Nonmelanoma Skin Cancers
Basal Cell and Squamous Cell Carcinomas
Gary S. Wood, Yaohui Gloria Xu, Juliet L. Aylward, Vladimir Spiegelman, Erin Vanness, Joyce M.C. Teng and Stephen N. Snow
Summary of Key Points
Incidence
• More than 2 million new cases of nonmelanoma skin cancer (NMSC) occur annually in the United States, including 80% basal cell carcinomas (BCCs), 20% squamous cell carcinomas (SCCs), and a few rarer types.
• Incidence is increasing 2% to 3% per year.
• Fifteen percent to 43% of solid organ transplant recipients will develop NMSC within 10 years.
Biological Characteristics
• Ultraviolet radiation from sun exposure is a major risk factor, causes mutations in key genes and explains the predilection of NMSC for sun-exposed skin.
• Hedgehog signaling pathway mutations are involved in BCC pathogenesis.
• p53 Mutations are involved in both SCC and BCC pathogenesis, as well as in the development of actinic keratoses, which are the precursors of SCCs.
• There are several histopathologic subtypes of each NMSC.
• The more infiltrative or poorly differentiated variants are more clinically aggressive (e.g., morpheaform BCC and spindle cell SCC).
Staging Evaluation
• TNM staging classifications exist for most types of NMSC and depend on clinical characteristics, pathological features and radiologic evaluation of the primary tumor, adjacent structures, lymph nodes, and viscera.
• BCCs that are large, deep, or infiltrative may be locally aggressive and recurrent, but metastasize only rarely (<0.05%).
• SCCs have a greater metastatic rate, especially those that are large, deep, have perineural invasion, or are located on the dorsal hands, lips, ears, penis, or sites of chronic infection, ulceration, or radiation.
Primary Therapy and Results
• Primary treatment for both BCCs and SCCs is surgical. Mohs surgery is preferred for ill-defined or aggressive lesions because it allows microscopic control of tumor margins.
• The 5-year recurrence rate for BCC is 1% for Mohs surgery compared to 5% for other types of surgical excision.
• Alternative primary therapies include various forms of physical destruction and radiation therapy.
• Interferons and inducers of interferons (e.g., imiquimod) are useful in selected cases. Retinoids, hedgehog pathway agents, and difluoromethylornithine are other promising chemopreventive and adjunctive modalities.
Locally Advanced and Metastatic Disease
• Local recurrence is a problem for large, deep, or histologically infiltrative variants. SCCs with these features may also metastasize. The 5-year survival for patients with metastatic SCC is <50%.
• The rarer forms of nonmelanoma skin cancer have a significantly more aggressive clinical course as compared with BCC and SCC. These include sebaceous carcinoma, Merkel cell carcinoma, dermatofibrosarcoma protuberans (DFSP), and cutaneous angiosarcoma.
• Combinations of surgery, radiation therapy, and chemotherapy can be used for metastatic disease.
1. She is interested in knowing what is the most appropriate treatment choice for her. What would you recommend and why?
A Mohs micrographic surgery. Regardless of the size or histologic subtype, Mohs surgery is the treatment of choice because her BCC is located in a high-risk anatomic location.
B Review pathological subtype. If it was superficial BCC, then topical treatment might be favored over Mohs micrographic surgery.
C Excision with 4-mm margins because it is a small tumor.
D Electrodessication and curettage (ED&C) because ED&C is efficient for such a small tumor.
E Use GDC-0449 (Vismodegib) because it is a new FDA-approved drug specifically targeting mutations in BCC.
2. It is her first skin cancer and she is extremely anxious about her long-term prognosis. She asks how to prevent new skin cancers. What is the most important thing for her to do to reduce her risk of skin cancer?
A Apply topical retinoid products at night.
B Visit her dermatologist every 6 months.
C Sign up for free skin cancer screening every year.
D Minimize exposure to ultraviolet light.
E Receive photodynamic therapy to reduce precancerous lesions.
