Non-melanoma skin cancer

Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)

What every physician needs to know:

Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) comprise the vast majority of non-melanoma skin cancers (NMSCs). NMSC is extremely common, with 20% of Americans affected over their lifetime. The estimated annual cost of treating NMSC in the United States is about $650 million. Sun protective practices help to minimize the incidence of NMSC, as sun exposure is the major modifiable risk factor. Mortality rates are low, metastases are infrequent, and NMSCs usually carry an excellent prognosis with appropriate treatment. However, morbidity secondary to local destruction of underlying soft tissue and bone can be significant. Recognizing high-risk tumor characteristics is crucial to selecting appropriate therapy, maximizing efficacy, and minimizing complications and recurrence.

Basal cell carcinoma

BCC is the most common cancer in humans, and overall mortality approaches zero. It accounts for 75-80% of all cases of NMSC and is increasing in incidence. BCC arises from uncontrolled growth of the basal cell layer, the lowermost portion of the epidermis and outermost portion of the hair follicle. Metastatic BCC has been reported but is extremely rare. There are several subtypes of BCC, with varying clinical features, histologic patterns, and clinical behavior.

Squamous cell carcinoma

SCC is the second most common type of NMSC, accounting for approximately 25% of cases. SCC arises from uncontrolled growth of abnormal keratinocytes that have invaded into the dermis. Actinic keratoses (AKs) are the typical precursor lesion of SCC and remain confined to a portion of the epidermis. A small percentage of AKs progress to SCC. SCC in-situ (also called Bowen’s disease) refers to intermediate lesions that involve the entire epidermis without dermal invasion.

Metastatic spread and mortality are uncommon with invasive SCC but are much more frequent than with BCC. Primary cutaneous SCCs may metastasize in 2-5% of cases. Higher risk SCCs, such as those on the lip or arising in areas of chronic inflammation recur more frequently and metastasize in 10-25% of cases. Basosquamous carcinoma is a tumor that shows histologic features of both SCC and BCC. It generally behaves similarly to a SCC and is therefore best treated as such.

Are you sure your patient has non-melanoma skin cancer? What should you expect to find?

Basal cell carcinoma

BCC has several generally recognized subtypes, including nodular, superficial, micronodular, and infiltrative/morpheaform. Each BCC subtype has typical clinical features and is associated with a characteristic histologic pattern and clinical behavior. It is not uncommon for individual BCCs to contain a mixture of histologic subtypes, with the most infiltrating component sometimes being present only at the deepest advancing border of the tumor.

Nodular basal cell carcinoma

Nodular BCCs (Figure 1, Figure 2) are the most common subtype, accounting for 60% of BCCs. They present as translucent papules or nodules, often described as “pearly,” with overlying telangiectasias and a rolled border. They most commonly occur on the head and neck.

Nodular BCC: Translucent nodule with overlying telangiectasias and crust.

Nodular BCC: Waxy, erythematous, telangiectatic papule.

Nodular BCCs tend to grow slowly, over months to years, and may eventually ulcerate. The term, “rodent ulcer,” was used in the past to describe large, ulcerated tumors. Nodular BCCs can eventually invade deeply, destroying subcutaneous structures including muscle, bone and adjacent anatomic structures. Nodular BCCs may rarely contain pigment, causing them to appear blue or black.

Superficial basal cell carcinoma

Superficial BCCs (Figure 3) commonly present as thin, erythematous, scaly patches, often resembling eczema, psoriasis, or tinea corporis. They commonly occur on the trunk and extremities but also present on the head and neck. Superficial BCCs range in size from a few millimeters to several centimeters in diameter, typically demonstrating horizontal rather than vertical growth. They can exhibit significant subclinical spread beyond apparent borders, leading to increased recurrence after surgery. Superficial BCCs can eventually grow more deeply.

Superficial BCC: Annular, scaly, erythematous plaque.

Micronodular basal cell carcinoma

Micronodular BCCs may present as papules or plaques with a firm border. They often appear similar to nodular BCCs. The histologic pattern of micronodular BCC is associated with increased aggressiveness, subclinical spread, and recurrence.

Infiltrative and morpheaform basal cell carcinoma

Infiltrative and morpheaform BCCs (Figure 4, Figure 5) often present as flat, reddish or white lesions, sometimes resembling a scar. They have poorly defined clinical borders and a histologic pattern of increased aggressiveness, subclinical spread and rate of recurrence.

