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What is Squamous Cell Carcinoma?
Causes and Risk Factors
Clinical Presentation and Symptoms
Diagnosis
Prognosis and Complications
Treatment
Prevention
Further Reading
Sources and Bibliography

What is Squamous Cell Carcinoma?

Squamous cell carcinoma (SCC) of the skin, also known as spinalioma, epidermoid carcinoma, or squamocellular carcinoma, is a malignant tumor of the skin and mucous membranes. It arises from keratinocytes, the primary cell type making up the outermost layer of the skin (the epidermis), or from the epithelial cells of skin appendages such as the nails, hair follicles, and sebaceous glands.

SCC is the second most common form of skin cancer after basal cell carcinoma, accounting for approximately 20% of all cutaneous malignancies. In the United States alone, it is estimated that over 1 million cases of SCC are diagnosed each year, with incidence rising steadily over recent decades due to aging populations, increased sun exposure, and the growing number of immunocompromised individuals.

Unlike basal cell carcinoma, which almost never spreads beyond the skin, squamous cell carcinoma has a genuine potential to metastasize. It typically spreads first through the lymphatic system and then via the bloodstream to distant organs. This makes early diagnosis and prompt treatment critically important. The overall metastasis rate for cutaneous SCC is approximately 2–5%, but this rises significantly in high-risk tumors and immunocompromised patients.

Epidemiologically, SCC occurs more frequently in men than in women, with a male-to-female ratio of approximately 2:1 to 3:1 depending on the population studied. It typically presents in the sixth to seventh decade of life, reflecting the cumulative nature of ultraviolet (UV) radiation damage over a lifetime. The most commonly affected anatomical sites are sun-exposed areas, particularly:

The face, especially the lower lip, nose, ears, and forehead
The scalp (particularly in bald or thin-haired individuals)
The back of the hands and forearms
The neck

Causes and Risk Factors

Squamous cell carcinoma of the skin does not arise from a single cause. Rather, it develops as the result of a complex interplay between environmental exposures, biological vulnerabilities, and immunological factors. Understanding these risk factors is essential not only for prevention but also for identifying individuals who warrant closer surveillance.

Ultraviolet (UV) Radiation: The Primary Cause

The most important causative factor in the development of cutaneous SCC is chronic exposure to ultraviolet radiation, primarily from the sun, but also from artificial sources such as tanning beds and UV lamps. The link between cumulative UV exposure and SCC is one of the most robustly established relationships in oncology.

UV radiation, particularly UVB radiation (wavelength 280–315 nm) and to a lesser extent UVA radiation (315–400 nm), causes skin cancer through two distinct mechanisms:

Direct DNA mutagenesis: UV radiation induces the formation of characteristic DNA lesions called cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts. These are abnormal bonds between adjacent pyrimidine bases (cytosine and thymine) in the DNA strand. If these mutations are not repaired by the cell’s DNA repair machinery before the cell divides, they become permanently incorporated into the genome. Over years and decades of repeated sun exposure, an accumulation of these mutations, particularly in tumor suppressor genes such as TP53, drives the transformation of a normal keratinocyte into a cancer cell.
Immunosuppression of the skin: UV radiation does not merely damage DNA; it also impairs the immune surveillance of the skin. It does so by reducing the density and function of Langerhans cells (the skin’s resident antigen-presenting immune cells), skewing the immune response toward a tolerogenic profile, and suppressing systemic cell-mediated immunity. This relative immunosuppression prevents the immune system from recognizing and eliminating pre-malignant and malignant cells, allowing them to proliferate unchecked.

There is a linear dose-response relationship between cumulative UV exposure and the incidence of SCC. The more UV radiation the skin accumulates over a lifetime, the higher the risk of developing the disease.

Individuals at highest risk from UV radiation are those with fair skin phototypes, specifically Fitzpatrick phototypes I and II, which are characterized by:

Very light or light skin
Blonde or red hair
Blue, green, or grey eyes
A tendency to burn easily and tan poorly or not at all
A high density of freckles

People with darker skin phototypes (III–VI) have significantly lower risk of SCC due to the photoprotective effect of melanin, though they are not completely immune.

