AUTHOR AND EDITOR INFORMATION

Section 1 of 8  

• Authors and Editors
• Introduction
• Clinical Presentation
• Differential Diagnosis
• Treatment
• Prognosis
• Multimedia
• References

INTRODUCTION

Section 2 of 8  

• Authors and Editors
• Introduction
• Clinical Presentation
• Differential Diagnosis
• Treatment
• Prognosis
• Multimedia
• References

Epidemiology

Basal cell carcinoma (BCC) is the most common cancer of white populations, with an estimated 900,000 cases per year in the United States. BCC most frequently occurs in light-skinned older patients with a history of ultraviolet (UV) exposure.

The incidence of BCC increases with age. In individuals aged 55-75 years, the incidence is about 100 times higher than the rate in those younger than 20 years. BCCs tend to begin after the age of 30 years and peak at the age of 70 years. It occurs more often in men than in women, likely because of their increased UV exposure.

The incidence of BCC also varies geographically. States that are close to the equator, such as Hawaii, have an incidence almost 3 times that of states in the Midwest, such as Minnesota. The incidence of BCC also varies globally. Australia has had some of the highest reported rates of BCC, with an increasing trend in incidence. Finland, on the other hand, has a low reported incidence of approximately one quarter that of Minnesota. However, the trend in Finland also appears to be increasing, especially in young women.

Etiology and molecular genetics

The etiology of BCC is unknown; however, evidence suggests that BCC may arise from the pluripotent cells in the basal layer or follicles of the skin. Mutations in the PATCHED (PTCH) gene, a negative regulator of hedgehog signaling, located on chromosome 9 appear to be responsible for the tumor growth in basal cell nevus syndrome (BCNS), an autosomal condition characterized by multiple BCCs. Mutations in the PTCH gene have also been reported in sporadic cases of BCC and xeroderma pigmentosum associated with BCC. A recent study that focused on cases of sporadic BCC showed that almost half of the tumors examined bore PTCH gene mutations, and the percentage and type of these mutations did not differ significantly among patient groups that had regular, multiple, or early-onset BCC.

The PTCH protein is a receptor for the hedgehog (HH) protein, a component of the sonic hedgehog (SHH) signaling pathway critical in embryonic development. When HH binds the PTCH receptor, the Smoothened (SMO) protein is released from PTCH-mediated inhibition. This cascade results in alterations in gene expression by the Gli transcription factor family. The HH pathway is constitutively active in BCCs in the absence of ligand due to mutations in PTCH of SMO. Mouse models show that continued HH signaling is required for growth of established BCCs. Little is known about how this cellular defect causes its tumorigenic effect.

UV-B radiation causes DNA damage on the p53 tumor-suppressor gene. About 50% of BCCs evaluated have mutations of this gene. In addition, frameshift mutations of the BAX gene (bcl-2–associated X protein) have been found in sporadic cases of BCC. A reduction of bcl-2 proteins is observed in the aggressive, infiltrative type of BCC.  A recent study also showed an association of a COX-2 gene variant with a lower risk of developing BCC in patients who underwent organ transplantation before the age of 50; this finding suggests a possible role for dysregulation of COX-2 expression in carcinogenesis. 

Predisposing factors include exposure to UV radiation, therapeutic radiation therapy, long-term exposure to arsenic, immunosuppression (eg, due to immunosuppressants or AIDS), HPV infection, chronic ulcers, scars, burns, certain genodermatoses (eg, BCNS, xeroderma pigmentosum, albinism, Bazex syndrome), and certain long-standing dermatoses (eg, nevus sebaceous, porokeratosis, linear epidermal nevi). Sunlight exposure during childhood and adolescence seems to be a risk factor. An increased number of BCCs, as well as an increased level of aggression, may be seen in immunosuppressed patients, such as renal transplant recipients.