Infiltrative BCC: Poorly defined, slightly erythematous, indurated plaque.

Infiltrative BCC: Ulcerated, scar-like plaque.

Squamous cell carcinoma

Actinic Keratosis

AKs, the precursor lesions of SCCs, may present initially as barely perceptible erythematous, scaly macules or patches. Early lesions are often easier to palpate than to see because they may feel “rough” but be inconspicuous. Advanced lesions are more well-defined and may present with thick scale and erythema. Patients commonly present with multiple AKs on sun-damaged skin, such as the face, scalp, and dorsal hands. SCC in-situ (Figure 6), also referred to as Bowen’s disease, characteristically presents as a scaly plaque with more pronounced erythema and well-defined borders on sun-damaged skin.

SCC in-situ/Bowen’s disease: Clearly demarcated, erythematous, scaly plaque

Squamous cell carcinoma

SCCs (Figure 7) present as hyperkeratotic papules, plaques, or nodules, usually on sun-exposed skin. They frequently ulcerate, crust and bleed. SCCs present on the extremities more commonly than BCCs, but they also occur on the head and neck. The lower lip is affected much more frequently than the upper lip due to increased sun exposure. SCCs may form in non sun-exposed regions in areas of chronic inflammation, such as ulcers, scars, and sites of previous chemical or radiation exposure. Metastatic SCC is uncommon but often presents as an enlarged, fixed, non-tender lymph node in the vicinity of the primary SCC.

Invasive SCC: Erythematous, eroded nodule.

Characteristic histologic patterns of BCCs and SCC are shown in Figure 8, Figure 9, Figure 10, Figure 11, Figure 12, Figure 13.

Nodular BCC: Large basaloid nests with palisading.

BCC with macronodular and micronodular features: Large and small basaloid nests in the same specimen.

Superficial BCC: Multi-focal basaloid downgrowths from the epidermis.

Infiltrative BCC: Infiltrating basaloid strands.

Well-differentiated SCC: Pinkish keratinocytes invading the dermis.

Beware of other conditions that can mimic disease non-melanoma skin cancer:

The differential diagnosis of NMSC is broad. NMSCs are commonly confused with a variety of benign and malignant growths and less commonly with inflammatory processes.

Nodular BCC:

SCC
Benign and malignant adenexal neoplasms
Fibrous papule (Figure 14)

Figure 14.

Fibrous papule: Firm, flesh colored papule.
Sebaceous hyperplasia (Figure 15)

Figure 15.

Sebaceous hyperplasia: Greasy-appearing flesh colored papule.
Seborrheic keratosis (Figure 16, Figure 17)

Figure 16.

Seborrheic keratosis: Solitary hyperpigmented, “stuck-on” plaque.

Figure 17.

Seborrheic keratoses: Numerous tan to black, greasy, “stuck-on” papules and plaques.
Amelanotic melanoma (melanoma lacking pigment)
Melanoma (Figure 18) can be confused with the pigmented variant of BCC

Figure 18.

Melanoma: Hyperpigmented, irregularly bordered plaque.

Superficial BCC:

AK (Figure 19)

Figure 19.

Actinic keratosis: Scaly, erythematous patch on sun-exposed skin.
SCC in-situ/Bowen’s disease
SCC
Eczematous patch, such as nummular eczema (Figure 20)

Figure 20.

Nummular excema: Scaly, erythematous, excoriated plaque.
Psoriasis (Figure 21)

Figure 21.

Psoriasis: Well-defined, annular, scaly, erythematous papules and plaques.
Tinea corporis (Figure 22)

Figure 22.

Tinea corporis: Annular, erythematous, scaly patch.

Micronodular BCC:

Nodular BCC and other lesions in its differential

Infiltrative/morpheaform BCC:

Scar
Morphea
Metastatic carcinoma

Actinic keratosis:

SCC in-situ/Bowen’s disease
SCC
BCC
Seborrheic keratosis
Verruca (wart) (Figure 23)

Figure 23.

Verruca: Exophytic, hyperkeratotic, verrucous papule.
Porokeratosis (Figure 24)

Figure 24.

Porokeratosis: Annular plaque with a hyperkeratotic rim.

SCC in-situ/Bowen's disease:

AK
SCC
BCC (especially the superficial variant)
Eczematous patch, such as nummular eczema
Lichen simplex chronicus
Psoriasis
Tinea corporis

SCC:

AK
SCC in-situ
Basosquamous carcinoma (Figure 25)

Figure 25.

