Paraganglioma and pheochromocytoma: Management of malignant disease

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/paragangliomas share overlapping characteristics that span histopathology, epidemiology, and even molecular pathobiology, they also have many differences in terms of their clinical behavior, aggressiveness and metastatic potential, biochemical findings, and association with inherited genetic syndromes.

Most pheochromocytomas/paragangliomas are benign. At least 10 percent of pheochromocytomas are malignant (as defined by the presence of metastases), while a larger proportion of paragangliomas (up to 25 percent) are malignant. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Familial paraganglioma and SDH pathogenic variants'.)

Although some paragangliomas, particularly those arising in the skull base and neck, do not present with symptoms of catecholamine excess, intratumoral metabolism of catecholamines to metanephrines (norepinephrine to normetanephrine, and epinephrine to metanephrine, respectively) occurs independently of catecholamine release. As a result, biochemical testing is indicated in every patient with a paraganglioma even if the patient does not present with a clinical picture of catecholamine hypersecretion. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Diagnosis'.)

Paragangliomas and pheochromocytomas are indistinguishable at the cellular level, and catecholamine-secreting paragangliomas often present clinically like pheochromocytomas with hypertension, episodic headache, sweating, tremor, and forceful palpitations. However, the distinction between pheochromocytoma and paraganglioma is an important one because of implications for genetic testing, risk stratification, and treatment.

As the understanding of pheochromocytomas and paragangliomas have evolved beyond the "10 percent rule" (ie, 10 percent familial, 10 percent malignant, 10 percent extra-adrenal), the implication for underlying genetic defect(s) on tumor location and malignant potential dictates the approach to workup of these entities. As such, genetic testing is recommended for all patients with a paraganglioma and pheochromocytoma [1]. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Hereditary syndromes' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Molecular pathogenesis' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Genetic testing' and "Pheochromocytoma in genetic disorders", section on 'Suggested approach'.)

This topic review will cover treatment for advanced metastatic pheochromocytoma/paraganglioma. The epidemiology, risk factors, molecular pathogenesis, histology, clinical manifestations, diagnosis, and genetic screening issues for paragangliomas and pheochromocytomas; locoregional treatment for pheochromocytomas; and locoregional treatment for paragangliomas are covered elsewhere. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology" and "Clinical presentation and diagnosis of pheochromocytoma" and "Paragangliomas: Treatment of locoregional disease" and "Treatment of pheochromocytoma in adults".)

MOLECULAR PATHOGENESIS — The study of familial paraganglioma/pheochromocytoma syndromes (also called hereditary paraganglioma/pheochromocytoma syndromes) has been very important in understanding the pathogenic mechanisms involved in both the familial as well as sporadic forms [2]. Several susceptibility genes have been established as playing a central role in the pathogenesis of both pheochromocytomas and paragangliomas [3]. Some of these represent inherited conditions (eg, pathogenic variants in the von Hippel-Lindau [VHL] tumor suppressor gene; the rearranged during transfection [RET] proto-oncogene; the neurofibromatosis type 1 [NF1] tumor suppressor gene; genes encoding for the four subunits [A, B, C, and D] of the succinate dehydrogenase [SDH] complex; a gene encoding the enzyme responsible for flavination of the SDHA subunit [SDHAF2]). Other pathogenic variants involve the gene-encoding transmembrane protein 127 (TMEM127), MYC-associated factor X (MAX), and hypoxia-inducible factor 2 alpha [HIF2A]) [2].

Germline pathogenic variants contributing to pheochromocytoma and paraganglioma have two general transcription signatures: cluster 1, genes encoding proteins that function in the cellular response to hypoxia; and cluster 2, gene-encoding proteins that activate kinase signaling. 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, whereas cluster 2 tumors are usually adrenal pheochromocytomas with an adrenergic biochemical phenotype.

Approximately 20 different pheochromocytoma/paraganglioma susceptibility genes have been reported (table 1):

●Cluster 1 – Cluster 1 germline pathogenic variants include: VHL, SDHD, SDHC, SDHB, SDHAF2, SDHA EGLN1 (PHD2), KIF1, IDH1, TMEM127, SDHA, MAX, HIF2, FH gene encoding fumarate hydratase, EGLN1 (PHD2), EGLN2 (PHD1), and KIF1B.

●Cluster 2 – Cluster 2 germline pathogenic variants include: RET, NF1, MAX, and TMEM127.

Genetic studies suggest that other genes and their associated molecular pathways may be involved in the pathogenesis of these tumors. These include a third cluster entailing a Wnt-altered pathway whose somatic mutations result in aggressive sporadic cases [4]. In this context, investigations are underway to uncover novel pathogenic variants in apparently "sporadic" cases. (See "Pheochromocytoma in genetic disorders".)