Histopathology

In general, BCCs are made up of nests of basaloid cells with peripherally palisading cells. The cells have hyperchromatic nuclei and scant cytoplasm. The nests of tumor cells are surrounded by stroma. Intercellular bridges are not visible on light microscopy. Mitotic figures are common. Ulceration is not uncommon in large tumors. In long-standing or aggressive lesions, extension is often diffuse or in the paths of cutaneous adnexae. Perineural invasion is seen in about 1% of cases, more frequently in aggressive forms of BCC. A variable inflammatory infiltrate is often present, usually with a majority of (CD4+) T cells.

Numerous morphologic subtypes have been described, including solid or nodular, micronodular, cystic, (multifocal) superficial, pigmented, adenoid, infiltrating, sclerosing, keratotic, infundibulocystic, metatypical, basosquamous, and fibroepitheliomatous types. Tumors with mixed patterns can be common, and other rare morphologic subtypes have also been described.

The solid (nodular) type accounts for approximately 70% of all cases. This type is characterized by islands of cells with peripheral palisading and disorganized central cells. Retraction spaces can usually be observed between the islands and stroma. Ulcerations may be seen in large tumors.

The micronodular type is similar to solid except the islands or nests are small, and the peripheral palisading can be less developed than it is in other types. This type is more likely to recur than the solid type.

The cystic type contains at least 1 cystic space near the center of some or all tumor nests; this space is caused by central tumor cell degeneration.

The (multifocal) superficial type is characterized by numerous small nests of tumor cells usually attached to the undersurface of the epidermis by a broad base. Approximately 10-15% of all BCCs are of this type. This is the most common pattern seen in BCCs of the shoulder.

The pigmented type histologically appears like the nodular type. Functional melanocytes are found among the tumor islands, and many melanophages are present in the stroma. Melanin is usually formed in the solid, micronodular, multifocal superficial, or follicular types. Pigmented type is most common in people of African American or Hispanic descent.

The adenoid type consists of strands of basaloid cells in a reticulate pattern, frequently with prominent stromal mucin. It may occur with the solid type.

The infiltrating type has an infiltrative rather than expansile growth pattern. Elongated strands of basaloid cells are seen, 4-8 cells thick, infiltrating between collagen bundles.

The sclerosing type accounts for approximately 5% of all BCCs. It consists of narrow, elongated strands and small nests of cells embedded in a dense, fibrous stroma.

The keratotic type resembles the solid type and its nests of basaloid cells with peripheral palisading. The island centers display keratinization and squamous differentiation.

The infundibulocystic type is rare and usually found on the face. It resembles the keratotic type. Nests are arranged in an anastomosing pattern and lack stroma. Many small, infundibular cystlike structures with keratinous material are present. Melanin is sometimes present.

The metatypical type is rare. In this type, nests and strands of cells mature into larger and paler cells, peripheral palisading, if any, is less developed than in other types. Prominent stroma, prominent mitotic activity, and many apoptotic cells may be present. This form may be best diagnosed when one evaluates a BCC with features between those of a nodular BCC and squamous cell carcinoma (SCC). These tumors are often aggressive, with an increased tendency for lymphatic and perineural spread.

The basosquamous type is controversial. It has been defined as a BCC differentiating into an SCC. It is made up of basaloid cells that are a larger, paler, and rounder than those of a solid BCC. It also consists of squamoid cells and intermediate cells. Some consider the diagnosis of this type most appropriate when one evaluates a tumor with contiguous areas of BCC and SCC. This type is considered to have metastatic potential.

The fibroepithelioma type consists of thin, anastomosing strands of basaloid cells in a prominent stroma.

CLINICAL PRESENTATION

Section 3 of 8  

• Authors and Editors
• Introduction
• Clinical Presentation
• Differential Diagnosis
• Treatment
• Prognosis
• Multimedia
• References

Up to 80% of BCCs occur on the head and neck. About 15% occur on the shoulders, back, or chest. A patient who has a history of 1 BCC, especially a truncal BCC, has an increased likelihood of developing another. About 60-70% of BCCs are accurately diagnosed despite their variable appearance.

Symptoms

Progressive growth of a lesion (may be accompanied by bleeding and/or ulceration) is indicative of BCC.

Signs

Skin findings include the following:

• Nodular BCC (the most common variant) is characterized by skin-colored, dome-shaped papules with telangiectasias and a pearly border. The lesions may be crusted or ulcerated, and they may be associated with intermittent bleeding.

