A 52-Year-Old Woman Experiencing Panic Attacks

Correct answer: C. Measuring blood metanephrines is the most sensitive and specific for diagnosis.

Considering the patient’s symptoms—wild and impressive blood pressure swings, palpitations, sweats, and "panic" reactions accompanying them—the diagnosis of pheochromocytoma, a neoplasm of chromaffin cells usually within the adrenal gland(s), comes into focus.

Discussion. Pheochromocytoma is rare condition (less than one per 1 million people encounter the condition)¹ in which a histologically benign adenoma, most often in the adrenal glands, causes symptoms due to abnormal release of excessive catecholamines into the circulation. These catecholamines cause the "classic triad" of headache, palpitations, and paroxysms of severe hypertension. Beyond the triad, pheochromocytoma can also be identified through two other pathways: (1) discovering an adrenal mass before its clinically active, such as abnormal catecholamine release, during imaging for a different condition. (2) genetic family testing after a first-line relative has been diagnosed with pheochromocytoma.

Despite its rarity, once a suspected pheochromocytoma is identified, the order of diagnostic methodology is biochemical testing, appropriate imaging, and, if not previously performed, genetic testing. Biochemical testing is appropriate since chromaffin cell tumors excessively secrete catecholamines into the blood, including metanephrines, epinephrine, norepinephrine, and dopamine, all of which are causes of the blood pressure swings, sweating, pounding heartbeat, and "panic" seen in patients with pheochromocytoma. Although physicians generally measure them all, metanephrines have 97% sensitivity and 93% specificity for pheochromocytoma.¹ 

Imaging to localize the tumor is needed such as contrast enhanced computed tomography (CT) and/or T2-weighted CT. However, based on the literature, magentic resonance imaging (MRI) are the studies of choice^1,2.

Finally, if not already performed, genetic testing for the presence of susceptibility genes should be performed since the need for more extended and detailed imaging as well as need for follow-up may change in genetic positive cases.¹ Genetic testing is now available for the 10 or so most common genetic lesions and markers that potentially result in pheochromocytoma as well as other adenomas such as parathyroid and/or other endocrine neoplasms like medullary thyroid cancer (hence the name multiple endocrine neoplasia syndromes).³ Almost all of these genetic mutations behave as autosomal dominants with variable penetrance such that family screening for a family with history of pheochromocytoma often yields other effected individuals who may develop a pheochromocytoma in up to 50% of the genetic positive cases³ when followed over time. Two well-known genetic mutants are the RET proto-oncogene and the VonHippel-Lindau gene.^1,3

Pheochromocytoma is treated via surgical removal of the tumor, which is the only curative treatment option.¹ The actual procedure itself has been markedly improved with the use of laparoscopic techniques, which has resulted in fewer perioperative complications ^4,5 and a reduction in hospital length of stay.

Much of the mortality and morbidity in pheochromocytoma relates to the catecholamine events prior to diagnosis and perioperatively. But even in the uncommon cases of metastatic disease, long-term survival is quite good, with the literature noting survival into the decades,¹ which makes Answer E incorrect. Both Answer A and B are incorrect considering that imaging for pheochromocytoma is not specific for diagnosis, but rather used after positive biochemical testing for accurate localization of tumor. Indeed, the diagnosis of pheochromocytoma requires both positive biochemical and imaging confirmation of mass. Answer D is incorrect because when isolated pheochromocytoma is diagnosed, 40% of patients will show the presence of a germ line mutation,³ which has consequences for follow-up intensity in the presenting patient and family.

Patient follow-up. The findings of paroxysms of labile, extreme hypertension with associated sweating, and pounding palpitation in a previously non-hypertensive patient prompted thoughts of thyroid disease and pheochromocytoma. A beta blocker, metoprolol, was immediately put in place and blood studies for thyroid disease and catecholamines were examined. The thyroid studies were within normal ranges, but all the catecholamines were markedly elevated including the metanephrines, which were normetanephrine 3.0 nmol/L (normal range is less than 0.5 nmol/L), and metanepherine 3.0 nmol/L (normal range is less than 0.9 nmol/L). Imaging studies revealed a 3.5 cm nodule in the left adrenal gland, which was removed surgically using laparoscopic methodology. The hospital course was uncomplicated and cautious weaning of perioperative alpha blockers and beta blockers was achieved. The patient is now normotensive. Genetic studies in the form of a panel of the most frequent pheochromocytoma genotypes were all negative. The patient is currently doing well and is normotensive at 6 months. She will be monitored clinically (eg, blood pressure), biochemically (eg, catecholamines) and radiologically (eg, scanning of the remaining adrenal gland and retroperitoneum) at 1-year intervals.

What’s The Take Home? Pheochromocytoma is a rare condition in which a histologically benign adenoma, generally in the adrenal glands, causes symptoms due to abnormal release of excessive catecholamines into the circulation, leading to the "classic triad" of headache, palpitations, and paroxysms of severe hypertension. Two other pathways of presentation, beyond the “triad”, are the abnormal adrenal gland mass finding on CT scanning for other reasons and as a result of family studies when a first-line relative has been diagnosed with pheochromocytoma.

The key initial testing for patients with the suspected diagnosis of pheochromocytoma is measuring blood catecholamines. The most sensitive and specific is metanephines, which are 97% sensitive and 93% specific—very powerful in both diagnosing or excluding the presence of pheochromocytoma. Once metanephrines are positive, detailed MRI and CT imaging needs be performed to localize the chromaffin tumor. Diagnosis is confirmed when BOTH catecholamines and a positive imaging study are present.

Patients with pheochromocytoma are surgically treated to remove the tumor. The advent of laparoscopic techniques has made this approach safer for the patient, reducing hospital length of stay. Still, preoperative, perioperative, and postoperative blood pressure control remains extremely important and requires teamwork by the surgeon, anesthesiologist, and intensive care physicians. Generally, a mixture of alpha-adrenergic blockers, beta blockers, and fluid titrations are required.

Along the way, genetic testing for a variety of known, usually autosomal dominant genotypes, which predispose to pheochromocytoma (as well as other adenomas and tumors) is indicated in all patients with pheochromocytoma and their first-line relatives. Although pheochromocytoma remains a dramatic syndrome, current diagnostic imaging and advanced surgical techniques have improved the long-term prognosis for this condition, which is excellent.

AFFILIATIONS
¹Lewis Katz School of Medicine at Temple University, Philadelphia, PA
²Department of Medicine, Temple University Hospital, Philadelphia, PA

CITATION
Rubin RN. A 52-year-old woman experiencing panic attacks . Consultant. 2024;64(5):e4. doi:10.25270/con.2024.05.000003

DISCLOSURES
The author reports no relevant financial relationships.

CORRESPONDENCE:
Ronald N. Rubin, MD, Temple University Hospital, 3401 N. Broad Street, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)

References

1. Neuman HPH, Young WF, Eng C. Pheochromocytoma and paraganglioma. N Eng J Med. 2019;381: 552-565.
2. Lenders JW, Pacak K, Welther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002;287:1427-1434.
3. Neuman HPH, Rausch B, McWhinney SR, et al. Germ line mutations in non-syndromic pheochromocytoma. N Eng J Med. 2002:346:1455-1466.
4. Gagner M, Breton G, Pherand D, Pomp A. Is laparoscopic adrenalectomy indicated for pheochromocytoma? Surgery. 1996:120:1076-1079.
5. Wang W, Li P, Wang Y, et al. Effectiveness and safety of laparoscopic adrenalectomy of large pheochromocytomas. Am J Surgery. 2015;210:230-235.

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