A UK national audit of the laboratory investigation of phaeochromocytoma and paraganglioma

Background Phaeochromocytomas and paragangliomas (PPGL) are catecholamine secreting tumours associated with significant morbidity and mortality. Timely diagnosis and management are essential. A range of laboratory tests can be utilised in the investigation of PPGL. There is scope for significant variation in practice between centres. We aimed to investigate how the laboratory investigation of PPGL is performed in laboratories across the United Kingdom. Methods A questionnaire consisting of 21 questions was circulated to Clinical Biochemistry laboratories in the United Kingdom via the Association for Clinical Biochemistry and Laboratory Medicine office. The survey was designed to allow audit against Endocrine Society Guidelines on the Investigation and Management of PPGL and to obtain information on other important aspects not included in these guidelines. Results Responses were received from 58 laboratories and the data were compiled. The majority of laboratories use either urine or plasma metanephrines in first-line testing for PPGL, although a number of different combinations of biochemistry tests are utilised in different centres. All laboratories measuring metanephrines or catecholamines in-house use LC or LC-MS/MS methods. There are some marked differences between laboratories in urine metanephrines reference ranges used and sample requirements. Conclusions There is evidence of good practice in UK laboratories (as assessed against Endocrine Society Guidelines) such as widespread use of urine/plasma metanephrines and appropriate analytical methodologies used. However, there is also evidence of variations in practice in some areas that should be addressed.

Malignant pheochromocytoma: pain, palpitation, perspiration and perplexities

A 60-year-old man presented with headache, giddiness, abdominal pain and palpitation. When evaluated outside for the same, the patient was diagnosed to have hypertension and started on antihypertensives for which he did not respond. ECG was suggestive of non-ST elevation myocardial infarction. The patient was subjected to a coronary angiogram, which was normal. Patient had multiple episodes of fluctuating blood pressures. CT of the abdomen showed a 7.1×5.6×8.2 cm mass in the left adrenal gland suggestive of a pheochromocytoma. Serum, urine metanephrines and normetanephrines were elevated. After discussing with the multidisciplinary team, the patient was stabilised with alpha blockers and taken up for laparoscopic left adrenalectomy. Histopathology was reported as pheochromocytoma with a Pheochromocytoma Adrenal Scaled Score of 10/20 suggestive of malignancy. This is one such case of a malignant pheochromocytoma, which was managed successfully despite the perplexities faced in stabilising the crisis followed by laparoscopic resection in a moribund patient.

Occurrence of Hepatocellular Carcinoma in a 40-Year-Old Male With MEN2A Syndrome

Background: Multiple Endocrine Neoplasia Type 2A (MEN 2A) is a genetic syndrome in which the patient is susceptible to the development of: 1. medullary thyroid carcinoma, 2. pheochromocytoma, and 3. parathyroid adenomas or hyperplasia. Our objective is to report the first occurrence of hepatocellular carcinoma in a young adult male with MEN 2A syndrome without prior liver disease. Clinical Case: A 40-year-old male was screened positive for the C634R point mutation of the RET Proto-Oncogene after his sister with MEN 2A syndrome had tested positive. The patient had no history of alcohol or drug abuse. His family history was remarkable for the deaths of his mother and maternal grandmother from unknown malignancies at the ages of 35 and 45 respectively. His physical exam revealed a BP of 135/85mm Hg, BMI 26 kg/m2 and palpable bilateral thyroid nodules. Lab tests included a calcitonin of 131 pg/ml, (0.0-8.4 pg/ml), calcium 11.4 mg/dL (8.4-10.3 mg/dL), parathyroid hormone (PTH) 1765 pg/ml (12-65 pg/ml), ALK PHOS 1856 U/L (20-120 U/L), ALT 16 U/L (<39 U/L), Albumin 4.1gm/dl (3.4-5.0gm/dl), plasma normetanephrine 0.95 nmol/L (0.00- 0.89 nmol L) and urine metanephrines 291 pg/d (62-207 pg/d). A CT scan demonstrated hyperdense 12 mm right and 5 mm left adrenal nodules, both confirmed MIBG positive. Neck ultrasound showed bilateral thyroid nodules, the largest measuring 1.1 x 0.8 x 1.1 cm in the right lobe and a 3.5 x 2.2 x 2.1 cm heterogeneous mass posterior to the right thyroid lobe. The patient was prepped with doxazosin and underwent a laparoscopic right adrenalectomy then 2 months later a total thyroidectomy with neck lymph node dissection, resection of the right parathyroid tumor mass and bilateral inferior parathyroid glands. Surgical pathology confirmed the right adrenal pheochromocytoma, multifocal bilateral medullary thyroid cancer with 1 of 70 neck lymph nodes positive and a single large parathyroid adenoma. He received levothyroxine to maintain euthyroidism. Within 6 months of his surgery, calcitonin was < 2 pg/ml, CEA 2.3 U/ml (<5.0 U/ml) and ALK PHOS 44 U/L. Urine metanephrines remained mildly elevated 291 pg/d (62-207 pg/d). Serial abdominal CT imaging revealed no change of the left adrenal mass but three new bi-lobar 1-2 cm enhancing liver lesions. CT guided needle biopsies of the liver masses revealed hepatocellular cancer without evidence of cirrhosis. The patient underwent successful thermal ablation of all 3 liver lesions. Laboratory evaluation was negative for Hepatitis A, B and C. His alpha fetal protein level has remained stable in the range of 4.7 to 5.8 ng/ml (<15ng/ml). Conclusions: This is the first reported case of hepatocellular carcinoma in a patient with MEN 2A syndrome who had no predisposing liver disease, raising suspicion that his germline RET mutation contributed to his liver cancer.