• Pigmented BCC manifests with features of the nodular type of BCC associated with black or brown pigmentation; therefore, this condition is more common in dark-skinned individuals than in others.

• Superficial BCC is characterized by an erythematous, scaly plaque that has a slightly raised border. This condition may be associated with erosion or crusting and is most commonly observed on the trunk.

• Morpheaform (sclerosing or infiltrating) BCC manifests as an indurated white-to-waxy plaque with ill-defined margins resembling a scar. This type of cancer is most commonly observed in the head and neck area.

• BCNS or Gorlin syndrome is an autosomal dominant disorder characterized by multiple BCCs, palmar and plantar pits, odontogenic keratocysts of the jaws, calcification of the falx cerebri, bifid ribs, hypertelorism, and partial agenesis of the corpus callosum. The lesions tend to develop between puberty and the age 35 years and appear as smooth, skin-colored papules resembling skin tags. This syndrome may be associated with medulloblastomas, cardiac fibromas, and ovarian fibromas.

Diagnosis

BCC is diagnosed on clinical examination and confirmed on skin biopsy. The resultant histopathologic classification is used to select the appropriate treatment modality. The usual histopathologic finding of nodular BCC consists of masses of basaloid cells with peripheral palisading of the nuclei.

DIFFERENTIAL DIAGNOSIS

Section 4 of 8  

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• Clinical Presentation
• Differential Diagnosis
• Treatment
• Prognosis
• Multimedia
• References

Nodular BCC

• Fibrous papule
• Sebaceous hyperplasia
• Nevus
• Seborrheic keratosis
• Amelanotic melanoma
• Adnexal neoplasms (generally trichoepitheliomas)

Pigmented BCC

• Malignant melanoma
• Pigmented seborrheic keratosis
• Angiokeratoma
• Traumatized nevus

Superficial BCC

• Nummular eczema
• Psoriasis
• Extramammary Paget disease
• Bowen disease

Morpheaform BCC

• Scar
• Localized scleroderma

TREATMENT

Section 5 of 8  

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• Treatment
• Prognosis
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• References

The main goal of treatment is to eradicate the tumor while maintaining the best cosmetic and functional results. For a small low-risk BCC, defined as a lesion less than 2 cm in diameter with a nonaggressive histopathology and located in an area that is not high risk, treatments may include electrodesiccation and curettage (3 cycles recommended), conventional excision (4-mm margins recommended), and cryosurgery (2 cycles of freezing to -50°C to -60°C recommended).

Other less common methods include use of intralesional interferon (reported cure rate <80%), intralesional bleomycin with electrochemotherapy (high cure rates reported but no long-term recurrence rates available), and topical 5-fluorouracil (long treatment with high 5-year recurrence rates).

Imiquimod (Aldara) is an immunomodulator thought to act by promoting apoptosis in skin cancer cells. It has been approved for only the treatment of superficial BCCs in low-risk sites. In 2 multicenter trials, 724 patients with superficial BCC were randomly assigned to receive topical imiquimod once daily 5-7 times per week for 6 weeks or placebo (vehicle alone). Histologic clearance rates were 82% and 79% for the 5- and 7-day treatment groups, respectively, compared with 3% for the placebo group.¹ In earlier trials, histologic cure rates neared 90% with once-daily application for 6-12 weeks.^{2, 3} Imiquimod may be a reasonable alternative in patients who are poor surgical candidates. Depending on the adverse effects, a once- or twice-daily regimen may be used.

The acetylenic retinoid tazarotene (Tazorac) can also be used to treat small low-risk BCCs. Tazarotene is thought to cause BCC regression by increasing apoptosis and by decreasing cell proliferation in the skin cancer cells. One case series involved the application of tazarotene 0.1% gel for 24 weeks in 154 small, superficial, and nodular BCCs (109 patients). Changes were followed up by dermoscopy and histologic examination. About 70.8% of the BCCs had clinical and dermoscopic regression of >50%, and 30.5% healed without recurrence after 3 years. Most unresponsive tumors showed keratotic differentiation.⁴

For patients who are poor surgical candidates or for those with lesions in difficult-to-treat areas, irradiation may be indicated.

