Understanding Non‑Melanoma Skin Cancers: Basal Cell and Squamous Cell Carcinoma

Non‑melanoma skin cancers (NMSCs) are the most common malignancies worldwide, yet they often receive less public attention than melanoma. The two principal forms—basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)—differ markedly in their biology, clinical behavior, and optimal management. Understanding these differences is essential for clinicians who perform preventive screenings and health checks, as well as for patients navigating diagnosis and treatment pathways.

Epidemiology and Public Health Impact

Basal cell carcinoma accounts for roughly 80 % of all NMSCs, while squamous cell carcinoma represents the remaining 20 %–30 %. Although each individual lesion carries a low mortality risk, the sheer volume of cases translates into a substantial burden on health‑care systems. In the United States alone, an estimated 4–5 million new NMSC lesions are diagnosed each year, with BCC outnumbering SCC by a factor of three to four. The incidence rises sharply after age 50, reflecting cumulative ultraviolet (UV) exposure, age‑related immunologic changes, and the increasing prevalence of immunosuppressive conditions.

Pathophysiology and Molecular Basis

Both BCC and SCC arise from keratinocyte lineage cells, yet the initiating genetic events diverge.

• Basal Cell Carcinoma – The hallmark of BCC is aberrant activation of the Hedgehog signaling pathway. Mutations in PTCH1 (the receptor that normally inhibits the pathway) or, less commonly, activating mutations in SMO (the downstream transducer) lead to unchecked cellular proliferation. Sporadic BCCs typically harbor somatic PTCH1 loss, while germline PTCH1 mutations underlie Gorlin‑Goldberg syndrome, a condition characterized by multiple early‑onset BCCs.

• Squamous Cell Carcinoma – SCC development is closely linked to cumulative DNA damage from UV‑B photons, which induces characteristic C→T transitions at dipyrimidine sites (the “UV signature”). Key tumor‑suppressor genes such as TP53 are frequently inactivated, and alterations in the NOTCH signaling cascade are common. In immunosuppressed patients, oncogenic human papillomavirus (HPV) infection can also contribute to SCC pathogenesis, particularly in the anogenital and peri‑oral regions.

Clinical Presentation and Subtypes

The visual appearance of BCC and SCC can be deceptively variable, and recognizing the classic patterns aids early referral for definitive diagnosis.

Basal Cell Carcinoma

• *Nodular BCC*: Pearly, translucent papules with telangiectasia; may ulcerate centrally (“rodent ulcer”).
• *Superficial BCC*: Scaly, erythematous patches that often mimic eczema; commonly found on the trunk.
• *Morphea‑like (sclerosing) BCC*: Indurated, scar‑like plaques that can be mistaken for morphea or scar tissue.
• *Pigmented BCC*: Dark brown or black lesions, more frequent in patients with darker skin phototypes.

Squamous Cell Carcinoma

• *Keratinizing (classic) SCC*: Firm, erythematous nodules or plaques with a hyperkeratotic surface; may ulcerate.
• *Bowen’s disease (SCC in situ)*: Flat, scaly, well‑demarcated lesions that can progress to invasive SCC if untreated.
• *Verrucous carcinoma*: Exophytic, warty growths with minimal metastatic potential, often arising on the oral cavity or plantar surfaces.
• *Marjolin ulcer*: SCC arising in chronic wounds or burn scars, characterized by aggressive behavior.

Diagnostic Workup

A definitive diagnosis hinges on histopathologic confirmation. The typical workflow includes:

1. Clinical Assessment – Detailed description of lesion size, depth, borders, and anatomic location.
2. Biopsy Technique –
• *Punch biopsy* (2–4 mm) for most lesions, providing full‑thickness dermal sampling.
• *Excisional biopsy* for small (< 1 cm) lesions where complete removal is feasible.
• *Incisional or shave biopsy* for larger or cosmetically sensitive areas, ensuring adequate depth to capture the dermal‑epidermal junction.
3. Histopathology –
• *BCC*: Basaloid cells with peripheral palisading, retraction artifact, and mucinous stroma.
• *SCC*: Atypical keratinocytes with intercellular bridges, keratin “pearls,” and variable degrees of differentiation.
4. Adjunctive Imaging – High‑resolution ultrasound or MRI may be employed for lesions with suspected deep invasion (e.g., periorbital BCC, SCC of the ear).
5. Staging – The American Joint Committee on Cancer (AJCC) 8th edition staging system for cutaneous SCC incorporates tumor size, depth of invasion, perineural involvement, and anatomic location. BCC is not staged formally because of its negligible metastatic potential, but high‑risk features (size > 2 cm, aggressive histologic subtype, location on the “mask” area) guide management intensity.

Management Strategies

Therapeutic decisions balance oncologic control, functional preservation, and cosmetic outcome.

Surgical Options

• *Standard Excision*: Wide local excision with 4–6 mm margins for low‑risk BCC; 6–10 mm for low‑risk SCC. Histologic margin control is essential.
• *Mohs Micrographic Surgery*: Tissue‑sparing technique offering 99 % cure rates for high‑risk BCC and SCC, especially in cosmetically or functionally critical sites (nose, eyelids, ears).
• *Curettage and Electrodessication*: Reserved for small, superficial BCCs on low‑tension skin; cure rates approach 90 % but lack histologic margin assessment.

