Journal of the Saudi Society of Dermatology & Dermatologic Surgery (2012) 16,41–51
King Saud University Journal of the Saudi Society of Dermatology & Dermatologic Surgery www.ksu.edu.sa www.jssdds.org www.sciencedirect.com
REVIEW ARTICLE Basal cell carcinoma: Topical therapy versus surgical treatment
Khalifa E. Sharquie a,*, Adil A. Noaimi b,1 a Scientific Council of Dermatology and Venereology, Iraqi Board for Medical Specializations, Iraq b Department of Dermatology and Venereology, College of Medicine, University of Baghdad, Iraq
Received 1 November 2011; revised 7 June 2012; accepted 7 June 2012 Available online 6 July 2012
KEYWORDS Abstract Basal cell carcinoma (BCC) is a non-melanoma skin cancer and is one of the commonest Basal cell carcinoma; malignancies of the skin encountered in daily clinical practice. It derives from non-keratinizing cells Topical therapy of BCC by that originate in the basal layer of the epidermis. It accounts for approximately 75% of all skin can- podophylline; cer in the world, and 53.2% in Iraqi patients. Generally, most BCC cases are sporadic, but it may Surgical treatment also appear in genetic disorders such as Gorlin’s syndrome, Rombo’s syndrome, and xeroderma pigmentosa (XP). If left untreated, BCC will continue to invade locally and may result in substantial tissue damage that compromises function and cosmetic look. Metastasis is an extremely rare event. The tumor characteristically develops on sun-exposed skin of lighter-skinned individuals. There are two main modalities of therapy including topical like: Imiquimod, 5-fluorouracil (5- FU), photodynamic therapy (PDT), radiation therapy (RT), topical & intralesional zinc sulfate and topical 25% podophylline. While surgical one consists of: Moh’s Micrographic excision, stan- dard excision, Curettage and desiccation (C&D), and cryosurgery. After extensive reviewing of all modalities of therapy, in addition to our experience, we can con- clude that all therapies could be effective in treatment of BCC. As each patient is unique so indi- vidualized treatment plan should be tailored to each one. ª 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
* Corresponding author. Address: Medical Collection Office, P.O. Box 61080 Postal Code 12114, Baghdad. Tel.: +964 7901468515; fax: +964 1 5372193. E-mail addresses: [email protected] (K.E. Sharquie), adilnoai [email protected] (A.A. Noaimi). 1 Tel.: +964 7901751642. Peer review under responsibility of King Saud University.
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2210-836X ª 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jssdds.2012.06.002 42 K.E. Sharquie, A.A. Noaimi
Contents
1. Introduction ...... 42 2. Clinical manifestations...... 43 2.1. Basal cell carcinoma sub-types ...... 43 2.1.1. Nodular basal cell carcinoma ...... 43 2.1.2. Pigmented basal cell carcinoma ...... 43 2.1.3. Superficial basal cell carcinoma ...... 43 2.1.4. Morpheaform (sclerosing) basal cell carcinoma ...... 43 2.1.5. Fibroepithelioma of pinkus ...... 43 2.2. Biologic behavior ...... 43 2.2.1. Local invasion ...... 43 2.3. Perineural invasion ...... 44 2.4. Metastasis ...... 44 2.5. Diagnosis ...... 44 2.6. Histopathology...... 44 3. Treatment...... 44 3.1. Topical therapy ...... 45 3.1.1. Chemical therapy ...... 45 3.1.2. Physical therapy...... 45 3.1.3. Imiquimod (5% cream)...... 45 3.1.4. 5-Fluorouracil (5-FU)...... 45 3.1.5. Interferon alfa-2b (intron A) ...... 46 3.1.6. Photodynamic therapy (PDT) ...... 46 3.2. Bleomycin-mediated electrochemotherpy of BCC ...... 46 3.2.1. Zinc sulfate ...... 47 3.2.2. Podophyllin 25% ...... 47 3.2.3. Radiation therapy (RT) ...... 47 3.2.4. Cryosurgery...... 48 3.2.5. Heat therapy ...... 48 3.2.6. Curettage and desiccation (C&D) ...... 48 3.2.7. Modified C & D...... 48 3.2.8. Standard excision ...... 48 3.3. Special management issues...... 48 3.3.1. Mohs micrographic surgery (MMS) ...... 48 3.4. Indications for Mohs surgery forbasal cell carcinoma (Carucci and Leffell, 2008; Rowe et al., 1989; Lawrence, 1999)49 3.4.1. Incompletely excised basal cell carcinoma...... 49 3.4.2. Neurotropic basal cell carcinoma...... 49 3.4.3. Metastatic basal cell carcinoma ...... 49 3.4.4. Course and prognosis ...... 49 4. Conclusions ...... 50 References...... 50
1. Introduction stratospheric ozone layer (Oikarinen and Raitio, 2000). If left untreated, BCC will continue to invade locally and may result Basal cell carcinoma (BCC) is the most common malignant in substantial tissue damage that compromises both function tumor in humans that derives from non-keratinizing cells that and cosmetic appearance. Metastasis is an extremely rare event originate in the basal layer of the epidermis. It accounts for (Crowson, 2006; Carucci and Leffell, 2008; Miller, 1991a,b). approximately 75% of all skin cancer in the world, and 53.2% BCC is more common in elderly individuals but is becoming in Iraqi patients (Akinci et al., 2008; Al-Waiz, 1998). Generally, increasingly frequent in people younger than 50 years of age most BCC cases are sporadic, but it may also appear in genetic (Crowson, 2006). The tumor characteristically develops on disorders such as Gorlin’s syndrome and xeroderma pigmentosa sun-exposed skin of lighter-skinned individuals, with 20% (Lacour, 2002). The majority of sporadic cases are induced by occurring on the nose. Men are affected slightly more often than sunlight, specifically UVB rays (Kim et al., 2002). The incidence are women. The distribution of the lesions does not correlate rate of this disease has been estimated to have increased between well with the area of maximum exposure to UVR in that BCCs 20% and 80% worldwide over the last three decades (Mikilineni are common on the eyelids, at the inner canthus and behind the and Weinstock, 2001). The overall increase in the number of ear, but uncommon on the back of the hand and forearm. The BCC over the last decades is attributed mostly to increased palm, sole and vermilion of the lips are rarely involved (Crow- UVR exposure due to both lifestyle changes and the depleted son, 