CASE REPORT Undiagnosed Pheochromocytoma Simulating Malignant Hyperthermia Nisha S. Ramani, MD,* Robert Stoppacher, MD,* Ajaykumar C. Morani, MD,† and Charles Catanese, MD* Introduction: Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors. They are surgically curable but can be lethal if remain undiagnosed. We report a patient earlier diagnosed with malignant hyperthermia but later found to have pheochromocytoma on autopsy. Case report: After a preprocedural pain block for elective right shoulder arthroscopy, a 53-year-old hypertensive white man developed chest pain. In the operating room, he had increased blood pressure. Postoperatively, his blood pressures dropped from 220/100 to 80/30 mm Hg. He later developed high fever with core temperature reaching a peak of 42.2°C, rapid breathing, and died after unsuccessful attempts to stabilize him. Autopsy: Autopsy revealed a tumor in his right adrenal gland, measuring 10 cm in greatest dimension and weighing 530 g. It was red brown with a hemorrhagic and cystic cut surface. A thin rim of yellow-orange adrenal cortex was visible at the margin of the tumor, indicating that it originated from the underlying adrenal medulla. The left adrenal gland was unremarkable. Sections showed hypercellular tumor with zellballen architecture. The tumor cells were round to oval with finely granular basophilic cytoplasm and mild pleomorphism. A 24-hour urine sample collected before his death showed greater than 22727 μg/g Ratio to Creatinine metanephrines and normetanephrine, indicating that the tumor was active and secreted high levels of catecholamine. The cause of death was established as the complications of pheochromocytoma in the settings of general anesthesia for shoulder arthroscopy. The manner of death was natural. Conclusions: Pheochromocytoma can mimic malignant hyperthermia, and it should always be considered and managed appropriately in such scenarios to avoid untoward consequences. Pathologists must also be aware of this when conducting an autopsy in cases with a previous clinical diagnosis of malignant hyperthermia. Key Words: autopsy, forensic pathology, postmortem (Am J Forensic Med Pathol 2017;00: 00–00) P heochromocytomas arise from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia. It is more common in females, with a female to male ratio of 6:4. Although the clinical presentation may be quite variable, the classic triad is episodic headache, sweating, and tachycardia in association with hypertension. The symptoms are due to the excessive production of catecholamines such as norepinephrine, epinephrine, and dopamine.1,2 Malignant hyperthermia is a rare autosomal dominant life-threatening condition that is usually triggered by exposure to the volatile general anesthetic drugs. It results from the defect located on chromosome 19q involving the ryanodine receptor. It presents as high fever, tachycardia, rapid breathing, and rhabdomyolysis. The presentation is due to a hypercatabolic state.3–5 There is an overlap of Manuscript received March 28, 2017; accepted May 18, 2017. From the *SUNY Upstate Medical University, Syracuse, NY; and †The University of Texas MD Anderson Cancer Center, Houston, TX. The authors report no conflict of interest. Reprints: Nisha S. Ramani, MD, Department of Pathology, SUNY Upstate Medical University, 750 E Adams St, Syracuse, NY 13210. E-mail: ramanin@upstate.edu. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0195-7910/17/0000–0000 DOI: 10.1097/PAF.0000000000000326 Am J Forensic Med Pathol • Volume 00, Number 00, Month 2017 the symptom between pheochromocytoma and malignant hyperthermia, and hence, cases of pheochromocytoma can be mistaken for malignant hyperthermia. Autopsy studies have indicated that a significant proportion of pheochromocytomas remains undiagnosed during life.6 CASE REPORT A 53-year-old white male was admitted to the hospital for elective shoulder repair. He had a history significant for hypertension and was on antihypertensive medications for the same. After a preprocedural pain block, he complained of chest pain. Results of electrocardiogram was normal. The pain resolved in 15 minutes. In the operating room, he developed high blood pressures. Postoperatively, his blood pressure dropped from 220/100 to 80/30 mm Hg. The labetalol and nitro drips were being continuously monitored and titrated accordingly. The patient was becoming increasingly hyperthermic during this time, reaching a peak of 42.2°C core temperature. He also developed pulmonary edema. The malignant hyperthermia national hotline was consulted and advised to start the protocol. A loading dose of dantrolene was given. His condition, however, continued to worsen. All efforts to stabilize the patient and attempts to save him were unsuccessful, and he died. Autopsy Examination The body was of a 53-year-old white male whose appearance was consistent with his age. External examination revealed an obese habitus with his body weight of 280 lbs, height of 69 in. and body mass index of 41.3 kg/m2. His internal organs were unremarkable except for the heart, which was severely enlarged with a weight of 650 g. The myocardium