INTRODUCTION Cutaneous squamous cell carcinoma (SCC) is a common cancer arising from malignant proliferation of the keratinocytes of the epidermis. Although it is locally invasive, SCCs usually remain localized and can be cured by a variety of techniques.
The available treatment options for localized disease include the following:
Early diagnosis and definitive treatment provide the best opportunity to cure cutaneous SCCs. In contrast to BCCs which only rarely metastasize, 5 to 10 percent of SCCs spread to regional lymph nodes or more distant sites with a relatively poor outcome.
Cryotherapy, electrosurgery, some types of radiation therapy (RT), and topical treatment can be used to treat superficial cutaneous SCCs and Bowen's disease, which is also known as squamous cell carcinoma in situ. In contrast, lesions that are more deeply invasive or have a higher risk of recurrence or metastasis generally require surgical excision, Mohs surgery, or more extensive RT.
The optimal approach for a specific case requires a consideration of the likelihood of the lesion recurring or metastasizing, cosmetic factors, and the expertise and resources of the treating physician. Special attention must be directed toward the preservation of form and function without sacrificing the opportunity for cure with lesions situated on or near cosmetically sensitive areas (eg, eyelids, lips, ears, nose, genitals, fingers).
The different treatment modalities and the indications for their use will be reviewed here, along with the prognosis and follow-up after treatment for a cutaneous SCC. The epidemiology and clinical features of cutaneous SCC are discussed elsewhere. (See "Epidemiology and clinical features of cutaneous squamous cell carcinoma").
TREATMENT FAILURE The risk of locoregional recurrence and
regional or distant metastasis is the most important factor in
determining the treatment for cutaneous SCC (show
Local recurrence Primary SCC of the skin has an overall five-year cure rate of greater than 90 percent after therapy . Recurrence rates depend on the size and location of the tumor, the treatment modality used, and the experience of the treating physician . Overall the recurrence of primary lesions is about 8 percent at five years, but it can be as high as 16 percent. Factors associated with an increased risk of recurrence include involvement of high-risk areas (eg, face, scalp, ears), large size (>2 cm), and unfavorable histology.
Regional and distant metastases Rates of metastasis from primary SCC are reported to be about 1 to 5 percent overall. About 85 percent of metastases occur in regional lymph nodes with the remainder occurring in distant sites such as the lungs, liver, brain, skin, and bone. Clinical situations with a high risk of regional or metastasis include the following:
LOW-RISK LESIONS Cutaneous SCCs that are small, do not invade beyond the subcutaneous tissue, arise from actinic keratoses or as a consequence of sun exposure, and do not have any of other high-risk features have a low frequency of recurrence and regional or distant metastases.
Cryotherapy, electrosurgery, superficial RT, and topical chemotherapy are all highly effective in properly selected patients.
Cryotherapy Cryotherapy destroys malignant cells by freezing and thawing. It is useful for small, well-defined, low-risk invasive SCCs and for Bowen's disease. In the most common cryosurgery technique, liquid nitrogen is applied to the tumor and a surrounding rim of normal-appearing skin (usually 3 mm). The frozen area is then allowed to thaw in an unaided fashion. In most cases, the tumor is refrozen to complete two freeze-thaw cycles; for Bowen's disease, a single freeze-thaw cycle may be sufficient . Tumor cell death is due to the formation of intra and extracellular ice crystals, hypertonicity, disruption of the phospholipid membrane, and vascular stasis
Cryosurgery does not permit histologic confirmation of the adequacy of treatment margins; thus, a substantial amount of training and experience is required to achieve consistently high cure rates.
Cryotherapy is fast, cost effective, and requires little if any anesthesia. Following treatment, there is usually moderate-to-severe swelling, pain, and oozing that resolve over days to weeks. The treated area subsequently sloughs, leaving behind an ulceration that heals over four to six weeks. This may result in residual hypopigmentation, permanent alopecia, and/or hypertrophic scarring that may be unacceptable to some patients. Treated areas on the lower extremities may take longer to heal.
