From Germ Cell Histogenesis to Precision Risk Stratification: Prognostic and Predictive Molecular Markers in Testicular Germ Cell Tumors—A Systematic Review

Background/Objectives: Testicular germ cell tumors (TGCTs) represent the most common solid malignancies in young adult men, with cure rates exceeding 95% under modern cisplatin-based therapy, yet a clinically relevant subset of patients still experiences treatment failure or long-term toxicity. This systematic review synthesizes peer-reviewed evidence, from database inception through 6 July 2026, on prognostic and predictive molecular markers in developmental and endocrine-sensitive testicular carcinogenesis. Methods: A PRISMA 2020-aligned search of MEDLINE/PubMed, Embase, Web of Science Core Collection, and the Cochrane Library was supplemented by registry-based evidence, reference-list screening, and contemporary guidelines to capture diagnostic, prognostic, and predictive biomarkers in TGCTs. The strategy encompassed classical serum markers, tissue-based molecular and immunohistochemical markers, miRNA/cfDNA liquid-biopsy assays, immune and resistance-related features, and validated clinicopathological risk models. Results: The review integrates classical serum biomarkers, pluripotency transcription factors, surface and oncofetal antigens, yolk-sac and trophoblastic markers, circulating microRNAs, methylated cell-free DNA, immune features, and updated clinicopathological risk models. Markers are graded as established, validated research, or emerging candidates. miR-371a-3p shows a high accuracy for active non-teratomatous TGCT, with pooled sensitivity of about 0.90 and specificity of approximately 0.86, but is negative in pure teratoma. AFP, β-hCG, and LDH are still required for staging and IGCCCG risk assignment. Conclusions: Despite the growing promise of biomarker-driven approaches in TGCT, no single serum, tissue, liquid-biopsy, immune, or resistance-associated marker has yet demonstrated sufficient clinical utility to replace comprehensive evaluation based on morphology, staging, histology, imaging, standard serum markers, and established clinicopathological risk assessment.