The Prognostic Value of Immunohistochemical Biomarkers in Medullary Thyroid Carcinoma: A Systematic Review and Meta-Analysis

Background: The prognosis and disease course of medullary thyroid carcinoma (MTC) can vary widely among patients. Effective risk stratification is important for ensuring timely treatment and personalized follow-up. Biomarkers can enhance risk stratification and guide the development of targeted anticancer therapies and imaging techniques. While numerous studies have explored various immunohistochemical biomarkers in MTC, an overview is still lacking. This study aimed to provide a comprehensive overview of immunohistochemical biomarkers and their role in the prognosis of MTC patients, with a primary focus on overall survival (OS). Methods: This review was preregistered in PROSPERO (CRD42023469437). A systematic search was performed using the online medical databases Embase, MEDLINE (Ovid), and Cochrane. Quality was assessed using an adapted scoring system based on the REMARK criteria and the Quality in Prognosis Studies tool. The primary outcome was OS. Secondary outcomes included other types of survival and associations with clinicopathological risk factors and recurrence. Results: Of 2992 studies, 108 were included, investigating 170 unique biomarkers and with sample sizes ranging from 11 to 327 participants. The majority (72%) were reported in only one article. A minority of studies were rated as high quality (28%). Markers of proliferation Ki-67 (Ki-67) and programmed cell death-ligand 1 (PD-L1) were significantly associated with OS (hazard ratio [HR]: 6.67, confidence interval [CI]: 1.43-31.18 and HR: 3.34, CI: 1.18-9.51). Conclusions: Our systematic review provides a comprehensive synthesis of the literature on immunohistochemical biomarkers in MTC and highlights the need for high-quality validation studies. Our meta-analysis confirms the prognostic value of Ki-67, although with varying certainty due to large differences in study quality. Furthermore, we describe the association of PD-L1 positivity with poorer OS, increased recurrence, and more aggressive clinicopathological features, which supports the rationale for further investigating the potential of anti-PD-1/PD-L1 immunotherapy for advanced MTC.