Clinical Reference / Therapeutic Strategies / Basal Cell Carcinoma

Basal Cell Carcinoma


Key Points

  • Basal cell carcinoma is (BCC) an extremely common skin cancer that typically presents late in life as a slow growing pearly papule with central ulceration on sun exposed areas. Other subtypes of BCC differ in their presentation.
  • Accurate and timely diagnosis is essential to guide the appropriate management of BCC, and a skin biopsy is recommended for diagnosis and to help guide treatment. When let untreated BCC are locally destructive but rarely metastasize.
  • Surgical excision is almost always the first-line treatment for BCC. Mohs micrographic surgery is a tissue-sparing surgical excision technique that may be used to remove lesions on the face or other body sites where wide excision is not feasible
  • Basal cell nevus syndrome (Gorlin syndrome) is a rare autosomal dominant genetic disorder characterized by frequent BCC, and should be suspected in any child presenting with BCC. Treatment with radiation is contraindicated in this population.

Introduction

Epidemiology

BCC is the most common cancer in humans. Men have higher rates than women (~2:1 men:women), and the median age at diagnosis is 68 years. Risk factors for the development of BCCs include exposure to UV light, arsenic and/or radiation, immunosuppression, older age, fair skin, male gender, and previous non melanoma skin cancers (NMSC).

Patients who are immunocompromised (HIV/AIDS, solid organ transplant, or bone marrow transplant patients; patients with lymphoma and leukemia; or  iatrogenically immunosuppressed patients) have an increased risk of BCC. The incidence of BCC among patients who have had organ transplants is approximately 5- to 10-fold higher than in the general population.

Pathophysiology

BCC is a malignant growth of the basal keratinocytes that is locally invasive but that rarely metastasizes.

Ultraviolet (UV) light plays a significant role in the pathogenesis of NMSC, including BCC. Unlike actinic keratoses that transform into squamous cell carcinoma (SCC), there is no clinical precursor lesion that leads to BCC.

On a molecular level, mutations in the p53 pathway have been implicated in SCC and BCC, whereas mutations in the hedgehog signaling pathway can cause BCCs. Mutations in this pathway, specifically the PTCH gene, are the most common genetic alteration in BCC.

Clinical Presentation

BCC typically presents on sun-exposed areas as a pearly papule, plaque, or nodule, sometimes with exaggerated telangiectasias or central ulceration. In general, BCCs are relatively slow-growing tumors and may develop over months to years and invade locally rather than metastasize. If left untreated, the tumor will progress to invade the subcutaneous tissue, muscle, or even bone. Perineural invasion occurs most often in aggressive or recurrent lesions. Even with very advanced lesions, metastatic disease is uncommon.

Several forms of BCC exist, including nodular (most common), superficial (erythematous, hyperkeratotic plaques), pigmented, and morpheaform (scar-like in appearance). The morpheaform type tends to behave more aggressively, with extensive local destruction. There are additional forms of BCC that have distinct histopathology, including infiltrative, micronodular, fibroepithelial, and infundibulocystic variants; however, they are less readily identified based on clinical features. Infiltrative and micronodular variants typically exhibit more locally invasive behavior than the common nodular and superficial types.

Basal Cell Nevus Syndrome (Gorlin syndrome)

Basal cell nevus syndrome (also known as Gorlin syndrome) is a rare, autosomal dominant genetic condition that is characterized by early onset BCCs. Patients harbor loss of function mutations in PTCH1 (which normally acts as a negative regulator of hedgehog signaling pathway) leading to increased hedgehog signaling, a known driver for BCC. Patients typically present in childhood and may develop hundreds of BCCs over a lifetime, varying in size from a pinpoint to > 5 cm. Associated findings may include include keratocystic odontogenic tumors,  palmar or plantar pits, macrocephaly, and skeletal deformities such as bifid ribs, teeth/jaw abnormalities (cysts), and, rarely, the development of tumors in other organs in addition to skin.

