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Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)

Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)
Authors:
Sumaira Z Aasi, MD
Angela M Hong, MBBS, MMed, PhD, FRANZCR
Section Editors:
Robert S Stern, MD
June K Robinson, MD
Deputy Editor:
Rosamaria Corona, MD, DSc
Literature review current through: Sep 2022. | This topic last updated: Sep 26, 2022.

INTRODUCTION — Cutaneous squamous cell carcinoma (cSCC) is a common cancer arising from malignant proliferation of the keratinocytes of the epidermis that has invaded into the dermis or beyond. cSCC in situ or Bowen's disease is defined as a tumor that is limited to the epidermis and has not invaded into the dermis. Treatment of cSCC is indicated since progression of the tumor may lead to local tissue destruction or metastasis resulting in significant morbidity or death. Early treatment provides the best opportunity to cure cSCC.

In contrast to basal cell carcinoma (BCC), which rarely metastasizes, around 2 to 5 percent of cSCCs metastasize to regional lymph nodes or more distant sites [1-3]. The approach to treatment is dependent upon the presence or absence of tumor features and patient characteristics that portend an increased risk for aggressive tumor behavior (table 1). cSCCs that do not have high-risk features have low frequencies of recurrence and metastasis.

The treatment of cSCC without features associated with aggressive behavior (low-risk cSCC) and the prognosis of cSCC will be reviewed here. The management of high-risk and metastatic cSCC, the treatment of keratoacanthomas, and the risk factors, clinical features, and diagnosis of cSCC are reviewed separately.

(See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)

(See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)

(See "Keratoacanthoma: Management and prognosis".)

(See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)

(See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".)

APPROACH TO MANAGEMENT

Risk assessment — Once the diagnosis of cSCC has been established by skin biopsy and histopathologic examination (see "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis"), the assessment of the risk of locoregional recurrence and regional or distant metastasis is the most important step to determine the treatment approach.

The initial evaluation of all patients should include physical examination of locoregional lymph nodes. For most localized cSCCs, this initial evaluation is sufficient and, if negative, no further work-up is required.

Characteristics that impact the risk for recurrence and metastasis include the tumor site, tumor depth, size, and histologic features, as well as patient characteristics and comorbidities (table 1). However, a consensus on the specific characteristics that define high-risk cSCC has not been established, and major entities such as the National Comprehensive Cancer Network (NCCN) and the American Joint Committee on Cancer (AJCC) have described dissimilar "high-risk" criteria (table 1 and table 2) [4].

We follow the NCCN criteria when categorizing tumors as high risk or low risk for determining the approach to treatment [5]. The features of high-risk cSCC are reviewed in greater detail separately. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)

Definition of low- and high-risk cutaneous squamous cell carcinoma — According to the 2021 NCCN guidelines, the risk stratification for cSCC based on risk factors for local recurrence, metastasis, or death are as follow [5]:

Low-risk cSCCs:

Well-defined, primary lesions <2 cm located on trunk or extremities (excluding pretibia, hands, feet, nail units, and ankles)

Primary tumor

Histopathologically well or moderately differentiated tumor, ≤6 mm in thickness and no invasion beyond subcutaneous fat, without perineural, lymphatic, or vascular invasion

High-risk cSCCs:

Lesions ≥2 cm located on trunk or extremities (excluding pretibia, hands, and feet)

Lesions of any size located on head, neck, hands, feet, pretibia, and anogenital area

Recurrent tumor

Histopathologically acantholytic (adenoid), adenosquamous (showing mucin production), or metaplastic (carcinosarcomatous) subtypes, with perineural, lymphatic, or vascular invasion

Very high-risk cSCC:

Lesions ≥4 cm on any location

Histopathologically poorly differentiated tumor, desmoplastic cSCC, >6 mm in thickness or invasion beyond the subcutaneous fat, tumor cells within the nerve sheath of a nerve lying deeper than the dermis

Lymphatic or vascular involvement

Additional individual high-risk factors in high-risk groups (eg, organ transplant recipients, other settings of immunosuppression, xeroderma pigmentosum) include the total number of tumors and the frequency of development [5].

