Introduction

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors that arise from adrenal and extra-adrenal chromaffin cells, respectively1,2. Anatomical location is used to distinguish between them. The tumors can produce and secrete catecholamines, which can result in paroxysmal hypertension, palpitations, headaches, sweating, and feelings of panic or anxiety3. Severe cardiovascular complications caused by catecholamine excess include sudden death, arrythmia, myocardial infarction, and cardiac failure. The incidence of PPGL is 0.8 individuals per 100,000, with 500–1600 new cases identified in the United States per year4,5. All PPGL cases were classified as malignant with the possibility of metastasis in the WHO Classification of Endocrine Tumors updated in 20176. The risk of metastasis is 10–20% in pheochromocytoma and up to 50% in paraganglioma7. PPGL is characterized by local invasion or distant metastases, which often makes it challenging to treat and results in poor prognosis8.

Despite recent advancements in the diagnosis and management of PPGL, the long-term outcomes of patients with metastatic or recurrent PPGL remain to be elucidated. Specifically, the prognosis and survival rates for these patients are not well-established.

The purpose of this study was to evaluate the long-term outcomes of patients with metastatic or recurrent PPGL, including overall survival rate and prognostic factors associated with survival rate. By identifying these factors, this study aims to elucidate the natural history of metastatic or recurrent PPGL to develop a prognostic model that can aid in clinical decision-making and improve outcomes for patients with this rare and challenging tumor.

Patients and methods

Patients

We reviewed 15 patients who were treated for metastatic or recurrent PPGL at our institution between January 2000 and January 2020. The study was approved by the Ethics Committee of Niigata University (IRB No. 2022 − 0112). Waiver of informed consent was granted by the Ethics Committee of Niigata University. All methods were performed in accordance with the relevant guidelines and regulations. The study was performed in accordance with the Declaration of Helsinki. Patient characteristics, including age at diagnosis of PPGL and metastatic or recurrent PPGL, sex, primary tumor location, endocrine status, and metastatic sites were obtained from their medical records.

Evaluation of catecholamine production included 24-hour urinary fractionated catecholamines, and/or fractioned metanephrines. Histopathologic slides were reviewed by a single experienced pathologist blinded to the clinical data to assess Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP)9,10. All patients were monitored by assaying blood pressure and plasma, urinary catecholamines, or urinary metanephrines every six months to one year to screen for local or metastatic recurrences. Imaging examinations, including computed tomography, were performed as appropriate at the physician’s discretion. We aimed to follow-up all patients who had undergone PPGL surgery for at least 10 years11,12.

Clinical outcomes

The primary outcome measures were overall survival (OS) from the time of diagnosis of metastatic or recurrent PPGL to death or last follow-up, and identifying prognostic factors associated with OS. Secondary outcomes included time to recurrence or metastasis, site of metastasis, and treatment modalities. Metastatic or recurrent disease was defined as follows: local recurrence as disease in nonchromaffin-derived tissues in the area of the primary tumor resection bed; and distant metastases as disease in nonchromaffin-derived tissues excluding the area of primary tumor. New primary disease in chromaffin-derived tissues not in the area of the primary tumor (new contralateral PPGL) were excluded from the present study. Patients with metastases were subdivided into synchronous and metachronous metastases groups. The synchronous metastasis group was defined as those who had metastatic lesions at the time of initial diagnosis of the primary tumor. The metachronous metastases group was defined as those who developed metastases after the initial time of diagnosis.

Statistical analysis

No statistical sample size calculations were conducted. OS was defined as the interval between the date of diagnosis of the first metastasis or recurrence and death or last follow-up. Survival curves were generated using Kaplan and Meier method, and differences between curves were evaluated by log-rank test. Mann-Whitney U test was used to compare unpaired parameters between the two subgroups. The test was two-sided and p < 0.05 was considered significant. All analyses were performed using SPSS version 25.0 J (SPSS Inc., Chicago, IL, USA).

