Paragangliomas are neuroendocrine neoplasms that arise from chief cells in extra-adrenal paraganglia of the peripheral nervous system. While previous chapters have expanded upon historical, diagnostic, and management issues pertaining to paragangliomas, this chapter will discuss the management and prognosis regarding multicentric paragangliomas, malignant tumors, catecholamine-secreting paragangliomas, high-risk anesthetic patients, and future directions. Due to the paucity of literature on these particular topics, studies analyzing other head and neck paragangliomas, as well as non-head and neck paragangliomas and pheochromocytomas, are reviewed when relevant to highlight special considerations in management.

The incidence of multicentric paragangliomas , including jugular, vagal, and carotid body, ranges from 1 to 80%, with more recent studies quoting between 10 and 20% [1, 2]. Al-Mefty and Teixeira reviewed 43 cases of what they defined as complex jugular paragangliomas (JP), observing multicentricity in 34.5% of patients [2]. Multicentricity is more common in familial cases, with one report observing that bilateral tumors occurred in 31.8% of familial cases and only 4.4% of sporadic cases [3]. However, recognizing that familial tumors tend to demonstrate more rapid growth, many hypothesize that multicentric tumors may be more likely diagnosed in familial cases due to differences in growth rates compared to nonfamilial cases [1]. Assessing a single institutional head and neck paraganglioma cohort, Szymanska et al. found that 16.6% (14/84) patients had two or more head and neck paragangliomas [1]. In 8 of those patients, 13 synchronous tumors were asymptomatic and thus discovered with imaging studies [1]. Assessing all 14 patients, 37 head and neck tumors were identified, 30 of which were synchronous, with the remaining seven metachronous, diagnosed between 2 and 18 years after removal of the first tumor [1]. In addition, eight cases of bilateral carotid body tumors were identified, which is the most commonly occurring bilateral paraganglioma, while no bilateral JPs were observed, reinforcing previously published data [1]. Genetic studies have noted that SDHD mutations, whether spontaneous or inherited, are more frequently associated with multiple paragangliomas [4].

Management of multicentric paragangliomas is complicated, especially when bilateral cervical or skull base tumors are present. Multicentricity raises questions of which tumors to treat, when, if, and with which modality given the significant risk of lower cranial nerve deficits [2]. Szymanska et al. emphasized that in the case of bilateral paragangliomas, surgical planning must depend upon the management plan of the contralateral tumor or tumors, such as deciding whether to sacrifice the ipsilateral internal carotid artery or pursue subtotal resection [1]. In the case of ipsilateral paragangliomas, both Szymanska et al. and Al-Mefty and Teixeira recommend concurrent excision of all ipsilateral paragangliomas [1, 2]. When confronted with bilateral JPs, Al-Mefty and Teixeira recommend that the contralateral side should only be treated surgically if there were no essential cranial nerve injuries after the first resection [2]. Szymanska and colleagues added that in patients with multicentric paragangliomas, specifically bilateral vagal and JPs, vagal function and hearing must be preserved on at least one side [1]. Given these considerations, in order to preserve vagal function on at least one side, some advocate for a wait-and-scan policy, recommending surgery in those patients with either life-threatening intracranial growth or progressive cranial nerve deficits [1, 5]. The factors and complexity associated with multicentric paragangliomas clearly highlight that these tumors should be managed with a multidisciplinary approach by an experienced center.

There is a no standard definition of a complex JP. Al-Mefty and Teixeira identified 43 patients with complex JPs, self-defined either by giant size, multiplicity, catecholamine hypersecretion, malignancy, associated lesions, or the patient that had undergone previous treatments with adverse outcomes that increased the surgical risk [2]. In these cases, Al-Mefty and Teixeira recommended that the surgeon should modify the surgical technique to minimize the risk of bilateral deficits, which may include avoiding facial nerve mobilization, maintaining the integrity of the medial jugular bulb to prevent lower cranial nerve injuries, accepting subtotal removal in an attempt to preserve lower cranial nerve function, abandoning blind-sac closure of the external ear canal, and considering radiosurgery for contralateral tumors [2].

Multiple issues must be considered when managing patients with JPs, regardless of the complexity. Given their generally benign nature, combined with historically morbid surgical outcomes, extra caution must be undertaken before treating elderly or medically infirm patients. Similarly, those patients with neurovascular compromise or who have undergone prior intervention require a complete investigation of their anatomy and discussion of their options. For instance, in those patients who have contralateral lower cranial nerve deficits, one may be more inclined to radiate an ipsilateral JP to avoid injuring the ipsilateral lower cranial nerves. Emphasizing the role for preoperative imaging, in patients that have undergone previous embolization or carotid artery occlusion, Al-Mefty and Teixeira state that the most important aspect of angiographic evaluation is identifying new feeding vessels [2]. Specifically, previous embolization or occlusion of the carotid artery leads to development of a new blood supply, which could increase the risk of arterial dissection, an important consideration during treatment planning [2].

