Risk factors determining prognosis of cutaneous SCC (Brantsch)
ForPrimary cutaneous SCC, resected to clear 3D-histology margins, no adjuvant RT
TL;DRNo metastases in tumours ≤2.0 mm thick; >6.0 mm metastasized in 14/90 (16%); desmoplasia drove local recurrence (HR 16.11) after margin-controlled resection.
Desmoplasia, which here included every case of perineural or perivascular invasion, carried local recurrence of 12/51 (24%) vs 8/564 (1%) despite tumour-free 3D-histology margins and no adjuvant RT. That is an RT-naive surgical baseline. It places the adjuvant RT question in desmoplastic/PNI or >6.0 mm tumours (LR 11/90, 12%), not in clear-margin thin SCC.
In resected cSCC with clear margins that is ≤2.0 mm thick and non-desmoplastic, this supports a very low expectation of metastasis or recurrence. It does not address whether adjuvant RT changes risk in desmoplastic or >6.0 mm tumours, because no pt received RT.
Desmoplasia, which included all PNI, carried LR of 12/51 (24%) vs 8/564 (1%) after clear margins with no adjuvant RT. This RT-naive baseline sets where adjuvant RT is worth weighing: desmoplastic/PNI or >6.0 mm tumours. The cohort cannot show that RT lowers that risk.
Clear 3D-histology margins with 2-10 mm safety margins held overall LR to 20 of 615 (3%), yet desmoplastic tumours still recurred locally in 24%. The first metastatic site was always a regional LN, which is why the authors raise SLNB and nodal ultrasound for high-risk pts.
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Prospective single-centre observational cohort following STROBE. Pts were resected between 1990 and 2001, follow-up closed Dec 2005, median f/u 43 mo. Cox models used forward selection, with a 200/415 learning-validation split for internal validation only.
615 assessable white pts with primary cutaneous SCC at any body site, median age 73, 5% immunosuppressed. Excluded: SCC in situ, keratoacanthoma, collision tumours, and recurrent SCC treated elsewhere.
No pt received adjuvant RT. Every resection reached tumour-free margins by 3D-histology, with re-excision as needed, so outcomes reflect surgery alone.
The source states the primary endpoints as time to metastasis and time to local recurrence, each measured from diagnosis of the primary. Seven candidate predictors were chosen a priori.
26 (4%) metastases and 20 (3%) local recurrences. No tumour ≤2.0 mm metastasized. The thinnest tumour that metastasized was 2.8 mm thick.
| Thickness | Metastasis | Local recurrence |
|---|---|---|
| ≤2.0 mm (n=207) | 0 | 1 |
| 2.1-6.0 mm (n=318) | 12 (4%) | 8 (3%) |
| >6.0 mm (n=90) | 14 (16%) | 11 (12%) |
| Endpoint | Factor | HR (95% CI) | p |
|---|---|---|---|
| Metastasis | Tumour thickness | 4.79 (2.22-10.36) | <0.0001 |
| Metastasis | Immunosuppression | 4.32 (1.62-11.52) | 0.0035 |
| Metastasis | Ear location | 3.61 (1.51-8.67) | 0.0040 |
| Metastasis | Horizontal size | 2.22 (1.18-4.15) | 0.0128 |
| Local recurrence | Tumour thickness | 6.03 (2.71-13.43) | <0.0001 |
| Local recurrence | Desmoplasia | 16.11 (6.57-39.49) | <0.0001 |
Clayman and colleagues reported LR in 12% (15 of 130) of primary SCC. Margin-controlled resection here gave 3% (20 of 615). The authors cite an Australian series of 266 pts with nodal disease that also supports tumour thickness over horizontal size.
Follow-up after the early period relied partly on mailed questionnaires to treating physicians. New field-cancerization SCC can mimic local recurrence. University referral may have enriched for poorly differentiated tumours.
Thickness, immunosuppression and desmoplasia outperformed Broders' grade and horizontal size as prognostic factors. The authors propose thickness-based T1-T3 cutoffs (≤2.0, 2.1-6.0, >6.0 mm) with "d" and "i" modifiers. The study does not test whether any treatment changes the high-risk course.
Single-centre prognostic cohort, model selected by forward selection with events per predictor below 5. Validated only internally; no external cohort.
- Does adjuvant RT reduce LR in desmoplastic/PNI or >6.0 mm cSCC? recruiting Study of a Strategy Integrating Adjuvant Radiation Therapy Versus Strategy Based on Monitoring in the Treatment of Carcinomas Spinocellular With High Risk of Recurrence Phase 3n=266 · primary completion 2031-06 · phase 3 adjuvant RT vs surveillance, high-risk cSCC, DFS
- Role of SLNB in high-risk cSCC recruiting Sentinel Lymph Node Biopsy for Cutaneous Squamous Cell Carcinoma of the Head and Neck Phase NAn=94 · primary completion 2026-09 · SLNB occult nodal rate, cN0 T2-T4 H&N cSCC
- External validation of thickness cutoffs in larger cohorts
📚 Sources · 📄 1 paper
The longer read
This cohort is one of the main sources behind the idea that depth, rather than diameter or grade, organises risk in cutaneous SCC. Its strongest result is the simplest one. In 207 tumours ≤2.0 mm thick there were no metastases, and only one local recurrence. A negative stratum that clean, in an unselected referral population followed for a median of 43 months, is harder to explain away than any of the hazard ratios. It is also the result least affected by the model-building problems below, because it is a raw count rather than a fitted estimate. Since metastases clustered in the first year and none appeared after year 4, the follow-up was long enough for this stratum.
The multivariate models deserve less confidence than their p-values suggest. With 26 metastases and 20 local recurrences against seven candidate predictors, the events-per-variable ratio is below the threshold the authors themselves cite. Forward selection in that setting tends to overfit and to inflate the size of the effects it keeps. The desmoplasia HR of 16.11 for local recurrence, with an interval running from 6.57 to 39.49, should be read as showing a large direction of effect rather than a precise magnitude. The learning-validation split helps a little, but the two samples come from the same centre, the same pathologists and the same surgical technique. In the learning sample, the second factor selected for metastasis was poor differentiation, which then failed in the validation sample. That instability is the warning.
For a radiation oncologist, this is a natural-history cohort, not an RT study. Every pt was resected to tumour-free margins under 3D-histology, and nobody received adjuvant RT. So the 24% local recurrence in desmoplastic tumours is a recurrence rate after clear margins with no adjuvant treatment. That matters because desmoplasia here was defined to include every case of perineural or perivascular invasion, the same histology that commonly prompts discussion of post-op RT. The cohort identifies where adjuvant RT is worth considering. It cannot say whether RT closes that gap, and nothing in it informs dose, volume or elective nodal coverage. The finding that the first metastasis was always a regional node supports the authors' focus on nodal staging and ultrasound surveillance. That pattern is also the clinical basis for thinking about the regional basin in high-risk pts.
The main limit on generalising is the surgery. Margin-controlled excision with re-excision to clearance likely explains why overall local recurrence was 3%, against the 12% Clayman and colleagues reported. A practice using conventional excision with standard margin assessment should expect higher baseline recurrence, so these strata may understate the absolute risk elsewhere. The cohort was also entirely white and mostly immunocompetent. With only 31 immunosuppressed pts, the immunosuppression HR rests on a handful of events and says little about transplant recipients.
The result would be wrong in its details if an external cohort with adequate events found the 6.0 mm cutoff drifting or the desmoplasia effect shrinking a long way. The ≤2.0 mm no-risk stratum is the part most likely to hold.