Bilateral pheochromocytoma: case series and review of treatment strategies based on genetic mutations

Introduction

Most pheochromocytomas (PCCs) are unilateral and sporadic; however, approximately 10% are bilateral and frequently associated with hereditary syndromes such as von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type 2 (MEN2), and neurofibromatosis type 1 (NF1) (1-3). The Cancer Genome Atlas (TCGA) study demonstrated that pathogenic germline variants are present in approximately 27% of PCC overall, and that up to 40% of cases harbor somatic driver alterations. Within this broad genetic context, bilateral PCC are characterized by a markedly higher germline burden, with pathogenic variants identified in 69–80% of cases, indicating a substantially greater contribution of hereditary predisposition compared with PCC overall (2). PCC with germline pathogenic variants are associated with an overall high risk of recurrence and malignant progression, although this risk varies by genotype. RET- and VHL-associated PCCs typically have a more indolent clinical course, whereas SDHB pathogenic variants significantly increase the risk of metastatic disease (4). Nevertheless, the overall diagnosis rate of genetic mutations in PCC remains relatively low (5), and previous guidelines have not typically accounted for individual genetic backgrounds.

The standard treatment for PCC is total adrenalectomy. However, bilateral adrenalectomy results in permanent adrenal insufficiency and requires lifelong corticosteroid replacement, which can significantly impair patient quality of life (QOL). Adrenal-sparing (partial) adrenalectomy offers the advantage of preserving endogenous steroid production and has demonstrated favorable functional outcomes in selected hereditary cases (6,7). Nonetheless, the risk of tumor recurrence in the residual adrenal tissue remains a concern.

At the Jikei University Hospitals, eight patients with bilateral PCCs were treated between 1976 and 2024 (Table 1). Of these, five underwent partial adrenalectomy, and long-term steroid replacement was successfully avoided in all of these cases. In this study, we present four representative cases of hereditary PCC, discuss their underlying genetic backgrounds and explore the clinical relevance of adrenal-sparing surgery. We also highlight the importance of incorporating personalized medicine into treatment strategies for bilateral PCCs. We present this article in accordance with the AME Case Series reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-683/rc).

Case presentation

Study methods

This study was conducted as a multicenter, retrospective case series. Consecutive patients who underwent surgery for bilateral PCC were included. Patients were treated at 4 institutions affiliated with Jikei University School of Medicine, Tokyo, Japan. The study period extended from January 1, 1976 to December 31, 2024. Data were collected retrospectively from medical records, operative reports, and pathology databases. Follow-up information was obtained from institutional databases and outpatient records. Eligible participants were patients who underwent adrenal surgery for bilateral PCC during the study period. Inclusion criteria were: (I) histologically confirmed PCC; and (II) bilateral disease treated with adrenal surgery. Exclusion criteria included: (I) unilateral PCC; (II) paraganglioma (PGL) without adrenal involvement; and (III) insufficient clinical or follow-up data. Consecutive cases meeting the inclusion criteria were identified from institutional surgical registries. Relevant patient characteristics, including age at diagnosis, sex, medical history, comorbidities, tumor stage, family history, smoking status, biochemical findings, and genetic background (if available), were recorded. Information on surgical procedures (partial vs. total adrenalectomy), perioperative management, postoperative complications, and long-term hormonal status was extracted. This was a retrospective study with no intervention; follow-up continued through March 31, 2025. In the absence of standardized, genotype-specific surveillance protocols for bilateral PCC, postoperative follow-up was performed at 3–6-month intervals in all patients, regardless of genetic background. Postoperative steroid replacement therapy was initiated at a dose of 50–100 mg/day immediately after surgery and gradually tapered to 10–15 mg/day by approximately 2 weeks postoperatively, at which point the patients were discharged. Thereafter, patients were followed up every 2–4 weeks in the outpatient clinic of the department of metabolism and endocrinology, where clinical assessment and laboratory examinations were performed to guide further steroid tapering. Steroid dose reduction or discontinuation was considered when normalization of plasma adrenocorticotropic hormone (ACTH) levels and a morning serum cortisol level >15 µg/dL were confirmed, in the absence of symptoms suggestive of adrenal insufficiency, such as fatigue or orthostatic hypotension, and when appetite and body weight remained stable. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for the publication of this case series and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Case 1: a 29-year-old woman

