Basal cell carcinoma (BCC) is defined as the malignant proliferation of the basal cells in the epidermis and its appendages. This is the most common type of skin cancer (80% of skin cancers). Fortunately, this is the type of skin cancer that has the least propensity of metastasis.
Etiology and Risk factors
Both environmental and genetic factors contribute to the development of BCC. Exposure to ultraviolet (UV) radiation in sunlight is the most important. Other established risk factors include chronic arsenic exposure, iatrogenic radiation therapy, long-term immune suppression, and the basal cell nevus syndrome from genetic predisposition and other risk factors that increase UV damage events.
- Sun exposure is the most important environmental cause of basal cell carcinoma. BCC, and most risk factors relate directly to a person’s sun exposure habits or susceptibility to solar radiation. Risk factors of increase susceptibility to UV induced DNA damaged from prolonged sunlight exposure increase all types of skin cancer including BCC.
- Individuals with genetic mutations abnormalities such as Albinism, xeroderma pigmentosum (seen in NER – nucleotide Excision Repair mutation) have higher chances of getting skin cancer in general. Other phenotypic difference that increase susceptibility to UV damage include those having fair skin (Caucasians), light-colored eyes, red hair, older age, childhood freckling.
- The age onset of sun exposure, the frequency and intensity of sun all plays a role in risk of BCC development.
- Childhood UV exposure seemed to be more important than exposure during adulthood. In addition, the frequency and intensity of sun exposure may also be important. Sun exposure in intermittent, intense increments increases the risk of basal cell carcinoma more than a same dose delivered more continuously over the same period of time.
Tanning beds (UVA mainly)
- The use of tanning beds may increase the risk for early development of basal cell carcinoma.
- Population-based case-control study on approximately 650 cases of BCC have shown that tanning bed users had a 60% increased risk of developing a BCC and SCC at or before the age of 50 years especially those who start using tanning beds at an earlier age.
- Therapeutic exposure to psoralen plus ultraviolet A light (PUVA) for cutaneous disorders such as psoriasis increases the risk of non-melanoma skin cancer, particularly SCC. The risk of BCC in patients treated with PUVA is lower than the risk for cutaneous SCC, but there is still a modest increase in risk for BCC compared to individuals without PUVA treatment.
- Broad band ultraviolet B (UVB) and narrow band UVB phototherapy appear to be less likely to promote the development of non-melanoma skin cancer than PUVA however, more research and studies are necessary to determine the true cancer causing potential of these therapies.
- Due to the association of basal cell carcinoma with UV light exposure, there are questions as to whether the use of photosensitizing medication can increase risk of development of BCC and SCC.
- An association between prior use of photosensitizing drugs such as tetracycline and increased risk for BCC has been documented in several observational studies. However, additional studies are necessary to clarify the relationship between photosensitizing drugs and BCC.
- Smoking increases the risk of squamous cell carcinoma (SCC) but there has been conflicting results to demonstrate the increase risk of BCC in smokers.
Chronic Arsenic Exposure
- Superficial multicentric basal cell carcinoma has been associated with chronic arsenic exposure.
- These exposure usually requires about 30 to 40 years duration typically via ingestion of contaminated medication, water and seafood etc.
- This risk factor is also associated with increased risk for SCC
- Chronic superficial ionizing radiation exposure has been associated with increased risk of developing non-melanoma skin cancer, including basal cell carcinoma. The pathogenesis has to do with damage to the DNA structures which ultimately lead to carcinogenesis.
- Immune suppression following HIV or medication induced after organ transplant have been associated with increased risk for basal cell carcinoma. While the extend of increase is more prominently for squamous cell carcinoma (SCC) skin cancer, immune suppression is a recognized risk factor for basal cell carcinoma.
- Patients whose immune system are chronically suppressed (such as HIV and solid organ transplant recipient) are therefore at increased risk for the development of basal cell carcinoma, although the increase in risk is less than that observed for SCC.
