Dermatology

Basal Cell Carcinoma

Are You Confident of the Diagnosis?

Basal cell carcinomaŠ(BCC) is the most common cancer in humans. There are nearly as many BCCs diagnosed each year as all other cancers combined. Patients often describe a slow-growing or persistent sore that will not heal or a “pimple” that persists for several months. The history frequently includes bleeding with minor trauma such as picking, shaving, washing, or drying with a towel. Most patients report a significant history of recreational or occupational sun exposure.

  • What you should be alert for in the history

In rare cases, BCC may result from a hereditary disease. If a patient presents at an early age with numerous BCCs and other characteristic findings, referral to a medical geneticist for genetic testing may be indicated to evaluate the patient for xeroderma pigmentosa, nevoidŠBCC syndrome (Gorlin syndrome), Rombo syndrome, Bazex syndrome, or other genetic disorders that predispose patients to large numbers of BCCs.

  • Characteristic findings on physical examination

On physical examination, the classic finding is an erythematous, pearly, telangiectatic papule often with a central erosion or ulcer. Approximately 80% of BCC cases are on the head and neck. It is often helpful to stretch the skin to visualize the lesion. Superficial BCCs may present as an erythematous macule. Morpheaform BCCs may present as a scar-like, hypopigmented depression (Figure 1, Figure 2, Figure 3).

Figure 1.

Some BCCs can become excoriated and irritated, making the differential diagnosis to include squamous cell carcinomas and other cutaneous cancers.(Photo courtesy of Chad Hivnor, MD)

Figure 2.

Classic appearance of BCC of pearly papule on the face.(Photo courtesy of Chad Hivnor, MD)

Figure 3.

Large (5x5 cm) superficial BCC that was treated as eczema for 5 years. (Photo courtesy of Chad Hivnor, MD)

In most cases, no other diagnostic studies are needed. Computed tomography (CT) or magnetic resonanceŠimaging may be indicated if there is suspicion for involvement of bone, parotid gland, orbit, nasal mucosa, external ear canal, or other vital structures.Š

  • Diagnosis confirmation

Other entities that may appear clinically similar to BCC include dermal nevi, sebaceous hyperplasia, lichenoid keratoses, actinic keratoses, squamous cell carcinomas (SCCs), fibrous papules, trichoepitheliomas, and occasionally amelanotic melanomas

In contrast to BCC, dermal nevi typically lack the translucency and erosion. Sebaceous hyperplasia usually has a yellowish hue and central depression without erosion. Lichenoid keratoses and actinic keratoses are usually flat-topped papules with scale and lack translucency and telangiectasia. SCCs are usually more hyperkeratotic and less translucent. Fibrous papules are characteristically white in color, dome-shaped, more uniform in shape and color, and lack translucency and erosion. Trichoepitheliomas may be clinically quite similar to BCC but are usually firm, flesh-colored, and lack erosion. Amelanotic melanomas are often mistaken for a BCC but often have focal areas of pigment.

A skin biopsy for histopathologic evaluation is necessary to make a definitive diagnosis of BCC. Most BCCs are readily identified on pathologic evaluation.ŠOccasionally, it may be difficult to distinguish BCCs on pathology from other basaloid neoplasms such as follicular and sebaceous neoplasms including benign follicular hamartomas, trichoepitheliomas, and sebaceous epitheliomas.

Who is at Risk for Developing this Disease?

Although no cancer registry formally collects information on BCC, it is estimated that 2.8 million BCCs are diagnosed annually in the United States. Approximately 3 of 10 Caucasians will develop a BCC during their lifetime. The incidence of BCC is increasing rapidly. Although BCC is most common among elderly men, gender differences have decreased over time. BCC incidence is increasing particularly rapidly among young women. This is presumably due to lifestyle factors leading to more sun exposure among women.

BCCs occur most commonly on the head and neck; however, approximately 20% of BCCs occur at non-sun-exposed sites. Although BCCs rarely metastasize or cause death, they can cause significant morbidity, particularly if they are not diagnosed and treated appropriately. If untreated, a BCC will continue to grow and invade surrounding tissues including subcutaneous fat, nerves, muscle, cartilage, bone, and other structures, which can lead to significant tissue destruction and disfigurement.