Artificial UV sources (sunbeds, tanning lamps) carry the same mutagenic risks as natural sunlight. A large body of evidence, including meta-analyses, confirms that sunbed use is associated with a significantly increased risk of SCC, with higher risk correlating with earlier age of first use.

Ionizing Radiation

Prolonged or repeated exposure to ionizing radiation (X-rays, gamma rays) is a recognized cause of SCC. This is particularly relevant for:

Patients who have undergone radiation therapy for other cancers and develop SCC within the irradiated field, often many years later.
Occupational groups historically exposed to high levels of ionizing radiation include radiologists in the early days of the specialty and, more relevant today, airline crew members, who receive higher-than-average cosmic radiation exposure due to the reduced atmospheric shielding at high altitude.

Human Papillomavirus (HPV)

Certain strains of human papillomavirus (HPV), particularly the so-called high-risk oncogenic strains such as HPV 16, 18, 31, and 33, are strongly associated with SCC of mucosal surfaces, especially:

The oropharynx (base of tongue, tonsils)
The anogenital region (vulva, vagina, penis, anus, perianal skin)
The oral cavity

HPV-related SCC has become increasingly prevalent over recent decades and is now responsible for a significant proportion of head and neck squamous cell carcinomas, particularly in younger, non-smoking individuals. HPV drives cancer development by producing viral oncoproteins (E6 and E7) that inactivate key tumor suppressor proteins (p53 and Rb), disrupting normal cell cycle control and enabling unrestricted proliferation.

In cutaneous SCC (as opposed to mucosal SCC), the role of HPV is less clearly defined but is increasingly recognized, particularly in immunocompromised patients.

Chemical Carcinogens

Several chemical substances have been associated with the development of SCC through their ability to induce DNA mutations and promote carcinogenesis:

Arsenic: Chronic exposure to inorganic arsenic (through contaminated drinking water, occupational exposure, or historical use in medicinal preparations) is a well-established risk factor for multiple skin cancers, including SCC. Arsenic-induced skin cancers often appear on non-sun-exposed areas such as the trunk and extremities.
Polycyclic aromatic hydrocarbons (PAHs): These chemical compounds, found in coal tar, soot, cigarette smoke, and various industrial products, are potent carcinogens. The historical observation of scrotal cancer in chimney sweeps, first described by Sir Percivall Pott in 1775, represents one of the earliest documented cases of occupationally induced SCC due to PAH exposure.
Petroleum products and industrial oils: Long-term occupational skin contact with mineral oils and certain cutting fluids has been linked to SCC.

Immunosuppression

The immune system plays a critical role in recognizing and eliminating pre-malignant and malignant cells. When this surveillance is compromised, the risk of developing SCC and other skin cancers rises dramatically.

Immunosuppression may arise from:

Infectious causes: HIV infection and AIDS substantially increase the risk of SCC, particularly at anogenital sites (often HPV-related)
Iatrogenic (medically induced) immunosuppression:
- Organ transplant recipients are at particularly high risk. Solid organ transplant patients receiving long-term immunosuppressive therapy (such as calcineurin inhibitors, azathioprine, or mycophenolate mofetil) have a 65–250 times greater risk of developing SCC compared to the general population. In transplant recipients, SCC is often multifocal, aggressive, and more likely to recur and metastasize.
- Patients on chronic high-dose corticosteroids (cortisone) or other immunosuppressive agents for autoimmune or inflammatory conditions are also at elevated risk.
- Patients receiving certain chemotherapy agents

Chronic Skin Conditions and Scarring

Squamous cell carcinoma can arise within areas of chronic skin inflammation, scarring, or non-healing wounds. This includes:

Chronic skin ulcers: SCC arising within a longstanding ulcer is known as a Marjolin’s ulcer, an aggressive and often advanced form of the disease because it may be overlooked and attributed to the underlying ulcer condition.
Old scars: SCC can develop within burn scars, surgical scars, or scars from chronic infections.
Chronic inflammatory dermatoses: Conditions such as lichen sclerosus, chronic discoid lupus erythematosus, and epidermolysis bullosa carry an increased risk of SCC development within affected skin areas.

