ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : -9 مورد

Management of malignant (metastatic) paraganglioma and pheochromocytoma

Management of malignant (metastatic) paraganglioma and pheochromocytoma
Author:
William F Young, Jr, MD, MSc
Section Editor:
Patrick Y Wen, MD
Deputy Editor:
Sonali M Shah, MD
Literature review current through: Apr 2025. | This topic last updated: Oct 18, 2024.

INTRODUCTION — 

Pheochromocytomas and paragangliomas are catecholamine-secreting neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla (in the case of pheochromocytomas) and from neuroendocrine cells of the extra-adrenal autonomic paraganglia (in the case of paragangliomas). While pheochromocytomas and paragangliomas share overlapping histopathology, epidemiology, and molecular pathogenesis, they have different clinical behavior, metastatic potential, biochemical findings, and association with inherited genetic syndromes (table 1).

This topic review will discuss the treatment for advanced malignant (metastatic) pheochromocytoma or paraganglioma. Related topics on pheochromocytoma and paraganglioma are discussed separately.

●(See "Clinical presentation and diagnosis of pheochromocytoma".)

●(See "Epidemiology, clinical presentation, and diagnosis of paragangliomas".)

●(See "Treatment of pheochromocytoma in adults".)

●(See "Locoregional management of paragangliomas".)

●(See "Pheochromocytoma and paraganglioma in genetic disorders".)

CLINICAL PRESENTATION

Incidence — Malignant (metastatic) pheochromocytomas and paragangliomas are uncommon tumors. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Epidemiology' and "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Epidemiology'.)

●Pheochromocytoma – Among all patients with pheochromocytoma, approximately 10 percent have metastatic disease. Metastatic disease can present as local invasion into the surrounding tissues and organs (eg, kidney and liver) or distant metastases to lymph nodes, bones, liver, and lungs [1]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Malignant potential'.)

Among pheochromocytomas/paragangliomas related to multiple endocrine neoplasia type 2 (MEN2), only 3 to 5 percent are metastatic. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Pheochromocytoma' and "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'MEN2'.)

●Paraganglioma – Among all patients with paragangliomas, between 20 to 25 percent have metastatic disease. Malignant skull base and neck paragangliomas most frequently metastasize to the cervical lymph nodes. By contrast, paragangliomas below the skull base and neck more frequently have distant metastases to the bones, liver, and lungs. (See "Locoregional management of paragangliomas", section on 'Risk of malignancy' and "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Overview'.)

The highest rates of metastatic disease are seen in paragangliomas associated with inherited pathogenic variants in the B subunit of the succinate dehydrogenase (SDHB) gene, which are usually abdominal and secretory. (See "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Familial paraganglioma and SDH pathogenic variants'.)

Symptoms — Metastatic pheochromocytoma and catecholamine-secreting paragangliomas often present with symptoms of catecholamine excess such as hypertension, episodic headache, sweating, tremor, and forceful palpitations. These are often the same symptoms as those associated with benign (localized) tumors. Abdominal pain may also develop due to metastatic growth of the tumor into the adjacent tissues and organs (eg, kidney and liver) [2]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Clinical presentation' and "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Clinical presentation and diagnosis'.)

By contrast, some paragangliomas (particularly those arising in the skull base and neck) do not present with symptoms of catecholamine excess and frequently are asymptomatic. However, intratumoral metabolism of catecholamines to metanephrines (ie, norepinephrine to normetanephrine, and epinephrine to metanephrine, respectively) can still occur independently of catecholamine release.

Timing of metastases — Although metastatic disease can be diagnosed at initial presentation (ie, synchronous metastases), it is more common to manifest during long-term surveillance following initial therapy for locoregional disease (ie, metachronous metastases). (See "Locoregional management of paragangliomas", section on 'Posttreatment surveillance' and "Treatment of pheochromocytoma in adults", section on 'Prognosis and monitoring'.)

In a retrospective series of 272 patients with metastatic pheochromocytoma or paraganglioma, synchronous and metachronous metastases were diagnosed in 35 and 65 percent of patients, respectively [3]. Metachronous metastases developed at a median of 5.5 years from the initial diagnosis. However, some metastases can also present as late as 50 years or more after the original diagnosis [3].

DIAGNOSIS — 

The diagnosis of malignant (metastatic) pheochromocytoma or paraganglioma is made based on tissue sampling and histopathologic confirmation of tumor deposits in tissues that do not normally contain chromaffin cells (eg, lymph nodes, liver, bones, lungs, and other distant metastatic sites) (picture 1 and picture 2). The histopathology of pheochromocytoma and paraganglioma are discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Histology and malignant potential'.)

PRETREATMENT EVALUATION

Imaging studies and biochemical assays — The pretreatment evaluation of malignant (metastatic) paraganglioma and pheochromocytoma, which is typically performed as part of the initial diagnostic evaluation, includes biochemical testing to assess for catecholamine secretion (plasma fractionated metanephrines and/or 24-hour urinary excretion of fractionated metanephrines, 3-methoxytyramine, and catecholamines) and imaging studies to assess the baseline extent of disease and surgical resectability (algorithm 1). These studies can be used as a baseline to assess treatment response. (See 'Assessing treatment response' below.)

Further details on the diagnostic evaluation of these tumors are discussed separately. (See "Clinical presentation and diagnosis of pheochromocytoma" and "Epidemiology, clinical presentation, and diagnosis of paragangliomas".)

Genetic testing — Germline genetic testing is also recommended for all patients with metastatic paraganglioma and pheochromocytoma since these tumors can either be sporadic or associated with various inherited genetic syndromes (table 1) [4-6]. Germline pathogenic variants that contribute to the development of pheochromocytoma and paraganglioma are classified into three general "clusters" [7,8]:

●Cluster 1 – Germline pathogenic variants in genes that encode proteins that function in the cellular response to hypoxia. These include: VHL, SDHD, SDHC, SDHB, SDHAF2, SDHA EGLN1 (PHD2), KIF1, IDH1, TMEM127, SDHA, MAX, EPAS1 (HIF2A), FH gene encoding fumarate hydratase, EGLN1 (PHD2), EGLN2 (PHD1), and KIF1B.

Cluster 1 tumors are mostly extra-adrenal paragangliomas (except in VHL where most tumors are localized to the adrenal) and nearly all have a noradrenergic biochemical phenotype.

●Cluster 2 – Germline pathogenic variants in genes that encode proteins that activate kinase signaling. These include: RET, NF1, MAX, TMEM127, and HRAS.

Cluster 2 tumors are usually adrenal pheochromocytomas with an adrenergic biochemical phenotype.

●Cluster 3 – Germline pathogenic variants in genes that encode proteins associated with Wnt-signaling. Germline pathogenic variants include: CSDE1 and UBTF::MAML3 fusions.

Cluster 3 tumors can have a noradrenergic or adrenergic biochemical phenotype.

Further details on hereditary pheochromocytoma and paraganglioma syndromes are discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Genetic testing' and "Pheochromocytoma and paraganglioma in genetic disorders".)

GENERAL PRINCIPLES OF THERAPY — 

There are no curative treatments for malignant (metastatic) pheochromocytoma or paraganglioma [9]. The goals of therapy include controlling tumor burden, palliating tumor-related symptoms, improving quality of life, and prolonging overall survival (OS).

Management of catecholamine secretion — All patients with metastatic pheochromocytoma or paraganglioma that is confirmed to be catecholamine-secreting must receive appropriate alpha- and beta-adrenergic blockage prior to initiating therapy for the primary tumor and associated metastatic disease using the same approach as those with benign (localized) disease. Such medical management is necessary to block the effects from possible massive catecholamine secretion from the tumor upon intervention. (See "Treatment of pheochromocytoma in adults", section on 'Combined alpha and beta-adrenergic blockade'.)

Management of the primary tumor — Following appropriate medical management, treatment of the primary tumor is usually addressed prior to proceeding with treatment of metastatic disease. For patients undergoing surgical resection of both the primary tumor and metastatic sites, the operations may be coordinated. (See 'Resectable metastases' below.)

●Patients with metastatic pheochromocytoma undergo surgical resection (adrenalectomy) of the primary tumor. Further details are discussed separately. (See "Treatment of pheochromocytoma in adults", section on 'Adrenalectomy'.)

●For patients with metastatic paragangliomas, locoregional management of the primary tumor is the same regardless of whether the tumor is localized or metastatic. Surgical resection of the primary tumor is the preferred approach for most patients. Radiation therapy (RT) is an alternative option in select cases of cervical and jugulotympanic skull base and neck paragangliomas. Further details are discussed separately. (See "Locoregional management of paragangliomas", section on 'Therapeutic approach at specific sites and outcomes'.)

In a retrospective study of 272 patients with malignant pheochromocytoma or paraganglioma, not undergoing primary tumor resection was associated with worsened OS [3].

Selection of therapy for metastatic disease — Selection of therapy for sites of metastatic disease is based on surgical resectability, symptoms, disease burden and location, and rate of disease progression (algorithm 2). A multidisciplinary approach to management is necessary and includes input from medical oncology, surgical oncology, and radiation oncology [9,10]. Clinical trial enrollment is encouraged where available.

RESECTABLE METASTASES — 

For most patients with malignant (metastatic) pheochromocytoma or paraganglioma and resectable metastases, we suggest surgical resection of all metastatic lesions rather than systemic therapy or other treatment approaches. We perform a complete surgical resection, if feasible; if not achievable, we perform incomplete cytoreductive resection with or without locoregional therapies such as radiation therapy (RT) or ablation. Surgical intervention should only be performed in centers of excellence for pheochromocytoma and paraganglioma.

Surgical resection of metastatic disease improves symptoms, reduces hormone secretion, prevents complications related to the tumor in a critical anatomic location, and improves the response to subsequent therapies [11-14]. Limited data also suggest that surgery (including incomplete resections/debulking procedures) is associated with prolonged overall survival (OS) and minimal morbidity [15-17].