The primary risk factors for BCC are fair skin (Fitzpatrick skin types I and II), extensive intermittent or cumulative lifetime UV exposure, and history of prior non-melanoma skin cancer. Other independent risk factors include red or blond hair, light eye color, and sensitivity to UV radiation. The major risk factor for development of BCC is a significant history of recreational or occupational exposure to UV radiation, including both sun exposure and tanning beds.

A widely disseminated estimate that 80% of a person's lifetime sun exposure occurs by age 18 has proven to be inaccurate. In fact, only 23% of lifetime sun exposure occurs by age 18, and mostŠlifetime sun exposure occurs as an adult. Patients with a history of prior non-melanoma skin cancer have a 40% to 50% risk of developing a BCC in the next 5 years.

A history of exposure to other forms of radiation including X-ray and Grenz-ray may also increase risk of BCC. Other risk factors include chronic arsenic exposure, treatment with oral methoxsalen (psoralen), and immunosuppression, which is most commonly seen among transplant patients.

What is the Cause of the Disease?

  • Etiology

  • Pathophysiology

Most BCCs are sporadic. BCCs typically arise from the epidermis and occasionally from the hair follicle outer root sheath. BCCs are thought to arise from pluripotent cells in the basal layer of the epidermis. Development of BCCs can result from mutations in a variety of genes. Some cases of BCC appear to result from UV-induced mutations in the p53 tumor suppressor gene that appear to prevent apoptosis of UV-damaged cells.

UV exposure causes DNA damage in the form of thymine dimers and suppresses local immune response and immune surveillance. Innate DNA repair mechanisms are unable to correct all UV-induced DNA damage; therefore, cumulative UV-induced DNA damage leads to mutations.

Mutations in the sonic hedgehog (SHH) signaling pathway appear to play an important role in BCC development.ŠThe SHH pathwayŠis a critical regulator of cell growth and differentiation during embryonic development. In adult tissues, the SHH pathway is mostly inactive;Šactivation of the pathway,Šhowever,Šcan lead to a variety of tumors, including BCC. Most BCCs have abnormalities in SHH genes. Most BCCs have loss-of-function mutations that inactivate patched homologue 1 (PTCH1), a transmembrane receptor that mediates inhibition of smoothened homologue (SMO) signaling. SMO is a protein that transmits SHH signaling to downstream genes. Less commonly, BCC may have gain-of-function mutations that constitutively activate SMO.

The SHH pathway also plays an important role in the nevoid BCC syndrome (Gorlin syndrome). Mutations in PTCH1 or SMO appear to cause tumor formation via constitutive activation of the signaling pathway.

TheŠSHH gene encodes a protein that initiates cell proliferation. SHH binds to PTCH, which then releases and activates SMO. When SHH is absent, PTCH inhibits SMO. Mutations in the PTCH gene prevent it from binding to SMO, as in the presence of SHH. Unbound SMO is constitutively activated, which allows continuous SHH signaling. Mutations in SMO may also allow unregulated signaling. Loss of inhibition of SMO and resulting activation of the SHH pathway results in increased expression of the GLI family of transcription factors, effectors of SHH signaling that promote cell proliferation and tumor growth.

Increasing understanding of the SHH pathway has led to development of targeted therapies, including Vismodegib. Other drugs that affect components of the SHH pathway include statins, vitamin D3, and rapamycin; however, these have not yet been studied in human clinical trials for treatment of BCC.Š

Systemic Implications and Complications

BCCs rarely metastasize, with estimates ranging from 0.0028% to 0.1%, however, a small number of patients may develop inoperable, life-threatening, locally advanced or metastatic tumors. This most commonly occurs with large (>10cm), ulcerated, neglected tumors. The prognosis for such tumors is poor, and the median survival time for patients with metastatic BCC is only 8 months.Š

In rare cases, BCCs can be associated with systemic disorders including xeroderma pigmentosa, nevoid basal cell carcinoma syndrome (Gorlin Syndrome), Rombo syndrome, and Bazex syndrome. In such cases, referral to a medical geneticist is indicated.