RISK OF MALIGNANCY AND IMPLICATIONS FOR PRIMARY THERAPY — The definition of malignancy in pheochromocytoma/paraganglioma is not always straightforward. Given that there is no combination of clinical, histopathologic, or biochemical features shown to reliably predict biologic behavior [5,6], pathologic evaluations generally provide little prognostic insight to predict risk of recurrence or metastases. A diagnosis of malignancy can only be made by identifying tumor deposits in tissues that do not normally contain chromaffin cells (eg, lymph nodes, liver, bone, lung, and other distant metastatic sites). (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Histology and malignant potential'.)

In patients with pheochromocytoma/paraganglioma, long-term surveillance should be conducted to assess for malignancy. (See "Paragangliomas: Treatment of locoregional disease", section on 'Posttreatment surveillance'.)

The incidence of malignancy depends on anatomic site and genetic background:

●Approximately 10 percent of pheochromocytomas are malignant compared with 20 to 25 percent of extra-adrenal abdominal/pelvic and mediastinal secretory paragangliomas. In the skull base and neck, malignancy is least common for jugulotympanic tumors (2 to 4 percent), slightly higher for carotid body tumors (4 to 6 percent), and highest for vagal tumors (10 to 19 percent). (See "Paragangliomas: Treatment of locoregional disease", section on 'Risk of malignancy'.)

●There are large differences between the familial syndromes and their risk for malignancy:

•The highest malignancy rates 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. These patients warrant screening for distant metastatic disease as part of the preoperative evaluation. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Familial paraganglioma and SDH pathogenic variants' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Screening for synchronous and metastatic disease'.)

•Only 3 to 5 percent of pheochromocytomas/paragangliomas related to MEN2 are malignant. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Pheochromocytoma' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'MEN2'.)

The above considerations should be used to inform surveillance frequency and modalities. Metastases may appear more than 50 years after the original presentation, providing the rationale for long-term, post-treatment surveillance after locoregional treatment of these patients [7]. (See "Paragangliomas: Treatment of locoregional disease", section on 'Posttreatment surveillance'.)

Among patients with malignant skull base and neck paragangliomas, metastases are most frequently found in the cervical lymph nodes. These data have led some to recommend selective lymph node dissection at the time of primary resection. Although outcomes of patients with regional nodal disease are better than those with distant metastases (five-year survival 77 versus 12 percent in the above noted series from the National Cancer Database [8]), adjuvant radiation therapy (RT) is frequently recommended. (See "Paragangliomas: Treatment of locoregional disease", section on 'Resection' and "Paragangliomas: Treatment of locoregional disease", section on 'Postoperative radiation therapy'.)

By contrast, patients with paragangliomas below the skull base and neck more frequently have distant metastases, most commonly to the bone, liver, and lung. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Overview'.)

While the presence of distant metastatic disease can have an adverse effect on prognosis, metastases do not necessarily represent a contraindication to local intervention. Interventions such as surgical debulking, ablation, or stereotactic RT represent effective options for primary management of recurrent or metastatic disease [9]. Even if surgical intervention does not result in complete debulking, it may still be considered with palliative intent to release tumor pressure on surrounding tissues or to decrease tumor mass [10]. A lower tumor burden can lead to a significant decrease in catecholamine secretion (for functioning tumors) as well as a lowered dose of agents used for adrenergic blockade. It can also improve the response to other therapeutic approaches. However, a survival advantage for surgical debulking has not been shown (see "Paragangliomas: Treatment of locoregional disease", section on 'Medical preparation for surgery').

For patients not amenable to surgery or for those that require additional postoperative therapy, a number of palliative options are available, including Iobenguane I-131 (therapeutic), chemotherapy, RT, cryoablation therapy, radiofrequency ablation therapy, ethanol injection, tumor embolization, and peptide receptor radionuclide therapy [9].

PROGNOSIS — The clinical course of metastatic pheochromocytoma/paraganglioma is highly variable, with reported five-year survival rates that range widely from 12 to 84 percent [8,11-21]. Some of this variability has to do with differing definitions of malignancy; the World Health Organization (WHO) considers that malignant pheochromocytomas/paragangliomas are only those with documented metastases to nodes or distantly, whereas the Armed Forces Institute of Pathology Fascicle for Tumors of the Adrenal Glands and Extra-Adrenal Paraganglia defines malignancy as "extensive local invasion or documentation of metastases." For the purpose of this review, we consider that malignant pheochromocytoma/paraganglioma requires the documentation of metastatic disease. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Histology and malignant potential'.)

Among malignant tumors, the survival rate may depend on the primary tumor site and sites of metastases. Outcomes are most variable for patients with malignant paragangliomas of the skull base and neck, most of which are nonsecretory. The following represents the range of findings:

●In one single institution series of 19 patients with malignant skull base and neck paraganglioma treated between 1970 and 2005, the five-year survival rate was 84 percent, despite the fact that 14 had distant metastases [16].

