What is the natural course of squamous cell skin cancer if left untreated?

Natural Course of Squamous Cell Skin Cancer

If left untreated, cutaneous squamous cell carcinoma (cSCC) will persist as a chronic lesion with potential for local invasion, perineural spread, regional lymph node metastasis, and distant metastasis, with mortality rates exceeding 70% once metastatic disease develops. 1, 2

Progression Patterns and Timeline

Local Behavior

• Most cSCC lesions persist and grow progressively if untreated, presenting initially as painless plaque-like or verrucous tumors that can ultimately progress to large, necrotic, and infected masses 1
• Unlike actinic keratoses (precursor lesions), established invasive cSCC rarely undergoes spontaneous regression 3
• Local invasion extends through the dermis into subcutaneous fat and deeper structures, with depth of invasion >2 mm marking a critical threshold for high-risk behavior 3, 1

Perineural Involvement

• Perineural invasion occurs in a subset of untreated tumors, manifesting clinically as pain, burning, anesthesia, paresthesia, facial paralysis, diplopia, or blurred vision depending on nerve involvement 3
• This complication significantly worsens prognosis and requires aggressive multimodal treatment when it develops 3

Metastatic Progression

• Regional lymph node metastasis represents the most common route of spread, with 70-80% of recurrences and metastases developing within 2 years of initial tumor appearance 3
• 95% of metastases are detected within 5 years if the tumor remains untreated or inadequately treated 3
• Once regional nodal involvement occurs, the risk of mortality increases dramatically, with disease-specific survival dropping to approximately 40% at 5 years even with aggressive treatment 3

Mortality Risk

• Metastatic cSCC carries a mortality rate exceeding 70% across multiple large studies, making it a lethal disease once spread occurs 1, 2
• Death results from uncontrolled locoregional disease or distant organ metastasis 2

Risk Factors Accelerating Progression

High-Risk Tumor Characteristics

• Tumors >2 cm in diameter, poorly differentiated histology, and invasion beyond 4 mm (Clark level IV/V) significantly increase metastatic risk 3, 1
• High-risk anatomic locations include the ear, lip, temple, genitalia, and areas of prior radiation or chronic scarring 3, 1
• Rapidly growing tumors represent an ominous clinical sign associated with aggressive behavior and increased mortality 3
• Desmoplastic, adenosquamous, and adenoid (acantholytic) histologic subtypes carry higher metastatic potential 3

Patient-Related Factors

• Immunosuppression dramatically accelerates progression, particularly in solid organ transplant recipients who develop more aggressive tumors with higher metastatic rates 3, 1
• Advanced age and previous history of skin cancer increase the likelihood of progression 3
• Male gender and age >75 years are associated with higher rates of metastatic disease 1

Geographic Distribution of Metastases

• Regional lymph nodes are the first site of metastasis in most cases, with parotid involvement representing a particularly poor prognostic factor for head and neck tumors 3
• Distant metastasis can occur to any organ once hematogenous spread develops 1

Clinical Presentation Evolution

• Initial lesions may be subtle, but untreated cSCC progresses to obvious clinical disease with ulceration, bleeding, and secondary infection 1
• Lymphadenopathy develops as nodal metastases occur, which may be the first sign prompting medical attention in neglected cases 1

Critical Timeframes

• The first 2 years represent the highest risk period for recurrence and metastasis, with 70-80% of adverse events occurring during this window 3
• Five-year surveillance captures 95% of metastatic events, though late recurrences beyond 5 years can still occur 3

Common Pitfalls in Understanding Natural History

• Do not assume small or well-differentiated tumors are safe if left untreated—multiple studies confirm that even tumors <2 cm and well-differentiated histology can metastasize 2
• Do not underestimate the mortality risk once metastasis occurs—this is not a benign disease in its advanced stages, with >70% mortality despite treatment 1, 2
• Recognize that cSCC behaves fundamentally differently from basal cell carcinoma, which rarely metastasizes, whereas cSCC has significant metastatic potential 3