As an example, in a retrospective study of 34 patients treated with surgery for malignant pheochromocytoma or paraganglioma, complete (R0) resection was achieved in 14 patients (41 percent) and incomplete resection in 30 patients (59 percent) [14]. For the entire study population, at a median follow-up of six years, five-year OS was 90 percent (median OS of 11 years). For those with R0 resection, 10-year disease-free survival (DFS) was 49 percent (median DFS of 4.6 years). Among the 23 patients with elevated preoperative fractionated metanephrines or catecholamines, 13 patients (56 percent) demonstrated normalized markers postoperatively, and most either remained fully off antihypertensive medications (11 patients) or had significant reductions in the number of medications required (seven patients). Symptom relief was also reported in 15 of 18 patients (76 percent) who were symptomatic prior to surgery. There was no perioperative mortality. Morbidity rate was 15 percent (5 of 34 patients) including complications of colocutaneous fistula, small bowel obstruction, lymphocele, empyema, and ureteral obstruction (one patient each).

●Medical management prior to surgery – Medical preparation prior to surgery to control excessive adrenergic stimulation from the tumor and perioperative hemodynamic management are discussed separately. (See "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery' and "Locoregional management of paragangliomas", section on 'General surgical principles'.)

●Coordinating resection of the primary tumor and metastases – For patients who are also undergoing resection of the primary tumor, coordinating resection with metastatic disease depends upon the location of the metastases and the length of the necessary anesthesia session. Primary tumors and metastatic disease that are proximally located can typically be resected during the same operation. For disease that is not completely resectable, one option for tumor debulking is cytoreductive (R2) resection, with or without locoregional therapies, such as RT or ablative therapies.

●Open surgical procedure – Open surgical procedures are typically performed in cases of proven or suspected metastatic disease [18]. Although laparoscopic approach to resection is generally preferred for benign (localized) pheochromocytomas or abdominal paragangliomas, metastatic tumors are often large or located in areas that are difficult to remove laparoscopically. If a primary tumor is also being resected, the capsule should not be entered surgically, if possible, as this predisposes to recurrence [19].

LIMITED UNRESECTABLE METASTASES — 

Patients with limited unresectable malignant (metastatic) disease may be appropriate candidates for locoregional therapies. Examples include those whose metastatic disease is isolated to a limited number of sites such as the liver, lungs, soft tissue, or bones.

●For patients with limited, unresectable metastases <1 cm that are asymptomatic, we suggest surveillance rather than locoregional or systemic therapy, given the lack of aggressive behavior of such tumors. (See 'Asymptomatic disease (surveillance)' below.)

●For patients with limited metastases that are ≥1 cm or symptomatic/progressive, we suggest locoregional therapy rather than surveillance or systemic therapy to improve symptoms and extend survival. Selection of therapy is based on tumor size and location, patient and provider preference, and treatment availability. As examples, for patients with bony metastases, options include radiation therapy (RT) or percutaneous thermal ablation, whereas for those with liver metastases, options include RT, percutaneous thermal ablation therapy, or transarterial chemoembolization (TACE).

The primary tumor should be treated prior to initiating locoregional therapy. (See 'Management of the primary tumor' above.)

Radiation therapy — RT at doses greater than 40 gray can provide local tumor control and relief of symptoms for metastatic tumors at a variety of sites, including the soft tissues, liver, and bone metastases [20,21]. Patients need to be monitored during RT, because RT-induced inflammation of the lesion can, in rare circumstances, induce massive catecholamine secretion and hypertensive crisis [22].

An observational study evaluated the use of RT in 41 patients with either primary paraganglioma (63 percent) or pheochromocytoma (37 percent) and 107 sites of disease [20]. Treatment intent was curative in 20 patients (30 lesions) and palliative in 21 patients (77 lesions). Treatment sites included bone (69 percent), soft tissue (30 percent), and liver (1 percent). The median (range) RT dose was 40 (range 6.5 to 70) gray. In the entire study population, five-year overall survival (OS) was 65 percent. For patients treated with curative and palliative intent, OS was 79 and 50 percent, respectively. Local control at five years was 81 percent for all lesions. External beam RT also improved symptoms in a majority (94 percent) of those with symptomatic lesions. There were no acute grade ≥3 treatment-related adverse events, including no hypertensive crises [20].

Local ablative therapy — Several nonsurgical, local ablative therapies are available for patients with metastases, including radiofrequency ablation, cryoablation, and percutaneous ethanol injection.

Percutaneous tumor ablation is most effective when limited to patients with one or a few relatively small (ideally, <3 to 4 cm) tumors. With careful attention to periprocedural management, percutaneous ablation may be safely performed for metastatic lesions at a variety of sites, including soft tissue, bone, lung, and liver [23-30]. As with other forms of local therapy including surgery and RT, any form of local ablation can induce massive catecholamine secretion and a hypertensive crisis; preprocedure medical preparation is needed. (See "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery' and "Locoregional management of paragangliomas", section on 'Medical preparation for surgery'.)

In a retrospective observational study of 31 patients with metastatic pheochromocytoma or paraganglioma, 123 lesions were treated with various nonsurgical ablative therapies (42 with radiofrequency ablation; 23 with cryoablation; and 4 with percutaneous ethanol injection [30]). At a median follow-up of 60 months, radiographic local control was achieved in 69 of 80 lesions (86 percent). Improvement in metastasis-related pain or symptoms of catecholamine excess was achieved in 12 of 13 procedures (92 percent). Thirty-three procedures (67 percent) had no known complications. Clavien-Dindo grade I, II, IV, and V complications occurred after seven (14 percent), seven (14 percent), one (2 percent), and one (2 percent) procedure(s), respectively [30].

Transarterial chemoembolization for liver metastases — For patients with multiple liver metastases that are not amenable to resection or nonsurgical methods of ablation, isolated case reports suggest benefit (decreased tumor bulk and improved symptom control) from transarterial chemoembolization (TACE) [31-35]. As with other forms of local therapy, TACE can induce massive catecholamine secretion and a hypertensive crisis; preprocedure medical preparation is needed. (See "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery' and "Locoregional management of paragangliomas", section on 'Medical preparation for surgery'.)

DIFFUSE UNRESECTABLE METASTASES — 

Some patients with malignant (metastatic) paraganglioma and pheochromocytoma may not have disease that is amenable to surgery or alternate locoregional therapies due to diffuse or widespread metastatic disease. For such patients, management options include surveillance or systemic therapy.

The primary tumor should generally be treated prior to initiating therapy. (See 'Management of the primary tumor' above.)

Asymptomatic disease (surveillance) — For patients who have asymptomatic, indolent disease, we suggest surveillance rather than systemic therapy, as treatment-related side effects may exceed the potential benefits of therapy [9]. Treatment may be initiated upon the development of symptoms and/or progressive disease.

The optimal surveillance schedule is not established. We monitor blood pressure and obtain biochemical testing (plasma-fractionated metanephrines or 24-hour urinary excretion of fractionated metanephrines, catecholamines, and 3-methoxytyramine) every three to four months. Patients who are symptomatic and/or have increases in their biochemical markers should be imaging with gadolinium-enhanced magnetic resonance imaging (MRI) or gallium Ga-68 dotatate positron emission tomography (PET)-computed tomography (CT) to evaluate for disease progression and initiation of systemic therapy. Patients with stable disease and no new symptoms may forego or undergo less frequent surveillance imaging and biochemical testing. (See 'Assessing treatment response' below.)

Symptomatic or progressive disease — For patients with disease that is symptomatic or progressive, we suggest initial treatment with cyclophosphamide, vincristine, and dacarbazine (CVD) rather than other systemic agents due to its high objective response rates (ORRs). (See 'Cyclophosphamide, vincristine, dacarbazine' below.)

For patients who are ineligible for or decline chemotherapy, alternative options for initial treatment include:

●Moderate to rapidly progressive disease – Sunitinib, cabozantinib, or radionuclide therapy. (See 'Sunitinib' below and 'Cabozantinib' below and 'Radionuclide therapy' below.)

●Slowly progressive disease – Somatostatin analogs (SSAs) (for somatostatin receptor [SSTR] positive disease only). (See 'Somatostatin analogs' below.)

Cyclophosphamide, vincristine, dacarbazine — CVD is the preferred initial systemic therapy for metastatic, progressive pheochromocytoma and paraganglioma due to its high and durable tumor response rates (particularly in those with high tumor burden or numerous bone metastases), reduction in tumor-specific and biochemical symptoms, and good tolerability profile.

●Efficacy – In a single-arm nonrandomized trial, 14 patients with metastatic pheochromocytoma were treated with CVD (cyclophosphamide at 750 mg/m2 intravenously [IV] on day 1, vincristine at 1.4 mg/m2 IV on day 1, and dacarbazine at 600 mg/m2 IV on days 1 and 2 of each 21- to 28-day cycle) [36,37]. At extended follow-up (median of 22 years) for this same cohort along with four other patients who met the original eligibility criteria, complete or partial objective responses were seen in 10 of 18 patients (56 percent) [36]. Biochemical responses were seen in 13 patients (72 percent). Patients with complete or partial tumor response received a mean of 27 cycles of CVD (median of 23 cycles). The median duration of response was 20 months, and the median overall survival (OS) was 3.3 years. All patients also experienced symptomatic improvement in performance status and blood pressure [37].

Observational studies have demonstrated similar efficacy for CVD or alternative formulations (eg, with or without vincristine and/or doxorubicin) [38-40]. As an example, in one retrospective series, 52 patients with progressive metastatic pheochromocytoma or sympathetic paraganglioma were treated with a variety of chemotherapy regimens, including cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CyVADIC; 19 patients); cyclophosphamide, doxorubicin, and dacarbazine (CyADIC; 12 patients); cyclophosphamide, vincristine, and dacarbazine (CyVDic; 10 patients); or other regimens (11 patients) [38]. Among the 52 evaluable patients, 17 patients (33 percent) responded to initial chemotherapy, including 13 with an objective tumor response (25 percent), and four with normalization of blood pressure. In two patients with initially unresectable tumors, the response to chemotherapy was sufficient to permit subsequent surgical excision. Responders, all of whom received a chemotherapy regimen that contained dacarbazine and cyclophosphamide, survived longer than nonresponders (median 6.4 versus 3.7 years). However, nonresponders also had significantly larger tumors (10 versus 5 cm) and a higher percentage of extra-adrenal primaries, two factors that are associated with decreased OS in pheochromocytoma or paraganglioma [41]. The five-year OS rate of the entire cohort was 51 percent.

