MANAGEMENT OF PHEOCHROMOCYTOMA IN THE SETTING OF ACUTE STROKE

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1 AACE Clinical Case Reports Rapid Electronic Articles in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Case Report ACCR MANAGEMENT OF PHEOCHROMOCYTOMA IN THE SETTING OF ACUTE STROKE Solomon Oak 1 *; Mahsa Javid, MD, DPhil 1,2 *; Glenda G. Callender, MD 1 ; Tobias *These authors contributed equally Carling, MD, PhD 1 ; and Courtney E. Gibson MD MS 1. From: 1 Department of Surgery, Section of Endocrine Surgery, Yale University School of Medicine, New Haven, Connecticut. 2 Medical University of South Carolina, Department of Surgery, Division of Oncologic and Endocrine Surgery, Charleston, South Carolina. Running title: Pheochromocytoma and stroke Address correspondence to: Courtney E. Gibson MD MS Assistant Professor of Surgery, Department of Surgery, Section of Endocrine, PO Box , New Haven, CT courtney.gibson@yale.edu

2 ABSTRACT Objective: Stroke is a rare presenting symptom of pheochromocytoma; therefore, a balance between adequate preoperative medical blockade and expedition of surgery to minimize the risk of further perioperative stroke is needed. However, currently there are no established guidelines regarding timing of surgery or length of preoperative blockade in these patients. We report a case of pheochromocytoma in a 53-year-old woman presenting with a hemorrhagic transformation of an ischemic stroke. We describe the clinical course, diagnosis and management, and discuss similar cases in the literature, and optimal preoperative management. Methods: We reviewed all clinical data and described the patient presentation and treatment. A comprehensive literature review of the topic was performed. Results: Pheochromocytoma in our patient presented as a combination of stroke, severe hypertension, and tachycardia. A CT scan, evaluation of catecholamine levels and 123 I-labeled metaoidobenzylguanidine (MIBG) scan confirmed pheochromocytoma. Hemodynamic stability was achieved after nine weeks of treatment with selective alphablockade and other antihypertensive medications, after which laparoscopic transabdominal adrenalectomy was performed. Despite a normal blood pressure at preinduction, the patient experienced six episodes of severe hypertension intraoperatively. There were no operative complications and hypertension resolved postoperatively. A review of the literature identified five similar cases, however, the optimal management of these patients remains unclear.

3 Conclusion: Our case highlights the importance of including pheochromocytoma in the differential diagnosis of patients with stroke. Optimal results may be achieved by ensuring at least six weeks of recovery following stroke, and inducing orthostatic hypotension for at least two weeks prior to the surgery. Key words: Adrenalectomy, stroke, preoperative blockade, catecholaminergic crisis, hypertension. Abbreviations: MIBG = 123I-labeled metaoidobenzylguanidine scan; CT = computed tomography; EKG = electrocardiogram; CTA = computed tomography angiography; SDHB = succinate dehydrogenase iron-sulfur subunit; TIA = transient ischemic attack; SBP = systolic blood pressure; AACE = American Association of Clinical Endocrinologists; AAES = American Association of Endocrine Surgeons; PET CT = positron emission tomography computed tomography.

4 INTRODUCTION Pheochromocytomas are rare catecholamine-secreting tumors originating from chromaffin tissues (1). In the United States, the annual incidence is 2-8 diagnoses per million populations (1). Most patients (70-80%) with pheochromocytoma are symptomatic (2). Of these, the vast majority (85-95%) present with sustained or paroxysmal hypertension due to excess catecholamine production from the tumor (2). If the catecholamine-induced hemodynamic disturbance is severe, neurological injuries such as stroke and profound cardiac complications may result (3). Presently, cure may only be achieved by surgical resection of the tumor, which itself presents a risk for further cardiovascular complications from excess catecholamine secretion during tumor manipulation (1). The preoperative administration of a receptor blockade regimen can attenuate the effect of released catecholamine intraoperatively (2). In patients presenting with stroke, the intraoperative manipulation of tumor may worsen the stroke and neurological injury. However, guidelines on the surgical management of such patients have not been established. It remains unclear what length of preoperative medical blockade is adequate to control hormone levels intraoperatively, while not risking further stroke in the preoperative period. We report a case of a patient with pheochromocytoma presenting with hemorrhagic transformation of an ischemic stroke.