A 29-year-old woman presented with numbness in both hands and predominantly in the right leg, along with dysphagia. She had a past medical history of hemangioblastoma of the medulla oblongata, which had been surgically resected at the age of 16 years. There was no significant family history of hereditary disorders, though her grandmother had hypertension. Neurological symptoms prompted the patient to visit a local clinic, where imaging revealed recurrence of the medullary hemangioblastoma. Surgical resection was planned. During the preoperative evaluation, abdominal computed tomography (CT) incidentally revealed bilateral adrenal tumors and a mass in the pancreatic tail. She was subsequently referred to the Jikei University Hospital for further assessment and management. Endocrinological testing showed an elevated 24-hour urinary normetanephrine (NMN) level of 5.92 mg/day (reference range, <0.9 mg/day). Abdominal plain CT revealed heterogeneous, hypodense masses in both adrenal glands, measuring 70 mm on the right and 40 mm on the left. A slightly hypodense mass with punctate calcifications was also identified in the pancreatic tail. On magnetic resonance imaging (MRI), these adrenal lesions demonstrated T2 hyperintensity (Figure 1, A_1-2). ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy demonstrated increased uptake in the adrenal lesions consistent with MRI findings, but no uptake was observed in the pancreatic mass (Figure 1, A₃). Based on these findings, a diagnosis of bilateral PCCs and a pancreatic neuroendocrine tumor (NET) was established. In order to prevent treatment prolongation and reduce the risks associated with repeated intra-abdominal interventions, bilateral adrenal surgery together with distal pancreatectomy and splenectomy was performed in a single stage. Surgical access was obtained via a Chevron incision with a vertical midline extension. After entering the peritoneal cavity, the ascending colon was mobilized to expose the right adrenal gland. The right superior adrenal vein branching from the inferior phrenic artery and the middle adrenal vein from the aorta were ligated. Three tumor nodules, arranged in a dumbbell-like fashion and located cranially within the right adrenal gland, were resected en bloc with an adequate margin, preserving adjacent normal adrenal tissue. A general surgeon performed distal pancreatectomy and splenectomy. The left adrenal gland was then addressed. After ligating the left middle adrenal vein, we resected the tumor while preserving approximately half of the remaining adrenal gland. The total operation time was 6 hours and 45 minutes, with an estimated blood loss of 450 mL. The resected right adrenal gland measured 75 mm × 45 mm × 35 mm and weighed 38 g, while the left measured 30 mm × 30 mm × 15 mm and weighed 4 g. Both lesions appeared as solid, yellow-brown tumors with surrounding residual adrenal tissue. Cystic degeneration and intratumoral hemorrhage were observed. There was no gross evidence of capsular rupture. Histologically, both adrenal tumors demonstrated nests of tumor cells with nuclear pleomorphism and basophilic to clear cytoplasm, separated by fibrovascular stroma. Partial fibrous capsule formation was noted, and some tumor cells were intermingled with normal adrenal cortex. No evidence of extra-capsular invasion was seen. These findings were consistent with PCCs, and complete surgical resection was confirmed. The resected pancreatic mass measured 65 mm × 60 mm × 58 mm and diagnosed as a Grade 2 NET (NET G2). The patient was discharged on oral hydrocortisone 10 mg/day, which was tapered and discontinued by 2 months after the surgery. Postoperative genetic testing confirmed a diagnosis of VHL disease. This case involves a synonymous VHL variant (c.342T>C, p.Gly114Gly); however, because it is located at a splice-related region, it is suspected to affect mRNA splicing and result in the production of an abnormal VHL protein. At 49 months after surgery, follow-up brain CT revealed asymptomatic recurrence of hemangioblastoma in the cerebellum, which has since been managed conservatively.

Figure 1 Preoperative imaging findings in four cases of bilateral pheochromocytoma. This figure summarizes the radiological characteristics of bilateral PCC in four cases using CT, T2-weighted MRI, and ¹²³I-MIBG scintigraphy. Arrows indicate the PCC lesions. (A) Image examination results for case 1. (A_1-2) T2-weighted MRI images show bilateral PCC. Image (A₁) represents an axial plane, and image (A₂) represents a coronal plane. (A₃) Increased uptake in both adrenal glands were observed on ¹²³I-MIBG scintigraphy. The arrows indicate the PCC. (B) Image examination results for case 2. (B_1-2) T2-weighted MRI scans. Image (B₁) represents an axial plane, and image (B2) a coronal plane. (B₃) Increased uptake in both adrenal glands was observed on ¹²³I-MIBG scintigraphy. The arrows indicate the PCC. (C) Image examination results for case 3. (C1) CT revealed PCC measuring 28 mm on the left and 17 mm on the right. (C_2-4) T2-weighted MRI scans are shown. Image (C_1-2) represents an axial section, and image (C_3-4) represents coronal sections. (C₅) Increased uptake in both adrenal glands was observed on ¹²³I-MIBG scintigraphy. The arrows indicate the PCC. (D) Image examination results for case 4. (D_1-2) CT revealed PCC measuring 30-mm tumor on the left (D₁) and a 23-mm tumor on the right (D₂). (D_3-4) Coronal sections of T2-weighted MRI demonstrate adrenal tumors: the left in image (D₃), and the right in image (D₄). (D₅) Increased uptake in both adrenal glands was observed on ¹²³I-MIBG scintigraphy. The arrows indicate the PCC. ¹²³I-MIBG, ¹²³I-metaiodobenzylguanidine; CT, computed tomography; MRI, magnetic resonance imaging; PCC, pheochromocytoma.

