Basal Cell Carcinoma

Synonyms and related keywords: BCC, basal cell epithelioma, BCE, basalioma, rodent ulcer, nodular BCC, noduloulcerative BCC, cystic BCC, pigmented BCC, morpheaform BCC, sclerosing BCC, superficial BBC, keratotic BBC, adenoid BBC, infiltrative BCC, Mohs micrographic surgery, Mohs surgery, basal cell cancer, skin cancer, cutaneous malignancy, skin malignancy, cutaneous cancer


INTRODUCTION

Background: Basal cell carcinoma (BCC) is the most common cutaneous malignancy in humans. These tumors typically appear on sun-exposed skin, are slow growing, and rarely metastasize. Neglected tumors can lead to significant local destruction and even disfigurement.

Pathophysiology: Although the exact etiology of BCC is unknown, a well-established relationship exists between BCC and the pilosebaceous unit, as tumors are most often discovered on hair-bearing areas. Tumors are currently believed to arise from pluripotent cells (which have the capacity to form hair), sebaceous glands, and apocrine glands. Tumors usually arise from the epidermis or the outer root sheath of a hair follicle.

Frequency:

• In the US: Each year in the United States, 900,000 people are diagnosed with BCC (550,000 male, 350,000 female). The estimated lifetime risk of BCC in the white population is 33-39% for men and 23-28% for women.

Mortality/Morbidity: Although BCC is a malignant neoplasm, it rarely metastasizes. The incidence of metastatic BCC is estimated at less than 0.1%. The most common sites of metastasis are the lymph nodes, the lungs, and the bones. Typically, basal cell tumors enlarge slowly and relentlessly and tend to be locally destructive. Periorbital tumors can invade the orbit, leading to blindness, if diagnosis and treatment are delayed. Perineural invasion can occur, leading to loss of nerve function.

Race: Although BCC is observed in people of all races and skin types, it is most often found in light-skinned individuals; dark-skinned individuals are rarely affected.

Sex: Historically, men are affected twice as often as women. The higher incidence in men is probably due to increased recreational and occupational exposure to the sun, although these differences are becoming less significant with changes in lifestyle.

Age: The likelihood of developing BCC increases with age. With the exception of basal cell nevus syndrome, BCC is rarely found in patients younger than 40 years.

CLINICAL

History: Patients often complain of a slowly enlarging lesion that does not heal and that bleeds when traumatized. As tumors most commonly occur on the face, patients often give a history of an acne bump that occasionally bleeds.

• Patients often have a history of chronic sun exposure.

• Recreational sun exposure (eg, sunbathing, outdoor sports, fishing, boating)

• Occupational sun exposure (eg, farming, construction)

• Occasionally, patients have a history of exposure to ionizing radiation. X-ray therapy for acne was commonly used until 1950.

• Occasionally, patients have a history of arsenic intake; arsenic is found in well water in some parts of the United States.

Physical: Clinical presentation of BCC varies by type.

• Nodular BCC

• Nodular BCC is the most common type of BCC and usually presents as a round, pearly, flesh-colored papule with telangiectases. As it enlarges, it frequently ulcerates centrally, leaving a raised, pearly border with telangiectases, which aids in making the diagnosis.

• Most tumors are observed on the face, although the trunk and extremities also are affected.

• Cystic BCC

• An uncommon variant of nodular BCC, cystic BCC is often indistinguishable from nodular BCC clinically, although it might have a polypoid appearance.

• Typically, a bluish-gray cyst-like lesion is observed. The cystic center of these tumors is filled with clear mucin that has a gelatin-like consistency.

• Pigmented BCC

• Pigmented BCC is an uncommon variant of nodular BCC that has brown-black macules in some or all areas, often making it difficult to differentiate from melanoma.

• Typically, some areas of these tumors do not retain pigment; pearly, raised borders with telangiectases that are typical of a nodular BCC can be observed. This aids clinically in differentiating this tumor from a melanoma.

