Atypical presentation of pheochromocytoma as acute ischemic stroke and pulmonary embolism, a case report

Abstract

Background: Pheochromocytoma is a rare catecholamine-secreting tumor that often presents with symptoms such as hypertension, palpitations, and sweating due to excessive hormone production. In some cases, the catecholamine-induced vasoconstriction and hypercoagulability associated with pheochromocytomas can lead to cerebrovascular accidents and venous thrombosis. We report a rare case of pheochromocytoma in a middle-aged man who initially presented with a stroke and later developed a pulmonary embolism.

Case Presentation: A 44-year-old gentleman presented with sudden right-sided weakness, numbness, and slurred speech, lasting for 6 h. His medical history included hypertension, for which he was on bisoprolol. On examination, he exhibited right-sided facial weakness, asymmetric smile, and motor weakness (0/5 on the right). Brain computed tomography angiography revealed an infarction in the left middle cerebral artery territory, complicated by hemorrhagic transformation. Seven days later, he developed severe left-sided abdominal and chest pain, sweating, and left upper quadrant tenderness. His labs showed leukocytosis, and chest radiography raised suspicion of pulmonary embolism (PE). A computed tomography (CT) pulmonary angiogram confirmed thrombi in the left lower lobe with moderate left pleural effusion. Abdominal ultrasound revealed a non-vascular mass near the left kidney, which was later identified as a 3.6 cm × 4.3 cm adrenal mass on CT. Biochemical tests confirmed pheochromocytoma. An FDG-PET scan suggested an intense FDG-avid left adrenal mass.

Conclusion: This case demonstrates the rare association between pheochromocytoma and thrombotic events. Atypical presentations can complicate diagnosis, highlighting the need for early testing. Surgery remains the primary treatment, with long-term follow-up due to the risk of recurrence.

Graphical abstract

Keywords

adrenal tumor / arterial thrombosis / catecholamines / ischemic stroke / pheochromocytoma

1 INTRODUCTION

Pheochromocytomas are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla. These tumors can arise sporadically or as part of hereditary syndromes[1]. They are characterized by the excessive secretion of catecholamines, including adrenaline, noradrenaline, and dopamine, resulting in a spectrum of clinical presentations. Common symptoms include episodic headache, sweating, and tachycardia, though hypertension—either sustained or paroxysmal—is the most frequently observed feature[2].

Pheochromocytoma is diagnosed via elevated plasma or urinary metanephrines and confirmed with computed tomography (CT) or magnetic resonance imaging (MRI). Surgical resection is the main treatment, typically preceded by medical therapy to manage blood pressure and minimize surgical risks[3].

While pheochromocytoma usually presents with well-known symptoms, its occurrence as an ischemic stroke is rare. Possible mechanisms include catecholamine-driven vasoconstriction, hypertension, and a prothrombotic state[4]. This highlights the need to consider pheochromocytoma in younger stroke patients, particularly those with hypertension or atypical features[5].

This case report highlights the incidental discovery of pheochromocytoma in a patient who presented with ischemic stroke. It emphasizes the necessity of evaluating secondary causes of stroke in younger individuals and explores the pathophysiological mechanisms linking pheochromocytoma to cerebrovascular complications.

2 CASE PRESENTATION

A 44-year-old Indian gentleman presented to the emergency department with sudden-onset weakness and numbness in his right arm and leg, symptoms onset were seven hours after waking up. He had gone to bed at midnight feeling well and reported no prior similar episodes. These neurological deficits were associated with slurred speech and word-finding difficulty. No additional neurological symptoms were reported, including seizures, headaches, dizziness, incontinence, photophobia, blurred vision, vision loss, trauma, or loss of consciousness.

He had a history of hypertension, managed with bisoprolol for three months. He had no prior hospitalizations, trauma, or surgeries. Family history was unremarkable. He worked an office job, was a former smoker (quit 5 years ago after 20+ years), did not drink alcohol, and maintained a healthy lifestyle with regular exercise.

On initial assessment, the patient was afebrile, with stable vitals (heart rate 85 bpm, blood pressure 153/92 mmHg). He was alert and oriented but had slurred speech. Cranial nerve exam showed right facial weakness, decreased facial sensation, and a positive Babinski sign on the right lower limb. Motor strength was 0/5 in the right upper limb and 5/5 on the left. Sensory loss to pinprick, light touch, and proprioception was noted on the right. Cerebellar testing was normal on the left but unassessable on the right. NIHSS score was 13. Systemic exam was otherwise unremarkable.

Initial investigations are summarized in Table 1.

CT head non-contrast showed subtle hypodensity noted in the left frontotemporoparietal region with reduced gray-white matter differentiation likely of acute infarct/ischemia (Figure 1).