5 CASE REPORT A 53-year-old woman with an ischemic stroke 13 days prior was transferred from an outside hospital to our tertiary referral center under the care of neurology. Her neurological symptoms included lightheadedness, hemiparesis, aphasia and cognitive impairment. Her past medical history included hypertension, type 2 diabetes, supraventricular tachycardia, and coronary artery disease. She was on beta-blockade and hydralazine for hypertension. The patient s blood pressure at the time of transfer was 220/120 mmhg. Computed tomography angiography (CTA) demonstrated a hemorrhagic conversion of a left anterior and middle cerebral artery ischemic stroke, with worsening edema and midline shift. She was placed on continuous electroencephalogram monitoring, which demonstrated expected poor function over the infarcted left hemisphere without seizures. The following was her course: On day one, nicardipine infusion (2.5 mg/hr) and labetalol (dose: 200 mg/q8hr) were used to control hypertension and tachycardia. Despite the treatment, the patient continued to be hypertensive (178/81 mmhg) and experienced an episode of supraventricular tachycardia. She was given hydralazine (10-20 mg prn) and metoprolol (5mg prn) for arrhythmia. On day three, an increased dose of labetalol (300 mg/q8hr) and nicardipine (5 mg/hr) lowered the blood pressure from 182/76 mmhg to 153/56 mmhg.

6 An abdominal CT scan, performed to investigate symptoms of constipation, incidentally revealed a 5.0 x 5.7 cm right adrenal mass. Upon consulting the endocrinology and endocrine surgery services, a differential diagnosis of pheochromocytoma or adrenal cortical carcinoma was made. Beta blockade was stopped due to concern for a potential pheochromocytoma. Biochemical analysis revealed a significant elevation of total urinary metanephrine levels at μg/24hr [normal upper limit: 832 μg/24hr]. Free plasma normetanephrine and metanephrine were also elevated at 45 nmol/l [<0.90 nmol/l] and 31 nmol/l [<0.50 nmol/l], respectively. A 123 I-labeled metaoidobenzylguanidine (MIBG) scan was requested to exclude malignant pheochromocytoma with visceral metastasis. The scan demonstrated increased radiotracer uptake at the expected location of the right adrenal gland with no other areas of increased activity, and confirmed a diagnosis of pheochromocytoma. On day four, alpha-blockade was initiated with doxazosin (3 mg/day) and nicardipine was discontinued. The patient s continuous tachycardia prompted EKG evaluation and telemetry, which confirmed multifocal atrial tachycardia and left ventricular hypertrophy. To control spikes in blood pressure (up to 204/96 mmhg), diltiazem and amlodipine were instituted. After attenuating the severe hypertensive symptoms on the seventh day of alpha-blockade, an adrenalectomy was planned. A multidisciplinary approach was used to decide the optimal timing for surgery. An extensive discussion took place to weigh the options of waiting until full alpha-blockade had taken effect, which could risk a further stroke prior to surgery, and proceeding with surgery at an earlier time which could potentially risk precipitating a further stroke during

7 surgery if the alpha-blockade was inadequate. In consultation with endocrinology and neurology, a decision was made to postpone the surgery until the patient had at least 6 weeks of recovery time since the stroke and adequate blockade as indicated in the Endocrine Society Clinical Practice Guidelines (i.e. blood pressure of less than 130/80 mmhg while seated and greater than 90 mmhg systolic standing target heart rate of bpm seated and bpm standing) (4). The operation was performed after nine weeks of alpha-blockade ten weeks after the stroke. Pre-induction blood pressure was 116/54 mmhg and heart rate was 71 bpm. A transabdominal laparoscopic adrenalectomy was performed uneventfully. The arterial blood pressure spiked over 180 mmhg, six times during the surgery. There were no operative complications. Pathology confirmed an 85 gram, 6.2 cm pheochromocytoma with normal succinate dehydrogenase iron-sulfur subunit (SDHB) expression. Postoperatively, the patient remained normotensive and was discharged without antihypertensive medications. She was admitted to a long-term rehabilitation facility for her stroke symptoms. The patient was referred to genetic counseling but was unable to attend. Follow-up visits at seven and 30-days confirmed the resolution of nonneurological pheochromocytoma symptoms. At eight months postoperatively, the patient s blood pressure (123/67 mmhg) and metanephrine levels were normal, however, the neurological symptoms of aphasia, facial droop, and paralysis were persistent.