Significant cosmetic disfigurement may result from skin cancers and their multiple treatments, and frequent clinical evaluation is necessary for close monitoring for tumor recurrence and development of new lesions.

Other genetic syndromes that are characterized by multiple BCCs include Bazex syndrome, Rombo syndrome, Brooke-Spiegler syndrome, and Muir-Torre syndrome, and xeroderma pigmentosum.

Initial Evaluation

The initial evaluation of BCC includes a complete history and physical examination.  A biopsy of the suspicious lesion is required to confirm the diagnosis should be performed before treating any lesion.

Under dermoscopy, BCCs show the presence of well focused arborizing vessels in conjunction with foci of microulceration. Features of pigmented BCCs also include large, blue-gray, ovoid nests, multiple blue-gray globules, leaf-like structures, and spoke-wheel areas.

Optical coherence tomography (OCT) imaging is a new, alternative method for diagnosing BCCs noninvasively and monitoring them; however, the availability and use of this technology are limited to a few specialized centers around the world.

The common histopathologic features of all types of BCCs include the presence of aggregations of basaloid keratinocytes within a fibromyxoid stroma. Retraction artifact between the basaloid nodules and stroma can aid in the diagnosis.

Nodular basal cell carcinoma: Pearly papules with exaggerated telangiectasias and central ulceration within.

Superficial basal cell carcinoma: Erythematous, scaly plaques with sharply demarginated borders. This variant favors the trunk and extremities.

Pigmented basal cell carcinoma: Pearly papules/plaques with pigmentation and typical dermatoscopic findings.

Morpheaform basal cell carcinoma: Scar-like, indurated, skin-colored, erythematous, or hypopigmented papules or plaques with dermal infiltration and telangiectasias. This type tends to behave more aggressively, with extensive local destruction.

Differential Diagnosis

Actinic KeratosisPink thin papules and plaques with overlying coarse and gritty scale. There may be associated erosion or hyperkeratosis.

Bowen’s Disease (Squamous Cell Carcinoma In Situ): Erythematous, hyperkeratotic papules or plaques with slight induration and crusting.

Treatment

General Principles of Management

The histologic subtype and anatomic location are important considerations in the management of BCCs and the determination of the optimal treatment. Although most subtypes are amenable to standard surgical excision, some, such as the infiltrative, morpheaform, and micronodular forms, are best treated with Mohs micrographic surgery. Superficial BCCs can be treated successfully with cryosurgery, curettage and electrodesiccation (C&E), topical imiquimod or 5-fluorouracil therapy, photodynamic therapy (PDT), or systemic therapy.

Initial Therapy

First-line Therapy

Surgical excision with a 4 mm margin of normal tissue is usually optimal. The specimen should be sent for a pathological evaluation to ensure adequacy of the excision. If the margins are positive, Mohs micrographic surgery or further resection with complete circumferential margin assessment should be performed. Surgical excision with margins has been reported to achieve 5-year disease-free rates of over 98% for BCC.

In cases when surgery is not possible (e.g., elderly persons, the debilitated, clinically indistinct margins or extensive areas) or contraindicated, radiation therapy can provide excellent results.

For superficial or small (under 1 cm) lesions of the trunk, cryosurgery and C&E provide an acceptable cure rate with good cosmetic outcomes. C&E scars may be unsightly, and so, this is not the preferred treatment for facial lesions and is not recommended for large primary BCC, morpheaform, or recurrent BCC. Complications of cryosurgery include scarring and postinflammatory pigmentary changes and should also be used with caution in cosmetically sensitive areas.