The hypertrophic scarring usually resolves slowly over approximately eight months. Hypopigmentation can persist for many years and may be a particular problem for darkly pigmented individuals or in cosmetically sensitive areas.
When performed by experienced clinicians, cosmetic results are generally excellent, and cure rates as high as 96 to 99 percent have been reported . Many of the SCCs treated with cryotherapy arise from actinic keratoses, and such SCCs tend to be slow-growing and rarely metastasize .
Cryosurgery is not indicated for recurrent, large, deeply invasive, poorly-defined and other high-risk cutaneous SCCs because of the increased risk of local recurrence and/or metastatic spread. However, it can be considered for patients with high-risk tumors who are unable to tolerate either Mohs or excisional surgery or the frequent visits necessary for radiation therapy.
Electrosurgery Electrosurgery, also called curettage and electrodessication (C&D), is useful for small, superficial, well-defined cutaneous SCCs that are located in noncritical, low-risk sites. Electrosurgery is a relatively quick, well-tolerated office procedure that spares adjacent healthy tissue. It is associated with a low complication rate, is relatively inexpensive, and usually gives favorable cosmetic results.
Cutaneous SCCs and BCCs have a distinctive "feel" that is distinctly different from normal healthy tissue. This "feel" guides the curettage of tumor tissue away from surrounding healthy tissue. By alternately curetting away tumor and then electrodessicating the ulcer base plus a rim of surrounding normal skin, cure rates of 96 percent or better have been reported in carefully selected cases . However, higher recurrence rates have been reported by others and the actual recurrence rate may be closer to 10 to 20 percent, particularly for Bowen's disease
As with cryosurgery, the main disadvantage of electrosurgery is the lack of histologic confirmation of the tumor margins, thereby limiting its use to small, well-defined primary (non-recurrent) low-risk tumors. In addition, the cosmetic outcome in areas such as the nose, face, lips, or ears can be inferior to that obtained with either surgical excision or Mohs surgery, particularly for younger patients in whom cosmesis is an important secondary objective.
Electrosurgery is contraindicated for recurrent, large, poorly-defined, and other high-risk tumors. Furthermore, it is inappropriate for tumors that invade into or beyond the subcutaneous tissues where the expected discriminating "feel" between cancerous and healthy tissue is lost. In this situation, electrosurgery should be abandoned in favor of surgical excision or Mohs surgery.
Electrosurgery should also be avoided on the mid-face (mid-nose, nasal alae and sulci, medial canthi, and nasolabial folds). The embryonic fusion planes in these areas are believed to offer little resistance to the early and deep invasion by cancer cells . If tumors in this area are partially treated, healing skin can bury residual tumor beneath scar tissue. By the time a recurrence is clinically evident, the tumor can be massive and curative treatment extremely difficult or impossible. Thus, SCCs located in the mid-face are better treated by standard excision or Mohs surgery. RT is an option for patients not able or willing to undergo surgery.
Radiation therapy Radiation therapy is an excellent option for the initial management of small, well-defined, primary SCCs, especially in older patients and those who are not surgical candidates.
Various techniques have been used, including superficial x-rays, electrons, and megavoltage photons; RT is usually administered in a fractionated schedule over several weeks, requiring as many as 30 treatments . For low risk cutaneous SCCs, the five-year cure rate is approximately 90 percent .
One of the major benefits of radiation therapy is its sparing of normal, healthy tissue, thereby permitting superior cosmetic results for tumors located on or around the lips, nose, and eyelids. These cosmetic results may deteriorate with time and are less favorable for larger tumors because of the higher doses of RT required .
Drawbacks associated with the use of RT include the lack of histologic control of tumor margins, high cost compared to other modalities, and the potential short- and long-term side effects associated with radiation. In addition, cutaneous SCCs that recur following RT may behave more aggressively than those that recur after surgery, with higher rates of local recurrence and metastases .