Basosquamous carcinoma: Translucent, yellowish papule with telangiectasias.
BCC
Keratoacanthoma (KA) (Figure 26) is often considered a variant of SCC. It typically presents as a rapidly enlarging, “volcano-like” hyperkeratotic papule or nodule, over the course of weeks. It frequently shows spontaneous regression over a period of months and is considered a benign lesion by some.

Figure 26.

Keratoacanthoma: Hyperkeratotic, “volcano-like” nodule with keratin debris-filled center.
Seborrheic keratosis
Verruca (wart)
Prurigo nodularis
Benign and malignant adenexal tumors
Atypical fibroxanthoma
Amelanotic melanoma (melanoma lacking pigment)

Which individuals are most at risk for developing non-melanoma skin cancer?

Many risk factors for developing BCC and SCC are similar but some are distinct. NMSC risk is related to both environmental and genetic factors, and patients who develop one NMSC are at higher risk for developing another.

Environmental Factors

The risk of developing NMSC is directly related to increased exposure to ultraviolet radiation (UVR), whether recreational or therapeutic. Studies have shown increased rates of BCCs and SCCs at latitudes closer to the equator where UVR is higher. Increased tanning bed usage also correlates with increased NMSC and melanoma.

Ultraviolet light is used to treat a variety of skin diseases, and psoralen and UVA light (PUVA) therapy is associated with increased NMSCs, especially SCCs. NMSCs induced by PUVA therapy are generally seen with long-term treatment after several hundred exposures. It appears that intermittent UVR overexposure is more important in the development of BCCs, while cumulative UVR is more important in the development of SCCs.

NMSC risk is closely related to skin phenotype. Individuals with fair skin, red hair, and freckles, who tan poorly and burn easily are more likely to develop NMSC. Individuals with darker skin and hair who tend to tan rather than burn are at lower risk. Fitzpatrick’s skin type can be graded on a scale from I to VI, depending on an individual’s propensity to burn, with type I individuals at highest risk.

Ionizing radiation has been used to treat a variety of benign and malignant cutaneous conditions. Individuals who have received ionizing radiation are at increased risk of developing NMSC, and the risk is generally dose dependent. The latency period between ionizing radiation exposure and NMSC development is often several decades.

Immunosuppressed patients are at significantly increased risk of developing NMSCs. Solid-organ transplant recipients are at 40-250 times greater risk of developing SCCs compared to the general population. These SCCs tend to be more aggressive, are often numerous, and can lead to significant morbidity and mortality.

Organ transplant patients are also at a 5-10 times greater risk of developing BCCs. There is often a period of several years between organ transplantation and the development of NMSCs. The duration and specific type of iatrogenic immunosuppression may be important, as well as the patient’s background UVR exposure history and skin phenotype.

Patients with human immunodeficiency virus (HIV) are at increased risk of developing human papilloma virus (HPV) associated SCCs, especially in the anal area. SCCs in HIV patients may be associated with typically low-risk HPV types such as HPV1, HPV2, HPV6, and HPV11 in addition to high-risk types.

High-risk oncogenic HPV strains, including HPV16 and HPV 18, are associated with SCCs in the general population. Smoking and a variety of occupational exposures, such as arsenic, tar, asbestos, petroleum, and pesticides predispose to developing SCC.

SCCs may arise in areas of chronic inflammation, including ulcers, erosive lichen planus, lichen sclerosis, chronic cutaneous lupus, and dystrophic epidermolysis bullosa. Such SCCs often behave more aggressively than SCCs arising on sun-damaged skin, so it is important to have a low threshold to biopsy new or changing lesions in an area of chronic inflammation.

Genetic Factors

Several rare genetic syndromes predispose to numerous NMSCs. Xeroderma pigmentosum and oculocutaneous albinism are associated with BCCs and SCCs, as well as melanoma. BCCs are seen in nevoid basal cell carcinoma syndrome, Bazex syndrome, and Rombo syndrome, whiles SCCs occur with epidermodysplasia verruciformis and recessive dystrophic epidermolysis bullosa (see Table III and Table IV in “What other clinical manifestations may help me to diagnose non-melanoma skin cancer?” section).

Table III.

