Chapter 17: Actinic Keratosis, Basal, and Squamous Cell Carcinoma

Actinic keratoses (AKs) are one of the most common skin findings in dermatology. AKs are benign neoplasms of the epidermis and are considered precursor lesions to nonmelanoma skin cancers. They are very common in sun-exposed areas of the skin, especially in the elderly patient. Ultraviolet light exposure is the main cause of AKs.

Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are the most common types of skin cancers and the most common cancers in the United States.¹ Both are commonly seen in sun-exposed areas of the skin and are readily treatable if detected early. BCCs are the most common type of skin cancer and rarely metastasize. SCCs are the second most common skin cancer and can metastasize to regional lymph nodes if not treated early. Sun avoidance, use of proper clothing and sun screens, and routine examinations are important for prevention of nonmelanoma skin cancers.

Introduction

Actinic keratoses (AKs) are precancerous lesions of the keratinocytes and are very common in the elderly Caucasian population. They typically occur on sun-exposed areas such as the head and neck areas, as well as the distal extremities. Ultraviolet (UV) light exposure is the most common cause of AKs, with a genetic predisposition also being important. An AK is a precursor lesion to SCC and should be treated with appropriate therapy.²

Pathophysiology

Actinic keratoses develop after intense or long-term exposure to UV light (natural or artificial). Chronic sun exposure may lead to p53 tumor suppressor gene mutation of individual keratinocytes in the epidermis.² The same genetic mutations are seen in AKs and SCCs. The mutations will lead to propagation of the abnormal keratinocytes leading to faster division of these cells and development of a clinically visible lesion. If left untreated, approximately 10% of actinic keratosis may become SCCs.

Clinical Presentation

History

Patients typically complain of a scaly rough lesion(s) on frequently sun-exposed areas such as the face, scalp, and ears. Dorsal hands and forearms in men and lower legs in women are also commonly affected areas. The lesions usually do not have any symptoms such as itching or pain. Patients often try to scratch off the overlying crust, only to have the scaly surface reform.

Physical Examination

Actinic keratoses can present as a solitary lesion or as a larger, diffuse plaque. Solitary lesions often appear as an ill-defined, scaly, rough, red plaque that is approximately 3 to 6 mm in diameter. The lesions can be slightly sensitive to touch. Solitary AKs can also present as a more keratotic papule with a thicker stratum corneum above the base of the lesion (Figure 17-1). This type of a lesion can resemble a cutaneous horn and is frequently referred to as a hypertrophic actinic keratosis. The plaque-type AKs are very common in chronically sun-exposed areas such as the scalp in balding men. These lesions are very ill-defined and seemingly appear to involve a larger area. They are also scaly and rough feeling and can be associated with subclinical SCCs.

Laboratory Findings

Histopathology of AKs exhibits partial thickness atypia of the epidermis of the skin. The abnormal keratinocytes may also involve the appendageal structures of the skin such as hair follicles. These lesions are described histologically as "actinic keratoses with appendageal involvement" and may need more aggressive and deeper penetrating treatments to reach the involved appendages or follicular structures.

Diagnosis

Actinic keratoses typically present as hyperkeratotic papules or as a scaly red plaque(s) in chronically sun-exposed areas of the face, scalp, ears, and dorsal hands and arms. They have a rough, gritty surface.

Differential Diagnosis

• ✓ Seborrheic keratosis: Presents as tan or brown well-defined papule or plaque without a gritty surface.

• ✓ Viral wart: Presents as a hyperkeratotic papule often with black dots representing thrombosed blood vessels.

• ✓ SCC: Presents as a larger more indurated lesion.

A skin biopsy may be needed to differentiate these lesions if the clinical exam is not diagnostic.

Management

There are many available options for treatment of actinic keratosis. These treatment modalities are often combined to offer the patients the most effective treatment options.

• Cryotherapy (Chapter 7) is the most commonly used treatment for AKs.³ Liquid nitrogen is applied to the lesions using a spray dispenser or a cotton applicator until a 1- to 2-mm rim of frost develops around the actinic keratosis. This method may lead to blister formation in the lesions and surrounding skin. The blister heals and desquamates with resolution of the AKs.