Situations in which RT should be avoided or is contraindicated include the following:
Topical 5-FU Topical 5-fluorouracil (5-FU) is approved by the United States Food and Drug Administration (FDA) for the treatment of actinic keratoses. Although topical 5-FU is not approved for the treatment of Bowen's disease and superficial SCCs, it is widely used in these diseases when other treatment modalities are impractical and for patients who refuse surgical treatment . It is especially valuable for situations in which postoperative healing is compromised, such as lesions that involve the lower extremity in elderly patients or those with venous stasis disease . Topical 5-FU is also useful to treat the widespread superficial SCCs due to arsenical dermatitis or xeroderma pigmentosum (XP).
Most studies report cure rates between 80 and 92 percent . Inadequate frequency and/or length of treatment, insufficient drug concentration, application to an insufficiently wide area around clinically obvious tumor, and improper tumor selection all can contribute to treatment failure. Local recurrences may also result from poor penetration of 5-FU into the epithelium of involved pilosebaceous units, the source of regenerative epithelium following destruction of the epidermis .
5-FU is applied as a 5 percent cream, twice daily for four to eight weeks, depending upon the response. Courses can be repeated as necessary for residual or recurrent disease. Efficacy may be enhanced by increasing the concentration and/or frequency of 5-FU application, using an occlusive dressing, or applying it in conjunction with a topical keratolytic agent (salicylic acid, lactic acid, ammonium lactate) or retinoic acid
An inflammatory reaction is expected with topical 5-FU, and its absence can be associated with a poor response to treatment. The inflammatory reaction to 5-FU is usually more intense in patients treated for Bowen's disease than for those with actinic keratoses or superficial BCCs.
Following discontinuation of 5-FU, healing generally occurs over two or more weeks, leaving residual erythema and hyperpigmentation that fade with time. Favorable cosmetic results are one of the primary advantages of topical 5-FU over other treatment modalities for patients with Bowen's disease.
Prior to treatment, patients should be thoroughly educated about the anticipated effects, including stinging, burning, pain, erythema, edema, erosions and ulceration with serous oozing, and possible secondary infections. It is not uncommon for patients to become social recluses during treatment because of the undesirable cosmetic effects.
If the patient cannot tolerate the intense inflammatory reaction, options include reducing the concentration of drug, applying an emollient such as chilled vaseline or hydrated petrolatum or an intermediate potency topical steroid , or the temporary or even permanent discontinuation of therapy.
Special care should be taken when applying 5-FU to areas near the eyes, lips, and nose because of increased sensitivity in these areas. In addition, patients should avoid intense sun exposure during treatment.
Unusual side effects include temporary reversible onycholysis and onychodystrophy, persistent telangiectasias, hypertrophic scarring in high-risk areas, and bullous pemphigoid.
Toxicity due to systemic drug absorption is rare, but serious side effects (eg, cardiac ischemia, enterotoxicity) have been reported in patients with an inherited deficiency of the metabolizing enzyme dihydropyrimidine dehydrogenase . (See "Enterotoxicity of chemotherapeutic agents", section on Fluoropyrimidines).
Topical 5-FU is contraindicated in the management of invasive lesions, except possibly for palliation of tumors not amenable to other more effective treatments.
Other topical approaches Photodynamic therapy (PDT) and the immune response modifier imiquimod are also approved by the FDA for the treatment of actinic keratoses. Both have been used to treat Bowen's disease and superficial SCCs, although experience with these approaches and evidence of efficacy are far more limited than with topical 5-FU.
Photodynamic therapy Photodynamic therapy (PDT) is based upon the ability of porphyrins, the photosensitizers, to produce cytotoxicity in the presence of oxygen after stimulation by light of an appropriate wavelength. This cytotoxicity in turn results in the selective destruction of superficial cutaneous SCCs. Although both topical (Levulan kerastick®, 5-aminolevulinic acid hydrochloride) and injectable (Photofrin®, porfimer sodium) formulations have been used, the topical preparation is preferred for cutaneous disease, since systemic porphyrin administration is associated with prolonged photosensitivity.