8 DISCUSSION Stroke is a rare presentation of pheochromocytoma. Although statistics on the prevalence of stroke as a presenting symptom of pheochromocytoma have not been reported, a review of the literature found six reports that discuss such cases. Five of these report pheochromocytoma patients presenting with a non-hemorrhagic stroke (3,5-8) while one reports a patient with a transient ischemic attack (TIA) (9). Similarly, a stroke in the context of paraganglioma was reported in two cases (10, 11). However, it is uncertain in these cases if the pheochromocytoma was the underlying cause of the stroke. In our patient, the four-fold increase of catecholamines, difficult hemodynamic stabilization, and relatively young age of hypertension and stroke onset stronglysuggest that the stroke was due to pheochromocytoma. Although not established, the timing of pheochromocytoma resection in stroke patients is discussed in 3 reports. Cohen reports an uneventful surgery with 2 weeks of alphablockade and recovery time after the stroke (7). Dagartzikas reports proceeding with surgical resection when no episodes of SBP > 160 mmhg were observed for 72 hours. No surgical complications were reported (6). Yebra reports performing the adrenalectomy 46 days after the stroke, but the duration of preoperative phenoxybenzamine blockade was unspecified. Although the neurological symptoms of speech alteration persisted, hypertensive symptoms were resolved within one year of surgery (8). The surgical timing following a stroke has been investigated for elective surgeries. Initially, it was thought that there was no association between surgical timing after a

9 stroke and perioperative complication following elective surgery (12). However, a more recent study reports that a history of stroke was associated with adverse surgical complications if the elective surgery took place within 9 months following the stroke (13). However, the study finding s generalizability to pheochromocytoma patients is uncertain, as the number of adrenal surgeries was not specified. For non-elective emergency surgeries, such as hip fracture repair, the optimal timing of surgery following a stroke still remains unclear (14). No randomized prospective studies have conclusively established the optimal preoperative blockade regimen and length even for non-urgent cases of pheochromocytoma. The most commonly used regimen is alpha-adrenergic blockade, but calcium channel blockers are also used (15). While the AACE/AAES guidelines recommend 1 to 3 weeks of alpha-adrenergic blockade, the length of optimal preoperative blockade remains controversial (15). Such uncertainties support the need for a systematic review of the optimal pre-operative blockade regimen and surgical timing for emergent cases of pheochromocytoma. Our case highlights the necessity to investigate secondary causes of hypertension in young patients. It is reported that the diagnosis is missed in about 20-30% of pheochromocytoma patients who present with minor symptoms, which has the potential to result in tragic consequences (3). Our patient had a long history of hypertension since a relatively young age. However, the underlying pheochromocytoma remained undiagnosed until the occurrence of the stroke. It is important to note that the beta

10 blockade was stopped as soon as there was suspicion that the patient may have a pheochromocytoma, in order to avoid further hypertensive crisis from unopposed alpha blockade. Although MIBG was used in our patient to rule out malignant pheochromocytoma with metastasis, studies have shown PET CT scans are also effective, if not better, for this evaluation, especially for patients with known metastasis (16, 17, 18). Despite the apparently benign pathology of most pheochromocytoma, the reported rate of postoperative recurrence is 6 to 23% (19). Our patient is still at risk of recurrence and will require life-long annual follow-up of plasma free metanephrine levels. CONCLUSION For stroke patients with no clear etiology, pheochromocytoma should be included in the differential diagnosis. Specific circumstances must be considered prior to deciding on a therapeutic strategy in individual cases. From our clinical experience, we recommend that patients with pheochromocytoma and stroke should undergo at least six weeks of recovery time and alpha blockade following the stroke, and achieve orthostatic hypotension for at least two weeks prior to adrenalectomy. DISCLOSURE The authors have no multiplicity of interest to disclose.

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12 FIGURE 1. Abdominal computed tomography scan demonstrating an enhancing 5.7 cm right adrenal mass with central low attenuation (left white-filled arrow). The left adrenal gland is unremarkable (right black-filled arrow).

13 FIGURE 2. Whole body 123 I-labeled metaiodobenzylguanidine (MIBG) scan demonstrating increased radiotracer uptake in the mid-right abdomen at the expected location of the right adrenal gland. No additional foci of abnormal uptake suspicious for MIBG-avid disease are demonstrated. Anterior scans- left and middle; posterior scanright.

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