Pheochromocytomas (PCC) are rare, neuro-endocrine tumors of the chromaffin cells. PCC arise from the adrenal medulla, whilst paragangliomas (PGL) arise from the paravertebral ganglia of the sympathetic chain [1, 2]. Both PCCs and PGLs present with paroxysmal hypertension, headaches, palpitations and diaphoresis due to excessive catecholamine excretion. Some patients can also present with local tumor symptoms such as abdominal pain [3]. However, because of the non-specific clinical presentation, which may overlap with many other medical disorders, they are also known as the ‘great mimic’. If left undiagnosed and untreated, PCC can become a life-threatening condition. Whilst there is no universally accepted definition for a pheochromocytoma crisis (PC), it is often characterized by multiple organ failure, hemodynamic instability, high fever, and encephalopathy [4]. PC is not synonymous with malignant hypertension, which is caused by sudden catecholamine release from the tumor. Importantly, several patients with PC have been reported to be normotensive or hypotensive at presentation [5, 6]. Newell et al. reported three cases of severe PC, which included four components: multi-organ system failure, severe hypertension and/or hypotension, high fever and encephalopathy [4]. Whitelaw
et al. expanded on this model to group together two distinct subtypes of PC, termed “type A crisis” and “type B crisis”. The type A crisis is used to describe a more limited crisis with hemodynamic instability without persistent hypotension, whereas the type B crisis referred to a severe presentation with sustained hypotension, shock and multi-organ dysfunction [3]. It would be possible for a patient to progress from a type A crisis to a type B in the course of the disease. The incidence of PC varies and can occur in up to 20% of patients with PCC or PGL [7]. With regards to prevalence, a retrospective cohort study by Scholten et al. found that between the years 1993 and 2011, 173 patients were operated on for PCC, but only 25 (14.45%) presented in crisis (type B as described above). In a literature review from January 2008 to February 2013, 106 cases of PC were identified [3]; 66 of these patients belonged to the type A group (62%) and 40 belonged to the type B group (38%). Of the 91 that survived, 62 were type A crises (68%) and 29 were type B (32%). Concerning the 15 patients that demised, 4 were type A (27%) and 11 were type B (73%). This is in keeping with the retrospective study above, as the type A, “non-crisis” group was also more prevalent there. PC is thought to occur secondary to a sudden massive release of catecholamines, however, the exact underlying pathophysiological mechanism has not yet been fully understood. A wide variety of precipitating factors has been suggested, including physical stimulus to the tumor, certain pharmacological administration, anesthesia and infection [3]. In addition, the severity and presentation of a PC varies greatly according to differences in the catecholamines that are released [8]. The most common presentations are hypertensive crisis and catecholamine cardiomyopathy [3]. Whilst abdominal pain, nausea, and dyspnea are also common; anemia, back pain, night sweats, and acidosis have also been reported [9]. Other manifestations of PC include cardiovascular (cardiomyopathy, myocardial infarction, arrhythmia, cardiogenic shock), respiratory (pulmonary embolism, acute respiratory distress syndrome, massive haemoptysis), neurological (ischemic or hemorrhagic stroke, encephalopathy, vertebral artery dissection, posterior reversible encephalopathy syndrome), gastrointestinal (ileus, bowel ischaemia, perforation), hepatic and renal injury [3, 7]. Diabetic ketoacidosis and lactic acidosis are also known to occur, albeit very uncommonly [2]. Because of the varied and often nonspecific presentation, many patients with PC remain undiagnosed [7]. Treatment for patients with PC should not be delayed, as it could lead to increased mortality. Our patient presented with the “typical” PCC manifestations and subsequently re-presented with a PC. The case did not meet the criteria for the type B crisis (shock, sustained hypotension) and as such, would be categorized as a type A crisis. 

A 17-year-old female of African ancestry presented to the Endocrine clinic with a 3-month history of intermittent anxiety,
sweating, palpitations and headaches. She was recently diagnosed with hypertension at her local clinic based on two consecutive elevated blood pressure (BP) readings (150/90mmHg and 160/100mmHg respectively). Systemic enquiry was positive for fatigue, unintentional weight loss and insomnia. She had no other significant medical or family history of note. On presentation, the patient was afebrile with a BP of 190/107mmHg and a regular pulse of 123 beats/min. Her systemic examination was all normal. Biochemical investigation revealed elevated urine normetanephrine level of 50435 (480-2424nmol/24hours) and metanephrines levels of 771 (264-1729nmol/24hours) (Table 1). Contrast enhanced computed tomography (CT) scan of the abdomen revealed a left adrenal mass measuring 34mm x 31mm x 30mm which was centrally necrotic, avidly enhancing with no calcifications noted. The mass measured 80 Hounsfield units with an absolute washout of 38%. The right adrenal gland was normal. A diagnosis of a left adrenal pheochromocytoma was made. She was put onto alpha and beta blockade to control the BP and her symptoms. As genetic testing for pheochromocytomas is not yet available in South Africa, a sample was sent to at an international accredited commercial laboratory, which yielded no genetic mutation. The patient was counselled regarding her diagnosis and the need for surgical intervention. However due to staunch cultural and religious beliefs, the patient and her parents refused further investigations (I-123 metaiodobenzylguanidine (MIBG) scan), as well as any surgical intervention. The social worker counselled the family extensively, however this was in vain as she still refused any treatment. She was then lost to follow-up.

