The Tortuous Way from Mammary Ductal Hyperplasia to Cancer. Why Are Only Certain Types of Hyperplasia at Higher Risk for Malignant Transformation?

Background: Mammary ductal hyperplasia represents a spectrum of benign proliferative breast lesions, some of which pose elevated risks for malignant transformation into ductal carcinoma in situ and invasive breast cancer. This narrative review explores why only specific types, particularly those with atypia, exhibit higher progression potential, synthesizing epidemiologic, histopathologic, molecular, and environmental insights. Methods: We re-viewed key literature from databases, including PubMed, focusing on classi-fication, risk stratification, genetic/epigenetic mechanisms, tumor microen-vironment dynamics, and modifiable factors influencing progression. Re-sults: Benign breast lesions are categorized into non-proliferative, prolifera-tive without atypia, and proliferative with atypia, such as atypical ductal hyperplasia and atypical lobular hyperplasia. Atypia represents a morpho-logic continuum toward low-grade ductal carcinoma in situ, driven by ge-netic alterations, epigenetic reprogramming, and changes in the tumor mi-croenvironment, including stromal remodeling, immune infiltration, hypox-ia-induced angiogenesis, and extracellular matrix degradation. Dietary fac-tors, such as high-fat intake and obesity, exacerbate progression through in-flammation, insulin resistance, and adipokine imbalance, while environ-mental toxins, including endocrine disruptors, pesticides, and ionizing radi-ation, amplify genomic instability. Conclusions: Understanding differential risks and mechanisms underscores the need for stratified surveillance, bi-omarker-driven interventions, and lifestyle modifications to mitigate pro-gression. Future research should prioritize molecular profiling for personal-ized prevention in high-risk hyperplasia.