Choice of treatment — The goals of primary treatment of cSCC are to ensure the complete removal of the primary tumor, prevent metastasis, and preserve cosmesis. For lesions located in cosmetically or functionally challenging areas, the pros and cons of various treatment options should be discussed by dermatologists, surgeons, and radiation oncologists [6]. For cSCC at low risk for local recurrence, treatment options include (algorithm 1) [7]:

Surgical excision, including Mohs micrographic surgery

Curettage and electrodesiccation

Cryotherapy

Photodynamic therapy

Radiation therapy (for nonsurgical candidates)

Although these treatments are commonly used in clinical practice, their efficacy has not been evaluated in randomized trials. Systematic reviews of observational studies have found insufficient data for definitive conclusions about the relative efficacy of available treatments [8-10]. Treatment recommendations are thus based upon limited evidence from observational studies, local guidelines, and clinical experience [7,8,11-14].

SINGLE LOW-RISK LESIONS

Surgery

Standard excision — We recommend standard surgical excision as the first-line treatment for low-risk cSCCs (algorithm 1). Excision usually can be performed in an outpatient setting under local anesthesia and is generally well tolerated.

Recommendations for surgical margins vary depending upon the risk for local recurrence. For low-risk lesions, we agree with the National Comprehensive Cancer Network (NCCN) guidelines and the American Academy of Dermatology guidelines, which recommend standard excision with 4 to 6 mm clinical margins of uninvolved skin to a depth of the mid- or deep subcutaneous adipose tissue for low-risk primary cSCCs [7,13]. The completeness of the procedure must be evaluated through histologic assessment of the specimen's margins.

Although surgical excision is the most frequently used treatment for cSCC, there are no randomized trials comparing different surgical margins for the treatment of cSCC. A systematic review of 12 observational studies that assessed tumor recurrence following surgical excision of invasive cSCC (1144 patients) found local recurrence rates ranging from 0 to 15 percent, with a pooled average local recurrence rate of 5.4 percent (95% CI 2.5-9.1 percent) [8]. The excision margins ranged from 2 to 10 mm; the average incomplete excision rate (eg, presence of tumor cells at or in proximity of the margins) was 8.8 percent and was highest for periocular lesions (15 to 37 percent).

A prospective study of 111 patients with 141 primary invasive cSCCs excised using Mohs micrographic surgery found that a margin of 4 mm cleared 95 percent of low-risk tumors, whereas a margin ≥6 mm was required to clear 95 percent of tumors with high-risk features [15]. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Surgery'.)

Incomplete excision — For incompletely excised cSCC, further excision with circumferential histologic margin control or Mohs micrographic surgery should be advised (algorithm 1). In patients who cannot tolerate surgery or in whom surgery is contraindicated, adjuvant radiation therapy should be considered.

Mohs surgery — Mohs surgery, a specialized tissue-sparing procedure that involves histologic assessment of 100 percent of the excised tumor margins, has also been used for the treatment of tumors without high-risk features, particularly for tumors in locations in which a tissue-sparing surgical modality is desired (eg, tumors in cosmetically or functionally sensitive areas where excision with a 4 to 6 mm margin may lead to significant cosmetic, anatomic, or functional distortion). (See "Mohs surgery".)

Nonsurgical destructive treatments

Curettage and electrodesiccation — Curettage and electrodesiccation (C&E) may be used for small, superficial, well-defined cSCCs that are located in noncritical, low-risk sites (algorithm 1). C&E 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.

cSCCs 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. C&E is performed by alternately curetting away the tumor and then electrodesiccating the ulcer base plus a rim of surrounding normal skin. (See "Minor dermatologic procedures", section on 'Curettage and electrodesiccation'.)

A limited number of uncontrolled studies have reported the recurrence rates after C&E. In a 2013 systematic review, the pooled analysis of seven studies, including a total of 1131 patients, most of whom with tumors <2 cm in diameter, found an average recurrence rate of 1.7 percent (95% CI 0.6-3.4 percent) [8]. In a 2022 systematic review that included 13 studies (2352 in situ or superficial invasive tumors), the recurrence rate was 2 percent (95% CI 1.1-3.0) [16].

The main disadvantage of C&E is the lack of histologic confirmation of the tumor margins, thereby limiting its use to small, well-defined, primary (nonrecurrent), 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.

C&E is contraindicated in the following situations:

Recurrent, large, poorly defined, and other high-risk tumors.