●Toxicity – Treatment with CVD is generally well tolerated. The most common toxicities are mild myelosuppression, peripheral neuropathy, and gastrointestinal toxicity [37].

Sunitinib — Sunitinib is an appropriate alternative to chemotherapy in patients with metastatic paraganglioma/pheochromocytoma and moderate to rapidly progressive disease. Sunitinib also demonstrated a nonstatistically significant trend towards improved progression-free survival (PFS) in a placebo-controlled randomized phase II trial [42].

We offer sunitinib at a dose of 37.5 mg orally daily until disease progression or unacceptable toxicity [42]. Although hypertension is a common side effect of sunitinib, it can safely be used to treat metastatic pheochromocytoma and secretory paraganglioma. Sunitinib should be initiated only after normal or near-normal blood pressure is achieved with combined alpha- and beta-adrenergic blockade. Patients must also have close follow-up visits and appropriate dose adjustments to antihypertensive agents, which are usually required after initiating sunitinib [43]. Further details on the management of hypertension and other toxicities associated with sunitinib are discussed separately. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Class side effects of all VEGF inhibitors' and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Initial observational studies and single-arm phase II clinical trials suggested clinical efficacy for sunitinib in malignant pheochromocytoma or paraganglioma [43-49]. Based on these data, sunitinib was evaluated in a placebo-controlled randomized phase II trial (FIRSTMAPP) [42]. In this study, 78 patients with metastatic progressive pheochromocytoma or paraganglioma (either sporadic or associated with an inherited syndrome) were randomly assigned to either oral sunitinib at 37.5 mg daily or placebo. Approximately one-third (32 percent) had a germline pathogenic variant in SDHx. Most patients (69 percent) had also received prior therapies (chemotherapy, iobenguane I-131 metaiodobenzylguanidine [MIBG] therapy, RT, ablative therapies, everolimus, interferon, SSAs, and/or peptide receptor radionuclide therapy). At a median follow-up of 30 months, results were as follows [42]:

●Entire study population – Sunitinib demonstrated a nonstatistically significant trend towards improved PFS relative to placebo (median PFS 8.9 [95% CI 5.5-12.7] versus 3.6 [95% CI 3.1-6.1] months; two-year PFS 17.6 [95% CI 8.7-32.5] versus 8.4 [median 2.7-23.7] percent), which would be clinically meaningful if true [42]. The difference in OS between the treatment arms was not statistically significant (median 26 versus 50 months; two-year OS 57 versus 58 percent). ORRs were higher for sunitinib than placebo (36 versus 8 percent), all of which were partial responses. Median duration of response with sunitinib was 12 months.

●Treatment-naïve disease – In subgroup analyses of patients with treatment-naïve disease, sunitinib demonstrated a trend towards improved PFS (hazard ratio [HR] 0.50) and higher ORR (27 versus 15 percent) relative to placebo [42].

●Treatment-refractory disease – In a subgroup analysis of patients who received prior therapy, sunitinib also demonstrated a trend towards improved PFS (HR 0.79) and higher ORR (43 versus 4 percent) relative to placebo.

●Other patient subgroups – Trends towards PFS benefit for sunitinib over placebo were also seen for those with SDHB pathogenic variants, bone metastases, and arterial hypertension.

The most frequent grade 3 or 4 toxicities for sunitinib and placebo were asthenia (18 versus 3 percent), hypertension (13 versus 10 percent), and back or bone pain (3 versus 8 percent). No new toxicity profiles were noted for sunitinib.

Cabozantinib — Cabozantinib is an appropriate alternative to chemotherapy for patients with metastatic paraganglioma/pheochromocytoma and moderately to rapidly progressive disease. In a phase II trial of 17 patients with malignant pheochromocytoma or paraganglioma, cabozantinib, a multikinase inhibitor that targets vascular endothelial growth factor receptor 2 (VEGFR2) and c-MET, demonstrated an ORR of 25 percent [50].

Radionuclide therapy — Systemic radionuclide treatment is an appropriate alternative to chemotherapy for patients with metastatic paraganglioma or pheochromocytoma and moderately to rapidly progressive disease. Radionuclide therapy employs beta-emitting isotopes that are coupled to either SSAs (ie, peptide receptor radionuclide therapy) or MIBG.

Peptide receptor radionuclide therapy — Patients with metastatic or recurrent pheochromocytoma or paraganglioma and moderately progressive disease whose tumors express SSTRs may benefit from peptide receptor radionuclide therapy with lutetium Lu-177 dotatate [51-56]. Treatment benefits include objective tumor responses and reduction in symptoms of catecholamine secretion. SSTR expression is determined by positive uptake on an SSTR-based imaging study, such as Ga-68 dotatate PET-CT [57-59]. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Somatostatin receptor-based imaging'.)

Pheochromocytomas and extra-adrenal paragangliomas express SSTRs at a level that is similar to that of neuroendocrine neoplasms [60-63]. Lu-177 dotatate is approved by the US Food and Drug Administration for the treatment of SSTR-expressing gastroenteropancreatic neuroendocrine tumors. Use of Lu-177 dotatate in SSTR-positive metastatic paraganglioma or pheochromocytoma is considered off-label since treatment approval has not been extended to pheochromocytoma and paraganglioma. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Lutetium Lu-177 dotatate'.)

Peptide receptor radiotherapy (PRRT) was evaluated in a meta-analysis of 12 observational studies that included 201 patients with advanced paraganglioma or pheochromocytoma. Most patients had received prior treatment such as surgery, chemotherapy, radiation therapy (RT), or other systemic therapies [56]. The ORR and disease control rates were 25 and 84 percent, respectively. Clinical and biochemical responses were seen in 61 and 64 percent of the patients, respectively. Similar tumor response rates were seen for therapy with Yttrium Y-90 and Lu-177 dotatate. Treatment was well tolerated with minimal grade 3 to 4 toxicity. Toxicities of PRRT are discussed separately. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Toxicity and risks'.)

Iobenguane I-131 MIBG — Although iobenguane I-131 MIBG is effective in the treatment of metastatic pheochromocytoma and paraganglioma, it has been discontinued from the United States market for commercial reasons; it may remain available in other areas.

●Patient selection – Treatment with iobenguane I-131 (therapeutic) is an option in patients with good uptake of iobenguane I-123 (diagnostic) by dosimetry who fall into one of the following clinical categories [64]:

•Unresectable, moderately progressive pheochromocytoma or paraganglioma

•Symptoms from disease that are not amenable to locoregional methods of control

•A high tumor burden and a low number of bone metastases

●Dosing, schedule, and toxicity – The optimal dose and treatment schedule of iobenguane I-131 (therapeutic) is not established. Most studies use different doses and schedules and include only a few patients [64]. There are no randomized trials comparing high-dose versus fractionated-medium doses of iobenguane I-131 (therapeutic) [11]. Some institutions with extensive experience use high-dose iobenguane I-131 (therapeutic) for selected patients with aggressive disease who can tolerate it. Thyroidal uptake of free iodide is prevented by giving an oral saturated solution of potassium iodide at 24 hours prior to planned administration and daily for 10 days post-therapy. At other institutions, medium-dose iobenguane I-131 (therapeutic) is used for patients with relatively indolent disease, with chemotherapy preferred over high-dose iobenguane I-131 (therapeutic) for those with more aggressive disease. (See 'Cyclophosphamide, vincristine, dacarbazine' above.)

Iobenguane I-131 (therapeutic) treatment can be repeated, usually at six-month intervals [65]. The optimal dosimetry is not established. Most studies have used single-therapy doses between 100 to 200 millicurie, with cumulative doses ranging from 557 to 2322 millicurie and averaging 400 and 600 millicurie [2,65-71]. At these doses, treatment is generally well tolerated with the main side effects being transient mild leukopenia and thrombocytopenia. Hypothyroidism was reported in 3 of 28 patients receiving cumulative doses of 111 to 916 millicurie in one series [70], and in 2 of 10 patients in a second report (average cumulative dose 310 millicurie) [72].

Patients should be counseled about the potential risks of long-term myelosuppression [69,73,74] and a possible increase in myelodysplasia and acute leukemia in long-term survivors [74,75]. It is not clear whether these risks are limited to those who receive high-dose therapy.

●Efficacy – The diagnostic and therapeutic value of MIBG is based upon its structural similarity with noradrenaline and a high affinity to (and uptake in) chromaffin cells. Radioactive iodine (I131) is attached to the MIBG molecule to produce iobenguane I-131 (therapeutic), which functions as a semiselective agent for malignant pheochromocytoma or paraganglioma. This treatment only works for the approximately 60 percent of tumors that take up MIBG as determined by iobenguane I-123 (diagnostic) scintigraphy [76-78]. A lower fraction of dopamine-secreting paragangliomas take up iobenguane I-123 (diagnostic) [79-81].

For patients with metastatic disease whose tumors secrete catecholamines and take up MIBG, the therapeutic value of iobenguane I-131 (therapeutic) to achieve symptom palliation and tumor regression or stabilization has been shown in observational case series [2,65-72,78,82,83]. ORRs are approximately 30 percent, and another 40 percent of tumors remain stable; less than 5 percent have a complete remission. Hormonal response (ie, decrease in catecholamine secretion) is reported in 45 to 67 percent of cases [2,69,70,78]. In general, better objective responses are achieved in patients with limited disease and in those with soft tissue rather than bone metastases [2].

There is some evidence that higher-dose regimens (single doses 500 to 800 millicurie) can result in sustained complete response in a small number of patients, albeit with a higher risk of potentially serious side effects [75,82]:

•In a phase II trial, 50 patients with metastatic pheochromocytoma or paraganglioma received single iobenguane I-131 (therapeutic) doses ranging from 492 to 1160 millicurie (6 to 19 millicurie/kg, median 12 millicurie/kg); cumulative doses ranged from 492 to 3191 millicurie [75]. Patients had to have successful peripheral blood stem cell harvest to receive >12 millicurie/kg. Overall, a complete response was achieved in 10 percent, a partial response in 20 percent, and 39 percent had stable disease/minor response (69 percent disease control rate). The five-year OS rate was 64 percent.

