Approach Considerations
Low-risk cutaneous squamous cell carcinoma (cSCC) on the trunk and extremities can be treated with electrodessication and curettage (ED&C). For invasive cSCC, surgical excision and Mohs micrographic surgery are the primary treatment options; with appropriate patient selection, these techniques have comparable cure rates. Radiation therapy is typically used as an adjuvant to surgery, to provide improved locoregional control, but it may be used as primary therapy in patients who are unable to undergo surgical excision.
Chemotherapy may be considered as adjuvant therapy in select highest-risk cases of cSCC. In particular, emerging evidence suggests that epidermal growth factor receptor (EGFR) inhibitors may be useful adjuncts to surgical treatment. Systemic chemotherapy may be considered for metastatic cSCC.
Prevention is an important aspect of managing cSCC. Given the central role that ultraviolet radiation (UVR) plays in the pathogenesis of cSCC, methods aimed at decreasing UVR exposure form the cornerstone of cSCC prevention. Several effective treatment modalities exist for precancerous skin lesions, including carcinoma in situ and actinic keratosis. Most of these treatments are easily performed in an outpatient setting.
Electrodessication and Curettage
ED&C is a simple technique that can be used to treat localized, superficial cSCC. This procedure destroys the tumor and a surrounding margin of clinically unaffected tissue via cauterization and scraping of the area with a curette. The process is repeated several times to maximize the probability of complete tumor extirpation.
The technique is based on the delineation of tumor margins with a curette, because tumor tissue is generally more friable than the surrounding normal tissue. ED&C is known to be very technique dependent, and cure rates improve with a practitioner's experience.
The thick scars that often occur after ED&C can delay the diagnosis of cancer recurrence. Consequently, ED&C should be used with caution in invasive cSCC. The procedure is not appropriate for certain anatomic locations (ie, eyelids, genitalia, lips, ears).
The main disadvantage of ED&C is that no specimen is available for margin evaluation, and most dermatologic surgeons believe the actual long-term cure rate for invasive SCC is much lower than that quoted in the literature. Nevertheless, the 5-year cure rates for small primary cSCC may be as high as 96%. Cure rates for high-risk tumors are much lower, although no well-controlled, prospective studies have been performed.
Tumor recurrence may result from failure of ED&C treatment to eradicate atypical cells residing deep in the hair follicles or in the dermis. Nonetheless, the procedure is fast, minimally invasive, well tolerated, and effective for properly selected lesions.
Surgical Excision
Standard excision with conventional permanent (ie, paraffin-embedded) tissue sections is a highly effective and well-tolerated therapy for primary cSCCs that lack high-risk features and are located in areas where tissue sparing is not critical. Surgical excision offers the advantages of histologic verification of tumor margins, rapid healing, and improved cosmesis.
Cure rates following simple excision of well-defined T1 lesions may be as high as 95-99%. The generally accepted 5-year cure rate for primary tumors treated with standard excision is 92%; this rate drops to 77% for recurrent cSCC.
A 4-mm margin of healthy tissue is recommended for lower-risk lesions. [46] In this category are well-differentiated tumors smaller than 2 cm in diameter that do not occur on the scalp, ears, eyelids, lips, or nose and do not involve subcutaneous fat. Therefore, simple excision is most valuable in the treatment of small primary SCCs on the trunk, extremities, or neck, where tissue sparing is less essential. [46] Recurrence rates after the excision of low-risk lesions range from 5-8%.
A 6-mm margin of healthy tissue is recommended for lesions that are larger than 2 cm, invasive to fat, or in high-risk locations (ie, central face, ears, scalp, genitalia, hands, feet). Given the cosmetic and functional impact of these wider margins, tumors in this latter category are often removed via Mohs surgery to achieve high cure rates while sparing normal tissue. The depth of an excision should always include a portion of the subcutaneous fat.
There is research investigating the efficacy of fluorescence-guided imaging in reducing the incidence of positive resection margins. This technique involves labeling tumor-specific targets, such as epidermal growth factor receptors, with fluorescently labeled tracers. A camera system can be used intraoperatively to identify the presence of these tracers, which may be suggestive of a positive resection margin, in the surgical bed. [47]
No large randomized studies have addressed the issue of appropriate margin size in cSCC, as has been done for melanoma. The recommendations for margin size should be taken only as rough guidelines, with the understanding that large, aggressive lesions frequently have substantial extension beyond the apparent superficial boundary. Therefore, a surgeon’s experience and judgment in planning surgical margins is paramount to the successful treatment of cSCC.
