Photo Credit: HT Ganzo
The following is a summary of “Recent progress in molecular classification of phaeochromocytoma and paraganglioma,” published in the September 2024 issue of Endocrinology by Boehm et al.
Phaeochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors originating from neural crest cells with a notably high heritability rate. Recent advancements in molecular profiling, including multi-omics and single-cell genomic technologies, have allowed the identification of up to seven distinct molecular subtypes, revolutionizing the understanding of these tumors’ genetic and molecular underpinnings. These subtypes are defined by specific genetic alterations involving pathways such as hypoxia-inducible factors (HIFs), the Krebs cycle, kinase signaling, and WNT signaling, as well as variations in chromaffin differentiation states, further illuminating the complexity of these tumors.
One of the hallmark features of PC and PG is their proangiogenic tumor microenvironment, primarily influenced by HIF pathway activity. This results in a robust vascular network, yet these tumors are generally considered “immune cold,” characterized by a high presence of macrophages but limited infiltration by other immune cells. This immune evasion presents a significant challenge for immunotherapeutic approaches. However, the distinct molecular signatures within these tumors provide critical insights into their behavior, particularly about metastatic potential. While certain molecular subtypes are associated with an elevated risk of metastasis, secondary mutations, particularly those affecting telomere maintenance genes such as TERT and ATRX, are typically required to drive the progression to a metastatic phenotype.
The role of molecular profiling in the management of PC and PG extends beyond risk stratification. It has opened new avenues for personalized medicine by identifying actionable therapeutic targets. For example, mutations in genes such as RET and EPAS1 have been identified, paving the way for developing molecularly targeted therapies. Additionally, radiopharmaceutical approaches, including somatostatin analogs and other radionuclide therapies, have shown promise in treating certain subtypes of these tumors. Furthermore, molecular profiling aids in determining the pathogenicity of genetic variants, which can be particularly valuable in familial cases, helping to assess the risk for affected family members and guide genetic counseling.
Despite these significant advances, the clinical implementation of molecular subtyping for prognosis and individualized treatment plans remains in its early stages. While molecular profiling holds great potential for nuanced prognostication and tailored therapeutic strategies, large-scale prospective clinical trials are necessary to validate these findings and ensure their widespread applicability in clinical practice. As research progresses, molecular profiling is poised to play a pivotal role in transforming the management of phaeochromocytomas and paragangliomas, offering more personalized, precise, and effective therapeutic options for patients facing these complex malignancies.
Source: sciencedirect.com/science/article/pii/S1521690X24001155