Brain perfusion and angiography CT revealed a matched perfusion defect in the left parietal and frontotemporoparietal lobes, representing an infarct, with an adjacent mismatched perfusion defect indicating a penumbra. Diffuse irregular narrowing of the left MCA was also noted (Figure 2). MRI showed multiple focal areas of diffusion restriction and T2/FLAIR hyperintensities in the cortical and subcortical regions of the left frontotemporoparietal area, adjacent to the left insula, consistent with an infarction in the left MCA territory.

Susceptibility-weighted imaging (SWI) demonstrated blooming artifacts, suggesting hemorrhagic transformation (Figure 3). Other investigations, including echocardiography and Holter monitoring, were unremarkable.

The patient remained stable and was improving until Day 7 of admission, when he reported severe abdominal pain in the left upper quadrant and left lower chest, accompanied by sweating, symptoms lasting for 1 h. He remained afebrile with a heart rate in the 70s and normotensive (134/85 mmHg). On examination, the patient was sweating and in pain, with tenderness on palpation of the left upper quadrant. Initial labs showed mild leukocytosis with normal hemoglobin and platelet counts. Chest X-ray showed blunting of the left costophrenic angle, and electrocardiogram (ECG) revealed the classic S1-Q3-T3 pattern (Figure 4). Given clinical suspicion for acute pulmonary embolism (PE), a CT pulmonary angiogram was performed, revealing acute segmental and sub-segmental thrombi in the left lower lobe and a moderate left pleural effusion. Nevertheless, the patient remained hemodynamically stable.

An abdominal ultrasound was requested to assess the abdominal pain and unexpectedly revealed a round, isoechoic, non-vascular structure posterior to the left kidney and below the spleen, measuring 3.73 cm × 3.17 cm (Figure 5).

CT abdomen was performed for further characterization and showed a large, homogeneous, left adrenal mass measuring 3.6 cm × 4.3 cm (Figure 6).

An MRI revealed a well-defined mass lesion measuring 4.3 cm arising from the left adrenal gland, which appeared slightly hypointense compared to renal parenchyma on T2-weighted imaging, with restricted diffusion. There was mild peripheral enhancement and a central non-enhancing scar with corresponding diffusion restriction (Figure 7).

Hormonal assays, including morning cortisol, DHEAS, aldosterone, plasma renin activity, and plasma renin ratio, were all within normal ranges (Table 2). Urine metanephrines revealed significantly elevated levels of adrenaline, noradrenaline, normetanephrines, and vanillylmandelic acid (VMA), along with elevated metanephrine creatinine ratios and VMA/creatinine ratios (Table 3), all consistent with pheochromocytoma.

A PET scan confirmed a large, intensely FDG-avid left adrenal mass, highly suspicious for malignancy (Figure 8). Vitals, blood glucose levels, and electrolytes being within normal range during the patient's hospital course, unlike the expected disturbances observed with pheochromocytoma. Due to the patient's recent stroke with hemorrhagic transformation, the case was reviewed in a multidisciplinary team meeting. It was decided that the patient would be a candidate for surgical resection of the left adrenal gland after 6 months, pending repeat imaging prior to the procedure.

3 DISCUSSION

Stroke as a manifestation of pheochromocytoma is rare but clinically significant, particularly given the high morbidity associated with cerebrovascular events. Although no robust epidemiological data specifically quantify the prevalence of stroke as a presenting symptom in pheochromocytoma, case reports and smaller studies suggest that elevated catecholamine levels play a central role[6]. These catecholamines, synthesized by the tumor and released into the circulation, exert potent vasoconstrictive effects on cerebral vasculature, reducing cerebral blood flow and promoting stasis—conditions that favor thrombosis formation. Additionally, catecholamines can directly injure the vascular endothelium, predisposing to dissection, rupture, and subsequent cerebral infarction[7,8].

Elevated catecholamine levels disrupt the balance of vascular endothelial factors such as nitric oxide (NO), prostacyclin, and endothelin, which regulate vascular tone and antithrombotic activity. NO synthase 1 and endothelin-1, predominantly localized in the central nervous system (CNS), are particularly affected, contributing to endothelial dysfunction[9]. Additionally, vascular smooth muscle cells (VSMCs), which are key regulators of hemostasis, are activated by norepinephrine via the phospholipase C pathway, leading to intracellular calcium increases and subsequent contraction through myosin light chain kinase activation. Independent pathways, such as Rho-kinase activation, further exacerbate VSMC contraction[10]. This excessive vasoconstriction creates localized vascular stasis, promoting thrombus formation and increasing the risk of ischemic stroke. Selective cerebral involvement may reflect the uneven distribution of endothelial products across vascular territories[9].