Non‑Surgical Options

• *Topical Therapies* – Imiquimod 5 % cream (immune response modifier) and 5‑fluorouracil (5‑FU) are effective for superficial BCC and SCC in situ, requiring patient adherence to a multi‑week regimen.
• *Photodynamic Therapy (PDT)* – Utilizes a photosensitizer (e.g., aminolevulinic acid) activated by a specific wavelength of light; indicated for superficial BCC and Bowen’s disease, offering excellent cosmetic results.
• *Cryotherapy* – Liquid nitrogen application for small, well‑demarcated lesions; less effective for infiltrative BCC or deep SCC.

Radiation Therapy

External beam radiation is a primary modality for patients who are poor surgical candidates (e.g., advanced age, comorbidities) or for lesions in anatomically challenging locations. Fractionated dosing (e.g., 50–70 Gy in 2–3 Gy fractions) yields cure rates comparable to surgery for SCC, while BCC responds well to lower total doses due to its radiosensitivity.

Systemic Therapies

• *Hedgehog Pathway Inhibitors* (vismodegib, sonidegib) are FDA‑approved for locally advanced or metastatic BCC when surgery or radiation is contraindicated.
• *Immune Checkpoint Inhibitors* (cemiplimab, pembrolizumab) have demonstrated durable responses in advanced SCC, particularly in immunocompetent patients.
• *Targeted Agents* – Ongoing trials explore EGFR inhibitors and PI3K pathway modulators for refractory SCC.

Special Considerations

Immunosuppressed Populations

Organ‑transplant recipients, patients with HIV/AIDS, and those on chronic immunosuppressive therapy exhibit a markedly increased incidence of SCC (up to 100‑fold) and a higher propensity for aggressive behavior, including perineural invasion and metastasis. Management in this cohort often necessitates lower thresholds for surgical excision, closer surveillance, and consideration of systemic immunotherapy despite the underlying immunosuppression.

Genetic Syndromes

• *Gorlin‑Goldberg (Nevoid Basal Cell Carcinoma) Syndrome*: Multiple early‑onset BCCs, odontogenic keratocysts, and skeletal anomalies. Prophylactic use of hedgehog inhibitors and regular dermatologic monitoring are recommended.
• *Xeroderma Pigmentosum*: Defective nucleotide excision repair leads to extreme UV sensitivity; both BCC and SCC arise at a young age, mandating aggressive early intervention and strict UV avoidance.

Occupational and Environmental Exposures

Chronic arsenic exposure (e.g., contaminated groundwater) and exposure to polycyclic aromatic hydrocarbons (PAHs) in certain industrial settings increase SCC risk, often presenting on the palms, soles, or dorsal hands. Recognition of these etiologies prompts targeted screening of at‑risk workers.

Follow‑Up and Surveillance Protocols

Given the high recurrence rates of NMSC—particularly for high‑risk SCC—structured post‑treatment surveillance is critical. A pragmatic schedule includes:

• First Year: Clinical skin examination every 3–4 months.
• Years 2–5: Semi‑annual visits, with earlier review if margins were close or perineural invasion was present.
• Beyond 5 Years: Annual examinations, with patient‑initiated visits for any new or changing lesions.

Adjunctive imaging (e.g., ultrasound of regional lymph nodes) is reserved for cases with clinically suspicious nodal disease or perineural spread. Documentation of lesion maps and photographic records enhances longitudinal assessment.

Emerging Research and Future Directions

The therapeutic landscape for BCC and SCC continues to evolve. Notable advances include:

• Combination Immunotherapy – Early-phase trials pairing PD‑1 inhibitors with CTLA‑4 blockade show synergistic activity in advanced SCC.
• Topical Hedgehog Inhibitors – Formulations designed for superficial BCC aim to reduce systemic exposure while maintaining efficacy.
• Molecular Profiling – Next‑generation sequencing of NMSC specimens is uncovering actionable mutations beyond the classic PTCH1/SMO and TP53 pathways, opening avenues for personalized targeted therapy.
• Artificial Intelligence (AI) in Dermoscopic Imaging – While not a substitute for histopathology, AI algorithms are being refined to triage suspicious lesions, potentially expediting referral for high‑risk BCC and SCC.

Patient Education and Shared Decision‑Making

Effective communication empowers patients to participate actively in their care. Key discussion points include:

• The rationale for choosing a particular treatment modality (e.g., cure rates, functional considerations, cosmetic outcomes).
• Expected postoperative course, wound care, and signs of recurrence that warrant prompt evaluation.
• The importance of adherence to follow‑up schedules, especially for individuals with prior high‑risk lesions or immunosuppression.

Providing written summaries, visual aids, and clear contact pathways enhances understanding and reduces anxiety.

In summary, basal cell carcinoma and squamous cell carcinoma dominate the spectrum of non‑melanoma skin cancers, each with distinct molecular drivers, clinical behavior, and therapeutic algorithms. Mastery of their nuances enables clinicians to deliver precise, evidence‑based care within preventive screening programs, while informed patients can navigate treatment decisions with confidence.