Hypoxia-inducible Factor 2α: A Key Player in Tumorigenesis and Metastasis of Pheochromocytoma and Paraganglioma?

Germline or somatic driver mutations linked to specific phenotypic features are identified in approximately 70% of all catecholamine-producing pheochromocytomas and paragangliomas (PPGLs). Mutations leading to stabilization of hypoxia-inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are associated with a higher risk of metastatic disease. Patients with metastatic PPGLs have a variable prognosis and treatment options are limited. In most patients with PPGLs, germline mutations lead to the stabilization of HIF2α. Mutations in HIF2α itself are associated with adrenal pheochromocytomas and/or extra-adrenal paragangliomas and about 30% of these patients develop metastatic disease; nevertheless, the frequency of these specific mutations is low (1.6–6.2%). Generally, mutations that lead to stabilization of HIF2α result in distinct catecholamine phenotype through blockade of glucocorticoid-mediated induction of phenylethanolamine N-methyltransferase, leading to the formation of tumors that lack epinephrine. HIF2α, among other factors, also contributes importantly to the initiation of a motile and invasive phenotype. Specifically, the expression of HIF2α supports a neuroendocrine-to-mesenchymal transition and the associated invasion-metastasis cascade, which includes the formation of pseudopodia to facilitate penetration into adjacent vasculature. The HIF2α-mediated expression of adhesion and extracellular matrix genes also promotes the establishment of PPGL cells in distant tissues. The involvement of HIF2α in tumorigenesis and in multiple steps of invasion-metastasis cascade underscores the therapeutic relevance of targeting HIF2α signaling pathways in PPGLs. However, due to emerging resistance to current HIF2α inhibitors that target HIF2α binding to specific partners, alternative HIF2α signaling pathways and downstream actions should also be considered for therapeutic intervention.

Cabergoline reduces 3-methoxytyramine in a SDHC patient with metastatic paraganglioma and prolactinoma

Summary We observed a novel therapeutic response with cabergoline in a male patient with a dopamine-secreting head and neck paraganglioma (HNPGL), macroprolactinoma and germline succinate dehydrogenase C mutation (SDHC). The macroprolactinoma was treated with cabergoline which gave an excellent response. He was found to have raised plasma 3-methoxytyramine of 1014 pmol/L (NR: 0–180 pmol/L); but it was unclear if this was a drug-induced phenomenon from dopamine agonist (DA) therapy. Cabergoline was stopped for 4 weeks and the 3-methoxytyramine level increased significantly to 2185 pmol/L, suggesting a biochemical response of his HNPGL. Subsequently, Gallium-68 Dotatate PET and MRI (Gallium-68 Dotatate PET/MRI) demonstrated a second lesion in the sacrum. Both the HNPGL and metastatic sacral deposit received external beam radiotherapy with a good biochemical and radiological response. Conclusion Our case report highlights the rare potential of germline SDHC mutations causing metastatic paraganglioma and concurrent pituitary tumours. Cabergoline treatment may lower elevated 3-methoxytyramine levels and, therefore, mask the biochemical evidence of metastatic disease but also may have therapeutic relevance in dopamine-secreting pheochromocytomas/paragangliomas (PPGLs). Learning points Several neuroendocrine tumours (NETs) express dopamine D2 and D4 receptors. In this case report, cabergoline significantly reduced plasma 3-methoxytyramine level in a patient with functional HNPGL. Cabergoline might have therapeutic relevance in dopamine-secreting PPGLs. Paragangliomas associated with SDHC mutation classically present with asymptomatic non-functional HNPGL and have rare metastatic potential. The association of pheochromocytoma or paraganglioma and pituitary adenoma is now a well-described rare association (<1%), designated as the three P association. While the three P association is most commonly seen with succinate dehydrogenase B and D mutations, it has also been described in patients with SDHA and SDHC mutations. Cabergoline treatment may lower elevated 3-methoxytyramine levels and mask the biochemical evidence of metastatic disease. Regular functional imaging with Gallium-68 Dotatate PET/MRI provides better evidence of metastatic disease.

A new technological approach in diagnostic pathology: mass spectrometry imaging-based metabolomics for biomarker detection in urachal cancer

Urachal adenocarcinomas (UrC) are rare but aggressive. Despite being of profound therapeutic relevance, UrC cannot be differentiated by histomorphology alone from other adenocarcinomas of differential diagnostic importance. As no reliable tissue-based diagnostic biomarkers are available, we aimed to detect such by integrating mass-spectrometry imaging-based metabolomics and digital pathology, thus allowing for a multimodal approach on the basis of spatial information. To achieve this, a cohort of UrC (n = 19) and colorectal adenocarcinomas (CRC, n = 27) as the differential diagnosis of highest therapeutic relevance was created, tissue micro-arrays (TMAs) were constructed, and pathological data was recorded. Hematoxylin and eosin (H&E) stained tissue sections were scanned and annotated, enabling an automized discrimination of tumor and non-tumor areas after training of an adequate algorithm. Spectral information within tumor regions, obtained via matrix-assisted laser desorption/ionization (MALDI)-Orbitrap-mass spectrometry imaging (MSI), were subsequently extracted in an automated workflow. On this basis, metabolic differences between UrC and CRC were revealed using machine learning algorithms. As a result, the study demonstrated the feasibility of MALDI-MSI for the evaluation of FFPE tissue in UrC and CRC with the potential to combine spatial metabolomics data with annotated histopathological data from digitalized H&E slides. The detected Area under the curve (AUC) of 0.94 in general and 0.77 for the analyte taurine alone (diagnostic accuracy for taurine: 74%) makes the technology a promising tool in this differential diagnostic dilemma situation. Although the data has to be considered as a proof-of-concept study, it presents a new adoption of this technology that has not been used in this scenario in which reliable diagnostic biomarkers (such as immunohistochemical markers) are currently not available.