Toxicities included grade 3 to 4 neutropenia in 87 percent and grade 3 or 4 thrombocytopenia in 87 percent; four patients experienced prolonged myelosuppression that required autologous hematopoietic cell rescue. Other serious toxicities included grade 4 acute respiratory distress syndrome and cryptogenic organizing pneumonia in two patients each, and myelodysplastic syndrome and concurrent acute leukemia in two patients who received multiple infusions of iobenguane I-131 (therapeutic). Hypothyroidism was not reported, although large doses of potassium iodide were administered to prevent uptake of iobenguane I-131 (therapeutic) by the thyroid, and three became hyperthyroid.

•In a retrospective study, 125 patients with metastatic pheochromocytoma or paraganglioma were treated with a median dose of 18,800 megabecquerels I-131 MIBG [84]. In these patients, median survival posttreatment was approximately four years.

-Among 88 patients with follow-up imaging, complete and partial response rates were 1 and 33 percent, whereas stable disease and disease progression rates were 53 and 13 percent, respectively. Median PFS was two years.

-Among 54 patients, over half (59 percent) demonstrated biochemical response, although half of these relapsed, with a median time to biochemical progression of 2.8 years.

-Among 83 patients, a majority (75 percent) reported improvement in pretreatment symptoms, consisting primarily of pain (42 percent), fatigue (27 percent), and hypertension (14 percent). At a median of 1.8 years, most experienced subsequent symptomatic progression (61 percent) [84].

Somatostatin analogs — A trial of SSA therapy (octreotide long-acting release or lanreotide) is an option to stabilize disease or palliate symptoms in patients with malignant SSTR-positive pheochromocytoma or paraganglioma who are ineligible for or decline other treatment options, based on limited data. SSTR expression is determined by positive uptake on an SSTR-based imaging study, such as Ga-68 dotatate PET-CT [57-59]. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Somatostatin receptor-based imaging'.)

Data for the use of octreotide for metastatic pheochromocytoma or paraganglioma are limited to case reports and observational studies. While most data suggest that the main benefit for octreotide is disease stabilization rather than objective tumor regression [85-91], a few studies report objective responses and short-term reduction of catecholamine secretion [92-94]. Studies with lanreotide also demonstrate mainly disease stabilization [95].

Other regimens — Other chemotherapy regimens with modest objective response rates in metastatic pheochromocytoma and paraganglioma include temozolomide monotherapy [96] (particularly among those with succinate dehydrogenase [SDH] B pathogenic variants, which are associated with hypermethylation of the promoter for O6-methylguanine-deoxyribonucleic acid [DNA] methyltransferase [MGMT] [97]); temozolomide plus thalidomide [98] or capecitabine [99]; single-agent gemcitabine [100]; gemcitabine plus docetaxel [101] or paclitaxel [102]; doxorubicin plus streptozocin [103]; or paclitaxel alone [104].

ASSESSING TREATMENT RESPONSE — 

Response assessment in patients being treated for malignant (metastatic) pheochromocytoma or paraganglioma is usually performed using both imaging studies and serial biochemical assays. Biochemical testing (eg, plasma-fractionated metanephrines and/or 24-hour urine-fractionated metanephrines, catecholamines, and 3-methoxytyramine) and imaging studies are usually assessed three months after initiating systemic therapy or radionuclide therapy; and approximately six months following radiation therapy (RT) or the initiation of a somatostatin analog (SSA).

●Imaging studies – Imaging studies that can be used for response assessment include gadolinium-enhanced MRI of the primary tumor site, and somatostatin receptor (SSTR)-based imaging with gallium Ga-68 dotatate positron emission tomography (PET)-CT.

•MRI – One of the unique features of metastatic pheochromocytoma or paraganglioma is their slow response to therapy, particularly to RT [20]. These tumors are known to regress slowly and usually partially after RT, and successfully treated tumors demonstrate residual masses, the presence of which does not necessarily indicate treatment failure. Paragangliomas are vascular tumors, and the malignant cells constitute only a small part of the tumor mass. It is thought that the vascular elements constitute the bulk of the tumor undergoing fibrosis after treatment. Stabilization or reduction in tumor size, decreased enhancement, and reduced T2 signal intensity on MRI have all been described and are indicative of local control [20,105].

•SSTR-based imaging – Functional SSTR-based imaging can also be used to assess tumor burden not seen on standard imaging modalities. SSTR-based imaging using Ga-68 dotatate PET-CT is frequently obtained as part of the diagnostic evaluation for metastatic pheochromocytoma and paraganglioma and offers a better option for assessing treatment response than other imaging studies [106-112]. Further details on diagnostic imaging studies for metastatic pheochromocytoma and paraganglioma are discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Screening for synchronous and metastatic disease' and "Clinical presentation and diagnosis of pheochromocytoma", section on 'Additional imaging'.)

●Biochemical testing – Biochemical assays can be used to assess treatment response. Such assays include plasma-fractionated metanephrines or 24-hour urinary excretion of fractionated metanephrines, catecholamines, 3-methoxytyramine, and serum chromogranin A (CgA). As with other neuroendocrine tumors, serum CgA levels correlate with disease burden, and serial measurements of this biomarker are mostly used to monitor response to treatment [113-118]. However, because of limited specificity, CgA is not useful for diagnostic purposes (table 2).

PROGNOSIS — 

For patients with malignant (metastatic) pheochromocytoma or paraganglioma, the average five-year overall survival (OS) is approximately 50 percent [16,17,38,41,66,119-125]. Prognosis is also influenced by primary tumor site, disease burden, and location of metastases, among other clinical factors.

●Metastatic pheochromocytoma – For patients with metastatic pheochromocytoma, five-year OS ranges between 34 to 60 percent, with some studies reporting 10-year OS rates of 25 percent [114]. However, other studies suggest that survival outcomes may be poorer with pheochromocytomas compared with paraganglioma, regardless of functionality. In one longitudinal observational study over two decades, pheochromocytoma presented more often with distant metastases and was associated with worsened five-year OS relative to paraganglioma (58 versus 80 percent) [126].

●Metastatic paraganglioma – For patients with malignant paragangliomas of the skull base and neck, survival outcomes are the most variable with five-year OS ranging between 12 to 84 percent [16,121,125]. In an observational study from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database of 86 cases of malignant (metastatic) head and neck paraganglioma, the five-year survival rate was 65 percent overall. For patients with regionally confined metastases, five-year OS was higher for those with confined versus distant metastases (82 versus 41 percent) [125]. Survival outcomes were also more favorable for primary carotid body tumors than other primary tumor sites (five-year OS 87 versus 48 percent).

●Prognostic factors – Other poor prognostic factors include male sex, older age, synchronous metastases, larger primary tumor size, elevated dopamine levels, and not undergoing primary tumor resection [3]. There was no difference in survival according to the presence or absence of an SDHB pathogenic variant. Patients with brain, liver, and lung metastases have a worse prognosis than those with isolated bone lesions [11].

The prognostic implications of molecular alterations for metastatic pheochromocytoma and paraganglioma are poorly understood. In a genomic profiling study of patients with metastatic disease, high mutational load, microsatellite instability, and somatic copy-number alteration burden were associated with alpha thalassemia/mental retardation-X linked (ATRX) and telomerase reverse transcriptase (TERT) gene alterations, which may serve as prognostic markers [127]. (See "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Histology and malignant potential'.)

INVESTIGATIONAL AGENTS

●Tyrosine kinase inhibitors – A study evaluating pazopanib, in patients with metastatic pheochromocytoma or paraganglioma was terminated due to slow accrual [128]. Other select tyrosine kinase inhibitors undergoing evaluation in clinical trials include axitinib and lenvatinib.

●Mechanistic target of rapamycin inhibitors – Studies are ongoing examining the benefit of everolimus, which inhibits the mechanistic target of rapamycin pathway. In one early study, five of seven patients with pheochromocytoma or paraganglioma exhibited disease stabilization, although there were no objective responses [129].

●Hypoxia-inducible factor 2 alpha (HIF2A) inhibitors – HIF2A is a main oncogenic driver of paraganglioma and pheochromocytoma [130]. HIF2A inhibitors, such as belzutifan, are active in cancers associated with von Hippel-Lindau disease [131] and are being investigated in those with paraganglioma and pheochromocytoma. As an example, belzutifan has activity in Pacak-Zhuang syndrome, a rare disease characterized by early-onset polycythemia vera and multiple paragangliomas [132]. (See "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera", section on 'EPAS1' and "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Molecular pathogenesis'.)

The use of HIF2A inhibitors to treat other tumors associated with von Hippel-Lindau disease is discussed separately. (See "Surveillance and management of von Hippel-Lindau disease".)

●Immunotherapy – Immune checkpoint inhibitors may have potential treatment efficacy in metastatic pheochromocytoma and paraganglioma. This approach remains investigational, and further randomized trials are necessary.

Many pheochromocytoma and paraganglioma tumors express programmed cell death ligand 1 (PD-L1), suggesting a role for immune checkpoint inhibitors [133]. Additionally, in the subgroup of tumors with pseudohypoxia-related molecular alterations, such as HIF2A, PD-L1 expression is increased via an HIF-dependent mechanism that affects T-cells activity repression in the tumor microenvironment [134,135]. (See "Principles of cancer immunotherapy", section on 'Immune checkpoint inhibitors'.)

In a phase II trial, 11 patients with metastatic pheochromocytoma and paragangliomas were treated with the PD-1 inhibitor pembrolizumab [136]. At a median follow-up of 18 months, the objective response, nonprogression, and clinical benefit rates were 9, 40, and 73 percent, respectively. Median progression-free and overall survival were 6 and 19 months respectively.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pheochromocytoma and paraganglioma".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (See "Patient education: Pheochromocytoma (The Basics)".)

SUMMARY AND RECOMMENDATIONS

●Clinical presentation

•Symptoms – Malignant (metastatic) pheochromocytomas and paragangliomas are uncommon tumors that present with symptoms of catecholamine excess such as hypertension, episodic headache, sweating, tremor, forceful palpitations, and/or abdominal pain. (See 'Incidence' above and 'Symptoms' above.)

•Timing of metastases – Although metastatic disease can be diagnosed at initial presentation (synchronous metastases), it is more common to manifest during long-term surveillance following initial therapy for locoregional disease (metachronous metastases). (See 'Timing of metastases' above.)

●Pretreatment evaluation – Pretreatment evaluation includes biochemical testing to assess for catecholamine secretion, imaging studies to assess the baseline extent of disease and surgical resectability, and genetic testing. (See 'Pretreatment evaluation' above.)