2006; Carucci and Leffell, 2008; Miller, 1991a,b). Risk fac- Basal cell carcinoma: Topical therapy versus surgical treatment 43 tors for BCC have been well characterized and include ultravio- areas of the head and neck but can occur anywhere on the body. let light (UVL) exposure, light hair and eye color, northern Features include translucency, ulceration, telangiectasia, and European ancestry, and inability to tan (Crowson, 2006). Pa- the presence of a rolled border. Characteristics may vary for dif- tients with BCC are at increased risk for melanoma but not ferent clinical sub-types, which include nodular, superficial, for other internal malignancies. Bower et al. reported that indi- morpheaform, and pigmented BCCs and Fibroepithelioma of viduals with BCC had a three folds increased risk for melanoma Pinkus (FEP) Carucci and Leffell, 2008; Miller, 1991a,b; Rich- but no increased risk for any other type of cancer (Crowson, ard et al., 2006; Habif, 2004. 2006; Carucci and Leffell, 2008; Miller, 1991a,b). The pathogenesis of BCC involves exposure to ultraviolet 2.1. Basal cell carcinoma sub-types light, particularly the ultraviolet B spectrum (290–320 nm) that induces mutations in tumor suppressor genes (Crowson, 2006; 2.1.1. Nodular basal cell carcinoma Carucci and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Is the most common clinical sub-type of BCC. It occurs most Habif, 2004). Some studies indicate that intermittent brief holiday commonly on the sun-exposed areas of the head and neck and exposures may place patients at higher risk than occupational appears as a translucent papule or nodule depending on dura- exposure (Carucci and Leffell, 2008; Miller, 1991a,b). Other fac- tion. There are usually telangiectasias and often a rolled bor- tors that appear to be involved in the pathogenesis include muta- der (Carucci and Leffell, 2008; Miller, 1991a,b; Richard tions in regulatory genes (Carucci and Leffell, 2008; Miller, et al., 2006; Habif, 2004; MacKie and Quinn, 2004). 1991a,b; Richard et al., 2006; Habif, 2004; MacKie and Quinn, 2004; McCormack et al., 1997; Kricker et al., 1995). The propen- 2.1.2. Pigmented basal cell carcinoma sity to develop multiple BCCs may be inherited and included among heritable conditions predisposing to the development of Is a sub-type of nodular BCC that exhibits increased melaniza- this epithelial cancer are nevoid basal cell carcinoma syndrome tion. It is commonly pigmented in Iraq. Pigmented BCC ap- or basal cell nevus syndrome (BCNS) (Gorlin’s syndrome), Ba- pears as a hyper pigmented, translucent papule, which may zex’s syndrome, and Rombo’s syndrome (Crowson, 2006; Caru- also be eroded. The differential diagnosis includes nodular cci and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Habif, melanoma (Carucci and Leffell, 2008; Miller, 1991a,b; Richard 2004; MacKie and Quinn, 2004; McCormack et al., 1997; Bale et al., 2006; Habif, 2004; MacKie and Quinn, 2004; McCor- et al., 1994). The role of the immune system in the pathogenesis mack et al., 1997). of skin cancer is not completely understood. Immunosuppressed patients with lymphoma or leukemia and patients who have re- 2.1.3. Superficial basal cell carcinoma ceived an organ transplant (Crowson, 2006; Carucci and Leffell, Occurs most commonly on the trunk and appears as an ery- 2008; Miller, 1991a,b; Richard et al., 2006; Habif, 2004; MacKie thematous patch, often well demarcated that resembles ecze- and Quinn, 2004; Sharquie et al., 2011; Sharquie et al., in press-a; ma. An isolated patch of ‘‘eczema’’ that does not respond to Sharquie et al., 2007) have a marked increase in the incidence of treatment should raise suspicion for superficial BCC (Carucci squamous cell carcinoma but only a slight increase in the inci- and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Habif, dence of BCC (Crowson, 2006; Carucci and Leffell, 2008; Miller, 2004; MacKie and Quinn, 2004; McCormack et al., 1997). 1991a,b; Richard et al., 2006; Habif, 2004; MacKie and Quinn, 2004; McCormack et al., 1997; Kricker et al., 1995; Bale et al., 2.1.4. Morpheaform (sclerosing) basal cell carcinoma 1994; Niazi and Lamberty, 1993; Sharquie et al., 2011; Sharquie et al., in press-a; Sharquie et al., 2007). While patients with auto- Is an aggressive growth variant of BCC with a distinct clinical immune diseases like pemphigus vulgaris have no tendency to de- and histological appearance. Lesions of morpheaform BCC velop skin malignancy(Sharquie et al., in press-b). Also, vitiligo as may have an ivory-white appearance and may resemble a scar autoimmune disease has protection against skin cancers although or a small lesion of morphea. Thus, the appearance of scar tis- lacking melanin and this is due to high P53 suppresser protein in sue in the absence of trauma or previous surgical procedure or the epidermis of patients with vitiligo. While on contrary, patients the appearance of atypical-appearing scar tissue at the site of a with albinism who are also lacking melanin have a high risk to de- previously treated skin lesion should alert the clinician to the velop skin cancers (Sharquie et al., 2011). Bastiaens et al., found possibility of morpheaform BCC and the need for biopsy that transplant recipients developed more BCCs on the trunk and (Crowson, 2006; Carucci and Leffell, 2008; Miller, 1991a,b; arms than did non-immunosuppressed patients. Patients with hu- Richard et al., 2006; Habif, 2004; MacKie and Quinn, 2004). man immunodeficiency virus infection develop BCCs at the same rate as immune-competent individuals, based on similar risk fac- 2.1.5. Fibroepithelioma of pinkus tors. Immuno-suppressed long-term alcoholics tend to develop Classically presents as a pink papule, usually on the lower infiltrative BCCs with increased frequency (Crowson, 2006; back. It may be difficult to distinguish from an acrochordon Carucci and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; or skin tags (Crowson, 2006; Carucci and Leffell, 2008; Miller, Habif, 2004; MacKie and Quinn, 2004; McCormack et al., 1997). 1991a).
