Skin Cancers
Melanoma, BCC, cSCC — systemic treatment options
DefinitionClick to collapse
Cutaneous squamous cell carcinoma (CSCC or SCC) is a malignant neoplasm arising from epidermal keratinocytes, representing the second most common skin cancer after basal cell carcinoma [1,2]. It originates from the squamous cells of the epidermis and can develop in situ (Bowen's disease) or as invasive carcinoma [3]. CSCC most frequently occurs on sun-exposed skin surfaces, with the head and neck being the most common site (accounting for the majority of cases), followed by the hands, forearms, and lower legs [4,5]. The anatomical boundaries extend from the epidermis through the dermis and can invade deeper structures including subcutaneous fat, muscle, cartilage, or bone in advanced cases [3,6]. For staging purposes, the AJCC 8th edition staging system is used for cutaneous carcinoma of the head and neck, defining Tis as carcinoma in situ, with invasive tumors staged from T1 to T4 based on size (>2 cm, >4 cm), depth of invasion (>6 mm or beyond subcutaneous fat), and involvement of structures like bone, nerves, or skull base [7,8]. CSCC can also arise in areas of chronic inflammation, scars (Marjolin's ulcer), or prior radiation therapy [4,9]. The disease can be locally destructive, cause disfigurement, and in rare cases (estimated 1.9% to 2.7% of all CSCC) metastasize to regional lymph nodes or distant sites [10,11].
EpidemiologyClick to collapse
SubtypesClick to collapse
Conventional Squamous Cell Carcinoma
The most common histologic type, characterized by keratinocyte atypia with varying degrees of differentiation (well, moderate, or poorly differentiated).
Adenosquamous Carcinoma
A rare and aggressive variant with both squamous and glandular (adenomatous) differentiation.
Sarcomatoid (Spindle Cell) Carcinoma
A high-risk variant composed of spindle-shaped cells with epithelial-mesenchymal transition, often with desmoplastic stroma.
Verrucous Carcinoma
A low-risk, well-differentiated variant with a warty, exophytic growth pattern and minimal invasive potential.
Acantholytic (Adenoid) Squamous Cell Carcinoma
Characterized by loss of intercellular bridges leading to a pseudoglandular appearance.
Basosquamous Carcinoma
A tumor with features of both basal cell carcinoma and squamous cell carcinoma, often behaving more aggressively like CSCC.
Infiltrative Squamous Cell Carcinoma
Characterized by irregular, angulated, and infiltrative growth patterns into the dermis and deeper tissues.
Molecular PathogenesisClick to collapse
The provided NCCN guideline does not detail specific genomic events, driver mutations, or signaling pathways in the molecular pathogenesis of cutaneous squamous cell carcinoma. It primarily focuses on clinical risk factors and management. However, the pathogenesis is understood to be driven by cumulative ultraviolet (UV) radiation exposure, which induces DNA damage, particularly in key tumor suppressor genes such as TP53 and oncogenes like RAS. In immunocompromised individuals (e.g., organ transplant recipients), additional pathways involving immune surveillance evasion and possibly viral oncogenesis (e.g., HPV) may contribute to the more aggressive behavior observed [4,5]. The document notes that CSCC develops more frequently and behaves more aggressively in settings of immunosuppression, which is associated with distinct clinicopathologic features such as diffuse/focal spindle cell morphology, HPV infection, and aggressive subclinical extension [19,20]. Genetic syndromes like xeroderma pigmentosum (XP) and recessive dystrophic epidermolysis bullosa (RDEB) dramatically predispose patients to aggressive CSCC due to defective DNA repair or structural integrity mechanisms [21,22].
Risk FactorsClick to collapse
Chronic Sun Exposure and Sunburns
The most recognized environmental carcinogen. Chronic sun exposure, total site-specific exposure, and number of site-specific sunburns are strongly correlated with development of SCC.
Indoor Tanning
Any exposure to indoor tanning increases the risk of SCC by 67%.
Light Skin Pigmentation
Individuals with light skin, hair, and eye color are at greatest risk for UV-induced SCC.
Actinic Keratoses (AKs) and Bowen's Disease
AKs and Bowen's disease (SCC in situ), if left untreated, can progress to invasive SCC.
Organ Transplantation and Immunosuppression
Immunosuppression (e.g., organ transplantation, lymphoma, CLL, drug-induced, HIV) is a major risk factor. Transplant recipients have a 5-fold to 113-fold increased incidence of SCC compared to the general population.
Scars and Chronic Wounds (Marjolin's Ulcer)
SCC can develop in scars from burns, chronic ulcers, or other injuries, known as Marjolin's ulcer. These lesions tend to be difficult to treat and have higher risk of recurrence.
Genetic Syndromes
Rare genetic syndromes greatly predispose individuals to SCC, including xeroderma pigmentosum (XP), recessive dystrophic epidermolysis bullosa (RDEB), and albinism.