Indications for Mohs micrographic surgery:

  • BCCs ≥ 6 mm located in high-risk areas (central face, nose, lips, eyelid, eyebrows, periorbital skin, chin, mandible, ears, preauricular and postauricular areas, temples, hands, feet) or ≥ 10 mm in other areas of the face (cheeks, forehead, scalp, and neck) or tumors ≥ 20 mm on the trunk or limbs.
  • Aggressive pathological features include perineural invasion, morpheaform, basosquamous, sclerosing, mixed infiltrative, or micronodular forms in any portion of the tumor.
  • Recurrent BCCs.
  • Lesions with clinically indistinct margins.
  • Previously excised lesions in which histologic margins were positive.
  • Tumors that will require extensive reconstruction to repair the surgical defect.

Alternative Therapy

Curettage and Electrodesiccation (C&E)

  • C&E is the process of alternatively scraping away tumor tissue with a curette down to a firm layer of normal dermis and denaturing the area by electrodessication.
  • 5-year cure rate reported to be between 91% and 97% for select patients.
  • Not recommended in areas with terminal hair growth, such as the scalp, pubic or axillary region, and beard region in males, due to the high risk of the tumor extending down follicular structures.
  • If subcutaneous tissue is reached during the procedure, conversion to standard excision should be done.
  • Side effects include hypopigmentation and scarring.
  • The use of curettage alone or curettage followed by imiquimod has been reported; however, larger studies are needed to confirm the efficacy of these treatments.

Topical Imiquimod 5% Cream

  • Imiquimod is a Toll-like receptor 7 agonist, which induces interferon-alpha and other cytokines to promote Th1-type immunity.
  • In general, imiquimod is used for the treatment of primary superficial BCCs in low-risk sites.
  • The selection of imiquimod over surgical excision for superficial BCCs includes patient-specific factors, such as preference to avoid surgery and potential comorbidities that are associated with surgical excision.
  • Most studies on imiquimod recommend application 5 times per week for a total of 6 weeks, with histological clearance rates of 80% to 85% 12 weeks after treatment. Cure rates (no recurrence after 3 and 5 years) of between 81% to 84% have been reported.
  • Local reactions, including erythema, edema, pain, vesicles, ulceration, and eschar formation are observed frequently. Topical imiquimod can be associated with systemic effects, including fatigue and an influenza-like illness.
  • Close clinical follow-up in the following months is necessary to monitor for adequate treatment and tumor recurrence.

5-Fluorouracil (5-FU) 5% Cream or Solution

  • 5-FU is a topically applied chemotherapeutic agent that has been approved by the US FDA for the treatment of superficial BCCs. Application is daily for up to 12 weeks.
  • Local reactions including erythema, edema, pain, vesicles, ulceration, and eschar formation are observed frequently.
  • Close clinical follow-up in the following months is necessary to monitor for adequate treatment and for tumor recurrence.

Photodynamic Therapy (PDT)

  • Although it is not approved by the US FDA for the treatment of BCCs, PDT is approved for this use in some European countries and may be considered for patients with many or refractory lesions—especially for superficial BCCs and certain thin nodular BCCs when surgery is contraindicated. This treatment is not recommended for high-risk BCC.
  • Superficial BCCs respond well to PDT, with primary clearance rates of 92% to 97% at 12 weeks and a 9% recurrence rate at 12 months. Low-risk thin nodular BCCs that are treated with PDT should be monitored frequently for recurrence, because the efficacy is typically not as good.
  • The cosmetic outcome of this treatment is considered to be superior to that of surgery.
  • A topical photosensitizer (aminolevulinic acid, such as Levulan Kerastick, and methyl aminolevulinate, such as Metvix) is applied to the skin in the medical office and allowed to incubate for 30–60 minutes or up to 3 hours (depending on the photosensitizer) prior to exposure to a light source for approximately 10–15 minutes, during which destruction of the tumor cells occurs.
  • Several different light sources are currently available for the activation of the photosensitizer:
      • Aktilite: 630 nm red LED light, 37 J/cm2.
      • BLU-U: 417 nm peak emission, 10 J/ cm2.
      • RhodoLED: red LED light, 635 nm peak emission, 37 J/c cm2.
      • Other light sources that emit red light with a continuous spectrum of 570–670 nm.
      • Lasers provide an additional form of light source for activation with deeper penetration.
      • PDT using daylight has been shown to be successful in the treatment of actinic keratoses (AKs) but has not been studied for the treatment of BCCs.
  • Strict photoprotection is necessary for 48 hours after PDT to avoid excessive photosensitization.
  • Post-procedure erythema, edema, and inflammation are expected and may linger for 5–7 days after each treatment.
  • Several treatments, at 3- to 4-week intervals, may be required.
  • Before the photosensitizer is applied, skin lesionsshould be prepared by removing superficial scale and crust by curettage; other techniques include topical keratolytics, tape stripping, microdermabrasion, fractional COlaser, microneedling, and elevation of skin temperature.
  • There are many variables that are associated with the efficacy of PDT, including irradiance, light source, photosensitizer, incubation time, skin preparation, frequency of treatments, and exposure time of light source. Therefore, close follow-up is needed to assess the efficacy and to monitor for recurrence.