Complications of excision include hematoma, seroma, infection, and wound dehiscence. Furthermore, histologic margins can be reported as negative when they are, in fact, positive (false negative), because the traditional bread-loaf method of tissue sectioning typically results in evaluation of less than 1% of the specimen’s margins. For this reason, cure rates for cSCC following excision do not significantly differ from cure rates following ED&C and may even be somewhat lower.
For patients at risk for metastatic spread to lymph nodes, the standard treatment is surgical excision of the primary lesion along with the involved lymph node basins. Skin cancers located in the periauricular region, frontotemporal scalp, and mid-face often drain via lymph nodes in the parotid gland. Consequently, the parotid is the most frequently involved site of metastatic spread. In cases that involve parotid involvement, a parotidectomy with or without a simultaneous neck dissection is the procedure of choice.
Sentinel lymph node biopsy
While positron emission tomography (PET)/CT imaging and ultrasonography can be useful tools in identifying metastatic disease, approximately 7% of patients with no findings on PET/CT scans have been found to have micrometastases when sentinel lymph node biopsy (SLNB) is performed. [48] Although this is comparable to the positive SLNB rate in melanoma, there is notable variability in metastatic detection. [49] With this in mind, the use of SLNB in the treatment of cSCC has been gaining interest.
A systematic review by Ahmed et al showed that among SLNB patients with T2 or greater cSCC of the head and neck area, 13.7% were found to have a positive sentinel lymph node. [50]
Bander et al found that positivity rates for SLNB in high-risk cSCC ranged between 11.3% and 24%. [51] The difference in positivity rates was thought to be related to the definition used for high-risk cSCC.
Practice guidelines published in the European Journal of Cancer in March 2020 noted that published studies relating to SLNB use in cSCC patients included a small number of subjects and were heterogeneous. [52] It was also pointed out that the prognostic utility of SLNB has not been established. Consequently, the guidelines were unable to recommend the use of SLNB in the treatment of cSCC outside a clinical trial setting. Select patients treated for cSCC may benefit from SLNB, but further research is needed in this area.
Mohs micrographic surgery
Mohs micrographic surgery is a specialized technique for removing many forms of skin cancer, including cSCC. Because of its numerous advantages, Mohs micrographic surgery is the procedure of choice in the following situations:
-
SCC in which tissue preservation is needed
-
Ill-defined SCC
-
Recurrent tumors
-
High-risk SCC
Mohs surgery, which was developed by Frederic E. Mohs in the 1930s, is a method of tumor excision in which the surgeon first excises the visible tumor with a small margin of normal tissue. Horizontal frozen sections are then prepared, and the entire margin is evaluated under the microscope. Areas that demonstrate residual microscopic tumor involvement are re-excised, and the margins are reexamined. This cycle is completed until no further tumor is visualized. [53]
The main advantage of this procedure over simple excision is the ability to histologically examine nearly 100% of the surgical margins (as compared with < 1% of the margin visualized via standard histologic sectioning) and to carefully map residual foci of invasive carcinoma, making incomplete excision much less likely than with standard pathologic processing.
In addition, the excised specimens are managed in a way that maintains orientation relative to the operative site. Consequently, Mohs surgery offers tissue sparing, which facilitates small, minimally disfiguring reconstructions of the resulting defects. Thus, it is considered ideal for removing small lesions on the face.
However, Mohs surgery is time consuming and highly dependent on technique. Moreover, it is ill suited for large, aggressive, or recurrent cSCC, in which the risk of recurrence or regional metastasis is high. In those cases, en bloc surgical excision is the standard method of treatment.