Prior Radiation Therapy
SCC arising in areas previously irradiated for unrelated conditions is a risk factor for recurrence or metastasis.
Chronic Inflammation
SCC arising from sites of chronic scarring or inflammation has increased rates of metastasis.
Male Sex
While not explicitly quantified in this guideline, SCC incidence is generally higher in males, likely due to greater cumulative sun exposure.
Increasing Age
Incidence increases with age, reflecting cumulative UV exposure.
Clinical FeaturesClick to collapse
Cutaneous squamous cell carcinoma (CSCC) typically presents as a sun-exposed skin lesion on the head, neck, hands, feet, pretibial, or anogenital areas, though it can also occur on the trunk and extremities [1, 5, 17, 28]. Lesions are often erythematous, scaly, nodular, ulcerated, or bleeding, and may arise from precursor lesions such as actinic keratoses or Bowen's disease [21, 29-31]. Symptoms can include pain, burning, stinging, anesthesia, paresthesia, facial paralysis, diplopia, or blurred vision, particularly when perineural invasion (PNI) is present [111, 112]. Rapid growth is a clinical feature that may indicate aggressive behavior [107, 108]. Signs on examination include well-defined or poorly-defined borders, induration, and surrounding erythema. High-risk features are suggested by larger tumor size (>2 cm), especially >4 cm, recurrent disease, immunosuppression, prior radiation or chronic inflammation, neurologic symptoms, poorly differentiated histology, high-risk subtypes (adenosquamous, sarcomatoid), deep invasion (>6 mm or beyond subcutaneous fat), PNI, and lymphovascular invasion [11, 34, 54, 74, 75, 85, 90, 92, 106, 114, 115, 131]. Atypical or missed presentations can occur in high-risk populations (e.g., organ transplant recipients, patients with lymphoma or HIV) where lesions may be difficult to assess clinically, leading to delayed diagnosis [45, 58-60, 100, 101]. Superficial biopsies may miss infiltrative histology present only at deeper margins [62, 63]. Lesions in the anogenital area may be mistaken for benign conditions, and actinic cheilitis on the lip requires careful evaluation [212-223]. Field cancerization, defined as UV-induced confluent dysplasia with diffuse actinic keratoses and superficial SCC, represents a precancerous state that warrants monitoring [140].
Red FlagsClick to collapse
Rapid growth tumor (growth rate >4 mm/month associated with higher risk of nodal progression) [107, 108].
Neurologic symptoms (pain, burning, anesthesia, paresthesia, facial paralysis, diplopia, blurred vision) suggesting perineural invasion [111, 112].
Immunosuppression (e.g., organ transplant recipients, lymphoma, chronic lymphocytic leukemia, HIV, drug-induced) [43-50].
High-risk anatomic location (head, neck, hands, feet, pretibial, anogenital area) [11, 34, 54, 55, 82, 86, 87].
Large tumor size (especially >2 cm, and particularly >4 cm) [34, 55, 85, 88, 90, 91].
Poorly differentiated histology [11, 34, 35, 54, 74, 82, 85, 90, 92, 97, 106, 107, 121].
High-risk histologic subtypes (adenosquamous or sarcomatoid) [122-128].
Deep invasion (>6 mm thickness or invasion beyond subcutaneous fat) [11, 34, 54, 74, 75, 85, 89-91, 97, 129, 131].
Perineural invasion (especially tumor cells within nerve sheath of nerve deeper than dermis or caliber ≥0.1 mm) [11, 34, 54, 74, 75, 82, 88, 90, 106, 113-115, 132-138].
Lymphovascular invasion [79, 92, 114, 115].
Recurrent disease [34, 88, 90, 92, 96, 97].
Site of prior radiation therapy or chronic inflammation [34, 35, 90, 92, 96, 103-106].
Palpable or radiographically suspicious regional lymph nodes [11, 82, 85, 97].
InvestigationsClick to collapse
Diagnostic
History and physical examination (H&P)
Initial assessment to evaluate lesion characteristics and identify risk factors.
Skin biopsy (should extend into dermis)
Essential for histologic confirmation and staging; superficial biopsies may miss invasive components.
Immunohistochemistry (IHC)
May be utilized as needed to help identify lymphovascular or nerve invasion, or to identify single tumor cells or small aggregates.
Staging
Complete skin and regional lymph node examination
To assess for additional primary tumors, in-transit lesions, or nodal metastases.
MRI with and without contrast
Preferred imaging modality for evaluating perineural disease or deep soft tissue involvement.
CT with contrast
Preferred for evaluating bone disease; also used for nodal staging.
FDG-PET/CT
Useful for evaluating nodal and distant metastatic disease.
Ultrasound
Can be used for assessment of regional lymph nodes; ultrasound-guided biopsy may be performed.
Fine-needle aspiration (FNA) or core biopsy of lymph nodes
To obtain pathologic confirmation of nodal metastases.
Excisional biopsy of lymph node
May be considered to confirm negative FNA or core biopsy if clinical suspicion remains high.