Radiotherapy (RT)

  • Different techniques of RT can be used in the treatment of BCC, including electron beam radiation therapy (EBRT) and brachytherapy (BT),
  • RT should be considered for older patients (> 70 years), patients with a preference for non-surgical treatments, and poor surgical candidates  including those who receive medications that affect coagulation and platelet function and those with significant comorbidities.
  • Tumors in locations that are considered not ideal for surgery, including nasal ala, nasal tip, nasal bridge, lower eyelid, medial canthus, and helix, and large, deep, or inoperable lesions, including those that extend into the cranial cavity, may be considered for RT.
  • RT can also be used preoperatively or postoperatively as adjunctive therapy for certain BCCs or patients.
  • RT should be avoided in younger patients for whom other treatment options are available, due to the many unwanted long-term side effects of radiation, such as permanent alopecia, radiation dermatitis, and a high risk for future NMSCs.
  • RT has local control rates of 90% to 95%, making it a cosmetically and functionally suitable treatment option.
  • The appropriate dose and schedule of therapy depend on the patient, type of radiation treatment, and tumor factors.
  • A field margin of 5–10 mm beyond macroscopic disease or a surgical site is usually adequate.

Observation

Early lesions in very elderly patients or in those with significant morbidity and poor prognosis from other diseases can often initially be observed, as the chance of morbidity or mortality from these lesions is extremely low.

Subsequent Therapy

  • Patient education with respect to pathogenesis and natural history of BCCs is essential. Sun protection must be stressed.
  • Monitoring for recurrence as well as new lesions during the first 2 years after diagnosis is very important. A total of 30% to 50% of patients with prior BCC will develop another BCC within 5 years.
  • Patients with a history of BCC should have a full-body skin examination every 6 months during the first 2 years. An annual full-body skin examination thereafter is indicated to identify future development of tumor recurrence and new skin cancers.

Unresectable, Recurrent, or Metastatic BCC

  • For unresectable disease, radiation therapy can be given with curative intent, even with large lesions.
  • For disease that recurs after surgical excision, re-excision should be performed if feasible, otherwise radiation therapy should be used.
  • For metastatic disease, or locally advanced disease not amenable to further surgery or radiation therapy, chemotherapy can be used, however, response rates are low. With the FDA approval of two hedgehog inhibitors, these have become the standard of care:

Vismodegib

  • Hedgehog inhibitor for the treatment of advanced local or metastatic basal cell carcinoma.
  • Vismodegib is FDA-approved for the treatment of adults with metastatic basal cell carcinoma or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.
  • Significant side effects include teratogenicity, muscle spasms and dysgeusia (often associated with significant weight loss), alopecia, asthenia, diarrhea, nausea, and fatigue.