Patients with xeroderma pigmentosa,Šan autosomal recessive disorder,Šare highly sensitive to UV radiation owing to inability to repair UV-induced DNA damage. Patients rapidly develop signs of UV damage in sun-exposed areas including sunburns and lentigines and develop skin cancers at an early age including BCC, SCC, and malignant melanoma. Patients may also develop ocular abnormalities including corneal opacities leading to possible blindness as well as neurologic deficits.

Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is an autosomal dominant disorder in which patients develop multiple BCCs, usually at an early age. The syndrome results from a mutation in the PTCH gene, which is part of theŠSHH signaling pathway. Patients are at risk for other tumors as well including medulloblastoma, meningioma, fetal rhabdomyoma, and ameloblastoma. Other common findings include odontogenic cysts, palmar or plantar pits, calcification of the falx cerebri, and rib abnormalities.

Rombo syndrome is an autosomal dominant disorder in which patients develop BCCs and trichoepitheliomas, which may appear similar on physical examination. Other findings of the syndrome include vermiculate atrophoderma, milia, hypertrichosis, and peripheral vasodilatation.

Bazex syndrome, also known as Bazex-Dupre-Christol syndrome, is an X-linked dominant disorder characterized by multiple BCCs. Other findings include follicular atrophoderma, most commonly seen on the dorsal hands, congenital hypotrichosis, and focal anhidrosis.

Treatment Options

Surgical Treatment

Mohs micrographic surgery

Excision with greater than 4mm margins

Electrodessication and curettage

Medical Treatment (Topical/Intralesional)

Imiquimod

5-FU (topical)

5-FU (intralesional)

IFN-alpha-2a or 2b (intralesional)

Physical Modalities

Cryosurgery

Photodynamic therapy

Radiation therapy

Medical Treatments (Systemic)

Vismodegib

Optimal Therapeutic Approach for this Disease

A wide variety of treatments are available for BCC. Surgical modalities, including electrodessication and curettage, excision, and Mohs micrographic surgery, are the first-line, definitive treatment for BCC. Medical treatments, such as imiquimod and fluorouracil, and physical modalities, including cryosurgery, photodynamic therapy, and radiation may be used in certain settings. Vismodegib, a targeted, systemic therapy, is now available for metastatic and inoperable BCCs. Selection of the most appropriate treatment requires consideration of many tumor and patient factors including the anatomic location, tumor size, histologic subtype, previous treatments, patient age, patient preference, and the patient's ability to tolerate surgery, among other factors. Although optimizing cosmetic outcome is important, the first priority must be complete removal or destruction of the tumor whenever possible.

Surgical Treatments

Surgical treatments generally have higher cure rates for BCC than medical therapies. Mohs surgery offers the highest long-term cure rate of any treatment modality; however, primary nodular BCCs under 2cm in diameter on the trunk and extremities are most commonly treated by electrodessication and curettage or excision.

Mohs micrographic surgery

Mohs micrographic surgery is the only technique that allows evaluation of the entire peripheral and deep surgical margin.ŠAlso,ŠMohs surgery offers the highest long-term cure rate of any treatment for BCC. Cure rates for primary BCC are 98% to 99%, and 94% to 96% for recurrent BCC. Mohs surgery allows evaluation of 100% of the tissue margin whereas traditional excision uses standard vertical “bread-loaf” sectioning, which allows evaluation of less than 1% of margin. Therefore, Mohs surgery allows smaller margins to be used than traditional excision and offers the highest cure rate while remaining tissue sparing.

Mohs surgery involves removal of the clinically apparent tumor and approximately 2mm of normal-appearing skin around the lesion. The tissue is mapped, sectioned, and inked. Frozen sections are prepared in an in-office laboratory that allows examination of the entire peripheral and deep margin. The Mohs surgeon evaluates the frozen section slides microscopically and maps the tissue. If residual tumor is present at any margin, further surgery can be performed only on the area where tumor is still present to conserve adjacent, normal tissue.

Mohs surgery is preferred for most tumors on the face as well as for high-risk tumors including ill-defined tumors, aggressive histologic subtypes, recurrent tumors, tumors greater than 2cm in diameter, and tumors in immunocompromised patients. Mohs surgery is more time and labor intensive than other techniques;ŠMohs surgery, however, is similar in cost to excision with permanent sections and is less costly than excision with frozen section pathology.