2. Clinical manifestations 2.2. Biologic behavior
The presence of any friable, non-healing lesion should raise the 2.2.1. Local invasion suspicion of skin cancer. Frequently, BCC is diagnosed in pa- tients who state that the lesion bled briefly then healed com- The greatest danger of BCC results from local invasion. In pletely, only to recur. BCC usually develops on sun-exposed general, BCC is a slow-growing tumor that invades locally 44 K.E. Sharquie, A.A. Noaimi rather than metastasizes (Crowson, 2006; Carucci and Leffell, Superficial BCC characterized microscopically by buds of 2008; Miller, 1991a,b; Richard et al., 2006). The doubling time malignant cells extending into the dermis from the basal layer is estimated to be between 6 months and 1 year. If left un- of the epidermis (Carucci and Leffell, 2008; Miller, 1991a,b; treated, the tumor will progress to invade subcutaneous tissue, Richard et al., 2006; Habif, 2004; MacKie and Quinn, 2004; muscle, and even bone. Tumors along the nasofacial or retro- McCormack et al., 1997). auricular sulcus may be extensive. Morpheaform BCC consists of strands of tumor cells The lesion, which encompassed an entire side of the face, embedded within a dense fibrous stroma. Tumor cells are clo- including the maxillary sinus, apparently doubled over a 10- sely packed and, in some cases, only one cell thick. Strands of year period and grew rapidly in the 2 years before hospital tumor extend deeply into the dermis. This cancer is often larger admission. This scenario occurs in the context of physical than the clinical appearance indicates. Recurrent BCC may or psychiatric disability that interferes with judgment or ac- also demonstrate infiltrating bands and nests of cancer cells cess to health care. Lethal extension to the central nervous embedded within the fibrous stroma of scar (Crowson, 2006; system from aggressive scalp BCC has been reported (Caru- Carucci and Leffell, 2008; Miller, 1991a,b; Richard et al., cci and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; 2006; Habif, 2004; MacKie and Quinn, 2004). Habif, 2004; MacKie and Quinn, 2004; McCormack et al., In Fibroepithelioma Pinkus long strands of interwoven 1997). basiloma cells are embedded in fibrous stroma. Histologi- cally, FEP shows features of reticulated seborrheic keratoses 2.3. Perineural invasion and superficial BCC (Carucci and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Habif, 2004; MacKie and Is uncommon in BCC and occurs most often in histological Quinn, 2004). aggressive or recurrent lesions. In one series, Niazi and Lam- berty identified perineural invasion in less than 0.2% of cases 3. Treatment (Carucci and Leffell, 2008; Niazi and Lamberty, 1993). The aims of any therapy selected for the treatment of BCC are 2.4. Metastasis to ensure complete removal and destruction of the primary tumor to prevent local recurrence and the need for further Occurs only rarely, with rates varying from 0.0028% to 0.55% therapeutic intervention. The enormous differences in the nat- (Padgett and Hendrix, 2001; Efudex (Fluorouracil) Topical ural history, biology of the different subtypes of BCC and the Solution and Cream (Product Pamphlet), 2000; Reymann, large number of treatment modalities available for the removal 1979). Involvement of lymph nodes and lungs is most com- and destruction of skin tumors mean that it is difficult to draw mon. Overall, squamous differentiation was present in 15% up rigid guidelines for the management of this common cancer. of the primary or metastatic tumors from the 170 cases re- Successful management of BCC requires a clear understanding viewed. Aggressive histological characteristics, including mor- of the clinic-pathological factors that affect prognosis and a pheaform features, squamous metaplasia, and perineural good theoretical and practical knowledge of the strengths invasion, have been identified as risk factors for metastasis and limitations of many different treatments available for the (Crowson, 2006; Carucci and Leffell, 2008; Miller, 1991a,b; treatment of BCCs. From published series on treatment out- Richard et al., 2006; Habif, 2004; MacKie and Quinn, 2004; comes, it is clear that successful treatment can be achieved McCormack et al., 1997). by any one of the large range of therapies, subjected to appro- priate matching of the treatment to the tumor characteristics (Carucci and Leffell, 2008; Miller, 1991a,b; Richard et al., 2.5. Diagnosis 2006; Habif, 2004; MacKie and Quinn, 2004). In most cases, treatment selection is usually based on a clin- The diagnosis is accomplished by accurate interpretation of the ical assessment which considers a number of factors that are skin biopsy results (Carucci and Leffell, 2008; Miller, 1991a,b; known to influence tumor prognosis. These factors include tu- Richard et al., 2006; Habif, 2004; MacKie and Quinn, 2004). mor size, tumor location, clinical subtype and ability to define tumor margin. In addition to the tumor characteristics, other factors such as the patient’s age, adequacy and success of pre- 2.6. Histopathology vious treatments and coexisting medical conditions that influ- ence tumor biology or treatment tolerability need to be Varies somewhat with sub-type, but most BCCs share some considered. For reasons that are still unclear, BCC recurring common histological characteristics. The malignant basal cells following radiotherapy is particularly difficult to eradicate by have large nuclei and relatively little cytoplasm. Usually, mito- conventional surgical excision and this needs to be taken into tic figures are absent. Frequently, retraction of stroma from tu- account when selecting the most appropriate therapy (Carucci mor islands is present, creating peritumoral lacunae that are and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Mac- helpful in histopathological diagnosis. Kie and Quinn, 2004). Destructive therapies used appropri- Nodular BCC accounts for half of all BCCs and is character- ately with careful tumor selection can offer an effective ized by nodules of large basophilic cells and stroma retraction. alternative to surgical excision for small primary tumors at Pigmented BCC shows histological features similar to those non-critical sites. A number of studies have shown that of nodular BCC but with the addition of melanin (Carucci and curettage and cautery of low-risk BCCs can give cure rates Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Habif, of up to 97%. Similar high cure rates have also been reported 2004; MacKie and Quinn, 2004). for cryotherapy for low-risk BCCs. Tumor size has an impor- Basal cell carcinoma: Topical therapy versus surgical treatment 45 tant effect on prognosis for BCCs and there is good evidence superficial basal cell carcinomas (BCCs). In two double-blind, that the recurrence rate following curettage and cautery or randomized, vehicle-controlled trials, clinical and histological cryotherapy increases significantly with increasing size (Caru- clearance rates for dosing five and seven times per week were cci and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; 75% and 73%, respectively, for superficial BCC. In another Habif, 2004; MacKie and Quinn, 2004). study, 10 of 19 nodular BCCs approximately 53% cleared after In addition to recurrence risk, it is also important to bear in treatment with Imiquimod. mind that the morbidity associated with cryotherapy also in- In general, adverse side effects are limited to local skin reac- creases with increasing size. Conventional surgical excision tions. Follow-up in case series has generally been shorter than with predetermined margins based on the clinical characteris- that in retrospective studies of recurrence rates after definitive tics of the tumor is regarded by many as