Biomarkers
No specific serum biomarkers are established for CSCC.
Diagnosis and staging rely on histopathology and imaging.
StagingClick to collapse
AJCC Cancer Staging Manual, 8th Edition (2017) for cutaneous carcinoma of the head and neck [1, 2].
T Categories
| Stage | Description |
|---|---|
| TX | Primary tumor cannot be assessed. |
| Tis | Carcinoma in situ. |
| T1 | Tumor ≤2 cm in greatest dimension. |
| T2 | Tumor >2 cm but ≤4 cm in greatest dimension. |
| T3 | Tumor >4 cm in maximum dimension or minor bone erosion or perineural invasion or deep invasion*. |
| T4a | Tumor with gross cortical bone/marrow invasion. |
| T4b | Tumor with skull base invasion and/or skull base foramen involvement. |
N Categories
| Stage | Description |
|---|---|
| NX | Regional lymph nodes cannot be assessed. |
| N0 | No regional lymph node metastasis. |
| N1 | Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(−). |
| N2a | Metastasis in a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE(−). |
| N2b | Metastases in multiple ipsilateral nodes, none >6 cm in greatest dimension and ENE(−). |
| N2c | Metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(−). |
| N3a | Metastasis in a lymph node >6 cm in greatest dimension and ENE(−). |
| N3b | Metastasis in any node(s) and clinically overt ENE [ENE(+)] or metastasis in any node(s) with ENE(+). |
M Categories
| Stage | Description |
|---|---|
| M0 | No distant metastasis. |
| M1 | Distant metastasis. |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| Stage 0 | Tis, N0, M0. | Carcinoma in situ, excellent prognosis. | ~100% | Curative with local therapy. |
| Stage I | T1, N0, M0. | Small tumor, low risk of metastasis. | ~98% | Curative with local therapy. |
| Stage II | T2, N0, M0. | Larger tumor, still localized. | ~90-95% | Curative with local therapy +/- adjuvant treatment based on risk factors. |
| Stage III | T3, N0, M0; or T1-3, N1, M0. | Advanced local disease or limited nodal involvement. | ~70-85% | Curative with multimodality therapy (surgery, RT, +/- systemic therapy). |
| Stage IV | T4, any N, M0; or any T, N2-3, M0; or any T, any N, M1. | Very advanced local disease, extensive nodal involvement, or distant metastases. | ~20-50% depending on extent | Palliative in metastatic setting; curative intent may be considered for selected cases with aggressive local-regional treatment. |
Staging Pearls
- *Deep invasion is defined as invasion beyond the subcutaneous fat or >6 mm (as measured from the granular layer of adjacent normal epidermis to the base of the tumor) [131].
- Perineural invasion for T3 classification is defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm in caliber, or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression [131].
- A designation of 'U' or 'L' may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below (L) [131].
- Clinical and pathological extranodal extension (ENE) should be recorded as ENE(−) or ENE(+) [131].
- This staging system applies to cutaneous squamous cell carcinoma, cutaneous carcinoma, basal cell carcinoma of the head and neck, and all other nonmelanoma skin carcinomas of the head and neck (except Merkel cell carcinoma) [1, 2].
- Risk stratification for treatment decisions often incorporates additional factors beyond AJCC staging, such as immunosuppression, tumor location, and histologic features [SCC-2].
Management PrinciplesClick to collapse
The primary goals of treatment for cutaneous squamous cell carcinoma (CSCC) are complete tumor removal and maximal preservation of function and cosmesis. Treatment decisions should be customized to account for individual factors and patient preference. Surgical approaches often offer the most effective means for cure, but considerations of function, cosmesis, and patient preference may lead to choosing radiation therapy (RT), topical therapy, or systemic therapy as primary treatment. Multidisciplinary consultation at a center with specialized expertise is recommended during treatment planning for patients with high-risk, very-high-risk, and locally advanced CSCC (laCSCC). Epidermally limited CSCC may be treated with nonsurgical options [SCC-3, SCC-E].
Curative
All patients with local, regional, or locally advanced disease
Multimodal treatment tailored to risk stratification. Includes surgery (standard excision, Mohs micrographic surgery, or other forms of peripheral and deep en face margin assessment [PDEMA]), RT, and systemic therapy. For very-high-risk and laCSCC, neoadjuvant or adjuvant systemic therapy may be considered. For field cancerization, topical therapies are used.
Palliative
Patients with regional recurrence or distant metastatic disease
Multidisciplinary consultation to discuss systemic therapy alone or in combination with RT. Clinical trial participation is encouraged.
Multidisciplinary consultation at a center with specialized expertise is recommended for treatment planning of high-risk/very-high-risk CSCC, very-high-risk CSCC with significant risk of metastasis, laCSCC, and when managing positive margins. Multidisciplinary teams should discuss options including systemic therapy and RT in select cases for laCSCC and S-ITM.