Adrenal Mass Hemorrhage Clinically Mimicking a Pheochromocytoma

Background: A pheochromocytoma is diagnosed clinically using correlation of clinical, imaging, and laboratory studies. We report the case of an adrenal mass hemorrhage that presented with significantly elevated urine metanephrines mimicking a pheochromocytoma. Clinical Case: A 59-year-old healthy woman presented to the ED with chest pain, left flank and upper quadrant pain associated with diaphoresis and palpitations. Vital signs were significant for a pulse of 92 bpm, and a BP of 213/88 mm Hg. Physical exam revealed tenderness to palpation on the left upper quadrant and left costovertebral angle. Laboratory tests were significant for an elevated D-dimer (2,449 ng/mL, reference range 215–499 ng/mL). CT abdomen with IV contrast showed a 3.5 x 2.9 cm round mass abutting the lateral limb of the left adrenal gland with surrounding fat stranding with suspicion of inflammation or hemorrhage. 24-hour urine metanephrines showed elevated metanephrine (7,227 mcg/24hr; reference range <400 mcg/24 hr) and normetanephrine (1,209 mcg/24hr; reference range 900 mcg/24 hr). In the setting of up trending cardiac enzymes and inferior-lateral ST segment depression, a cardiac catheterization was performed which was unrevealing. She was discharged from the hospital and referred to endocrinology. On that visit, ~ 1 month after the patient was admitted to the hospital, plasma metanephrines were ordered which showed mildly elevated plasma metanephrine (0.83 nmol/L; reference range <0.5 nmol/L) and normetanephrine (1.2 nmol/L; reference ranges <0.9 nmol/L). An MRI abdomen with and without contrast revealed a 2.7 x 2.2 x 1.8 cm nodule arising from the lateral limb, with loss of signal on in-phase images suggestive of blood products. Plasma metanephrines and MRI findings ruled out the diagnosis of a pheochromocytoma. Conclusion: To our knowledge, few cases of an adrenal mass hemorrhage clinically mimicking a pheochromocytoma have been reported. Although the inpatient clinical presentation of our patient was consistent with this, the outpatient plasma metanephrines and MRI were not. An adrenal adenoma hemorrhage should be considered as a potential differential diagnosis for elevated metanephrines, which can clinically mimick a pheochromocytoma. References: (1)Sekos K, Short T, Ing SW. Adrenal hemorrhage due to hypercoagulable state mimicking pheochromocytoma. Journal of Clinical and Translational Endocrinology: Case Report. 8. 9–12. 2018.(2)Wordsworth S, Thomas B, Agarwal N, Hoddell K, Davies S. Elevated urinary cathecholamines and adrenal haemorrhage mimicking phaechromocytoma. BMJ Case Reports. 2010.

