Functional paraganglioma of the pancreatic head: A case report and review of literature

Abstract

BACKGROUND

Pheochromocytoma and paraganglioma (PGL) are a rare group of neuroendocrine neoplasms with characteristic genetic diversity and catecholamine secretion patterns. They arise from non-neuronal and non-epithelial neuroendocrine cells of the paraganglia, and have the highest rate of heritability among all tumors.

CASE SUMMARY

A 76-year-old woman presented with the complaint of dizziness that had persisted for one week. She had a 30-year history of hypertension. Despite long-term use of antihypertensive drugs, her blood pressure was not effectively controlled. A tumor was subsequently found in the head of the pancreas by computed tomography and magnetic resonance imaging and she was initially diagnosed with an aneurysm. On December 21, 2021, she underwent resection of the retroperitoneal tumor and pancreatic repair surgery. However, after postoperative pathological analysis and immunohistochemistry, the diagnosis was revised to PGL. After two years and eight months of follow-up, the tumor did not recur or metastasize, and her blood pressure returned to normal without taking antihypertensive drugs.

CONCLUSION

The possibility of PGL should be considered when a tumor is identified and patients have catecholamine secretion related symptoms that are difficult to control with medications.

Key Words: Pancreatic paraganglioma; Pancreatic tumor; Paraganglioma; Metanephrines; Immunohistochemistry; Case report

Core Tip: We report a rare case of paraganglioma (PGL) of the pancreatic head in a patient with a history of persistent hypertension. Due to atypical clinical presentation and imaging features, it is difficult to differentiate PGL from peripancreatic tumor. PGL may induce persistent clinical symptoms related to hypertension without causing other clinical manifestations that draw the attention of from patients over a long period. In order to improve the diagnostic accuracy of pancreatic PGL, the combination of tests for specific biomarkers (metanephrines/normetanephrines is recommended) and imaging examinations based on individual circumstances is highly recommended. Surgery is still recommended as the mainstay of treatment.

INTRODUCTION

Pheochromocytoma (PCC) originates from the adrenal medulla, whereas paraganglioma (PGL) arise from extra-adrenal paraganglia[1]. PGLs are a rare group of vascular neuroendocrine tumors of paraganglionic origin. According to the fourth edition of the World Health Organization classification of endocrine tumors, instead of benign or malignant, PGLs are now categorized as either metastatic or nonmetastatic[2]. The overall incidence of PCC/PGL varies from 0.04/100000 to 0.95/100000 per year, showing an increasing trend over time[3]. In this context, PGLs comprise 15% of PCCs and PGL[4]. The most common site of occurrence is the carotid body, retroperitoneum and base of the skull; therefore, pancreatic PGL (PPGL) is rare[5]. In this study, we report a case of a PGL in the head of the pancreas with dizziness as the only chief complaint and hypertension as the only known disease.

CASE PRESENTATION

Chief complaints

A 76-year-old female presented with dizziness for one week.

History of present illness

Thirty years ago, the patient was diagnosed with hypertension, and she took valsartan tablets (80 mg once daily) to lower her blood pressure. Despite the medication, her blood pressure did not decrease.

History of past illness

The patient was previously in good health.

Personal and family history

She denied any family history of malignant tumors.

Physical examination

On admission to the hospital, the patient underwent a comprehensive physical examination. The results indicated that, apart from a blood pressure measurement of 151/81 mmHg, the patient presented with a soft and non-tender abdomen, devoid of any malformations or palpable masses. No other abnormal findings were detected during the examination.

Laboratory examinations

A battery of laboratory examinations encompassing routine blood work, urinalysis, assessments of liver and kidney function, electrolyte analyses, and tumor marker screenings was conducted, all of which returned normal results.

Imaging examinations

Given that neither the patient’s physical examination nor the laboratory examination results were sufficient to elucidate the disease etiology, we proceeded to incorporate imaging examinations into the diagnostic workup. Ultrasound revealed a swollen mass in the head of the pancreas. A contrast computed tomography (CT) scan of the upper abdomen revealed a mass in the head of the pancreas. An enhanced scan revealed blood vessel penetration. Dilated blood vessels were observed in the center of the mass (Figure 1A and B). A contrast magnetic resonance imaging (MRI) scan of the right abdominal area (pancreatic head) revealed a tumor approximately 3.2 cm × 4.0 cm × 5.2 cm in size. The border was clear, the T1 weighted imaging signal was slightly low, and the T2 weighted imaging signal was mainly high. Within the small patchy low signal, the diffusion weighted imaging signal was high. The apparent diffusion coefficient tumor scan signal was an equal signal, the enhanced arterial scan showed patchy enhancement in the center of the lesion, and the delayed scan showed nonenhancement within the strip of patchy area (Figure 1C and D). In combination with CT findings, we suspected that the mass was an aneurysm.