Syndrome	Inheritance/Genetic Defect (if known)	Associated Features
BCCs
Nevoid basal cell carcinoma syndrome(Gorlin syndrome)	AD, PTCH^a	Palmoplantar pits, odontogenic keratocysts,epidermal inclusion cysts, frontal bossing, bifid ribs, calcification of the falx cerebri, medulloblastoma in children, ovarian fibromas, extreme sensitivity to ionizing radiation.
Bazex syndrome	Bazex syndrome	Follicular atrophoderma, milia, hypohidrosis, hypotrichosis, epidermal inclusion cysts.
Rombo syndrome	AD	Vermiculate atrophoderma, hypotrichosis, milia, trichoepitheliomas, blepharitis, cyanosis.
SCCs
Epidermodysplasiaverruciformis	AR, EVER1^b and EVER2^b	Numerous, chronic HPV-associated flat warts (especially HPV5 and HPV8), SCC transformation from flat warts.
Dystrophic epidermolysis bullosa	AR or AD, Collagen 7	Mucocutaneous blisters at the site of trauma, dystrophic nails and teeth, SCCs arise at sites of scarring.
BBCs, SCCs and melanomas
Xeroderma	AR, multiple xeroderma pigmentosum genes	Extreme sun sensitivity, neurologic abnormalities, eye abnormalities.
Oculocutaneous albinism	AR, tyrosinase, P-gene^c, TYRP-1^c	Pigment decreased-to-absent in skin, hair, and eyes, decreased visual acuity.

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; EVER1, epidermodysplasia verruciformis-1 gene; EVER2, epidermodysplasia verruciformis-2 gene; HPV, human papillomavirus; TYRP-1, tyrosinase-related protein-1.

^a The PTCH gene, a member of the Patched gene family, functions as a tumor suppressor and is an important regulator of cell growth via the sonic hedgehog signaling pathway.

^b EVER1 and EVER2 encode proteins that likely play an important role in cell-mediated immunity and susceptibility to human papillomavirus infection.

^c The P-gene and tyrosinase-related protein-1 play an important role in normal pigmentation.

Table IV.

Keratoacanthoma variant	Pattern of presentation
Ferguson-Smith	Multiple self-involuting KAs in young adults, sometimes transmitted in an autosomal dominant manner.
Gryzbowski	Generalized, non-involuting KAs.

What laboratory and imaging studies should you order to characterize this patient's tumor? How should you interpret the results and use them to establish prognosis and plan initial therapy?

Most cases of NMSC do not require laboratory work-up or imaging studies because they are local processes only. Proper evaluation always requires a history, with special attention to risk factors, physical examination, and a skin biopsy.

The NMSC must initially be characterized as either low-risk or high-risk, based on clinical and histopathologic features (Table I). High-risk features are associated with a higher likelihood of recurrence. The features below have been established by the National Comprehensive Cancer Network (NCCN), based upon review of the literature and consensus opinions of expert clinicians in the field. The NCCN has set forth treatment guidelines for NMSC taking these features into account, and these treatments will be discussed in detail, below.

Low and high-risk features for NMSC recurrence.

If any high-risk features are present, then the NMSC should be considered a high-risk tumor. Because appropriate treatment modalities often differ for low-risk and high-risk tumors, this distinction is important.

Imaging

Imaging and further systemic work-up of NMSCs is recommended only in rare cases of locally advanced or systemic disease. Computed tomography (CT) scan is often preferred to assess for bone and lymph node involvement, whereas magnetic resonance imaging (MRI) is often preferred to assess soft tissue and peripheral nerves. MRI is recommended whenever perineural invasion is suspected based on clinical examination or histopathologic findings.

Lymph node evaluation

A clinical lymph node examination should be performed on all patients with a SCC to help identify those rare instances of regionally metastatic disease. If lymph nodes are palpable, or if they appear abnormal on imaging studies, then a tissue diagnosis of the lymph node is required. Fine-needle aspiration (FNA) is often the first choice because it is less invasive than open lymph node biopsy. However, if a FNA is equivocal or inadequate, then further re-evaluation, repeat FNA, or open lymph node biopsy should be considered.

Sentinel lymph node biopsy (SLNB) may occasionally be considered as part of the diagnostic work-up of clinically localized “very high-risk” SCCs. However, further studies are needed to better define its utility. “Very high-risk” SCC is a poorly defined term, due to lack of evidence and consensus, but may include SCCs believed to be at a significantly increased risk of metastasizing. Suggested “very high-risk” factors have included perineural invasion of a named nerve, the presence of several high-risk features (see Table I), or extension into deep underlying structures such as bone.

Staging

Table II. TNM staging of non-melanoma skin cancer.