Sonidegib

  • Another hedgehog pathway inhibitor that is also approved by the FDA for the treatment of adult patients with locally advanced BCC that has recurred following surgery or radiotherapy or who are not candidates for surgery or radiotherapy.
  • Similar objective response rate between 200 mg/day and 800 mg/day, but the higher dose is associated with greater adverse effects.
  • Common adverse effects include muscle spasms, dysgeusia, alopecia, nausea, weight decrease, and fatigue. Elevated creatinine is also frequently observed and is one of the most common Grade 3–4 adverse events, along with elevated lipase.

Basal Cell Nevus Syndrome (Gorlin syndrome)

Initial Therapy

  • Surgical excision of all tumors is the best therapy and is performed if possible following the guidelines for the management of routine BCCs.
  • Genetic counseling and examination of family members are important.
  • Strict sun protection (avoidance) must be stressed.
  • Evaluate the patient for associated conditions, especially jaw cysts and malignancies.

Subsequent Therapy

  • PDT may be helpful for field treatment of multiple lesions and early treatment of clinically occult lesions.
  • RT is not indicated for patients with basal cell nevus syndrome and for morpheaform BCCs, which are relatively radioresistant, and radiation itself may lead to future NMSCs in this already vulnerable population.
  • Vismodegib and sonidegib may be considered for the treatment of multiple and/or aggressive BCCs; however, the age and reproductive ability of the patient should be considered prior to the start. Significant side effects including teratogenicity, muscle spasms, dysgeusia (often associated with significant weight loss), alopecia, diarrhea, nausea, and fatigue may limit the use of these drugs.
  • Vismodegib has also been used for prophylaxis in patients with nevoid BCC syndrome.

Prognosis

The prognosis depends to a large degree on the subtype and how advanced the lesions is. With adequate local therapy, cure rates exceed 90%. With metastatic BCC, median survival is 33.4 months with vismodegib therapy.

Pitfalls

  • Do not underestimate the potential for cosmetic disfigurement due to BCC. Attempts should be made to identify lesions early and to eradicate each one completely.
  • In the case of a non-healing ulcer on the skin, always exclude the diagnosis of a skin tumor.
  • Following surgical removal of skin tumors, a histopathological examination is necessary to confirm the clinical diagnosis and excision margins.
  • RT should be avoided in younger patients, patients with basal cell nevus syndrome, and those with DNA repair deficiencies (such as xeroderma pigmentosum), due to an increased risk of subsequent skin cancers in these patients.

Warning Signs and When to Refer

When to Refer to Dermatology

Dermatologists who are familiar with its presentation, diagnosis, and management best manage BCC. Failure to diagnose and correctly manage these tumors may lead to advanced disease and significant cosmetic deformity.

When to Refer to Other Specialties

Children presenting with basal cell carcinoma should be referred for genetic testing.

Clinical Cases

Case 1

Initial Presentation

  • 42-year-old man with a slowly enlarging lesion on the right infraorbital cheek
  • No prior history of skin malignancy
  • Patient is otherwise healthy
  • Skin exam: 5 x 7 mm pearly plaque with central dell and prominent telangiectasias; a full-body skin examination does not identify any other suspicious lesions

Diagnosis

  • Biopsy reveals nodular and micronodular BCC

Treatment

Referral for Mohs surgery with repair (indications: histopathology, proximity to eye)

Follow-up

  • 3 months for full-body skin examination
  • Photoprotection recommended

Case 2

Initial Presentation

  • 50-year-old woman with a scaly lesion on the back of unknown duration
  • No prior history of skin malignancy
  • Patient is otherwise healthy
  • Skin exam: 8 x 8 mm sharply demarcated pink plaque with minimal scale; a full-body skin examination does not identify any other suspicious lesions

Diagnosis

  • Biopsy reveals superficial BCC

Treatment

  • The patient is offered surgical excision, photodynamic therapy, and imiquimod cream treatment and opts for imiquimod
  • Imiquimod 5% cream is applied daily to the lesion for 6 weeks