Smoking and Alcohol

Cigarette smoking and alcohol consumption are particularly important risk factors for SCC of the lips, oral mucosa, and oropharynx. The combination of tobacco and alcohol exposure has a synergistic effect; the risk in people who both smoke and drink heavily is far greater than the sum of either risk alone. Tobacco carcinogens directly mutate DNA in mucosal cells, while alcohol acts as a solvent that enhances mucosal penetration of carcinogens and has additional immunosuppressive and direct genotoxic effects.

Pre-existing Skin Lesions

Certain pre-existing skin conditions, particularly actinic keratoses (solar keratoses) and Bowen’s disease (squamous cell carcinoma in situ), are considered precancerous and may progress to invasive SCC if left untreated. These will be discussed further in the clinical presentation section.

Clinical Presentation and Symptoms

Squamous cell carcinoma of the skin is a heterogeneous disease that can appear in various clinical forms depending on its site of origin, the underlying tissue involved, and the stage of development. Recognizing these presentations is crucial for early diagnosis.

SCC Arising on the Skin (Cutaneous SCC)

Cutaneous SCC may arise:

De novo (on previously healthy, normal-appearing skin), or
From pre-existing precancerous lesions, most commonly from an actinic keratosis or Bowen’s disease

Actinic keratoses (AK) are rough, scaly patches that develop on chronically sun-damaged skin. They are considered the most important precursor lesion for SCC; the annual risk of transformation of a single AK to invasive SCC is estimated at approximately 0.025–0.1%, but many patients have dozens of lesions and the risk accumulates over time. It is estimated that up to 65% of all invasive SCCs arise from pre-existing AKs.

Bowen’s disease represents squamous cell carcinoma in situ, a full-thickness dysplasia of the epidermis that has not yet broken through the basement membrane. It presents as a slowly enlarging, well-demarcated, erythematous (reddish), scaly or crusted patch that may be mistaken for eczema, psoriasis, or a fungal infection. The estimated risk of progression to invasive SCC is approximately 3–5%.

Early-Stage Cutaneous SCC

In the early phase, cutaneous SCC typically presents as:

A raised lesion, either papular (less than 1 cm in diameter) or nodular (greater than 1 cm)
Erythematous (red) in color, with an irregular, poorly defined border
A rough, thickened, hyperkeratotic (scaly) surface, which may sometimes feel like sandpaper or have a horn-like protrusion
Occasional central ulceration: the surface may break down and form a non-healing sore
Tenderness or bleeding on contact, particularly with more advanced lesions
Sometimes surrounded by a zone of sun-damaged or actinic keratotic skin

Advanced-Stage Cutaneous SCC

As the tumor grows, it becomes:

A larger plaque or nodule with an irregular, sometimes lobulated surface
Increasingly hyperkeratotic and ulcerated: the central portion may form a crater-like ulcer covered by a crust or necrotic debris
Indurated (hardened) on palpation, due to infiltration of the underlying dermis and, in advanced cases, subcutaneous tissue
Fixed to underlying structures in very advanced cases, losing the normal skin mobility over it

SCC Arising on Mucous Membranes and Mucocutaneous Junctions

SCC can also arise from the mucous membranes and the transitional zones between skin and mucosa, including:

The oral cavity (lips, tongue, floor of mouth, buccal mucosa)
The anogenital region (anus, perianal skin, vulva, vagina, penis, glans)
Other mucosal surfaces (such as the larynx, esophagus, and nasal mucosa, though these are generally considered separate disease entities)

As with cutaneous SCC, mucosal SCC may arise de novo or may be preceded by pre-cancerous lesions such as:

Leukoplakia: a white patch or plaque on the mucosa that cannot be scraped off and cannot be classified as any other condition. Oral leukoplakia has a malignant transformation rate of approximately 1–2% per year.
Erythroplakia: a red, velvety patch on the mucosa that cannot be attributed to any other cause. Erythroplakia carries a much higher risk of malignant transformation than leukoplakia, with up to 50% of cases.
Lichen sclerosus (lichen sclerosatrophicus): a chronic inflammatory dermatosis that primarily affects the anogenital skin and is associated with an increased risk (approximately 2–5%) of developing SCC in affected areas.