The reported cure rates with PDT in small series vary from 46 to 100 percent for superficial SCC . However follow-up is short and the long-term efficacy of this approach is uncertain. Factors influencing outcome include different methods of photosensitizer administration, variability in the types and methods of light exposure, the definition of recurrent disease (clinically detected versus histologically assessed), and the length of follow-up. Additional disadvantages associated with PDT include the high number of treatments required and the associated discomfort.
Although PDT has been used to treat penile SCC in situ (erythroplasia of Queyrat), its efficacy in this setting is uncertain. Invasive SCC and melanoma have been reported following PDT, and this approach cannot be considered a standard treatment. (See "Carcinoma of the penis: Epidemiology; risk factors; and clinical presentation").
Imiquimod Imiquimod cream (Aldara®) is a topical immune response modifier approved by the FDA for the treatment of anogenital warts. Its antitumor effects are thought to be mediated by the stimulation of local cytokine production, cell-mediated immunity, and possibly the promotion of apoptosis .
Imiquimod has been used to treat both Bowen's disease and superficial SCCs . Imiquimod is applied once daily to the involved area for up to 16 weeks. The required course of treatment is significantly longer than with topical 5-FU, and this can create difficulty in patient compliance.
The efficacy of imiquimod was illustrated by a small trial in which 31 patients with biopsy-proven Bowen's disease were randomly assigned to 16 weeks of treatment with 5 percent imiquimod or placebo  . Eleven of 15 patients treated with imiquimod had complete resolution of disease, with no relapses seen at nine months. In contrast, none of the 16 patients treated with placebo responded. Three of the patients treated with imiquimod required cessation of treatment because of toxicity.
Larger randomized trials are necessary to define the optimal dosing schedule and the role of this approach compared to other treatments.
HIGH-RISK LESIONS Aggressive treatment is required for high-risk lesions to maximize the likelihood of cure with the initial treatment. Surgery, using either conventional excision or the Mohs technique, is the primary approach in this setting. Postoperative RT is an important supplement when regional lymphatic spread is present or local excision cannot completely remove the primary lesion.
Surgical excision Surgical excision is the most widely used treatment for high-risk cutaneous SCCs. It is well-tolerated, extremely effective, and the completeness of the procedure can be evaluated through histologic assessment of the specimen's margins. Excision can usually be performed in an outpatient setting under local anesthesia, although patients with deeply invasive or regionally metastatic lesions may require a more extensive procedure. Five-year cure rates are reported to be 92 and 77 percent for primary and recurrent SCCs, respectively .
Recommendations for surgical margins vary depending upon the risk of local recurrence . Well-defined, small (<2 cm) SCCs lacking any high-risk features require a 4 mm margin of normal tissue around the visible tumor to result in a 95 percent histologic cure rate. Primary SCCs that are 2 cm in diameter, poorly differentiated, in high-risk sites, or invade subcutaneous tissues require larger margins to achieve similar histologic cure rates.
Patients with recurrent tumors, tumors arising within chronic ulcers or radiation sites, or SCCs with perineural extension also need more extensive procedures. Since tumor growth is often asymmetric, these high-risk tumors are better treated by Mohs surgery if possible.
Mohs surgery � Mohs micrographic surgery is the treatment of choice for high-risk localized cutaneous SCCs and SCCs located in cosmetically sensitive or critical areas because of its high cure rate and ability to spare normal tissue . Reported five-year cure rates for primary and recurrent SCCs are about 97 and 90 to 94 percent respectively. For all categories of high-risk SCCs, cure rates are consistently higher with Mohs surgery than with other modalities (show table).
Mohs surgery is performed in the outpatient setting under local anesthesia and is generally well-tolerated. The tumor, together with a small rim of clinically normal-appearing tissue, is excised at an oblique angle in a series of stages, and microscopically evaluated by the surgeon. Histologic findings are then precisely correlated with the lesion through the use of a diagram (Mohs map) drawn by the surgeon following the stepwise excision of the tumor.