Surgical excision

Surgical excision with at least 4mm margins offers cure rates close to 95% for small (<1cm), primary, nodular BCC and allows pathologic evaluation to confirm clear margins. Excision,Šhowever,Šis dependent on the surgeon's experience and skill and is more labor and time intensive than electrodessication and curettage (ED&C). Excision may be less desirable for small tumors in low-risk locations or for elderly or disabled patients who may have difficulty tolerating a longer surgical procedure.

Electrodessication and curettage

ED&CŠis an efficient treatment and offers an acceptable cure rate of 90% or higher for low-risk tumors including superficial BCC and nodular BCC less than 2cm on the trunk and extremities.ŠA recent retrospective study showed that low-risk BCCs treated by curettage alone achieved similarŠ5-year cure rates toŠtraditional ED&C.

ED&C is generally the least expensive treatment option for BCC.ŠIt is,Šhowever,Šsomewhat operator-dependent, is a “blind” technique, and does not allow pathologic evaluation of tissue to confirm clear margins. ED&C may produce cosmetically acceptable scars but often results in hypopigmented, atrophic or hypertrophic scars that are less aesthetic than the fine linear scars resulting from excision by a dermatologic surgeon. The technique depends on the contrast between friable tumor tissue and firm, normal dermis; therefore, it is inadvisable for tumors invading into subcutaneous fat, recurrent tumors, or aggressive BCC subtypes including morpheaform, infiltrating, and micronodular tumors.

Medical Treatments (Topical/Intralesional)

Topical medical treatments for BCC include topical chemotherapy agents and immune-modulating agents. In general, such treatments are best reserved for small, superficial BCC in low-risk locations, such as the trunk and extremities. Both topical imiquimod and topical fluorouracil are FDA-approved for treatment of superficial BCCs less than 2 cm in diameter.

Imiquimod

Imiquimod, applied five times weekly, has achieved cure rates of approximately 80% for superficial BCC in studies. Imiquimod, available as a 5% or 3.75% cream,Šstimulates a local immune response to the tumor via activation of Toll-like receptors 7 and 8. Imiquimod appears to recruit lymphocytes, dendritic cells, and macrophages to the local area. Imiquimod stimulates prominent cytokine release, mediated predominantly by interferon, and leads to apoptosis and tumor regression.

The most common imiquimod treatment regimen is once-daily application on weekdays (5 times weekly) for 6 weeks. Treatment,Šhowever,Šshould be continued until clinical clearance of the tumor is achieved or an alternate treatment is selected. In addition, some patients may not tolerate 5 times weekly application, and less frequent application over a longer period is sometimes necessary. In some cases, topical imiquimod has been used to treat small, nodular BCCs in low-risk locations, but cure rates are lower than for superficial BCCs.

Adverse effects may include erythema, stinging, burning, pruritus, ulceration, dyspigmentation, and scarring as well as occasional systemic flu-like symptoms. Care should be taken if patients note no adverse effects as lack of erythema and irritation. This may indicate lack of efficacy in a subset of patients.Š

Imiquimod should be used with caution in patients with autoimmune diseases, such as lupus, and those who are immunosuppressed, such as transplant and HIV patients. Flare of autoimmune disease, particularly systemic and subacute cutaneous lupus, is possible with imiquimod use. Imiquimod should be considered in such patients only if other treatment options have failed or are impractical. Patients should be monitored closely for potential autoimmune disease flares.

The cost of treatment with imiquimod, including medication and office visits, is similar to the cost of office-based surgical excision and repair.

Topical 5-fluorouraci

Topical 5-fluorouracil (5-FU) has demonstrated cure rates of 90% for superficial BCC. 5-FU interferes with DNA and RNA synthesis by blocking the methylation reaction of deoxyuridylic acid to thymidylic acid, which impedes cell growth and division and leads to tumor cell apoptosis. Topical 5-FU 5% cream is typically applied twice daily for 6 weeks. Both topical 5-FU and imiquimod pose a risk of incomplete treatment. A BCC may appear to be clear clinically, yet pathologic evaluation may showŠresidual areas of tumor that are not clinically apparent.