What therapies should you initiate immediately i.e., emergently?

Emergent therapies are rarely required for treatment of NMSC. For high-risk patients with aggressive SCCs that may grow rapidly and metastasize more frequently, urgent diagnosis and treatment is important to minimize morbidity and mortality.

What should the initial definitive therapy for the cancer be?

Many therapeutic modalities can be considered for the treatment of NMSCs. When selecting the optimal treatment several principles can generally be followed, but treatment should remain individualized. The presence of any high-risk features, predicting an increased likelihood of recurrence or metastasis, must be recognized (see Table I). It is also important to consider the expected functional and cosmetic outcomes, as well as patient preferences.

Surgical therapies are the mainstay of treatment for local NMSCs, including curettage and electrodessication, surgical excision, and Mohs micrographic surgery, depending on the situation. Radiation therapy is utilized less frequently but remains a viable option for some patients. Topical therapies may be appropriate in certain situations. In rare cases of metastatic SCC or BCC, chemotherapy and systemic biologic modifiers may be used.

Surgical Therapies

Curettage and electrodessication

This technique can be considered for the treatment of certain low-risk NMSCs (see Table I). It is mostly used to treat superficial or nodular BCCs, SCC in-situ, or smaller, well-differentiated SCCs. It involves removal of the abnormal tumor cells with a sharp curette, followed by electrodessication at the base of the lesion. This sequence is typically repeated two or three times. Tumor cells are poorly cohesive and feel “soft” compared to the surrounding, healthy dermis, allowing for differentiation. Cure rates can be as high as 97-98% with appropriate tumor selection.

Curettage and electrodessication does not allow for histologic margin assessment, and operator experience is important to achieve high cure rates. Adipose tissue cannot be differentiated from tumor on the basis of feel, so if fat is reached during curettage and electrodessication, an excision should be performed. Extension of abnormal cells down adenexal structures may occur, leading to increased recurrence in hair-bearing areas. Cosmetic results are variable, with hypertrophic scarring on the trunk not uncommon.

Surgical excision

Surgical excision is a commonly used method to treat NMSCs. It is generally recommended for treatment of low-risk NMSCs (see Table I) and involves removal of the tumor plus a margin of clinically normal-appearing tissue. Erythema surrounding a SCC should be considered part of the tumor. A 4mm margin for excision of BCCs and a 4-6mm margin for excision of SCCs that are clinically well-circumscribed and less than 2cm in diameter results in a cure rate of approximately 95%. Narrower margins can lead to higher rates of recurrence and are insufficient.

Surgical excision allows for intra-operative or post-operative histologic examination of the margins for tumor clearance, unlike curettage and electrodessication.

Methods of wound closure include side-to-side repair, skin flap or graft, or healing by secondary intention. Side-to-side repair is performed most commonly, typically resulting in a thin, whitish scar. Flap-closure is not recommended without intra-operative verification of clear margins, because tissue rearrangement can complicate further tumor resection if it is needed.

Mohs micrographic surgery (MMS) is a specialized surgical technique most commonly utilized for the treatment of NMSCs with high-risk features. When indicated, MMS offers distinct advantages over standard surgical excision, including a superior cure rate and maximal tissue conservation. The Mohs technique involves complete intra-operative margin assessment of frozen histologic sections. By comparison, standard “breadloaf” examination of a surgical excision samples only about 1% of the total margin.

Recurrence rates for primary BCCs have been shown to be 1% with MMS and 10% with standard surgical excision; and for primary SCCs they are 3% and 11% respectively. Treatment of recurrent NMSCs is associated with higher recurrence rates for all modalities, but MMS remains superior to standard surgical excision.

Improved functional and cosmetic outcomes with MMS are possible because smaller margins of healthy tissue need to be removed compared to surgical excision. Tissue sparing can be especially important on the head and neck, as well as other locations including the hands, feet, genitalia, and pretibial areas. While MMS is primarily indicated for the treatment of NMSCs with high-risk features, it may be considered for low-risk tumors when functional or cosmetic outcome will be suboptimal with other treatments.

Radiation therapy

Radiation as the primary treatment of NMSCs is generally reserved for non-surgical candidates. Cure rates achieved are typically lower than with surgery, and cosmetic outcomes are variable. Candidates are usually over the age of 60 because radiation increases the long-term risk of causing malignancy. Radiation therapy can also be useful for the treatment of in-transit SCC satellite metastases. It may be recommended as an adjuvant treatment, following surgery, for advanced disease.