●On the other hand, in another report of 86 cases of malignant head and neck paraganglioma reported to the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2009, the five-year survival rate was 65 percent overall; for those with regionally confined metastases (n = 47), it was 82 percent, compared with 41 percent for those with distant metastases (n = 39) [21]. Outcomes were more favorable for carotid body tumors than for malignant tumors at other sites (five-year survival 87 versus 48 percent).

●An earlier report of data on 59 cases of malignant paraganglioma of the skull base and neck extracted from the National Cancer Database demonstrated a five-year survival rate of 77 percent for regionally-confined metastases, but only 12 percent for patients with distant metastatic disease [8].

●Among patients with metastatic pheochromocytoma/secretory paraganglioma, reported five-year survival rates are 34 to 60 percent, averaging approximately 50 percent [11-15,17-20,22]. Even 10-year survival rates of 25 percent are reported [22]. However, others report that outcomes are poorer with pheochromocytomas compared with paraganglioma, regardless of functionality [23]. In this study, pheochromocytomas presented more often with distant metastases and with larger tumors; overall survival at five years was 58 percent compared with 80 percent for paraganglioma.

●In a retrospective series of 272 patients with metastatic pheochromocytoma or paraganglioma, the median age at detection was 39 (range, 7 to 83 years), with synchronous metastases in 96 (35 percent) patients [7]. Metachronous metastases developed in 176 (65 percent) at a median of 5.5 years (range, 0.3 to 53.4 years) from the initial diagnosis. Median overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Shorter survival correlated with male sex, older age at the time of primary tumor, synchronous metastases, larger primary tumor size, elevated dopamine levels, and not undergoing primary tumor resection. There was no difference according to type of primary tumor or presence of SDHB pathogenic variant.

Prognosis is impacted by tumor burden, location of metastases, and rate of progression; patients with brain, liver, and lung metastases tend to have a worse prognosis than do those with isolated bone lesions [24].

MEDICAL MANAGEMENT OF CATECHOLAMINE SECRETION — Symptoms of catecholamine excess from functioning malignant pheochromocytoma/paragangliomas are the same as those associated with benign tumors. Among patients with malignant disease, symptoms may develop as a result of metastatic growth of the tumor [25].

Symptoms of catecholamine excess typically include episodic hypertension, headache, palpitations, and sweating. The diagnosis is confirmed by elevated catecholamine metabolites in plasma and/or raised 24-hour urinary excretion of fractionated metanephrines and catecholamines. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Diagnosis' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Catecholamine hypersecretion'.)

As in patients with benign disease, symptoms of catecholamine excess can be controlled with combined alpha- and beta-adrenergic blockade. (See "Treatment of pheochromocytoma in adults", section on 'Combined alpha and beta-adrenergic blockade'.)

RESPONSE ASSESSMENT — Response assessment in patients being treated for advanced pheochromocytoma/paraganglioma is usually performed using a combination of radiographic imaging and serial assays of fractionated metanephrines, fractionated catecholamines, and chromogranin A (CgA).

One of the unique features of pheochromocytoma/paraganglioma is their slow response to therapy, particularly to radiation therapy (RT) [26]. 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 magnetic resonance imaging (MRI) have all been described and are indicative of local control [26,27].

Functional imaging can play a defined role in the management of disease, especially in the assessment of tumor burden not seen on standard imaging modalities. Some have suggested the superiority of metabolic (functional) imaging with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) rather than anatomical cross-sectional imaging with computed tomography (CT) [28,29], but this is not a standard approach to response assessment at most institutions. For example, tumors harboring SDHB/SDHD (genes encoding for the B and D subunits of the succinate dehydrogenase [SDH] complex) pathogenic variants have been associated with false negative results on 18F-FDOPA (6-[18F]-L-fluoro-L-3, 4-dihydroxyphenylalanine) PET/CT. This finding provides a rationale to screen for such mutations in patients with 18F-FDOPA negative PET/CT imaging [30,31]. PET/CT using the somatostatin receptor-based tracer gallium Ga-68 DOTATATE offers a better option than FDG-PET for functional PET imaging of extra-adrenal paragangliomas [32-36]. Highly sensitive functional imaging can allow more accurate staging of patients with advanced disease.

CgA is co-stored and co-released with catecholamines from chromaffin cells. Because of limited specificity, CgA is not useful for diagnostic purposes (table 2).

However, as with other neuroendocrine tumors, serum CgA levels correlate with disease burden, and serial measurement of CgA is mostly used to monitor response to treatment [22,37-41].

THERAPEUTIC OPTIONS — Initial observation coupled with frequent follow-up could be considered an option for asymptomatic patients, given the indolent course in some subgroups of patients. For many patients with indolent tumors, treatment-related side effects may exceed the potential benefit of therapy [9]. (See 'Prognosis' above.)

However, for symptomatic patients or those with progressive metastatic disease, there are several therapeutic strategies for control of tumor burden. A multidisciplinary approach to management is optimal [9,42].

