Management of Cutaneous Squamous Cell Carcinoma
Risk Stratification
All cutaneous squamous cell carcinomas must be stratified into low-risk versus high-risk categories before treatment, as this fundamentally determines the surgical approach and follow-up intensity. 1
High-risk features include: 1
- Tumor size ≥2 cm in diameter
- Depth of invasion ≥4 mm or Clark level V
- Poor histologic differentiation
- Perineural invasion (especially nerves ≥0.1 mm diameter)
- Lymphovascular invasion
- Invasion of fascia, muscle, or bone
- Recurrent tumor
- Immunosuppressed patient
- High-risk anatomic locations: ear, lip, scalp, eyelids, nose, genitalia, hands, feet
Low-risk features include: 2
- Size <2 cm diameter
- Depth <4 mm
- Well-differentiated histology
- Sun-exposed sites (excluding lip and ear)
Biopsy and Pathologic Evaluation
Obtain adequate tissue via punch biopsy, shave biopsy, or excisional biopsy—the technique depends on lesion morphology and location, but depth must be sufficient to assess invasion. 1
The pathology report must document: 1, 3
- Degree of cellular differentiation
- Depth of invasion (in millimeters and Clark level)
- Perineural invasion (with nerve diameter if ≥0.1 mm)
- Lymphovascular invasion
- Invasion of deeper structures (fascia, muscle, bone)
- Margin status
- Presence of inflammation or infiltrative growth patterns
If the initial biopsy is inadequate for accurate diagnosis or risk stratification, repeat biopsy before definitive treatment. 1, 3
Surgical Treatment
Low-Risk Primary cSCC
For low-risk primary cSCC, perform standard excision with 4-6 mm clinical margins extending to mid-subcutaneous adipose tissue with histologic margin assessment. 1, 2 This achieves approximately 5.4% local recurrence rates. 1, 3
Curettage and electrodesiccation (C&E) may be considered for low-risk primary cSCC in non-terminal hair-bearing locations. 1, 2 However, this lacks histologic margin control and should be reserved for truly low-risk lesions.
High-Risk Primary cSCC
Mohs micrographic surgery (MMS) is the recommended treatment for high-risk cSCC, achieving 3.1% five-year recurrence rates compared to 8.1% for standard excision. 1, 3 For tumors ≥2 cm, MMS achieves 25.2% recurrence versus 41.7% with standard excision; for poorly-differentiated cSCC, 32.6% versus 53.6%; and for recurrent cSCC, 10% versus 23.3%. 3
Standard excision may be considered for select high-risk tumors, but exercise strong caution when selecting any treatment modality without complete margin assessment for high-risk disease. 1 If standard excision is performed for high-risk tumors, use linear repair, skin graft, or healing by second intention—delay complex tissue rearrangement until negative margins are confirmed. 1
Staging and Evaluation
Primary Tumor Assessment
All patients with cSCC should be discussed at a multidisciplinary meeting with dermatologist, surgeon, pathologist, and oncologist to review histology and plan staging/treatment. 1
For tumors ≥5 cm diameter or overlying difficult anatomical sites (tendons, nerves, vessels), obtain MRI to assess extent; use CT if MRI unavailable. 1
Regional Lymph Node Evaluation
If regional lymph nodes are clinically palpable, perform ultrasound-guided fine-needle aspiration (FNA); if FNA is inconclusive after repeat attempts, proceed to surgical biopsy. 1 Patients with cSCC often have reactive lymphadenopathy from chronic inflammation, but metastatic disease must be ruled out. 1
If nodal metastases are confirmed by FNA or surgical biopsy, offer regional lymph node dissection. 1 However, elective nodal dissection without proven involvement should not be performed due to morbidity from lymphedema. 1
Distant Metastasis Staging
Perform staging for distant metastases in patients with: 1
- Primary SCC ≥5 cm maximum diameter
- Symptoms suggesting metastatic spread (localized bone pain, abnormal liver function, dyspnea)
- Confirmed regional lymph node metastases
FDG-PET with CT scanning is the preferred modality where available. 1 Note that non-specific uptake may occur from chronic wounds, reactive lymph nodes, esophagus, and bone marrow in some patients, requiring correlation with CT findings. 1
If PET unavailable, use CT or MRI of chest, abdomen, and pelvis; if CT unavailable, consider abdominal ultrasound and/or bone scan. 1
Non-Surgical Treatment
Radiation Therapy
If surgical therapy is not feasible or preferred, radiation therapy (superficial radiation, brachytherapy, external electron beam) can be considered for low-risk tumors, understanding that cure rates may be lower than surgery. 1, 2 Radiation may be useful palliatively for inoperable cSCC or for subcutaneous, lymph node, and distant metastases. 1
Other Modalities
Cryosurgery may be considered for low-risk cSCC only when more effective therapies are contraindicated or impractical. 1, 2 This lacks histologic margin control and should be reserved for exceptional circumstances.
Topical therapies (imiquimod, 5-fluorouracil) and photodynamic therapy are not recommended for treatment of cSCC based on available data. 1, 2
Management of Metastatic Disease
Regional and Distant Metastases
For regional lymph node metastases, perform surgical resection with or without adjuvant radiation therapy and possible systemic therapy. 1 For inoperable disease, consider combination chemoradiation therapy. 1
For distant metastatic disease, epidermal growth factor receptor inhibitors (cetuximab, panitumumab) and cisplatin (single agent or combined with 5-fluorouracil) may be considered, though data are limited. 1
Multidisciplinary consultation and management is mandatory for patients with locoregional or distant metastases, particularly in immunosuppressed individuals. 1
Special Considerations for Immunosuppressed Patients
In solid organ transplant recipients with high-risk or metastatic cSCC, consider dose reduction of immunosuppressive agents and minimize calcineurin inhibitors (cyclosporine, tacrolimus) and antimetabolites (azathioprine) in favor of mTOR inhibitors (sirolimus) when appropriate. 1 However, recent data show sirolimus may not reduce post-transplant cSCC risk. 1
Follow-Up and Surveillance
Perform in-office screening for new primary skin cancers (including basal cell carcinoma, cSCC, and melanoma) at least annually, adjusting frequency based on individual patient risk. 1, 2 After one cSCC diagnosis, the 5-year probability of another non-melanoma skin cancer is 40.7%; after multiple cSCC, this increases to 82%. 1
For high-risk lesions, include clinical assessment of regional lymph node basins in the physical examination. 1
Counsel patients regarding: 1, 2
- Risk for new primary skin cancers (relative risk for melanoma is 1.99-2.58 after NMSC diagnosis)
- Need for self-surveillance and family-assisted examination of difficult-to-see areas
- Sun protection, sun avoidance, and tanning bed avoidance
Critical Pitfalls to Avoid
Never perform standard excision with inadequate margins for high-risk cSCC—the recurrence rates are unacceptably high compared to MMS. 1, 3
Never delay closure confirmation until after complex tissue rearrangement for high-risk tumors—always confirm negative margins first. 1
Never perform elective lymph node dissection without proven nodal involvement—the morbidity outweighs benefit. 1
Never use topical therapies or photodynamic therapy as primary treatment for invasive cSCC—these are inadequate and risk undertreating aggressive disease. 1, 2