Early mucosal SCC presents as a whitish or erythematous papular lesion with indistinct borders and a tendency to ulcerate. As it progresses, it forms a plaque or nodule that on palpation feels firm and hard, and which infiltrates the underlying tissues. Mucosal SCCs, particularly those of the lip, floor of mouth, and anogenital region, are often more rapidly invasive and metastatic than their cutaneous counterparts and should therefore be managed with particular vigilance.

Verrucous Carcinoma: A Special Variant

Verrucous carcinoma is a distinct clinico-pathological variant of squamous cell carcinoma. It is a low-grade malignancy, meaning it grows slowly and rarely metastasizes, but it can cause significant local tissue destruction. It can affect both mucous membranes and skin, and characteristically presents as a large, exophytic, warty (verrucous), cauliflower-like mass that can reach several centimeters in diameter. Over time, it infiltrates and destroys the underlying deep tissues.

Recognized subtypes include:

Carcinoma cuniculatum: presents on the plantar surface of the foot as a deeply infiltrating, sinus-tract-forming tumor. The name comes from the Latin for “rabbit warren”, reflecting the complex burrowing channels the tumor creates within deep tissues.
Oral florid papillomatosis: a verrucous carcinoma of the oral cavity, presenting as extensive warty growths on the gingiva, hard palate, or tongue.
Buschke-Löwenstein tumor (giant condyloma acuminatum): a large verrucous carcinoma affecting the genitals and perianal region, typically associated with HPV infection (particularly HPV types 6 and 11).

Diagnosis

The diagnosis of squamous cell carcinoma requires an integrated approach that combines clinical evaluation with histopathological confirmation. No diagnosis of SCC should be made on clinical grounds alone; tissue biopsy and histological examination are always required for certainty.

Clinical History (Anamnesis)

The diagnostic process begins with a thorough clinical history, in which the physician gathers information about:

The duration and evolution of the lesion (how long it has been present, how it has changed over time)
Any associated symptoms (bleeding, pain, discharge)
History of previous skin cancers or pre-cancerous lesions
Cumulative sun exposure history (occupational and recreational)
Use of tanning beds
History of radiation therapy
Immune status (HIV infection, organ transplant, immunosuppressive medications)
Family history of skin cancer
Tobacco and alcohol use
Occupational exposures (arsenic, hydrocarbons)

Clinical Examination

A dermatologist or other trained clinician will carefully examine the lesion, noting its:

Size, shape, color, and borders
Surface characteristics (smooth, scaly, keratotic, ulcerated)
Consistency on palpation (soft, firm, indurated)
Depth of apparent invasion
Relationship to surrounding structures (freely mobile vs. fixed)
Presence of satellite lesions or regional lymphadenopathy

Dermoscopy (also called dermatoscopy or epiluminescence microscopy), the examination of the skin using a handheld magnifying device with polarized light, is a valuable non-invasive adjunct. It can reveal internal structures of the lesion not visible to the naked eye, improving diagnostic accuracy and helping to differentiate SCC from other skin lesions.

