any residual tumour. This may be repeated. As excision combination with curettage for treatment of low-risk BCCs, margins are being destroyed it is advisable to confirm the but supportive data is generally lacking. diagnosis and determine the histological subtype with a preoperative biopsy, especially for facial lesions, unless a very confident clinical diagnosis can been made. 3. Non Surgical Management For standard curettage and electrocautery recurrence rates have been reported to be between 7.7% [12] and 19% 3.1. Radiotherapy. Radiotherapy can be used to treat pri- [30] at 5 years. Recurrence rates have been found to be much mary, recurrent or incompletely excised BCCs. It encom- higher for facial lesions and recurrent disease [30, 31]. A passes superficial X-ray and electron beam. Brachytherapy prospective study of 69 re-excised BCC wounds immediately is used for contoured surfaces. The cure rates are over 90% after curettage and electrocautery found residual tumour in for most skin lesions [12]. It may be used on tumours that 47% of head and neck wounds and 8.3% of trunk and limb occur in areas where surgery would either be technically wounds [32]. Curettage is very operator dependant; however, difficult or would result in unacceptable amounts of tissue a retrospective study of curettage alone reported a 5-year cure destruction. Radiotherapy therefore plays an important role rate of 96% for nonaggressive BCC, and tumours involving in the management of head and neck BCCs. Tumours of more than 50% of the deep edge of the specimen were found the lower eyelid, inner canthus, lip, nose, and ear may be to have an increased risk of recurrence [33]. amenable to radiotherapy [39]. However, the upper eyelid is A randomised controlled trial comparing a double freeze not an appropriate site for radiotherapy due to keratinization thaw cycle of cryosurgery after curettage with standard of the conjunctiva, lesions on the ear must be treated with excision for nonaggressive BCC of the head and neck caution due to the risk of damage to the underlying cartilage reports recurrence rates of 17.6% and 8.2%, respectively and the bridge of the nose is particularly susceptible to [34]. However, there are other studies that report much radionecrosis. Radiotherapy may be a good option for elderly lower recurrence rates than this. Lindemalm-Lundstam and patients with very large BCCs of the scalp. Radiotherapy is Dalenback ¨ report a 1.5% recurrence rate following curettage not appropriate for recurrent BCCs or patients with Gorlin’s and cryosurgery for head and neck BCCs after a median syndrome or with connective tissue disease. It tends not followup of 34-months [35]. to be used in younger patients as skin cancers can arise Given the disproportionate amount of residual tumour from radiotherapy field scars and long term cosmetic results on head and neck wounds and higher recurrence rates are poor. Side effects include radionecrosis, atrophy, and curettage and electrocautery is not considered first line telangiectasia. Treatment in fractions over several visits may treatment for BCCs on the face. produce better cosmetic outcomes than a single fraction 4 Journal of Skin Cancer treatment. However, a daily regimen for a period of weeks on the eyelid, this time treated with 5% imiquimod once may be a significant inconvenience to the patient as opposed daily, 5 days/week for 6 weeks, reports that all tumors showed to a single surgical treatment. histopathological remission within 3 months of starting A randomised trial by Avril et al. [40]comparing treatment, and sustained clinical remission was documented radiotherapy to surgical excision for facial BCC of less than in each patient after 24–28 months’ followup. The authors 4 cm found 4 year recurrence rates to be 7.3% and 0.7%, acknowledge that treatment tolerability was difficult in 7 respectively. Cosmetic outcome also significantly favoured patients with local effects being most problematic, but all surgical excision at 4 years with 87% of patients assessing the symptoms disappeared when treatment ended and final surgical scar as good, compared to 69% after radiotherapy aesthetic results were rated as excellent. They conclude that (P< .01) [41]. 5% imiquimod is a useful alternative to surgery in patients with periocular BCCs when other therapies have failed or are In addition, radiotherapy tends to be more expensive not possible. than any other form of treatment. A recent prospective study Studies have also been done investigating the combi- by Lear et al. in Canada [42] looked at the cost of MMS nation of curettage of nBCC prior to the use of topical and radiotherapy for 49 BCCs. The authors found the cost of imiquimod. Results have been variable with recurrence rates radiotherapy to be significantly greater and state direct costs ranging from 6% [50] to 10% [51]. of a “5-year cure” to be $952 (range $644–1,647) for MMS Effective treatment with imiquimod is dependent upon and $3,758 (range $3,564–4,675) for radiotherapy. tissue penetration. sBCC may be more amenable to topical We believe radiotherapy is a good treatment option for treatments as a result of their minimal depth of invasion. The facial BCCs located at difficult sites in patients who are not increased depth of nodular tumours results in incomplete able to tolerate surgery. tumour penetration with the drug and hence lower clearance rates. 