• Field therapy is used for more diffuse and numerous AKs. Several topical creams are available. 5-Fluorouracil (5-FU) (eg, Efudex, Carac) is a topical cream that has been available for decades and is commonly used for treatment of widespread lesions. 5-FU is a pyrimidine analog and incorporates into DNA and RNA of keratinocytes, leading to cell death and inflammation.⁴ Another common topical treatment is imiquimod (eg, Aldara) that works by stimulating T lymphocytes against the abnormal keratinocytes.³ In 2012 ingenol mebutate (Picato) was approved for actinic keratosis. This medication causes necrosis of AKs within 2 to 3 days of use.⁵ All topical field therapies caused intense inflammation in the treated sites (Figure 17-2).³

• Photodynamic therapy (PDT) has gained greater popularity for treatment of AKs. In PDT, a chemical such as aminolevulinic acid is applied to the AKs and with exposure to light of the proper wavelength, the molecule is converted into protoporphyrin IX, a powerful photo-sensitizer, inside the abnormal keratinocyte. An energy-rich singlet oxygen species is generated causing membrane disruption and cell death.⁶

If an AK does not resolve or recurs after treatment, a biopsy may be indicated to rule out an underlying SCC or BCC.

Sunscreen with SPF 30 or greater should be applied to all areas not covered by hats or clothing.

Indication for Consultation

Actinic keratosis that involve a large surface area or that do not respond to therapy should be referred to dermatology for field treatment options such as topical treatments and/or PDT.

Patient Information

• American Academy of Dermatology: www.aad.org/skin-conditions/dermatology-a-to-z/actinic-keratosis

• PubMed Health: www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001830/

Introduction

Basal cell carcinoma (BCC) is by far the most common type of cancer and skin cancer in the United States. It is estimated that there are 1.2 to 1.5 million new cases each year in the United States with incidence rising annually.¹ Fortunately, these are slow-growing, localized tumors with only rare metastatic potential. BCCs are more common in the elderly Caucasian population, but can be seen in the younger age group including patients in their twenties and thirties. Intense sun exposure or artificial UV light especially prior to age 18 is the primary cause of BCCs with family history and light-colored skin, hair, and eyes being important risk factors. Although less common, BCCs can appear in non-Caucasian patients.

Pathophysiology

Basal cell carcinomas are cancers of the epidermal keratinocytes of the hair follicles and the epidermis. They develop after intense or chronic UV light exposure. Ionizing radiation from therapeutic radiation therapy can also promote development of BCCs. Exposure to intense UV light leads to DNA mutation in the tumor suppressor genes of the sonic hedgehog pathway in keratinocytes. Mutations in the PTCH (patched) gene and in the tumor suppressor gene, p53 gene, are also important in the development of BCCs.² Patients with basal cell nevus syndrome (Gorlin's syndrome) develop hundreds of BCCs due to a genetic mutation in the sonic hedgehog pathway.

Clinical Presentation

History and Physical Examination

There are several types of BCCs, thus, the history and clinical presentations can vary depending upon the subtype. BCCs most commonly occur on frequently sun-exposed areas such as the head and neck.

• Nodular basal cell carcinoma: Nodular BCC is the most common type subtype of BCCs. Patients often complain of a pimple-like lesion that does not heal or heals and then bleeds again. The lesions are often sore when touched or scratched. They typically appear as a translucent pearly papule with erythema, telangiectasia, and well-defined rolled borders most commonly on the head and neck region, especially the central face (Figure 17-3A and B). As the tumor grows, the center of the tumor often ulcerates creating a crater-like appearance. Thus, these lesions have been referred to as a "rodent ulcer" in the past. Occasionally, a nodular BCC can be pigmented giving an appearance of a melanoma or suspicious pigmented lesion (Figure 17-4).

• Superficial basal cell carcinoma: This is the second most common subtype of BCC. Patients often complain of a chronic area of "eczema." The lesions may be pruritic or sensitive to touch, but they typically do not bleed. These lesions appear as an erythematous patch or flat topped plaque with well-defined borders typically on the head and neck area, but also commonly appear on the trunk or extremities (Figure 17-5). They are often misdiagnosed and treated as eczema or psoriasis. Unlike nodular, superficial BCCs lack the translucent and telangiectatic appearance, but can have a slightly raised, rolled border.

