TOPLINE

Among 510 patients with cutaneous squamous cell carcinoma (CSCC) who developed metastasis during follow-up in Netherlands, 46% initially had low-stage American Joint Committee on Cancer eighth edition (AJCC8) T1/T2 tumours. Even among adequately treated cases, 47% of metastatic events arose from initial AJCC8 T1/T2 primary tumours.

METHODOLOGY

• Researchers identified 668 patients with metastatic CSCC (skin, regional lymph node, and/or distant metastasis) from the Dutch Keratinocyte Cancer Collaborative who were diagnosed from January 2021 to June 2024.
• Overall, 510 patients developed metastasis during a median follow-up of 2.22 years, whereas 158 had metastasis at baseline; patient, tumour, and treatment characteristics for primary CSCC were manually recorded by registrars from the Netherlands Cancer Registry.
• AJCC8 and Brigham and Women's Hospital (BWH) stages were calculated using available risk factors. Adequate treatment was defined as complete surgical removal with negative margins, including standard excision or margin-controlled surgery, or adjuvant radiotherapy after positive or uncertain margins.
• Disease progression, including recurrences and regional and distant metastases, until May 2025 was registered; the researchers analysed the proportion of metastatic cases arising from low-stage primary tumours and treatment completeness.

TAKEAWAY

• Among patients who developed metastasis during follow-up, 46% (236/510) had a low-stage AJCC8 T1/T2 primary tumour, and 61% had a BWH T1/T2a tumour. The larger number of T1 tumours that later metastasised likely reflected their greater frequency at baseline.
• The majority of primary CSCCs were managed surgically (500/510; 98%), and 384 of 500 cases (77%) had complete excision; among tumours with incomplete excision or unknown margins, only 21 received additional radiotherapy, whereas 95 of 116 (82%) received no further treatment.
• Even with adequate treatment, 47% (190/405) of metastatic events developed from an initial AJCC8 T1/T2 primary tumour; in the subgroup of directly completely excised tumours, 58% (150/258) still had metastasis from T1/T2 CSCC.
• Similar patterns were seen with BWH T1/T2a staging. The findings indicated that intrinsic tumour biology, not only incomplete treatment, drove much of the metastatic burden.

IN PRACTICE

"DKCC [Dutch Keratinocyte Cancer Collaborative] data show that AJCC8 T1/T2 CSCC tumours contribute to almost half the metastatic pool, even when adequately treated. This indicates metastatic burden is primarily driven by intrinsic biological risk missed by current staging rather than treatment failure," the authors of the study wrote.

SOURCE

The study was led by Loes M. Hollestein, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, Netherlands. It was published online on July 22, 2026, in the Journal of the European Academy of Dermatology & Venereology.

LIMITATIONS

The study relied on registry-based data, which may have had residual misclassification. Current staging also missed important prognostic factors such as differentiation grade and lymphovascular invasion, and changing patient-level factors including immunosuppression may have affected the metastatic risk.

DISCLOSURES

This study was funded by Sanofi Genzyme and Regeneron. Some authors disclosed serving as advisory board members and having other ties with various sources. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.