The guidelines do not specify explicit performance status criteria for treatment eligibility. However, the decision between curative surgery/RT and systemic therapy is influenced by patient fitness, comorbidities, extent of disease, and risk of functional or cosmetic defects. For nonsurgical candidates, definitive RT or systemic therapy should be considered.
Management PathwaysClick to collapse
Branching: Clinical presentation of diffuse actinic keratoses and superficial (in situ) SCC
Branching: Risk factors for local recurrence, metastases, or death (SCC-2), Treatment options (SCC-4)
Branching: Risk factors for local recurrence, metastases, or death (SCC-2), Pathologic findings, Resectability
Branching: Risk factors for local recurrence, metastases, or death (SCC-2), Neoadjuvant therapy consideration
Branching: Definition: primary or recurrent extensive disease where surgery and/or RT may not result in cure or may produce significant functional impairment, Resectability, Curative intent feasibility
Branching: Palpable or radiographically concerning lymph nodes, Pathologic confirmation, Surgical resectability
Branching: Geographic footprint of S-ITM, Resectability
Branching: Risk status (local, regional, metastatic)
Pretreatment EvaluationClick to collapse
History and Physical
Pathology
Imaging
Risk Stratification
Consultation
SurgeryClick to collapse
Surgical approaches often offer the most effective and efficient means for accomplishing cure. The primary goals are complete tumor removal and maximal preservation of function and cosmesis.
Surgical approaches are customized to account for individual factors, patient preference, tumor size, location, and risk features.
Tissue rearrangement (e.g., flap reconstruction, extensive undermining) should not be undertaken until clear margins are identified.
For tumors being considered for SLNB, delay reconstruction if not able to close primarily with minimal undermining.
If invasion to parotid fascia is noted, superficial parotidectomy may be indicated.
Procedures
Curettage and Electrodesiccation (C&E)
Mohs Micrographic Surgery or Excision with Peripheral and Deep En Face Margin Assessment (PDEMA)
Shave Removal
Standard Excision with Postoperative Margin Assessment
Sentinel Lymph Node Biopsy (SLNB)
Regional Lymph Node Dissection
Radiation TherapyClick to collapse
RT is a primary treatment option for nonsurgical candidates or when patient preference and other factors lead to its choice. It is also used adjuvantly for positive margins or high-risk features after surgery, and for regional disease.
Principles
- Refer to the ASTRO Guideline on Definitive and Postoperative Radiation Therapy for Basal and Squamous Cell Cancers of the Skin for general indications and dose recommendations [1].
- Protracted fractionation is associated with improved cosmetic results and should be utilized for poorly vascularized or cartilaginous areas.
- For extensive perineural invasion (PNI) or involvement of named nerves (particularly in the head and neck region), consider including the course of the cranial nerve proximally.
- Perineural tumor spread (PNTS), defined as clinically or radiographically apparent macroscopic spread along nerves, warrants comprehensive coverage of the involved and potentially interconnected cranial nerve pathways.
- RT is contraindicated for genetic conditions predisposing to skin cancer (e.g., basal cell nevus syndrome [Gorlin syndrome]) and relatively contraindicated for patients with connective tissue diseases (e.g., scleroderma).
- Given higher complication rates, reirradiation should not be routinely utilized for recurrent disease within a prior radiation field.
- Consider elective nodal irradiation (ENI) in cases of multiple high-risk pathologic features, especially in immunocompromised patients.
- Recommendations for external beam RT (EBRT) apply to both photons and electrons.
- Image-guided radiation therapy (IGRT) is considered best practice when treating with intensity-modulated radiation therapy (IMRT), proton beam radiotherapy, or 3D conformal radiation.
- Application of bolus over the primary tumor should be considered to ensure full dose to the surface.
- Radiation treatments should be given by a practicing radiation oncologist with radiation physics support.