• Morpheaform (sclerosing) BCC

• Morpheaform BCC is an uncommon variant in which tumor cells induce a proliferation of fibroblasts within the dermis and an increased collagen deposition (sclerosis) that clinically resembles a scar. The tumor appears as a white or yellow, waxy, sclerotic plaque that rarely ulcerates.
• Because the tumor infiltrates in thin strands between collagen fibers, treatment is difficult, and the clinical margins are difficult to distinguish. Mohs micrographic surgery is the treatment of choice for this type of BCC.

• Superficial BCC

• Superficial BCC clinically appears as an erythematous, well-circumscribed patch or plaque, often with a whitish scale. Occasionally, minute eschars may appear within the patch or plaque.

• The tumor appears multicentric, with areas of clinically normal skin intervening among clinically involved areas.

Causes: The exact cause of BCC is unknown, although environmental factors that are believed to predispose patients to this disorder include the following:

• Exposure to sunlight, the most frequent association (UVB, 290-320 nm, which causes sunburn, is believed to play a greater role in the development of BCC than UVA.)

• Exposure to artificial ultraviolet light (eg, tanning booths, ultraviolet light therapy)

• Ionizing radiation exposure (eg, x-ray therapy for acne)

• Arsenic exposure through ingestion (eg, arsenic used as a medicinal agent, predominantly Fowler's solution of potassium arsenite that was used to treat many disorders, including asthma and psoriasis). A contaminated water source has been the most common source of arsenic ingestion.

• Immunosuppression: Immunosuppression has been associated with a modest increase in the risk of BCC. Therefore, recipients of organ or stem cell transplants have a higher lifetime risk of developing BCC.

• Xeroderma pigmentosum: This autosomal recessive disease results in the inability to repair UV-induced DNA damage. Pigmentary changes are seen early in life followed by the development of BCC, squamous cell carcinoma, and malignant melanoma. Other features include corneal opacities, eventual blindness, and neurological deficits.

• Nevoid BCC syndrome (basal cell nevus syndrome, Gorlin syndrome): This autosomal dominant disorder results in the early formation of multiple odontogenic keratocysts, palmoplantar pitting, intracranial calcification, and rib anomalies. Various tumors such as medulloblastomas, meningioma, fetal rhabdomyoma, and ameloblastoma also can occur.

• Bazex syndrome: Features include follicular atrophoderma ("ice pick" marks, especially on dorsal hands), multiple BCCs, and local anhidrosis (decreased or absent sweating).

• History of previous nonmelanoma skin cancer (BCC or squamous cell carcinoma): Persons who have been diagnosed with one nonmelanoma skin cancer are at increased risk of developing additional tumors in the future. The risk of developing new nonmelanoma skin cancers is reported to be 35% at 3 years and 50% at 5 years after an initial skin cancer diagnosis.

DIFFRENTIALS

Malignant Melanoma

Other Problems to be Considered:

Squamous cell carcinoma
Squamous cell carcinoma in situ (Bowen disease)
Actinic keratosis
Sebaceous hyperplasia
Fibrous papule
Desmoplastic trichoepithelioma
Nevi, melanocytic

WORKUP

Lab Studies:

• Since BCC rarely metastasizes, laboratory and imaging studies are rarely clinically indicated in patients presenting with localized lesions. A skin biopsy is often required to confirm the diagnosis and determine the histologic subtype. Most often, a shave biopsy is all that is required. However, in the case of a pigmented lesion where there may be difficulty distinguishing between pigmented BCC and melanoma, an excisional biopsy may be indicated.

Histologic Findings: Several histologic types of BCC exist, some of which are important because the clinical detection of tumor margins is more difficult with certain histologic types. The characteristic cells of BCC have a large, uniform, oval, nonanaplastic-appearing nucleus with little cytoplasm. The nuclei resemble that of the basal cells of the epidermis, although they have a larger nuclear-to-cytoplasmic ratio and lack intercellular bridges. A mitotic figure is very rarely observed.

The connective tissue stroma surrounding the tumor islands is arranged in parallel bundles and often shows young fibroblasts immediately adjacent to the tumor. Artificial retraction of the stroma from the tumor islands is frequently observed histologically. Additionally, the stroma is often mucinous.