Bilateral Pheochromocytoma Due to Von Hippel Lindau With Adrenal-Sparing Adrenalectomy in a Child

Background: More than 40% of pediatric pheochromocytoma or paragangliomas have associated underlying genetic germline mutation. (1) Clinical Case: We present an 8-year-old male who arrived the emergency department with hypertension to 170/115. MRI of the abdomen revealed bilateral well demarcated adrenal masses with central necrosis. Urine metanephrines showed elevated normetanephrine of 15244 µg/24 hr (reference range, 58 - 670 µg/24 hr) and normal urine metanephrines. Urinary vanillylmandelic acid was mildly elevated 35 mg/gCr and homovanillic acid was normal. MIBG scan revealed increased radiotracer activity correlating to the bilateral adrenal masses without evidence of metastasis. Diagnosis of bilateral pheochromocytomas was made. Genetic testing revealed a novel, heterozygous, pathogenic variant of VHL tumor suppressor gene, consistent with Von Hippel-Lindau syndrome. Perioperative blockade was achieved with prazosin, amlodipine, and metoprolol. Due to low likelihood of metastasis in pheochromocytomas due to VHL, adrenal sparing bilateral adrenalectomy was attempted and resulted in 15% sparing of left adrenal gland vs radial bilateral adrenalectomy. (2) Clinical Lessons: 1. Endocrine etiologies of hypertension, although rare, are important causes of hypertension in the pediatric population. 2. Genetic testing prior to surgical intervention could determine surgical course and preservation of adrenals. 3. A multidisciplinary approach to care and referral to a center with experienced surgery, oncology, nephrology, endocrinology, anesthesiology, critical care and genetics is crucial to maximizing outcomes with pheochromocytoma. Reference: 1. NGS in PPGL (NGSnPPGL) Study Group, Toledo RA, Burnichon N, Cascon A, Benn DE, Bayley JP, Welander J, Tops CM, Firth H, Dwight T, Ercolino T, Mannelli M, Opocher G, Clifton-Bligh R, Gimm O, Maher ER, Robledo M, Gimenez-Roqueplo AP, Dahia PL. Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol. 2017 Apr;13(4):233–247. 2. King KS, Prodanov T, Kantorovich V, Fojo T, Hewitt JK, Zacharin M, Wesley R, Lodish M, Raygada M, Gimenez-Roqueplo AP, McCormack S, Eisenhofer G, Milosevic D, Kebebew E, Stratakis CA, Pacak K. Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol. 2011 Nov 1;29(31):4137–42.

A Tale of Two Cities: Do They Have the Same Destination: Asymptomatic Pheochromocytomas: Biochemically Functioning vs Non Functioning

Background: Pheochromocytomas (PHEOs) are enterochromaffin tumors arising from the adrenal gland. Their diagnosis and preoperative preparation is crucial due to high morbidity and mortality rates with unrecognized, undiagnosed PHEOs. Case 1: 62-year-old male with a medical history of HCC, noted to have right adrenal adenoma measuring 1.7 x 1.6 cm. Denied any symptoms and normotensive on exam. A PET scan done showed a hypermetabolic right adrenal nodule concerning for malignancy. Serum metanephrines were 45 pg/ml (nl <57 pg/ml) and total plasma metanephrines were 172 pg/ml (nl <205 pg/ml). A CT guided biopsy was consistent with a PHEO. Other labs included: 24 hour urine metanephrines: 155 mcg (nl 90–315), total metanephrines: 520 (nl 224–832) and vanillylmandelic acid was 3.6 (nl <6.0). 24-hour urine epinephrine: 10 mcg (nl 2–24), norepinephrine:57 mcg (nl 15–100) and dopamine: 421 (normal 52–480). Case 2: 55 year old male with UTI and flank discomfort, noted to have incidental 8cm Right adrenal mass noted concerning for malignancy. Also denied any symptoms and normotensive. Plasma fractionated metanephrines 938 (ref <206), metanephrine 279,Normetanephrine 659(ref <148), 24 hr urine metanephrines=1176mcg/24 hr (90–315), Normetanephrines 1487 (122–676), 24 hr urine total metanephrines 2663 (224–832). He is refusing α and β blockade due to normotension in preparation for surgery. Discussion: It is important to suspect, confirm, localize, treat, and PHEOs for several reasons. Most of these tumors hypersecrete catecholamines, and if untreated, cardiovascular morbidity and mortality are high. Another reason to encourage case detection is that, for familial disease, detection of a tumor in the proband may result in earlier diagnosis and treatment in other family members. Alpha-blockade is usually used prior to resection of Pheochromocytomas. However, the data available in the literature regarding alpha blockade for “truly asymptomatic” functioning or non functioning Pheochromocytomas is scarce. However what is unique to our cases is that they both are normotensive and asymptomatic and refusing preoperative preparation. Conclusion: Asymptomatic PHEO are becoming more common presentation given Pheochromocytomas are rare. Are the genetics and biochemical nature any different than classic pheos? Are we supposed to manage them the same way? Would we rethink current guidelines for managing normotensive or nonfunctioning pheochromocytomas pre operatively? We also would like guidelines on how to prepare such truly asymptomatic patients prior to surgery. We refer to Endocrine Society guidelines for management of such tumors.