Results

Between January 2000 and January 2020, a cohort of 15 cases (nine males and six females) with metastatic or recurrent PPGL were administered medical care. Throughout this period, 65 surgical interventions were carried out, targeting the primary tumors of PPGL. Within the group of 15 patients afflicted with metastatic recurrence of PPGL, a subset of five individuals who had previously received surgical treatment for primary PPGL tumors before the advent of the year 2000 was included. The characteristics of the 15 patients are shown in Table 1. Twelve (80.0%) patients had adrenal and three (20.0%) had extra-adrenal sites (paraganglioma). The locations of extra-adrenal pheochromocytoma included the urinary bladder in one patient (6.7%). In all cases, the primary tumor was totally resected (open adrenalectomy: nine cases, laparoscopic adrenalectomy: five cases, partial cystectomy: one case). None of the patients underwent partial adrenalectomy. The mean age at initial diagnosis of PPGL was 41.4 years (range 11–79 years). The mean age at metastatic or recurrent PPGL was 51.9 years (range 11–83 years). The median time to metastasis or recurrence was 5.8 years (range 0–46 years) including one (6.7%) synchronous and 14 (93.3%) metachronous metastases. Unexpectedly, we experienced a case of bone metastasis 46 years after surgery on the primary tumor. The mean tumor diameter was 6.5 cm (range 2.5–16.0 cm). Four patients had asymptomatic PPGL. The most common metastatic sites were bone (seven cases: 46.7%), lung (five cases: 33.3%), liver (two case: 13.3%), lymph node (four cases: 26.7%) and peritoneum (four cases: 26.7%). Germline mutation testing for mutation in genes that predispose to PPGL, such as succinate dehydrogenase gene mutation, was not performed.

Table 1 Clinical characteristics of patients (n = 15).
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Resectable metastatic lesions were removed by surgery. Unresectable lesions were treated with a combination of cyclophosphamide, vincristine, and dacarbazine (CVD) chemotherapy13 and/or radiotherapy containing 131I- metaiodobenzylguanidine (MIBG)14. In cases of slow progression, we opted for observation. Patients had been treated with surgery in seven cases (46.7%), CVD chemotherapy in four cases (26.7%), 131I-MIBG radiotherapy in three cases (20.0%), radiotherapy in two cases (13.3%), sunitinib in one case (6.7%)15, and metyrosine in one case (6.7%)16. The detailed sequential treatments and their results are shown in Supplementary Table 1.

Median follow-up was 4.8 years. Kaplan-Meier estimates of survival are shown in Fig. 1. The overall 5-,10-, and 15-year survival rates were 73.3%, 62.9%, and 31.4%, respectively. The median OS for the 15 patients was 11.0 years. Seven of the 15 patients died during the study period. Five patients died of disease progression, one patient died of Takotsubo cardiomyopathy and one patient died of cerebral hemorrhage after diagnosis of metastatic or recurrent PPGL. Of the seven patients who died, four died within 2 years. We compared factors in the rapid progression group of patients that died within 2 years with those in the non-rapid progression group and found significant differences in the age at initial diagnosis of PPGL (P = 0.003) and PASS (P = 0.016) (Table 2). Surgical intervention was significantly associated with a greater probability of OS (P = 0.010, Fig. 2) and PASS ≥ 7 for the primary tumor was a poor prognostic factor (P = 0.040). OS was not significantly correlated with the site of the primary tumor (adrenal vs. extra-adrenal), age, sex, size of the primary tumor, or metastasis location by log rank test. Results of the analysis are further detailed in Table 3.

Fig. 1
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Overall survival in patients with metastatic or recurrent PPGL.

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Fig. 2
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Overall survival in patients diagnosed with metastatic or recurrent PPGL with or without surgical intervention.

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Table 2 Comparison between rapid progression and non-rapid progression groups.
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Table 3 Log rank analysis of the association of prognostic factors with OS.
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Discussion

The present study provides novel insights into the clinical course and prognosis of metastatic or recurrent PPGL based on a retrospective analysis of 15 cases. We aimed to evaluate the long-term outcomes of patients with metastatic or recurrent PPGL and identify the prognostic factors associated with OS. Our analysis revealed two main findings.