the most appropriate surgical management (Carucci and Leffell, 2008; Miller, therapy for most nodular BCCs and provides a specimen for 1991a,b; Richard et al., 2006; Huber et al., 2004; Vidal et al., histological examination and assessment of the lateral and 2004; Berman et al., 2003; Moore and Strober, 2008; Love deep margins. Information from studies of Mohs’ surgical et al., Dec 2009; Padgett and Hendrix, 2001). (MMS) specimens has provided useful information about the Although the exact mode of action in treating BCC is not probability of achieving complete excision in tumors with known, a few suggested mechanisms follow: lymphocytes, den- predetermined margins in different sized BCCs (Carucci and drites cells, and macrophages may be recruited into the area of Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Habif, Imiquimod application. These cells may be activated via toll- 2004; MacKie and Quinn, 2004; Rowe et al., 1989; Lawrence, like receptors 7 and 8 (both of which recognize Imiquimod 1999). So treatment of BCC could be divided into topical or as a legend) to release cytokines, particularly tumor necrosis surgical therapies. factor-alpha, interferon-alpha, and interleukin 6. Antitumor effects, such as apoptosis; may then proceed, thereby inducing tumor regression. Induction of tumor suppressor function via 3.1. Topical therapy the Notch signaling pathway in superficial BCCs has also been suggested as a mechanism of Imiquimod (Carucci and Leffell, Topical therapy could be divided into chemical and physical 2008; Miller, 1991a,b; Richard et al., 2006; Huber et al., 2004; therapies and in all varieties of topical therapies safe margin Vidal et al., 2004; Berman et al., 2003; Moore and Strober, 2–4 mm should be included by these interventions: 2008; Love et al., Dec 2009; Padgett and Hendrix, 2001). The current recommended dosing frequency for the treatment 3.1.1. Chemical therapy of superficial BCC is 5 times per week for 6 weeks, but the By using drugs, chemicals to be applied topically or injected frequency and duration should be tailored to the individual intralesionally are like Imiquimod 5% cream, 5-fluorouracil patient’s response and ability to tolerate the medication. Many 5% cream, veniblastin, bleomycin, solasodine glycoalkaoilds, application schedules have been used, ranging from 3 times per zinc sulfate, 25% podophyllin (Carucci and Leffell, 2008; Mill- week to twice daily 7 d/wk. The duration of treatment varies er, 1991a,b; Richard et al., 2006; Habif, 2004; MacKie and from 6 to 16 weeks. Superficial BCC cure rates of 70–100% Quinn, 2004; Sharquie et al., 2005; Punjabi et al., 2007; Heller, should be expected after a 6-week course of 5-times-per-week 1996; Sharquie et al., 2012; Huber et al., 2004; Vidal et al., application, as shown in studies. Topical Imiquimod has also 2004; Berman et al., 2003; Moore and Strober, 2008; Love been used to treat small, nodular BCCs in low-risk locations, et al., Dec 2009; Padgett and Hendrix, 2001; Efudex (Fluoro- but cure rates have been lower than those with superficial uracil) Topical Solution and Cream (Product Pamphlet), BCCs (Carucci and Leffell, 2008; Miller, 1991a,b; Richard 2000; Reymann, 1979; Kim et al., 2004). et al., 2006; Huber et al., 2004; Vidal et al., 2004; Berman et al., 2003; Moore and Strober, 2008; Love et al., Dec 2009; Padgett and Hendrix, 2001). 3.1.2. Physical therapy Although successful use of Imiquimod in immunosup- Using either, light therapy (PDT) or cooling lesions through cryo- pressed populations (e.g., transplantation patients) without therapy or applying heat by using electrotherapy desiccation. systemic complications has been documented, it has not been In all modalities of treatment biopsy is strongly recom- widely studied, nor have safety and efficacy been established. mended before treatment because patients may need further Imiquimod should be used cautiously in patients with autoim- therapy if any one of these topical modes fails (Carucci and mune disease. Additionally, its high cost may prohibit its use in Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Habif, some patients (Carucci and Leffell, 2008; Miller, 1991a,b; 2004; MacKie and Quinn, 2004; Foley, 2005). Richard et al., 2006; Huber et al., 2004; Vidal et al., 2004; The general indications for topical therapies are: small size, Berman et al., 2003; Moore and Strober, 2008; Love et al., multiple lesions, advancing age, contraindication for surgery, Dec 2009; Padgett and Hendrix, 2001). immunosuppressed patients with BCC like renal transplant, superficial lesions, cost benefit, surgery phobia and cosmetic 3.1.4. 5-Fluorouracil (5-FU) squeals. Topical 5-fluorouracil is sometimes used to treat small, super- ficial BCCs. It is a fluorinated pyrimidine that ‘‘blocks the 3.1.3. Imiquimod (5% cream) methylation reaction of deoxyuridylic acid to thymidylic acid. Is a Toll-like receptor 7 agonist and is believed to induce inter- In this manner fluorouracil interferes with the synthesis of feron-a and other cytokines to boost T helper 1 type immunity. deoxyribonucleic acid (DNA) and to a lesser extent inhibits Imiquimod 5% cream has been used successfully to treat the formation of ribonucleic acid (RNA). Since DNA and 46 K.E. Sharquie, A.A. Noaimi
RNA are essential for cell division and growth, the effect of 2004; Moore and Strober, 2008; Padgett and Hendrix, 2001; fluorouracil may be to create a thymine deficiency which pro- Kim et al., 2004). vokes unbalanced growth and death of the cell. In properly se- lected (e.g., thin) tumors, cure rates of approximately 80% 3.1.6. Photodynamic therapy (PDT) have been obtained. It is generally applied twice daily and Photodynamic therapy for BCCs has been used for more than must be used for at least 6 weeks for the treatment of superfi- 20 years (Carucci and Leffell, 2008; Miller, 1991a,b; Richard cial BCC (Carucci and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Moore and Strober, 2008; Padgett and Hendrix, et al., 2006; Moore and Strober, 2008; Love et al., Dec 2009; 2001; Foley, 2005). PDT is the process of using specific wave- Padgett and Hendrix, 2001; Efudex (Fluorouracil) Topical lengths of light to photoexcite porphyrins that have been ap- Solution and Cream (Product Pamphlet), 2000; Reymann, plied to neoplastic and preneoplastic cells. This increased 1979). Percutaneous absorption of 5-fluorouracil is its major energy is rapidly absorbed by adjacent tissue oxygen, causing limiting factor; it penetrates only 1 mm into the skin. New the formation of singlet oxygen radicals. These radicals rapidly vehicles that may enhance absorption of 5-fluorouracil are react with adjacent tissue and destroy it. Five aminolevulinic being investigated. One advantage of 5-fluorouracil use is that acid (ALA-PDT) is the only US Food and Drug Administra- it can act on BCCs that are not large enough to be seen with tion approved photo reactive molecule for PDT in the United the unaided eye. Therefore, it may be used in patients with ba- States, and it is only approved for actinic keratoses. It is sal cell nevus syndrome or in individuals prone to develop photoactivated with blue light for 1000 s after 1 h of incuba- many BCCs to preemptively treat subclinical tumors. Patients tion (Carucci and Leffell, 2008; Miller, 1991a,b; Richard with BCCs that are treated with 5-fluorouracil should be mon- et al., 2006; Moore and Strober, 2008; Padgett and Hendrix, itored carefully because not all tumors completely respond. 2001; Foley, 2005). Although its use is off label, PDT has been Cosmetic results tend to range from good to excellent with used for treatment and prevention of BCCs, including patients the use of 5-fluorouracil. Although it is not inexpensive, it does with immunosuppression and nevoid BCC syndrome. Shallow cost less than Imiquimod (Carucci and Leffell, 2008; Miller, tumors, such as superficial BCCs, respond most consistently. 