showed gross left ventricular hypertrophy with left ventricular wall thickness of 1.7 cm. The left main coronary artery and the proximal left and right coronary vessels showed mild atherosclerosis. Severe pulmonary edema was also evident. The right adrenal gland showed a well-circumscribed tumor weighing 530 g and measuring 10  8  7.5 cm. The mass was red brown, and the cut surface of the mass revealed hemorrhagic, cystic, and focally necrotic cut surface (Fig. 1A). Relicts of the yellow-orange adrenal cortex were visible grossly at the margin of the tumor (Fig. 1B). It was clearly visible that the tumor originated from the overlying adrenal gland. The left adrenal gland demonstrated an orange-yellow cortex that was clearly demarcated from the underlying soft and red-brown medulla and appeared unremarkable. Hematoxylin and eosin sections of the adrenal mass showed hypercellular tumor cells with focal areas of hemorrhage and cystic degeneration. At lower magnification (Fig. 2A), the tumor cells showed classic zellballen pattern (ie, alveolar architecture) in thin vascular network. At high magnification (Fig. 2B), the tumor cells showed fine, granular, lightly basophilic cytoplasm and round to oval nuclei with stippled chromatin and fairly prominent nucleoli. Scattered tumor cells showed slight nuclear pleomorphism and rare mitotic figures were also seen. Immunohistochemical stains showed that the tumor cells were positive for neuroendocrine www.amjforensicmedicine.com Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 1 Am J Forensic Med Pathol • Volume 00, Number 00, Month 2017 Ramani et al FIGURE 1. A and B, Gross image of the cut surface of the tumor showing hemorrhagic, cystic, and focally necrotic cut surface. markers synaptophysin and chromogranin, confirming the diagnosis of pheochromocytoma (Fig. 3). Before his death, clinicians did consider pheochromocytoma as a possibility and sent his blood and urine for biochemical investigations. The sample of his urine collected before his death showed that the 24-hour urinary metanephrines and normetanephrine were greater than 22727 μg/g Ratio to Creatinine (reference range for urinary metanephrines for ages ≥18 years is 44–261 μg/24 hours and urinary normetanephrines for ages 50–59 years is 128–484 μg/ 24 hours). These findings demonstrate that the tumor was active, secreting high levels of catecholamines. DISCUSSION Pheochromocytoma can present with varying clinical manifestations such as hypertensive emergencies, acute cardiac event, neurological manifestations, or acute respiratory distress syndrome. Lactic acidosis and high fever can also be seen. Lack of previous hypertension does not eliminate the possibility of pheochromocytoma. It may present as a hypermetabolic state during anesthesia that can be seen with thyrotoxicosis, acute sepsis, and malignant hyperthermia. The mortality in such cases is very high, and appropriate management is very important.7,8 Muscle rigidity has not been described in pheochromocytoma and is frequently associated with malignant hyperthermia. However, muscle rigidity may be absent in nearly 25% of the cases of malignant hyperthermia. Other clinical manifestations of malignant hyperthermia include myoglobinuria, elevated or rapidly increasing temperature, severe mixed metabolic and respiratory acidosis, and high creatinine kinase levels. An analysis of reports of malignant hyperthermia events to the North American Malignant Hyperthermia Registry for 1987 to 2006 found that elevated or rapidly increasing temperature was among the first FIGURE 2. A, (10) Hematoxylin and eosin stain showing tumor cells with zellballen architecture (ie, alveolar pattern). B, (40) Hematoxylin and eosin stain showing tumor cells with finely granular lightly basophilic cytoplasm. 2 www.amjforensicmedicine.com © 2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Am J Forensic Med Pathol • Volume 00, Number 00, Month 2017 Undiagnosed Pheochromocytoma FIGURE 3. A, (20) Immunohistochemical stain synaptophysin showing its expression by the tumor cells. B, (20) Immunohistochemical stain chromogranin showing its expression by the tumor cells. three signs of a malignant hyperthermia event in more than 60 % of patients with a mean temperature of 39.1°C.9 Our decedent had high fever with a core temperature of 42.2°C, no myoglobinuria, no metabolic and respiratory acidosis, and slightly elevated creatinine kinase levels (creatine phosphokinase = 346 U/L, reference range = 20–200 U/L). Hence, sometimes, it is challenging to differentiate pheochromocytoma from malignant hyperthermia specifically in the perioperative period, as seen in this case. All patients with pheochromocytoma need to undergo preoperative α-adrenergic blockade. β-Blockade and adrenal palpation are contraindicated. Adrenal palpation is known to aggravate catecholamine secretion and β-blockers can induce pulmonary edema and are contraindicated in cases without previous adequate α blockade. In cases of inability to differentiate malignant hyperthermia from pheochromocytoma, supportive treatment that is identical for both the conditions such as cooling, bicarbonate, dantrolene, and