Follow-up

  • Follow-up evaluation at 8-12 weeks
  • The patient reports significant erythema, crusting, and inflammation at the site of imiquimod application, which has now subsided. There is no evidence of persistent skin cancer at the treatment site
  • A full-body skin examination is performed and does not identify any other suspicious lesions
  • Follow-up evaluation at 3-6 months for full-body skin examination
  • Photoprotection recommended

Case 3

Initial Presentation

  • 47-year-old man presents for evaluation of a new lesion on the arm that has been growing over 3 months
  • No prior history of skin cancer
  • Patient is otherwise healthy
  • Skin exam: 1.2 x 0.8 cm pearly plaque with telangiectasias on the right arm; a full-body skin examination does not reveal additional suspicious lesions

Diagnosis

  • Biopsy reveals nodular BCC

Treatment

  • Surgical excision with 3mm margins with complex linear closure; the excisional specimen is sent to pathology to determine adequacy of surgical margins
  • Follow-up in 2 weeks for suture removal and again at 3 months for full-body skin examination

Follow-up

  • A full-body skin examination at 3 months is performed, and no suspicious lesions are identified.  The surgical excision is well healed without evidence of recurrence
  • Photoprotection recommended
  • Follow-up evaluation at 3-6 months for full-body skin examination

References

Basset-Seguin N, Hauschild A, Grob JJ, et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open label trial. Lancet Oncol. 2015; 16(6): 725-736. doi: 10.1016/S1470-2045(15)70198-1

Bolognia JL, Shaffer JV, Cerroni L.  Dermatology. 4th edition. Elsevier: New York, 2017.

Gunaratne DA, Veness MJ. Efficacy of hypofractionated radiotherapy in patients with non-melanoma skin cancer: Results of a systematic review. J Med Imaging Radiat Oncol. 2018 Mar 9. doi: 10.1111/1754-9485.12718. [Epub ahead of print]

Migden MR, Chang ALS, Dirix L, Stratigos AJ, Lear JT. Emerging trends in the treatment of advanced basal cell carcinoma. Cancer Treat Rev. 2018; 64: 1-10. doi: 10.1016/j.ctrv.2017.12.009.

Morton CA. A synthesis of the world’s guidelines on photodynamic therapy for non-melanoma skin cancer. G Ital Dermatol Venereol. 2018 Feb 7. [Epub ahead of print] doi: 10.23736/S0392-0488.18.05896-0

Morton CA, McKenna KE, Rhodes LE, British Association of Dermatologists Therapy guidelines and Audit Subcommittee and the British Photodermatology Group. Guidelines for topical photodynamic therapy: update. Br J Dermatol. 2008; 159(6): 1245-1266. doi: 10.1111/j.1365-2133.2008.08882.x

Morton CA, Szeimies RM, Sidoroff A, Braathen LR. European guidelines for topical photodynamic therapy part 1: treatment delivery and current indications – actinic keratoses, Bowen’s disease, basal cell carcinoma. J Eur Acad Dermatol Venereol. 2013; 27(5): 536-544. doi: 10.1111/jdv.12031

Nguyen BT, Gan SD, Konnikov N, Liang CA. Treatment of superficial basal cell carcinoma and squamous cell carcinoma in situ on the trunk and extremities with ablative fractional laser-assisted delivery of topical fluorouracil. J Am Acad Dermatol. 2015; 72(3): 558-560. doi: 10.1016/j.jaad.2014.11.033.

National Comprehensive Cancer Network. Website. NCCN Guidelines version 1.2018 Basal Cell skin cancer. https://www.nccn.org/professionals/physician_gls/default.aspx

National Comprehensive Cancer Network. Website. NCCN version 2.2018 – October 6, 2017. Squamous Cell Skin Cancer. NCCN Evidence Blocks. https://www.nccn.org/professionals/physician_gls/default.aspx

Sekulic A, Migden, Basset-Seguin N. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017; 17: 332. doi: 10.1186/s12885-017-3286-5

Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012; 366(23): 2171-2179. doi: 10.1056/NEJMoa1113713