●Management of catecholamine secretion – All patients with metastatic pheochromocytoma or paraganglioma that is confirmed to be catecholamine-secreting must receive appropriate alpha- and beta-adrenergic blockage prior to initiating therapy for the primary tumor and associated metastatic disease, using the same approach as those with benign (localized) disease. (See 'Management of catecholamine secretion' above.)

●Management of the primary tumor – Following appropriate medical management, treatment of the primary tumor (with either surgery or radiation therapy [RT]) is usually addressed prior to proceeding with treatment of metastatic disease. For patients undergoing surgical resection of both the primary tumor and metastatic sites, the operations may be coordinated. (See 'Management of the primary tumor' above and 'Resectable metastases' above.)

•Patients with metastatic pheochromocytoma undergo surgical resection (adrenalectomy) of the primary tumor. (See "Treatment of pheochromocytoma in adults", section on 'Adrenalectomy'.)

•For patients with paraganglioma, locoregional management of the primary tumor is the same regardless of whether the tumor is localized or metastatic. Surgical resection of the primary tumor is the preferred approach for most patients. RT is an alternative option in select cases of cervical and jugulotympanic skull base and neck paragangliomas. Further details are discussed separately. (See "Locoregional management of paragangliomas", section on 'Therapeutic approach at specific sites and outcomes'.)

●Management of metastases – Selection of therapy for sites of metastatic disease is based on surgical resectability, symptoms, disease burden and location, and rate of disease progression (algorithm 2). Multidisciplinary management is necessary. Clinical trial enrollment is encouraged where available.

•Resectable metastases – For most patients with resectable metastases, we suggest surgical resection of all metastatic lesions rather than systemic therapy or other treatment approaches (Grade 2C). We perform a complete surgical resection, if feasible; if not achievable, we perform an incomplete cytoreductive resection with or without locoregional therapies such as RT or ablation. Surgical intervention should only be performed in centers of excellence for pheochromocytoma and paraganglioma. Surgical resection of metastatic disease improves symptoms, reduces hormone secretion, prevents complications related to tumor in a critical anatomic location, and improves the response to subsequent therapies. Limited data also suggest that surgery (including incomplete resection/debulking procedures) is associated with prolonged overall survival (OS) and minimal morbidity. (See 'Resectable metastases' above.)

•Limited unresectable metastases

-For patients with limited, unresectable metastases <1 cm that are asymptomatic, we suggest surveillance rather than locoregional or systemic therapy (Grade 2C) given the lack of aggressive behavior of such tumors. (See 'Limited unresectable metastases' above.)

For patients with limited metastases that are ≥1 cm or symptomatic/progressive, we suggest locoregional therapy rather than surveillance or systemic therapy (Grade 2C) to improve symptoms and extend survival. Selection of therapy is based on tumor size and location, patient and provider preference, and treatment availability. As examples, for patients with bony metastases, options include RT or percutaneous thermal ablation, whereas for those with liver metastases, options include RT, percutaneous thermal ablation therapy, or transarterial chemoembolization (TACE).

•Diffuse unresectable metastases – For patients with diffuse unresectable metastases, management is based on symptoms and the rate of disease progression. (See 'Diffuse unresectable metastases' above.)

-Asymptomatic disease – For patients with asymptomatic, indolent disease, we suggest surveillance rather than systemic therapy (Grade 2C). (See 'Asymptomatic disease (surveillance)' above.)

-Symptomatic and progressive disease – For patients with symptomatic or progressive disease, we suggest initial treatment with cyclophosphamide, vincristine, and dacarbazine (CVD) rather than other systemic agents (Grade 2C), due to high objective response rates. (See 'Cyclophosphamide, vincristine, dacarbazine' above.)

For those who are ineligible for or decline chemotherapy, alternate options include sunitinib, cabozantinib, or radionuclide therapy (for moderately to rapidly progressive disease) and somatostatin analogs (SSAs; for slowly progressive, somatostatin receptor [SSTR]-positive disease only). (See 'Sunitinib' above and 'Cabozantinib' above and 'Radionuclide therapy' above and 'Somatostatin analogs' above.)

●Treatment response – Treatment response is assessed using both imaging studies (gadolinium-enhanced MRI of the primary tumor site and gallium Ga-68 dotatate positron emission tomography [PET]-CT) and biochemical testing (eg, plasma-fractionated metanephrines and/or 24-hour urine-fractionated metanephrines, catecholamines, and 3-methoxytyramine). These studies are usually assessed three months after initiating systemic therapy or radionuclide therapy; and approximately six months following RT or the initiation of an SSA. (See 'Assessing treatment response' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Sally E Carty, MD, FACS, and Aymen Elfiky, MD, MPH, MSc, MBA, who contributed to earlier versions of this topic review.

