Introduction

Squamous cell carcinoma of the skin or cutaneous squamous cell carcinoma is the second most common form of skin cancer in the United States, behind basal cell carcinoma. Squamous cell carcinoma has precursor lesions called actinic keratosis, exhibits tumor progression and has the potential to metastasize in the body. Ultraviolet (UV) solar radiation is the primary risk factor in the development of cutaneous squamous cell carcinoma and the cumulative exposure received over a lifetime plays a major part in the development of this cancer. Surgical excision is the primary treatment modality for cutaneous squamous cell carcinoma, with Mohs micrographic surgery being the preferred excisional technique for squamous cell carcinoma of the head and neck, and in other areas of high risk or squamous cell carcinoma with high-risk characteristics. Radiation therapy is reserved for squamous cell carcinoma in older patients or those who will not tolerate surgery, or when it has not been possible to obtain clear margins surgically. Adjuvant radiotherapy is commonly after surgical treatment in very high tumors. Immunosuppression significantly increases the risk of squamous cell carcinoma over the course of an individual’s life. Metastasis is uncommon for squamous cell carcinomas arising in areas of chronic sun exposure, but it can take place, and the risk is increased in immunosuppressed patients. Patients with cutaneous squamous cell carcinoma should be examined regularly and remember to use measures to protect from UV damage.[1][2][3]

Etiology

UV solar radiation is the most common cause of squamous cell carcinoma. However, long-term exposure to cancer-causing chemicals, such as tar in cigarettes, can also lead to the development of squamous cell carcinoma. Other possible causes include a site of a severe burn scar, and ulcer or sore present for many years and some types of human papillomavirus (HPV), especially in the genital area.[4][5]

Epidemiology

Squamous cell carcinoma is the second most common form of skin cancer in the United States behind basal cell carcinoma. More than one million squamous cell carcinoma cases are diagnosed in the United States each year. Historically, a ratio of squamous cell carcinoma to basal cell carcinoma incidence of 3:1 has been reported, but more recent studies suggest that the ratio may be closer to 1:1. Furthermore, it has been reported that, with increasing age, the ratio trends toward squamous cell carcinoma occurrence. Squamous cell carcinoma most commonly appears after the age of 50 in areas of past sun exposure, and typically occurs in males with light skin and light eyes who have a history of UV solar radiation exposure. However, anyone with a history of significant UV exposure, whether from past medical treatment or the sun, is at an increased risk. Squamous cell carcinoma is also very prevalent in patients that are immunosuppressed and can develop into aggressive subtypes in these patients.[6][7][8]

Pathophysiology

UV radiation is accepted as the major risk factor for squamous cell carcinoma of the skin. Mutations in the p53 gene are the most common genetic abnormalities found in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma. Tanning lamp usage, therapeutic UV exposure, and ionizing radiation are all well-known risk factors for the development of squamous cell carcinoma, likely through the p53 pathway. The p53 protein stops cells with mutated or damaged DNA from replicating.  If the p53 gene becomes mutated through the ways discussed above, then the p53 protein is rendered non-functional, and cells with damaged DNA, such as those found is squamous cell carcinoma can replicate.

History and Physical

Clinically, squamous cell carcinoma arises in a background of sun-damaged skin often from precursor lesions called actinic keratoses. The most common areas for squamous cell carcinoma to occur are the face, neck, bald scalp, extensor forearms, dorsal hands, and shins. The color varies from flesh toned to erythematous with variable degrees of scale, crusting, ulceration, and hyperkeratosis. Occasionally, telangiectases with or without active bleeding may be present. Squamous cell carcinoma can be flat, nodular, and even plaque-like in some cases with significant induration and/or subcutaneous spread noticeable on palpation. Squamous cell carcinoma can occasionally be painful and tender, and these may be signs of perineural invasion.