Topical therapies

Topical therapies can be considered for certain shallow, low-risk tumors, including AKs, superficial BCCs, and SCC in-situ. Cure rates are generally lower than with surgical treatments. NCCN guidelines recommend that topical therapies be reserved for instances when surgery or radiation is contraindicated or impractical. A patient with multiple, low-risk lesions may benefit. Topical therapy should not be used for deeper BCCs or invasive SCCs, as penetration may not reach the dermis; cure rates tend to be lower, and the superficial treatment can sometimes “mask” residual, untreated deeper tumor.

5-fluorouracil (5-FU) and imiquimod creams are topical therapies that preferentially target and destroy rapidly dividing, abnormal epidermal cells. Irritation occurs at the site of application and can be severe. 5-FU is a chemotherapeutic that is generally used once or twice daily for weeks to months. Imiquimod is a topical immunomodulator that upregulates several cytokines, including interferons. Treatment is usually daily for 6-8 weeks.
Photodynamic therapy (PDT) is a topical therapy that works by irradiating the skin with a light source after a topical photosensitizer has been applied to the area. It is most commonly used to treat AKs. PDT includes pain and a sunburn-like reaction.
Cryotherapy is a non-invasive treatment that destroys cells through application of liquid nitrogen. It is generally used to treat AKs or benign cutaneous lesions. Efficacy for NMSCs is lower, and scarring and pigmentary change are expected with aggressive freezing.

Management of large lesions or locoregional spread

Cutaneous SCC metastatic to lymph nodes occurs uncommonly, and treatment recommendations are complex. Treatment of head and neck nodal positive disease generally includes neck dissection with lymph node sampling. Based upon the results, radiation therapy, with or without chemotherapy, or observation may be offered to the patient. Treatment of trunk or extremity nodal positive disease includes regional lymph node dissection possibly followed by radiation therapy.

Functional outcome of exceptionally large and invasive NMSCs, impinging upon or threatening adjacent structures, may be maximized through a multidisciplinary approach. Optimal care may involve, but is not limited to treatment by Mohs, ENT, plastics, and oculoplastic surgeons, medical oncologists, and radiation oncologists.

Management of metastatic disease

The extremely rare instances of regional or distant metastatic BCC or distant metastatic SCC are best managed by a multidisciplinary tumor board. Though evidence is limited and prognosis remains poor, clinical trials of chemotherapeutics and biologic response modifiers have shown sporadic success. Regression of extremely advanced BCCs with the use of GDC-0449 (vismodegib, Eviredge), an inhibitor of PTCH/Hedgehog (Hh) pathway signaling, has been noted (see Pathophysiology section) and this agent was recently FDA approved.

Vismodegib should be considered only in patients where further surgery and radiation therapy are contraindicated. Common side effects include alopecia. weight loss, nausea and vomiting, diarrhea, constipation, fatigue, muscle spasms, and fatigue. For patients who do respond, progression and recurrence after stopping therapy is likely. Interestingly, the antifungal agent itraconazole also inhibits the Hh pathway and has induced regressions in advanced BCC.

Cisplatin, either as monotherapy or a component of multi-agent chemotherapy with systemic 5-FU, methotrexate, bleomycin, doxorubicin, or retinoids, has shown efficacy in the treatment of distant metastatic SCC. Other treatments that have shown benefit include capectabine, a prodrug of 5-fluorouracil, and cetuximab, a monoclonal antibody inhibitor of the epidermal growth factor receptor.

Selected treatment regimens (based primarily on case reports and case series) are listed below:

Squamous Cell Carcinoma

Cisplatin 100 mg/m²; IV day 1
plus 5-FU 650 mg/m²;/d CI days 1-5
plus Bleomycin 15 mg IV day 1 then 16 mg/m²;/d CI days 1-5
(repeat cycle every 21-28 days)
Interferon-alfa 5 million IU/m² SC three times weekly
13-Cis-retinoic acid 1mg/kg PO daily
Cisplatin 20 mg/m²; IV weekly

Basal Cell Carcinoma

Vismodegib (Eviredge) 150 mg PO daily
Carboplatin AUC 6 IV day 1
plus Paclitaxel 135 mg/m²; IV day 1
(repeat cycle every 21 days)
Cisplatin 75 mg/m²; IV day 1
plus Paclitaxel 135 mg/m²; IV day 1
(repeat cycle every 21 days)

What other therapies are helpful for reducing complications?