Histologically, BCC is divided into 2 categories: undifferentiated and differentiated. BCC with little or no differentiation is referred to as solid BCC and includes pigmented BCC, superficial BCC, sclerosing BCC, and infiltrative BCC (a histologic subtype). Differentiated BCC often has slight differentiation toward cutaneous appendages, including hair (keratotic BCC), sebaceous glands (BCC with sebaceous differentiation), or tubular glands (adenoid BCC). Noduloulcerative (nodular) BCC usually is differentiated.

Histologic types can be summarized as follows:

• Noduloulcerative BCC, which is the most common type, generally consists of large, round or oval tumor islands within the dermis, often with an epidermal attachment. Artificial retraction of the tumor islands from the surrounding stroma is commonly seen.
• Micronodular BCC is similar to the noduloulcerative type, although the tumor islands are small (often less than 15 cells in diameter).
• Pigmented BCC consists of large, round or oval tumor islands containing large amounts of melanin within melanocytes and melanophages.
• Cystic BCC consists of large, round or oval tumor islands within the dermis with mucin present within the center of the island.
• Infiltrative BCC is a common type of BCC in which strands of basaloid tumor cells are seen infiltrating between collagen bundles.
• Morpheaform or Sclerosing BCC consists of elongated strands of basaloid cells that lead to the adjacent formation of a dense fibrous stroma.
• Superficial BCC consists of buds of basophilic cells within the papillary and occasionally superficial reticular dermis, but they are attached to the epidermis.

TREATMENT

Medical Care: In nearly all cases, the recommended treatment modality for BCC is surgery. While newer, nonsurgical therapeutic modalities are future possibilities, currently available medical modalities are considered to be experimental, with cure rates less than that of surgical modalities.

• 5-fluorouracil applied twice daily for 2-12 weeks of treatment can be effective in treating superficial BCC, with a reported cure rate as high as 93%. The use of 5-fluorouracil for other types of BCC is generally not recommended because it may not penetrate deeply enough into the dermis to eradicate all tumor cells. Irritation and crusting is common and expected, although significant irritation and discomfort are not uncommon.

• In a small study by Greenway et al, 1.5 million IU interferon alfa-2b injected intralesionally 3 times per week for 3 weeks resulted in clearing 3 cases of primary nonrecurrent BCC and 5 cases of primary superficial BCC. Because larger studies are needed, most practitioners consider this an experimental therapeutic modality. Acetaminophen can be administered to patients who experience the flulike symptoms associated with this therapy.

• Imiquimod cream has been used recently for the treatment of BCC. Small studies have shown cure rates of up to 88% for superficial BCC and nodular BCC. Studies for other histologic types of BCC are currently underway. Imiquimod is only FDA approved for the treatment of superficial BCC. Treatment is usually initiated 3 times per week and advanced as tolerated to once daily and even twice daily if tolerated to maintain mild-to-moderate skin irritation.

Surgical Care: The goal of therapy for patients with BCC is removal of the tumor with the best possible cosmetic result. By far, surgical modalities are the most studied, most effective, and most used treatments for BCC. The effectiveness of surgical modalities depends heavily on the surgeon's skills; considerable differences in cure rates have been observed among surgeons. Modalities used include electrodesiccation and curettage, excisional surgery, Mohs micrographically controlled surgery, and cryosurgery. Ionizing radiation, although a nonsurgical modality, should be considered in select patients and is discussed below.

Selection of the modality depends on whether the tumor is primary or recurrent, as well as on its location, size, and histologic type. The American Academy of Dermatology has published guidelines regarding the treatment of BCC.

• Electrodesiccation and curettage: After adequate anesthesia is administered to the patient, the tumor is scraped using a curette, and then the base and lateral margins are electrodesiccated. This is repeated twice.

• Advantages: Electrodesiccation and curettage is a short procedure (less than 5 min) and is effective in treating primary nodular and superficial BCC. Cure rates are as high as 95%.
• Disadvantages: The procedure is operator-dependent and often leaves a white atrophic scar. It is less effective on the nose, and the tumor often tracks down pilosebaceous units. This procedure is less effective in treating infiltrating BCC, micronodular BCC, morpheaform (sclerosing) BCC, and recurrent BCC than Mohs micrographic surgery, which is believed to be the treatment of choice in most instances.