Evaluation

A skin biopsy is mandatory in all patients with suspected squamous cell carcinoma. Histopathologically, squamous cell carcinoma is notable for irregular nests, cords and sheets of neoplastic keratinocytes invading the dermis. Lesion thickness is of particular importance when predicting risk for metastasis with a thickness more than 4 mm associated with a higher risk. Immunoperoxidase staining for cytokeratins 5/6/AE1/AE3 is useful in situations where the diagnosis is in question, especially with poorly differentiated squamous cell carcinoma.[9][10]

Treatment / Management

Surgery is the primary means of treatment for squamous cell carcinoma of the skin. Mohs micrographic surgery is the treatment of choice for squamous cell carcinoma of the head and neck. Mohs Surgery is also the treatment of choice for squamous cell carcinoma in immunosuppressed patients, recurrent squamous cell carcinoma, squamous cell carcinoma with aggressive histologic features, and squamous cell carcinoma greater than or equal to 2 mm of depth. Actinic keratosis with focal squamous cell carcinoma and squamous cell carcinoma in situ may or may not be treated with various modalities, including Mohs surgery, curettage or excision, depending on clinical and histologic circumstances. As an aid in decision-making, the American Academy of Dermatology has developed guidelines available as a smartphone app listed under “Mohs Appropriate Use Criteria (AUC).” These guidelines help to select those cases that would most benefit from the Mohs procedure, while conserving health care expenditures. Other therapies include oral or topical retinoids to help reduce the risk of development of squamous cell carcinoma. Photodynamic therapy and topical 5-fluorouracil (5FU) or imiquimod may also be used to decrease the development of squamous cell carcinoma. For in situ disease, electrodesiccation with curettage, or topical treatment with 5FU and imiquimod have been used successfully.[11][12][13]

Patients with cutaneous squamous cell carcinoma should be counseled in the protection of their skin from UV damage through the use of sunscreen, protective clothing and avoidance of the sun during periods of maximal intensity. Also, they should be followed regularly, with the actual frequency based on their frequency of squamous cell carcinoma development. Patients with a history of a few squamous cell carcinomas and some actinic keratoses may be followed every six to 12 months, while those with many squamous cell carcinomas or aggressive tumors likely will need to be seen much more often.

Differential Diagnosis

• Other skin cancers like basal cell cancer, melanoma
• Actinic keratosis
• Burns
• Scar tissue
• Pyoderma gangrenosum

Staging

High risk features:

• Perineural invasion
• Thickness of lesion greater than 2 mm
• Lesion on the ear 
• Poorly differentiated lesion

Complications

• Metastases
• Local invasion
• Pain
• Loss of function
• Poor aesthetics
• Death

Consultations

Dermatologist

Oncologist

Pearls and Other Issues

Avoidance of UV damage throughout a patient's life is of the utmost importance in preventing squamous cell carcinoma. Daily application of sunscreen above 30 SPF has been shown to decrease the risk of actinic keratoses and can help to prevent squamous cell carcinoma in patients. If a clinician is concerned about a possible squamous cell carcinoma in a patient they should immediately obtain a biopsy for tissue diagnosis and structure a treatment plan based on the pathology report they receive.

Enhancing Healthcare Team Outcomes

The majority of skin cancers can be prevented. Besides the physician, the nurse and the pharmacist play a vital role in patient education. The patient must be told to avoid excessive sun exposure and use sunscreen when going out. Tanning beds should be avoided and one should wear protective clothing that covers the arms and upper body. Further, the patient must be told to avoid the sun between 10 am to 4 pm. Finally, all patients should be taught how to perform a skin examination and see a healthcare provider if there is any skin lesion that suddenly changes in its growth or shape. To date, there is no evidence that the use of herbs or other supplements can prevent skin cancer, and the patient should be told not to rely on these treatments.[14][3][14] (Level V)

Outcomes

Small squamous cell cancer lesions can be excised and are not fatal but they can add significant morbidity depending on their location. Most squamous cell cancers around the head and neck region require complex surgery, which even in the best of hands can lead to poor cosmesis. Further, the cost of management of these cancers is escalating each year, and the patient is often burdened with huge copayments. Advanced squamous cell cancers have a poor prognosis with a 5-year survival rate below 40%. With larger lesions, tumor recurrence is also a problem despite wide excision. Local recurrences have been reported in 10-18% of cases.[15][16] (Level V)

Questions

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References

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