Advanced Squamous Cell Carcinoma: Progression and Treatment

Squamous cell carcinoma (SCC) is a common skin and mucosal cancer that becomes significantly harder to treat in advanced stages. Once it spreads beyond localized lesions, it can invade deeper tissues, lymph nodes, and distant organs, leading to poor outcomes if not managed effectively.

Advancements in molecular profiling, immunotherapy, and targeted treatments have expanded options for patients. Understanding tumor evolution and its interaction with the surrounding environment is key to improving diagnostics and therapies.

Risk Factors And Etiology

Advanced SCC develops due to environmental exposures, genetic predispositions, and cellular alterations that drive malignancy. Chronic ultraviolet (UV) radiation exposure is a major risk factor for cutaneous SCC. Repeated UV-induced DNA damage leads to mutations in tumor suppressor genes like TP53, impairing growth regulation and repair. This damage, if unrepaired, contributes to genomic instability and uncontrolled proliferation.

Beyond UV radiation, chemical carcinogens influence SCC in mucosal tissues such as the oropharynx, esophagus, and lungs. Tobacco smoke contains polycyclic aromatic hydrocarbons and nitrosamines, which induce DNA mutations. Alcohol enhances mucosal absorption of carcinogens and generates acetaldehyde, a metabolite that causes DNA cross-linking and chromosomal damage. The combined effect of tobacco and alcohol is particularly evident in head and neck SCC.

Human papillomavirus (HPV) infection is a well-established cause of oropharyngeal SCC. High-risk subtypes like HPV-16 and HPV-18 integrate into the host genome and express viral oncoproteins E6 and E7, which inactivate tumor suppressors p53 and pRb. This leads to unchecked cell cycle progression and resistance to apoptosis. HPV-driven SCCs often have distinct molecular profiles and respond differently to treatment, highlighting the need for precise diagnosis.

Chronic inflammation and immunosuppression also contribute to SCC, particularly in individuals with long-standing wounds, burns, or inflammatory conditions like lichen planus or discoid lupus erythematosus. Persistent tissue damage creates a microenvironment rich in pro-inflammatory cytokines and reactive oxygen species, which promote tumorigenesis. Immunosuppressed individuals, such as organ transplant recipients and those with HIV/AIDS, face a heightened risk due to reduced immune surveillance.

Tumor Progression And Staging

SCC advances through histopathological and molecular changes that drive aggressive behavior. It begins with dysplastic keratinocytes exhibiting abnormal proliferation and architectural disorganization. Precancerous lesions, such as actinic keratoses or carcinoma in situ, remain confined to the epithelium. Over time, accumulated genetic alterations disrupt cell cycle regulation, reduce adhesion molecule expression like E-cadherin, and activate invasion-promoting pathways.

Once SCC breaches the basement membrane, it becomes invasive, infiltrating the dermis or deeper mucosal tissues. Tumor cells upregulate matrix metalloproteinases (MMPs), enabling local spread. Perineural invasion, a hallmark of aggressive SCC, can cause pain, sensory deficits, and higher recurrence risk. Tumors deeper than 2 mm or larger than 6 mm in diameter have an increased likelihood of metastasis.

As SCC progresses, lymphatic spread becomes a defining feature. Cervical, axillary, or inguinal lymph node involvement is common in mucosal SCCs of the head and neck, esophagus, and anogenital regions. Sentinel lymph node biopsy (SLNB) assesses nodal involvement, with positive findings correlating with worse prognoses. Extracapsular spread, where tumor cells extend beyond the lymph node capsule, complicates treatment and increases systemic dissemination risk.

Distant metastasis, the most advanced stage, occurs when tumor cells enter the bloodstream and colonize distant organs like the lungs, liver, or bones. Unlike basal cell carcinoma, which rarely metastasizes, SCC has a well-documented capacity for systemic spread, particularly in immunocompromised individuals. Pulmonary metastases are the most frequent distant site, often presenting as multiple nodular lesions on imaging. Prognosis at this stage is poor, with five-year survival rates dropping significantly.

Molecular Features

The molecular landscape of advanced SCC is shaped by genetic mutations, epigenetic changes, and dysregulated signaling pathways. TP53 mutations are among the most common, disrupting DNA damage repair and apoptosis. CDKN2A mutations inactivate p16INK4a, a regulator of the G1-S cell cycle transition, promoting unchecked proliferation.

Oncogenic pathways also become hyperactivated. The epidermal growth factor receptor (EGFR) pathway is frequently upregulated, either through gene amplification or activating mutations, leading to sustained mitogenic signaling. This is particularly pronounced in SCCs of the lung and head and neck, where EGFR-targeted therapies have shown mixed success. The PI3K/AKT/mTOR pathway further enhances tumor survival by promoting metabolic adaptability and resistance to apoptosis. PIK3CA mutations, which activate PI3K, have been identified in a subset of SCCs.

Epigenetic modifications influence SCC by altering gene expression without changing DNA sequences. Promoter hypermethylation of tumor suppressors like RASSF1A and MLH1 leads to transcriptional silencing, impairing cell cycle control and DNA repair. Histone modifications, particularly increased acetylation at oncogene loci, create an open chromatin state that promotes invasion and metastasis. These changes contribute to tumor heterogeneity and therapy resistance.

Tumor Microenvironment

The tumor microenvironment (TME) plays a crucial role in SCC progression. Cancer-associated fibroblasts (CAFs) secrete growth factors like transforming growth factor-beta (TGF-β) and fibroblast growth factor (FGF), promoting tumor proliferation and invasion. CAFs also remodel the extracellular matrix, increasing collagen deposition and cross-linking, which enhances resistance to therapy. This desmoplastic reaction creates a physical barrier that limits drug penetration.

Hypoxia, a hallmark of the SCC microenvironment, arises as tumors outgrow their vascular supply. Hypoxia-inducible factors (HIFs) activate genes involved in angiogenesis, glucose metabolism, and epithelial-mesenchymal transition (EMT). Vascular endothelial growth factor (VEGF) promotes new blood vessel formation, but these vessels are often disorganized and inefficient, exacerbating hypoxic stress. This fuels tumor heterogeneity, as hypoxic cells develop more aggressive traits and greater resistance to apoptosis.

Diagnostic Approaches

Diagnosing advanced SCC requires histopathological evaluation, imaging, and molecular profiling. Clinical assessment includes examining lesion size, depth, and ulceration, which correlate with aggressiveness. Dermoscopy aids in distinguishing SCC from benign lesions, but biopsy remains essential. Hematoxylin and eosin (H&E) staining reveals cellular atypia, keratin pearl formation, and invasion depth. Immunohistochemical markers like p63 and cytokeratin 5/6 confirm squamous lineage, particularly in poorly differentiated cases.

Imaging techniques assess disease extent and metastasis. High-resolution ultrasound evaluates tumor thickness and perineural invasion in cutaneous SCC. Computed tomography (CT) and magnetic resonance imaging (MRI) provide detailed views of deep tissue involvement and lymph node metastases, with MRI offering better soft tissue contrast. Positron emission tomography (PET)-CT enhances staging accuracy by detecting distant metastases. Molecular profiling, including next-generation sequencing, identifies actionable mutations like EGFR amplifications or PIK3CA alterations, guiding targeted therapy selection. These tools help clinicians tailor treatment strategies.

Therapeutic Classes

Treatment for advanced SCC depends on tumor location, molecular characteristics, and disease extent, often requiring multimodal strategies.

Surgical and Radiation Therapy

Surgical resection is the preferred treatment for localized but advanced SCC when clear margins can be achieved. Wide local excision or Mohs micrographic surgery is used for cutaneous SCC to minimize recurrence while preserving healthy tissue. When surgery is not feasible, radiation therapy is a critical alternative. Intensity-modulated radiation therapy (IMRT) precisely targets tumor cells while sparing normal structures. Postoperative radiation is recommended for patients with positive margins, perineural invasion, or extracapsular lymph node spread to improve local control.

Systemic Therapies

For metastatic or unresectable SCC, systemic therapies play a key role. Platinum-based chemotherapy, including cisplatin and carboplatin, interferes with DNA replication and is often combined with 5-fluorouracil (5-FU) or taxanes for greater efficacy. However, immune checkpoint inhibitors have transformed treatment. Anti-PD-1 antibodies like cemiplimab and pembrolizumab enhance immune recognition of tumors, leading to durable responses in some patients. Targeted therapies, such as EGFR inhibitors like cetuximab, provide additional options for SCCs driven by EGFR signaling, though effectiveness varies. Ongoing research focuses on combination regimens to maximize treatment benefits while minimizing resistance.