5-FU is slightly less expensive than imiquimod. Adverse effects may include erythema, stinging, burning, pruritus, and hypopigmentation.

In rare cases of patients prone to numerous BCCs, such as those with Gorlin syndrome, topical imiquimod and 5-FU may be used for field treatment of high-risk areas to reduce the development of additional BCCs. In theory, these agents can treat early, subclinical BCCs that are not yet clinically evident.

Intralesional 5-fluorouracil

Intralesional 5-FU has demonstrated cure rates for BCC of more than 80% in some studies. Intralesional 5-FU is typically administered in doses of 50mg once or twice weekly for 3 to 5 weeks. Intralesional 5-FU is associated with local reactions including pain, necrosis, and ulceration.

Intralesional interferon alfa-2

Intralesional Interferon alfa-2a and alfa-2b have demonstrated cure rates of more than 70% for small nodular BCCs and superficial BCCs. Both agents are typically administered as 1.5mU intralesional injections, 3 times per week for 3 to 5 weeks.

In general, intralesional interferons are associated with flu-like symptoms, including fever, chills, malaise, fatigue, myalgia, arthralgia, and headache. Other disadvantages of intralesional interferon include local pain, patient inconvenience, and cost. Intralesional interferon is contraindicated in patients with autoimmune disease or a history of organ transplant. Rarely, laboratory abnormalities have been noted including transient leukopenia, neutropenia, or thrombocytopenia and transient increased liver enzymes.

Physical Modalities

Physical modalities including photodynamic therapy, cryosurgery, and radiation therapy may be effective for BCC in certain settings. Such modalitiesŠare less invasive than surgery but offer no pathologic evaluation to confirm clear margins.

Cryosurgery

Cryosurgery is less commonly used than other modalities but can be employed for low-risk BCC and offers cure rates of 90% or higher. Cryosurgery is an efficient treatment but is operator-dependent. Some degree of pain or discomfort and postoperative swelling is expected owing to the freeze-thaw cycle and necrosis of tumor tissue.

Cryosurgery may produce good cosmetic results, particularly in fair-skinned patients, butŠhypopigmentation is common and scarring may be less predictable than with other treatments. The best candidates for cryosurgery are patients with low-risk lesions, fair skin (Fitzpatrick Type I), and those who are unable or unwilling to tolerate a more invasive surgical procedure.

Photodynamic therapy

Photodynamic therapy (PDT) is a newer modality in which a photosensitizing porphyrin is applied to tumor tissue in the physician's office. When this porphyrin is activated by specific wavelengths of light, toxic oxygen-free radicals are generated and selectively destroy tumor tissue while causing minimal damage to surrounding normal skin. PDT cure rates for BCC in studies range from 70% to 80%.

5-Aminolevulinic acid (ALA) and methyl aminolevulinate (MAL) are the only PDT agents that are FDA-approved in the United States. Treatment of BCC is considered off-label since PDT is FDA-approved only for treatment of actinic keratoses. As with other nonsurgical modalities, superficial BCCs respond better to PDT treatment than deeper tumors or more aggressive histologic subtypes. PDT is usually well tolerated and provides excellent cosmetic results;Šsurgical excision,Šhowever,Šhas significantly higher cure rates for nodular BCC than ALA-PDT.

For ALA-PDT, the traditional treatment regimen is 1 hour of incubation followed by blue-light photoactivation for 1000 seconds (16 minutes, 40 seconds). Various PDT treatment regimens have been employed using various light sources and lasers. Laser light (such as pulse-dye laser) may be more effective for small lesions, whereas non-laser light sources (such as red light or blue light) are preferable for field treatment of larger cutaneous areas. In addition, non-laser polychromatic light may be preferable when using different photosensitizers. Treatment regimens may also vary the porphyrin incubation time and occlusion time.

MAL-PDT is FDA-approved for the treatment of actinic keratosis only. In Europe, MAL-PDT has received approval for treatment of superficial BCC and appears to be more effective than ALA-PDT. MAL-PDT has achieved 3-month complete response rates of 85% to 93% for superficial BCC and 75% to 82% for nodular BCC. Porfimer, which is administered intravenously, can cause generalized photosensitivity that may last for several months. Other PDT agents remain under investigation.