Case 2: a 66-year-old woman

A 66-year-old woman was referred to our hospital for further evaluation and treatment following detection of markedly elevated serum carcinoembryonic antigen (CEA, 346 ng/mL) and calcitonin levels (>1,600 pg/mL) at a local clinic. Her past medical history included hypertension and type 2 diabetes mellitus. Her family history was notable for colorectal cancer in both parents and breast and colorectal cancer in two of her three siblings. Contrast-enhanced CT revealed bilateral adrenal masses and enlargement of the right thyroid lobe. Endocrinological studies showed markedly elevated urinary catecholamines: adrenaline 64.0 µg/day, noradrenaline 278.5 µg/day, and dopamine 870.3 µg/day. Urinary metanephrines (MN) were mildly elevated: MN 0.41 mg/day and NMN 0.44 mg/day. Serum calcitonin was significantly elevated at 4,000 pg/mL. Abdominal contrast-enhanced CT revealed a 40 mm left adrenal mass and a 15mm right adrenal mass, both showing contrast enhancement and internal hypodense areas suggestive of cystic degeneration. MRI demonstrated T2 hyperintensity in the corresponding lesions (Figure 1, B_1-2). ¹³¹I-MIBG scintigraphy revealed strong uptake in the left adrenal mass and mild but above-physiological uptake in the right adrenal gland (Figure 1, B₃). Ultrasonography (US) of the thyroid showed an enlarged right lobe (44 mm × 16 mm × 25 mm) with irregular margins, coarse calcifications, and increased internal vascularity, consistent with a suspicious malignant thyroid mass. The left lobe measured 8 mm × 7 mm × 6 mm and appeared unremarkable. Based on these findings, the patient was diagnosed with bilateral PCCs and suspected MEN2. A two-stage surgical approach was adopted: laparoscopic left adrenalectomy was performed first, followed by laparoscopic right adrenal-sparing adrenalectomy 2 months later. During the left adrenalectomy, the central adrenal vein was ligated, and the entire gland was resected. The operation lasted 180 minutes, with minimal blood loss (<50 mL). In the subsequent right adrenal-sparing surgery, the tumor was identified caudal to the central adrenal vein, which was preserved. The tumor was excised from the surrounding normal adrenal tissue. This operation lasted 151 minutes, with blood loss again <50 mL.

Pathological examination revealed both the left (35 mm × 30 mm × 15 mm) and right adrenal tumors (20 mm × 13 mm × 12 mm, 4 g) were consistent with PCC. Capsular and periadrenal fat invasion was observed in both specimens. Postoperatively, the patient was discharged on oral hydrocortisone 25 mg/day, which was tapered and discontinued by 4 months after the second surgery. At 5 months postoperatively, due to persistent suspicion of thyroid malignancy, the patient underwent total thyroidectomy with central neck dissection and autotransplantation of parathyroid tissue. Histopathology confirmed medullary thyroid carcinoma with negative surgical margins. At 5 years of follow-up, the patient remains disease-free, with no evidence of recurrence of PCC or medullary thyroid carcinoma, and requires neither steroid replacement nor antihypertensive medication. In this case, medullary thyroid carcinoma, PCC, and hyperthyroidism had already been diagnosed, raising strong clinical suspicion of MEN2. Based on these characteristic clinical findings, genetic testing was not performed at the discretion of the attending physician.

Case 3: a 26-year-old man

A 26-year-old man was referred to the Jikei University Hospital for evaluation of bilateral adrenal tumors, which had been incidentally discovered during CT scan performed in the pediatric department of our hospital to investigate persistent fever and lymphadenopathy. His past medical history was notable for hypertension. His family history was significant for VHL disease in both his mother and younger sister. Endocrinological studies revealed elevated urinary catecholamines: adrenaline 27.5 µg/L, noradrenaline 274.9 µg/L, and NMN 1.06 mg/L. Chest contrast-enhanced CT demonstrated well-demarcated nodules measuring 28 mm in the left adrenal gland and 17 mm in the right adrenal gland (Figure 1, C₁). Unenhanced abdominal MRI demonstrated T2-hyperintense nodular lesions in the bilateral adrenal glands (Figure 1, C_2-4). ¹²³I-MIBG scintigraphy showed increased uptake corresponding to both adrenal lesions (Figure 1, C₅). Based on these findings, the patient was diagnosed with bilateral PCCs. VHL disease was suspected based on the family history. Laparoscopic left adrenalectomy was performed first, followed by laparoscopic right adrenal-sparing adrenalectomy 8 months later. In the left adrenalectomy, the central adrenal vein was ligated, and the tumor was completely resected. The operation time was 50 minutes with minimal blood loss. During the right adrenal-sparing surgery, the upper two-thirds of the adrenal gland exhibited a tumor mass, while the lower one-third retained normal architecture. The tumor was excised to preserve the remnant adrenal tissue. The main adrenal vein, which drained toward the tumor side, was ligated. The operation lasted 79 minutes, with minimal blood loss.