• Curettage (without desiccation): After adequate anesthesia is administered to the patient, the tumor is scraped using a curette. This is often repeated twice more.
  • Advantages: This is a short procedure (less than 5 min) and is effective in treating primary nodular and superficial BCC. Cure rates may be as high as 95%, although it has been studied less than electrodesiccation and curettage. This procedure is believed by some to have a better cosmetic outcome than electrodesiccation and curettage.
  • Disadvantages: This procedure is not widely accepted and not commonly performed. The procedure is operator-dependent and often leaves a white atrophic scar. It is less effective on the nose, and the tumor often tracks down pilosebaceous units. This procedure is less effective in treating infiltrating BCC, micronodular BCC, morpheaform (sclerosing) BCC, and recurrent BCC than Mohs micrographic surgery, which is believed to be the treatment of choice in most instances.

• Curettage with erbium: YAG laser ablation: After adequate anesthesia is administered to the patient, the tumor is scraped using a curette. The newly formed ulcer is then ablated along with a narrow (less than 1 mm) margin of adjacent epidermis. This is often repeated 2 more times.
  • Advantages: This is a short procedure (less than 5 min) and is effective in treating primary nodular and superficial BCC. Cure rates may be as high as 95%, although it has been studied less than electrodesiccation and curettage. This procedure is believed by some to have a better cosmetic outcome than electrodesiccation and curettage.
  • Disadvantages: This procedure is less commonly performed than electrodesiccation and curettage. The procedure is operator-dependent and may leave a white atrophic scar. It is less effective on the nose, and the tumor often tracks down pilosebaceous units. This procedure is less effective in treating infiltrating BCC, micronodular BCC, morpheaform (sclerosing) BCC, and recurrent BCC than Mohs micrographic surgery, which is believed to be the treatment of choice in most instances.

• Surgical excision: After adequate anesthesia is administered to the patient, a No. 15-blade or 10-blade scalpel is used to incise down to the subcutis. To increase the likelihood of complete tumor removal, one must remove a margin of normal-appearing skin in order to remove all clinically invisible tumor extension. The larger the amount of clinically normal-appearing skin removed, the higher the cure rate, although the more extensive removal leaves a larger surgical defect and a poorer cosmetic result in most patients. In most circumstances, a 3- to 4-mm margin of normal, clinically uninvolved skin is removed.

• Advantages: Surgical excision usually produces good-to-excellent cosmetic results and cure rates as high as 95%.
• Disadvantages: Surgical excision is operator-dependent, as those more experienced may be better at detecting tumor margins. Excision is less effective in treating tumors without clearly defined clinical margins (eg, infiltrating BCC, micronodular BCC, morpheaform [sclerosing] BCC), and is far less effective in treating recurrent BCC than it is in treating primary BCC.

• Mohs micrographically controlled surgery: After adequate anesthesia is administered to the patient, the clinically apparent tumor is often removed by curettage or excision. The surgeon then removes a thin layer of tissue (called stage I), usually less than 1 mm in thickness, of surrounding epidermis and either dermis or subcutis, which then is examined under the microscope. The tumor is removed and processed to allow for localization of any tumor that might persist. This process allows the surgeon to take additional sections (stages) from the location where the tumor persists.

• Advantages: Mohs micrographically controlled surgery has the highest cure rate of any treatment modality (99% for primary BCC, 90-95% for recurrent BCC), spares as much uninvolved skin as possible, and is the treatment of choice for infiltrating BCC, micronodular BCC, morpheaform (sclerosing) BCC, and recurrent BCC.
• Disadvantages: Mohs micrographic surgery is time consuming, and patients might require additional anesthesia before each stage.

• Cryosurgery: Liquid nitrogen is applied to the clinically apparent tumor. A temperature probe is inserted into the skin at a lateral margin. Treatment stops when the temperature at the lateral margins reaches -60°C.
  • Advantages: Cryosurgery has good cosmetic results and good cure rates when treating tumors with well-defined clinical margins (eg, nodular BCC). The procedure is a good option for patients who are not surgical candidates.
  • Disadvantages: Cryosurgery is operator-dependent, as accurate clinical detection of tumor margins increases the effectiveness of treatment.