High-risk BCCs include the following:

• Recurrent or incompletely excised BCC
• Primary BCC with indistinct borders
• Lesions located in high-risk (the H, or mask) areas, which involve mainly the embryonic fusion planes such as the eyelids, nose, ear, nasolabial folds, upper lip, vermillion border, columella, periorbital region, temples, preauricular and postauricular areas, and the scalp
• Lesions that develop in cosmetically and functionally important areas, such as the face, the genitals, anal and perianal regions, hands and feet, and the nail unit areas
• Tumors with aggressive clinical behavior, eg, tumors that are growing rapidly or > 2 cm
• Tumors with aggressive histologic subtype
  • BCC-sclerosing (morpheaform)
  • Basosquamous (metatypical or keratinizing)
  • Perineural, periappendageal, or perivascular invasion
  • Infiltrating
  • Adenoidal
  • Multicentric
• Tumors that develop in sites with previous radiation therapy
• Tumors that develop in immunosuppressed patients

The treatment of choice is Mohs micrographic surgery because this technique offers the highest cure rate (98-99%) with maximal conservation of normal tissue. The following is a list of treatments and their 5-year recurrence rates for primary BCCs:

• Surgical excision - 10.1%
• Radiation therapy - 8.7%
• Curettage and electrodesiccation - 7.7%
• Cryotherapy - 7.5%
• All non-Mohs modalities - 8.7%
• Mohs micrographic surgery - 1.0%

These rates are probably affected by the fact that clinicians use cryotherapy and curettage and desiccation mostly on smaller and better-demarcated lesions.

PROGNOSIS

Section 6 of 8  

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• Differential Diagnosis
• Treatment
• Prognosis
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• References

BCC is a slow-growing tumor that invades and destroys surrounding tissues. The 5-year recurrence rate is about 5%, but it depends on the type of treatment. The rate is 1% for BCCs treated with Mohs surgery. Most reports show that the distance to the closest resection margin is an important predictor of recurrence.

Recurrences usually occur 4-12 months after initial treatment, and the risk of developing a second lesion is about 40%. Recurrence is most common for BCCs on the nose and nasolabial fold, but this observation may be secondary to lack of adequate margins obtained in these areas. Infiltrative, micronodular, and multifocal types are more likely than nodular types to recur.

Tumors occurring after radiotherapy tend to be more aggressive and infiltrative than other tumors. Metastasis is rare but has been reported with rates of 0.01-0.1%. Metastases most often originate from large, ulcerated tumors. Metastases usually occur in regional lymph nodes. Follow-up visits are scheduled 3 months after therapy and every 6 months to 1 year thereafter for the life of the patient.

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

MULTIMEDIA

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• Differential Diagnosis
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Media file 1:  Nodular basal cell carcinoma. Nodular aggregates of basalioma cells are present in the dermis and exhibit peripheral palisading (PP) and retraction artifact (RA). Melanin is also present in the tumor and in the surrounding stroma, as observed in pigmented basal cell carcinoma. Image courtesy of Michael L. Ramsey, MD.
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Media file 2:  Histology of superficial basal cell carcinoma. Nests of basaloid cells are observed budding from the undersurface of the epidermis. Image courtesy of Michael L. Ramsey, MD.
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Media file 3:  Keratotic basal cell carcinoma. Rare type characterized by keratocysts.
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Media file 4:  Infiltrative basal cell carcinoma. Tumor cells are arranged in narrow strands, and mucin-rich stroma is often present.
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Media file 5:  Micronodular basal cell carcinoma often has an absence of retraction artifact. The characteristic histology is small size and uniformity of the tumor nodules.
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Media file 6:  Basosquamous basal cell carcinoma. Foci of neoplastic cells with squamous differentiation are present.
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REFERENCES

Section 8 of 8

• Authors and Editors
• Introduction
• Clinical Presentation
• Differential Diagnosis
• Treatment
• Prognosis
• Multimedia
• References

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Article Last Updated: Aug 16, 2007