If microscopic margins are positive, their precise locations are noted on the Mohs map and another specimen is taken only from the involved areas. This tissue is evaluated in a similar fashion, and the process is repeated until all margins are negative for residual tumor.
By excising the specimen at an oblique angle, Mohs surgery allows histologic evaluation of 100 percent of the peripheral margin. In contrast, routine histologic processing of a standard surgical excision specimen permits evaluation of less than 1 percent of the tumor margins. This clinicopathologic correlation during surgery is responsible for the improved cure rates with Mohs surgery.
Following complete resection of the tumor, the defect is either closed immediately (using either a primary side-to-side closure, local flap, graft, or more rarely a distant flap) or allowed to heal secondarily, depending upon the details of the individual case. Closure can be performed either by the Mohs surgeon or coordinated with another surgeon (eg, plastic or oculoplastic surgeon) if necessary.
The primary disadvantages of Mohs surgery are the prolonged duration of the procedure (generally two to four hours) and its greater cost compared to other treatment options.
The considerations in determining the role of Mohs surgery in cosmetically important areas that are not at high risk for recurrence is similar to that for basal cell carcinoma.
Locoregional disease Determining the extent of disease is critical to maximize the likelihood of long-term control. The initial evaluation of all patients should include physical examination of locoregional lymph nodes. For most localized SCCs, this initial evaluation is sufficient and, if negative, no further work-up is required.
Patients with high-risk, clinically node-negative primary lesions and those with clinically enlarged lymph nodes may require radiographic imaging (computed tomography [CT] or magnetic resonance imaging [MRI]), fine needle aspiration, or lymph node biopsy. Depending upon the results of these tests, regional lymph node dissection may be warranted. (See "Management of the clinically negative neck in head and neck cancer").
For cutaneous SCCs of the head and neck area, occult nodal disease is seen in up to 20 percent of patients, depending upon the site of the primary tumor . The sentinel lymph node biopsy technique is being evaluated for its ability to detect microscopic involvement in patients with high-risk cutaneous SCCs involving the head and neck region who have no evidence of lymph node involvement
Treatment RT is used to treat incompletely excised primary SCCs. In one series, local tumor control was achieved in 87 percent of cases. In addition, patients with regional lymph node spread can be treated with RT, either alone or in conjunction with surgery.
Adjuvant RT for selected patients with completely excised nonmetastatic SCCs with aggressive clinical or histologic features (eg, large size or perineural invasion) has been recommended. However, its effectiveness in this setting is not clearly established .
Metastases to the parotid gland and adjacent lymph nodes are a particularly difficult problem with SCCs arising in the head and neck area . Superficial or total parotidectomy may be required, and efforts to spare the facial nerve may increase the risk of local recurrence. As a result, postoperative RT may need to be considered. In patients with isolated parotid lymph node metastases <3 cm in diameter, five year survival rates of 75 to 80 percent have been reported with combined modality therapy .
PROGNOSIS The overall prognosis for patients with cutaneous SCC is excellent and mortality is rare. In the United States, the estimated yearly disease-specific mortality rate is about 1 percent. Studies from Australia and Denmark, which have more well-established registration systems for cancer incidence and mortality, report an estimated overall mortality rate of 3 to 4 percent. In the Australian report, one-half of deaths occurred in patients with inoperable or recurrent regional disease without evidence of distant metastases.
Treatment of primary SCCs results in an overall five-year cure rate of greater than 90 percent . When the initial treatment is unsuccessful, disease is most likely to recur either locally or in regional lymph nodes. Distant metastases are generally limited to patients who have recurred locally or in regional lymph nodes, or in those whose original tumor was neglected and left untreated for a prolonged period or was misdiagnosed. Although local and locoregional therapy can salvage many patients who recur, the risk of distant metastases and delayed mortality increases markedly.