Histopathological analysis confirmed PCCs in both adrenal specimens: the left tumor measured 35 mm × 30 mm × 25 mm, and the right 20 mm × 19 mm × 13 mm. The Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) scores were 4 for the left tumor (histological type: 0, cellularity: 1, comedo-type necrosis: 0, vascular/capsular invasion: 1, Ki-67 labeling index: 1, catecholamine type: 1) and 3 for the right tumor (histological type: 0, cellularity: 1, comedo-type necrosis: 0, vascular/capsular invasion: 0, Ki-67 labeling index: 1, catecholamine type: 1), indicating intermediate differentiation. The postoperative course was uneventful, and the patient was discharged on oral hydrocortisone 15 mg/day, which was gradually tapered and discontinued at 7 months postoperatively. However, 9 months after the initial surgery, follow-up imaging revealed a 25-mm, well-demarcated mass adjacent to the left side of the inferior vena cava. ¹²³I-MIBG scintigraphy showed increased uptake, consistent with recurrent PCC. Given its asymptomatic nature and stable size, a conservative approach was chosen. Follow-up CT at 3 years and 4 months postoperatively showed no increase in tumor size. The patient subsequently relocated and discontinued follow-up at the Jikei University Hospital. In this case, VHL was strongly suspected based on the family history and the pathological features of the PCC. Although genetic testing was recommended, it was not performed because of patient-related circumstances, including relocation.

Case 4: a 47-year-old man

A 47-year-old man was referred to the Jikei University Hospital for further evaluation following the incidental discovery of bilateral adrenal tumors on non-contrast abdominal CT performed during a workup for hypertension. He had no relevant past medical history. His family history was notable only for prostate cancer in his father. Endocrinological studies revealed elevated urinary catecholamines and their metabolites: adrenaline 46.2 µg/day, noradrenaline 207.4 µg/day, dopamine 750.9 µg/day, MN 1.46 mg/day, NMN 0.72 mg/day, vanillylmandelic acid (VMA) 7.5 mg/day, and creatinine-corrected VMA 5.81 µg/mg·Cr. These findings supported a diagnosis of catecholamine-secreting tumors. Contrast-enhanced abdominal CT revealed well-demarcated nodules in the adrenal glands measuring 30 mm on the left and 23 mm on the right (Figure 1, D_1-2). T2-weighted MRI showed hyperintense nodular lesions in both adrenal glands (Figure 1, D_3-4). ¹²³I-MIBG scintigraphy demonstrated increased uptake in both adrenal lesions (Figure 1, D₅). No mass or enlargement was observed in the pancreas. US of the neck revealed a mass in the left lobe of the thyroid gland, but no findings strongly suggestive of malignancy. A diagnosis of bilateral PCCs was established. The patient underwent laparoscopic left adrenal-sparing surgery, followed by laparoscopic right total adrenalectomy 4 months later. Intraoperatively, three central adrenal veins were identified on the left side; two drained into the tumor, while one drained into the remaining normal adrenal tissue. The veins draining the tumor were ligated using a LigaSure device, and the tumor was excised while preserving most of the normal adrenal gland. The procedure lasted 2 hours and 39 minutes with minimal blood loss. Four months later, the patient underwent laparoscopic right adrenalectomy. The central adrenal vein was ligated, and the tumor was excised completely. The procedure lasted 2 hours and 42 minutes with minimal blood loss. Histopathological examination of the left adrenal tumor (27 mm × 27 mm × 25 mm) confirmed PCC with no evidence of extracapsular invasion. The Pheochromocytoma of the Adrenal gland Scaled Score (PASS) was 2 points (profound nuclear pleomorphism: 1, nuclear hyperchromasia: 1). The right adrenal tumor (30 mm × 25 mm × 20 mm) was also consistent with PCC. The surgical margin was positive, and the PASS score was 1 point (nuclear hyperchromasia: 1). The postoperative course was uneventful. Hydrocortisone was discontinued on postoperative day 4 after the first surgery. Six years postoperatively, the patient remains free from recurrence or metastasis. The thyroid lesion continues to be monitored via ultrasonography, with no malignant features observed to date. Genetic testing has not been performed. Although MEN2 was strongly suspected based on clinical features, invasive procedures, including biopsy of the thyroid lesion, as well as genetic testing, were not performed following shared decision-making with the patient.