Patients must be instructed to avoid UV exposure following PDT because such exposure may lead to erythema and rapid development of sunburns. Patients may be photosensitive for up to 48 hours. PDT has also been used as field treatment for BCC patients who are immunosuppressed and those with nevoid BCC syndrome.

Radiation Therapy

Radiation therapy (RT) can offer cure rates of approximately 90% for primary BCCs. This is lower than cure rates obtained with treatment by Mohs micrographic surgery or excision. RT may be useful for elderly or debilitated patients who cannot tolerate surgery or for rare inoperable tumors. Although more common forŠSCCŠthan BCC, postoperative radiation is sometimes used if surgery has failed to achieve clear margins.

Disadvantages of RT include high cost, patient inconvenience, higher rate of recurrence, and adverse effects. Full radiation treatment typically requires 15 to 30 treatment sessions over 2 to 6 weeks. Higher numbers of treatment sessions at lower radiation dose fractions generally provide better cosmesis but involve greater patient inconvenience and higher cost.

Following radiation therapy, initial cosmetic results may be good to excellent; however, long-term cosmetic results tend to be suboptimal. In a large retrospective review, the proportion of BCC sites treated by RT with good or excellent long-term cosmetic outcomes was only 63%, which was significantly lower than ED&C or surgical excision. Recurrent BCC in previously irradiated areas are often very aggressive and difficult to treat and are best treated with Mohs micrographc surgery. Reconstruction options are also limited in irradiated skin due to fibrosis and compromised vasculature.

Radiation oncologists typically treat BCC with superficial/orthovoltage x-ray radiation or electron beam radiation (EBR). Superficial X-rays have a useful depth ofŠ5mm or less and are best suited for superficial skin cancers. Electron beam radiation is more commonly available and may be used for superficial tumors with careful treatment planning. National Comprehensive Cancer Network (NCCN) guidelines recommend 5mm to 10mm RT margins for BCC less than 2cm and 15mm to 20mm margins for tumors greater than 2cm. An additional 5mm margin is often added for poorly defined lesions; therefore, irradiated areas can be significantly larger than the clinical tumor.

Early RT adverse effects may include redness, tenderness, warmth, xerosis, pruritus, peeling, oozing, and ulceration. Late adverse effects may include skin atrophy, scarring, telangiectasia, hyperpigmentation, alopecia, non-healing ulcers, and subsequent development of skin cancers in the treated area. Mucosal surfaces tend to tolerate RT well, whereas areas subjected to frequent trauma, such as the hands and feet, are less well suited to RT.

Medical Treatments (Systemic)

VismodegibVismodegib is a small-molecule inhibitor of smoothened homologue (SMO), part of the hedgehog signaling pathway. This first-in-class molecularly-targeted agent was approved by the FDA on January 30, 2012 for the treatment of adults with metastatic or locally advanced BCC that has recurred following surgery or who are not candidates for surgery or radiation. Additionally, studies have shown a significant reduction in number of new BCCs in patients with basal cell nevus syndrome, however its long-term use is limited by its toxicity profile. Dosing for vismodegib is 150mg daily until tumor progression, intolerable toxicity, or intolerable adverse effects. Studies have shown response rates ranging between 30 to 60% with lower overall response rates and greater proportion of partial response rates in patients with metastatic disease compared to those with locally advanced disease. Median duration of response was 7.6 months for patients with metastatic disease and 9.5 months for those with locally advanced disease. Patients who respond to vismodegib must remain on the medication in order to prevent recurrence. A subset of patients have BCCs with primary resistance to vismodegib. Another subset of patients who initially respond develop secondary clinical resistance. These clinical non-responders are due to mutations in Smo which prevent inhibition by vismodegib, alternative mutations downstream of Smo signaling, and baseline molecular heterogeneity in tumor cells. Essentially all patients experience treatment-related adverse events, with the most common including muscle spasms (80%), alopecia (83%), and dysgeusia (70%). Moderate to severe-grade adverse events occurred in approximately 50% of patients. Serious adverse events occurred in 22-32% of patients. Due to its toxicity profile which may limit its long-term use, further research on vismodegib as a neoadjuvant therapy are currently under investigation. Other systemic treatments Numerous molecularly-targeted compounds are currently under investigation for the treatment of BCCs. Sonidegib, a second Smo inhibitor, was recently approved by the FDA on July 24, 2015 for the treatment of locally advanced BCCs that have recurred following surgery or radiation and for those patients who are not candidates for surgery or radiation. Other hedgehog pathway inhibitors include itraconazole and arsenic trioxide (ATO). Itraconazole, a common and generally well-tolerated antifungal agent, inhibits Smo at a site distinct from vismodegib. While monotherapy leaves significant residual hedgehog pathway activity, preliminary studies suggest a synergistic effect when combined with vismodegib as well as an inhibitory activity on vismodegib-resistant Smo mutations. ATO, which inhibits the hedgehog signaling pathway downstream of Smo, similarly showed potency in tumors with vismodegib-resistant Smo mutations and a synergistic activity when combined with itraconazole. Clinical trials for both itraconazole and ATO are currently underway. In instances of metastatic or inoperably large locally advanced BCCs, case reports also indicate response to combination systemic chemotherapy regimens, particularly cisplatin and doxorubicin and paclitaxel-containing regimens.ŠIn these cases it may be necessary to consider consultation with an oncologist for systemic chemotherapy orŠenrollment in a clinical trial.Š