Dose Frameworks
| Name | Total Dose | Dose Per Fraction | Fractions | Schedule | Indication |
|---|---|---|---|---|---|
| Adjuvant RT | BED10 of 60–79 Gy | 1.8–2 Gy | 30–33 | Conventional fractionation (five daily treatments per week) | Postoperative setting for positive margins or high-risk features. |
| Adjuvant RT Hypofractionation | BED10 of 48–70 Gy | 2.5–6 Gy | 5–20 | Hypofractionated | Alternative fractionation schedules. |
| Definitive EBRT Conventional | BED10 of 70–84 Gy | 1.8–2 Gy | 33–42 | Conventional fractionation | Definitive treatment for primary tumors. |
| Definitive EBRT Hypofractionation | BED10 of 48–72 Gy | 2.5–7 Gy | 5–22 | Hypofractionated | Definitive treatment, especially for older patients or those unable to attend protracted course. |
| Regional Disease Conventional | 66–70 Gy (gross), 60 Gy (dissected basins), 50–66 Gy (PNTS) | 1.8–2 Gy | 25–35 | Conventional fractionation | Postoperative or definitive treatment of regional lymph node disease. |
| S-ITM RT | 50–70 Gy | Varies | Varies | Over 5–7 weeks | For resected or unresected satellitosis/in-transit metastasis. |
Approaches
| Name | Dose Fractionation | Concurrent Chemotherapy | Indication | Key Trial | Toxicities |
|---|---|---|---|---|---|
| Definitive External Beam RT (EBRT) | See dose frameworks above. | May be considered in select cases for laCSCC after multidisciplinary discussion. | Nonsurgical candidates with local, regional, or locally advanced disease. | Poor cosmetic outcomes (telangiectasia, skin pigmentation changes, fibrosis), non-healing ulcers (especially for SCC in situ), soft tissue/cartilage/bone necrosis, decreased sensation, cataracts (periorbital lesions). | |
| Adjuvant EBRT | See dose frameworks above. | Consider concurrent systemic therapy for high-risk regional disease with ENE or incompletely resected nodes. | Positive margins after surgery or high-risk features (PNI, tumor ≥6 cm, recurrent, etc.). | As above. | |
| Brachytherapy | Custom surface mold applicators: 3 Gy x 16 fractions (daily) or 5 Gy x 8 fractions (2x/week). Interstitial brachytherapy: Goal BED10 at least 60 Gy (e.g., 4.4 Gy x 10 fractions BID). Shielded single channel applicators: 3 Gy x 12–16 fractions (daily). | Not specified. | Particularly for head and neck sites. Surface applicators for superficial tumors (<5 mm depth). Interstitial for deeper tumors. | Potential for tissue necrosis, poor cosmesis. | |
| Isolated Limb Infusion/Perfusion (ILI/ILP) | Melphalan-based regimens. | N/A (regional chemotherapy). | Useful in certain circumstances for limb-only S-ITM with progression on/contraindications to standard therapies. | Wieberdink toxicity (regional). |
Systemic TherapyClick to collapse
Systemic therapy is used in various settings: neoadjuvant for very-high-risk or laCSCC, adjuvant for extremely high-risk features, concurrent with RT for select laCSCC or regional disease, and alone for unresectable, recurrent, or metastatic disease. Immune checkpoint inhibitors (cemiplimab-rwlc, pembrolizumab) are preferred in many settings.
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Follow-up and Response Assessment
Timing
Follow-up schedules are based on risk status and occur at regular intervals after primary treatment. 70% to 80% of CSCC recurrences develop within 2 years of initial therapy, so close follow-up during this period is critical.
Response Logic
-
Local disease: H&P with complete skin and regional lymph node exam at intervals based on risk (low, high, very high). Consider imaging if clinical exam insufficient or appreciable risk of subclinical recurrence.
-
Regional/S-ITM disease: H&P with complete skin and regional lymph node exam at intervals. Consider imaging as above.
-
Recurrence: Local recurrence treated per pathways for high-risk/very-high-risk CSCC (SCC-5 and SCC-6). Locally advanced recurrence per SCC-7. New regional disease per SCC-8 and SCC-10. Regional recurrence or distant metastases per multidisciplinary consultation.
Imaging Recommendations
-
Imaging modality and targeted area at discretion of treating team based on suspected extent of disease (local, regional, metastatic).
-
Histologic confirmation sufficient for local recurrence, but MRI with and without contrast can assess extent of local disease.
-
For nodal or distant metastases, histologic analysis and/or other imaging modalities for confirmation and gauge extent of disease.
-
Surveillance imaging of regional nodal basin and to evaluate for distant metastatic disease, ideally based on multidisciplinary board recommendation.
Biopsy Or Salvage Logic
-
Actinic keratoses that have atypical appearance or do not respond to appropriate therapy should be biopsied for histologic evaluation.
-
For positive margins after surgery, re-excision if feasible, or RT, or systemic therapy if curative RT not feasible.
-
Under highly selective circumstances and in context of multidisciplinary consultation, resection of limited metastases can be considered.
SurveillanceClick to collapse
Clinical Follow Up Schedule
- Low-risk: Every 3–12 months for 2 years, then every 6–12 months for 3 years, then annually for life.
- High-risk: Every 3–6 months for 2 years, then every 6–12 months for 3 years, then annually for life.
- Very-high-risk: Every 3–6 months for 2 years, then every 6 months for 3 years, then every 6–12 months for life.
- Patients with regional/S-ITM disease: Every 2–3 months for 1 year, then every 2–4 months for 1 year, then every 4–6 months for 3 years, then every 6–12 months for life.
- Complete skin and regional lymph node examination at each visit.
Imaging Strategy
- Imaging is not routine for all patients. Consider imaging if clinical exam is insufficient for following disease or if there is appreciable risk of subclinical local or nodal recurrence.
- For locally extensive or metastatic disease: MRI with and without contrast is preferred for perineural disease or deep soft tissue involvement; CT with contrast is preferred for bone disease.