Histopathological Examination (Biopsy)

The definitive diagnosis of SCC is made by histopathological examination of a tissue sample obtained by biopsy. Depending on the size and location of the lesion, the biopsy may be:

Incisional biopsy: removal of a representative portion of the lesion for diagnostic purposes
Excisional biopsy: complete removal of a small lesion with a margin of surrounding normal tissue, which is both diagnostic and potentially therapeutic

Under the microscope, the pathologist will look for the characteristic features of SCC:

Nests and cords of atypical keratinocytes proliferating from the epidermis into the dermis and, in more advanced cases, the subcutaneous fat (hypodermis)
Keratin pearls: concentric whorls of keratinized squamous cells, a hallmark of well-differentiated SCC
Nuclear atypia: enlarged, irregularly shaped, hyperchromatic nuclei in the tumor cells
Mitotic figures: evidence of rapid cell division, including abnormal (atypical) mitoses
Inflammatory infiltrate: a surrounding reaction of the body’s immune cells, typically lymphocytes and plasma cells
Solar elastosis: degeneration of the elastic fibers of the dermis, appearing as basophilic amorphous material. This is a marker of chronic UV damage to the skin

The pathologist will also assign a histological grade to the tumor (well-differentiated, moderately differentiated, or poorly differentiated) based on how closely the tumor cells resemble normal squamous epithelium, which has important prognostic implications.

Differential Diagnosis

SCC must be distinguished from several other conditions that can look similar clinically:

Actinic keratosis (especially hypertrophic AK): a precursor lesion that has not yet invaded the dermis; differentiation requires histological examination
Bowen’s disease (SCC in situ): full-thickness epidermal dysplasia without dermal invasion
Leukoplakia and erythroplakia: mucosal pre-cancerous lesions
Basal cell carcinoma (BCC): typically presents with a rolled, pearly border with overlying telangiectases (arborizing dilated capillaries) and a central ulcer. This is distinct from the keratotic surface of SCC; however, both may ulcerate, and biopsy is essential for differentiation
Keratoacanthoma: a rapidly growing, dome-shaped nodule with a central keratin-filled crater that closely resembles SCC both clinically and histologically. Many authorities now consider keratoacanthoma to be a low-grade or “well-differentiated” variant of SCC that has a tendency for spontaneous resolution, but it should be treated as SCC given the diagnostic uncertainty and the risk of overlooking a true invasive carcinoma.
Viral warts (verrucae): caused by HPV, they can resemble verrucous SCC; biopsy is often necessary for differentiation
Amelanotic melanoma: rare but important to exclude, especially for pigmented or atypical lesions
Inflammatory dermatoses: conditions such as psoriasis, eczema, or contact dermatitis may mimic early SCC, particularly Bowen’s disease

Staging Investigations

Once a diagnosis of SCC is confirmed histologically, staging investigations may be indicated to assess whether the cancer has spread to regional lymph nodes or distant organs. These are particularly recommended for high-risk tumors (large size, high grade, perineural invasion, deep invasion, immunosuppressed patients, or clinical suspicion of lymph node involvement):

Clinical examination of regional lymph nodes: palpation of the draining lymph node basins
Ultrasound of regional lymph nodes: a non-invasive, sensitive method for detecting enlarged or morphologically abnormal nodes; fine-needle aspiration cytology (FNAC) of suspicious nodes can be performed under ultrasound guidance
CT scan (computed tomography): evaluates regional lymph nodes and distant metastases, particularly in advanced or high-risk cases
MRI (magnetic resonance imaging): particularly useful for assessing perineural invasion and deep tissue involvement, especially for tumors of the head and neck
PET-CT scan: can be used for staging of advanced or recurrent SCC with suspected distant metastases

Prognosis and Complications

The great majority of squamous cell carcinomas, particularly those diagnosed early when they are small and have not spread beyond the skin, carry an excellent prognosis. When treated appropriately, the 5-year cure rate for localized, low-risk SCC approaches 95% or better.

However, SCC is a potentially metastatic disease, and it is essential not to underestimate it. Understanding the factors that determine prognosis helps guide treatment intensity and follow-up planning.

Prognostic Factors

The following clinical and histological factors are recognized determinants of prognosis in cutaneous SCC:

1. Histological Differentiation (Tumor Grade)

Well-differentiated SCC (G1): tumor cells closely resemble normal squamous epithelium, produce abundant keratin, and grow relatively slowly. These tumors have a lower tendency to recur and metastasize.
Moderately differentiated SCC (G2): intermediate behavior.
Poorly differentiated SCC (G3): tumor cells look markedly abnormal, produce little or no keratin, and grow and spread more rapidly. Poorly differentiated tumors have a significantly higher risk of local recurrence and distant metastasis.