Radiation Therapy
Radiation therapy as primary treatment for cSCC is typically reserved for patients who are unable to undergo surgical excision. More frequently, radiation therapy is used as an adjuvant to surgery for improved locoregional control. Postoperative radiotherapy is considered for tumors that exhibit perineural invasion or other high-risk features and for those that involve regional metastasis. [54]
No comparative studies of surgery versus surgery plus adjuvant radiotherapy for high-risk SCC have been performed. With no clear evidence of benefit and the potential of significant morbidity, clinical judgment is required in deciding which patients should receive adjuvant radiation. One systematic review suggests that adjuvant radiation be considered in patients with uncertain or positive surgical margins or advanced nerve involvement. [55]
Systemic Treatment
Chemotherapy
Adjuvant chemotherapy
Adjuvant medication may be considered in select highest-risk cases of cSCC. Options include oral 5-fluorouracil (5-FU) and epidermal growth factor receptor (EGFR) inhibitors. Treatment should be administered through oncology treatment centers. Although survival data are lacking, these medications are generally well tolerated, with few adverse effects.
One study found that the use of topical 5-FU 1% is effective as an adjuvant to surgical excision in treating patients with localized ocular surface squamous neoplasia. Although frequent short-term complications were noted, a low rate of local recurrence was found; a full course is usually tolerated, and serious complications in the study were uncommon. [55]
Chemotherapy
A variety of different chemotherapeutic agents have been used to treat metastatic cSCC. Although many of these agents have an established role in chemotherapy for mucosal head and neck squamous cell carcinoma, high-quality data is frequently lacking for their use in cSCC. Among the most common nontargeted agents used in cSCC are cisplatin and carboplatin, 5-FU, and taxanes.
Cetuximab, a chimeric immunoglobulin G1 monoclonal antibody that inhibits EGFR, has been reported as successful in multiple case reports [56, 57, 58, 59] High-quality studies examining these agents in high-risk cSCC are needed.
Immunotherapy
Immunotherapy, especially with programmed death ligand 1 (PD-L1) inhibitors, may be considered in advanced cSCC. The programmed death 1 (PD-1) receptor is expressed on T cells, binding to its ligand (PD-L1) and inhibiting T-lymphocyte functions. PD-L1 is expressed in cSCC tumors, and its expression correlates with risk of metastasis. [4]
Approved by the US Food and Drug Administration (FDA) in October 2018, the PD-L1 inhibitor cemiplimab (Libtayo) became the first treatment specifically approved for patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or curative radiation. [60]
Approval followed results from EMPOWER-CSCC-1, a multicenter, open-label, nonrandomized phase 2 trial, and two advanced expansion cohorts. The investigators found an objective response rate of 47% among patients with metastatic disease, and 49% in those with locally advanced cSCC. [61]
In June 2020, the FDA approved pembrolizumab (Keytruda) for the treatment of patients with recurrent or metastatic cSCC that is incurable via surgery or radiation.
Approval was based on efficacy data from the multicenter, nonrandomized, open-label KEYNOTE-629 clinical trial. Patients (n=105) received pembrolizumab 200 mg IV every 3 weeks until the disease progressed, toxicity became unacceptable, or a maximum of 24 months had passed, with the cohort demonstrating an objective response rate of 34%. [62]
Treatment of Conjunctival Squamous Cell Carcinoma
Excisional biopsy is the treatment of choice for conjunctival SCC. For extremely large lesions, incisional biopsy may be performed. However, strict notation of the biopsy site and minimal handling of the surrounding tissues are imperative to prevent seeding of the tumor. Surgical excision is best performed under the operating microscope.
Removal of a cuff of normal conjunctival tissue surrounding the lesion is prudent, and an episclerectomy at the base of the lesion is also advisable if it is adherent to the sclera, in order to remove any superficial cells infiltrating the sclera.
Involved corneal tissues may be best removed following treatment with 100% ethanol. The tissues superficial to the Bowman layer are removed easily in a single sheet, which is sent to the laboratory for analysis. Care should be taken not to incise into the Bowman membrane.
Cryotherapy is performed, in a double freeze-thaw manner, to the edges of the uninvolved conjunctiva and Tenon capsule. It also can be applied to the involved limbal area. The exposed sclera occasionally is treated with 100% ethanol to devitalize any remaining tumor cells. All excised tissues are submitted for histopathologic analysis.
Reconstruction is performed with direct closure, local flaps, or free conjunctival grafts. Extensive lesions with orbital involvement require exenteration.