- For nodal or distant metastases: histologic analysis and/or other imaging modalities (CT, FDG-PET/CT) can be used for confirmation and to gauge extent of disease.
- Imaging modality and targeted area should be at the discretion of the treating team based on the suspected extent of disease.
Laboratory Monitoring
Not specified in the source. Routine laboratory monitoring is not detailed; however, standard laboratory tests may be performed as clinically indicated during systemic therapy.
Supportive Follow Up
- Patient education: strict sun protection, self-examination of the skin (monthly), and for those with regional disease, self-examination of lymph nodes.
- Follow-up with a dermatologist is strongly recommended if the patient meets criteria: past or imminent solid organ, marrow, or hematopoietic cell transplant; ≥1 cutaneous melanomas in the past 5 years; or ≥4 nonmelanoma skin cancers in the past 5 years.
- Adjust frequency of follow-up based on risk of recurrence or development of new primary tumors.
- Consider prophylactic measures in high-risk patients (e.g., oral retinoids, nicotinamide).
ComplicationsClick to collapse
Disease-Related
| Complication | Management |
|---|---|
| Local recurrence | Managed per the appropriate pathway for primary treatment (SCC-5, SCC-6). |
| Locally advanced disease (laCSCC) | Multidisciplinary discussion and multimodality treatment including neoadjuvant and adjuvant therapy (SCC-7). |
| Satellitosis/In-transit metastasis (S-ITM) | Multidisciplinary discussion; options include systemic therapy with or without local therapies such as radiation therapy or surgery (SCC-9). |
| Regional lymph node metastasis | Surgical excision of primary tumor and regional lymph node dissection, with consideration of adjuvant radiation therapy and systemic therapy depending on pathologic findings (SCC-8, SCC-10). |
| Distant metastatic disease | Multidisciplinary consultation to discuss systemic therapy alone or in combination with radiation therapy; consider clinical trials (SCC-11). |
| Disfigurement and functional impairment | Surgical planning to maximize preservation of function and cosmesis; reconstructive surgery may be required. |
Supportive CareClick to collapse
Supportive care for CSCC patients focuses on managing treatment-related toxicities, preserving function, and ensuring quality of life. Multidisciplinary involvement is key.
Not explicitly detailed in the source; however, nutritional support may be necessary for patients undergoing intensive chemotherapy or experiencing significant mucositis or dysphagia.
Not specified in the source. General antiemetic guidelines for chemotherapy regimens (e.g., 5-HT3 antagonists, dexamethasone) should be followed.
Not specified in the source. Use of granulocyte colony-stimulating factor (G-CSF) should follow institutional guidelines for chemotherapy-induced neutropenia prophylaxis.
Not explicitly mentioned. Venous thromboembolism (VTE) prophylaxis should be considered per standard risk assessment and institutional protocols, especially during periods of reduced mobility or with certain chemotherapies.
Pain management is not detailed but is an essential component. Analgesics should be tailored to the type and severity of pain, considering potential neuropathic components from perineural invasion or treatment.
Patient education is emphasized, including sun protection, self-examination, and understanding of the disease. Psychological support may be needed to address body image concerns, anxiety, or depression related to diagnosis and treatment.
Not mentioned. Dental care may be relevant for patients with head and neck CSCC, especially those receiving radiation therapy to the head and neck region.
PrognosisClick to collapse
Cutaneous squamous cell carcinoma (CSCC) generally has a good prognosis, with a 5-year survival rate of approximately 98%. However, treatment continues to evolve to improve quality of life and minimize recurrence. Metastatic CSCC is rare, occurring in an estimated 1.9% to 2.7% of all cases, with nodal metastases and distant metastatic disease estimated at 3.7% and 0.4%, respectively. One-third of deaths from CSCC occur from local disease alone.