Discussion

Epidemiology of hereditary pheochromocytoma/paraganglioma (PPGL)

PPGL has been referred to as “rule of 10s” and was previously thought to include 10% hereditary, bilateral, extra-adrenal, and malignant lesions (1). Recent research has challenged the traditional “rule of 10s” for PCCs and PGLs, indicating that hereditary cases are more common than previously thought. Subsequently, Takayanagi et al. reported, in Japanese cohort extra-adrenal lesions as 9.9%, bilateral lesions as 8.2%, and hereditary lesions as 5.0% (8). A study reported in 2017 by TCGA analyzed 173 PPGL samples collected from multiple institutions. The study found that 6% of cases were bilateral, and 27% of cases had some type of germline mutation. Detailed genetic analysis revealed that many cases had not yet been diagnosed with genetic mutations (2). Germline mutations have been reported in 69–80% of cases of bilateral PCC. When bilateral PCC is detected, it is necessary to consider genetic testing of family members, keeping in mind the possibility of a hereditary disease (3,9,10).

Currently, large-scale genetic analysis is being conducted, and approximately 20 genes have been identified as causing somatic or germline mutations in PCC. The most commonly affected genes include SDHB (9%), VHL (4%), RET (6%), NF1 (3%), SDHD (2%), MAX (1%), TMEM127 (0.6%) and EGLN1 (0.6%) from TCGA study (2). Notably, 7–15% of apparently sporadic cases carry germline mutations (11,12). In bilateral lesions, unlike the genetic mutation profile of solitary PCC, VHL (34%), RET (17%), MAX (7%), TMEM127 (7%), and SDHB (3%) were reported, and the proportion of genetic mutations was higher than in cases of unilateral PCC (10). In addition to bilateral cases, other factors that increase the risk of germ cell mutations include young age at onset, multiple tumors, and tumors outside the adrenal glands (11,12). In cases with these characteristics, it is necessary to diagnose not only germline gene abnormalities that are expected to be passed on to the next generation, but also whether there are any underlying genetic tumor syndromes (MEN2A, MEN2B, VHL disease, NF1). Although genetic inheritance patterns vary depending on the mutated gene, many are autosomal dominant (AD), meaning that there is a 50% chance that the child of a carrier will inherit the mutation from their parent, and family screening is recommended (Table 2) (2,5,13-20). Among them, SDHD and SDHAF2 undergo maternal imprinting, so even if mutations are inherited from the mother, tumors rarely develop, and one or more generations may be skipped (21,22). Genes that cause PPGL have been identified through TCGA analysis and are grouped into pseudohypoxia (cluster 1: SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, EPAS1, and EGLN1) (Figure 2A), kinase signaling (cluster 2: RET, NF1, TMEM127, MAX, HRAS, FGFR1, and MET) (Figure 2B), and Wnt-altered (cluster 3: CSDE1 or MAML3) (2,14). Each is thought to be associated with different biochemical and clinical phenotypes (23,24). Pseudohypoxia type promotes tumor cell proliferation and angiogenesis by activating hypoxic signaling pathways due to abnormalities in the tricarboxylic acid cycle (TCA cycle) and HIF pathway within mitochondria. Compared to other subtypes, it is characterized by early onset, extra-adrenal lesions, norepinephrine dominance, and a high risk of metastasis (25). Wnt-altered types promote cell proliferation and invasion through activation of Wnt/β-catenin signaling. Adrenal primary tumors are characterized by a high risk of metastasis (2,26,27). Kinase signaling types contribute to tumor formation by activating signaling pathways involved in cell proliferation and differentiation. Compared to other subtypes, it tends to occur at an older age, originate in the adrenal glands, be adrenaline-dominant, have a low risk of metastasis, and accumulate MIBG (2,14,19). Among these genetic mutations, SDHB mutations have been reported in several studies to be highly malignant, and it is speculated that prognosis varies depending on the type of genetic mutation (28,29). A meta-analysis of 948 cases showed that patients with SDHB gene mutations and those with high norepinephrine and dopamine secretion levels had a higher risk of metastasis (30). Since the presence or absence of metastasis has been reported to be associated with cause of death, it is conceivable that classification based on driver gene mutations could be a prognostic factor (31,32). The meta-analysis results showed that classification based on driver gene mutations, including SDHB, was not an independent factor associated with survival (30).

Figure 2 Molecular pathways and genetic clusters associated with pheochromocytoma and paraganglioma. This schematic illustrates the key molecular pathways involved in the pathogenesis of PPGL, categorized into three major genetic clusters: (A) cluster 1 (pseudohypoxia pathway), (B) cluster 2 (kinase signaling pathway). The figure was created based on information from BioRender.com [2025]. Source: https://app.biorender.com/biorender-templates. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; FAD, flavin adenine dinucleotide; FH, fumarate hydratase; IDH, isocitrate dehydrogenase; MDH2, malate dehydrogenase 2; PHD, prolyl hydroxylase domain; PPGL, pheochromocytoma/paraganglioma; VHL, von Hippel-Lindau tumor suppressor.

Germline mutations in hereditary syndromes associated with PCC

Several driver gene mutations are known to contribute to the development of PCC, particularly in the context of hereditary tumor syndromes. Among these, germline mutations play a critical role.