2. Tumor Size (Diameter)

Tumors with a diameter greater than 2 cm carry approximately double the risk of local recurrence and triple the risk of metastasis compared to tumors smaller than 2 cm.
Very large tumors (>4 cm) are considered high-risk regardless of other features.

3. Depth of Invasion

SCC confined to the epidermis and superficial dermis carries a much lower risk of metastasis than tumors that have penetrated deeply into the reticular dermis, subcutaneous fat, or underlying structures (muscle, cartilage, bone).
Perineural invasion, the presence of tumor cells tracking along the sheaths of nerves, is a particularly concerning histological finding. It is associated with significantly higher risks of local recurrence and distant spread, as well as the potential for intracranial extension in tumors of the head and neck.

4. Rate of Growth

Rapidly growing SCC (particularly keratoacanthoma-like variants that have not spontaneously regressed) tend to be more aggressive.

5. Anatomical Location

Mucosal SCC (lip, oral cavity, anogenital region) carries a higher risk of recurrence and metastasis than purely cutaneous SCC.
Certain cutaneous locations also carry higher risk: the ear, the non-hair-bearing lip, the temple and preauricular area, and the genitalia.
Tumors arising within chronic scars, ulcers, or on previously irradiated skin tend to behave more aggressively.

6. Recurrence

SCC that has already recurred once (post-treatment recurrence) carries a substantially worse prognosis than primary (previously untreated) tumors. Recurrent tumors tend to behave more invasively and are more difficult to cure.

7. Immunosuppression

As discussed, immunocompromised patients, particularly solid organ transplant recipients, develop SCCs that are more aggressive, more likely to be multifocal, and carry a significantly higher risk of metastasis compared to immunocompetent individuals.

Metastatic Spread

The metastatic potential of SCC is real and should not be dismissed. Metastasis occurs in a predictable pattern:

Regional lymph nodes (most common first site): the primary lymph nodes draining the site of the tumor (e.g., parotid and cervical nodes for tumors of the face and scalp; axillary nodes for arm tumors; inguinal nodes for lower extremity or anogenital tumors) are the most common initial site of spread.
Distant organs (less common, but serious): once the cancer has reached the lymph nodes, it may subsequently spread hematogenously (via the bloodstream) to:
- The lungs
- The liver
- The bones
- The brain

Metastatic SCC is a serious condition with significantly reduced survival rates. The 5-year survival for patients with lymph node metastases from cutaneous SCC is approximately 25–35%, and for those with distant metastases it drops further. This underscores the importance of early detection and complete initial treatment.

Treatment

The treatment of squamous cell carcinoma is individualized based on the tumor’s characteristics (size, location, grade, depth of invasion), the patient’s overall health and immune status, and the available resources and expertise. The goal of treatment is complete eradication of the cancer with the best possible cosmetic and functional outcome.

Surgical Excision: The Gold Standard

Surgical excision is the primary and preferred treatment for most cutaneous and mucosal SCCs. It offers several key advantages:

Complete removal of the tumor in the majority of cases
Provides tissue for histopathological examination, confirming the diagnosis and verifying the completeness of excision (clear margins)
Offers the possibility of cure with a single procedure in most early-stage tumors

Surgery is most often performed under local anesthesia as an outpatient or day-surgery procedure. Standard excision involves removing the tumor with margins of at least 4–6 mm of normal-appearing skin on all sides. Wider margins (10 mm or more) may be recommended for high-risk tumors.

The specimen is sent for histopathological examination, and the margins are carefully evaluated. If tumor cells are found at or close to the edges of the excised specimen (positive or close margins), further surgery (re-excision) is generally recommended.