Hypertension, a hallmark of pheochromocytoma, plays a critical role in stroke pathophysiology. Hypertensive crises, frequently observed in pheochromocytoma patients, may overwhelm cerebrovascular autoregulation, resulting in ischemic or hemorrhagic events[11]. Notably, paroxysmal hypertension induced by unopposed α-adrenergic receptor stimulation—particularly following β-blocker administration—can precipitate hypertensive encephalopathy, characterized by diffuse ischemic injury across multiple small vascular territories rather than a single vessel distribution[12]. Sympathomimetic agents can also induce arterial spasms in peripheral, coronary, and cerebral arteries, further compounding the risk of transient ischemia or infarction[13]. Despite the rare incidence of pheochromocytoma, it is crucial for clinicians to maintain a high index of suspicion, particularly in patients presenting with early-onset or refractory hypertension, to avoid life-threatening complications such as stroke[14].

Pheochromocytoma is also associated with venous thrombosis, including cases involving the inferior vena cava and iliofemoral veins. Anatomical compression from the tumor and prolonged hypertension may alter blood flow, leading to stasis and vascular endothelial damage[15,16]. Moreover, pheochromocytomas often exhibit paraneoplastic features that promote a hypercoagulable state. For example, catecholamines stimulate platelet activation and release procoagulant factors, further exacerbating thrombophilia[17].

Genetic syndromes such as von Hippel-Lindau (VHL) mutations add another layer of complexity. These mutations disrupt hypoxia-inducible factor (HIF) pathways, resulting in polycythemia and a predisposition to venous thromboembolism[18]. Erythropoietin-like activity, isolated from some pheochromocytomas, has been implicated in polycythemia, with resolution following tumor resection. Elevated hematocrit levels in such cases are often attributed to reduced plasma volume rather than increased red cell mass[19].

These mechanisms underscore the importance of investigating secondary causes of stroke and hypertension in younger patients, particularly those without traditional risk factors. Pheochromocytoma exemplifies such conditions and often remains undiagnosed in 20%–30% of cases, leading to delays in treatment and potentially severe outcomes[20]. The diagnosis typically relies on elevated plasma or urinary metanephrine levels, followed by imaging techniques such as CT, MRI, or specialized molecular imaging to localize the tumor. For instance, 68Ga-DOTATATE PET imaging has proven superior for detection and staging, especially in cases where 123/131I-MIBG shows limitations[21].

Treatment primarily involves surgical resection, with the approach tailored to the tumor's size and invasiveness. Laparoscopic adrenalectomy is preferred for localized pheochromocytomas, while open surgery is reserved for larger or invasive tumors[22]. In metastatic cases, systemic therapies such as radionuclide treatments like 131I-MIBG or peptide receptor radionuclide therapy (PRRT) and tyrosine kinase inhibitors, such as sunitinib, provide symptom relief and disease control. These systemic options, though effective, require integration into personalized treatment plans that consider tumor genotype and growth rate[23].

Emerging targeted therapies, including HIF-2α inhibitors such as belzutifan, offer promising results for managing aggressive or unresectable pheochromocytomas[24]. These inhibitors disrupt hypoxia-inducible factor pathways, which are often aberrantly activated in pheochromocytoma and paragangliomas due to underlying genetic mutations. Advances in these therapeutic strategies are reshaping the landscape of care, allowing for more tailored and potentially curative approaches in previously challenging cases[25].

This case underscores the rarity of pheochromocytoma presenting with acute ischemic stroke, highlighting the intricate interplay of neuroendocrine and vascular mechanisms. While pheochromocytomas are well-recognized for causing refractory hypertension, their direct association with cerebrovascular events remains an uncommon phenomenon. The simultaneous presentation of a hemorrhagic transformation and abdominal pain leading to an incidental adrenal mass discovery further distinguishes this case. Such a constellation of symptoms illustrates the atypical and multifaceted nature of pheochromocytoma, where its manifestations can obscure the underlying diagnosis, particularly in the context of an acute neurological emergency. This case provides a compelling example of the diagnostic challenges posed by rare causes of stroke, urging clinicians to maintain a high index of suspicion for endocrine etiologies in younger patients without conventional vascular risk factors. From an educational standpoint, this case serves as a pivotal reminder of the need for comprehensive and multidisciplinary evaluation in atypical stroke presentations.

4 CONCLUSION

Pheochromocytoma-associated stroke exemplifies the interplay of neurohormonal, hemodynamic, and thrombotic mechanisms. Comprehensive evaluation, including consideration of paraneoplastic and genetic factors, is essential for timely diagnosis and management. As awareness grows, early identification and tailored interventions may reduce the burden of stroke and other vascular complications in pheochromocytoma patients.

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