• Sclerotic/morpheaform basal cell carcinomas: This is the most aggressive subtype of BCC. Patients often complain of a chronic "scar" or the lesion goes unnoticed for years. Clinically, they appear as a scar-like plaque (Figure 17-6) that often lacks other features of nodular or superficial BCCs. Therefore, they can grow to be a large and deep tumor before clinical detection. Morpheaform BCCs can be slightly erythematous, but can also be lighter colored than the surrounding normal skin. The borders are very ill-defined making the diagnosis and treatment more difficult. They typically affect the head and neck region, but can appear anywhere on the body. Recurrent BCCs from a previously treated BCCs can often develop into sclerotic and morpheaform BCCs.

Laboratory Findings

The histopathology of a nodular BCC shows aggregates of basophilic, uniform, hyperchromatic cells clumped together in nests in the dermis and subcutis; in a superficial BCC the nests are superficial with limited dermal invasion. In sclerotic/morpheaform BCCs, the cells appear in an infiltrative and poorly differentiated pattern with only a few cell layers that resemble more of a scar than a typical BCC.

Diagnosis

The most common presentation of a nodular BCC is a pearly shiny papule with telangiectasia. A superficial BCC presents as a flat erythematous patch or plaque. A sclerotic BCC resembles a scar with very ill-defined borders.

Differential Diagnosis

For nodular BCC

• ✓ Intradermal nevus: Presents as a well-circumscribed skin-colored papule without telangiectasia or pearly surface.

• ✓ Inflamed seborrheic keratosis: Presents as a reddish scaly papule that can be shiny, but lacks the telangiectasia.

• ✓ SCC: Tends to be more of a keratotic red papule.

• ✓ Melanoma or dysplastic nevus: Pigmented nodular BCCs may have very dark pigmentation that closely mimics a melanocytic lesion.

For superficial BCC

• ✓ Large actinic keratosis: Tends to be more scaly or keratotic and less contiguous.

• ✓ SCC in situ: Similar to an actinic keratosis, tends to be more keratotic or scaly.

• ✓ Dermatitis: Should respond to topical steroids.

For sclerotic/morpheaform BCC

• ✓ Scar: Scars have well-defined borders while a sclerotic BCC typically has ill-defined borders.

Management

Treatment of BCCs can vary depending on multiple factors including the BCC subtype, location, previous treatment, size, and the patient's overall health.

Standard Excision

A BCC can be excised in a fusiform or elliptical technique. The tumor is identified and excised with the recommended 4 mm margins. The specimen is sent to pathology for processing and evaluation of margins and the defect is reconstructed. Vertical sectioning is performed, therefore not all of the margins are evaluated. The cure rate for standard excisions is 90% to 95% using 4 mm margins. This is a common and effective method for treatment of basal cell skin cancers of the trunk and extremities where tissue sparing is not as critical.⁷

Electrodessication and Curettage

In this procedure, the tumor is curetted aggressively and then treated with electrodessication. For a proper technique, this cycle is repeated three times. This is an effective treatment for treatment of superficial BCC where the tumor is superficially located. The cure rate for electrodessication and curettage treatment of BCCs is near 90%. This technique can be used for nodular BCCs if the tumor is small and well defined. It is not recommended for treatment of sclerotic or morpheaform BCCs.⁷

Mohs Micrographic Surgery

Mohs Micrographic Surgery (MMS) is the most effective method of treatment of BCCs.⁷ In MMS, the dermatologic surgeon acts as the surgeon and the pathologist. The tumor is excised with narrow (1 to 2 mm) margins and is processed using the Mohs-specific horizontal frozen technique. This allows for visualization of the complete deep and lateral margins of a single section on a glass slide. The specimen is stained using hematoxylin and eosin, then examined carefully for any evidence of tumor. If tumor is present at a margin, the Mohs surgeon will remove further tissue only in the direction of where the tumor is present. Once the tumor has been successfully removed, the defect can be reconstructed safely knowing that the margins are clear.