3.2. Topical 5% Imiquimod Cream (Aldara). Imiquimod is Imiquimod may be an alternative to surgery for patients an immune response modifier. It acts by binding to toll-like with primary facial superficial BCCs, but long-term clear- receptor. This induces proinflammatory cytokine production ance is not as good as some of the other treatment modalities. and subsequent cytotoxic T cell mediated cell death. It is It is not recommended for recurrent disease but is a good licensed for use in the treatment of sBCCs. treatment option for elderly frail patients and patients who Vehicle-controlled studies in the treatment of small sBCC are not keen on surgical treatment. by Geisse et al. [43] have reported reasonable results. Twelve weeks following the 6 week treatment course the clearance 3.3. Photodynamic Therapy (PDT). Photodynamic therapy rates were 82% (5x/week), 79% (7x/week) and 3% (vehicle (PDT) involves the destruction of sensitised cells by an only). Moderate to severe local site reactions occurred in 87% irradiating light source. A prodrug, either 5-aminolaevulinic with erosions and ulceration in 36% and 22%, respectively. acid (ALA) or methyl aminolaevulinic (MAL), is applied However, it is worth noting that facial BCCs were not to the skin. This is converted intracellularly into protopor- included in this study. Schulze et al. [44] found similar phyrin IX by the tumour cells. In the presence of intense clearance rates following a 6 weeks course of 7x/week topical red or blue light, a cytotoxic reaction occurs with reactive imiquimod, with a 80% histological clearance compared oxygen in the cell-membranes of tumour cells containing to 6% for vehicle alone. However, long term clearance protoporphyrin IX and so the tumour cells are destroyed rates are lower. A prospective study of 182 patients who with sparing of uninvolved skin. received topical imiquimod applied 5x/week for 6 weeks gave Superficial BCCs have been shown to achieve 87% clearance rates of 69% at 5-years [45]. clearance [52]. A prospective randomized study comparing There is some data to suggest that imiquimod may PDT and standard surgical excision for the treatment of be used in the treatment of nBCCs. A randomized dose- nBCCs found 5 years recurrence rates to be 14% and response study reported that 6 weeks after treatment with 4%, respectively; however, cosmesis was better for PDT either a 6- or 12-week course of 7x/week imiquimod histo- with 87% of patients rating the cosmetic outcome as good logical clearance rates were 71% and 76%, respectively [46]. compared to 54% for surgery [53]. PDT has also been A further randomized trial on nBCCs reported complete compared with cryosurgery in the treatment of both sBCC clinical clearance in 78% following 3x/week imiquimod. and nBCC. Clinical recurrence rates at 12 months of 5% However, 8 weeks later excision revealed residual BCC in (PDT) and 13% (cryosurgery) were underestimates, as 13% of the patients considered to have shown complete histology demonstrated residual BCC in 25% and 15% of clinical clearance [47]. cases, respectively [54]. In terms of studies specifically focusing on the treatment Vinciullo et al. [55] reported 102 patients with sBCCs of facial BCCs with 5% imiquimod Vun and Siller [48]report and nBCCs regarded as “difficult to treat” (defined as large a retrospective study of 19 lesions involving 12 patients. A and/or central facial lesions, or patients at increased risk of once-daily treatment regimen for up to 9 weeks was used surgical complications) who received MAL-PDT treatment. to treat both superficial and nodular basal cell carcinomas Histologically confirmed clearance rates at 3 months were on the face. The authors report a clearance rate of 89.5% at 93% (sBCC) and 82% (nBCC). The authors used a time-to- an average of 39 months of followup. Another more recent event approach to estimate sustained lesion clearance rates of study from 2010 [49] of fifteen patients with nodular BCCs 82% (sBCC) and 67% (nBCC) at 24 months. Journal of Skin Cancer 5 Due to the clearance rates being lower than for surgical [7] P.T.Ting, R. Kasper,and J. P. Arlette, “Metastatic basal cell carcinoma: report of two cases and literature review,” Journal treatments, PDT is not generally recommended for manage- of Cutaneous Medicine and Surgery, vol. 9, no. 1, pp. 10–15, ment of nodular BCCs on the head or neck. While primary superficial BCCs on the face may be amenable to treatment [8] C. B. Ko, S. Walton, and K. Keczkes, “Extensive and fatal is not recommended for recurrent disease. basal cell carcinoma: a report of three cases,” British Journal of Dermatology, vol. 127, no. 2, pp. 164–167, 1992. 3.4. Topical 5-Fluorouracil 5% (Efudex). 5-fluorouracil is a [9] D. Costantino, L. Lowe, and D. L. Brown, “Basosquamous fluorinated pyrimidine that blocks the methylation reaction carcinoma—an under-recognized, high-risk cutaneous neo- of deoxyuridylic acid to thymidylic acid and in doing plasm: case study and review of the literature,” Journal of Plastic, Reconstructive and Aesthetic Surgery, vol. 59, no.4,pp. so destabilises DNA. 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