Local therapy

Resection — There are no curative treatments for metastatic pheochromocytoma/paraganglioma. However, both the primary and metastatic lesions should be resected, if possible [43,44]. Resection may improve symptoms, reduce hormone secretion, prevent complications related to a critical anatomic location, and improve the efficacy of subsequent therapies [24,44-46]. Resection may also possibly improve survival, although there are no clinical trial data to support this [47]. Although the five-year survival rate is less than 50 percent, many of these patients have prolonged survival and minimal morbidity [8,11].

Surgical intervention should only be performed in centers with experience in handling patients with malignant pheochromocytoma/paraganglioma. Preoperative control of the effects of excessive adrenergic stimulation, and preoperative, as well as intraoperative, volume expansion are necessary. General surgical principles, including medical preparation for surgery and intraoperative hemodynamic management, are addressed elsewhere. (See "Paragangliomas: Treatment of locoregional disease", section on 'General surgical principles'.)

Although a laparoscopic approach to resection is generally preferred for benign pheochromocytomas/paragangliomas, malignant tumors are often large or located in areas that are difficult to remove laparoscopically. In cases of proven or suspected malignancy, open procedures are recommended [48]. If a primary tumor is being resected, the capsule should not be entered surgically, if possible, as this predisposes to recurrence [49].

Some authors suggest administration of Iobenguane I-131 (therapeutic) after resection of a malignant catecholamine-secreting pheochromocytoma/paraganglioma that takes up meta-iodobenzylguanidine (MIBG) as determined by Iobenguane I-123 (diagnostic) scanning [50]. However, there are no data demonstrating a survival or relapse-free survival benefit for "adjuvant" Iobenguane I-131 (therapeutic) treatment after resection of metastatic disease. We suggest not pursuing this approach, which is in keeping with treatment guidelines for pheochromocytoma/paraganglioma from the National Comprehensive Cancer Network and others [10,24,51].

Radiation therapy — It was previously thought that malignant pheochromocytomas/paragangliomas were relatively radioresistant [52]. However, external beam radiation therapy (EBRT) at doses >40 Gy can provide local tumor control and relief of symptoms for tumors at a variety of sites, including the soft tissues of the skull base and neck, abdomen, and thorax, as well as painful bone metastases [26].

Data supporting the use of EBRT are as follows:

●In a series of 17 patients with malignant paraganglioma who received EBRT, 76 percent had local control or clinically significant symptomatic relief for at least one year or until death [53]. Of the five patients with widespread systemic metastases and areas of bulky symptomatic tumor who received sequential Iobenguane I-131 (therapeutic) and EBRT, all irradiated areas showed a durable objective response; all patients eventually experienced out of field systemic progression requiring other treatment.

●A retrospective observational study evaluated the use of EBRT in 41 patients with either primary paraganglioma (63 percent) or pheochromocytoma (37 percent) and 107 sites of disease [26]. 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) EBRT dose was 40 (range 6.5 to 70) Gy.

In the entire study population, five-year overall survival was 65 percent. For patients treated with curative and palliative intent, overall survival was 79 and 50 percent, respectively. Local control at five years was 81 percent for all lesions. EBRT 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 [26].

The use of EBRT for primary treatment of skull base and neck paragangliomas, and the utility of stereotactic radiosurgery for primary treatment of jugulotympanic skull base and neck paragangliomas is discussed in detail elsewhere. (See "Paragangliomas: Treatment of locoregional disease", section on 'Primary radiation therapy' and "Paragangliomas: Treatment of locoregional disease", section on 'Radiation therapy'.)

Patients need to be monitored during RT, because RT-induced inflammation of the lesion can induce massive catecholamine secretion and a hypertensive crisis [54].

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

Results are best if percutaneous tumor ablation is 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, and liver [55-62]. 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 "Paragangliomas: Treatment of locoregional disease", 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 [62]). At 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) procedures, respectively [62].

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) [63-67]. As with other forms of local therapy, TACE can induce massive catecholamine secretion and a hypertensive crisis; preprocedure medical preparation is needed. (See "Paragangliomas: Treatment of locoregional disease", section on 'Medical preparation for surgery'.)

Systemic therapy

Radionuclide therapy — Systemic radionuclide treatment employs beta-emitting isotopes that are coupled to either MIBG or somatostatin analogs.

MIBG — 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 semi-selective agent for malignant pheochromocytoma/paraganglioma. This treatment only works for the approximately 60 percent of tumors that take up MIBG as determined by Iobenguane I-123 (diagnostic) scintigraphy [68-70]. A lower fraction of dopamine-secreting paragangliomas take up Iobenguane I-123 (diagnostic) [71-73]. External beam RT abolishes the ability of these tumors to take up MIBG, making Iobenguane I-131 (therapeutic) treatment ineffective in any irradiated site [14].

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 many small case series [14,25,50,70,74-81]. Objective response rates 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 [25,70,77,78]. In general, better objective responses are achieved in patients with limited disease and in those with soft tissue rather than bone metastases [25].