Properly collected plasma metanephrines excludes PPGL after false positive screening tests

Context False positive results are common for pheochromocytoma/paraganglioma(PPGL) real-world screening. Objective Determine the correlation between screening urine and seated plasma metanephrines in outpatients where PPGL was absent, compared to meticulously prepared and supine-collected plasma metanephrines with age-adjusted references. Design Retrospective cohort study Setting Databases from a single-provider provincial laboratory(2012-2018), a validated PPGL registry and a manual chart review from a specialized endocrine testing unit. Patients PPGL registry data excluded known PPGL cases from the laboratory database. Outpatients having both urine and plasma metanephrines <90 days apart. Methods The correlation between urine and seated plasma measures along with the total positivity rate. All cases of plasma metanephrines drawn in the endocrine unit were reviewed for test indication and test positivity rate. Results There were 810 non-PPGL pairs of urine and plasma metanephrines in the laboratory database; 46.1% of urine metanephrines were reported high. Of seated outpatient plasma metanephrines drawn a median of 5.9 days later, 19.2% were also high (r=0.33 and 0.50 for normetanephrine and metanephrine, respectively). In contrast, the meticulously prepared and supine collected patients(n=139, 51% prior high urine metanephrines) had <3% rate of abnormal high results in patients without known PPGL/adrenal mass. Conclusions There was a poor-to-moderate correlation between urine and seated plasma metanephrines. Up to 20% of those with high urine measures also had high seated plasma metanephrines in the absence of PPGL. Properly prepared and collected supine plasma metanephrines had a false positive rate of <3% in the absence of known PPGL/adrenal mass.

Postpartum pheochromocytoma-induced takotsubo syndrome

A postpartum patient with acute-onset dyspnoea and hypotention, associated with reduced left ventricular function requiring intensive blood pressure control, was initially misdiagnosed as having peripartum cardiomyopathy. Her clinical symptoms rapidly resolved. Echocardiography revealed reversible left ventricular dysfunction with apical ballooning and coronary angiography was normal. Based on these findings, we diagnosed takotsubo syndrome. Over the next two months, the patient experienced repeated bouts of elevated sympathetic activity. On workup, we found an adrenal mass and elevated urine metanephrines. After adrenalectomy, histology confirmed pheochromocytoma. Our patient had the rare diagnosis of postpartum pheochromocytoma-induced takotsubo syndrome.

Functional bladder paraganglioma: An odd presentation of haematuria

Introduction: Bladder paraganglioma is a rare tumour of chromaffin cell origin. Few cases have been reported in the literature. Case report: A 59-year-old female with no known co-morbidities presented with catecholamine-related symptoms, haematuria, elevated blood pressures and raised urine metanephrines. A sonar and computed tomography scan confirmed a bladder mass shown to be active on iodine-131 meta-iodobenzylguanidine. Partial cystectomy was performed. Conclusion: Although bladder paraganglioma is rare, clinicians need to be aware of how such cases may present and the necessary work-up to confirm the diagnosis. Surgery is the treatment of choice, and long-term follow-up of these patients is necessary to detect recurrence or metastases. Level of evidence: 4.