Highlights
– The DKCC is the first nationwide longitudinal real-world registry of advanced cutaneous squamous cell carcinoma (CSCC), capturing locally advanced, recurrent, and metastatic disease across the Netherlands.
– Approximately 8.0% (95% CI 7.4–8.6) of all diagnosed CSCC in 2021 were classified as locally advanced; in 2021–2022, 920 advanced CSCC patients entered the DKCC cohort.
– Median time to recurrence or metastasis after AJCC T3/T4 primary CSCC was short (recurrence: 11 months [IQR 6–19]; metastasis: 9 months [IQR 6–17]), supporting intensified early follow‑up and rapid treatment pathways.
– A non‑negligible proportion of metastatic episodes (6% of skin-only metastases to 20% of distant metastases) did not receive treatment, highlighting potential gaps in access, patient selection, or goals-of-care planning.
Background / Disease burden
Cutaneous squamous cell carcinoma (CSCC) is one of the most commonly diagnosed cancers in fair-skinned populations. Most CSCCs are cured by local excision or topical/local therapies, but a minority progress to locally advanced, recurrent, or metastatic disease — phenotypes associated with substantial morbidity, complex multidisciplinary care, and higher mortality. Despite its frequency, high-quality, population-level longitudinal data on advanced CSCC outcomes, treatment patterns, and timing of progression are limited. Such data are crucial for service planning, guideline development, and benchmarking the real-world impact of emerging systemic therapies (notably PD‑1 inhibitors) in routine practice.
Study design
The Dutch Keratinocyte Cancer Collaborative (DKCC) is a nationwide observational database designed to capture longitudinal real-world data on advanced CSCC in the Netherlands. Advanced CSCC cases were identified using the nationwide pathology database (PALGA) with a validated algorithm. From these detections, the Netherlands Cancer Registry performed manual registration for a selection of 500 patients per year, including all metastatic cases, all recurrences, and a random sample of locally advanced CSCC cases. Registered variables included tumour characteristics, diagnostic procedures, disease progression, and treatments. Data linkage to the Netherlands Organ Transplant Registry allowed identification of immunosuppressed patients; municipal records provided vital status. The present report describes case ascertainment and outcomes for cases diagnosed in the 2021–2022 period and provides prevalence estimates for locally advanced CSCC in 2021.
Key findings
The DKCC investigators provide several clinically relevant results with implications for follow-up intensity, resource allocation, and therapeutic decision-making.
Prevalence and cohort size
Using the PALGA-based algorithm and registry linkage, the authors estimated that 8.0% (1846/23,065; 95% CI 7.4–8.6) of all CSCC diagnosed in 2021 represented locally advanced disease. Between 2021 and 2022, 920 patients with advanced CSCC were registered in the DKCC database, reflecting the real-world throughput of advanced cases nationwide.
Progression patterns and timing
A notable proportion of metastatic patients had an antecedent recurrence before metastasizing: 13/51 (25.5%) of patients with skin metastasis, 63/296 (21.3%) with regional lymph node metastasis, and 20/72 (27.8%) with distant metastasis had prior recurrent CSCC. For AJCC T3/T4 primary tumours, the median time to recurrence was 11 months (IQR 6–19), and the median time to metastasis was 9 months (IQR 6–17). These medians underscore that the highest risk period for progression is within the first year after diagnosis of high-stage primary lesions.
Treatment patterns and unmet needs
Treatment delivery for metastatic episodes varied by metastatic site. For skin-only metastasis, 6% (4/67) of episodes received no treatment; for regional nodal metastasis the proportion unmanaged was not specified here; for distant metastases 20% (17/83) of episodes had no treatment recorded. These untreated episodes may reflect patient preference for palliative care, comorbidity, limited access to systemic therapy, late presentation, or documentation gaps—each with different implications for clinical practice and health services.
Strengths of the DKCC dataset
The DKCC combines nationwide pathology surveillance (PALGA) with focused manual abstraction to enrich clinical detail for advanced disease. Linkage to transplant and municipal registries improves case-level characterization (immunosuppression status, survival). The approach balances efficiency (algorithmic case-finding) with depth (manual chart abstraction for advanced cases), producing a pragmatic template for other jurisdictions seeking to build registries of rare but high-impact cancer outcomes.
Expert commentary
The DKCC fills an important evidence gap for advanced CSCC. Several points merit emphasis for practicing clinicians, health systems leaders, and researchers.
Clinical implications
First, the high percentage of locally advanced CSCC among all CSCC diagnoses (≈8%) indicates a substantial downstream demand for multidisciplinary oncology services, reconstructive surgery, imaging, and systemic therapy. Health systems should anticipate this burden when planning pathways and resource allocation.
Second, the short median time to recurrence and metastasis after AJCC T3/T4 primaries (9–11 months) supports a policy of closer surveillance during the first 12–18 months after diagnosis of high-stage tumours. This interval is when clinicians should have a low threshold for diagnostic imaging and multidisciplinary review if new signs or symptoms appear.
Third, the observation that a meaningful minority of metastatic episodes were untreated raises questions about treatment accessibility, eligibility (performance status, comorbidities), and patient goals. The advent of PD‑1 inhibitors (e.g., cemiplimab) has transformed outcomes for many patients with advanced CSCC; real-world registries like DKCC are needed to quantify uptake, real-world effectiveness, and barriers to therapy in routine practice.
Registry methodology and generalizability
DKCC’s hybrid approach—automated detection followed by manual verification and abstraction for advanced cases—offers a scalable model that preserves detail for clinically important subsets without the cost of full population-level abstraction. Other countries could adapt this model using their national pathology or cancer registry infrastructures. However, generalizability may be limited by differences in healthcare organization, referral patterns, and population demographics; similarly, sampling only 500 patients/year for manual abstraction may miss granular temporal trends or less common subgroups unless sampling strategies are periodically reviewed.
Limitations and potential biases
Real-world registry data are subject to incomplete documentation, variable diagnostic workup intensity, and selection bias from the sampling strategy (complete capture of metastatic/recurrent cases but sampled locally advanced cases). Funding by industry (Sanofi Genzyme/Regeneron) is transparently reported; investigators and readers should consider potential influences on study design or reporting, although the dataset originates from national registries and linked administrative sources, mitigating some risk of sponsor-driven data selection.
Conclusion / Summary
The DKCC provides the first nationwide, longitudinal window into advanced CSCC in a high-income health system. Key clinical takeaways are that locally advanced disease represents a meaningful proportion of all CSCC, the highest risk for recurrence and metastasis occurs early (median 9–11 months for AJCC T3/T4 tumours), and a noteworthy proportion of metastatic episodes receive no oncologic treatment. For clinicians, these findings justify intensified early follow-up for high-stage primaries, prompt multidisciplinary assessment of recurrences, and proactive planning for systemic therapy access. For health policymakers, the data quantify service needs and endorse registry-based surveillance as a pragmatic route to continuous quality improvement.
Research and practice gaps
Important unanswered questions include the reasons for non-treatment of metastatic episodes, outcomes stratified by immunosuppression status (transplant recipients), real-world effectiveness and safety of PD‑1 inhibitors in registry cohorts, cost and quality-of-life outcomes, and international comparability of advanced-CSCC incidence. Future DKCC analyses could address these gaps by reporting survival outcomes, treatment-specific responses, and subgroup analyses for immunosuppressed patients.
Funding and clinicaltrials.gov
The DKCC project was funded by Sanofi Genzyme/Regeneron. No specific clinicaltrials.gov registration is reported for this registry study in the source article.
References
1. Hollestein LM, Eggermont CJ, Louwman MWJ, et al. Longitudinal data on advanced cutaneous squamous cell carcinoma from the Dutch Keratinocyte Cancer Collaborative (DKCC): a nationwide real-world database study. Lancet Reg Health Eur. 2025 Oct 18;59:101501. doi: 10.1016/j.lanepe.2025.101501. PMID: 41158417; PMCID: PMC12556279.
2. Migden MR, Rischin D, Schmults CD, et al. PD‑1 blockade with cemiplimab in advanced cutaneous squamous‑cell carcinoma. N Engl J Med. 2018;379(4):341–351. doi:10.1056/NEJMoa1805131.
3. Amin MB, Edge SB, Greene FL, et al., editors. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.