Figure 1 Computed tomography and magnetic resonance imaging findings. A: A Non-contrast-enhanced computed tomography scan showing a mass of approximately 3.2 cm × 4.1 cm × 5.0 cm in size at the lower edge of the liver and pancreatic head (orange arrow: Pancreas); B: Computed tomography enhancement showing the passage of blood vessels within the tumor, with patchy areas without enhancement and dilated blood vessels in the center (orange arrow: Pancreas); C: Non-contrast-enhanced magnetic resonance imaging in the pancreatic head; D: Magnetic resonance imaging enhanced arterial scan showed patchy enhancement in the center of the lesion and the delayed scan showed non-enhancement in the strip of patchy areas.

FINAL DIAGNOSIS

Following postoperative pathological analysis and immunohistochemistry, the diagnosis was changed to PGL (Figures 2 and 3).

Figure 2 Postoperative microscopic images. A: Heterogeneous cells arranged in organoid or chrysanthemum-shaped clusters [Hematoxylin and eosin (HE): 50 ×]; B: Cells with increased nucleoplasmic ratios and eosinophilic cytoplasm (HE: 100 ×); C: Interstitial fibrous tissue proliferation and myxoid degeneration (HE: 200 ×); D: Irregular nuclear membranes. finechromatin.no necrosis formation (HE: 400 ×).

Figure 3 Immunohistochemistry findings. A: Cluster of differentiation 56 (+); B: Chromogranin A (+); C: Antigen identified by monoclonal antibody Ki-67 (+, 2%-3%); D: Synaptophysin (+) (magnification 200 ×).

TREATMENT

We subsequently informed the patient of the suspected aneurysm. Upon obtaining her informed consent, we made a decision to carry out resection of the mass. Initial blood pressure was controlled by administering oral antihypertensive drugs, namely valsartan capsules (80 mg once daily) and amlodipine (5 mg once daily). Valsartan capsules and amlodipine were discontinued immediately once the blood pressure dropped to an operable range, that is, when the blood pressure was below 140/90 mmHg. During the resection procedure, a round mass in the pancreatic head was discovered. The surrounding connective tissue was subsequently freed, the vascular branches entering the tumor were ligated, and the tumor was completely removed. Tumor removal and an intraoperative rapid histological examination were performed. Rapid intraoperative pathology revealed that the tumor was to be treated as benign. Subsequent, examination confirmed that there was no pancreatic duct loss, and the pancreas was repaired. The surgical incision was gradually closed layer by layer.

OUTCOME AND FOLLOW-UP

Two years and eight months after surgery, the tumor did not recur or metastasize, and the patient’s blood pressure returned to normal without additional antihypertensive medication.

DISCUSSION

The prevalence of PCC and PGL ranges between 0.2% and 0.6% among hypertensive outpatients[6-9]. PPGL is even rarer among PGL occurring outside the adrenal gland, as there are only 6 cases of functional PPGL (12%) in 50 clinical cases of PPGL reported globally in the English-based literature. Elderly females are predominant with a male-to-female ratio of 8:17 among all patients, and the mean age at first diagnosis in PPGL patients was 52 years (range from 19 to 85 years, Supplementary Table 1)[10-47]. PPGL often presents as a solid mass in the head of the pancreas, which is rarely cystic and occasionally occurs in the tail and body. Non-functional PGL is clinically silent and usually found based on imaging diagnosis, while high-level catecholamines (CAs) secretion, persistent hypertension, palpitations, and paroxysmal headaches are frequently observed in cases of functional PGL[48]. Abdominal pain, lumbar pain, constipation or dyspepsia are the most common onset symptoms as they were observed in 32 cases, while 16 patients presented no symptoms and were diagnosed after physical examinations. In addition, CA secretion induced symptoms such as hypertension, palpitations, headache or malaise were major symptoms in 2 cases.

In the case reported in this paper, the patient was diagnosed with hypertension 30 years previously and regularly took antihypertensive drugs. Therefore, it is difficult to trace the relevant information and clarify the sequence between hypertension and tumor occurrence. PGL has been reported to have a relatively higher overall survival rate and disease-specific survival rate (73.3% and 80.5% respectively) compared to PCC (54.0% and 73.0% respectively), which makes long-term survival with the tumor possible[49]. Combined with the data in the table, it is evident that the size of the tumor did not invariably correlate with either the manifestation or absence of symptoms, or with the severity. Primary tumor diagnosis at an older age (P = 0.0011), male sex (P = 0.014), major adverse cardiovascular events, synchronous metastases (P < 0.0001), larger tumor size (P = 0.0039), increased dopamine levels (P = 0.0195), and failure to remove the primary tumor, have been highlighted as risk factors correlated with PGL progression[50,51].