vasodilation can be given. Dantrolene does not have any side effects on the patient and was used in our case as well.3,4 Pheochromocytomas have an excellent prognosis if diagnosed and managed appropriately. They have a 5- and 10-year survival rate of 92% and 80%, respectively.10 Sutton et al6 reviewed 54 autopsy-proven cases of pheochromocytoma seen at the Mayo Clinic for the 50-year period. In 24% of the autopsies, pheochromocytoma had been correctly diagnosed in life. In remaining 76% of the autopsies, pheochromocytoma was not suspected clinically; however, hypertension was present in both these scenarios in 54% of the cases.6 Due to such high mortality among undiagnosed cases, certain criteria are established for screening. Patients with early onset of hypertension at younger than 20 years, those with severe hypertension (eg, >160 mm Hg systolic or >100 mm Hg diastolic) or with family history of multiple endocrine neoplasia syndromes, must be screened for pheochromocytoma.11,12 Astuti et al13 and Prasad et al14 described the susceptibility of developing pheochromocytoma with germline succinate dehydrogenase “B” subunit and succinate dehydrogenase “D” subunit mutations. Inactivating succinate dehydrogenase “B” subunit and succinate dehydrogenase “D” subunit mutations have been associated with familial pheochromocytoma, hereditary paraganglioma-pheochromocytoma syndromes, and sporadic pheochromocytoma. These findings suggest that these mutations are an important cause of pheochromocytoma susceptibility.13,14 This case demonstrates the importance of autopsies in establishing an exact cause of death. This case also illustrates the significance of active endocrine tumors as a rare cause of sudden death. © 2017 Wolters Kluwer Health, Inc. All rights reserved. The biochemical hallmark is secretion of catecholamines causing dramatic elevations in blood pressure, which is regarded as a typical clinical sign of this tumor. It should be kept in mind that the classical clinical picture of this tumor is not always present and the clinical symptoms can be very variable, so that clinicians should be aware of these unusual features, with regard to the diagnosis pheochromocytoma. Pathologists should also be aware of this rare cause of death especially in those cases, which present as malignant hyperthermia.15 CONCLUSIONS Hypermetabolic response during anesthesia and surgery is unusual and can be from several etiologies such as thyroid storm, malignant hyperthermia, and pheochromocytoma. This case illustrates how pheochromocytoma can mimic malignant hyperthermia, and it should always be considered and managed appropriately in such scenarios to avoid untoward consequences. Pathologists should also be aware of this when conducting autopsy in cases with previous clinical diagnosis of malignant hyperthermia. REFERENCES 1. Tsirlin A, Oo Y, Sharma R, et al. Pheochromocytoma: a review. Maturitas. 2014;77(3):229–238. 2. Aguilo F, Tamayo N, Vazquez-Quintana E, et al. Pheochromocytoma: a twenty year experience at the University Hospital. P R Health Sci J. 1991; 10(3):135–142. 3. Allen GC, Rosenberg H. Phaeochromocytoma presenting as acute malignant hyperthermia—a diagnostic challenge. Can J Anaesth. 1990;37 (5):593–595. 4. Crowley KJ, Cunningham AJ, Conroy B, et al. Phaeochromocytoma—a presentation mimicking malignant hyperthermia. Anaesthesia. 1988;43 (12):1031–1032. 5. Ezri T, Soroker D. Phaeochromocytoma presenting as MH. Can J Anaesth. 1991;38(5):685. 6. Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc. 1981;56(6):354–360. 7. Uchida N, Ishiguro K, Suda T, et al. Pheochromocytoma multisystem crisis successfully treated by emergency surgery: report of a case. Surg Today. 2010;40(10):990–996. 8. Zardawi IM. Phaeochromocytoma masquerading as anxiety and depression. Am J Case Rep. 2013;14:161–163. www.amjforensicmedicine.com Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 3 Am J Forensic Med Pathol • Volume 00, Number 00, Month 2017 Ramani et al 9. Larach MG, Gronert GA, Allen GC, et al. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110(2):498–507. 10. Porcaro AB, Novella G, Ficarra V, et al. Incidental adrenal pheochromocytoma. Report on 5 operated patients and update of the literature. Arch Ital Urol Androl. 2003;75(4):217–225. 11. Zdrojowy-Wełna A, Bednarek-Tupikowska G. Challenges in the diagnosis of pheochromocytoma and paraganglioma syndrome. Neuro Endocrinol Lett. 2014;35(5):355–358. 12. Cicala MV, Sartorato P, Mantero F. Incidentally discovered masses in hypertensive patients. Best Pract Res Clin Endocrinol Metab. 2006;20(3):451–466. 4 www.amjforensicmedicine.com 13. Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001;69(1):49–54. 14. Prasad C, Oakley GJ 3rd, Yip L, et al. A novel mutation in the succinate dehydrogenase subunit D gene in siblings with the hereditary paraganglioma-pheochromocytoma syndrome. SAGE Open Med Case Rep. 2014;2:2050313X14553520. 15. Krane NK. Clinically unsuspected pheochromocytomas. Experience at Henry Ford Hospital and a review of the literature. Arch Intern Med. 1986; 146(1):54–57. © 2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.