Table 1: Biochemical investigations.

*HPLC-high performance liquid chromatography.

Eight months later, the patient re-presented to a peripheral hospital with a history of sudden-onset severe dyspnea, significant hemoptysis, and altered mental status. Upon examination, she was febrile (38.4°C), hypoxemic (SaO2 86% on room air), and tachycardic (148 beats/min), with labile BP (190/110 mmHg on presentation). The patient was intubated and sedated with propofol and midazolam and was transferred across to our tertiary care hospital. Her chest radiograph revealed extensive consolidation and air bronchograms with obscuration of the right hemidiaphragm in keeping with right lower lobe pneumonia. A sputum specimen was sent for Mycobacterium tuberculosis (TB) polymerase chain reaction (PCR) testing, which came back positive and sensitive to Rifampicin. She was initiated on first line anti-tuberculosis therapy (rifampicin, isoniazid, pyrazinamide and ethambutol as a combination tablet). A diagnosis of a PC precipitated by a lobar pneumonia and pulmonary TB was made. She remained hemodynamically unstable in the intensive care unit (ICU) with labile BPs (Figure 1). Alpha blockade with doxazosin (cardura) was re-initiated. Dihydropyridine calcium-channel blockers were added to assist with BP control, and βeta1adrenoreceptor blockers were used to control the tachycardia.

Figure 1: Labile blood pressure in the intensive care unit.

Table 2: Biochemical investigations of the patient on re-presentation.

After multidisciplinary discussions with critical care, endocrinology and surgery, the patient had a laparoscopic left adrenalectomy 1 week later after adequate alpha and beta blockade was achieved.

She underwent a successful adrenal mass removal (55mm x 30mm x 25mm and weighing 3g). Histopathological examination of the mass revealed a zellballen appearance consistent with the diagnosis of a PCC (Figure 2). Immunohistochemistry staining showed strong and diffuse cytoplasmic positivity in the chief cells for synaptophysin and chromogranin (Figure 3 – Panel A and B respectively).

Figure 2: This high-power (400 x magnification) hematoxylin and eosin (H&E) stain view shows classic Zellballen pattern with the chief cells having abundant clear to granular eosinophilic cytoplasm and regular, even nuclei.

Figure 3A: Synaptophysin staining shows strong and diffuse cytoplasmic positivity in the chief cells.

Figure 3B: Chromogranin staining shows strong and diffuse cytoplasmic positivity in the chief cells.

48 hours post-tumor resection, the patient showed marked clinical improvement with normalization of her vital signs and stabilization of her BP. After a brief period in ICU, she was transferred to the ward and subsequently discharged back to the referring hospital for rehabilitation and to continue her anti-tuberculosis therapy. Unfortunately, she suddenly demised 2 months later. The family declined an autopsy. We postulate the cause of death was due to a possible pulmonary embolus (PE).

Our patient initially presented with a three-month history of intermittent anxiety and the classic triad of sweating, palpitations and headaches with a new diagnosis of hypertension. This clinical picture was in keeping with a PCC.

The diagnosis was confirmed biochemically and radiological features were in keeping with that of a PCC. She was put onto an alpha and beta blockade to manage her BP and symptoms and offered surgical resection of the tumor; but refused due to cultural and religious beliefs.

The patient defaulted all treatment and presented to a peripheral hospital 8 months later with features consistent with a PC. She was transferred to a tertiary care facility and admitted to the ICU where she had to be re-initiated on alpha blockade. Calcium-channel blockers and beta-blockers were also utilized to help manage the BP and HR. In addition; she was diagnosed with Pulmonary TB. Once stabilized she was successfully operated on. 48 hours later her vital signs stabilized adequately for her to be discharged from ICU to the ward.

Her subsequent demise 2 months later, was sudden and unexpected and was most likely due to a PE. She had multiple risk factors for a PE which included prolonged bed rest and anti-tuberculosis treatment.

