Introduction
Pheochromocytoma and paraganglioma (PPGL) are rare tumors of the adrenal medulla, with an incidence approximately of 0.6 cases per 100,000 inhabitants/year, which recognize a genetic, germinal or somatic basis in up to 50% of cases [1]. Pheochromocytoma has also been defined as the “ten percent tumor”: in 10% of cases, it occurs in children; in 10% of cases, it is extra-adrenal; in up to 10% of cases, it is bilateral (in adults); in 10% of cases it is multicentric; in 10% of cases, it arises as a familial syndrome [1]. In 2017, the World Health Organization classified endocrine tumors and included chromaffin tumors among the malignant ones because of their metastatic potential [2]. In particular, metastatic forms represent approximately 5-26% and are characterized by a highly heterogeneous prognosis [3]. Currently, because of the rarity of these tumors, it is challenging to identify reliable prognostic factors for metastasis. One of the significant problems in patients affected by pheochromocytoma is the management of side effects due to the release of catecholamines (CA) by the tumor, which is associated with a high cardiovascular risk with hypertension as a common clinical feature, often forgotten as the possible cause [4] and important gastrointestinal complications (e.g., constipation, intestinal infarction) burdened by a significant increase in mortality. Atypical cardiovascular manifestations include transient left ventricular dysfunction and ventricular tachycardia [5]. A particular condition associated with PPGL is Takotsubo syndrome (TS), also known as acute stress cardiomyopathy due to its connection to physical or emotional stress. This syndrome is characterized by a transient systolic dysfunction of the left ventricle associated with akinesis of its apex that mimics acute coronary syndrome but without angiographic evidence of coronary disease. Increased levels of catecholamines due to PPGL may trigger TS through sympathetic nervous system hyperactivation [6]. PPGL-TS is more common in younger patients than primary TS, and it is associated with a more severe presentation and a much higher percentage of complications, including multiorgan failure [5, 6]. Alphalytics, such as phenoxybenzamine or doxazosin, are the therapy of choice to counteract the negative effect of catecholaminergic excess, normalize blood pressure levels, and allow blood volume expansion.
Beta-blockers can be introduced, exclusively following an adequate alpha-adrenergic blockade, to control any associated tachycardia and acute coronary events [7]. However, calcium antagonists may represent an alternative therapeutic approach for blood pressure control when alphalytics and beta-blockers-based therapy is inefficient [7]. Metyrosine, an inhibitor of CA synthesis, can be used in case of failure of the above therapies. However, its use is limited due to side effects at the central nervous system level (e.g., drowsiness, agitation, and, rarely, parkinsonism) [1]. For the non-metastatic PPGL, the gold standard treatment is adrenalectomy, which can be total (TA) by removing both adrenal glands or partial (PA) by attempting to remove only the tumors to preserve adrenal hormonal function [1, 8]. TA is associated with permanent adrenal insufficiency, requiring lifelong corticosteroid replacement therapy with a risk of a life-threatening Addisonian crisis [3].
Moreover, recent studies have also reported that lifelong use of steroid hormone therapy is associated with reduced quality of life and increased mortality [3, 9]. Most of the published reports have focused on the long-term outcome only of surgical complications and life-long corticosteroid replacement therapy without any consideration of hypertension development. There is still a need for long-term outcomes for cardiovascular risk factors such as hypertension.