Iobenguane I-131 (therapeutic) treatment can be repeated, usually at six-month intervals [50]. The optimal dosimetry is not established. Most of the published reports have used single therapy doses between 100 to 200 mCi, with cumulative doses ranging from 557 to 2322 mCi and averaging 400 and 600 mCi [14,25,50,74,75,77-79]. 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 111-916 mCi in one series [78], and in 2 of 10 patients in a second report (average cumulative dose 310 mCi) [80].

There is some evidence that higher-dose regimens (single doses 500 to 800 mCi) can result in sustained complete response in a small number of patients, albeit with a higher risk of potentially serious side effects [76,82]:

●In a phase II study, 50 patients with metastatic pheochromocytoma/paraganglioma received single Iobenguane I-131 (therapeutic) doses ranging from 492 to 1160 mCi (6 to 19 mCi/kg, median 12 mCi/kg); cumulative doses ranged from 492 to 3191 mCi [82]. Patients had to have successful peripheral blood stem cell harvest to receive >12 mCi/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 overall survival 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 toxicity 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 observational study, 125 patients with metastatic pheochromocytoma/paraganglioma were treated with a median dose of 18,800 MBq 131I MIBG [83]. In these patients, median survival post-treatment 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 progression-free survival was two years.

•Among 54 patients, over half (59 percent) demonstrated biochemical response, although half of these relapsed, with a median time to laboratory 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, 61 percent of these patients experienced subsequent symptomatic progression [83].

Treatment with Iobenguane I-131 (therapeutic) should be considered in patients with good uptake of Iobenguane I-123 (diagnostic) by dosimetry who fall into one of the following categories:

●Unresectable progressive pheochromocytoma/paraganglioma

●Symptoms from disease that is not amenable to locoregional methods of control

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

For patients with rapidly progressive tumors or bone-predominant extensive disease, chemotherapy is a preferred option even if Iobenguane I-123 (diagnostic) scintigraphy is positive [10].

Given the fact that most studies use different doses of Iobenguane I-131 (therapeutic) and schedules, and include only a few patients, specific recommendations as to the best dose and treatment schedule cannot be made [10]. Multicenter studies are required to reach a consensus on the efficacy of high-dose versus fractionated medium doses of Iobenguane I-131 (therapeutic) [24]. Some institutions with extensive experience with this compound use high-dose Iobenguane I-131 (therapeutic) for selected patients with aggressive disease who are able to 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.

Patients should be counseled about the potential risks of long-term myelosuppression [77,84,85], and a possible increase in myelodysplasia and acute leukemia in long-term survivors [82,85]. It is not clear whether these risks are limited to those who receive high-dose therapy.

Peptide receptor radioligand therapy — Pheochromocytomas and extra-adrenal paragangliomas express somatostatin receptors at a level that is similar to that of other neuroendocrine tumors, including gastroenteropancreatic neuroendocrine tumors [86-89]. As with other neuroendocrine tumors, patients whose metastatic or recurrent pheochromocytoma/paraganglioma expresses somatostatin receptors (as determined by positive uptake with ¹¹¹In-pentetreotide or where available, positron emission tomography [PET] imaging using gallium-68-labeled somatostatin analogs such as gallium Ga-68 DOTATATE [90-92]) may benefit from therapy using radiolabeled somatostatin analogs. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs'.)

The most commonly used radionuclides are Yttrium-90-labeled DOTA⁰-Tyr³-octreotide (⁹⁰Y-edotreotide, ⁹⁰Y-dotatoc) and lutetium Lu-177 dotatate (¹⁷⁷Lu-Dotatate). The efficacy of ⁹⁰Y-dotatoc and ¹⁷⁷Lu-Dotatate for malignant paraganglioma/pheochromocytoma has been described in isolated case reports and small series [93-96]. As examples:

●In a report of 28 patients with progressive, surgically incurable pheochromocytoma/paraganglioma received ⁹⁰Y-dotatoc alone or sequentially with ¹⁷⁷Lu-Dotatate [96]. The best response was two partial remissions, five minor responses, and 13 cases of stable disease (disease control rate, 71 percent). At a mean follow-up of 19 months, 10 of the 20 patients with an objective response or stable disease still had not progressed, and there were only two cases of mild hematologic toxicity and no renal insufficiency.

●In another report, 30 patients (17 with parasympathetic paragangliomas, 10 with sympathetic metastatic paragangliomas, and 3 with metastatic pheochromocytoma) were treated with up to four cycles of ¹⁷⁷Lu-Dotatate with an intended dose of 7.4 Gbq per cycle [97]. Partial responses were seen in seven patients (23 percent) and stable disease in 20 patients (67 percent); three patients (10 percent) had progressive disease. Median progression-free survival in patients with parasympathetic paragangliomas, those with sympathetic paragangliomas, and those with metastatic pheochromocytoma was 91, 13, and 10 months, respectively. Grade 3 or 4 subacute hematotoxicity occurred in six patients (20 percent). Two patients experienced a reversible subacute adverse event (cardiac failure) following possible catecholamine release [97].