Minimizing ultraviolet radiation exposure

Public awareness and education about sun-protective behaviors is necessary to minimize NMSCs. Decreasing UVR exposure is important. Wearing hats, tightly-woven sun-protective clothing, and avoiding mid-day sunlight between 10 AM and 4 PM when UVR is most intense is recommended.

Liberal application of sunscreens is helpful but should not be used as a means to prolong exposure. A broad spectrum sunscreen with a sun-protection factor (SPF) of at least 30 is recommended. Patients should understand that using sunscreens alone does not provide adequate protection. Sunscreens are not efficient at blocking all ultraviolet wavelenghths, they wash off with activity and sweating, and they need to be applied in sufficient amounts for maximal protection.

Treatment of Actinic Keratoses

Treatment of AKs by destructive methods, such as cryotherapy, or by topical treatments, such as 5-FU or imiquimod, can help to minimize the progression of precancerous lesions to SCC.

Retinoids

The off-label use of oral retinoids as prophylaxis for SCC can be beneficial in certain high-risk patients. Retinoids are frequently effective in reducing the development of new primary SCCs and may be considered in patients with a history of multiple SCCs. To prescribe retinoids safely, it is important to be familiar with several potentially serious side effects including hyperlipidemia, liver function abnormalities, and severe birth defects. For patients who tolerate retinoids, long-term therapy and laboratory monitoring is required.

Minimizing immunosuppression

Immunosuppressive medications predispose to NMSCs, and minimizing total immunosuppression levels may be a useful adjunct to reduce NMSC morbidity and mortality, especially due to SCCs. Conventional immunosuppressives, such as cyclosporine may increase NMSCs through both a direct oncogenic effect, as well as through decreased tumor immune surveillance.

Rapamycin/sirolimus is a newer alternative anti-rejection immunosuppressant, shown to have antiproliferative effects in-vitro and in-vivo, through inhibition of the mTOR pathway. Rapamycin appears to be protective against the development of NMSCs. Further studies will help define malignancy risks more clearly. Consultation with the patient’s transplant specialist may be helpful.

What should you tell the patient and the family about prognosis?

The vast majority of BCCs have an excellent prognosis, and mortality is exceedingly uncommon. The natural history of untreated BCCs is for slow, but progressive growth, without metastases. The goal of treatment is complete removal without recurrence. Recurrence is more likely with high-risk BCCs (see Table I).

Metastases are extremely rare. Localized SCCs also have an excellent prognosis, and the goal of therapy is complete removal without recurrence. Low-risk SCCs (see isplatin 20 mg/m²; IV) arising on sun-damaged skin rarely metastasize. High-risk SCCs are more likely to recur and occasionally metastasize.

SCC that is metastatic to regional lymph nodes or distant organs carries a much worse prognosis. Reported five year survival rates have ranged from 22-56% for patients with positive regional lymph nodes and are generally even lower for patients with distant metastases.

Significant morbidity from BCCs and SCCs can occur through impingement upon and invasion of adjacent anatomic structures, such as the nose, ears, or eyes. Good functional and cosmetic outcome is an important goal of therapy in these cases and may be facilitated by a multidisciplinary approach (see “Treatment” section).

Patients should understand that development of one NMSC puts them at an increased risk of developing additional NMSCs and melanoma. Patients should receive regular follow-up skin examinations by the physician (see “Follow-up surveillance and therapy/management of recurrences section”), learn how to perform a self skin examination, and be educated about and practice sun-protective behaviors (see “What other therapies are helpful for reducing complications?” section). Any new growth should be brought to the attention of the physician.

What if scenarios.

A biopsy of a potential NMSC should adequately sample the lesion. A superficial shave biopsy may be appropriate for very superficial lesions, but for thicker lesions the biopsy should include the deep reticular dermis (deep shave, punch, excisional, or incisional biopsy). Sometimes high-risk BCCs demonstrate an aggressive histologic growth pattern only towards the lesion’s base.

Improper selection of therapy based on the NMSC’s features, poor surgical technique, and inadequate surgical margins lead to increased recurrence and morbidity. Selection of an appropriate therapy, and surgeon skill and experience lead to improved results.

Follow-up surveillance and therapy/management of recurrences.

Monitoring for the recurrence or development of a new NMSC is an important aspect of proper treatment. Follow-up full body skin examinations are recommended for patients with a history of BCC or SCC, and a local lymph node examination should also be performed with a history of SCC.