By Stage
| Stage | Five Yr Survival | Context |
|---|---|---|
| Tumor <4 cm vs ≥4 cm | 3-year disease-specific survival (DSS) rates are 93% for lesions <4 cm and 67% for lesions ≥4 cm (P = .0003). | Based on a large prospective study. |
| Thickness ≤2 mm vs >2 mm | Prospective data show metastasis rates of 0% for tumors ≤2.0 mm in thickness, 4% for tumors 2.1 to 6.0 mm, and 16% for tumors >6.0 mm. | Risk of recurrence and metastasis is significantly higher for lesions with thickness >2 mm. |
| Depth of invasion beyond subcutaneous fat | Invasion into the subcutaneous fat significantly increases rates of recurrence and metastasis. | Several studies show higher risk. |
| Perineural invasion | Perineural invasion (PNI) is associated with increased risks of recurrence, metastasis, and death. Poorer outcomes are associated with the presence of clinical symptoms and extent of neuronal involvement. | Tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm. |
| Nodal disease | 5-year disease-free survival (DFS) and disease-specific survival (DSS) estimates range from 59% to 83% and 63% to 83%, respectively, for patients with regional involvement treated with surgery plus adjuvant radiation therapy. | Regional nodal involvement significantly increases the risk of recurrence and mortality. |
| N2 disease with immunosuppression | 5-year survival is 52% for immunosuppressed patients (e.g., transplant recipients or those with hematologic malignancies), compared to 72% for immunocompetent patients. | According to the AJCC 7th edition. |
Prognostic Factors
- Anatomic location (head, neck, hands, feet, pretibia, anogenital area are high-risk)
- Tumor diameter (≥2 cm and especially ≥4 cm)
- Clinical borders (poorly defined)
- Primary vs. recurrent disease
- Immunosuppression
- Site of prior radiation therapy or chronic inflammation
- Rapid growth tumor
- Neurologic symptoms
- Degree of differentiation (poorly differentiated)
- Histologic subtype (adenosquamous, sarcomatoid)
- Depth of invasion (>6 mm or invasion beyond subcutaneous fat)
- Perineural involvement (tumor cells within nerve sheath of a nerve deep to dermis or ≥0.1 mm caliber)
- Lymphovascular invasion
Follow UpClick to collapse
Post Curative Treatment
Follow-up schedules are stratified by risk category: for low-risk patients, every 3–12 months for 2 years, then every 6–12 months for 3 years, then annually for life; for high-risk patients, every 3–6 months for 2 years, then every 6–12 months for 3 years, then annually for life; for very-high-risk patients, every 3–6 months for 2 years, then every 6 months for 3 years, then every 6–12 months for life. This is based on the high rate of recurrence within the first 2 years (70%–80% of recurrences develop within 2 years).
Surveillance Rationale
Continued long-term surveillance is essential because 13%–50% of patients will develop another SCC within 5 years, representing at least a 10-fold increase in risk compared to the general population. Patients with prior SCC are also at increased risk of developing cutaneous melanoma and BCC. Close follow-up during the first 2 years is critical due to the peak recurrence period.
Late Effects Screening
- Screening for secondary malignancies, especially in patients who received prior radiation therapy.
- Monitoring for long-term radiation sequelae: telangiectasia, fibrosis, non-healing ulcers, necrosis, decreased sensation, cataracts.
- Assessment of functional and cosmetic outcomes after surgery or radiation.
- Surveillance for treatment-related toxicities from systemic therapies (e.g., endocrinopathies from immunotherapy).
Recurrence Patterns
Most recurrences occur within 2 years of initial therapy. Local recurrence rates vary by treatment modality (e.g., 3.1% for primary CSCCs treated with Mohs). Recurrent tumors are at higher risk of metastasis. Risk factors for recurrence after treatment include larger subclinical extension, more Mohs stages, perineural invasion, and certain histologic features.
Key TrialsClick to collapse
| Acronym | Full Name | Year | N | Intervention | Comparator | Population | Primary Endpoint | Key Result | Secondary Outcomes | Practice Change | Journal |
|---|---|---|---|---|---|---|---|---|---|---|---|
| ADJUVANT CEMIPLIMAB TRIAL | Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma | 2025 | 415 | Adjuvant cemiplimab (350 mg every 3 weeks for 12 weeks, then 700 mg every 6 weeks for up to 36 weeks) or placebo. | Placebo | Patients with local or regional CSCC after postoperative radiation therapy at high risk for recurrence due to nodal or non-nodal features. | Disease-free survival (DFS) | At median follow-up of 24 months, estimated DFS was 87% with cemiplimab vs 64% with placebo. | Cemiplimab led to lower risks of locoregional recurrence and distant recurrence; higher grade ≥3 adverse events than placebo (23.9% vs 14.2%). | Established adjuvant cemiplimab as category 1 preferred for patients with extremely high-risk nodal and non-nodal features following adjuvant radiation therapy. | New England Journal of Medicine |
| KEYNOTE-629 | Pembrolizumab for Locally Advanced and Recurrent/Metastatic Cutaneous Squamous Cell Carcinoma | 2021 | 100 | Pembrolizumab 200 mg every 3 weeks. | None (single-arm) | Patients with locally advanced, recurrent, or metastatic CSCC. | Objective response rate (ORR) | ORR of 34% to 50%, complete response (CR) of 4% to 17%, partial response (PR) of 25% to 33%. | Safety and efficacy in different subgroups. | Supported pembrolizumab as a preferred systemic therapy option for locally advanced, recurrent, or metastatic CSCC when curative surgery or radiation is not feasible. | Annals of Oncology |
