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Introduction: Capable of generating excess catecholamines, untreated extra-adrenal paragangliomas (PGL) result in severe cardiovascular morbidity and mortality. Increasingly, a hereditary basis can be identified to underlie PGLs, though such data is largely absent in non-Caucasian populations. Case 1: A 43 yr. old Kinyarwanda-speaking woman from DR Congo presented with left lower extremity edema and hypertension, with blood pressure of 154/86 while on spironolactone, HCTZ and furosemide. Ultrasound was negative for a DVT; abdominal CT revealed a 3 cm necrotic mass, inferior to the duodenum and abutting the IVC and aorta, as well as 2 bladder wall lesions. EUS-guided FNA revealed a keratin-negative neuroendocrine tumor. Urinary 24hr norepinephrine (NE) was high at 185 mcg [15–80]. Urinary 24hr normetanephrine (NM) was high at 1404 mcg [119-451; hypertensive <900]. MIBG scan confirmed avidity in the aortocaval mass. Despite lack of bladder uptake on MIBG, pathology similarly pointed to PGL. Surgery included excision of bladder, pelvic nodes, uterus, and aortocaval tumor. Post-op, urinary 24hr NE was 18 mcg and NM was 297 mcg, both normal. One year later, MIBG/SPECT and CT of the abdomen were negative for recurrence. A GeneDx panel of 12 PGL/PCC mutations was negative. Case 2: An unrelated 41 yr. old Kinyarwanda-speaking woman from Rwanda, with prior history of preeclampsia and multiple miscarriages, presented with palpitations, headaches and hypertension. Echo showed a 4 cm mass posterior to the left atrium; the mass was18F-FDG PET-avid. Video-assisted thoracoscopy was performed yet the tumor’s vascularity precluded a biopsy. Biopsy of mediastinal mass after performing thoracotomy was consistent with PGL. Plasma NM was high at 7.1 nmol/l (<0.90), consistent with PGL and she underwent complete removal of the tumor. Testing for SDHB mutation was negative. Symptoms resolved and antihypertensives were discontinued. Follow-up plasma NM was 0.55 nmol/l 1-year post op and remained normal for six years of follow-up. Discussion: Less than 10% of PGLs are known to involve the mediastinum or bladder (1). In familial PGL, the most commonly identified non-syndromic mutations involve SDHD, SDHAF2, SDHB, SDHD, SDHC, VHL, and MAX. Tumorigenesis in a sizable fraction of PGLs is not well understood. Conclusion: We present two cases of extra-adrenal PGL, both exhibiting similar age, sex and geographic ancestry. Our cases raise questions that require active investigation regarding additional environmental and/ or genetic factors which might predispose to PGLs in uncommon anatomic sites. References: (1) Erickson D et al. J Clin Endocrinol Metab, 2001 (2) Martins et al. Int J of Endocrinol, 2014
Capable of generating excess catecholamines, untreated extra-adrenal paragangliomas (PGLs) result in severe cardiovascular morbidity and mortality. Increasingly, a hereditary basis can be identified to underlie PGLs, though such data are largely absent in populations of non-European descent. We present two patients with PGL, both exhibiting similar age, sex, and geographic ancestry. Our patients are unrelated, Kinyarwanda-speaking females from the Democratic Republic of the Congo. The first patient presented with lower extremity edema and poorly controlled hypertension and was found to have multifocal PGL in the abdomen and bladder, proven by biopsy and treated with surgical excision. Our second patient presented with palpitations, shortness of breath, headache, and hypertension, was found to have mediastinal PGL, and underwent surgical excision. Genetic testing was negative in both cases. The first patient has not shown recurrence based on active surveillance with imaging and biochemical testing. There is a concern for recurrence in the second patient, eight years after diagnosis, which is currently being investigated. Our second patient lived at a high altitude for most of her life, pointing toward a possible role of hypoxia in the pathogenesis of her tumor development. Our cases raise questions that require active inquiry regarding additional environmental and/or genetic factors that might predispose to PGLs in uncommon anatomic sites and in understudied, vulnerable populations.
BACKGROUND: The phosphaturic, bone-derived hormone FGF23, mediates bone loss in TIO. Tumor resection typically results in skeletal healing and reversal of biochemical defects. Case: A 45-year-old Caucasian man with no past medical history presented with non-traumatic fractures of bilateral metatarsals. Over the subsequent 2 years, he sustained fragility stress fractures in bilateral femurs, eventually rendering him non-ambulatory; though he continued to work as a property manager in an office setting. History included 30 pack-years of smoking as well as osteochondrosarcoma in his mother. Labs showed a low phosphorus at 2.1 mg/dL [2.7–4.5], along with calcium 8.8 mg/dL [8.4–10.4], iPTH 48 pg/mL [12–88], and ALP of 155 [IU]/L [34–104]. 25-OH vitamin D and 1,25-(OH)2 vitamin D were 27 ng/mL [30–80] and 12 pg/mL [20–80], respectively. Free testosterone was 4.4 ng/mL [5–21] and LH 2.2 mIU/mL [3.0–10.0]. Other pituitary hormones and brain MRI were unremarkable. Vitamin D3, calcitriol, phosphate and testosterone were prescribed. Testosterone was discontinued 6 months later, after diagnosis with DVT/PE. Incidental rib fractures on CXR prompted a 3-phase 99Tc-MDP bone scan, revealing multiple sites of uptake: ribs, scapulae, sternum, thoracolumbar spine, sacrum, bilateral ankles and feet. DXA revealed T-scores of -2.8 in the spine and -1.9 in the femoral neck. Labs pointed to ongoing phosphate wasting, despite compliance with calcitriol 0.25 mcg, cholecalciferol 5000 IU and phosphorus 2250 mg in divided doses. Calculated TRP was 64% [>80%] and TmP/GFR 1.74 mg/dL [2.5–4.5], consistent with low phosphate reabsorption. Urine 24-hour calcium was 244.8 mg. Testing for causal mutations of hypophosphatemic rickets and osteogenesis imperfecta was negative. FGF23 was within the reference range at 138 RU/mL [LabCorp ELISA 44–215], interpreted as inappropriately normal given ongoing phosphate loss. This prompted a search for a suspected TIO locus. Two years after presentation, 18F-FDG-PET exhibited a hypermetabolic focus at the left suprapatellar recess. Biopsy was consistent with a mesenchymal tumor and chromogenic in situ hybridization (Mayo Clinic) was positive for FGF23 mRNA. After surgical resection of the 1.7 cm tumor, serum FGF23 declined to <50 RU/mL and was 90 RU/mL 3 weeks later [Mayo <180 RU/mL]. Calcitriol and phosphorus supplementation were discontinued. One year post-operatively phosphorus was 3.6 mg/dL [2.5–5.0], with a normal calcium, iPTH and 25-OH vitamin D. Lumbar spine T score improved to -1.0 (+46.43%). Conclusion: A high clinical index of suspicion is required for TIO in the setting of phosphaturic osteomalacia, particularly with a normal serum FGF23. Recently, similar microRNA profiles were noted in osteosarcomas and TIO1. This, along with our patient’s family history raises the question of a possible predisposition to skeletal neoplasms. 1. Green et al. Bone Reports, 2017.
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