Endocrine Abstracts

A 48-year-old woman with complex cyanotic congenital heart disease due to dextrocardia was found to have a urachal remnant during routine ultrasound as part of her cardiac monitoring. Unexpected, excision via partial cystectomy without any hypertensive crisis identified 12 mm bladder paraganglioma [PGL], with local metastases to bladder (distinct from primary lesion) and lymph nodes (pT2b N1). Post operatively (following histopathology diagnosis), biochemistry demonstrated marked catecholamine excess (plasma normetadrenaline 7072 pmol/l (<1180 pmol/l), metadrenaline 485 pmol/l, plasma 3-methoxytyramine <120 pmol/l) and she was commenced on doxazocin 4 mg BD. Subsequent functional imaging (Dotatate PET) identified multiple avid lesions including bilateral neck PGLs, a 3 cm mediastinal PGL, and a small PGL between pulmonary artery and aorta. Retrospective review showed evidence of these masses on earlier scans as far back as 2012, with gradual but progressive enlargement of thoracic PGLs. Resection was considered; however, the mortality risk for thoracic surgery was estimated at 10% and instead she was initiated on monthly Lanreotide injections (current dose 120 mg). She remains clinically and biochemically stable; and radiologically all PGL have remained stable on annual MRI and cardiac CT over last 3 years. Hypoxia is an important driver of tumorogeneses; however, many tumours demonstrate hypoxia-associated changes (e.g., HIF pathway activation, angiogenesis, and the Warburg metabolic effect) without hypoxia being present, which phenotype is termed pseudohypoxia. The role of pseudohypoxia in PPGL is well-recognised, with PPGL-associated germline mutations identified in multiple respiratory-associated genes (e.g. SDHx) and HIF pathway genes (e.g., EPAS, EGLN2). Conversely, PPGLs are more common in individuals living in high altitudes, smokers, and individuals with cyanotic heart disease. In particular, recent studies have found evidence of somatic EPAS1 mutations in multiple cases of pheochromocytoma and PGL. The current individual has chronic hypoxia, with polycythaemia (Hb 165-183 g/l; Haematocrit 0.531-0.580; SDHB immunohistochemistry was positive, excluding SDHx mutations; and panel germline genetic testing (14 genes) did not identify pathogenic variants in pseudohypoxia genes, nor any other PPGL-associated genes. Sequencing of EPAS1 hotspot regions in archived resected tumour tissue and germline DNA was undertaken; however, this did not identify any pathogenic variants. Nonetheless, the clinical picture suggests that lifelong hypoxaemia may be driving development of multiple PPGLs in this patient. This case suggests potential new gene discovery driving hypoxia associated PPGL, requiring further research.