Long-term potential side effects of therapy with radiolabeled somatostatin analogs may include loss of renal function, pancytopenia, and myelodysplastic syndrome/acute leukemia [84].

In January 2018, lutetium Lu-177 dotatate (¹⁷⁷Lu-Dotatate) received US Food and Drug Administration approval for treatment of somatostatin receptor-expressing gastroenteropancreatic neuroendocrine tumors; approval was not extended to paraganglioma/pheochromocytoma. Use in this setting remains investigational, and should only be considered if the tumor expresses somatostatin receptors. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs' and "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis", section on 'Lutetium Lu-177 dotatate'.)    

Octreotide — The therapeutic effect of treating metastatic pheochromocytoma/paraganglioma with the somatostatin analog octreotide has been analyzed in a few studies with small patient numbers, and the results are mixed:

●Case reports suggest benefit for octreotide in producing objective responses in a small number of patients with advanced malignant paraganglioma [98,99] and for short-term reduction of catecholamine secretion in a patient with pheochromocytoma [100].

●On the other hand, others have failed to show benefit for short-term octreotide administration either for control of catecholamine secretion or for preoperative reduction in tumor size [101-104]. None of these studies reported rates of tumor stability; at least in the setting of metastatic gastroenteropancreatic neuroendocrine tumors, the main benefit of somatostatin analogs is in disease stabilization rather than objective tumor regression. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Benefits' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Somatostatin analogs'.)

Based upon this limited amount of data, the utility of somatostatin analog therapy for tumor control or palliation of symptoms in patients with malignant pheochromocytoma/paraganglioma remains unclear. However, a therapeutic trial of octreotide could be considered in a patient who is not yet a candidate for more toxic systemic treatment options.

Cytotoxic chemotherapy — Systemic chemotherapy should be considered for patients with unresectable and rapidly progressive pheochromocytoma/paraganglioma and patients with high tumor burden or a large number of bone metastases.

Most literature reports evaluating cytotoxic chemotherapy for progressive metastatic paraganglioma predominantly involve patients with retroperitoneal sympathetic catecholamine-secreting tumors. The most extensive data are from studies using various combinations of cyclophosphamide, dacarbazine, vincristine, and doxorubicin [15,105-107]. The following illustrates the range of findings:

●An early trial of CVD (cyclophosphamide [750 mg/m² on day 1], vincristine [1.4 mg/m² on day 1], and dacarbazine [600 mg/m² on days 1 and 2] of each 21- to 28-day cycle) reported high response rates and symptomatic improvement with this regimen in 14 patients [108]. Details of the regimen and long-term outcomes (median follow-up 22 years) in this cohort, as well as four others who met the original eligibility criteria for the trial, were described in a later report [106]. Overall, 10 of 18 patients (56 percent) had a complete or partial objective response to therapy, and three others had a "minor response" [106]. Biochemical responses were seen in 13 (72 percent). Patients whose tumors were scored as complete or partial response received a mean of 27.4 cycles of CVD (median of 23 cycles). The median duration of response was 20 months (range 7 to 126 months), and the median survival for all patients was 3.3 years from the start of chemotherapy [106]. Treatment was well tolerated, with the most prominent side effects being "mild" myelosuppression, peripheral neuropathy, and gastrointestinal toxicity [108].

●The largest single-institution retrospective series of chemotherapy included 52 patients with progressive metastatic pheochromocytoma or sympathetic extra-adrenal paraganglioma who received a variety of chemotherapy regimens, including cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CyVADIC, n = 19); cyclophosphamide, doxorubicin, and dacarbazine (CyADIC, n = 12); cyclophosphamide, vincristine, and dacarbazine (CyVDic, n = 10); or a variety of other regimens (n = 11) [15]. Of the 52 evaluable patients, 17 (33 percent) responded to frontline 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 overall survival in pheochromocytoma/paraganglioma [20]. The overall survival rate of the entire cohort at five years was 51 percent.

●Single case reports and small series suggest that these tumors may also respond to temozolomide alone [109], particularly among those with succinate dehydrogenase (SDH) B pathogenic variants, which are associated with hypermethylation of the promoter for O6-methylguanine-DNA methyltransferase [MGMT] [110]; temozolomide plus thalidomide [111] or capecitabine [112]; single agent gemcitabine [113]; gemcitabine plus docetaxel [114] or paclitaxel [115]; doxorubicin plus streptozocin [116]; or paclitaxel alone [117]. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Familial paraganglioma and SDH pathogenic variants'.)

Molecular targeted therapies — Tyrosine kinase inhibitors (TKIs) are a class of agents that interfere with cancer growth and metastatic progression by blocking angiogenesis through the vascular endothelial growth factor receptor (VEGFR) and other pathways. Sunitinib, a vascular endothelial growth factor (VEGF) TKI, has demonstrated efficacy and manageable toxicity in patients with paraganglioma/pheochromocytoma.