Radiation therapy may be used as adjunctive therapy in cases of extensive lesions with poorly defined margins and as palliative therapy in cases in which the patient cannot tolerate extensive surgery.
Conjunctival intraepithelial neoplasia
Topical cytotoxic therapy (ie, 5-FU, mitomycin C [MMC]) has been used to treat conjunctival intraepithelial neoplasia and to debulk large carcinomas before surgical excision. Orbital invasion may be observed despite topical therapy, however, and careful monitoring of patients on these agents is warranted. [63, 64]
Despite its significant potential for deleterious effects on limbal stem cells, mitomycin C 0.04% is effective as a neoadjuvant or postoperative agent in the treatment of conjunctival intraepithelial neoplasia and primary acquired melanosis. Its utility is less well proven for truly invasive tumors, such as melanoma and carcinoma. [65]
Prevention
Given the central role that UVR plays in the pathogenesis of cSCC, methods aimed at decreasing UVR exposure form the cornerstone of cSCC prevention. The evidence behind other measures to prevent cSCC is lacking; eg, large, well-controlled studies have failed to show a beneficial role for dietary supplements, including selenium, beta-carotene, retinol, and isotretinoin, in the prevention of skin cancers. [66, 67, 68, 69]
Reduction of UV exposure
Reduction of UVR exposure can be accomplished as follows:
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Avoiding excessive sun exposure
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Avoiding artificial sources of UV light (eg, tanning beds)
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Using sunscreen
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Wearing protective clothing
Limiting outdoor activities (especially between 10 am and 4 pm) should be recommended to all patients, particularly fair-skinned, elderly patients. Even young patients should be advised to take precautions against excessive sun exposure, to reduce the risk of developing cutaneous malignancies in future.
Sunscreens
Patients who are at risk for cSCC but are not able to avoid sun exposure should use sunscreen scrupulously when outdoors. Sunscreen should be reapplied every 30 minutes during acute sun exposure. Several randomized, controlled clinical trials have shown a protective role for the daily application of a broad-spectrum sunscreen in the prevention of new actinic keratoses and new cSCC. [68, 70, 71]
The efficacy of UV protection is measured by its sun protection factor (SPF), which is the ratio of the least amount of UVB radiation that will induce erythema on covered skin to the amount of UVB required to generate the same amount of erythema on uncovered skin. It is often described as the amount of additional time a person can spend in the sun with protection versus without protection. For patients at risk for cSCC, the minimum recommended SPF is 30 or higher.
All patients should be advised to protect their eyelids from sun exposure. Physical sunblocks with the active ingredients of zinc oxide or titanium oxide provide the most complete protection from UVA and UVB rays. [72] Alternatively, a combination chemical sunblock of octocrylene, ecamsule, and avobenzone also provides excellent broad-spectrum UV protection. [73]
Clothing
Clothing is the simplest method of protection; however, it is often inadequate. For example, a cotton T-shirt has an SPF of less than 10, which decreases sharply when the cloth is wet. Hats with a wide brim or extra-long bill may offer additional protection. Clothing with a high SPF rating is available, but these are often expensive and restrictive.
Skin cancer screening
Current recommendations from the American Cancer Society for skin screening call for a skin examination every 3 years for persons aged 20-39 years and annually after age 40 years. The American Academy of Dermatology recommends annual screening for all patients. However, the US Preventive Services Task Force found insufficient evidence to issue a recommendation either for or against skin examination by a primary care clinician or patient skin self-examination, for the early detection of skin cancer in the adult general population. [74]
Treatment of Precancerous Lesions
Several effective treatment modalities exist for precancerous skin lesions, including squamous cell carcinoma in situ (SCCIS) and actinic keratosis. Most of these treatments are easily performed in an outpatient setting.