Local recurrence rates depend upon the size and location of the tumor, the treatment modality used, and the experience of the treating physician. Overall the recurrence rate of primary lesions is about 8 percent at five years, but it can be as high as 16 percent. Following the initial treatment, approximately 75 percent of recurrences develop within the first two years and 95 percent within five years
In patients who develop metastatic disease, regional lymph nodes are the first site of involvement in about 85 percent of cases, with the remainder occurring in distant sites (eg, lungs, liver, brain, skin, bone). Although regional disease can sometimes be managed effectively with surgery and/or RT, the occurrence of regional lymph node metastases places the patient at increased risk for the subsequent development of distant metastases.
Both regional lymph node and distant metastases are associated with a markedly increased risk of disease-related mortality. Overall survival rates for patients with regional lymph node metastases are about 25 to 35 percent at five years and less than 20 percent at ten years . In patients with distant metastases, the five-year survival rate is less than 10 percent .
Second skin cancers Patients with a history of a nonmelanoma skin cancer have a much higher incidence of a second skin cancer (SCC, BCC, or melanoma) compared to the general population, presumably because all of these tumors share common risk factors . After a primary SCC, the estimated risk for any second nonmelanoma skin cancer is about 50 percent at five years, and the risk of another SCC is estimated to be about 18 percent at three years and 30 percent at five years .
The risk of a second skin cancer is greatest in the first year after primary diagnosis, because of increased surveillance after the initial diagnosis . Patients at an especially high risk for a second skin cancer include those with more than one previous SCC, fair-skinned individuals, and those who are immunosuppressed.
Other systemic cancers Cutaneous SCC has been associated with an increased incidence of cancers of the salivary glands, oropharynx, and respiratory tract, possibly related to the use of tobacco products as a common risk factor. In a series of almost 26,000 patients with cutaneous SCC in Sweden, there was an approximately two-fold increase in risk of developing a systemic cancer compared to the risk in the general population. An almost two-fold increase in hematopoietic and lymphoproliferative malignancies has also been observed.
Despite the modest increase in risk, routine evaluation for systemic malignancy is not indicated in healthy individuals who are diagnosed with primary cutaneous SCCs.
FOLLOW-UP All patients treated for cutaneous SCC need surveillance for the early recognition and management of treatment-related complications, local or regional recurrences, and the development of new skin cancers. We recommend that patients be seen every three to six months for the first two years, then yearly thereafter.
The examination should include inspection of the treated area for visible signs of recurrence and palpation of the skin and adjacent structures (including lymph nodes) to evaluate for possible deeper recurrence or regional metastasis. Asking patients about any visible, textural, or sensory changes involving the treated area can often be a helpful clue of a subclinical or deeper recurrence. In addition, patients should be encouraged to perform interim skin self-examinations and to see their health care provider for any new skin growths or other suspicious lesions.
Any suspicious areas should be biopsied. For suspected deep recurrences, a deeper punch biopsies may be required. Early detection and treatment may prevent an incurable local recurrence.
SUMMARY AND RECOMMENDATIONS Cutaneous squamous cell carcinomas (SCCs) are common lesions that are cured with local therapy in over 90 percent of cases. SCCs have a higher potential for local recurrence and regional or distant metastases than basal cell carcinomas. Delayed diagnosis or inadequate treatment can result in increased morbidity or death.
The risk of local regional recurrence and regional or distant metastasis is the most important factor in determining the treatment for cutaneous SCC. Situations with a high risk of recurrence or metastasis include the following:
Low risk SCCs and Bowen's disease � We recommend local treatment with either cryotherapy or electrosurgery. The specific choice of treatment modality depends upon the experience of the physician, cosmetic factors, and patient preference.
High-risk SCCs We recommend Mohs surgery or conventional surgical excision for the treatment of high-risk tumors to maximize local tumor control and minimize cosmetic damage to normal tissues
Follow-up Careful follow-up is required to evaluate for evidence of local recurrence, regional or distant metastasis, or treatment-related complications. We generally reassess patients every three to six months for two years and then annually after the initial diagnosis and treatment of SCC.