The VHL gene is responsible for VHL disease, a hereditary syndrome characterized by hemangioblastomas of the central nervous system and retina, renal cell carcinoma, PCC, and pancreatic tumors. The incidence of PCC in VHL patients is reported to be 10–20%, of which approximately 40% are bilateral (33). The leading causes of death in VHL disease are central nervous system hemangioblastomas and renal cell carcinoma, accounting for over 95.6% of mortality (34). Specifically, hemangioblastomas contribute to 66.2% and renal cell carcinoma to 29.4% of mortality (34). Although mortality due to renal cell carcinoma has declined with the establishment of standardized treatment protocols, hemangioblastoma remains an independent poor prognostic factor for overall survival (35). Common sites of hemangioblastoma include the cerebellum, spinal cord, retina, and medulla, with the cerebellum being the most frequently involved. While cerebellar and spinal lesions can often be resected early with favorable outcomes, medullary lesions are associated with significant neurological morbidity and high surgical risk, even when small (34). MEN2 is an AD hereditary syndrome caused by pathogenic variants in the RET proto-oncogene and is classified into MEN2A and MEN2B subtypes (36). MEN2A is characterized by medullary thyroid carcinoma, PCC, and primary hyperparathyroidism, whereas MEN2B presents with an earlier-onset and more aggressive form of medullary thyroid carcinoma, PCC, and characteristic features such as mucosal neuromas and a marfanoid habitus. Large clinical series have demonstrated that MEN2B patients develop disease manifestations at a significantly younger age than MEN2A patients. In particular, the median age at diagnosis of PCC has been reported to be approximately 34 years (range, 17–60 years) in MEN2A and 25 years (range, 18–40 years) in MEN2B. In both MEN2A and MEN2B, PCC occurs in approximately 50% of patients, and 60–80% of PCC cases are bilateral (37). Although both subtypes share RET as the causative gene, MEN2B is most caused by a single pathogenic variant, RET M918T, accounting for more than 95% of cases, and is frequently observed as a de novo mutation, resulting in the absence of a family history in many patients (36,38). Importantly, the leading cause of mortality in MEN2 is medullary thyroid carcinoma, which accounts for 80–90% of MEN2-related deaths and often progresses aggressively during infancy or early childhood, particularly in MEN2B (39,40). Consequently, early recognition of MEN2 subtype and appropriate genetic and clinical risk stratification are essential for optimizing surgical timing and long-term outcomes.

In the present study, Cases 1 and 3 were diagnosed with VHL disease, while Cases 2 and 4 were diagnosed with or suspected of having MEN2. It is essential to remain vigilant in the long-term follow-up of such patients, as these hereditary syndromes are associated with life-threatening neoplasms beyond PCC.

The NF1 gene, responsible for NF1, predisposes to a variety of tumors, including neurofibromas, optic pathway gliomas, and PCC. The prevalence of PCC in NF1 patients is reported to be 0.1–5.7% (41), with many cases being asymptomatic and detected incidentally (42). Most PCC in NF1 are unilateral, with bilateral tumors reported in 10–20% of cases (43). The major causes of mortality in NF1 are malignant peripheral nerve sheath tumors and central nervous system tumors; death due to PCC is rare (44).

In addition to VHL, RET, and NF1, other germline mutations implicated in PCC include SDHx genes (SDHB, SDHD), MAX, and TMEM127. Among these, SDHB mutations are notable for their high metastatic potential (approximately 40%), and are considered the subtype with the highest genomic instability and malignancy rate (4), often associated with poor prognosis.

Surgical treatment for hereditary PCC

The primary treatment for PCC is surgical removal, and laparoscopic adrenalectomy is currently considered the standard treatment (45). Robotic adrenalectomy has emerged as a viable alternative to laparoscopic adrenalectomy, which remains the gold standard for most adrenal surgeries (46). In patients with bilateral PCC, adrenalectomy of both adrenal glands is also recommended; however, postoperative adrenal insufficiency leads to the need for lifelong steroid supplementation, which significantly impairs the patient’s QOL. Even if it is a unilateral PCC, hereditary PCC may eventually require bilateral adrenalectomy due to the development of new lesions in the contralateral adrenal gland and recurrence in the remaining adrenal gland over a long period of time after total adrenalectomy on the affected side. Therefore, special care must be taken in selecting treatment options for hereditary PCC (18,47). All patients who underwent bilateral adrenalectomy developed adrenal insufficiency and became steroid-dependent. Among patients with adrenal insufficiency after adrenalectomy, 18% experienced at least one adrenal crisis during a median follow-up period of 8 years, and 13% developed iatrogenic Cushing’s syndrome (6). The concept of organ-preserving surgery was introduced in 1999 to avoid postoperative glucocorticoid and mineralocorticoid replacement (7). Partial adrenalectomy is considered appropriate for tumors located in the anterior region and measuring 4 cm or less in diameter. When the tumor diameter exceeds 5 cm, it becomes difficult to preserve the normal adrenal gland (48). It has been reported that the adrenal vein can be preserved and that no resection margin is necessary. By selecting cases carefully, partial adrenalectomy can be performed safely. Approximately one-third of the adrenal glands must be spared for normal glucocorticoid and mineralocorticoid secretion (49). In cases where adrenal-sparing surgery was performed using partial resection for bilateral PCC, only 23.5% of cases developed adrenal insufficiency postoperatively, and steroid replacement was actually avoided in many cases (6). On the other hand, partial adrenalectomy is associated with a higher risk of postoperative recurrence compared to adrenalectomy. Recurrence of PCC in the preserved ipsilateral adrenal gland occurs in 8–13% of patients, most of whom have VHL and MEN2 (6,50). Despite undergoing total adrenalectomy, 0.7% of patients developed recurrent PCC in the adrenal gland. However, it is clear that the recurrence rate in the ipsilateral adrenal gland is high with partial resection (6). The recurrence and metastasis rates of solitary PCC have been reported to be 3.2% in a meta-analysis (51). In a report of 625 cases of PCC, adrenal metastasis occurred in 8 cases (1.3%), of which 1 case (0.3%) underwent total adrenalectomy and 7 cases (2%) underwent partial adrenalectomy, with no significant difference observed (6). Among the eight patients with metastatic PCC, four had germline mutations in VHL, one in MAX, and one in RET, suggesting that the presence of genetic abnormalities, rather than the surgical procedure, may influence the occurrence of metastasis.