- As mentioned, the increased risk for SCC skin cancer is more significant than BCC. The risk for BCC after solid organ transplantation tend to increase linearly whereas for SCC, the risk increases exponentially.
- Although the increased risk for BCC in immune suppressed individuals are clearly elucidated, the association between use of systemic corticosteroid and BCC has not been clearly demonstrated.
- Genetic variation among individuals may play a role their susceptibility to basal cell carcinoma. Some genetic variants that have been associated with increased risk of BCC correlate with light skin pigmentation. This include albinism and fair skinned individuals.
- Another genetic component that may play a part in BCC risk is the master tumor suppressor P53.
- Other genes that play a role in BCC risk is the CTLA-4 gene that affect the immune response. The CTLA-4 gene, also known as Cytotoxic Lymphocyte-Associated Antigen-4 (CTLA-4) is expressed on regulatory T cells and is involved in UV-induced immune tolerance. UV exposure may therefore induce CTLA-4 expression and cause immune suppression.
Several inherited disorders have been shown to predispose individuals to basal cell carcinoma.
Basal cell nevus syndrome
- The basal cell nevus syndrome, also known as (nevoid basal cell carcinoma syndrome) or (Gorlin syndrome) is an autosomal dominant disorder that is caused by germline mutations of the human patched gene (PTCH). Patients with such genetic predisposition have developmental anomalies as well as tumors at birth. Multiple basal cell carcinoma are usually present by age 35.
- PTCH1 gene: This gene is a tumor suppressor gene located on chromosome 9 in patients with the familial basal cell nevus syndrome. Mutation can also be acquired and present as sporadic BCC and BCC associated with xeroderma pigmentosum.
- Most have these patients have the following clinical presentations:
- Macrocephaly, frontal bossing and widely spaced eyes
- Calcification of the falx cerebri
- Bifid ribs
- Palmar and plantar pitting
- Bone cysts (especially in the mandible)
- The epidermolysis bullosa (EB) syndromes are a group of mechanobullous skin diseases that share a common feature of blister formation occurring with little or no trauma
- Nevus sebaceous is a rare congenital hamartoma of the skin composed of epidermal, follicular, sebaceous, and apocrine elements. Basal cell carcinoma has been shown to arise within nevus sebaceous in rare conditions (1%).
Symptoms and Clinical Presentations
Most (60%) of the BCC lesions occur on the face and neck, 27% on the trunk and about 20% on the upper and lower extremities. The clinical presentation of BCC can be divided into three groups, based upon lesion histopathology: Nodular, Superficial, and Morpheaform.
- Nodular BCCs comprise about 60% of BCC cases. They typically present on the face as a pink, pearly or flesh-colored papule. The lesion usually has a pearly (translucent) appearance and a telangiectatic vessel is commonly seen within the papule. Ulceration is frequent and often described with the term “rodent ulcer”.
- About 30% of BCCs are superficial BCCs. Men usually have a higher incidence of superficial BCC than women. They tend to grow slowly and vary in size from several millimeters to several centimeters in diameter if untreated.
- Unlike nodular BCC that most often occur on the face , superficial BCCs most commonly occur on the trunk, and classically present as slightly scaly patches, or pink to reddish thin plaques.
- The core of the lesion may show an atrophic appearance with surrounding rimmed with fine translucent papules. When illuminated, a shiny quality may be evident when a superficial BCC.
- Sometimes, a brown black spotty pigment may be present and cause confusion with melanoma.
- Morpheaform BCC or sclerosing BCCs constitute about 5-10% of basal cell carcinoma.
- Morpheaform BCC lesions are usually smooth with a flesh-color that are commonly described as erythematous papule or plaque that can be atrophic will ill defined borders.
Clinicians who have a trained eye can usually diagnosed BCC clinically. However, a skin biopsy is usually performed to provide histologic confirmation of the diagnosis.