Patient Management

Most dermatologists recommend follow-up consisting of complete skin examinations at least every 6 toŠ12 months. More frequent follow-up is often recommended if patients have developed multiple tumors in a short timeŠor continue to develop new, suspicious lesions at subsequent visits.

In high-risk patients such as transplant patients on high-dose immunosuppressant medications and patients with genetic skin cancer syndromes, follow-up everyŠ3 months or sooner may be indicated.ŠThe standard recommendation for following immunosuppressed patients, such as heart transplant patients,Šusually depends on the degree of immunosuppression and skin cancer history including the numberŠof prior skin cancers, how rapidly they developed, and how many new skin cancers the patient has developed over the past 1 to 2 years.ŠŠ

Patients with a history of prior BCC are at risk both for recurrence and development of new, unrelated tumors. Compared with the general population, individuals with a prior history of BCC have a 30% greater risk of developing another BCC unrelated to the original tumor. All previous BCC sites should be monitored for signs of recurrence. Worrisome signs and symptoms include an erythematous macule, papule, or erosion within or adjacent to the site of prior treatment or patient reports of bleeding.

Patients should be counseled regarding UV avoidance and protection. Patients should be encouraged to use broad-spectrum sunscreens with sun protection factor of 30 or higher with reapplication every 2 hours, wear a broad-brimmed hat during outdoor activities, andŠengage in outdoor activities before 10ŠAM and after 4 PM. Even among older patients, UV avoidance and protection appears to decrease the risk of developing additional non-melanoma skin cancers.

Unusual Clinical Scenarios to Consider in Patient Management

In rare cases, neglected or multiply-recurrent BCCs on the face, particularly the nose or ear, may lead to surgical defects that cannot be reconstructed. This may occur when a large or aggressive tumor has widely infiltrated cartilage of the nose or ear. When such an advanced tumor requires removal of the majority of the underlying nasal or auricular structure, prostheses may offer more acceptable aesthetic results, superior patient acceptance, and less patient morbidity than extensive reconstructive surgery.

Other scenarios when prostheses may be considered include complex defects with a compromised local blood supply, such as prior sites of irradiation. In some cases, a combination of surgical reconstruction and prosthetic devices may be used. Silicone prostheses offer similar surface texture and hardness to human skin and are used most commonly in the United States.

The lip is another cosmetically sensitive location where BCCs can arise. In contrast to squamous cell carcinoma, they more commonly appear on the upper lip. Lip BCCs are also more common in women than in men. ŠMohs surgery remains an excellent option for BCCs on the lip.Š

What is the Evidence?

Dawn, A, Lawrence, N. "Significant difference in nonmelanoma skin cancers of the upper and lower lip". Dermatol Surg. vol. 39. 2013. pp. 1252-7.

(Review of all nonmelanoma skin cancers of the lip treated at a single practice over a 5-year period.)