This rapid and efficient method of tumor removal has the highest cure rate (nearly 99%) for treatment of BCCs. Mohs micrographic surgery is most commonly used for following indications as listed in Table 17-1.^8,9

Topical Treatments

Imiquimod has been reported to be effective in the treatment of some types of BCCs. In the United States, imiquimod and 5% topical fluorouracil are approved for treatment of superficial BCCs. This is an option for patients not willing or unable to undergo a surgical procedure.⁷

Photodynamic Therapy

PDT is approved for treatment of BCC in Europe and Australia, but not in the United States. However, PDT is becoming more widely used for treatment of superficial BCC on the trunk and extremities.⁷

Systemic Therapy

Oral vismodegib (Erivedege), a Hedgehog pathway inhibitor, was approved in 2012 for patients with metastatic BCC or locally advanced BCC that has recurred following surgery, or who are not candidates for surgery or radiation therapy.¹⁰

Indications for Consultation

The majority of BCC are treated by dermatologists and dermatologic surgeons in the United States. Once the diagnosis of BCC has been confirmed, the patient should be referred to an appropriate specialist for the definitive treatment unless the primary care provider has previous experience and adequate knowledge of these tumors and treatments.

Patient Information

• American Academy of Dermatology: www.aad.org/skin-conditions/dermatology-a-to-z/basal-cell-carcinoma

• Skin Cancer Foundation: www.skincancer.org/skin-cancer-information/basal-cell-carcinoma

• PubMed Health: www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001827/

Introduction

Cutaneous squamous cell carcinoma (SCC) is the second most common skin cancer after BCC with over 400,000 new cases annually in the United States. Generally, the incidence ratio of BCCs over SCCs is 4:1. However, this ratio is reversed in solid organ transplant patients where SCCs are more common than BCCs by a 4:1 ratio.² Unlike BCCs, SCCs have the potential for local and distant metastasis. UV exposure is the most common cause of SCC.

Pathophysiology

SCCs are malignant tumors of epidermal keratinocytes. AKs are often precursor lesions for SCC. Intense UV exposure or cumulative UV DNA damage may lead to p53 tumor suppressor gene mutations and development of AKs and ultimately SCC.¹¹ Other factors that have been associated with SCC development include human papillomavirus (HPV), burns and scars, ionizing radiation, chronic inflammation, arsenic exposure, and tobacco use. Certain genetic syndromes can also promote SCC development, including xeroderma pigmentosum, oculocutaneous albinism, and dystrophic epidermolysis bullosa.¹¹

Clinical Presentation

History and Physical Examination

As with BCCs, patients may complain of a wart or pimple-like lesion on sun-exposed skin that grows slowly with episodes of bleeding and tenderness. Most SCCs occur on sun-exposed areas such as the face, scalp in balding men, dorsal hands and forearms, and lower legs especially in women. SCCs commonly arise from an area of extensive photodamage with diffuse AK. They typically resemble wart-like lesions that occasionally bleed and are tender to the touch.

There are several subtypes of SCC:¹¹

Squamous cell carcinoma in situ is limited to the epidermal layer without dermal invasion. Unlike an actinic keratosis that has partial thickness atypia, SCC in situ has full thickness atypia and often is described as an intraepidermal carcinoma. SCC in situ typically occurs on sun-exposed areas with extensive photodamage. It appears as a rough, erythematous, keratotic papule or plaque that often resembles an AK, but with more induration or tenderness (Figure 17-7). SCC in situ and AKs may be present on the same lesion with gradual transition from partial atypia to full thickness atypia.

Bowen's disease is a SCC in situ that presents as a well-demarcated, erythematous plaque with minimal scale and is often located on the lower extremities particularly in women (Figure 17-8). This lesion is often misdiagnosed as eczema or psoriasis or even superficial BCC. Any SCC in situ has potential for becoming invasive if not treated appropriately.

Erythroplasia of Queyrat is a SCC in situ on the penile shaft, usually in uncircumcised men. This lesion appears as a non-scaly, erythematous, thin plaque on the shaft or corona of the penis (Figure 17-9) that may be present for years and is often misdiagnosed as dermatitis or a candida infection.