First, we identified the long-term outcome of metastatic or recurrent PPGL. The 5-, 10-, and 15-year survival rates after metastasis or recurrent diagnosis were 73.3%, 62.9%, and 31.4%, respectively, which is consistent with previous studies17,18. Our findings indicate that the time from PPGL diagnosis to metastatic or recurrent diagnosis was 5.8 years (median) and the most common sites of metastasis were bone, lung, lymph node, and peritoneum. In excessive amounts, released catecholamines can lead to serious cardiovascular manifestations, including hypertensive emergencies involving end-organ damage that can progress to multisystem failure and death19,20. In this study, patients died of stroke and Takotsubo cardiomyopathy. The clinical courses of metastatic or recurrent PPGL are diverse. From the perspective of disease progression, patients were divided into two groups: a rapid progression group consisting of patients that died relatively rapidly, and a non-rapid progression group consisting of patients that survived for a longer period of time. There were significant differences in age at initial diagnosis and PASS between the groups.

Second, we identified prognostic factors associated with OS. Patients who underwent surgery for metastasis or recurrent lesion had a significantly better prognosis (P = 0.010). Surgery for recurrent/metastatic disease was associated with better survival rates. We performed palliative surgery for patients with confirmed metastatic disease in whom disease eradication was impossible, which aimed to reduce tumor burden and minimize the effects of excess catecholamine secretion21. However, detailed data is lacking and there is little evidence for such an approach, with previous studies consisting of single case reports22,23. Our study adds to this literature by demonstrating that surgery intervention is associated with better outcomes in patients with metastatic or recurrent PPGL. Surgery can lead to complete resection of the tumor and prevent further spread of the disease. In addition, surgical resection can provide symptomatic relief and improve the patient’s quality of life (QOL)19.

PASS and GAPP are two histopathological grading systems used to evaluate the risk of malignancy in PPGL. The PASS scoring system, introduced by Thompson et al. evaluates various features of the tumor, such as cellularity, nuclear pleomorphism, mitotic rate, and necrosis, to provide a total score ranging from 0 to 209. A higher PASS is associated with a higher risk of malignancy, with scores of 4 or higher indicating a higher likelihood of malignant behavior. Although the PASS grading system is established for pheochromocytoma only, some studies classify paraganglioma according to the PASS system, and the results suggest that the PASS system also has a similar ability to predict the malignant behavior of paraganglioma24,25,26,27,28.

The GAPP grading system, introduced by Kimura et al., evaluates tumor size, invasion, and vascular invasion, among other factors, to provide a total score ranging from 0 to 1010. Both systems aim to improve the accuracy of diagnosing and grading PPGL. Despite the usefulness of the PASS and GAPP, there are still unknown aspects of their application such as their ability to predict prognosis after the actual metastasis or recurrence has occurred, and usefulness to guide treatment decisions. In the present study, we aimed to address these unknown aspects and provide a better understanding of the clinical utility of the PASS and GAPP scoring systems in the diagnosis and management of PPGL.

The prognosis of metastatic or recurrent PPGL is a major concern for clinicians and patients, as these tumors have a poor prognosis and limited treatment options. Our study revealed significantly higher PASS in the rapid progression group. In addition, patients with PASS ≥ 7 for the primary tumor had a significantly worse prognosis (P = 0.040). Our study adds to this literature by demonstrating that PASS can also predict outcomes in patients with metastatic or recurrent PPGL. The relationship and prognosis for PASS and GAPP in the setting of metastatic or recurrent PPGL remain to be elucidated, because the scoring systems are designed to distinguish between benign and malignant tumors.

The limitations of the present study include its retrospective nature, relatively small number of cases due to the low PPGL incidence, and data from a single institution. Our observations should be interpreted with caution. Further multicenter and large-scale studies were warranted.

Conclusion

In conclusion, this retrospective analysis provides valuable insights into the clinical course and prognosis of metastatic or recurrent PPGL, highlighting the heterogeneity of the disease and identifying age at initial diagnosis and PASS as significant prognostic factors. Our findings suggest that surgical intervention is a pivotal factor associated with improved prognosis and higher survival rates, underscoring its importance in reducing tumor burden, controlling excess catecholamine secretion, and enhancing QOL. The potential utility of the PASS and GAPP scoring systems in assessing clinical course warrants further investigation through multicenter studies with larger cohorts. Despite the limitations of our study, our findings contribute to the understanding of metastatic or recurrent PPGL, guide personalized treatment strategies, and emphasize the need for further research to optimize disease management and prognosis.