1991a,b; Richard et al., 2006; MacKie and Quinn, 2004; Surgical excision has been shown to be significantly more effec- Moore and Strober, 2008; Love et al., Dec 2009; Padgett and tive than ALA-PDT in the treatment of nodular BCC. The Hendrix, 2001; Efudex (Fluorouracil) Topical Solution and strongest support for PDT as a modality for BCCs comes with Cream (Product Pamphlet), 2000; Reymann, 1979). data on thin lesions treated with methylaminolevulinate (used outside the United States), but at least one long-term follow- 3.1.5. Interferon alfa-2b (intron A) up trial has also shown surgical excision to be superior. Protein product manufactured with recombinant DNA technol- Marmur et al. reviewed photodynamic therapy for non-mela- ogy. Mechanism of antitumor activity not clearly understood; noma skin cancer and reported recurrence rates ranging from however, direct antiproliferative effects against malignant cells 0% to 31% for BCC. Various protocols have been followed to and modulation of host immune response may be important achieve varying levels of success––increasing the incubation (Carucci and Leffell, 2008; Miller, 1991a,b; Richard et al., time, increasing occlusion time, and using longer and/or 2006; MacKie and Quinn, 2004; Moore and Strober, 2008; deeper-penetrating wavelengths of light (e.g., red light or Padgett and Hendrix, 2001; Kim et al., 2004). Interferon alfa- pulse-dye laser). Many patients continue to prefer PDT 2b has shown some success in treating small (<1 cm), nodular, because of its short healing time, excellent cosmetic and rela- and superficial BCCs. It is administered intralesionally, 3 times tive affordability (Carucci and Leffell, 2008; Miller, 1991a,b; per week for 3 weeks. The recommended dose is 1.5 million units Richard et al., 2006; Moore and Strober, 2008; Padgett and per injection (total of 13.5 million U). In appropriate BCC tu- Hendrix, 2001; Foley, 2005). mors, cures rates of up to 80% have been obtained. Interferon has not become a mainstay in BCC treatment because of its cost, 3.2. Bleomycin-mediated electrochemotherpy of BCC the inconvenience of multiple visits, the discomfort of adminis- tration, and its adverse effects. Flu like symptoms, which are dose related, are common with the doses administered to treat It is a new technique, electroporation, enhances the antitumor BCCs. Cardiovascular, myelodepressive, and neurologic ad- effects of a variety of chemotherapeutic agents. When used in verse effects are less common with this treatment than with oth- combination with conventional chemotherapy, the procedure ers. Because interferon is an immune stimulant, it should not be is termed electro-chemotherapy. used to treat BCC in transplant recipients or in individuals with Exposure of cancerous tissues to pulses of electricity during autoimmune diseases (Carucci and Leffell, 2008; Miller, electrochemotherapy appears to increase cell membrane per- 1991a,b; Richard et al., 2006; MacKie and Quinn, 2004; meability and thus intracellular access to cytotoxic drugs. Elec- Moore and Strober, 2008; Padgett and Hendrix, 2001; Kim trical pulses were delivered to tumor nodules by means of et al., 2004). caliper electrodes after systemic doses of bleomycin were Interferon alfa-2b has been used for nodular BCC in a ran- administered. Vital signs were closely monitored during appli- domized, placebo-controlled multicenter studies (172 subjects). cation of the electrical pulses. Complete response was seen in Intralesional injections of 1.5 million U were administered two lesions. Only minimal local or systemic side effects were 3 times/wk for 3 wk yielded 86% complete-response rate; noted in response to the therapy (Carucci and Leffell, 2008; 29% for placebo. Similar study did not show efficacy for Miller, 1991a,b; Richard et al., 2006; Sharquie et al., in morpheaform or aggressive BCCs (Carucci and Leffell, 2008; press-b; Moore and Strober, 2008; Love et al., Dec 2009; Padg- Miller, 1991a,b; Richard et al., 2006; MacKie and Quinn, ett and Hendrix, 2001). Basal cell carcinoma: Topical therapy versus surgical treatment 47
3.2.1. Zinc sulfate epidermodysplasia verruciformis (EDV) and syndromes that Zinc is one of essential trace elements and zinc sulfate has been are liable for BCC to malignancies or in patients with surgery used in many medical conditions especially skin diseases as a phobia (Sharquie et al., 2007; Sharquie et al., 2008; Sharquie topical or systemic oral drug; it is used topically in treatment et al., in press-c; Sharquie et al., 2009; World Health Organiza- of severe herpes simplex infection, plane warts, melasma, tion, 2001; Al-Hamdi et al., 2007; Sharquie et al., 2006; Shar- superficial fungal infection and provides antioxidant photo quie et al., 2008). protection for the skin. Intralesional zinc sulfate is found to Most recently zinc sulfate solution 25% was reported as an be an effective therapy for cutaneous leishmaniasis, BCC, effective topical therapy in the treatment of actinic keratosis xeroderma pigmentosa (XP) and in treatment of viral warts (Sharquie et al., 2012). (Sharquie et al., 2005; Punjabi et al., 2007; Heller, 1996; Shar- quie and Al-Azzawi, 1996; Sharquie et al., 2007; Sharquie 3.2.2. Podophyllin 25% et al., 2008). A recent single blind study (Sharquie et al., 2012), using topical Through an open-label case interventional work performed 25% podophyllin resin in compound tincture of benzoin in 2003, intralesional 2% zinc sulfate solution has been used in showed 96% success rate in treatment of BCC and the details the treatment of BCC (Sharquie et al., 2005). of this study is as follow: Lesions were treated with 25% top- Eleven patients (10 males and one female) with BCC were ical podophyllin solution once weekly for 6 weeks. Follow up included in this study; they had 100 lesion/s ranging from 1 after clinical cure was done every 3 months up to 18 months to 46 per patient (one of the patients had Gorlin’s syndrome) to recording any sign and symptom of recurrence. (13.72 ± 9.18) median of 2. Their ages ranged from 46 to 70 Thirty-five patients with basal cell carcinoma completed the (61.18 ± 9.60) years, while the duration of the disease was be- study: 28 (80%) males and 7 (20%) females with males to fe- tween 7 months and 36 years (11 ± 11.35 ± 8.49) (median: 2). males ratio 4:1, their ages ranged from 30 to 87 (64.114 ± A total of 100 lesions of BCC, (48 [48%] nodular, 45 [45%] 12.68) years, and the duration of the disease ranged from superficial pigmented, 6 [6%] noduloulcerative and 1 [1%] cys- 2 months to 30 years (6.88 ± 4.83). The size of lesions ranged tic) were infiltrated with zinc sulfate solution mixed up with from 0.8 to 1.9 (1.454 ± 0.239) cm. The total podophyllin appli- 2% xylocain. The sites of lesions were 43 (43%) on the scalp, cations number ranged from 2 to 6 (4.65 ± 1.055) sessions. The 34 (34%) face, 21 (21%) cheek and 2 (2%) on the chest. The total numbers of treated lesions were 100 lesions: 64 (64%) nod- number of injections for each lesion ranged from 1 to 4 ular, 31 (31%) pigmented, 3 (3%) basosquamous, and 2 (2%) (2.06 ± 0.9661) injections. All lesions showed clinical cure: superficial. 