Mohs Micrographic Surgery

For high-risk SCCs, particularly those in cosmetically sensitive or anatomically complex areas (such as the nose, ears, eyelids, and lips), as well as recurrent tumors, tumors with perineural invasion, or large tumors, Mohs micrographic surgery (MMS) is considered the standard of care at many specialized centers.

Mohs surgery is a specialized surgical technique in which the tumor is removed one thin layer at a time. Each layer is immediately processed and examined under the microscope while the patient waits. If tumor cells are found at any margin, the surgeon removes an additional layer from precisely that area and re-examines it. This process continues until all margins are clear. Mohs surgery achieves the highest cure rates for SCC (5-year cure rates of 92–99% depending on tumor characteristics) while maximally preserving healthy surrounding tissue.

Sentinel Lymph Node Biopsy

For high-risk SCCs with a significant risk of lymph node spread (large tumors, poorly differentiated tumors, perineural invasion, immunocompromised patients), sentinel lymph node biopsy (SLNB) may be considered to evaluate the first draining lymph nodes without performing a full lymph node dissection. This technique, widely used in melanoma management, is increasingly being employed in high-risk SCC to guide treatment decisions.

Radiation Therapy

Radiation therapy (radiotherapy) is an important treatment modality for SCC, used in several scenarios:

As primary treatment for tumors that are not amenable to surgery (due to size, location, extent of invasion, or patient medical fitness)
As adjuvant treatment after surgery for high-risk tumors (positive or close margins, perineural invasion, lymph node involvement) to reduce the risk of local recurrence
As palliative treatment for advanced, unresectable, or metastatic disease to control tumor growth and relieve symptoms

Modern radiation therapy techniques, including intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT), allow precise delivery of high doses of radiation to the tumor while minimizing exposure to surrounding healthy tissues.

Electrodesiccation and Curettage (EDC)

This technique, in which the tumor is scraped away with a curette and the base is then treated with an electrocautery device to destroy remaining cancer cells, may be used for small, low-risk, well-defined SCCs in non-critical locations. It is generally not recommended for high-risk SCCs, as it does not allow assessment of margins.

Cryotherapy

Cryotherapy (destruction of tissue by freezing with liquid nitrogen) may be used for very small, well-defined, superficial SCCs or precancerous lesions (actinic keratoses, Bowen’s disease) in selected cases. Like EDC, it does not allow margin assessment and is not suitable for high-risk tumors.

Topical Treatments

For superficial precancerous lesions and very early, superficial SCC (particularly Bowen’s disease/SCC in situ), certain topical treatments may be appropriate:

5-Fluorouracil (5-FU) cream: an anti-cancer agent that causes the selective destruction of rapidly dividing abnormal cells
Imiquimod cream: an immune response modifier that stimulates the local immune system to attack and destroy pre-malignant and malignant cells
Ingenol mebutate and diclofenac gel: used primarily for field treatment of multiple actinic keratoses

These topical treatments are generally not used for invasive SCC (as opposed to SCC in situ or AK).

Systemic Therapies for Advanced or Metastatic SCC

Until recently, options for patients with locally advanced or metastatic SCC not amenable to surgery or radiation were limited. The landscape has changed significantly with the introduction of:

Immunotherapy (PD-1 Inhibitors)

Cemiplimab (Libtayo®): a PD-1 immune checkpoint inhibitor approved by the FDA and EMA for the treatment of advanced cutaneous SCC (locally advanced or metastatic disease) not curable by surgery or radiation. Clinical trials have demonstrated objective response rates of approximately 44–47% in this setting.
Pembrolizumab (Keytruda®): another PD-1 inhibitor with demonstrated activity in advanced SCC of the skin and head and neck.

These drugs work by removing the “brakes” that cancer cells apply to the immune system, allowing T cells to recognize and attack the tumor.

Epidermal Growth Factor Receptor (EGFR) Inhibitors

Cetuximab: an anti-EGFR monoclonal antibody that has shown activity in advanced head and neck SCC, often used in combination with chemotherapy or radiation.