  1. Zelinka T, Musil Z, Dušková J, et al. Metastatic pheochromocytoma: does the size and age matter? Eur J Clin Invest 2011; 41:1121.
  2. Loh KC, Fitzgerald PA, Matthay KK, et al. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. J Endocrinol Invest 1997; 20:648.
  3. Hamidi O, Young WF Jr, Iñiguez-Ariza NM, et al. Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years. J Clin Endocrinol Metab 2017; 102:3296.
  4. Neumann HPH, Young WF Jr, Eng C. Pheochromocytoma and Paraganglioma. N Engl J Med 2019; 381:552.
  5. Neumann HP, Young WF Jr, Krauss T, et al. 65 YEARS OF THE DOUBLE HELIX: Genetics informs precision practice in the diagnosis and management of pheochromocytoma. Endocr Relat Cancer 2018; 25:T201.
  6. Kantorovich V, Pacak K. Pheochromocytoma and paraganglioma. Prog Brain Res 2010; 182:343.
  7. Jhawar S, Arakawa Y, Kumar S, et al. New Insights on the Genetics of Pheochromocytoma and Paraganglioma and Its Clinical Implications. Cancers (Basel) 2022; 14.
  8. Gimenez-Roqueplo AP, Robledo M, Dahia PLM. Update on the genetics of paragangliomas. Endocr Relat Cancer 2023; 30.
  9. Young WF. Metastatic Pheochromocytoma: In Search of a Cure. Endocrinology 2020; 161.
  10. Andersen KF, Altaf R, Krarup-Hansen A, et al. Malignant pheochromocytomas and paragangliomas - the importance of a multidisciplinary approach. Cancer Treat Rev 2011; 37:111.
  11. Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 2007; 3:92.
  12. Joseph L. Malignant phaeochromocytoma of the organ of Zuckerkandl with functioning metastases. Br J Urol 1967; 39:221.
  13. Ellis RJ, Patel D, Prodanov T, et al. Response after surgical resection of metastatic pheochromocytoma and paraganglioma: can postoperative biochemical remission be predicted? J Am Coll Surg 2013; 217:489.
  14. Strajina V, Dy BM, Farley DR, et al. Surgical Treatment of Malignant Pheochromocytoma and Paraganglioma: Retrospective Case Series. Ann Surg Oncol 2017; 24:1546.
  15. Huang KH, Chung SD, Chen SC, et al. Clinical and pathological data of 10 malignant pheochromocytomas: long-term follow up in a single institute. Int J Urol 2007; 14:181.
  16. Lee JH, Barich F, Karnell LH, et al. National Cancer Data Base report on malignant paragangliomas of the head and neck. Cancer 2002; 94:730.
  17. Eisenhofer G, Bornstein SR, Brouwers FM, et al. Malignant pheochromocytoma: current status and initiatives for future progress. Endocr Relat Cancer 2004; 11:423.
  18. Adjallé R, Plouin PF, Pacak K, Lehnert H. Treatment of malignant pheochromocytoma. Horm Metab Res 2009; 41:687.
  19. Li ML, Fitzgerald PA, Price DC, Norton JA. Iatrogenic pheochromocytomatosis: a previously unreported result of laparoscopic adrenalectomy. Surgery 2001; 130:1072.
  20. Breen W, Bancos I, Young WF Jr, et al. External beam radiation therapy for advanced/unresectable malignant paraganglioma and pheochromocytoma. Adv Radiat Oncol 2018; 3:25.
  21. Fishbein L, Bonner L, Torigian DA, et al. External beam radiation therapy (EBRT) for patients with malignant pheochromocytoma and non-head and -neck paraganglioma: combination with 131I-MIBG. Horm Metab Res 2012; 44:405.
  22. Teno S, Tanabe A, Nomura K, Demura H. Acutely exacerbated hypertension and increased inflammatory signs due to radiation treatment for metastatic pheochromocytoma. Endocr J 1996; 43:511.
  23. McBride JF, Atwell TD, Charboneau WJ, et al. Minimally invasive treatment of metastatic pheochromocytoma and paraganglioma: efficacy and safety of radiofrequency ablation and cryoablation therapy. J Vasc Interv Radiol 2011; 22:1263.
  24. Mamlouk MD, vanSonnenberg E, Stringfellow G, et al. Radiofrequency ablation and biopsy of metastatic pheochromocytoma: emphasizing safety issues and dangers. J Vasc Interv Radiol 2009; 20:670.
  25. Wood BJ, Abraham J, Hvizda JL, et al. Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer 2003; 97:554.
  26. Maithel SK, Fong Y. Hepatic ablation for neuroendocrine tumor metastases. J Surg Oncol 2009; 100:635.
  27. Pacak K, Fojo T, Goldstein DS, et al. Radiofrequency ablation: a novel approach for treatment of metastatic pheochromocytoma. J Natl Cancer Inst 2001; 93:648.
  28. Venkatesan AM, Locklin J, Lai EW, et al. Radiofrequency ablation of metastatic pheochromocytoma. J Vasc Interv Radiol 2009; 20:1483.
  29. Cozzi PJ, Englund R, Morris DL. Cryotherapy treatment of patients with hepatic metastases from neuroendocrine tumors. Cancer 1995; 76:501.
  30. Kohlenberg J, Welch B, Hamidi O, et al. Efficacy and Safety of Ablative Therapy in the Treatment of Patients with Metastatic Pheochromocytoma and Paraganglioma. Cancers (Basel) 2019; 11.
  31. Hidaka S, Hiraoka A, Ochi H, et al. Malignant pheochromocytoma with liver metastasis treated by transcatheter arterial chemo-embolization (TACE). Intern Med 2010; 49:645.
  32. Watanabe D, Tanabe A, Naruse M, et al. Transcatheter arterial embolization for the treatment of liver metastases in a patient with malignant pheochromocytoma. Endocr J 2006; 53:59.
  33. Takahashi K, Ashizawa N, Minami T, et al. Malignant pheochromocytoma with multiple hepatic metastases treated by chemotherapy and transcatheter arterial embolization. Intern Med 1999; 38:349.
  34. Homma K, Hayashi K, Wakino S, et al. Primary malignant hepatic pheochromocytoma with negative adrenal scintigraphy. Hypertens Res 2006; 29:551.
  35. Tanaka S, Ito T, Tomoda J, et al. Malignant pheochromocytoma with hepatic metastasis diagnosed 20 years after resection of the primary adrenal lesion. Intern Med 1993; 32:789.
  36. Huang H, Abraham J, Hung E, et al. Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer 2008; 113:2020.
  37. Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 1988; 109:267.
  38. Ayala-Ramirez M, Feng L, Habra MA, et al. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer 2012; 118:2804.
  39. Patel SR, Winchester DJ, Benjamin RS. A 15-year experience with chemotherapy of patients with paraganglioma. Cancer 1995; 76:1476.
  40. Edström Elder E, Hjelm Skog AL, Höög A, Hamberger B. The management of benign and malignant pheochromocytoma and abdominal paraganglioma. Eur J Surg Oncol 2003; 29:278.
  41. Ayala-Ramirez M, Feng L, Johnson MM, et al. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab 2011; 96:717.
  42. Baudin E, Goichot B, Berruti A, et al. Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial. Lancet 2024; 403:1061.
  43. Ayala-Ramirez M, Chougnet CN, Habra MA, et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab 2012; 97:4040.
  44. Joshua AM, Ezzat S, Asa SL, et al. Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma. J Clin Endocrinol Metab 2009; 94:5.
  45. Jimenez C, Cabanillas ME, Santarpia L, et al. Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors. J Clin Endocrinol Metab 2009; 94:386.
  46. Hahn NM, Reckova M, Cheng L, et al. Patient with malignant paraganglioma responding to the multikinase inhibitor sunitinib malate. J Clin Oncol 2009; 27:460.
  47. Park KS, Lee JL, Ahn H, et al. Sunitinib, a novel therapy for anthracycline- and cisplatin-refractory malignant pheochromocytoma. Jpn J Clin Oncol 2009; 39:327.
  48. O'Kane GM, Ezzat S, Joshua AM, et al. A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial. Br J Cancer 2019; 120:1113.
  49. Nasca V, Prinzi N, Coppa J, et al. Sunitinib for the treatment of patients with advanced pheochromocytomas or paragangliomas: The phase 2 non-randomized SUTNET clinical trial. Eur J Cancer 2024; 209:114276.
  50. Jimenez C, Habra MA, Campbell MT, et al. Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma (the Natalie Trial): a single-arm, phase 2 trial. Lancet Oncol 2024; 25:658.
  51. Cecchin D, Schiavi F, Fanti S, et al. Peptide receptor radionuclide therapy in a case of multiple spinal canal and cranial paragangliomas. J Clin Oncol 2011; 29:e171.
  52. van Essen M, Krenning EP, Kooij PP, et al. Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J Nucl Med 2006; 47:1599.
  53. Garkavij M, Nickel M, Sjögreen-Gleisner K, et al. 177Lu-[DOTA0,Tyr3] octreotate therapy in patients with disseminated neuroendocrine tumors: Analysis of dosimetry with impact on future therapeutic strategy. Cancer 2010; 116:1084.
  54. Forrer F, Riedweg I, Maecke HR, Mueller-Brand J. Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Q J Nucl Med Mol Imaging 2008; 52:334.
  55. Zandee WT, Feelders RA, Smit Duijzentkunst DA, et al. Treatment of inoperable or metastatic paragangliomas and pheochromocytomas with peptide receptor radionuclide therapy using 177Lu-DOTATATE. Eur J Endocrinol 2019; 181:45.
  56. Satapathy S, Mittal BR, Bhansali A. 'Peptide receptor radionuclide therapy in the management of advanced pheochromocytoma and paraganglioma: A systematic review and meta-analysis'. Clin Endocrinol (Oxf) 2019; 91:718.
  57. Buchmann I, Henze M, Engelbrecht S, et al. Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2007; 34:1617.
  58. Kowalski J, Henze M, Schuhmacher J, et al. Evaluation of positron emission tomography imaging using [68Ga]-DOTA-D Phe(1)-Tyr(3)-Octreotide in comparison to [111In]-DTPAOC SPECT. First results in patients with neuroendocrine tumors. Mol Imaging Biol 2003; 5:42.
  59. Mamede M, Carrasquillo JA, Chen CC, et al. Discordant localization of 2-[18F]-fluoro-2-deoxy-D-glucose in 6-[18F]-fluorodopamine- and [(123)I]-metaiodobenzylguanidine-negative metastatic pheochromocytoma sites. Nucl Med Commun 2006; 27:31.
  60. Hubalewska-Dydejczyk A, Trofimiuk M, Sowa-Staszczak A, et al. [Somatostatin receptors expression (SSTR1-SSTR5) in pheochromocytomas]. Przegl Lek 2008; 65:405.
  61. Saveanu A, Muresan M, De Micco C, et al. Expression of somatostatin receptors, dopamine D₂ receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas. Endocr Relat Cancer 2011; 18:287.
  62. de Herder WW, Hofland LJ. Somatostatin receptors in pheochromocytoma. Front Horm Res 2004; 31:145.
  63. Mundschenk J, Unger N, Schulz S, et al. Somatostatin receptor subtypes in human pheochromocytoma: subcellular expression pattern and functional relevance for octreotide scintigraphy. J Clin Endocrinol Metab 2003; 88:5150.
  64. Chen H, Sippel RS, O'Dorisio MS, et al. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas 2010; 39:775.
  65. Mukherjee JJ, Kaltsas GA, Islam N, et al. Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG]. Clin Endocrinol (Oxf) 2001; 55:47.
  66. Fitzgerald PA, Goldsby RE, Huberty JP, et al. Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG). Ann N Y Acad Sci 2006; 1073:465.
  67. Schlumberger M, Gicquel C, Lumbroso J, et al. Malignant pheochromocytoma: clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases. J Endocrinol Invest 1992; 15:631.
  68. Safford SD, Coleman RE, Gockerman JP, et al. Iodine -131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma. Surgery 2003; 134:956.
  69. Gedik GK, Hoefnagel CA, Bais E, Olmos RA. 131I-MIBG therapy in metastatic phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 2008; 35:725.
  70. Shapiro B, Sisson JC, Wieland DM, et al. Radiopharmaceutical therapy of malignant pheochromocytoma with [131I]metaiodobenzylguanidine: results from ten years of experience. J Nucl Biol Med 1991; 35:269.