Tumors that invade into or beyond the subcutaneous tissues, where the expected discriminating "feel" between cancerous and healthy tissue is lost.

Tumors located in terminal hair-bearing areas, as the tumors can extend down the hair follicles.

Tumors located on the midface (midnose, 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 [17]. If tumors in this area are partially treated, healing skin can bury the 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.

In these situations, C&E should be abandoned in favor of surgical excision, including Mohs surgery.

Cryotherapy — Cryotherapy destroys malignant cells by freezing and thawing. Tumor cell death is due to the formation of intracellular and extracellular ice crystals, hypertonicity, disruption of the phospholipid membrane, and vascular stasis [18]. Since cryotherapy does not permit histologic confirmation of the adequacy of treatment margins, it may be used for small, well-defined, low-risk invasive cSCCs (algorithm 1) and for Bowen's disease (cSCC in situ) (picture 1). (See 'Bowen's disease (squamous cell carcinoma in situ)' below.)

In the most common cryotherapy 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. A temperature of -50°C (-58°F) is needed to cause destruction of malignant lesions. (See "Minor dermatologic procedures", section on 'Cryotherapy (cryosurgery)'.)

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, or hypertrophic scarring that may be unacceptable to some patients. Hypopigmentation can persist for many years and may be a particular problem for individuals with highly pigmented skin or patients with cSCCs in cosmetically sensitive areas.

Based upon data from observational studies, the recurrence rate after cryotherapy appears to be low. A systematic review of observational studies including eight studies (with a total of 273 patients) that assessed recurrence rates for invasive cSCC after cryotherapy found a pooled average recurrence rate of 0.8 percent (95% CI 0.1-2.2 percent) after treatment with a double freeze-thaw cycle [8].  

Contraindications to cryotherapy are shown in the table (table 3).

Photodynamic therapy — Photodynamic therapy (PDT) is based upon the ability of porphyrins to produce cytotoxicity in the presence of oxygen after stimulation by light of an appropriate wavelength. PDT is not recommended for the treatment of invasive cSCC, due to high recurrence rates associated with PDT [19]. In a review of eight observational studies, including 119 invasive cSCCs that had apparently responded to PDT, the pooled average recurrence rate was 26.4 percent (95% CI 12.3-43.7 percent) [8]. (See "Photodynamic therapy".)

Radiation therapy

Indications — Radiation therapy is generally not used as monotherapy for low-risk cSCCs. However, radiation therapy may be an effective, nonsurgical option for primary cSCCs in select patients, specifically in older patients who are poor surgical candidates (algorithm 1) [11].

More often, patients may receive radiation to the sites of high-risk tumors as an adjuvant therapeutic measure aimed at reducing the likelihood for local recurrence following surgical excision with clear margins or as a salvage therapy for patients with incompletely resected tumors [20-23]. Guidelines from the NCCN and the American College of Radiology (ACR) recommend the use of adjuvant radiation therapy for tumors that exhibit extensive perineural or large nerve involvement [7]. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Radiation therapy'.)

Efficacy — There are no randomized trial data comparing surgery with radiation therapy. However, a number of large case series report high local control rates of over 90 percent:

A 2013 systematic review and meta-analysis of observational studies evaluated the local recurrence rates in patients treated with radiation therapy for primary cSCC [8]. The pooled analysis of data from seven studies (761 patients) of external beam radiation therapy for primary cSCC found an average local recurrence rate of 6.4 percent (95% CI 3-11 percent). The pooled analysis of data from six     studies (88 patients) treated with brachytherapy for primary cSCC found an average local recurrence rate of 5.2 percent (95% CI 1.6-10.5 percent), similar to that of conventional surgical excision.

Similar results were provided by a 2021 systematic review of 46 studies that included 3185 patients treated with various types of radiation therapy as monotherapy [24]. The pooled analysis of data showed a local recurrence rate of 7.2 percent after a median follow-up time of 4 to 88 months.

One of the benefits of radiation therapy is usually an acceptable cosmetic result for tumors located on or around the lips, nose, and eyelids [25]. The long-term cosmetic outcome depends on the fractionation of the radiation therapy and the size of tumor. In a study with a median follow-up of 5.8 years, more than 92 percent of patients reported a good to excellent cosmetic outcome; the cosmetic outcome was dependent on the size of the lesion (99 percent in tumors <1 cm and 92 percent in tumors 1 to 3 cm) [21].