| CEMIPLIMAB LA/METASTATIC CSCC | Cemiplimab in Locally Advanced Cutaneous Squamous Cell Carcinoma: Phase 2, Single-Arm Trial | 2020 | 78 | Cemiplimab 3 mg/kg every 2 weeks. | None (single-arm) | Patients with locally advanced CSCC. | Objective response rate (ORR) | ORR of 44% to 54%, CR of 0% to 13%, PR of 31% to 50%. | Duration of response, safety. | Established cemiplimab as a preferred systemic therapy option for locally advanced CSCC when surgery or radiation is not feasible. | Lancet Oncology |
| CEMIPLIMAB NEOADJUVANT | Neoadjuvant Cemiplimab for Stage II to IV Cutaneous Squamous-Cell Carcinoma | 2022 | 79 | Neoadjuvant cemiplimab (3 mg/kg every 2 weeks for up to 4 doses) prior to surgery. | None (single-arm) | Patients with stage II to IV CSCC considered for surgery. | Pathologic complete response (pCR) | 51% pCR and 13% pathologic major response. | Safety, surgical outcomes. | Supported consideration of neoadjuvant cemiplimab for borderline resectable, unresectable, or high-morbidity surgery cases. | New England Journal of Medicine |
| NIVOLUMAB CSCC | First-Line Nivolumab in Patients with Locally Advanced or Metastatic Cutaneous Squamous-Cell Carcinoma | 2022 | 24 | Nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks. | None (single-arm) | Patients with advanced CSCC. | Best objective response rate (ORR) | Best ORR of 58.3%, no CRs reported. Median PFS 12.7 months, median OS 20.7 months. | Duration of response, safety. | Provided evidence for nivolumab as an other recommended systemic therapy option. | Cancer |
| CALCIPOTRIOL/5-FU FIELD CANCERIZATION | Randomized Trial of Calcipotriol Combined with 5-Fluorouracil for Skin Cancer Precursor Immunotherapy | 2017 | 101 | Topical calcipotriol plus 5-fluorouracil (5-FU). | Vehicle plus 5-FU. | Patients with extensive actinic keratoses. | Cumulative probability of remaining free from disease progression over 1500 days. | Calcipotriol/5-FU group had significantly higher proportion disease-free at 1500 days. Fewer participants developed CSCC on treated face/scalp within 3 years (7% vs 28%; HR 0.215; P = .032). | Duration of prophylaxis against SCC. | Established topical calcipotriene/fluorouracil as a preferred treatment for field cancerization. | Journal of Clinical Investigation |
Clinical PearlsClick to collapse
- Pearl 1: Risk category assignment for local CSCC should be based on the highest risk factor present. The high-risk group has elevated risk of local recurrence; the very-high-risk group has elevated risk of both local recurrence and metastasis.
- Pearl 2: Mohs micrographic surgery (or other forms of PDEMA) is the preferred surgical technique for very-high-risk CSCC because it allows intraoperative analysis of 100% of the excision margin, leading to lower recurrence rates.
- Pearl 3: For patients with very-high-risk nodal and non-nodal features and postoperative negative margins following adjuvant radiation therapy, adjuvant cemiplimab-rwlc is category 1 preferred (based on a phase III trial showing improved DFS).
- Pearl 4: Neoadjuvant cemiplimab-rwlc should be considered for very-high-risk tumors with nonreactive non-keratoacanthomatous rapid growth, in-transit metastasis, borderline resectability, or where surgery alone may not be curative or may result in significant functional limitation.
- Pearl 5: Immunosuppressed patients (especially transplant recipients) are at significantly higher risk for multiple and aggressive CSCCs; consider modifying immunosuppression and using mTOR inhibitors.
- Pearl 6: Regular sunscreen use and oral nicotinamide may reduce the development of new AKs and CSCCs in high-risk patients.
- Pearl 7: Follow-up schedules should be tailored to risk category and adjusted based on the frequency of tumor development. Most recurrences occur within 2 years of initial therapy.
- Pearl 8: For radiation therapy, protracted fractionation is associated with improved cosmetic results and should be utilized for poorly vascularized or cartilaginous areas. Re-irradiation should not be routinely utilized for recurrent disease within a prior radiation field.
Special SituationsClick to collapse
Organ transplant recipients and other immunosuppressed patients
Field cancerization/confluent epidermal dysplasia
Genetic syndromes predisposing to CSCC (e.g., xeroderma pigmentosum, recessive dystrophic epidermolysis bullosa)
CSCC with perineural invasion (PNI)
Recurrent CSCC
Guidelines ResourcesClick to collapse
NCCN Clinical Practice Guidelines in Oncology: Squamous Cell Skin Cancer
ASTRO Guideline on Definitive and Postoperative Radiation Therapy for Basal and Squamous Cell Cancers of the Skin
AJCC Cancer Staging Manual, 8th Edition
European Interdisciplinary Guideline on Invasive Squamous Cell Carcinoma of the Skin
Guidelines for the Management of People with Cutaneous Squamous Cell Carcinoma
Find a Genetic Counselor Tool
Protective FactorsClick to collapse
- Regular sunscreen use (reduces rate of development of new AKs and CSCCs) [57,58]
- Oral nicotinamide (may reduce development of CSCCs by enhancing DNA repair and reducing UV-induced immunosuppression) [59,60]
- Aggressive treatment of precancers (can prevent development of subsequent invasive tumors) [41]