EADO classification of difficult‐to‐treat cutaneous squamous cell carcinoma in transplant recipients

Dear Editor,

Several staging systems exist for cutaneous squamous cell carcinoma (cSCC), yet none has universal uptake. We use the American Joint Committee on Cancer (AJCC‐8) staging system for reporting and treatment planning, and when histopathology permits, assign the Brigham and Women's Hospital (BWH) classification to isolate high‐risk disease. ¹ , ² Recent studies in high‐risk cSCC show that nodal status and host factors drive prognosis, refining risk stratification. ³ , ⁴ The European Association of Dermato‐Oncology (EADO) proposes a management‐oriented classification to identify difficult‐to‐treat (DTT) cSCC and guide tumour‐board decisions, mirroring its operational staging proposal for basal cell carcinoma. ⁵ , ⁶ Under this framework, easy‐to‐treat tumours can be managed with simple excision or radiotherapy and have no multiplicity, local advancement or nodal/visceral spread. ⁵

AJCC captures anatomical extent, while BWH refines primary‐tumour risk according to diameter, thickness, differentiation grade and perineural invasion, ¹ , ² whereas the EADO system translates stage and clinical context into management groups based on resectability, multiplicity and spread. An AJCC I limb tumour that is easily resectable is easy‐to‐treat; the same stage on the nasal ala or eyelid, requiring major reconstruction, qualifies as EADO Group 1, and AJCC I with multiple synchronous lesions as Group 2. Some AJCC III (T3N0M0) tumours fall into Group 3, AJCC III‐IVA with nodal disease into Group 4, and AJCC IVC into Group 5, making treatment difficulty explicit at anatomically challenging sites.

We retrospectively reviewed invasive cSCC in solid‐organ transplant recipients (SOTR) at a single tertiary centre (2010‐2025; 148 patients; 251 invasive cSCC; 742 patient‐years) and applied the EADO classification to identify and stratify DTT cases (Figure 1). We found 94 DTT tumours (37%) in 55 patients, and the EADO distribution was Group 1, 65%; Group 2, 10%; Group 3, 3%; Group 4, 16%; Group 5, 6%. Groups 1‐2 were mainly treated with excision (often with complex reconstruction), some Group 3 cases received radiotherapy, Group 4 combined lymphadenectomy and radiotherapy, with cemiplimab in selected patients, and Group 5 received systemic therapy. The proportion of DTT tumours did not differ by transplant type (p = 0.136).

FIGURE 1.

EADO case sheet illustrating a Group 1 difficult‐to‐treat (DTT) cutaneous squamous cell carcinoma (cSCC): An ulcerated T3N0M0 lesion with perineural invasion on the left pinna of a 77‐year‐old kidney transplant recipient (ECOG 0) receiving chronic immunosuppression and anticoagulation. DTT status is driven by advanced age, aggressive histology and the need for non‐organ‐sparing surgery with a high risk of aesthetic deformity and functional impairment. The patient also had a synchronous desmoplastic cSCC on the right temple (later metastatic), fulfilling criteria for Group 2; however, as this tumour is already classified as Group 1 under the EADO system, the case is counted as Group 1 and ‘multiple tumours’ is ticked on the EADO form. EADO, European Association of Dermato‐Oncology.

We created an alluvial map cross‐tabulating AJCC‐8 stage with EADO management groups (Figure 2). Most AJCC I tumours (n = 121) are easy‐to‐treat (108/121; 89%) with a small DTT subset in Group 1 (n = 10) and Group 2 (n = 3). AJCC II behaves similarly: 11/15 (73%) are easy‐to‐treat and 4 fall into Group 1. In AJCC III (n = 97), complexity increases: 47 tumours map to Group 1 and 38 remain easy‐to‐treat, with smaller numbers in Group 2 (n = 6), Group 3 (n = 3) and Group 4 (n = 3). Nodal disease maps almost entirely to Group 4, including all IVA (7/7) and IVB (2/2), whereas metastatic disease (AJCC IVC, n = 9) splits between Group 4 (n = 3) and Group 5 (n = 16).

FIGURE 2.

Alluvial diagram linking American Joint Committee on Cancer (AJCC)‐8 stage (left) to EADO management categories (right) in invasive cSCC (n = 251). Stream widths are proportional to tumour counts; colours denote AJCC‐8 stage. AJCC reflects anatomical extent, whereas EADO translates stage plus clinical context into treatment‐difficulty groups based on resectability, multiplicity and spread: Easy‐to‐treat, readily resectable; Group 1, technically challenging resection/reconstruction at critical sites (e.g. nasal ala/eyelid) despite low stage; Group 2, multiple synchronous tumours; Group 3, locally advanced without nodal/distant disease (subset of AJCC III, e.g. T3N0M0); Group 4, regional nodal disease (AJCC III‐IVA); Group 5, distant metastasis (AJCC IVC).

These findings highlight the burden of DTT tumours in SOTR, a setting where conventional surgery often entails functional or cosmetic morbidity, or is not feasible, and systemic immunotherapy may jeopardize graft survival. ⁷ Although case series describe clinical benefit from conventional intralesional therapies (methotrexate, 5‐fluorouracil, interferon‐α2b, bleomycin, electrochemotherapy) and emerging oncolytic virotherapy (T‐VEC) or intratumoural immunotherapy, ⁸ , ⁹ , ¹⁰ evidence is still limited. Dedicated trials are still needed to define optimal regimens that balance tumour control with graft tolerance in SOTR. In this context, developing effective intralesional treatment strategies and new systemic organ‐sparing approaches may add further value.

By systematically flagging DTT tumours, the EADO classification brings patients earlier to multidisciplinary teams, promotes organ‐sparing strategies and generates structured cohorts to evaluate new treatment modalities that minimize rejection risk. In summary, using EADO alongside AJCC and BWH improves management of DTT cSCC by making difficulty explicit and linking anatomical stage to management pathways, thereby complementing anatomical staging and potentially broadening intralesional options in difficult disease.

FUNDING INFORMATION

The authors have nothing to report.

CONFLICT OF INTEREST STATEMENT

None declared.

ETHICAL APPROVAL

Approved by the Vall d'Hebron University Hospital Ethics Committee (PR(AG)367/2020).

ETHICS STATEMENT

The patients in this manuscript have given written informed consent to the publication of their case details.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.