Several reports have stressed the importance of emergency treatment for PC to avoid significant morbidity and mortality [5, 10]. However due to the rarity of the condition, there are no universally accepted guidelines and treatment recommendations are limited to case reports, expert opinion or single center series [11]. Whilst management does have to be tailored to each individual case depending on which organ system is involved, there are some common approaches [2]. Ideally patients presenting with PC should be managed in an ICU setting with appropriate monitoring and circulatory support.

Intravenous fluid resuscitation is very likely to be needed in both type A and type B crisis; together with, or before, the commencement of alpha-blockade to prevent severe hypotension [3]. This is due to the fact that sympathetic vasoconstriction results in relative intravascular hypovolemia. Caution should be used with patients displaying cardiovascular complications (cardiomyopathy, left ventricular failure) as pulmonary oedema and fluid overload can rapidly develop with overzealous fluid resuscitation.

The most widely accepted initial pharmaceutical treatment for managing a PC is the use of alpha blockade [3]. It is recommended that this be done in a cautious and sustained manner in an attempt to reverse the vasoconstriction and hypertension which may be present [3, 4]. The choice of drug is left up to the supervising clinician. In the retrospective cohort study by Scholten et al., phenoxybenzamine was used for all patients at least ten days pre- operatively. It is non-competitive, non-selective, long acting, and can be titrated to effect [2]. With our patient, doxazosin was used as an alternative due to phenoxybenzamine not being available. The use of doxazosin is increasing in popularity due to its selective blockade of the alpha-1 receptors which results in a more favorable side effect profile.

In catecholamine overstimulation, activation of beta 2 receptors cause vasodilation, which attenuates the hypertensive and vasoconstrictive effects seen during a PC. Using a beta-blocker before an alpha-blocker disables this moderating effect and allow unopposed alpha-adrenergic activity, thus worsening the crisis [3]. As such, it is recommended that a beta-blocker be added to the regimen after appropriate alpha blockade has been achieved to counter reflex tachycardia or tachyarrhythmia [3].

There are a small number of case reports describing the use of calcium-channel blockers (CCB) as the sole drug to control BPs in PCs [12]. It is worth remembering that CCB do not prevent all the hemodynamic changes, however its use has been associated with low morbidity and mortality [13]. In our case, beta blockers and calcium-channel blockers were added on to the alpha-blockade regimen prior to surgical intervention.

The definitive management of a PC is surgical resection of the PCC or PGL itself. The purpose of medical stabilization pre-surgery is to prevent catecholamine-induced, serious and potentially life- threatening complications intra-operatively [14]. Attempting to manage a PC conservatively is associated with increased mortality. However, surgery is not without its own significant risk of morbidity and mortality. In a review by Koyabashi et al., high mortalities were noted with emergency surgeries carried out during a PC in patients with ruptured or hemorrhaging PCC [15]. Therefore, timing of the operation is crucial to achieve a favorable outcome.

During the management of a PC, if the patient remains unstable and/or the medical stabilization has failed, the role for emergency adrenalectomy becomes apparent. The advent of laparoscopic surgery has also reduced postoperative morbidity, length of hospital stay and expense when compared to open laparotomies [2]. Laparoscopic cases also have a low complication rate of below 8% and a conversion rate to open laparotomy of 5% [16]. In a case report and literature review by Kakoki et al., the importance of emergency surgery is highlighted when medical management has failed; they reviewed reports where all cases of PCC without surgical resection resulted in death, despite conservative therapy (5/12 [42%] cases were not operated on all demised) [17]. This can be compared to a case series by Meijs et al., where four individuals with PCC were operated on and the mortality rate was only 16.7% [11].

As with our case, medical stabilization was carried out in an ICU setting with fluid resuscitation and a combination of pharmacological therapy. Once the patient was deemed clinically and hemodynamically stable, successful emergency surgery was carried out. The patient improved markedly in terms of vital signs and BP normalization post-operatively; such that she was discharged from ICU to a medical ward and eventually to her referral hospital.

We report a case of life-threatening and rapidly progressive PC. Due to PCC and PGLs frequently mimicking other conditions, clinicians should have a high index of suspicion for a PC in patients with unexplained shock, multi-organ failure, lactic acidosis and hypertensive crisis. Timely recognition and rapid medical management are required to stabilize a patient in PC, prior to definitive surgical treatment. Emergency surgery is very important in achieving a favorable outcome.

The patient gave verbal and written consent for this case report. Ethics approval was granted from the Human Research Ethics Committee (Medical) from the University of the Witwatersrand (M210484) and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

We acknowledge the Intensive care unit and the surgical department of Helen Joseph Hospital.

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