For the first two years after a new diagnosis of local NMSC, an examination is generally recommended every 6-12 months for BCCs and every 3-6 months for SCCs.
After 2 years, full body skin examinations are generally recommended every 6-12 months.

The timing of follow-up skin examinations is shortened for patients with regionally metastatic SCCs. It may also be shortened for very high-risk patients who develop multiple and/or aggressive NMSCs, such as solid-organ transplant recipients, making treatment more difficult. Patients should be educated about sun-protective practices and conduct monthly self-examinations for new or changing lesions.

Further treatment is required when positive margins are found on histologic sections after local NMSC excision. In most cases, MMS or comparable surgery with complete margin assessment is advised. However, conventional re-excision may be repeated for low-risk NMSCs on the trunk or extremities. If negative margins are unachievable by MMS or comparable surgical treatment, then radiation therapy should be considered.

Locally recurrent NMSCs should be treated as high-risk disease because recurrence is a high-risk feature (see Table I). Treatment guidelines for local, regional, and distant recurrence of BCCs and SCCs, have been established by the NCCN. A discussion of these primary and adjuvant treatments can be found above (see “What should the initial definitive therapy for the cancer be?” section).

Solid-organ transplant patients with recurrent SCCs may benefit from a decrease in immunosuppressive treatment or substituting rapamycin for conventional immunosuppressive therapies (see “What should the initial definitive therapy for the cancer be?” section).

Pathophysiology

The pathophysiologies of BCC and SCC are distinct. However, development of both BCCs and SCCs involves specific gene mutations. The accumulation of genetic errors imparts a survival advantage on these cells, causing uncontrolled proliferation, decreased cell death, and eventual tumor formation.

For many years it has been hypothesized that BCCs arise from the basal cell layer, the lowermost cell layer of keratinocytes in the epidermis and the outermost portion of hair follicles. How this relates to our newer understanding of stem cells and cancer stem cells is unclear. The major pathophysiologic model for BCC development involves the PTCH (Patched) gene system, a tumor suppressor often mutated in BCCs. PTCH encodes the sonic hedgehog transmembrane receptor that normally inhibits smoothened (SMO), a G protein receptor.

A loss-of-function mutation in PTCH leads to constitutive activation of this cell-signaling pathway and uncontrolled cell growth. PTCH mutations are seen in both the inherited nevoid basal cell carcinoma syndrome and many sporadic BCCs. Mutations in p53 and CDKN2A (INK4A) are seen in some BCCs.

It has also been hypothesized for many years that SCCs arise from keratinocytes within the squamous cell layers of the epidermis, but their relationship to epidermal stem cells and cancer stem cells has not yet been delineated. The pathophysiologic model for development of UVR-induced SCC involves a multi-step process of progressive damage to keratinocytes.

Exposure to UVR leads to the accumulation of mutations in keratinocytes, most commonly in p53 and ras. Low-grade cellular dysplasia may progress to high-grade dysplasia with the evolution of AKs to SCC in-situ and eventually to invasive SCC. Less frequently mutated genes in SCC include CDKN2A and PTCH. Immunosuppression, DNA repair deficiencies, and carcinogens other than UVR likely also cause genetic errors, but the mechanisms are less well understood.

As our understanding of underlying disease mechanisms continues to improve, promising molecular-targeted treatments for BCCs and SCCs will be on the horizon. GDC-0449 and cetuximab (see “What should the initial definitive therapy for the cancer be?” section) are experimental, targeted treatments that may offer a glimpse into the future.

What other clinical manifestations may help me to diagnose non-melanoma skin cancer?

NMSC in the setting of a genetic syndrome occur rarely, but there are several syndromes that predispose to multiple NMSCs (Table III). In these cases, NMSCs may be multiple and associated with other findings. If a genetic syndrome is considered, asking about other syndrome specific manifestations and gathering a family history is important. Physical examination should also focus on characteristic findings of the suspected syndrome.

Keratoacanthomas (KAs) are a low-grade malignancy, considered by many to be a variant of SCC. KAs typically present abruptly and resolve spontaneously over several months. KAs may rarely present in an eruptive manner (Table IV), giving the physician a clue to the diagnosis.

What other additional laboratory studies may be ordered?

Genetic testing for PTCH mutations may rarely be considered if nevoid basal cell carcinoma syndrome is suspected. It is available through several laboratories across the country. Genetic testing of BCCs may become more important in the future if targeted molecular therapies become available.

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