BASAL CELL CARCINOMA
Basal cell carcinoma (BCC) is the most common malig- nancy in humans. Its true incidence is unknown, but the number of BCCs diagnosed each year easily surpasses the number of all other malignancies combined. It is estimated to affect approximately 25% to 33% of the U.S. Caucasian population over their lifetimes. The yearly number of BCCs diagnosed is quickly approaching 1 million. BCC rarely metastasizes or causes mortality. The real crisis it presents is in the significant morbidity and cost to the health care system. The vast majority of these lesions are located on the head and neck region and are of considerable cosmetic concern. The major morbidity involved is the significant disfigurement that these locally invading tumors can inflict.
Clinical Findings: The prototypical BCC is described as a pearly red papule with telangiectasias that has a rolled border and a central dell or ulceration. They occur with highest frequency in sun-exposed areas of the skin. Most BCCs start as a small red macule or papule and slowly enlarge over months to years. Once this occurs, the tumor may be friable and may bleed easily with superficial trauma. The tumors most commonly range in size from 1 mm to 1 cm. However, neglected tumors can be enormous and have been reported to cover areas up to 60 cm2 or more. They affect males and females with equal frequency. BCCs are more common in individuals with Fitzpatrick type I skin and decrease in frequency as one moves across the skin type spectrum. Fitzpatrick type VI skin has the lowest incidence of BCC, but these individuals still can develop these tumors. BCCs occur with an increasing frequency with age. They are uncommon in childhood, with the exception of the association of childhood BCCs with the nevoid BCC syndrome (also called basal cell nevus syndrome or Gorlin’s syndrome).
The tumors are most likely to occur (>80%) on the head and neck region. The trunk is the next most common area. The vermilion border, the palms and soles, and the glans theoretically should not develop BCCs because these areas are devoid of hair; however, they can be affected by direct extension from a neighboring tumor. These tumors rarely metastasize, and those that do are most often neglected large tumors or tumors in immunosuppressed patients. BCC most commonly metastasizes to regional lymph nodes and the lung.
Many clinical variants of BCC exist, including superficial, pigmented, nodular, and sclerotic or morpheaform variants. There are many other histological variants. Clinically, a superficial BCC manifests as a very slowly enlarging, pink or red patch without eleva- tion or ulceration. If left alone for a long enough period, it will develop areas of nodularity or ulceration. Nodular BCCs are probably the most common variant; they manifest as the classic pearly papule with telangiectasias and central ulceration. The pigmented variant can mimic melanoma and is often described as a brown or black papule or plaque with or without ulceration. Early on, these types of BCCs can appear as pearly papules or plaques with minute flecks of brown or black pigmentation. Patients with the sclerotic or morpheaform version often have larger tumors at presentation because of their slow, inconspicuous growth pattern. These slow-growing tumors are almost skin colored and have ill-defined borders. They tend not to ulcerate until they have become large, and this often delays the seeking of medical advice. These tumors can mimic the appearance of scar tissue, which can also hinder making the diagnosis. Eventually, the tumor enlarges enough to cause ulceration or superficial erosions, and the diagnosis is made. The sclerotic BCC is often much larger than the other variant types at the time of diagnosis.
The most important genetic syndrome associated with the development of BCCs is the nevoid BCC syndrome. This syndrome is inherited in an autosomal dominant fashion and is caused by a defect in the patched 1 gene, PTCH1. This gene is located on chromosome 9q22. It encodes a tumor suppressor protein that plays a role in inhibition of the sonic hedgehog signaling pathway. A defect in the patched protein allows for uncontrolled signaling of the smoothened protein and an increase in various cell signaling pathways, ultimately culminating in the development of BCCs. Patients with nevoid BCC syndrome also may have odontogenic cysts of the jaw, palmar and plantar pitting, various bony abnormalities, and calcification of the falx cerebri. Frontal bossing, mental delay, and ovarian fibromas are only a few of the associated findings that can be seen in this syndrome.
Other rare syndromes in which BCCs can be seen include xeroderma pigmentosa, Bazek’s syndrome, and Rombo syndrome.
Pathogenesis: Risk factors associated with the devel- opment of BCC include cumulative exposure to ultra- violet radiation and ionizing radiation. In the past, arsenic exposure was a well-recognized cause of BCCs, and arsenic pollution is still a concern in some areas of the world. Since the advent of organ transplantation, there has been an increase in the development of skin cancers in immunosuppressed organ recipients. The incidences of BCC, squamous cell carcinoma, and mel- anoma are all increased in these chronically immunosuppressed patients. Mutations of various genes have also been implicated in the pathogenesis of BCCs, including PTCH1, p53 ( TP53), sonic hedgehog (SHH), smoothened (SMO), and the glioma-associated oncogene homolog 1 (GLI1). However, it is still believed that most BCCs are sporadic in nature.
The greatest amount of information is known about the pathogenesis of BCC in the nevoid BCC syndrome. The genetic defect in the PTCH1 gene allows for uncontrolled signaling of the smoothened signaling pathway. This pathway initiates uncontrolled signaling of the GLI1 transcription factors, which ultimately leads to uncontrolled cell proliferation.
Histology: Many histological subtypes have been described, and a tumor can show evidence of more than one subtype. The most common subtypes are the nodular and superficial types. These tumors arise from the basaloid cells of the follicular epithelium. The tumor always shows an attachment to the overlying epidermis. The tumor extends off the epidermis as tumor lobules. These lobules are basophilic in nature and show clefting between the basophilic cells and the surrounding stroma. The cells have a characteristic peripheral palisading appearance. The cells in the center of the tumor lobules are disorganized. The ratio of nuclear to cytoplasmic volume in the tumor cells is greatly increased. Mitoses are present, and larger tumors usually have some evidence of overlying epider- mal ulceration. The tumor is contiguous and does not show skip areas. The nodular form of this tumor extends into the dermis to varying degrees, and its depth of penetration is dependent on the length of time it has been present.
The superficial type is also quite common. The tumor does not extend into the underlying dermis but appears to be hanging off the bottom edge of the epidermis. It has not yet penetrated the dermal-epidermal barrier. There are numerous other histological subtypes of BCC including micronodular, adenoid, cystic, pigmented, infiltrative, and sclerosing varieties.
Treatment: Various surgical and medical options are available, and the therapy should be based on the location and size of the tumor and the wishes of the patient. Tumors on the face are most often treated with Mohs micrographic surgery. This surgical technique allows for the highest cure rate and is tissue sparing, resulting in the smallest possible scar. It is more labor intensive than a routine elliptical excision. Most BCCs can be treated with an elliptical excision or electrodessication and curettage.
Medical therapy with imiquimod or 5-fluorouracil has also been shown to be useful in selected BCCs, usually the small, superficial type. One of the newest treatments is photodynamic therapy. It is performed by applying aminolevulinic acid to the skin tumor and then exposing the area to visible blue light. An oral inhibitor of the smoothened protein, called GDC-0449, has shown excellent results in patients with the nevoid BCC syndrome.