Iwasaki, JK, Srivastava, D, Moy, RL, Lin, HJ, Kouba, DJ. "The molecular genetics underlying basal cell carcinoma pathogenesis and links to targeted therapeutics". J Am Acad Dermatol. vol. 66. 2012. pp. e167-78.

(Excellent recent review of the role of the SSH signaling pathway in the pathogenesis of BCC and novel targeted therapies.)

Kim, J, Aftab, BT, Tang, JY, Kim, D, Lee, AH, Rezaee, M. "Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists". Cancer Cell. vol. 23(1). 2013 Jan 14. pp. 23-34.

(An excellent basic/translational science article which reviews the biology of acquired resistance to vismodegib and demonstrates in vitro and in vivo efficacy of itraconazole and ATO as alternative hedgehog pathway inhibitors.) Š

Love, WE, Bernhard, JD, Bordeaux, JS. "Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review". Arch Dermatol. vol. 145. 2009. pp. 1431-8.

(Comprehensive, systematic review of clearance rates and adverse effects of topical imiquimod and 5-FU for BCC.)

Micali, G, Lacarrubba, F, Nasca, MR, Ferraro, S, Schwartz, RA. "Topical pharmacotherapy for skin cancer: Part II". Clinical applications. J Am Acad Dermatol. vol. 70. 2014. pp. 979.e1-12.

(Evidence-based analysis of topical treatments for skin cancer.)

Rubin, AI, Chen, EH, Ratner, D. "Basal-cell carcinoma". N Engl J Med. vol. 353. 2005. pp. 2262-9.

(Excellent review of BCC epidemiology, pathophysiology, and treatment options. Excellent pathogenesis diagram.)

Sekulic, A, Migden, MR, Lewis, K, Hainsworth, JD, Solomon, JA, Yoo, S. "ERIVANCE BCC Investigators. Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-momnth update of efficacy and safety of vismodegib in advanced BCC". J Am Acad Dermatol. vol. 72(6). 2015 Jun. pp. 1021-6.

(Follow-up of patients enrolled in a pivotal phase-II multicenter clinical trial of vismodegib for advanced BCCs.)

Silverman, MK, Kopf, AW, Grin, CM, Bart, RS, Levenstein, MJ. "Recurrence rates of treated basal cell carcinomas. Part 2: Curettage-electrodessication". J Dermatol Surg Oncol. vol. 17. 1991. pp. 720-6.

(Retrospective study analyzing recurrence rates for primary BCCs treated by ED&C at a single center over a 27-year period.)

Silverman, MK, Kopf, AW, Bart, RS, Grin, CM, Levenstein, MS. "Recurrence rates of treated basal cell carcinomas. Part 3: Surgical excision". J Dermatol Surg Oncol. vol. 18. 1992. pp. 471-6.

(Retrospective study analyzing recurrence rates for primary BCCs treated by surgical excision at a single center over a 27-year period.)

Sobanko, JF, Okman, J, Miller, C. "Vismodegib: A Hedgehog Pathway Inhibitor for Locally Advanced and Metastatic Basal Cell Carcinomas". J Drugs Dermatol. vol. 12. 2013. pp. s154-5.

(Review of mechanism of action and clinical trial data for Vismodegib.)

Ventarola, DJ, Silverstein, DI. "Vismodegib-associated hepatotoxicity: A potential side effect detected in postmarketing surveillance". J Am Acad Dermatol. vol. 71. 2014. pp. 397-398.

(While hepatotoxicity may occur in patients on vismodegib, it remains to be determined if this is a true association.)

Telfer, NR, Colver, GB, Morton, CA. "Guidelines for the management of basal cell carcinoma". Br J Dermatol. vol. 159. 2008. pp. 35-48.

(British evidence-based guidelines for the management of BCC developed by the British Association of Dermatologists.)

Tierney, EP, Hanke, CW. "Cost effectiveness of Mohs micrographic surgery: review of the literature". J Drugs Dermatol. vol. 8. 2009. pp. 914-22.

(Review and analysis of recent studies comparing the cost-effectiveness of Mohs surgery with other treatment modalities for non-melanoma skin cancer.)
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