  71. Rachh SH, Abhyankar S, Basu S. [¹³¹I]Metaiodobenzylguanidine therapy in neural crest tumors: varying outcome in different histopathologies. Nucl Med Commun 2011; 32:1201.
  72. Shilkrut M, Bar-Deroma R, Bar-Sela G, et al. Low-dose iodine-131 metaiodobenzylguanidine therapy for patients with malignant pheochromocytoma and paraganglioma: single center experience. Am J Clin Oncol 2010; 33:79.
  73. Gulenchyn KY, Yao X, Asa SL, et al. Radionuclide therapy in neuroendocrine tumours: a systematic review. Clin Oncol (R Coll Radiol) 2012; 24:294.
  74. Sze WC, Grossman AB, Goddard I, et al. Sequelae and survivorship in patients treated with (131)I-MIBG therapy. Br J Cancer 2013; 109:565.
  75. Gonias S, Goldsby R, Matthay KK, et al. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol 2009; 27:4162.
  76. van der Harst E, de Herder WW, Bruining HA, et al. [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas. J Clin Endocrinol Metab 2001; 86:685.
  77. Pacak K, Ilias I, Adams KT, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med 2005; 257:60.
  78. Noto RB, Pryma DA, Jensen J, et al. Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent Pheochromocytoma or Paraganglioma. J Clin Endocrinol Metab 2018; 103:213.
  79. Foo SH, Chan SP, Ananda V, Rajasingam V. Dopamine-secreting phaeochromocytomas and paragangliomas: clinical features and management. Singapore Med J 2010; 51:e89.
  80. Proye C, Fossati P, Fontaine P, et al. Dopamine-secreting pheochromocytoma: an unrecognized entity? Classification of pheochromocytomas according to their type of secretion. Surgery 1986; 100:1154.
  81. Van Der Horst-Schrivers AN, Osinga TE, Kema IP, et al. Dopamine excess in patients with head and neck paragangliomas. Anticancer Res 2010; 30:5153.
  82. Rose B, Matthay KK, Price D, et al. High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma. Cancer 2003; 98:239.
  83. Rutherford MA, Rankin AJ, Yates TM, et al. Management of metastatic phaeochromocytoma and paraganglioma: use of iodine-131-meta-iodobenzylguanidine therapy in a tertiary referral centre. QJM 2015; 108:361.
  84. Thorpe MP, Kane A, Zhu J, et al. Long-Term Outcomes of 125 Patients With Metastatic Pheochromocytoma or Paraganglioma Treated With 131-I MIBG. J Clin Endocrinol Metab 2020; 105:e494.
  85. Lamarre-Cliche M, Gimenez-Roqueplo AP, Billaud E, et al. Effects of slow-release octreotide on urinary metanephrine excretion and plasma chromogranin A and catecholamine levels in patients with malignant or recurrent phaeochromocytoma. Clin Endocrinol (Oxf) 2002; 57:629.
  86. Invitti C, De Martin I, Bolla GB, et al. Effect of octreotide on catecholamine plasma levels in patients with chromaffin cell tumors. Horm Res 1993; 40:156.
  87. Plouin PF, Bertherat J, Chatellier G, et al. Short-term effects of octreotide on blood pressure and plasma catecholamines and neuropeptide Y levels in patients with phaeochromocytoma: a placebo-controlled trial. Clin Endocrinol (Oxf) 1995; 42:289.
  88. Duet M, Guichard JP, Rizzo N, et al. Are somatostatin analogs therapeutic alternatives in the management of head and neck paragangliomas? Laryngoscope 2005; 115:1381.
  89. Tonyukuk V, Emral R, Temizkan S, et al. Case report: patient with multiple paragangliomas treated with long acting somatostatin analogue. Endocr J 2003; 50:507.
  90. van Hulsteijn LT, van Duinen N, Verbist BM, et al. Effects of octreotide therapy in progressive head and neck paragangliomas: case series. Head Neck 2013; 35:E391.
  91. Jha A, Patel M, Baker E, et al. Role of 68Ga-DOTATATE PET/CT in a Case of SDHB-Related Pterygopalatine Fossa Paraganglioma Successfully Controlled with Octreotide. Nucl Med Mol Imaging 2020; 54:48.
  92. Tenenbaum F, Schlumberger M, Lumbroso J, Parmentier C. Beneficial effects of octreotide in a patient with a metastatic paraganglioma. Eur J Cancer 1996; 32A:737.
  93. Kau R, Arnold W. Somatostatin receptor scintigraphy and therapy of neuroendocrine (APUD) tumors of the head and neck. Acta Otolaryngol 1996; 116:345.
  94. Koriyama N, Kakei M, Yaekura K, et al. Control of catecholamine release and blood pressure with octreotide in a patient with pheochromocytoma: a case report with in vitro studies. Horm Res 2000; 53:46.
  95. Fischer A, Kloos S, Maccio U, et al. Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses. J Clin Endocrinol Metab 2023; 108:2676.
  96. Bravo EL, Kalmadi SR, Gill I. Clinical utility of temozolomide in the treatment of malignant paraganglioma: a preliminary report. Horm Metab Res 2009; 41:703.
  97. Hadoux J, Favier J, Scoazec JY, et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer 2014; 135:2711.
  98. Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 2006; 24:401.
  99. Nozières C, Walter T, Joly MO, et al. A SDHB malignant paraganglioma with dramatic response to temozolomide-capecitabine. Eur J Endocrinol 2012; 166:1107.
  100. Mora J, Cruz O, Parareda A, et al. Treatment of disseminated paraganglioma with gemcitabine and docetaxel. Pediatr Blood Cancer 2009; 53:663.
  101. Pipas JM, Krywicki RF. Treatment of progressive metastatic glomus jugulare tumor (paraganglioma) with gemcitabine. Neuro Oncol 2000; 2:190.
  102. Kamoshima Y, Sawamura Y, Hokari M, et al. Craniocervical paraganglioma with numerous pulmonary metastases--case report. Neurol Med Chir (Tokyo) 2008; 48:401.
  103. Chow SN, Seear M, Anderson R, Magee F. Multiple pulmonary chemodectomas in a child: results of four different therapeutic regimens. J Pediatr Hematol Oncol 1998; 20:583.
  104. Kruijtzer CM, Beijnen JH, Swart M, Schellens JH. Successful treatment with paclitaxel of a patient with metastatic extra-adrenal pheochromocytoma (paraganglioma). A case report and review of the literature. Cancer Chemother Pharmacol 2000; 45:428.
  105. Mukherji SK, Kasper ME, Tart RP, Mancuso AA. Irradiated paragangliomas of the head and neck: CT and MR appearance. AJNR Am J Neuroradiol 1994; 15:357.
  106. Janssen I, Blanchet EM, Adams K, et al. Superiority of [68Ga]-DOTATATE PET/CT to Other Functional Imaging Modalities in the Localization of SDHB-Associated Metastatic Pheochromocytoma and Paraganglioma. Clin Cancer Res 2015; 21:3888.
  107. Janssen I, Chen CC, Millo CM, et al. PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 2016; 43:1784.
  108. Tan TH, Hussein Z, Saad FF, Shuaib IL. Diagnostic Performance of (68)Ga-DOTATATE PET/CT, (18)F-FDG PET/CT and (131)I-MIBG Scintigraphy in Mapping Metastatic Pheochromocytoma and Paraganglioma. Nucl Med Mol Imaging 2015; 49:143.
  109. Hofman MS, Lau WF, Hicks RJ. Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation. Radiographics 2015; 35:500.
  110. Poeppel TD, Binse I, Petersenn S, et al. 68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors. J Nucl Med 2011; 52:1864.
  111. Han S, Suh CH, Woo S, et al. Performance of 68Ga-DOTA-Conjugated Somatostatin Receptor-Targeting Peptide PET in Detection of Pheochromocytoma and Paraganglioma: A Systematic Review and Metaanalysis. J Nucl Med 2019; 60:369.
  112. Kan Y, Zhang S, Wang W, et al. 68Ga-somatostatin receptor analogs and 18F-FDG PET/CT in the localization of metastatic pheochromocytomas and paragangliomas with germline mutations: a meta-analysis. Acta Radiol 2018; 59:1466.
  113. Grossrubatscher E, Dalino P, Vignati F, et al. The role of chromogranin A in the management of patients with phaeochromocytoma. Clin Endocrinol (Oxf) 2006; 65:287.
  114. Szalat A, Fraenkel M, Doviner V, et al. Malignant pheochromocytoma: predictive factors of malignancy and clinical course in 16 patients at a single tertiary medical center. Endocrine 2011; 39:160.
  115. Bílek R, Safarík L, Ciprová V, et al. Chromogranin A, a member of neuroendocrine secretory proteins as a selective marker for laboratory diagnosis of pheochromocytoma. Physiol Res 2008; 57 Suppl 1:S171.
  116. Cleary S, Phillips JK, Huynh TT, et al. Chromogranin a expression in phaeochromocytomas associated with von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2. Horm Metab Res 2007; 39:876.
  117. d'Herbomez M, Gouze V, Huglo D, et al. Chromogranin A assay and (131)I-MIBG scintigraphy for diagnosis and follow-up of pheochromocytoma. J Nucl Med 2001; 42:993.
  118. Baudin E, Gigliotti A, Ducreux M, et al. Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours. Br J Cancer 1998; 78:1102.
  119. Young AL, Baysal BE, Deb A, Young WF Jr. Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. J Clin Endocrinol Metab 2002; 87:4101.
  120. Goldstein RE, O'Neill JA Jr, Holcomb GW 3rd, et al. Clinical experience over 48 years with pheochromocytoma. Ann Surg 1999; 229:755.
  121. Moskovic DJ, Smolarz JR, Stanley D, et al. Malignant head and neck paragangliomas: is there an optimal treatment strategy? Head Neck Oncol 2010; 2:23.
  122. Amar L, Baudin E, Burnichon N, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab 2007; 92:3822.
  123. Sisson JC, Shulkin BL, Esfandiari NH. Courses of malignant pheochromocytoma: implications for therapy. Ann N Y Acad Sci 2006; 1073:505.
  124. Nomura K, Kimura H, Shimizu S, et al. Survival of patients with metastatic malignant pheochromocytoma and efficacy of combined cyclophosphamide, vincristine, and dacarbazine chemotherapy. J Clin Endocrinol Metab 2009; 94:2850.
  125. Sethi RV, Sethi RK, Herr MW, Deschler DG. Malignant head and neck paragangliomas: treatment efficacy and prognostic indicators. Am J Otolaryngol 2013; 34:431.
  126. Goffredo P, Sosa JA, Roman SA. Malignant pheochromocytoma and paraganglioma: a population level analysis of long-term survival over two decades. J Surg Oncol 2013; 107:659.
  127. Calsina B, Piñeiro-Yáñez E, Martínez-Montes ÁM, et al. Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma. Nat Commun 2023; 14:1122.
  128. Pazopanib Hydrochloride in Treating Patients With Advanced or Progressive Malignant Pheochromocytoma or Paraganglioma. National Cancer Institute clinical trial NCT01340794. US National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT01340794 (Accessed on July 15, 2019).
  129. Oh DY, Kim TW, Park YS, et al. Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas. Cancer 2012; 118:6162.
  130. Tella SH, Taïeb D, Pacak K. HIF-2alpha: Achilles' heel of pseudohypoxic subtype paraganglioma and other related conditions. Eur J Cancer 2017; 86:1.
  131. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med 2021; 385:2036.
  132. Kamihara J, Hamilton KV, Pollard JA, et al. Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome. N Engl J Med 2021; 385:2059.
  133. Pinato DJ, Black JR, Trousil S, et al. Programmed cell death ligands expression in phaeochromocytomas and paragangliomas: Relationship with the hypoxic response, immune evasion and malignant behavior. Oncoimmunology 2017; 6:e1358332.
  134. Chouaib S, Noman MZ, Kosmatopoulos K, Curran MA. Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer. Oncogene 2017; 36:439.
  135. Fanciulli G, Di Molfetta S, Dotto A, et al. Emerging Therapies in Pheochromocytoma and Paraganglioma: Immune Checkpoint Inhibitors in the Starting Blocks. J Clin Med 2020; 10.
  136. Jimenez C, Subbiah V, Stephen B, et al. Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas. Cancers (Basel) 2020; 12.
Topic 86953 Version 41.0