Topical application of 5-FU or imiquimod is effective in treating precancerous skin lesions. Similarly, liquid nitrogen cryotherapy or electrocautery and curettage may be used, with cure rates reported at greater than 95%. The risks associated with cryotherapy include transient pain, edema, and blistering. Hypopigmentation and alopecia are also common and may be permanent, so treatment of hair-bearing areas and in darkly pigmented individuals is generally not recommended. [75]
Many patients with light skin and a history of extensive sun exposure develop epidermal atypia in the form of actinic keratosis and SCCIS over large areas of their skin. Most of these patients also develop multiple invasive cSCCs. The management of such patients is highly labor intensive and involves the following steps:
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Surgically remove all tumors that clinically appear to have to have an invasive (dermal) component and confirm clearance of histologic margins
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Evaluate for underlying immunosuppression, such as from chronic lymphocytic leukemia or from overimpairment of the immune system by immunosuppressive or immunomodulatory therapy; if this last is suspected, discuss with the patient’s other doctors whether the immunosuppression can be safely remedied or lessened
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Perform field treatment of the areas of epidermal atypia
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Follow the patient closely for recurrence of actinic keratosis/SCCIS and for new invasive SCCs; field treatment may need to be repeated every 6-12 months to keep precursor actinic keratosis and SCCIS lesions to a minimum
Options for field treatment include topical chemotherapy with 5-FU or photodynamic therapy. Imiquimod has limited utility in diffuse disease because adverse effects increase when this agent is applied to large surface areas. If 5-FU therapy is planned, remove any hyperkeratotic lesions with a curette just before beginning therapy, to enhance penetration of the medication to the basal layer.
5-florouracil, capecitabine, and diclofenac sodium
A full course of 5-FU therapy is twice-daily administration for 4 weeks. However, even if the newer, low-concentration 5-FU cream is used (0.5% vs previously available 5% concentration), significant discomfort and irritation are inevitable, and residual erythema at the site of application may persist for months. Patients who cannot tolerate this duration may try shorter courses and then resume treatment after a healing phase. Subsequent treatments become more tolerable as the epidermal damage is corrected.
An oral form of a 5-FU prodrug (capecitabine), which is approved by the US Food and Drug Administration (FDA) for other forms of cancer, may be considered in patients with diffuse SCCIS over large skin areas on which topical 5-FU is difficult to apply. However, studies of efficacy have not yet been performed.
Topical diclofenac sodium gel has been approved for the treatment of actinic keratoses. Twice-daily applications for 60-90 days may similarly clear actinic damage, with the longer course potentially offset by a lesser degree of cutaneous irritation.
Photodynamic therapy
Actinic keratosis can also be treated with photodynamic therapy, which uses light, a photosensitizing drug, and oxygen to induce targeted cell death of neoplastic or abnormal tissue. In this treatment, sensitization of the target tissue is selective and occurs through the topically or systemically administered photosensitizing agent. The resulting photochemical reaction causes inflammation and destruction of the targeted lesion(s) via highly reactive oxygen intermediates and free radicals.
Photodynamic therapy is used primarily to treat large numbers of actinic keratoses in a single session. SCCIS is also amenable to photodynamic therapy, although a wide range of recurrence rates (0-52%) has been reported. Research is ongoing to assess the suitability of using photodynamic therapy for treating cSCC in patients who are not candidates for surgical resection or for early stage cSCC in cosmetically sensitive areas. [76, 77]
The efficacy of topical medications for the treatment of actinic damage is difficult to measure because biopsies are rarely performed before and after treatment (to compare results). Instead, improved skin appearance is used as a gauge for apparent resolution of early SCCIS lesions. For a full discussion of treatment of these lesions, see Actinic Keratosis.
Consultations
Most cases of cSCC are easily and successfully treated by dermatologists or Mohs surgeons. In certain cases, however, such as the following, a multidisciplinary approach may be needed:
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Large or deep tumors in which excision and reconstruction under local anesthesia is not feasible
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Surgical margins that are not clear or are in doubt
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Nodal or distant metastasis
A multidisciplinary approach using Mohs micrographic surgery performed in conjunction with an otolaryngologist, a plastic surgeon, or both may aid in completely removing deeply invasive SCC, preserving a vital structure (eg, the facial nerve), and facilitating the reconstruction of a large operative defect.
For example, Mohs micrographic surgery may be used in cases of SCC of the scalp that involve bone, to establish peripheral margins to the level of the galea. This would be followed by resection of the deep margin, including bone, with the patient under general anesthesia, performed by a head and neck or plastic surgeon. A surgical focus on the deep margin and reconstruction often spares the patient hours of anesthesia time, lowering surgical morbidity.