18 (18%) lesions after first injection, 52 (52%) lesions after Ninety-six (96%) lesions in 32 patients showed complete second injection, 29 (29%) lesion after third injection, and cure with 2–6 sessions while 4 lesions in 3 patients showed one (1%) lesion after fourth injection. Local redness, swelling, partial response with 6 sessions Biopsy from 21 cured lesions and tenderness were observed in all lesions. After 2–3 days lo- in 21 patients showed complete clearness apart from one with cal necrosis with black eschar appeared in all treated lesions residual malignant cells. All the patients did not show clinical that stayed for 10–14 days and then fell down leaving atrophic recurrence, during the follow up period up to 18 months. scar. This scar gradually disappeared over time leaving a good Inflammatory reactions were noted in all treated lesions as cosmetic appearance at the end of 8 months follow up. No pa- redness, edema and juicy skin 36–72 h after topical podophyl- tient complained of any systemic side effects. Follow up for lin applications. After 3–5 days the reaction became more 8 months showed no residual malignant cells which proved exaggerated and ulceration developed, ended with crust by histopathological examination. The mechanism of action formation. cannot be speculated, although it has been reported that zinc No evidence of systemic side effects was seen and this had sulfate has local cytotoxic effects. Similarly, zinc sulfate cause been confirmed clinically and by laboratory tests during the local necrosis in the treatment of verruca vulgaris and cutane- sessions and 1 months later. Minimal or no scarring was ous leishmaniasis through intralesional injection. So the mode noticed. of action of local injection is mainly through necrosis of lesion- Topical 25% podophyllin solution is a new therapeutic al tissue. In comparison with other modes of injections like ble- modality in treatment of basal cell carcinoma which gave omycin and interferon alfa-2b, these drugs are associated with 96% cure, and it is highly recommended as alternative therapy systemic side effects like flu like illness as with interferon alfa- in all type of basal cell carcinoma, single and multiple and for 2b also they take long duration to achieve healing of lesion in all ages especially for elderly patients and those who have sur- comparison with intralesional 2% zinc sulfate solution. gery phobia. In further work, topical 15–35% zinc sulfate solution was No important side effects were noticed apart from erythema used twice daily in treatment of hundreds of BCC lesions and irritations will be considered a sign of positive reaction to and showed very high successful rate. Also, topical 15–35% the drug (Sharquie et al., 2012). zinc sulfate solution was applied on lesions in patients with XP and gave very encouraging therapeutic and prophylactic 3.2.3. Radiation therapy (RT) results (Sharquie et al., 2007; Sharquie et al., 2008; Sharquie Is effective as primary treatment for a variety of BCCs. For et al., in press-c; Sharquie et al., 2009; World Health Organiza- most BCCs, cure rates approach 90%. It is especially useful tion, 2001; Al-Hamdi et al., 2007; Sharquie et al., 2006; for patients who cannot easily tolerate surgery, such as elderly Sharquie et al., 2008). or debilitated individuals. Irradiation can also be a useful ad- Zinc sulfate solution whether through topical or intrale- junct when patients have aggressive tumors that were treated sional way is indicated for treatment of multiple lesions, in pa- surgically or when surgery has failed to clear the margins of tients that are genetically prone to malignancies like XP, the tumor. Radiation is also an excellent option in patients 48 K.E. Sharquie, A.A. Noaimi who refuse surgery because of the size of a lesion or its prox- passed over the treated area without touching the lesion until imity to vital structures (Carucci and Leffell, 2008; Miller, we notice boiling of the lesion (Sharquie personal communica- 1991a,b; Richard et al., 2006). tion, 1995). Initial cosmetic results tend to be good, and this therapy By using this maneuver we raise the cure rate to almost can be less disfiguring than surgical excision. However, long- 100% with very low recurrence rate by destroying any residual term results after several years can be deforming. Another dis- malignant cells. advantage of this technique is that surgical margins cannot be examined. Tumors recurring in previously radiated sites tend 3.2.8. Standard excision to be aggressive and extensive and difficult to treat and recon- Compared with non-excisional techniques, standard surgical struct. Radiation therapy remains an important, feasible op- excision offers the advantage of histological evaluation of the tion in selected patients with BCC (Carucci and Leffell, removed specimen. Although standard excision is appropriate 2008; Miller, 1991a,b; Richard et al., 2006; MacKie and for many BCCs, cure rates for standard excisional surgery are Quinn, 2004). inferior to those for Mohs Micrographic Surgery (MMS) in cases of primary morpheaform BCCs, recurrent BCCs, and 3.2.4. Cryosurgery tumors located in high-risk anatomic sites (Carucci and Leffell, Is another destructive modality that has been used in the treat- 2008; Miller, 1991a,b; Richard et al., 2006; MacKie and ment of BCC. Two freeze–thaw cycles with a tissue tempera- Quinn, 2004; Rowe et al., 1989; Lawrence, 1999). Wolf and ture of À50 C(À58 F) are required to destroy BCC. In Zitelli demonstrated that margins of 4 mm were adequate for addition, a margin of clinically normal tissue must be de- 95% of non-morpheaform BCCs smaller than 2 cm in stroyed to eradicate sub-clinical extension. Cryosurgery lacks diameter when treated by standard excision (Carucci and Lef- the benefit of histological confirmation of tumor removal. fell, 2008; Miller, 1991a,b; Richard et al., 2006; MacKie and Kuflik and Gage reported 99% cure rates in 628 patients Quinn, 2004; Rowe et al., 1989; Lawrence, 1999). Johnson, followed for 5 years. Possible complications of cryosurgery Tromovitch, and Swanson reported a 96.7% cure rate when include hypertrophic scarring and post-inflammatory pigmen- the excision included a 2-mm margin beyond the area defined tary changes. Another serious potential adverse outcome is the by curettage. Tumor was present in 64 of 403 curette margins obscuring of tumor recurrence by fibrous scar tissue. Any re- and in 12 of 403 excision margins. The histological sub-type cent change in a cryosurgery scar after normal healing is com- was aggressive in 11 of 12 cases with positive excision margins. pleted should raise the suspicion of recurrent BCC (Carucci Margins of 5 mm are necessary for primary morpheaform and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Mac- BCC or recurrent BCC. Excision of primary BCC should ex- Kie and Quinn, 2004). tend to fat to ensure adequate tumor removal (Carucci and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Habif, 3.2.5. Heat therapy 2004; MacKie and Quinn, 2004). By applying the heated electrocautery probe above lesions but no touch and through the irradiated infrared light exposure 3.3. Special management issues which causes heating of the tissues until boiling followed by destruction of lesion. This mode of therapy is strongly indi- 3.3.1. Mohs micrographic surgery (MMS) cated in small lesions of all types of BCC (Sharquie personal Offers superior histologic analysis of tumor margins while per- communication, 1995). mitting maximal conservation of tissue compared with stan- dard excisional surgery. Rowe, Carroll, and Day report a 3.2.6. Curettage and desiccation (C&D) recurrence rate of 1% for primary BCCs treated by MMS. Is one of the most frequently used treatment modalities for This was superior to the rate for other modalities, including BCC. The C&D is operator dependent as was shown by Kopf standard excision (10%), curettage and desiccation (C&D) et al., who identified a significant difference in cure rate be- (7.7%), Radiotherapy (RT) (8.7%) and cryotherapy (7.5%). tween patients treated by private practitioners (94.3%) and Recurrent BCCs treated by MMS reappeared at a rate of those treated by residents (81.2%). Spiller and Spiller reported 5.6%, which was again superior to the rate for other modali- a cure rate of 97% in 233 patients. Cure rate decreased with ties, including excision (17.6%), RT (9.8%), and C&D the increasing size lesion: for lesions smaller than 1.0 cm, the (40%). MMS is the treatment of choice for morpheaform, cure rate was 98.8%; for lesions between 1.0 and 2.0 cm, poorly delineated, incompletely removed, and otherwise 95.5%; and for lesions larger than 2.0 cm, 84%. Recurrences high-risk primary BCCs (Carucci and Leffell, 2008; Miller, were noted most often on the forehead, temple, ears, nose, 1991a,b; MacKie and Quinn, 2004; Sharquie et al., 2011; Rowe and shoulders. C&D is not recommended for large primary et al., 1989; Lawrence, 1999). It is the preferred treatment for BCC, morpheaform BCC, or recurrent BCC (Carucci and Lef- recurrent BCC and for any BCC that occurs at a site where tis- fell, 2008; Miller, 1991a,b; Richard et al., 2006; MacKie and sue conservation is desired. MMS is particularly useful in Quinn, 2004). treating BBCs at high-risk anatomic sites, including the embry- onic fusion planes represented by the nasofacial junction and retroauricular sulcus (Carucci and Leffell, 2008; Miller, 3.2.7. Modified C & D 1991a,b; Richard et al., 2006; Habif, 2004; MacKie and Quinn, After full curettage and desiccation, we do boiling the base and 2004; McCormack et al., 1997; Kricker et al., 1995; Bale et al., the margin of curetted and desiccated BCC through heating 1994; Niazi and Lamberty, 1993; Sharquie et al., 2011; Rowe the electrocautery probe to become red in color and then et al., 1989; Lawrence, 1999). Basal cell carcinoma: Topical therapy versus surgical treatment 49
3.4. Indications for Mohs surgery for basal cell carcinoma When perineural invasion is detected; every effort should be (Carucci and Leffell, 2008; Rowe et al., 1989; Lawrence, 1999) made to clear the tumor, preferably by MMS. Patients with gross perineural invasion manifested by neurologic symptoms 1- Location on a high-risk anatomic site including mask would benefit from preoperative magnetic resonance imaging area of face, scalp, anatomic fusion planes, periorbital to assess extent of tumor spread. Classic examples include area/eyelid. brow paralysis due to involvement of the temporal branch of 2- Tumor > 2 cm. the facial nerve and mid-face paresthesias secondary to 3- Aggressive histologic sub-type. involvement of the trigeminal nerve (Carucci and Leffell, 4- Recurrent tumor. 2008; Miller, 1991a,b; Richard et al., 2006). 5- Incompletely excised basal cell carcinoma. 6- Location on previously irradiated skin. 3.4.3. Metastatic basal cell carcinoma 7- Immunosuppression of patient after solid organ Although it is exceedingly rare, the possibility of metastatic transplantation. disease exists and may need to be addressed. If nodal disease 8- Indistinct clinical border. is suspected on surgical examination, lymph node biopsy and 9- Situation requiring conservation of normal tissue to pre- imaging studies, as well as evaluation by medical and surgical serve function and cosmetics. oncologists, are indicated. Platinum-based chemotherapy has 10- Situation requiring highest achievable probability of been used with modest results in treatment of metastatic cure to preserve function and cosmetics. BCC; however, rapid clinical response was reported using a combination of cisplatin and paclitaxel (Carucci and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; MacKie and 3.4.1. Incompletely excised basal cell carcinoma Quinn, 2004). The most widely cited article, and the one on which most Most recently FDA approved drug called Erivedge (vis- authors who advocate wait-and-see approach despite positive modegib) capsule for treatment of BCC. Erivedge is an oral tumor margins base their rationale, was published by Gooding medicine designed to selectively inhibit abnormal signaling in et al. (1965). A wait-and-see approach was taken in 66 patients the Hedgehog pathway, which is an underlying molecular dri- with positive margins and those patients were followed for at ver of BCC (Tang and Marghoob, 2011; Amin et al., 2010; least 5 years. The recurrence rate was 34.8% (a figure which Von Hoff et al., 2009; Yauch et al., 2008; Fan et al., 2004; would decrease to 19% if patients who did not complete the Dierks et al., 2007; Low and de Sauvage, 2010; McMahon 5 years of follow-up due to death or other reasons were not et al., 2003; Chen et al., 2002). excluded). Patients with clinical recurrence successfully under- The FDA approved vismodegib for the treatment of ad- went surgery or radiotherapy. With these findings, the authors vanced BCC on January 30th 2012.The indication is for concluded that, in view of the indolent nature of this tumor, BCC that has metastasized or relapsed after treatment with when faced with the presence of positive tumor margins in the surgery, or for those who are not candidates for surgery or initial excision, it is preferable to wait and see and then treat radiation. A boxed warning associated with this drug will only in patients with clinical recurrence (Gooding et al., 1965). state that use of this drug can result in embryo-fetal death A wait-and-see approach might be the most appropriate in or severe birth defects. Women need to be advised to use con- small primary basal cell carcinomas that have positive lateral traception and men need to be aware of the risk of vismode- margins, occur at sites other than the ears or the center of gib exposure through semen. In conclusion, vismodegib the face, and have a nodular or superficial histology, and in el- represents the first FDA-approved drug for use in advance derly patients with multiple complaints or a short life expec- forms of the most common skin cancer. Further clinical re- tancy. In contrast, re-excision seems to be most appropriate search will hopefully expand upon the indications for this in high risk recurrent tumors that meet one or more of the fol- Shh inhibitor and future studies result in the addition of vis- lowing criteria: tumors located on the ears or center of the modegib to the treatment armamentarium for those with face, greater than 2 cm in diameter, recurrent lesions, previ- operable BCC (Chen et al., 2002; Rudin et al., 2009; Tang, ously treated by radiotherapy, and tumors comprising 2011; Roche Media Release, 2011; NIH Hedgehog Inhibitor aggressive histological types including perineural, periadnexal, Clinical Trials Locator; FDA approves vismodegib for ada- or perivascular invasion and tumors with an infiltrative vanced basal cell carcinoma.). appearance. Positive deep margins should also be considered for aggressive treatment (Telfer et al., 1999; Sterry, 2006; 3.4.4. Course and prognosis Dandurand et al., 2006). With appropriate treatment, the prognosis for most patients Although no conclusive evidence is available, the studies with BCC is excellent. Control rates as high as 99% have been analyzed and common sense suggests that a wait-and-see ap- achieved by MMS. Although tumor control rates for primary proach in patients with aggressive tumors may be risky and tumors are high, patients must be monitored for recurrence that a flexible approach that combines monitoring, surgery, and development of new primary BCCs. The risk for develop- and radiotherapy (or other treatments) may achieve good out- ment of a second primary BCC ranges from 36% to 50%. Peri- comes in less aggressive tumors (Rı´os-Buceta, 2007). odic full-body skin examinations and counseling about sun protection are recommended for any patient with a history 3.4.2. Neurotropic basal cell carcinoma of BCC. This is especially important because patients with a Perineural invasion by BCC is a rare event (< 0.2% of cases) history of BCC are at increased risk for melanoma (Carucci Carucci and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006. and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Mac- Kie and Quinn, 2004). 50 K.E. Sharquie, A.A. Noaimi