References

1 : Metastatic pheochromocytoma: does the size and age matter?

2 : The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients.

3 : Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years.

4 : Pheochromocytoma and Paraganglioma.

5 : 65 YEARS OF THE DOUBLE HELIX: Genetics informs precision practice in the diagnosis and management of pheochromocytoma.

6 : Pheochromocytoma and paraganglioma.

7 : New Insights on the Genetics of Pheochromocytoma and Paraganglioma and Its Clinical Implications.

8 : Update on the genetics of paragangliomas.

9 : Metastatic Pheochromocytoma: In Search of a Cure.

10 : Malignant pheochromocytomas and paragangliomas - the importance of a multidisciplinary approach.

11 : Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.

12 : Malignant phaeochromocytoma of the organ of Zuckerkandl with functioning metastases.

13 : Response after surgical resection of metastatic pheochromocytoma and paraganglioma: can postoperative biochemical remission be predicted?

14 : Surgical Treatment of Malignant Pheochromocytoma and Paraganglioma: Retrospective Case Series.

15 : Clinical and pathological data of 10 malignant pheochromocytomas: long-term follow up in a single institute.

16 : National Cancer Data Base report on malignant paragangliomas of the head and neck.

17 : Malignant pheochromocytoma: current status and initiatives for future progress.

18 : Treatment of malignant pheochromocytoma.

19 : Iatrogenic pheochromocytomatosis: a previously unreported result of laparoscopic adrenalectomy.

20 : External beam radiation therapy for advanced/unresectable malignant paraganglioma and pheochromocytoma.

21 : External beam radiation therapy (EBRT) for patients with malignant pheochromocytoma and non-head and -neck paraganglioma: combination with 131I-MIBG.

22 : Acutely exacerbated hypertension and increased inflammatory signs due to radiation treatment for metastatic pheochromocytoma.

23 : Minimally invasive treatment of metastatic pheochromocytoma and paraganglioma: efficacy and safety of radiofrequency ablation and cryoablation therapy.

24 : Radiofrequency ablation and biopsy of metastatic pheochromocytoma: emphasizing safety issues and dangers.

25 : Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases.

26 : Hepatic ablation for neuroendocrine tumor metastases.

27 : Radiofrequency ablation: a novel approach for treatment of metastatic pheochromocytoma.

28 : Radiofrequency ablation of metastatic pheochromocytoma.

29 : Cryotherapy treatment of patients with hepatic metastases from neuroendocrine tumors.

30 : Efficacy and Safety of Ablative Therapy in the Treatment of Patients with Metastatic Pheochromocytoma and Paraganglioma.

31 : Malignant pheochromocytoma with liver metastasis treated by transcatheter arterial chemo-embolization (TACE).

32 : Transcatheter arterial embolization for the treatment of liver metastases in a patient with malignant pheochromocytoma.

33 : Malignant pheochromocytoma with multiple hepatic metastases treated by chemotherapy and transcatheter arterial embolization.

34 : Primary malignant hepatic pheochromocytoma with negative adrenal scintigraphy.

35 : Malignant pheochromocytoma with hepatic metastasis diagnosed 20 years after resection of the primary adrenal lesion.

36 : Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients.

37 : Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine.

38 : Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience.

39 : A 15-year experience with chemotherapy of patients with paraganglioma.

40 : The management of benign and malignant pheochromocytoma and abdominal paraganglioma.

41 : Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators.

42 : Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial.

43 : Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas.

44 : Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma.

45 : Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors.

46 : Patient with malignant paraganglioma responding to the multikinase inhibitor sunitinib malate.

47 : Sunitinib, a novel therapy for anthracycline- and cisplatin-refractory malignant pheochromocytoma.

48 : A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial.

49 : Sunitinib for the treatment of patients with advanced pheochromocytomas or paragangliomas: The phase 2 non-randomized SUTNET clinical trial.

50 : Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma (the Natalie Trial): a single-arm, phase 2 trial.

51 : Peptide receptor radionuclide therapy in a case of multiple spinal canal and cranial paragangliomas.

52 : Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma.

53 : 177Lu-[DOTA0,Tyr3] octreotate therapy in patients with disseminated neuroendocrine tumors: Analysis of dosimetry with impact on future therapeutic strategy.

54 : Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma.

55 : Treatment of inoperable or metastatic paragangliomas and pheochromocytomas with peptide receptor radionuclide therapy using 177Lu-DOTATATE.

56 : 'Peptide receptor radionuclide therapy in the management of advanced pheochromocytoma and paraganglioma: A systematic review and meta-analysis'.

57 : Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours.

58 : Evaluation of positron emission tomography imaging using [68Ga]-DOTA-D Phe(1)-Tyr(3)-Octreotide in comparison to [111In]-DTPAOC SPECT. First results in patients with neuroendocrine tumors.

59 : Discordant localization of 2-[18F]-fluoro-2-deoxy-D-glucose in 6-[18F]-fluorodopamine- and [(123)I]-metaiodobenzylguanidine-negative metastatic pheochromocytoma sites.

60 : [Somatostatin receptors expression (SSTR1-SSTR5) in pheochromocytomas].

61 : Expression of somatostatin receptors, dopamine D₂receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas.

62 : Somatostatin receptors in pheochromocytoma.

63 : Somatostatin receptor subtypes in human pheochromocytoma: subcellular expression pattern and functional relevance for octreotide scintigraphy.

64 : The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer.

65 : Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG].

66 : Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG).

67 : Malignant pheochromocytoma: clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases.

68 : Iodine -131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma.

69 : 131I-MIBG therapy in metastatic phaeochromocytoma and paraganglioma.

70 : Radiopharmaceutical therapy of malignant pheochromocytoma with [131I]metaiodobenzylguanidine: results from ten years of experience.

71 : [¹³¹I]Metaiodobenzylguanidine therapy in neural crest tumors: varying outcome in different histopathologies.

72 : Low-dose iodine-131 metaiodobenzylguanidine therapy for patients with malignant pheochromocytoma and paraganglioma: single center experience.

73 : Radionuclide therapy in neuroendocrine tumours: a systematic review.

74 : Sequelae and survivorship in patients treated with (131)I-MIBG therapy.

75 : Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma.

76 : [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas.

77 : Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour.

78 : Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent Pheochromocytoma or Paraganglioma.

79 : Dopamine-secreting phaeochromocytomas and paragangliomas: clinical features and management.

80 : Dopamine-secreting pheochromocytoma: an unrecognized entity? Classification of pheochromocytomas according to their type of secretion.

81 : Dopamine excess in patients with head and neck paragangliomas.

82 : High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma.

83 : Management of metastatic phaeochromocytoma and paraganglioma: use of iodine-131-meta-iodobenzylguanidine therapy in a tertiary referral centre.

84 : Long-Term Outcomes of 125 Patients With Metastatic Pheochromocytoma or Paraganglioma Treated With 131-I MIBG.

85 : Effects of slow-release octreotide on urinary metanephrine excretion and plasma chromogranin A and catecholamine levels in patients with malignant or recurrent phaeochromocytoma.

86 : Effect of octreotide on catecholamine plasma levels in patients with chromaffin cell tumors.

87 : Short-term effects of octreotide on blood pressure and plasma catecholamines and neuropeptide Y levels in patients with phaeochromocytoma: a placebo-controlled trial.

88 : Are somatostatin analogs therapeutic alternatives in the management of head and neck paragangliomas?

89 : Case report: patient with multiple paragangliomas treated with long acting somatostatin analogue.

90 : Effects of octreotide therapy in progressive head and neck paragangliomas: case series.

91 : Role of 68Ga-DOTATATE PET/CT in a Case of SDHB-Related Pterygopalatine Fossa Paraganglioma Successfully Controlled with Octreotide.

92 : Beneficial effects of octreotide in a patient with a metastatic paraganglioma.

93 : Somatostatin receptor scintigraphy and therapy of neuroendocrine (APUD) tumors of the head and neck.

94 : Control of catecholamine release and blood pressure with octreotide in a patient with pheochromocytoma: a case report with in vitro studies.

95 : Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses.

96 : Clinical utility of temozolomide in the treatment of malignant paraganglioma: a preliminary report.

97 : SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma.

98 : Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors.

99 : A SDHB malignant paraganglioma with dramatic response to temozolomide-capecitabine.

100 : Treatment of disseminated paraganglioma with gemcitabine and docetaxel.

101 : Treatment of progressive metastatic glomus jugulare tumor (paraganglioma) with gemcitabine.

102 : Craniocervical paraganglioma with numerous pulmonary metastases--case report.

103 : Multiple pulmonary chemodectomas in a child: results of four different therapeutic regimens.

104 : Successful treatment with paclitaxel of a patient with metastatic extra-adrenal pheochromocytoma (paraganglioma). A case report and review of the literature.

105 : Irradiated paragangliomas of the head and neck: CT and MR appearance.

106 : Superiority of [68Ga]-DOTATATE PET/CT to Other Functional Imaging Modalities in the Localization of SDHB-Associated Metastatic Pheochromocytoma and Paraganglioma.

107 : PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma.

108 : Diagnostic Performance of (68)Ga-DOTATATE PET/CT, (18)F-FDG PET/CT and (131)I-MIBG Scintigraphy in Mapping Metastatic Pheochromocytoma and Paraganglioma.

109 : Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation.

110 : 68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors.

111 : Performance of 68Ga-DOTA-Conjugated Somatostatin Receptor-Targeting Peptide PET in Detection of Pheochromocytoma and Paraganglioma: A Systematic Review and Metaanalysis.

112 : 68Ga-somatostatin receptor analogs and 18F-FDG PET/CT in the localization of metastatic pheochromocytomas and paragangliomas with germline mutations: a meta-analysis.

113 : The role of chromogranin A in the management of patients with phaeochromocytoma.

114 : Malignant pheochromocytoma: predictive factors of malignancy and clinical course in 16 patients at a single tertiary medical center.

115 : Chromogranin A, a member of neuroendocrine secretory proteins as a selective marker for laboratory diagnosis of pheochromocytoma.

116 : Chromogranin a expression in phaeochromocytomas associated with von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2.

117 : Chromogranin A assay and (131)I-MIBG scintigraphy for diagnosis and follow-up of pheochromocytoma.

118 : Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours.

119 : Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene.

120 : Clinical experience over 48 years with pheochromocytoma.

121 : Malignant head and neck paragangliomas: is there an optimal treatment strategy?

122 : Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas.

123 : Courses of malignant pheochromocytoma: implications for therapy.

124 : Survival of patients with metastatic malignant pheochromocytoma and efficacy of combined cyclophosphamide, vincristine, and dacarbazine chemotherapy.

125 : Malignant head and neck paragangliomas: treatment efficacy and prognostic indicators.

126 : Malignant pheochromocytoma and paraganglioma: a population level analysis of long-term survival over two decades.

127 : Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma.

128 : Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma.

129 : Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas.

130 : HIF-2alpha: Achilles' heel of pseudohypoxic subtype paraganglioma and other related conditions.

131 : Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.

132 : Belzutifan, a Potent HIF2αInhibitor, in the Pacak-Zhuang Syndrome.

133 : Programmed cell death ligands expression in phaeochromocytomas and paragangliomas: Relationship with the hypoxic response, immune evasion and malignant behavior.

134 : Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer.

135 : Emerging Therapies in Pheochromocytoma and Paraganglioma: Immune Checkpoint Inhibitors in the Starting Blocks.

136 : Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas.