Photo Credit: Md Saiful Islam Khan

A recent review showed that tumor budding was consistently associated with a higher risk for nodal metastases in patients with cutaneous squamous cell carcinoma.

Tumor budding (TB) shows promise as an independent risk factor for nodal metastasis in patients with cutaneous squamous cell carcinoma (cSCC), according to a systematic review published in Clinical and Experimental Dermatology.

cSCC is the second most common cancer globally, yet precise staging systems to stratify its risk remain inadequate, wrote Pedro Gil-Pallares and colleagues.

“A recent study, which included a large dataset of metastatic and non-metastatic cSCC, compared the ability of four staging systems to predict cSCC behavior, concluding that further improvement and refining of current cSCC staging is essential,” Gil-Pallares and the coauthors said.

TB is associated with poorer prognosis in diseases such as colorectal cancer and oral SCC. The authors explained that ongoing studies aim to clarify TB assessment’s role in other cancers, including cSCC.

“Although most authors use a TB assessment method similar to that utilized for colorectal cancer, there is still no formal consensus on recommendations for TB reporting, and it is not currently included in the cSCC staging systems,” the researchers said. “With this systematic review and a meta-analysis, we aimed to provide a comprehensive evaluation of the current evidence on the prognostic significance of TB in predicting NM in cSCC and, therefore, high-risk cSCC.”

High TB Linked to Metastases

To find relevant articles on the prognostic role of TB in cSCC, two reviewers independently searched PubMed, Web of Science, Embase, and Cochrane databases for English or Spanish language articles published up to October 1, 2023. The reviewers screened titles and abstracts using specific keywords and included studies that examined the association between TB and nodal metastasis in histologically confirmed, invasive cSCC.

The researchers only included prospective or retrospective studies meeting these criteria, excluding non-comparative studies, letters, and posters.

Out of 117 screened articles, only six were included in the review. These six studies were retrospective, comprised of 793 patients, and were conducted across various countries, including Spain, Japan, the United States, and Chile. The studies varied in their patient selection criteria, with differences in tumor thickness, size, anatomical location, and the inclusion or exclusion of immunosuppressed patients. Despite these differences, all studies had a low risk for bias, scoring between 8 and 9 on the Newcastle–Ottawa Scale.

The meta-analysis revealed a significant association between high TB and nodal metastasis in cSCC. All studies defined tumor buds as foci of less than five cells at the invasive front; one study also assessed buds intratumorally. Five studies defined high TB as having five or more buds, while two others followed ITBCC grading.

High TB was consistently associated with a higher risk for nodal metastasis across all studies (OR, 13.29; 95% CI, 5.55–31.86; P<0.001). The researchers’ analysis showed moderate heterogeneity but no significant outliers, indicating consistent findings across the studies (Table).

Additionally, the analysis confirmed that the results were robust, with no excessive influence from any single study. The researchers conducted further statistical tests and did not detect significant publication bias.

Potential to Refine cSCC Staging

Given their findings, the review authors emphasized that including TB in staging systems for cSCC could help guide management decisions for individual patients.

“TB is a simple, cheap, and reproducible histopathological feature that does not require specific equipment for its identification, which could help identify the best candidates for sentinel lymph node biopsy or adjuvant therapies, among other options,” Gil-Pallares and the coauthors concluded.

“Although further validation studies are needed to consolidate the role of TB in the management of cSCC, the consistent findings across sensitivity analyses reinforce the importance of incorporating TB assessment into clinical practice, which could improve risk stratification and offer individualized strategies for patients with cSCC.”