Case presentation
Here, we presented a successful case of TA in a young patient affected by pheochromocytoma. Early in 2009, a 24-year-old man was referred to our second-level outpatient hypertension clinic by his family practitioner because of resistant hypertension diagnosed a year before and already treated with a combination of angiotensin-converting enzyme inhibitors plus calcium antagonists plus thiazide diuretics according to the guidelines available at that time. The anamnesis revealed tachycardia, cephalalgia, paroxysmal hypertension, weight loss, and fatigue worsening in the last few months. At physical examination, no specific signs were detected. Only flushing could be appreciated. Search for secondary hypertension was suggested by age and referred symptoms. Thus, blood tests for measurement of renin, aldosterone, corticosteroids, and catecholamines in plasma and urine and renal and adrenal ultrasound are indicated. Ultrasound evaluation was performed at the same time of the office visit, and physical examination showed a 4-cm right and 6-cm left solid adrenal formation isoechoic compared with the liver. The suspicion of pheochromocytoma was made, and while attending the results of lab tests, alpha-1 blockers were added to better manage symptoms according to the evidence at that date [10]. The diagnosis of pheochromocytoma was then confirmed by the elevation of urinary and plasma-free metanephrines (> 1000 μg/day and > 500 pg/mL, respectively). The tumor localization was assessed by metaiodobenzylguanidine ([123I] MIBG) scintigraphy whole body [10], showing a bilateral accumulation (Fig. 1A), thus further confirming the diagnosis. A computed tomography (CT scan) was finally performed to provide a better anatomical definition of the bilateral formation. Once all the diagnostic work-up was completed, a surgical consult was requested. A TA was proposed and performed upon the patient’s acceptance. As shown in Figure 1B, two solid masses were removed. The patient’s recovery was complete and fast, and discontinuation of all antihypertensive medication was made a few weeks after surgery. The patient had regular follow-ups for the first year after surgery and then every three years. In 2024, the patient is still maintaining a healthy status, requiring corticosteroid replacement therapy. More important, he did not develop hypertension. The ultrasound evaluation during the last office visit showed no new masses at adrenal levels. A combined positron emission tomography (PET)/CT scan confirmed the ultrasound report (Fig. 2). It showed no F-18 fluorodeoxyglucose (FDG) uptake in the glands’ putative location and the whole body (Fig. 3).
Discussion
The case presented in this article is, to our knowledge, one of the longest follow-ups in hypertensive patients affected by bilateral pheochromocytoma underwent TA. The patient was successfully treated in 2009, remaining in a healthy status without developing hypertension for up to 16 years. However, a corticosteroid replacement therapy was required, but no local tumor recurrence occurred. Despite the lifelong use of steroid hormone replacement, the patient has reported a good quality of life. Most of the published reports indicate that surgical removal of the adrenal glands is effective in the resolution of hypertension in the short term [11, 12], but no data are available in the long term [13].
Hypertension is diagnosed in up to 90% of patients with PPGL in both forms, sustained and paroxysmal [13]. It is considered curable with surgery [13] but with conflicting results in the mid-term since, in some studies, up to 65% were already hypertensive at 1 year post-surgery [14]; in others, the majority of patients were reported normotensive [13].
Post-surgery hypertension seems to be not related to the surgical technique [8]. Our patient has been treated with TA. It is still a matter of debate who might be the better candidate for partial adrenalectomy (PA), also known as cortical-sparing adrenalectomy [8]. It is a surgical procedure with the main intent to preserve a small, vascularized, tumor-free part of adrenal tissue to maintain adrenal hormone secretion [8]. Still, the risk of recurrence, the higher incidence of local relapses, and the development of metastasis are some significant concerns related to this technique [8]. Because of the recurrences, long-term surveillance in patients treated with PA is recommended [1]. Endocrine Society Clinical Practical Guidelines recommend PA for bilateral pheochromocytoma but with a low level of evidence [1].
Conclusions
Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors producing catecholamines. These molecules are the main responsible for serious cardiovascular and gastrointestinal complications. The lack of guidelines for the management of these tumors makes them a challenge for clinicians. The case we presented showed how TA was a successful choice for our patient but with the price of a lifelong need for corticosteroid replacement therapy. Hypertension can be definitely cured after pheochromocytoma removal, even for the bilateral forms.
Authors’ contributions
ET wrote the bulk manuscript with LM, CF and RS. The manuscript was edited by FN with GC and PG. The author(s) read and approved the final manuscript.
Availability of data and materials
There was no data associated with this case report.
Competing interests
There were no conflicts of interest from any of the authors.
Consent for publication
Written consent was obtained from the patient.
Ethics approval and consent to participate
Not applicable.
Funding
None declared.