Following adrenalectomy and partial resection, 63 deaths were confirmed out of 625 cases. Of these, 31 (49%) were due to metastatic thyroid cancer associated with MEN2, 3 (5%) were due to metastatic PCC, 2 (3%) were due to adrenal crisis, 7 (11%) were due to VHL complications, and 20 cases (32%) were due to complications unrelated to PCC. No deaths associated with adrenal recurrence were observed, and since reoperation is possible even after local recurrence, differences in surgical procedures are unlikely to have a direct impact on prognosis (6). In a large-scale randomized controlled trial (RCT) targeting MEN2 cases, the postoperative course was observed in 438 patients who underwent adrenalectomy and 114 patients who underwent partial adrenalectomy. The recurrence rate in the adrenal gland preserved after partial adrenalectomy was 2.6% (4 cases), while the rate of recurrence in the contralateral adrenal gland in patients who underwent adrenalectomy was 2.5% (11 cases). The study reported that there was no significant difference in the rate of recurrence or new lesions between the two surgical procedures (47). Rather, complications caused by genetic disorders are considered to be prognostic factors. Specifically, it is necessary to be aware of thyroid cancer associated with MEN2 and central nervous system hemangioblastomas and retinal hemangioblastomas associated with VHL (34,52). Evidence supporting adrenal partial resection for bilateral PCC has been accumulating, but whether to resect only the tumor or the entire adrenal gland remains an unresolved issue. Various guidelines {Endocrine Society [2014], SAGES [2020], European Society of Endocrinology (ESE) guidelines [2016] and Japanese Society of Endocrinology [2025]} still only accept partial adrenalectomy as an option (5,53,54). Although partial adrenalectomy is considered an option for selected patients, its use in individuals harboring SDHB pathogenic variants is not generally recommended, given the substantially increased risk of recurrence and metastatic disease, which may offset the benefits of adrenal cortical preservation (55).

Postoperative follow-up policy

PPGL has a reported postoperative recurrence rate of 15–20%, and the period until recurrence varies widely, ranging from onset within a few months to onset more than 20 years later, so long-term follow-up is necessary (56,57). Approximately 0–14% of cases show recurrence in the remaining adrenal gland after approximately 10 years of observation (33,58-60). In sporadic PPGL, 70.9% of cases recurred within 10 years, 82.3% within 15 years, and 17.7% of all cases recurred after 15 years (57). With advances in genetic mutation diagnosis, it has become clear that PPGL with genetic mutations has a higher recurrence rate than sporadic PPGL. In particular, in cases with SDHB mutations, 57% of patients experienced recurrence despite an observation period of 4.8 years, suggesting a high metastasis rate for SDHB mutations (61). Of the 70 cases in which adrenalectomy was performed for PCC associated with VHL disease, 21 cases (30%) developed contralateral PCC during a median observation period of 7.9 years (62). In MEN2, 67 cases (27%) were reported among 248 cases during a 13-year observation period (47). Among genetic mutations, differences in recurrence rates were observed depending on the cluster. In a joint study with other institutions, the recurrence rate was very high at 47.5% for the pseudohypoxia type, but conversely, there was no difference between the kinase signaling type at 14.9% and the sporadic PPGL at 14.7% (58). In addition to local recurrence, postoperative surveillance should also address the risk of distant metastasis and multifocal disease, particularly in biologically high-risk tumors (63). Tumor size has emerged as an important predictor, with larger tumors requiring closer follow-up, especially those in extra-adrenal or SDHB-associated tumors and 5 cm in adrenal tumors without SDHB variants (64-66). Recent studies have further highlighted the prognostic relevance of molecular features, including ATRX or TERT alterations, an immune-cold tumor microenvironment, and cluster 1-related genotypes, all of which are associated with increased risks of recurrence and metastatic progression (2,4,63,67). Therefore, individualized follow-up guidelines for PPGL based on the causative gene are required. There are also reports that specifically propose follow-up methods based on mutant genes (59). Postoperative follow-up for PPGL has traditionally been based on systematic and regular follow-up, including annual biochemical tests and imaging evaluations as needed, according to various guidelines. However, in recent years, the importance of individualized long-term management tailored to high-risk cases, such as those with genetic abnormalities, early onset, or large tumors, has been emphasized by groups such as the European Society of Hypertension’s Working Group on Endocrine Hypertension in 2020. There is a growing shift from uniform annual follow-ups to flexible lifetime management tailored to individual risk levels (68). The algorithm in the Japanese Society of Endocrinology guidelines revised in 2025 also recommends lifelong follow-up for cases with a high risk of recurrence or metastasis, including young patients, primary tumor diameter of 5 cm or more, PGL cases, norepinephrine-producing tumors without epinephrine production, and cases with positive gene mutations (Figure 3) (69). In the future, as genetic testing becomes easier, it is expected that individualized follow-up plans will be created for each genetic mutation.