Invasive SCCs have extension into the dermis and beyond and are typically categorized histologically by the grade of keratinocyte differentiation (well, moderate, poor, and infiltrative). Clinically, invasive SCC appears as a solitary hyperkeratotic pink nodule or papule on sun-exposed areas (Figure 17-10). An invasive SCC has the potential for metastasis, especially if there is perineural invasion or if the lesions are histologically aggressive with poor differentiation or infiltrative pattern. Lower lips and ears are particularly susceptible areas for SCC development with potential risk for regional lymph node metastasis. Solid organ transplant patients can develop SCCs in all areas with risk for metastasis and local recurrence.

Keratoacanthomas are invasive SCC with a unique clinical history and presentation. They appear and grow quickly in matter of weeks and appear as a solitary symmetrical erythematous nodule with a central hyperkertotic core that resembles a larger molluscum contagiosum lesion (Figure 17-11).

Verrucous Carcinomas are invasive SCCs that present as verrucous warty-like plaques usually on plantar feet or on distal fingers. These long-standing lesions are often treated for years as common warts without resolution. Verrucous carcinomas are thought to arise from HPV-induced abnormal keratinocytes.

Laboratory Findings

The histopathology of SCC in situ shows abnormal keratinocytes involving the entire thickness of the epithelium. Invasive SCCs are graded based on degree of keratinocyte differentiation. Well-differentiated SCCs have a higher level of keratinization and are more localized. Poorly differentiated SCCs have no or very limited keratinization and less differentiation. These lesions may have a more spindle cell appearance with higher risk of metastasis and local recurrence. They may have perineural invasion and involve deeper layers of the skin with wider subcutaneous extension. Infiltrative SCC have a desmoplastic scar-like appearance with single cell strands infiltrating the dermis and subcutis. These lesions may be missed with typical hematoxylin and eosin (H&E) staining and may need specialized immunohistochemical stains.

Diagnosis

A SCC typically presents as a hyperkeratotic erythematous papule or plaque on sun damaged skin.

Differential Diagnosis

• ✓ Viral wart: Presents as a hyperkeratotic papule, but with less redness, typically on palmar and plantar surfaces.

• ✓ BCC: Tends to be less scaly and have a more pearly surface with telangiectasia.

• ✓ Seborrheic keratosis: Tends be more well defined with a verrucous pigmented keratotic surface.

• ✓ Dermatitis: Tends to have a less well-defined border than a SCC and responds to topical steroids.

Management

Suspected lesions should be biopsied for confirmation of the diagnosis of SCC as well as histologic grading if indicated. Shave biopsy is sufficient if the lesion is adequately sampled into the superficial dermis. An invasive SCC may be under diagnosed as a SCC in situ or an AK if the biopsy transects through the atypical epithelium only.

Most SCCs are treated by surgical removal either by fusiform excision or Mohs micrographic surgery. For fusiform excision, the typical margin is 4 mm as in excision of BCCs. Mohs micrographic surgery indications are listed in Table 17-1. For SCC with poor differentiation or spindle cell features, the risk for metastasis is higher and proper staging with sentinel lymph node biopsy or lymph node dissection as well as radiologic examination is recommended.¹¹

Electrodessication and currettage, topical treatments such as imiquimod, and PDT have been successful in the treatment of SCC in situ lesions. However, the clinician must be aware of the risk of recurrence and metastatic disease and should limit the usage of these treatments for selected SCCs.

Indications for Consultation

Generally, a well-differentiated SCC may be excised appropriately by a surgically trained healthcare provider. Any SCC in high-risk area or a tumor with more aggressive features should be evaluated by a dermatologist and dermatologic surgeon for proper diagnosis, staging, and treatment.

Patient Information

• American Academy of Dermatology: www.aad.org/skin-conditions/dermatology-a-to-z/squamous-cell-carcinoma

• PubMed Health: www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001832/

• Skin Cancer Foundation: www.skincancer.org/skin-cancer-information/squamous-cell-carcinoma

• American College of Mohs Surgery: www.skincancermohssurgery.org/mohs-surgery/faqs.php