However, initial favorable cosmetic results may deteriorate over the following several years and are generally less favorable for larger tumors because of the larger treatment field and higher doses of radiation required [20]. As an example, scarring and ectropion may occur as late complications of radiotherapy treatment of periocular tumors, requiring complex reconstructive procedures to restore function [26]. A fully fractionated course of radiation therapy can minimize long-term fibrosis [27].

Drawbacks and contraindications — Drawbacks associated with the use of radiation therapy include the lack of histologic control of tumor margins, daily attendance of radiation therapy for several weeks, high cost, and the potential short-term and long-term side effects associated with radiation (table 4). Of particular concern are some site-specific adverse effects, such as permanent alopecia within the radiation therapy field or fibrosis causing ectropion resulting from irradiation of the lower eyelid region.

Relative contraindications for radiation therapy are:

Younger patients (age <60). Radiation-induced malignancies following small field superficial radiotherapy for skin cancers are rare but must be considered when recommending radiation therapy to younger patients. These patients should be discussed in a multidisciplinary team setting with input from a surgeon, radiation oncologist, and dermatologist.

Sites of poor vascularity or healing and wear and tear sites (eg, the hands, feet, and pretibial area). These areas are subjected to greater trauma and tension and may be more likely to break down and ulcerate as a result of the atrophy and poor vascularity of irradiated tissue.

Location over cartilage area. The risk of late soft tissue and cartilage necrosis can be minimized with fractionated treatment (<5 percent), and this is related to increasing tumor size and larger doses per fraction.

Recurrent cSCCs, which are not low-risk cSCCs, that have been previously irradiated because of the potential damage to normal tissues from high cumulative doses of radiation.

Verrucous carcinoma, since several reports have documented anaplastic transformation with subsequent widespread metastases following radiation therapy [28-30].

Techniques — Various techniques have been used, including superficial radiographs, electrons, megavoltage photons, and brachytherapy [20,31,32].

External radiotherapy fractionation — The fraction size (dose per fraction) is the most important determining factor of late effect. Using a smaller fraction size (2 Gy per fraction) gives better sparing of the late effect than larger fraction size (>3 Gy per fraction). In order to maximize long-term cosmetic and functional outcome, the standard dose fractionation of 2 Gy per fraction to a total dose of 60 Gy is recommended.

However, there is marked variation in dose prescription depending on patient factors (age, comorbidity) and tumor factors (size, location). In a United Kingdom study, radiation oncologists were asked to prescribe the dose and fractionation in a variety of clinical scenarios (various locations, sizes, and ages), and a total of 24 dose fractionation schedules were used, ranging from 18 Gy in a single fraction to 66 Gy in 33 fractions [33].

For older patients, often of poorer performance status, daily treatment over six weeks may be logistically difficult. Therefore, hypofractionated treatment (higher dose per fraction in fewer number of fractions) should be considered. Acceptable alternative fractionations are 30 to 33 Gy in 5 to 6 fractions (2 fractions per week), 40 Gy in 10 fractions, 45 Gy in 15 fractions, and 50 Gy in 20 fractions to 55 Gy in 25 fractions. In a 2018 systematic review of 40 studies including over 12,000 irradiated nonmelanoma skin cancers, hypofractionated treatment provided a local control rate of over 90 percent [34].

The treatment target volume is defined by clinical mark-up, and customized lead mask/cutout is used to define treatment field. Either superficial energy radiation (50 to 150 kVp) or electron (6 to 12 MeV) can be used. An appropriate energy is selected to ensure 90 percent isodose at the desired depth of the target. Superficial energy radiation should be selected based on dose depth tables of half value layer, filter, kV, and mA for the individual machine. Superficial energy radiation has the maximum dose (DMax) on the skin surface, whereas DMax of electron is not on the skin surface; therefore, a tissue equivalent bolus material is needed on the skin to build-up the DMax to the skin surface.