In situation where the clinical diagnosis for BCC is certain and the tumor lack clinical features of high risk recurrence, the doctor may choose to do a biopsy while definitive treatment is performed such as electrodessication and curettage. In contrast, some doctors may choose to forego biopsy and just treat the lesion when there are no features of high risk recurrence.
However, some doctors may choose to do biopsy for any type of skin cancer just to be safe in case an aggressive tumor is missed and cause inappropriate management.
To reduce the chance of inappropriate for patient mismanagement, the following are pointers that many doctors will proceed with biopsy when present:
- The patient lacks a prior history of BCC
- The lesion exhibits clinical features suggestive of a BCC with a high-risk for recurrence
- The diagnosis is uncertain or the lesion exhibits features atypical for BCC
Treatment and Management
Basal cell carcinomas (BCCs) can present with a variety of clinical and pathologic features. The choice of therapy depends on the lesion characteristic, patient factors. Some of the treatment options include the following:
- Electrodesiccation and curettage (ED&C)*
- ED&C is a fast and efficacious treatment for BCC. However, this procedure does not allow histologic confirmation of tumor. It is most often used for low risk superficial or nodular BCCs found on the trunk or upper/lower extremities.
- ED&C is not recommended for BCC suggestive of high risk recurrence.
- In addition, the hypopigmented scar that develops after treatment limits its use on cosmetically sensitive areas such as the face
- Surgical excision
- Surgical excision of BCC is used for the treatment of both low and high risk recurrence BCC.
- It is a highly efficacious treatment that can be performed faster than Mohs surgery and is relatively in expensive. The excised tissue sample are typically also sent for pathology evaluation for tumor margin.
- Mohs micrographic surgery
- Mohs surgery is a specialized surgical technique that effectively control tumor margin and at the same time minimize the amount of normal tissue resected.
- This procedure is usually reserved for tumors that are of high risk of recurrence and for situations where tissue sparing is warranted such as cosmetic reasons.
- Topical Therapy
- Topical medication for treatment of BCC includes 5-fluorouracil (5-FU) and imiquimod. These 2 agents need to be applied for weeks to months with concomitant inflammatory reactions at the lesion.
- 5-Fluorouracil interferes with DNA synthesis by inhibiting thymidylate synthetase, hence, prevent rapidly proliferating cells (which are most sensitive to this medication) to die. There is limited evidence to support the use of 5-FU for treatment for superficial BCC. 5-FU is only considered if superficial BCC in a noncritical location.
- Imiquimod cream is an immune response modifier used for treatment of low risk superficial BCC. This medication promotes apoptosis in skin cancer cells by interfering with the anti-apoptotic pathways in tumor cells. It also stimulated the immune system (mainl macorphages and dendritic cells to produce cytokines that stimulate the cell mediated immune system. Hypopigmentation may develop after treatment, including itch, redness, bleeding and sometimes pain. Some studies have suggested using imiquimod on nodular form of BCC but the results are only modest and typically co-treated with surgical procedures.
- Intralesional Therapy
- Intralesional therapies are not commonly used due to limited efficacy and multiple side effects. Commonly used intralesional agents include interferons, 5-fluorouracil (5-FU) and bleomycin. There is limited evidence and result for intralesional 5FU and bleomycin.
- Due to limited evidence of efficacy, there use are generally reserved for patients in whom surgical therapy is not an option, especially in the setting of lesions at high risk for recurrence.
- Radiation therapy
- Radiation therapy, like intralesional agent treatment are options for patients who are poor candidates for surgical intervention and have high risk recurrences and have long term adverse effects.
- Photodynamic therapy
- Photodynamic therapy (PDT) is another procedures where light and porphyrins are used to cause tumor cell death. PDT lead to a high concentration of porphyrins within the tumor cells and the ability to focus light on the involved area. It has a cure rate of up to 90% used for superficial and nodular BCC. This technique is not approved for use by the FDA by has been used in many European countries