Figure 3 Recommended follow-up protocol after surgery for pheochromocytoma and paraganglioma based on the 2025 Clinical Practice Guideline by the Japan Endocrine Society. This flowchart illustrates the recommended schedule for postoperative surveillance of patients with PPGL. The protocol is based on preoperative catecholamine excess and stratifies follow-up according to biochemical and imaging test results. For patients with biochemical evidence of excess catecholamines preoperatively, regular follow-up is suggested at 1–2 weeks, 2–6 months, and annually until 10 years after surgery, with lifelong follow-up for high-risk individuals. In cases with abnormal findings at any stage, imaging is recommended to assess for recurrence. Patients without preoperative biochemical evidence are followed primarily by imaging. Biochemical tests include spot urinary metanephrine fractionation and blood catecholamine fraction. Imaging tests include CT, MRI, ¹²³I-MIBG scintigraphy, and ¹⁸F-FDG PET. ¹²³I-MIBG, ¹²³I-metaiodobenzylguanidine; ¹⁸F-FDG PET, ¹⁸F-fluorodeoxyglucose positron emission tomography; CT, computed tomography; MRI, magnetic resonance imaging; PPGL, pheochromocytoma/paraganglioma.

Although this multicenter experience offers valuable insights, the retrospective nature and limited sample size may restrict the generalizability of our findings. In addition, given the long study period spanning from 1976 to 2024, substantial advances in diagnostic imaging, surgical techniques (including the transition from open to laparoscopic approaches), and the availability of genetic testing for bilateral PCC have occurred. These era-dependent changes may have introduced temporal bias, potentially influencing both treatment strategies and clinical outcomes.

Conclusions

In our experience with eight cases of bilateral PCC, adrenal-sparing surgery was successfully performed in five patients, all of whom avoided the need for long-term steroid replacement. Among these cases, recurrence of hemangioma or PGL was observed in two patients with VHL disease, while tumor control remained favorable in patients with MEN2 or suspected MEN2. These findings support the feasibility and functional benefit of partial adrenalectomy in selected hereditary cases, highlighting the importance of individualized, gene-informed management strategies and long-term surveillance.

Recent advances in genetic analysis have clarified that the risk of recurrence and metastasis in hereditary PCC varies according to the specific gene mutation involved. Patients with hereditary syndromes carry a higher risk of developing bilateral disease compared to those with sporadic PCC. In this context, partial adrenalectomy, aimed at removing the tumor while preserving normal adrenal gland, offers the advantages of avoiding postoperative steroid replacement without compromising oncological outcomes. Reported recurrence and mortality rates for adrenal-sparing surgery are comparable to those for total adrenalectomy, supporting its use as a viable surgical option in selected cases. Nonetheless, current clinical guidelines still position this approach as optional. Moreover, follow-up strategies for PPGL are evolving toward risk-adapted lifelong surveillance. High-risk features such as younger age, tumor size ≥5 cm, presence of PGL, norepinephrine-producing tumors lacking epinephrine secretion, and positive genetic mutations are warranted long-term individualized follow-up to ensure early detection of recurrence and optimized outcomes. To address these issues, large-scale, multicenter prospective cohort studies are warranted.

Acknowledgments

We would like to express our gratitude to the JIKEI-YAYOI Collaborative Group for providing the data source.

Footnote

Reporting Checklist: The authors have completed the AME Case Series reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-683/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-683/prf

Funding: This work was supported by JSPS KAKENHI (No. 24K18590).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-683/coif). K.I. reports receiving support from JSPS KAKENHI (No. 24K18590). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for the publication of this case series and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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