The prognosis for patients with recurrent BCC is favorable, Gooding, C.A., White, G., Yatsuhashi, M., 1965. Significance of although recurrent tumors are more likely to appear again and marginal extension in excised basal-cell carcinoma. N. Engl. J. to behave aggressively. Patients with a history of recurrent dis- Med. 273, 923–924. ease must be monitored more frequently for the development Habif, T.P., 2004. Premalignant and malignant non-melanoma skin tumours, fourth ed.. In: Clinical Dermatology a Color Guide to of further recurrences and new primary tumors. For the rare Diagnosis and Therapy, vol. 21 Mosby-Yearbook Inc., pp. 736– patient with metastatic disease, prognosis is poor, with a mean 743. survival of 8–10 months from the time of diagnosis (Carucci Heller, R., 1996. Bleomycin medicated electrochemotherapy of basal and Leffell, 2008; Miller, 1991a,b; Richard et al., 2006; Mac- cell carcinoma. J. Am. Acad. Dermatol. 34 (1), 82–86. Kie and Quinn, 2004). Huber, A., Huber, J.D., Skinner, R.B., 2004. Topical Imiquimod treatment for nodular basal cell carcinomas: an open-label series. 4. Conclusions Dermatol. Surg. 30 (3), 429–430. Kim, M., Park, H.J., Baek, S., 2002. Mutations of the P53and PTCH gene in basal cell carcinoma: UV mutation signature and strand After extensive reviewing of all modalities of treatment in addi- bias. Dermatol. Sci. 29 (1), 1–6. tion to our experience, we can conclude that all therapies Kim, K.H., Yavel, R.M., Gross, V.L., 2004. Intralesional interferon whether topical or surgical are effective mode of treatment alpha-2b in the treatment of basal cell carcinoma and squamous and there are no absolute contraindications for any of them cell carcinoma: revisited. Dermatol. Surg. 30 (1), 116–120. and each therapy should be tailored to each patient. Kricker, A., Armstrong, B.K., English, D.R., Heenan, P.J., 1995. Does Moh’s surgery although it is good and precise type of ther- intermittent sun exposure cause basal cell carcinoma? A case– apy but unfortunately it is carried out only in few centers in the control study in Western Australia. Int. J. Cancer 60, 489–494. World and it takes long time and highly costly therapy, in Lacour, J.P., 2002. Carcinogenesis of basal cell carcinoma: genetics and molecular mechanism. Br. J. Dermatol. 146 (Suppl. 61), 17–19. addition to its psychological trauma to the patients. Lawrence, C.M., 1999. Mohs micrographic surgery for basal cell carcinoma. Clin Exp. Dermatol. 24, 130–133. References Love, W.E., Bernhard, J.D., Bordeaux, J.S., Dec 2009. Topical imiquimod or fluorouracil therapy for basal and squamous cell Akinci, M., Aslan, S., Morkoc, F., Cetin, A., 2008. Metastatic basal carcinoma: a systematic review. Arch. Dermatol. 145 (12), 1431– cell carcinoma. Acta Chir. Belg. 108 (2), 269–272. 1438. Al-Hamdi, K.I., Al-Waiz, M.M., Al-Kinani, L.C., 2007. Treatment of Low, J.A., de Sauvage, F.J., 2010. Clinical experience with Hedgehog psoriasis with zinc sulphate cream 2.5% in comparison with pathway inhibitors. J. Clin. Oncol. 28, 5321–5326. clobetasol propionate cream. Int. J. Dermatol. 6, 1531–3018. MacKie, R.M., Quinn, A.G., 2004. Non-melanoma skin cancer and Al-Waiz, M.K.E., 1998. Skin cancer in Iraq: an epidemiological study. other epidermal skin tumours, seventh ed.. In: Burns, T., Breathnach, Iraqi Med. J. 47, 1–4. S., Cox, N., Griffiths, C. (Eds.), . In: Rook’s Textbook of Amin, S.H., Tibes, R., Kim, J.E., Hybarger, C.P., 2010. Hedgehog Dermatology, vol. 36 Blackwell Publishing Company, London, p. 19. antagonist GDC-0449 is effective in the treatment of advanced McCormack, C.J., Kelly, J.W., Dorevitch, A.P., 1997. Differences in basal cell carcinoma. Laryngoscope 120, 2456–2459. age and body site distribution of the histological sub-types of basal Bale, A.E., Gailani, M.R., Leffell, D.J., 1994. Nevoid basal cell cell carcinoma. A possible indicator of differing causes. Arch. carcinoma syndrome. J. Invest. Dermatol. 103, 126S. Dermatol. 133, 593. Berman, B., Sullivan, T., De Araujo, T., 2003. Expression of Fas- McMahon, A.P., Ingham, P.W., Tabin, C.J., 2003. Developmental receptor on basal cell carcinomas after treatment with Imiquimod roles and clinical significance of hedgehog signaling. Curr. Top. 5% cream or vehicle. Br. J. Dermatol. 149 (Suppl. 66), 59–61. Dev. Biol. 53, 1–114. Carucci, J.A., Leffell, D.J., 2008. Epidermal and appendageal tumors, Mikilineni, R., Weinstock, M.A., 2001. Epidemiology of skin cancer. seventh ed.. In: Wolff, Klaus, Goldsmith, Lowell A., Katz, Stephen In: Atlas of Clinical Oncology: Skin Cancer. BC Decker, London, I., Gilchrest, Barbara A., Paller, Amy S., Leffell, David J. (Eds.), . UK, pp. 1–15. In: Fitzpatrick’s Dermatology in General Medicine, vol. 21 Miller, S.J., 1991a. Biology of basal cell carcinoma. I. J. Am. Acad. McGraw Hill Book Company, New York, pp. 1007–1015. Dermatol. 24, 1–13. Chen, J.K., Taipale, J., Cooper, M.K., Beachy, P.A., 2002. Inhibition Miller, S.J., 1991b. Biology of basal cell carcinoma. II. J. Am. Acad. of Hedgehog signaling by direct binding of cyclopamine to Dermatol. 24, 161–175. Smoothened. Genes Dev. 16, 2743–2748. Moore, M.M., Strober, B.E., 2008. Topical and intralesional cytotoxic Crowson, A.N., 2006. Basal cell carcinoma: biology, morphology and agent, seventh ed.. In: Wolff, K., Goldsmith, L.A., Katz, S.I., clinical implications. Mod. Pathol. 19 (Suppl. 2), S127. Gilchrest, B.A., Paller, A.S., Leffell, D.J. (Eds.), . In: Fitzpatrick’s Dandurand, M., Petit, T., Martel, P., Guillot, B., 2006. Management Dermatology in General Medicine, vol. 220 McGraw-Hill-Com- of basal cell carcinoma in adults clinical practice guidelines. Eur. J. pany, New York, p. 2124. Dermatol. 16, 394–401. Nelson, R. FDA approves vismodegib for adavanced basal cell Dierks, C., Grbic, J., Zirlik, K., et al., 2007. Essential role of stromally carcinoma. Available from:
Punjabi, S., Cook, L.J., Kersey, P., Marks, R., 2007. Solasodine Sharquie, K.E., Noaimi, A.A., Kadir, N.O., 2009. Topical therapy of glycoalkaloids: a novel topical therapy for basal cell carcinoma. A xeroderma pigmentosa with 2% zinc sulphate solution. Iraqi double-blind, randomized, placebo controlled, parallel group, Postgrad. Med. J. 13, 36–39. multicenter study. Int. J. Dermatol. 47 (1), 78–82. Sharquie, K.E., Al-Mushhadani, S.A., Noaimi, A.A., Abbas, M.Y., Reymann, F., 1979. Treatment of basal cell carcinoma of the skin with 2011. Acquired epidermodysplasia verruciformis in kidney trans- 5-fluorouracil ointment. Dermatologica 158 (5), 368–372. plant patients. J. Saudi Soc. Dermatol. Dermatol. Surg. 15, 53–56. Richard, B.O., William, D.J., Timothy, G.R., 2006. Andrew’s Diseases Sharquie, K.E., Noaimi, A.A.; Mohsin, S.Y., 2011. Frequency of of the Skin, Clinical Dermatology, 10th ed. WB Saunders Com- autoimmune diseases and estimation of P53 among vitiligo pany, Philadelphia, pp. 641–643. patients. Thesis for Fellowship of Iraqi Board for Medical Rı´os-Buceta, L., 2007. Management of basal cell carcinomas with Specializations in Dermatology and Venerevlogy. positive margins. Actas Dermosifiliogr. 98, 679–687. Sharquie, K.E., Noaimi, A.A., Al-Zoubaidi, M.S., 2012. Treatment of Roche Media Release, 2011. Pivotal study showed vismodegib basal cell carcinoma by topical 25% podophyllin solution. Thesis helped shrink tumours or heal lesions in people with rare form for Fellowship of Iraqi Board for Medical Specializations in of advanced skin cancer. Seventh European Association of Dermatology and Venerevlogy. Dermato-Oncology. Nantes, France. Available from: