Table 1.

Core risk factors for cutaneous squamous cell carcinoma risk assessment

Risk factor	Prognostic value	Evidence	Caveats to clinical utility
Perineural invasion	Consistent evidence supports PNI of large caliber (≥ 0.1 mm) or named nerves being a poor prognostic factor. However, minimal or small caliber nerve PNI has limited support. Evidence is inconsistent as to the independent prognostic value in multivariate analysis, likely due to co-occurrence of high-risk factors	Presence is significant risk factor for:  - LR [2, 20, 21, 30]  - NM [2, 19, 22–25]  - DSD [2, 19, 21, 26, 31] Large caliber is significant risk factor for:  - LR [18, 29]  - NM [18, 28, 29]  - DSD [18, 28, 29] Small caliber with co-factors is a significant risk factor for all outcomes [28] Presence is not a significant risk factor for: - LR [35–37] - NM [21, 35–37] - DSD [35, 36]	- Occurrence is rare - Often not measurable at biopsy - Caliber measurement recently recognized by AJCC-8 and BWH, delay in - incorporation into studies
Differentiation	Consistent and well-documented evidence supports poor histological differentiation as a prognostic factor and independent predictor of outcomes. Moderate differentiation is also often associated with poor outcomes, albeit with less supporting evidence	Poor differentiation significant predictor for:  - LR [2, 19, 21, 42, 43]  - NM [2, 19, 21, 22, 24, 25, 39–41, 45]  - DSD [19, 21, 35, 44] Moderate differentiation significant predictor for:  - NM [22, 25]	- Histopathologic discordance is wide-spread - Tumor heterogeneity can complicate consistency in reporting
Depth of invasion	Consistent evidence supports depth of invasion, defined as beyond the subcutaneous fat, as an independent prognostic factor. Invasion depth of > 6 mm is consistently seen to result in poor outcomes, while intermediate depths (2–5.99 mm) have also shown prognostic relevance	> 6 mm significant predictor for:  - LR [2] (> 2 mm also), [35] (> 2 mm also)  - NM [2] (> 2 mm also), [22] (> 2 mm also)  - DSD [14] Beyond subcutaneous fat significant predictor for:  - LR [2, 36]  - NM [2, 19, 26, 36]  - DSD [2, 19, 26] Beyond subcutaneous fat not significant predictor for:  - LR [19]  - DSD [36] > 6 mm not significant predictor for:  - DSD [2]	- Absence of uniform reporting and a standardized measure contributes to data heterogeneity - Breslow depth not routinely reported due to high number of cases making detailed pathology difficult [49] and that the stratum granulosum skin layer is often lost
Location/size	The most recent and substantial evidence support that tumors > 2 cm in diameter are at higher risk for poor outcomes. A majority of tumors are located in the head & neck area and have shown more aggressive behavior when compared to other body sites. Tumors located on the ear and lip are most commonly associated with the highest risk (thought to be due to lack of subcutaneous fat at these locations, allowing for greater potential for deep invasion), yet inconsistent data has caused dispute	Size (measured as a continuous variable) is significant predictor for:  - LR [37, 50]  > 2 cm is significant predictor for:  - LR [51]  - NM [2, 24, 25]  - DSD [2, 14, 19, 31] > 2 cm is not significant:  - NM [22, 40, 44] Lip is a high-risk location for:  - NM [2, 12, 19, 22, 25]  - DSD [2, 19] Lip is not a high-risk location for:  - LR [2, 21, 37, 51]  - NM [21, 52]  - DSD [14, 21] Ear is a high-risk location for:  - LR [21]  - NM [2, 19, 21, 22, 25, 37, 52, 54]  - DSD [2, 19, 21] Ear is not a high-risk location for:  - LR [2, 51]  - DSD [14] Lower and upper extremities are not a high-risk location for:  - NM [55]  - DSD 55	- Once metastasis is present, size measurement is not an effective prognostic tool - Some debate of ≥ 2 cm as definitive size for upstaging - Analyses of size measured in entire cohort, not specific to body location

AJCC-8 American Joint Committee on Cancer staging manual, 8th edition, BWH Brigham and Women’s Hospital staging, DSD disease-specific death, LR local recurrence, NM nodal metastasis, PNI perineural invasion