The development of functional PGL commonly accompanies overproduction of CAs, therefore, accurate measurement of CAs and their metabolites is of great significance for clinical decision-making. Measuring metanephrine (MN) in blood and urine is considered the gold standard for functional PGL diagnosis, with a sensitivity of 99% for incidental and hereditary PGL and a specificity of 95% for heritability (89% for incidentals), which is better than any test combination. If the concentration of MN is only 2-4 times above normal values, the evaluation should be performed at baseline and 3 hours after oral administration of 0.3 mg clonidine (clonidine test), and suppression lower than 40% indicates PGL. In addition, the diagnostic sensitivity and specificity of chromogranin A are 83%-86% and 76%-98%, respectively, which could also be an alternative or complement[52-56].

In our case, the examination of MN and normetanephrine was overlooked initially, but CT and MRI scanning were performed instead for localization and diagnosis. Also, endoscopic ultrasound-guided fine-needle aspiration was not conducted due to the risks of mass metastasis. Homogeneity or heterogeneity can be observed in masses on contrast enhanced CT in PPGL patients, together with necrosis, hemorrhage or calcification; however, the appearance may be similar to an aneurysm. On contrast enhanced MRI, the typical appearance of salt-and-pepper can be found in cases of PGL, which is formed by the rapid flow cavity in the enlarged tumor blood vessels and hypersignal areas secondary to slow flow and internal hemorrhage of the tumor[57]. CT is still regarded as the optimal modality for localization and diagnosis of PPGL due to its cost-effectiveness, remarkable sensitivity, relatively short scanning duration, as well as excellent spatial resolution capabilities in thoracic, abdominal, and pelvic regions. If MN biochemical test results are positive, enhanced CT scanning is recommended[58,59]. Single photon emission CT and positron emission tomography can also be considered due to their high sensitivity and specificity for specific molecular targets, such as norepinephrine transporter and L-amino acid transporter 1, but are costly and radioactive[58]. Genetic testing in routine practice is highly recommended for any patients diagnosed with PGL by the working group on endocrine hypertension of the European Society of Hypertension, as genetic alterations explain 80% of all cases[60]. New genes or new presentations of known genes associated with PGL development include DNA methyltransferase 3 alpha, dihydrolipoamide S-succinyltransferase, SUCLG2a, mastermind like transcriptional coactivator 3 fusions, RET fusions, and patients may benefit from related genetic counseling and clinical surveillance[61].

The therapy of choice is surgery whenever possible for PGL. As the major potential postoperative complications consist of hypertension, hypotension and rebound hypoglycemia, multidisciplinary efforts from the surgeon, anesthetist and cardiologist during the perioperative period are demanded. A crucial factor for the treatment lies in making sufficient preoperative preparations, including control of hypertension and blood volume improvement[62]. The use of α-blockers (prazosin, doxazosin, and terazosin, etc.) is mandatory for 7 to 30 days in the preoperative management of PGL patients undergoing tumor resection in order to prevent hypertensive crises and cardiac arrhythmias[63]. However, α-blockers can induce dilation of constricted blood vessels, and blood volume deficiency. Therefore, blood volume should be routinely expanded preoperatively with crystalloid and colloid fluids to avoid severe postoperative hypotensive events. It is generally accepted that good preoperative fluid circulation is manifested by a stable blood pressure below 130/80 mmHg, heart rate between 60 and 80 beats per minute, and the absence of paroxysmal headache, dizziness, palpitations, excessive sweating, warm extremity ends and red nail beds[64]. During the operation, the key points include minimizing tumor compression, ensuring the integrity of the tumor envelope, monitoring the patient’s vital signs and maintaining the patient’s internal environmental homeostasis[65]. On the basis of the above treatment, all patients who have been diagnosed with PGL require life-long and personalized follow-up in accordance with their underlying germline or somatic mutations, together with disease characteristics[66].

CONCLUSION

PGL can be diagnosed according to a high secretion level of CA via serum MN/normetanephrine and special imaging characteristics, including homogeneous masses and salt-and-pepper appearance, before surgery and/or postoperative pathology with or without typical clinical features. The recommended management of PGL should be multidisciplinary, involving surgeons, cardiologists and anesthetists.