3. A 60-year-old white man working in the construction business presents with a biopsy-proven SCC on the vermillion lower lip. He is otherwise healthy and he is not a smoker. There has been a rough red patch for 3 years prior to the recent development of a painful, ulcerated plaque with ill-defined margins. A deep shave skin biopsy reveals invasive SCC with perineural invasion. No prior treatment. What factor is most likely to elevate his risk of developing lymph node metastasis?
4. Which of the following statements regarding Merkel cell carcinoma is correct?
A Merkel cell carcinoma is also known as trabecular carcinoma because the most common histologic subtype is the trabecular variant.
B Merkel cell polyomavirus (MCPyV) is associated with poor prognosis and can be used as a novel therapeutic target.
C Similar to other cutaneous cancers, the value of sentinel lymph node biopsy (SLNB) is still uncertain in cases of Merkel cell carcinoma.
D The clinical presentation of Merkel cell carcinoma is relatively specific; therefore, it should not be misdiagnosed by an experienced physician.
E Most cases of Merkel cell carcinoma are managed by wide local excision along with sentinel lymph node biopsy, followed by adjuvant radiotherapy to the primary site and the regional lymph node draining system.
5. A 75-year-old white male presents with a painless, rapidly enlarging subcutaneous tumor on his vertex for 2 months. A biopsy confirms the diagnosis of cutaneous angiosarcoma. How would you counsel this patient?
A Cutaneous angiosarcoma (CAS) is a rare, extremely malignant tumor originating from endothelial cells of vascular or lymphatic differentiation.
B The exact etiology of CAS remains unclear. However, chronic lymphedema and prior radiotherapy are well-recognized risk factors.
C Because of its rapidly progressive, infiltrative and multifocal nature, achieving local control and prevention of metastasis in CAS has been a challenge. In some series, survival rates were only 10% to 20% after 5 years.
D He will be most likely treated with wide local excision followed by postoperative adjuvant radiotherapy with large doses and wide treatment fields.
1. Answer: A. Reviewing the pathological report and knowing the histologic subtype are important prior to attempting any treatment. However, regardless of the size or histologic subtype of this BCC, given its high-risk location, Mohs micrographic surgery provides the best cure rate with tissue sparing in this relatively young patient who has no contraindication to surgery. Topical treatment is in general not recommended for BCC in high-risk locations, such as the nose, because of its suboptimal cure rate. Other choices, such as excision with blind margins, ED&C and GDC-0449, are not suitable for a small primary BCC on nose.
2. Answer: D. Photoprotection to minimize UV light exposure has been proven to be the most important preventive measure for reducing the risk for common nonmelanoma skin cancers, such as BCC and SCC. Topical retinoids are chemopreventive agents. They are important, but not as critical as UV avoidance. Photodynamic therapy is also helpful; however, it normally targets actinic keratoses, precursors of SCC rather than BCC. BCC account for the vast majority of nonmelanoma skin cancers.
3. Answer: C. Although location on the lip is recognized as a risk factor for metastasis, perineural invasion carries greater risk for local recurrence and distant metastasis. SCC of the lower lip has a 15% risk of metastasis. Lesions with perineural involvement have a 35% metastatic rate. SCC transformed from precursor actinic keratosis is generally considered less aggressive. The risk of metastasis of SCC derived from actinic keratosis is low (0.5% to 3.7%) compared with SCC arising in radiation-induced SCC and chronic osteomyelitis (20% and 31%, respectively).
4. Answer: E. The most common histologic subtype is the intermediate cell type, whereas the trabecular variant is the least common type. MCPyV is an exciting finding relevant to the pathogenesis of Merkel cell carcinoma; however, its impact on the course of disease and prognosis is not clear. SLNB is routinely recommended for patients diagnosed with Merkel cell carcinoma. SLNB is positive in approximately one-third of patients who were otherwise negative by physical examination. Clinical morphology of Merkel cell carcinoma is rather nondescript. When suspected, a low threshold for skin biopsy is recommended for histologic and immunohistochemical confirmation of the disease.