Metastatic disease also requires aggressive management by a multidisciplinary team. Surgical treatment of metastatic disorder may require the expertise of an otolaryngologist, a general surgeon, or a surgical oncologist. Adjuvant or palliative radiotherapy may be administered by a radiation oncologist. A medical oncologist should be consulted if systemic chemotherapy is considered for metastatic disease.
Long-Term Monitoring
With exposure to risk factors, patients require vigilant follow-up care even after successful treatment, because they continue to be at risk for development of additional cutaneous skin malignancies (eg, basal cell carcinoma and SCC of the eyelid). The incidence of multiple primaries is 40% in long-term survivors. Therefore, minimization of modifiable risk factors and early detection of new skin cancers are essential to improve prognosis.
Low-risk tumors are usually cured with appropriate surgical therapy; however, patients who develop 1 SCC have a 40% risk of developing additional SCCs within the next 2 years. This risk likely becomes even greater as more time elapses. Thus, patients with a history of SCC should be evaluated with a complete skin examination every 6-12 months.
Patients with high-risk tumors require skin and lymph node examinations at 3- to 6-month intervals for at least 2 years after diagnosis. In very ̶ high-risk cases, surveillance with CT scanning or MRI may be considered. Recurrent lesions should be treated aggressively. Success in treating recurrences with topical mitomycin C has been reported. In areas of bare sclera, however, pyogenic granulomas occasionally occur soon after tumor excision. These lesions typically respond quickly to topical steroid treatment and must be differentiated from recurrent tumor.
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Large, sun-induced squamous cell carcinoma (SCC) on the forehead/temple. Image courtesy of Glenn Goldman, MD.
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Preauricular and helical scars (black arrows) from prior excisions are noted in a patient who presented with cervical metastases (white arrow) from an occult cutaneous squamous cell carcinoma.
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Contrast-enhanced, axial computed tomography (CT) scan of a patient with soft tissue invasion of the right parotid gland (arrow) by an ulcerative cutaneous squamous cell carcinoma.
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Large, neglected cutaneous squamous cell carcinoma of the right ear that requires wide local excision via auriculectomy and reconstruction. The risk of lymph node metastasis with this deeply ulcerative tumor is high enough to warrant elective neck dissection.
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Squamous cell carcinoma in situ (Bowen disease). Courtesy of Hon Pak, MD.
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Extensive conjunctival squamous cell carcinoma of the left eye. The patient had limbal and corneal involvement temporally, as well as scleral invasion with intraocular spread. A malignant cellular reaction in the anterior chamber was present. The patient was treated with a lid-sparing exenteration.
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A 35-year-old man with human immunodeficiency virus (HIV) infection presented with a 2-year history of a slowly enlarging, left lower eyelid lesion; incisional biopsy revealed squamous cell carcinoma.
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Axial magnetic resonance image (MRI) of a large squamous cell carcinoma of the left lower eyelid with invasion of the anterior orbit.
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A large, ulcerated, invasive squamous cell carcinoma of the left lower eyelid. This patient also had perineural invasion of the infraorbital nerve extending into the cranial base.
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Progressively severe atypia. The epithelium to the left is close to normal, but the epithelium to the right shows full-thickness atypia (ie, carcinoma in situ). This image illustrates carcinogenesis, the process whereby cells exposed to a carcinogen become cancerous over time.
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Squamous cell carcinoma. The lesion closely approximates the specimen in the previous image. Field cancerization is illustrated; that is, if >1 cell is exposed to a carcinogen, >1 cell becomes cancerous. Note the marked inflammatory-cell response. Should limited biopsy reveal only severe atypia with a severe inflammatory response, the lesion should be investigated further, because a cancer is likely nearby.
Tables
Stage |
Primary Tumor |
Regional Lymph Nodes |
Distant Metastasis |
Stage 0 |
Tis |
N0 |
M0 |
Stage I |
T1 |
N0 |
M0 |
Stage II |
T2 |
N0 |
M0 |
Stage III |
T3 |
N0 |
M0 |
T1-3 |
N1 |
M0 |
|
Stage IV |
T4 |
N0 |
M0 |
Any T |
N2-3 |
M0 |
|
Any T |
Any N |
M1 |