Sunitinib — Sunitinib is a potent inhibitor of multiple tyrosine kinase receptors, including VEGFR1 and VEGFR2, platelet-derived growth factor receptor (PDGFR) beta, KIT, fms-like tyrosine kinase 3 (FLT3), and rearranged during transfection (RET). Studies suggest utility for sunitinib in patients with malignant pheochromocytoma/paraganglioma [118-123]:

●In an open-label phase II trial (SNIPP), among 25 patients with metastatic pheochromocytoma or paraganglioma receiving sunitinib, the disease control rate was 83 percent (70 percent with stable disease and 13 percent with a partial response), and median progression-free survival was 13 months [123]. All three of the patients who experienced a partial response had a RET or SDH pathogenic variant. Grade ≥3 toxicities included fatigue and thrombocytopenia. Three patients discontinued therapy due to hypertension or cardiac events.

●In a retrospective study, 17 patients with progressive metastatic pheochromocytoma/sympathetic paraganglioma were treated with sunitinib monotherapy [122]. Of 14 evaluable patients, three had a partial response (21 percent), and five had stable disease (36 percent). Median progression-free survival was 4.1 months. Median overall survival of the entire group was 27 months.

Although hypertension is one of the most common side effects of sunitinib, the drug can safely be used in patients with pheochromocytoma and secretory paraganglioma as long as strict follow-up and aggressive antihypertensive dose adjustments are performed. Sunitinib should be initiated only after normal or near normal blood pressure is achieved with combined alpha- and beta-adrenergic blockade. After treatment initiation, additional antihypertensive drugs or a dose increase is usually required. For example, in the retrospective study discussed above, 14 of 17 patients developed hypertension secondary to excessive catecholamine secretion, although six of these eventually became normotensive. Besides hypertension, the most common side effects were diarrhea, hand-foot syndrome, sore mouth, and fatigue.

Sunitinib is also being evaluated in a European randomized, placebo-controlled phase II trial of sunitinib in patients with advanced malignant pheochromocytoma/paraganglioma (First International Randomized Study in Malignant Progressive Pheochromocytoma and Paraganglioma [FIRST-MAPPP] trial). Given the rarity of these conditions, eligible patients should be encouraged to enroll.

Other targeted agents

●Tyrosine kinase inhibitors – Cabozantinib, a multikinase inhibitor that targets VEGFR2 and c-MET, is undergoing clinical trial evaluation in patients with malignant pheochromocytoma/paraganglioma (NCT02302833).

A study evaluating pazopanib, another VEGF TKI, in patients with malignant pheochromocytoma/paraganglioma was terminated due to slow accrual [124].

Other select TKIs 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 (mTOR) pathway. In one early study, five of seven patients with pheochromocytoma/paraganglioma exhibited disease stabilization, although there were no objective responses [125].

●HIF2A inhibitors – Hypoxia-inducible factor 2 alpha (HIF2A) is a main oncogenic driver of paraganglioma and pheochromocytoma [126]. HIF2A inhibitors, such as belzutifan, are active in cancers associated with von Hippel-Lindau disease [127] 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 [128]. (See "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera", section on 'EPAS1 mutations' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Molecular pathogenesis'.)

The use of HIF2A inhibitors in other tumors associated with von Hippel-Lindau disease is discussed separately. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease", section on 'Hypoxia-inducible factor 1 and 2' and "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Management'.)

●Checkpoint inhibitor immunotherapy – Checkpoint inhibitor immunotherapy may have potential treatment efficacy in pheochromocytoma/paraganglioma. This approach remains investigational, and further randomized trials evaluating immunotherapy in these patients are necessary.

Many pheochromocytoma and paraganglioma tumors express programmed death ligand 1 (PD-L1), suggesting a role for checkpoint inhibitor immunotherapy that targets PD-L1 or PD-1 (programmed cell death protein-1) [129]. 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 [130,131]. (See "Principles of cancer immunotherapy", section on 'Checkpoint inhibitor immunotherapy'.)

In a phase II trial, 11 patients with metastatic pheochromocytoma and paragangliomas were treated with the PD-1 inhibitor pembrolizumab [132]. At 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".)

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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

●Pathogenesis – Pheochromocytomas and paragangliomas are catecholamine-secreting neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla (in the case of pheochromocytomas) and the extra-adrenal autonomic paraganglia (in the case of paragangliomas). Paragangliomas can arise in the skull base and neck (where the majority are nonsecretory), or below the neck in the thorax or abdomen (where the majority are secretory) (see 'Introduction' above).

●Risk of malignancy – Most pheochromocytomas/paragangliomas are benign. Approximately 10 percent of pheochromocytomas are malignant (as defined by the presence of metastases) compared with 20 to 25 percent of extra-adrenal abdominal and mediastinal secretory paragangliomas. In the skull base and neck, malignancy is least common for jugulotympanic tumors (2 to 4 percent), slightly higher for carotid body tumors (4 to 6 percent), and highest for vagal tumors (10 to 19 percent).