Treating a large volume over an area of curvature (eg, the large area of the scalp and limbs) can be technically challenging. For patients with extensive disease over convex surfaces (eg, scalp or limbs), volumetric modulated arc therapy (VMAT) is a particularly useful technique to provide superior target volume coverage and sparing of the underlying organ at risk [35,36]. VMAT delivers radiation by a moving gantry with dynamic modulation of the beam by multileaf collimators. The use of custom-made, three-dimensional (3D) printed boluses provides advantages over manual boluses in terms of improved reproducibility and dose distribution (picture 2) [37,38].

Brachytherapy — Brachytherapy involves delivery of radiation from a source in direct or close contact to the skin by using a surface mold, specialized shielded applicator, or interstitial implantation of applicator. It is not commonly used for the treatment of cSCC and requires expertise in treatment setup and planning. In suitable patients, brachytherapy may be an efficient and well-tolerated treatment that offers excellent cosmesis; however, long-term cure rates have not been determined. No standard dose schedule can be recommended, and total doses are based on clinician's experience and the size and location of the lesions. Recommendations based upon case series studies and expert opinion have been published by the Groupe Européen de Curiethérapie and the European Society for Radiotherapy and Oncology (GEC-ESTRO) [39].

Topical therapies — Topical therapies, including topical fluorouracil and imiquimod, are not indicated for the management of invasive cSCC, except possibly for palliation of tumors not amenable to other, more effective treatments [40].

MULTIPLE LOW-RISK LESIONS — The treatment of multiple low-risk lesions, a phenomenon not uncommonly seen on lower extremities in older adult patients, can be quite challenging. These lesions typically occur on a background of diffuse actinic skin damage with multiple actinic keratoses. It is thus critical to carefully assess the patient and the sites involved. In patients with multiple diffuse and similar-appearing lesions on the lower extremities, biopsies of a few representative lesions may be sufficient to ascertain the diagnosis while minimizing wounds. However, clinically concerning (ie, large, painful, rapidly growing) ulcers/lesions should be sampled to rule out high-risk invasive cSCC and treated accordingly.

Often, because of the diffuse nature and high burden of lesions, surgery may not be adequate or cause morbidity in terms of multiple wounds as well as surgical fatigue of the patient. Field or systemic therapy is often used. Limited evidence from small case series indicates that field therapy with topical fluorouracil used as "chemowraps" may be effective in decreasing the burden of multiple low-risk cSCCs as well as clearing the surrounding actinic keratoses. This treatment modality involves applying topical fluorouracil on the site with some type of occlusive bandage (plastic wrap and or modified Unna boot) over a period of a few days per week for several weeks in order to elicit an inflammatory reaction and allows for treatment of a broad area at one time [41,42].

This treatment is effective but requires a motivated and compliant patient. Moreover, the patient must be monitored for adverse effects of systemic absorption of topical fluorouracil, especially if erosions develop in the treated areas [43]. Signs of fluorouracil systemic toxicity include fever and chills, nausea and vomiting, diarrhea, anemia, neutropenia, thrombocytopenia, abdominal pain, generalized pain, and discomfort [43].

In addition, there are anecdotal reports and an author's personal experience on the beneficial effect of low-dose systemic retinoids (ie, acitretin, isotretinoin) in patients with diffuse, superficial cSCCs of the lower extremities. However, the patient has to be maintained on the systemic retinoid for several months, with concurrent problems in adherence due to the side effects of the drug (eg, cheilitis, hypertriglyceridemia, hepatotoxicity, alopecia). The drug must be tapered very slowly as a rebound phenomenon can occur.

Radiation therapy is not an option for multiple cSCCs of the lower extremities, as it can lead to significant skin breakdown and nonhealing wounds.

BOWEN'S DISEASE (SQUAMOUS CELL CARCINOMA IN SITU) — Treatment options for Bowen's disease (cSCC in situ) include surgical excision, curettage and electrodesiccation (C&E), photodynamic therapy (PDT), cryotherapy, topical fluorouracil, and imiquimod. However, there is limited evidence from high-quality studies to guide the choice of therapy. In particular, there are no randomized trials evaluating surgical treatments for Bowen's disease. A systematic review of nine randomized trials (363 patients), most of which were of poor methodologic quality, concluded that PDT, cryotherapy, topical fluorouracil, and imiquimod are all effective in clearing Bowen's disease lesions, although comparative data are insufficient to recommend one treatment over another [9].

Surgical excision — Surgical excision with a 4 to 6 mm margin may be indicated for small, isolated Bowen's disease lesions [7,44]. In a retrospective, single-institution study of 79 Bowen's disease lesions, the complete excision rate was 94 percent for lesions excised with a 5 mm margin, compared with 88 percent for those excised with a <5 mm margin [45]. (See "Principles and overview of nail surgery", section on 'Squamous cell carcinoma'.)

Nonsurgical destructive treatments — Nonsurgical therapies for Bowen's disease include:

Curettage and electrodesiccation — Curettage and electrodesiccation (C&E) is a simple and effective treatment modality for Bowen's disease [44]. C&E is a well-tolerated office procedure performed under local anesthesia, is associated with a low complication rate, is relatively inexpensive, and usually gives favorable cosmetic results.

Cryotherapy — Cryotherapy is a simple and inexpensive treatment modality for Bowen's disease, particularly in patients with multiple lesions. A single 30-second freeze-thaw cycle may be sufficient to achieve complete clearance of the lesion [44,46]. Drawbacks of cryotherapy include local discomfort and pain, risk of ulceration, especially for lesions on the lower legs, and long healing times.

Photodynamic therapy — Photodynamic therapy (PDT) is a treatment option for Bowen's disease, especially for large lesions (>3 cm in diameter) [9,19,47]. Studies have demonstrated initial clearance rates of 88 to 100 percent at three months and sustained clearance of 68 to 89 percent at 1.5 to 4 years after one to two cycles of methyl aminolevulinate-photodynamic therapy (MAL-PDT) [48-51].

MAL 16.8% cream is available in Europe, Canada, Australia, and other countries but not in the United States. (See "Photodynamic therapy", section on 'Topical photosensitizing medications'.)

A randomized study comparing MAL-PDT with placebo-PDT, cryotherapy, or topical fluorouracil for the treatment of Bowen's disease found that MAL-PDT was superior in efficacy to topical fluorouracil and placebo-PDT and was less painful than cryotherapy [48]. (See "Photodynamic therapy".)

Another small, randomized trial found that a single session of ablative fractional laser (AFL)-assisted MAL-PDT was more effective than MAL-PDT alone administered in two sessions one week apart for the treatment of Bowen's disease of the lower extremities [52]. At 3, 12, and 60 months, the complete response rates for AFL-MAL-PDT were 93, 87, and 85 percent, respectively, compared with 76, 55, and 45 percent for MAL-PDT alone. Local adverse events, including erythema, crusting, hyperpigmentation, burning sensation, and pruritus, occurred in nearly all patients in both treatment groups but resolved within one week without complications.

Topical therapies

Topical fluorouracil — Although topical fluorouracil is not approved for the treatment of Bowen's disease, it is widely used for this indication and for patients who refuse surgical treatment [53-55]. It is especially valuable for large lesions (>3 cm in diameter) and in situations in which postoperative healing is compromised, such as lesions that involve the lower extremity in older adult patients or patients with venous stasis disease [56]. Topical fluorouracil is also useful to treat the widespread cSCC in situ lesions that may occur in arsenical dermatitis or xeroderma pigmentosum. (See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Xeroderma pigmentosum' and "Arsenic exposure and poisoning".)

For the treatment of Bowen's disease, topical fluorouracil 5% cream is applied twice daily for two to eight weeks, depending upon location and response. Treatment courses of four weeks (once daily for one week, then twice daily for three weeks) with this formulation have resulted in clinical cure rates of 48 and 56 percent in small, randomized trials [48,57]. Longer treatment courses may result in higher clearance rates [58]. In one small, uncontrolled study in which the 5% cream was administered twice daily for an average of eight weeks, clinical cure occurred in 85 percent of patients (average follow-up time = 4.6 years) [59].

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 [53,54,60]. Local recurrences may also result from poor penetration of topical fluorouracil into the epithelium of involved pilosebaceous units, the source of regenerative epithelium following destruction of the epidermis [61].

Courses can be repeated as necessary for residual or recurrent disease. Efficacy may be enhanced by using an occlusive dressing, or applying it in conjunction with a topical keratolytic agent (salicylic acid, lactic acid, ammonium lactate) or retinoic acid [53,54].

An inflammatory reaction is expected with topical fluorouracil, and its absence can be associated with a poor response to treatment. Following discontinuation of fluorouracil, 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 fluorouracil 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 of visible sites, like the face, 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 petroleum gel or hydrated petrolatum or an intermediate-potency topical steroid (table 5), or the temporary or even permanent discontinuation of therapy. (See "Topical corticosteroids: Use and adverse effects".)

Special care should be taken when applying fluorouracil 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 [62,63]. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Fluorouracil'.)

Imiquimod — Imiquimod is a topical immune response modifier approved for the treatment of anogenital warts, actinic keratoses, and superficial basal cell carcinomas. Its antitumor effects are thought to be mediated by the stimulation of local cytokine production, cell-mediated immunity, and, possibly, the promotion of apoptosis [64-66].

Imiquimod has been used off-label to treat Bowen's disease [56,67-70]. Treatment regimens vary, with most requiring daily application for 6 to 16 weeks. The required course of treatment is significantly longer than with topical fluorouracil, and the inflammatory response can be quite dramatic. These factors can create difficulty in patient compliance and result in lower cure rates. Although a small, randomized trial and several small, uncontrolled studies have demonstrated cure rates ranging from 73 to 88 percent, large, well-designed, prospective, double-blind studies with long-term follow-up and histologic confirmation of clinical response are lacking [58].

In addition to its use as a single agent, daily applications of topical imiquimod have been successfully combined with topical fluorouracil to treat patients who had failed to respond to monotherapy with one or the other of these agents [71].

Despite the reports of the efficacy of imiquimod, invasive cSCC has developed following treatment in at least two cases, one of which had clinically responded to the initial treatment [72].

HIGH-RISK LESIONS — The management of cSCC at high risk of local recurrence is discussed in detail separately. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)

SQUAMOUS CELL CARCINOMA IN ORGAN TRANSPLANT RECIPIENTS — The management of cSCC in organ transplant recipients is reviewed elsewhere. (See "Prevention and management of skin cancer in solid organ transplant recipients".)

PROGNOSIS

Primary tumor — The overall prognosis for patients with a primary cSCC is excellent, with an overall five-year cure rate of >90 percent [73]. In the United States, the estimated yearly disease-specific mortality rate is approximately 1 percent [74,75], while in Australia and Denmark, which have more well-established registration systems for cancer incidence and mortality, an estimated overall mortality rate of 3 to 4 percent has been reported [1,76].

When the initial treatment is unsuccessful, disease is most likely to recur either locally or in regional lymph nodes, with approximately 75 percent of recurrences developing within the first two years and 95 percent within five years [73]. Rates of metastasis from primary cSCC are reported to be around 2 to 5 percent overall [1-3].

The occurrence of regional lymph node metastases places the patient at increased risk for the subsequent development of distant metastases. Approximately 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. Distant metastases are generally limited to patients who recurred locally or in regional lymph nodes, or to those whose original tumor was neglected and left untreated for a prolonged period or was misdiagnosed.

The risks for local recurrence and distant metastasis are impacted by tumor characteristics and patient characteristics (table 1). In a prospective study including 615 assessable patients with cSCC who were referred to a single center for primary surgical excision and followed-up for a median period of 43 months, multivariate analysis showed that the main prognostic factors for metastasis were tumor thickness >2 mm (hazard ratio [HR] 4.79, 95% CI 2.22-10.36), immunosuppression (HR 4.32, 95% CI 1.62-11.52), location on the ear (HR 3.61, 95% CI 1.51-8.67), and tumor diameter >2 cm (HR 2.22, 95% CI 1.18-4.15) [2].

The size and depth of tumors are included in the tumor, node, metastasis (TNM) staging system for cSCC (table 2). (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Staging'.)

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 approximately 25 to 35 percent at 5 years [1,73,77,78] and less than 20 percent at 10 years [79]. In patients with distant metastases, the five-year survival rate is less than 10 percent [73,79].

Patients with recessive dystrophic epidermolysis bullosa and cSCC constitute an exception to the favorable prognosis associated with cSCC. Although cSCCs in these patients are well differentiated, they are biologically aggressive, with a high incidence of metastases. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Skin cancer'.)

Second skin cancers — Patients with a history of a skin cancer have a much higher incidence of a second skin cancer (cSCC, basal cell carcinoma [BCC], or melanoma) compared with the general population, presumably because all of these tumors share common risk factors [80-84]. After a primary cSCC, the estimated risk for any second nonmelanoma skin cancer is approximately 50 percent at five years [80,85], and the risk of another cSCC is estimated to be approximately 18 percent at three years and 30 percent at five years [86].

The risk of a second skin cancer is greatest in the first year after primary diagnosis because of increased surveillance after the initial diagnosis [82,85]. Patients at an especially high risk for a second skin cancer include those with more than one previous cSCC, fair-skinned individuals, and those who are immunosuppressed.

Other second cancers — Epidemiologic data suggest that cSCC is associated with an increased incidence of cancers at other sites [82,87-91]. Increased mortality among patients with other types of cancer who have a history of cSCC has also been reported [92].

An increased incidence for other cancers in individuals with cSCC was demonstrated by a cohort study that followed a group of over 19,000 persons over a 16-year follow-up period [87]. People with either confirmed cSCC or BCC had an overall twofold increased risk of second malignancies (including lung, colon, and breast cancer), after adjusting for differences in sex, age, body mass index, smoking status, and educational level. The study was based upon nonmelanoma skin cancers ascertained through a cancer registry of pathologically confirmed tumors and may not be representative of all people with such skin cancers. As such, the reported risk is likely to be overestimated.

Although these observations suggest an increased risk of other cancers, routine evaluation for systemic malignancy is not indicated in healthy individuals who are diagnosed with primary cSCC or BCC.

FOLLOW-UP — All patients treated for cSCC need surveillance for the early recognition and management of treatment-related complications, local or regional recurrences, and the development of new skin cancers. We suggest that patients be seen every three to six months for the first two years, then yearly thereafter. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Follow-up'.)

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, deeper punch biopsies may be required. Early detection and treatment may prevent an incurable local recurrence.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonmelanoma skin cancer" and "Society guideline links: Cutaneous squamous cell carcinoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Skin cancer (non-melanoma) (The Basics)")

SUMMARY AND RECOMMENDATIONS

The risk of local, regional, or distant recurrence is the most important factor in determining the approach to the treatment of cutaneous squamous cell carcinoma (cSCC). (See 'Risk assessment' above and 'Definition of low- and high-risk cutaneous squamous cell carcinoma' above.)

The goals of primary treatment of cSCC are to ensure the complete removal of the primary tumor, prevent metastasis, and preserve cosmesis. Treatment options for cSCC with features that suggest a low risk for recurrence and metastasis are surgical excision, radiation therapy, curettage and electrodesiccation (C&E), and cryotherapy. (See 'Choice of treatment' above.)

For most patients with low-risk cSCCs, we suggest surgical excision rather than destructive treatments (algorithm 1) (Grade 2C). The main benefit of surgical excision over destructive treatment is that it allows for histologic confirmation of tumor margins. The accepted standard for surgical margins is 4 to 6 mm. Mohs surgery can be used if there is concern that standard excision would result in a poor cosmetic or functional outcome. (See 'Surgery' above.)

Alternatives to surgical excision may be used in select circumstances as follows:

For patients with small, superficial, nonrecurrent cSCCs that are located in noncritical, low-risk sites, destructive treatments such as (C&E) or cryotherapy may be a reasonable alternative to surgical excision. However, the lack of histologic confirmation of the tumor margins is a major drawback of these techniques. (See 'Curettage and electrodesiccation' above and 'Cryotherapy' above.)

For patients who are not candidates for surgery (eg, older patients with lesions located on cosmetically or functionally sensitive areas), radiation therapy is a nonsurgical treatment option. (See 'Radiation therapy' above.)

Patients with small isolated lesion of Bowen's disease (cSCC in situ) can be treated with surgical excision, C&E, cryotherapy, topical fluorouracil, or imiquimod. Large lesions (>3cm) may be treated with photodynamic therapy, if available, or topical fluorouracil. (See 'Bowen's disease (squamous cell carcinoma in situ)' above.)

Careful follow-up is required to evaluate for evidence of local recurrence, regional or distant metastasis, and 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 cSCC. (See 'Follow-up' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Timothy K Chartier, MD, now deceased, who contributed to an earlier version of this topic review.

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