Chemotherapy

Systemic chemotherapy (typically platinum-based regimens such as cisplatin or carboplatin, often combined with 5-FU or taxanes) may be used for patients with metastatic SCC who are not candidates for immunotherapy or whose disease has progressed on immunotherapy.

Management of Regional Lymph Nodes

For patients in whom regional lymph node metastases are confirmed (by biopsy or imaging), treatment typically involves:

Therapeutic lymph node dissection: surgical removal of the involved lymph node basin
Adjuvant radiation therapy to the lymph node basin, particularly in high-risk cases (multiple positive nodes, extranodal extension)
Systemic therapy (immunotherapy or chemotherapy) in selected cases with high metastatic burden

Prevention

Given that chronic UV radiation exposure is the single most important cause of cutaneous SCC, sun protection represents the most effective primary prevention strategy. The principles are simple and well-established:

Sun Protection Measures

Avoid peak-hour sun exposure: UV radiation is most intense between 10 am and 4 pm. If possible, schedule outdoor activities in the early morning or late afternoon.
Seek shade: Use natural shade (trees, buildings) and artificial shade (umbrellas, canopies) when outdoors.
Wear protective clothing: Long-sleeved shirts, long trousers, wide-brimmed hats (with at least a 3-inch brim to protect the face, ears, and neck), and UV-blocking sunglasses. Clothing labeled with a UV protection factor (UPF) provides the most reliable sun protection.
Apply broad-spectrum sunscreen: Use a sunscreen with SPF 30 or higher (SPF 50+ is preferable for very fair-skinned individuals or intense sun exposure) that protects against both UVA and UVB radiation. Apply generously and evenly to all sun-exposed areas at least 20–30 minutes before going outdoors, and reapply every two hours and immediately after swimming or sweating. Do not rely on sunscreen as the only form of sun protection; it should complement, not replace, other protective measures.
Avoid sunbeds and tanning lamps: There is no safe level of artificial UV tanning. Sunbeds should be avoided entirely.

Skincare and Monitoring

Perform regular self-examination of the skin: Familiarize yourself with the appearance of your skin, including moles, birthmarks, blemishes, and any spots, and check for changes monthly. Look for any new growths, sores that do not heal, or changes in the appearance of existing spots.
Attend regular skin cancer screening appointments with a dermatologist if you are at high risk (fair skin, multiple actinic keratoses, personal or family history of skin cancer, immunosuppression, significant cumulative sun exposure).
Treat pre-cancerous lesions promptly: Actinic keratoses and Bowen’s disease should be treated by a dermatologist to prevent progression to invasive SCC.

Lifestyle Measures

Quit smoking: Particularly important for reducing the risk of SCC of the lip, oral mucosa, and oropharynx.
Limit alcohol intake: Alcohol amplifies the carcinogenic effect of tobacco on mucosal surfaces and has independent adverse effects.
Manage immunosuppression carefully: Immunosuppressed patients, particularly solid organ transplant recipients, should be under regular dermatological surveillance, as their risk of SCC is dramatically elevated. In some transplant patients, modification of the immunosuppressive regimen (e.g., switching from calcineurin inhibitors to mTOR inhibitors such as sirolimus, which have anti-cancer properties) may be considered in consultation with the transplant team.

HPV Vaccination

Vaccination against human papillomavirus (HPV) with vaccines such as Gardasil 9, which protects against 9 HPV strains including high-risk types 16 and 18, is highly effective at preventing HPV-related SCC of the anogenital region and oropharynx. Vaccination is recommended for adolescents (both male and female) before the age of sexual debut, but may also be beneficial for older individuals who have not previously been vaccinated.

Occupational Safety

Workers with occupational exposure to UV radiation (outdoor workers), ionizing radiation (aircraft crew, radiology and nuclear medicine personnel), arsenic, or polycyclic aromatic hydrocarbons should follow appropriate occupational health and safety guidelines to minimize their exposure. This includes using personal protective equipment, adhering to safe work practices, and undergoing regular occupational health surveillance.

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Squamous Cell Carcinoma of the Skin: Causes, Symptoms, Diagnosis, and Treatment