Among patients with malignant skull base and neck paragangliomas, metastases are most frequently limited to the regional lymph nodes. In contrast, patients with paragangliomas below the skull base and neck most frequently have distant metastases, most commonly to the bone, liver, and lung. While the presence of distant metastatic disease has an adverse effect on prognosis, metastases do not necessarily represent a contraindication to resection of the primary tumor, particularly if the metastases are surgically resectable. (See 'Risk of malignancy and implications for primary therapy' above.)

●Prognosis – The prognosis of metastatic pheochromocytoma/paraganglioma is variable. Long-term survival is possible even in the presence of distant metastatic disease, but five-year survival rates are ≤50 percent. Long-term surveillance should be conducted to assess for malignancy. (See 'Prognosis' above and 'Risk of malignancy and implications for primary therapy' above and "Paragangliomas: Treatment of locoregional disease", section on 'Posttreatment surveillance'.)

●Treatment approach – A proposed treatment algorithm for malignant pheochromocytoma/paraganglioma is provided (algorithm 1).

●Management of catecholamine excess – Symptoms of catecholamine excess should be controlled using combined alpha- and beta-adrenergic blockade. (See 'Medical management of catecholamine secretion' above.)

●Surgical resection – We suggest resection of both the primary and metastatic lesions, if possible (Grade 2C). Even if complete eradication is not achievable, a cytoreductive incomplete resection can improve symptoms, reduce hormone secretion, prevent complications related to tumor in a critical anatomic location, and improve the response to subsequent therapies. However, there is no evidence that surgical debulking prolongs survival in patients with metastatic disease. (See 'Resection' above.)

Preoperative control of the effects of excessive adrenergic stimulation is necessary using combined alpha- and beta-blockade. In addition, preoperative and intraoperative treatment with volume expansion is required to prevent intraoperative hypotension. (See "Paragangliomas: Treatment of locoregional disease", section on 'Medical preparation for surgery'.)

●Alternative local therapies to surgery – Several other forms of local therapy are available if resection is not feasible:

•External beam radiation therapy – For patients who are not candidates for resection, local control of bulky symptomatic disease, particularly painful bone metastases, can be achieved with external beam radiation therapy (EBRT). (See 'Radiation therapy' above.)

•Percutaneous ablation – Percutaneous ablation of metastatic lesions at a variety of sites, including soft tissue, bone, and liver, may be safely performed using radiofrequency ablation, cryoablation therapy, or ethanol injection if there is careful attention to periprocedural management. (See 'Nonsurgical ablative therapy' above.)

•Transarterial chemoembolization – Transarterial chemoembolization (transcatheter arterial chemoembolization) is another option for local control of liver metastases in patients with multiple liver-isolated metastases that are not amenable to resection or nonsurgical methods of ablation. (See 'Transarterial chemoembolization for liver metastases' above.)

•Management of catecholamine secretion – Any form of local therapy can induce massive catecholamine secretion and a hypertensive crisis; preprocedure medical preparation is needed. (See "Paragangliomas: Treatment of locoregional disease", section on 'Medical preparation for surgery'.)

●Indications for Iobenguane I-131 (therapeutic) – Approximately 60 percent of pheochromocytomas/paragangliomas take up meta-iodobenzylguanidine (MIBG) as determined by Iobenguane I-123 (diagnostic) scintigraphy. For patients with MIBG-positive tumors who have unresectable, symptomatic progressive disease that is not amenable to locoregional methods of control, or those with a high tumor burden who have a low number of bone metastases, we suggest Iobenguane I-131 (therapeutic) rather than systemic chemotherapy as a first-line approach (Grade 2C). There is no consensus as to the relative efficacy of high-dose versus fractionated medium doses of Iobenguane I-131 (therapeutic), and specific recommendations as to the best dose and treatment schedule cannot be made. (See 'MIBG' above.)

●Indications for chemotherapy – For patients with rapidly progressive tumors or disease that is predominantly localized to the skeleton, chemotherapy is preferred even if Iobenguane I-123 (diagnostic) scintigraphy is positive. Although the optimal regimen is not established, we suggest combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine (Grade 2C). (See 'Cytotoxic chemotherapy' above.)

●Targeted therapies – Preliminary studies suggest that sunitinib may be an active agent, and further data on its utility, as well as that of other multikinase inhibitors, are needed; hypertension is a prominent side effect. Sunitinib can be safely used, even for patients with symptoms of catecholamine excess, as long as strict follow-up and aggressive antihypertensive dose adjustments are performed. (See 'Molecular targeted therapies' above.)

●Immune checkpoint inhibitors – Limited expression data and a small phase II trial of pembrolizumab suggest a possible role for immune checkpoint inhibitors (ICIs) in select tumor subsets. However, the results of a number of ongoing randomized controlled trials (RCTs) are required to properly assess the therapeutic value in advanced cases.

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.