Epitheliomas, Basal Cell

Synonyms and related keywords: basal cell epitheliomas, basal cell cancer of the skin, basaloma, basalioma, rodent ulcer, basal cell carcinoma, BCC, skin cancer, skin tumor, basal cell nevus syndrome, Gorlin-Goltz syndrome or nevoid basal cell carcinoma syndrome, NBCCS, ultraviolet light, UV light, trichoblastic carcinoma, trichoblastoma, fibroepithelioma of Pinkus, epithelial tumor



INTRODUCTION

Background: Basal cell carcinoma (BCC) is the most common skin tumor. Tumor size can vary from a few millimeters to several centimeters in diameter. BCC is a nonmelanocytic skin cancer (ie, an epithelial tumor) that arises from basal cells, small round cells found in the lower layer of the epidermis. Basal cells invade the dermis but seldom invade other parts of the body. Although BCC rarely spreads to other parts of the body, tumors can continue to grow, making surgical removal essential. If BCC is not diagnosed early and removed surgically, it can cause severe disfigurement.

BCC has a high frequency rate in adult males who have a long history of unprotected exposure to ultraviolet (UV) light. BCC can develop on unexposed areas; cases of BCC of the prostate have been reported. In a few patients, the contributing factors are contact with arsenic, tar, coal, paraffin, certain types of industrial oil, radiation exposure, scars (ie, burn complications), xeroderma pigmentosum, vaccinations, or even tattoos.

The DNA of certain genes is often damaged in patients with BCC; therefore, inheritance may be a factor. Most DNA alterations result from damage caused by exposure to sunlight.

Pathophysiology: The incidence of BCC increases with age, and most cases occur in patients older than 55 years; however, the damaging effects of the sun begin at an early age. The results may not appear for 20-30 years.

Patient geographical location affects the risk of developing skin cancer. In fact, BCC is related to lifetime exposure to UV radiation and a history of sunburn. The damaging effects of the sun are cumulative. The skin can repair superficial damage, but the underlying damage remains, including DNA damage. The damage worsens with each successive sun exposure, causing a lifetime progression. This damage reduces the ability of DNA to control cell growth and division and, in some situations, this progression results in cancer.

Almost all forms of BCC have mutations in the gene encoding the Hedgehog (Hh) receptor molecule, a signaling pathway playing a pivotal role in cell differentiation. At least three forms of this protein are known: sonic HH (SHH), Indian HH (IHH), and desert HH (DHH).

Frequency:

• In the US: Researchers report nearly 800,000 new cases of BCC each year (ie, approximately 2% of all cancer deaths).

• Internationally: The highest rates of skin cancer occur in South Africa and Australia, areas that receive high amounts of UV radiation. BCC accounts for 80% of all skin cancers but is the least likely cancer to behave in a malignant fashion and metastasize. BCC differs from squamous cell carcinoma, which accounts for 16% of skin cancers, because squamous cell carcinoma is much less common and more life threatening.

Mortality/Morbidity: Sunburns appear to increase the risk of BCC; however, this association is difficult to prove since most sunburns occur when patients are children. BCC risk is higher in farmers, fishermen, and other patients with frequent but intermittent sun exposure.

Race: The risk of BCC is greater for people who have type 1 or type 2 skin. BCC is the most common skin cancer in whites and is very rare in people with skin that is darkly pigmented.

• Type 1 skin - People with very fair skin, red or blond hair, freckles, always burn, never tan

• Type 2 skin - People with fair skin, burn easily, tan minimally

Sex: Although women are reporting cases of BCC more than in the past, men still outnumber them significantly. The male-to-female ratio is approximately 2.1:1.

Age: Patients aged 50-80 years are affected most often (mean age, 55 y); however, BCC can develop in teenagers and now appears frequently in fair-skinned patients aged 30-50 years.

CLINICAL

History: People who sunburn are more likely to develop skin cancer than those who do not; however, sunlight damages the skin with or without sunburn. Consider BCC in any patient with a history of a sore or skin anomaly that does not heal within 3-4 weeks and occurs on sun-exposed skin, especially if it is dimpled in the middle. These tumors may take many months or years to reach even 1 cm in diameter.

Physical:

• Tumor characteristics

• BCC mostly occurs on the face, head (scalp included), neck, and hands. BCC rarely develops on the palms and soles.

• BCC usually appears as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury.

• BCCs may have one or more visible and irregular blood vessels, an ulcerative area in the center that often is pigmented, and black-blue or brown areas.

• Large BCCs may have oozing or crusted areas. The lesion is not painful, grows slowly, and does not itch or hurt.