• Ionizing radiation: Superficial x-ray is usually administered as 10 treatments of 4 gray (Gy) (400 rad). Electrons (electron beam) can be used and has gained favor over superficial x-rays by many radiation oncologists.
  • Advantages: Ionizing radiation is a good treatment option for patients who are not surgical candidates, especially those patients who have facial tumors.
  • Disadvantages: Radiation therapy requires multiple visits. Treatment results in radiation damage and, therefore, should be reserved for older patients. Radiation therapy is less effective for nonfacial tumors.

Activity: Instruct patients to avoid sun exposure and other possible predisposing factors (eg, ionizing radiation, arsenic ingestion, tanning beds).

MEDICATION

The goal of drug therapy is to eradicate malignant superficial basal cells.

Drug Category: Antineoplastic agents -- The most common chemotherapeutic agent used in superficial BCC is topical 5-fluorouracil.

Drug Name	5-Fluorouracil (Efudex, Carac, Fluoroplex) -- Used topically for the management of superficial BCC. Interferes with DNA synthesis by blocking methylation of deoxyuridylic acid and inhibiting thymidylate synthetase and, subsequently, cell proliferation.
Adult Dose	Apply bid (Carac may be applied qd), in sufficient amount to cover lesions, for a minimum of 3 wk; only the 5% strength is recommended; therapy might be required for up to 10-12 wk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity, potentially serious infections
Interactions	None reported
Pregnancy	X - Contraindicated in pregnancy
Precautions	Incidence of inflammatory reactions can occur with occlusive dressings; porous gauze dressings can be applied for cosmetic reasons without increase in reaction

Drug Name	Imiquimod (Aldara) -- Precise mechanism for superficial BCC is unknown. May increase tumor infiltration by lymphocytes, dendritic cells, and macrophages. Indicated for biopsy-confirmed primary superficial BCC in adults with normal immune systems. Additionally, tumors must not exceed 2 cm in diameter on certain areas of the body. Indicated only when surgical methods are not appropriate.
Adult Dose	Apply cream to treatment area (including 1 cm of skin surrounding tumor) 5 d/wk at bedtime for 6 wk; leave on for 8 h, then wash area
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Medical follow-up is essential to ensure cancer has responded adequately to treatment; may cause redness, swelling, and sore development at application site; may cause itching or burning

FOLLOW-UP

Further Outpatient Care:

• Patients who are diagnosed with BCC have a 35% chance of developing another tumor within 3 years and a 50% chance of developing another (not recurrent) BCC within 5 years. Therefore, regular skin screenings are recommended.

Deterrence/Prevention:

• Avoid possible potentiating factors (eg, sun exposure, ionizing radiation, arsenic ingestion, tanning beds). The regular use of sun-protecting clothing (ie, wide-brimmed hat and long-sleeved shirts) is recommended when possible when outdoors. The regular application and reapplication of sunscreen is recommended prior to sun exposure.

Patient Education:

• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article, Skin Cancer.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Making the diagnosis

• Occasionally, suspected tumors may require more than a single biopsy to make the diagnosis; therefore, with a high clinical index of suspicion, a second biopsy may be needed to obtain a pathological diagnosis of BCC.

• In many states, the physician or surgeon who clinically suspects a tumor is equally liable for a missed histologic diagnosis. Obtain a second biopsy of highly suspicious lesions.

• Treatment options: When BCC is diagnosed, discuss all of the available treatment options with the patient. For tumors that are more difficult to treat (ie, infiltrative BCC, morpheaform [sclerosing] BCC, micronodular BCC, and recurrent BCC) or those in which the sparing of normal (noncancerous) tissue is paramount, Mohs micrographic surgery should be considered.

Special Concerns:

• Tumor locations for high risk of recurrence: Tumors on the nose or T-zone of the face have a higher incidence of recurrence.
• Histologic types of BCC at higher risk for recurrence include the following:

• Morpheaform (sclerotic) BCC
• Micronodular form BCC
• Infiltrative BCC
• Superficial (multicentric) BCC

• Other factors that contribute to a higher recurrence rate include the following:

• Recurrent tumors (those that have been treated previously)

• Large tumors (>2 cm)

• Deeply infiltrating tumors