Highlights from the Literature 4
Association of Patient Risk Factors, Tumor Characteristics, and Treatment Modality with Poor Outcomes in Primary Cutaneous Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis
By Jeffrey F. Scott, MD, FACMS
With a topic as rich in new and evolving literature as poor outcomes in cutaneous squamous cell carcinoma (cSCC), a systematic review and meta-analysis is always refreshing for the busy Mohs surgeon. Zakhem at al. performed just such a contemporary and rigorous study investigating patient risk factors and tumor characteristics associated with poor treatment outcomes in cSCC.1
After identifying 5279 records through database searching, the authors analyzed 129 studies on poor outcomes in cSCC for their systematic review and meta-analysis and confirmed the association of established risk factors (e.g. invasion beyond subcutaneous fat, perineural invasion >0.1 mm, poor differentiation, desmoplastic stroma, lymphovascular invasion, immunosuppression) with poor patient outcomes. The team also began to define the influence of emerging risk factors (e.g. PD-L1 expression, EGFR expression, ulceration, tumor budding) that deserve additional study.
Additionally, the authors report that Mohs surgery was found to have the lowest proportion of poor outcomes among all treatment modalities for cSCC, further validating the use of Mohs surgery as first-line treatment for high-risk cSCC. Moreover, this is important because the data presented suggest that immunosuppression predicts poor outcomes similarly to several Mohs AUC features including aggressive tumor features and size >2 cm. Yet currently, Mohs surgery carries an uncertain AUC designation for immunosuppressed patients with smaller, (<1 cm) non-aggressive cSCC on area L sites (trunk/extremities). Might it be time to modify the Mohs AUC to indicate appropriateness of Mohs surgery for all cSCC in immunosuppressed patients regardless of anatomic site based on the totality of evidence?
This updated systematic review and meta-analysis has at least three important implications for the staging and prognostication of cSCC. First, immunosuppression, a critical patient risk factor that is not captured in our current staging systems (AJCC 8th edition or BWH), was found to be a significant risk factor for every poor outcome assessed (local recurrence, nodal metastasis, any metastasis, disease-specific death) except distant metastasis.2 Not including immunosuppression limits the scope of our current staging systems and the data even suggest that patients with different causes of immunosuppression may have different risk profiles. Second, a number of tumor characteristics identified as high-risk in this study are also lacking from our current staging systems, including desmoplastic stroma, lymphovascular invasion, and poor differentiation (lacking from AJCC 8th edition only), all of which were associated with poor outcomes similarly to perineural invasion.3 It may be time to re-investigate the incorporation of these histologic and architectural tumor characteristics into our staging systems. Finally, regarding tumor size, this study confirms that the most important risk stratification occurs at the 2 cm size threshold, as found in the BWH staging system. In contrast, the AJCC 8th Edition designates 2-4 cm tumors as T2 and those >4 cm as T3.3 The utility of the >4 cm T3 designation used by the AJCC 8th Edition may need to be re-examined given the data presented in this current study.
In summary, this updated systematic review and meta-analysis of risk factors associated with poor outcomes in cSCC reveals that several risk factors, including immunosuppression, LVI, and desmoplastic stroma, were all consistently associated with poor outcomes despite being absent from current staging systems. As we continue to refine our staging systems, these tumor and patient characteristics should be strongly considered for inclusion for more accurate risk stratification and to aid with developing work-up, treatment, and surveillance protocols.
References:
- Zakhem GA, Pulavarty AN, Carucci J, et al. Association of patient risk factors, tumor characteristics, and treatment modality with poor outcomes in primary cutaneous squamous cell carcinoma: A systematic review and meta-analysis. JAMA Dermatol. 2023;159(2):160-171.
- Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013;149(4):402-410.
- Amin MB, Edge SB, Frederick L, et al. The AJCC Cancer Staging Manual, 8th Edition. Springer; 2017.