• BCC subtypes

• The nodular subtype is the most common and specific form of BCC. Nodular BCC typically appears as a white-grayish, firm nodule (eg, similar to a mushroom cap), often is centrally ulcerated, and typically has enrolled and well-defined margins.

• The morpheaform subtype is the most difficult subtype to diagnose. This subtype typically appears as a scarring, firm plaque but, because of indistinct clinical tumor margins, is difficult to treat adequately with traditional therapies.

• The superficial subtype often is multiple, most often developing on the upper trunk or shoulders. The tumor grows slowly and appears as a pink or brown scaly patch, sometimes with a raised border.

• The sclerosing subtype is the most destructive form of BCC and is a variant of the nodular subtype. The sclerosing subtype involves a firm, large area, which is gray-whitish in color, with ill-defined margins. If untreated, ulcerations occur, causing a deep and large erosion of the soft tissues (eg, dermis, muscle, connective fascia, aponeurosis) and bone under the skin.

• BCC also is described as a basal cell nevus syndrome (ie, Gorlin syndrome), an autosomal dominant inherited condition that cannot be distinguished histologically from an ordinary tumor. The gene responsible for this syndrome is located on chromosome 9q, and chromosome abnormalities develop in some patients. Multiple BCCs, from one to hundreds, may occur in patients with this syndrome. Multiple BCCs begin to appear after puberty on the face, trunk, and extremities. Mental retardation may occur but is uncommon. In many cases the tumors are highly invasive and involve areas of the face, especially the regions around the eyes and nose. Other associated features of the Gorlin syndrome (fortunately uncommon) include the following:

• Congenital agenesis of the corpus callosum and medulloblastoma

• Odontogenic jaw cysts

• Bifid ribs and pectus excavatum

• Absent or undescended testes

• Mesenteric lymphatic cysts

• Palmar and plantar pits

• Ectopic calcification (particularly of the falx cerebri)

• Ocular and skeletal abnormalities (eg, hypertelorism, shortening of the fourth and fifth metacarpals)

Causes: Recent studies demonstrate a high incidence of p53 gene mutations in BCC. Researchers speculate that UV sunlight may play an important role in the genesis of this mutation; however, genetic involvement has been demonstrated in the Gorlin syndrome only. The following factors contribute to the risk of developing BCC:

• Skin type

• Amount and nature of accumulated sun exposure over lifetime, especially during childhood

• Personal and family skin cancer history

• Past medical history

• Occupational and recreational activities

• Patient lifestyle (eg, amount of sun exposure)

DIFFERENTIALS

Angiofibroma
Molluscum Contagiosum

Other Problems to be Considered:

Dermatitis
Eczema
Intradermal nevus
Lichenoid benign keratosis
Psoriasis
Ringworm
Sebaceous hyperplasia
Squamous cell carcinoma
Fibroepithelioma of Pinkus (see Histology)

WORKUP

Lab Studies:

• No laboratory studies for BCC are available.

Imaging Studies:

• No imaging studies are available for early diagnosis of BCC.

• Current imaging techniques (eg, ultrasound, CT scan, MRI, scintigraphy) may help to detect the rare metastases.

Procedures:

• To diagnose BCC, perform a skin biopsy of the affected area and the surrounding healthy tissue. This procedure often is curative.

Histologic Findings: A histopathologic examination of paraffin-embedded sections of BCC usually reveals solid cellular strands, collections of cells with dark-staining nuclei and scant cytoplasm. The peripheral cell mass is in a palisade arrangement that resembles the basal layer of the epidermis, sometimes with pseudocystic aspects, and with a variable number of mitoses. The characteristic mucinous stroma develops around the invading tumor. Each subtype of BCC has a specific histologic pattern (ie, desmoplastic reaction of the morpheaform type, stromal islands separated by basal cells strands of the fibroepithelial type). Cells from recurrent BCC often show squamous aspects.

According to some studies, including a recent paper that appeared in The American Journal of Dermatopathology, the so-called fibroepithelioma of Pinkus, considered to be a premalignant skin condition, must be considered as a fenestrated variant of BCC.

Staging: BCC rarely metastasizes and usually is not staged, unless the cancer is very large and is suspected of spreading to other parts of the body. BCC staging may be similar to the staging of squamous cell carcinoma, according to the following scheme:

• Stage 0: Cancer involves only the epidermis and has not spread to the dermis.

• Stage I: Cancer is not large (ie, less than 2 cm) and has not spread to the lymph nodes or other organs.

• Stage II: The cancer is large (ie, >2 cm) but has not spread to lymph nodes or other organs.

• Stage III: The cancer has spread to tissues beneath the skin (eg, muscle, bone, cartilage), and/or has spread to regional lymph nodes, but has not spread to other organs.

• Stage IV: The cancer can be any size and has spread to other organs.

TREATMENT

Medical Care: The therapy of BCC varies according to cancer size, depth, and location. Dermatologists may perform many of the therapies in an outpatient setting. Most therapies are well established and widely applied; yet researchers still are studying some (eg, photodynamic therapy with photosensitizers) and awaiting further reports. Ideally, the treatment options should be evaluated jointly among surgeon, dermatologist, and radiotherapist on the basis of histologic diagnosis.

• Cryotherapy: This therapy uses liquid nitrogen to freeze small superficial lesions, which leaves little scarring. Most patients suffer pain and swelling after the area thaws. Generally, this procedure is not recommended for BCC, especially for morpheaform lesions, deeply invasive and ulcerated lesions, or recurring tumors with ill-defined borders.

• 5-fluorouracil (5-FU): Applying fluorouracil locally may help clinicians to manage BCC in selected patients (eg, for cancers limited to the more superficial layer of skin in elderly patients who do not tolerate other, more aggressive treatment). Apply the drug twice daily for several weeks. During treatment, patients may feel intense inflammation, but scars are unusual. The recurrence rate is very high.

• Radiotherapy: BCCs usually are radiosensitive, and radiotherapy can be used for advanced and extended lesions or when surgery is not suitable (eg, patients who are allergic to anesthetics, on anticoagulant therapy, or have a tendency to form keloids). This type of therapy is contraindicated in young patients because of the high risk of scars, lesions on the trunk and extremities, or cancer recurrence (eg, especially in those previously treated with radiation).

• Systemic retinoids: Many reports show some efficacy for currently available systemic retinoids, but the long-term toxicity of these agents limits their application for most patients.

• Interferons: BCC patients show variable responses to intralesional administration of alpha and gamma interferons.

• Molecular therapy - the next frontier: As well as many other cancers, BCC is related to a malfunction of specific regulatory proteins of cellular proliferation and viability. In particular, reports indicate that almost all forms of BCC result from mutations of the Hh protein. Such specific proteins may represent promising targets for the therapy for BCC.

Surgical Care: As already reported, knowledge of the behavior of the different clinical and pathologic types of BCC is essential in choosing the appropriate therapy. The traditional surgical options involve the use of simple excision, cryosurgery, electrodesiccation, and curettage. BCC recurrence after irradiation makes surgery mandatory.

• Excision: Cut out the lesion, and stitch the skin. This procedure normally is performed during a skin biopsy procedure, leaving at least 4 mm of healthy tissue around the tumor borders. Excision is the best treatment.

• Curettage/cauterization: A single practitioner may perform this combined technique, which allows tumor removal by scraping. The lesion is scratched with a curette and the base cauterized with an electric current to stop the bleeding. This procedure also may be performed for patients with nodular lesions that are less than 2 cm in diameter with well-defined borders. The wound usually heals rapidly without stitches, often with a nonaesthetic scar. The curettage and cauterization procedure is not suitable for patients with morpheaform lesions, for patients with cardiac pacemakers, for the treatment of deeply invasive and ulcerated lesions, or for patients whose recurring tumors have ill-defined borders.

• Mohs surgery: Mohs first performed this procedure, which is a specialized microsurgical technique used for either morpheic or recurrent BCC or BCC appearing on nearby face structures. After a local anesthetic is administered to numb the area, the lesion is shaved off layer by layer. Each layer is checked through the microscope until the entire tumor has been removed. This procedure requires considerable time and is available only in a few centers. According to many authors, this procedure is the standard of care for BCC treatment.

• Plastic surgery: This procedure is very useful for treating lesions larger than 3 mm or for those in a difficult location. Sometimes, surgeons perform this procedure after a simple excision to obtain a more aesthetic result. To perform this procedure, a skin graft or flap is created to repair the defect after excision. This technique is especially useful to reduce the amount of scarring or when rapidly closing a wound.

• Laser surgery: This procedure removes lesions by using a carbon dioxide laser that uses high-energy rays to damage cancer cells and to stop their growth. Routine techniques are not useful in patients with a high risk of bleeding. After treatment, some changes in skin may develop, which may become noticeable many years later.

MEDICATION

Because of surgery efficacy and good patient prognosis, drugs usually are not administered. Drugs and external beam radiotherapy are useful in patients with recurrence or advanced and destructive disease (eg, rodent ulcer, widespread metastases).

Tretinoin, bexarotene, and isotretinoin are being studied as potential therapeutic options. These are mediators of cell differentiation and proliferation, apoptosis, and reproduction. They induce cancer cells to mature, thereby eliminating abnormal proliferation. Therapeutic trials are ongoing in selected patients.

Interferons (alfa and beta) are also being used experimentally. These drugs usually act similarly to native interferons. In vitro, interferon beta seems to have greater antiproliferative effects than interferon alfa.

Because of the experimental therapeutic application of retinoids and interferons, no concordance exists about choice of therapeutic regimens.

Drug Category: Topical antineoplastics -- Topical administration of antineoplastic drugs stops cellular proliferation without (or minimizing) adverse effects.

Drug Name	Fluorouracil (Efudex, Fluoroplex) -- Response to 5-FU identified by degree of blistering, erosion, and necrosis of lesion. After this evolution ends, re-epithelization begins, which may continue 1-2 months after treatment. Treatment may cause local itching, pain, and hyperpigmentation. Used topically for management of superficial BCCs. Interferes with DNA synthesis by blocking methylation of deoxyuridylic acid, inhibiting thymidylate synthetase, and subsequently affecting cell proliferation. Only the 5% strength recommended.
Adult Dose	Apply topically bid for minimum of 3 wk in amount sufficient to cover lesions; therapy may be required for as long as 10-12 wk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; potentially serious infections; pregnancy
Interactions	None reported
Pregnancy	X - Contraindicated in pregnancy
Precautions	Instruct patient to avoid sun exposure, which may exacerbate necrotic reaction of treated area; inflammatory reactions may occur with occlusive dressings; porous gauze dressing may be applied for cosmetic reasons without increase in reaction

FOLLOW-UP

Further Outpatient Care:

• Surgery or radiotherapy often leaves a small scar.

• Temporary blistering is common after cryotherapy.

• Since patients who previously had a BCC may be at a higher risk of developing either another BCC or a different tumor, recommend a yearly follow-up study.

• Instruct the patient and family to prevent further skin damage by using sunscreen with a high sun protection factor (SPF).

Deterrence/Prevention:

• Instruct patients to avoid sun exposure, particularly during the middle of the day (ie, 11:00 am to 3:00 pm), which is the most dangerous time. Also, the sun's rays are especially intense in sunny climates and at high altitudes.

• Educate the patient that use of sunscreens with at least a 15 SPF rating is very useful for any skin cancer prevention. Prevention also includes wearing long sleeves, pants, a hat with a broad brim, and sunglasses with UV protection.

• Children

• Instruct parents to protect their children's skin with sunscreen or protective clothing to reduce risk of BCC later in life.

• Advise parents not to expose children younger than 12 months to direct sunlight and to cover up children aged 12-24 months with a hat, shirt, and a small amount of sunscreen (eg, more than 15 SPF) on the remaining exposed areas.

• For children older than 2 years, instruct parents to consider using sunscreens with SPF 15 or more, covering the child's skin with clothing, or restricting the child to shaded areas.

• Self-examination for skin changes

• Educate patients on how to recognize any unexplained changes in their skin, especially changes that last for more than 3-4 weeks. Also, educate patients on how to examine their own skin. The knowledge of mole distribution on the skin is helpful.
• Tell the patient to first look at the front and back of his or her body in the full-length mirror, using a hand mirror. The patient then should turn and look at each side of the body with the arms raised. Next, the patient should bend the elbows and look carefully at forearms, the back of upper arms, and the palms.
• Instruct the patient to sit down and check the backs of the legs and feet, including the spaces between the toes and bottoms of the feet.

• The patient should use the hand mirror to look at the back of the neck and scalp, the back, and the breeches.

• A dermatologic examination is recommended every 3 years for patients aged 20-40 years and every year for patients older than 40 years.
• Currently, researchers are investigating chemoprevention with systemic administration of retinoids as cancer preventive agents in patients at high risk for developing BCC; however, the utility of these agents will take several years to evaluate.

Complications:

• BCC often is misdiagnosed as ringworm or dermatitis and may be treated as such. If left untreated, a BCC enlarges, reaching considerable size or bleeding.

• Although BCC rarely metastasizes, a tumor can extend beneath the skin to the bone, causing considerable local damage due to tissue destruction. This process leads to an ulcer that is sometimes known as ulcus rodens or a rodent ulcer.

• Fewer than 1% of BCCs spread to another site in the body; however, after treatment, which is curative in more than 95%, BCC may develop in new sites. Recommend appropriate prolonged or lifelong follow-up care.

Prognosis:

• Prognosis is excellent, with a survival rate of 100% for BCC that has not spread to other sites.

Patient Education:

• The American Cancer Society recommends a dermatologic examination every 3 years for patients aged 20-40 years and every year for patients older than 40 years.

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

MISCELLANEOUS

Medical/Legal Pitfalls:

• Failure to diagnose BCC

• Failure to consider the aesthetic consequences of the treatments

• Failure to obtain a treatment consent (ie, explaining all procedures and possible complications)