Piazza et al. described the case of a patient with a right-sided jugular and vagal paraganglioma with the absence of the contralateral internal carotid artery [6]. Though Al-Mefty and Teixeira do not believe that carotid artery sacrifice is ever warranted, stating that they can consistently develop a plane between the tumor and adventitia, in the case described by Piazza et al., the patient had a contralateral carotid body paraganglioma excised 15 years previously, wherein their left internal and common carotid artery had been ligated [2, 6]. In the follow-up report, Piazza and colleagues emphasize the role of preoperative imaging to determine the vascular involvement of the paraganglioma, specifically to determine if the carotid wall is involved [6]. Though they suggested that permanent balloon occlusion is the most effective method to manage an extensively infiltrated internal carotid artery, having only one carotid artery is an absolute contraindication to the technique [6]. Given that the right-sided internal carotid artery was irregular and stenotic, and unable to perform a balloon occlusion, Piazza and colleagues stented the artery in the cervical and intratemporal segments, followed by embolization 7 weeks later with surgical excision 2 days following embolization [6]. They reported that stenting the carotid reinforced the arterial wall, assisting surgical dissection in a subadventitial plane, thus reducing the risk of vessel injury during surgery [6]. Nonetheless, any patient who undergoes stenting requires lifelong antiplatelet therapy, with thrombosis and distal embolization as the main risks [6]. In Piazza and colleagues’ case, Doppler ultrasound was performed at the time of discharge, in addition to 6 and 18 months following surgical excision, with the carotid artery remaining patent throughout [6].

Piazza et al. did acknowledge that continued observation and a by-pass procedure were two other options available for the patient, though neither are without risks [6]. Another alternative is radiotherapy, with some authors supporting its use in situations when surgery would require reconstruction or ligation of the carotid artery [7]. However, Piazza and colleagues disagree with radiotherapy, believing it should be reserved for small residual tumors following subtotal resection, elderly patients, and those patients with contralateral cranial nerve deficits [6]. And while subtotal resection is another option, many surgeons struggle with how much resection is too much or too little. Wanna and colleagues reported the subtotal surgical resection outcomes of 12 patients with advanced JPs and intact lower cranial nerves, concluding that residual tumor was less likely to grow if more than 80% of the tumor was resected [8]. Sanna and colleagues, reviewing their experience of 53 Fisch class C and D JPs, noted that dominant sigmoid sinuses, absence of collateral flow on temporary occlusion of the internal carotid artery, and advanced age with a poor general condition were factors that led to subtotal resections [9].

In addition to neurovascular issues, giant tumors with significant intracranial involvement also add a layer of complexity to patient management. Sanna and colleagues tend to stage the resection in patients with large intracranial involvement, but in those rare cases when an anesthetically high-risk patient has significant brainstem compression, they prefer to sufficiently decompress the brainstem during the initial stage [9]. In contrast, Al-Mefty and Teixeira do not stage tumors with intradural extension [2].

The first reported case of a metastatic temporal bone paraganglioma was in 1949, with metastasis to the liver [10]. Since then, few additional cases have been identified. Nonetheless, several studies have attempted to investigate their incidence, as well as factors that predict their development. It is estimated that less than 5% of all types of paragangliomas are malignant, occurring most commonly in vagal tumors [1]. Brewis et al. estimated an incidence between 1 and 4%, while Lee and colleagues reviewed the National Cancer Database records from 1985 to 1996 and found 59 malignant paragangliomas, estimating an incidence rate between 6 and 24% for non-adrenal paraganglia [11, 12]. Manolidis and colleagues reviewed the incidence of temporal bone paraganglioma malignancy in a large skull base center, defining malignancy as the presence of tumor located in a regional lymph node or within distant organs [13]. They identified nine malignant cases, or 6.3% of all JPs [13]. But while the range of incidence rates may be the result of sampling biases, to date, no chemical, biological, or histopathological feature has been able to distinguish nonmalignant paragangliomas from malignant paragangliomas. Though Lack writes that two of the following three criteria are required to define malignancy, mitotic abnormalities, lymphatic and vascular invasion, and central necrosis, it is generally recognized that metastases are identified when paraganglionic cells are found in another tissue where neuroendocrine cells are not normally present, outside the original tumor bed, with identical cytological features between the aberrant tissue and primary tumor [14, 15]. However, a recent study that assessed 365 patients with pheochromocytoma and paraganglioma metastases showed that plasma levels of a dopamine metabolite, methoxytyramine, are a possible useful biomarker in detecting metastases [16].

In an earlier study reviewing 53 previously published JPs with metastases, Brewis and colleagues sought to determine various characteristic features of metastatic JPs, comparing sites and presenting features, age, and gender, among other characteristics, to nonmetastatic JPs [11]. They identified 100 metastasis sites, including bone (33), most frequently to the vertebrae, followed by lungs (23), lymph nodes (19), liver (9), and other sites (16) [11]. Comparing the various features of these tumors with nonmetastatic JPs, only pain and a lower incidence of hearing loss were significantly more likely to occur in metastatic tumors as compared to nonmetastatic tumors [11]. Manolidis and colleagues noted that malignant paragangliomas tend to have more severe symptomatology, with more rapid progression and more advanced staged disease at the time of presentation as compared to benign paragangliomas [13].

Similarly, Chapman and colleagues reviewed all types of paragangliomas at one institution, seeking to identify features that suggested malignant behavior [17]. In identifying 84 paragangliomas, seven were malignant, six of which were carotid body tumors, with one vagal paraganglioma [17]. They found that malignancy was associated with younger patients, as well as pain at presentation [17]. Appreciating that all patients with metastases demonstrated perineural invasion, Chapman and colleagues hypothesized that the perineural invasion is the likely cause of the pain [17]. And like previous reports, they identified no common imaging findings that differentiated between benign and malignant paragangliomas [17]. However, the authors noted that the collective presence of multiple histologic features in a single tumor, such as poor circumscription and invasion through the fibrous capsule, perineural invasion, lymphovascular invasion, high cellularity with a diffuse growth pattern, widespread profound nuclear pleomorphism, increased or atypical mitotic figures, and necrosis, may predict metastatic disease and a poorer prognosis [17].

Other studies have suggested that tumors larger than 5 cm in diameter, greater than 80 g in weight, or recurrent tumors are all clinical signs that may suggest malignancy [18]. Remine and colleagues suggested that catecholamine-secreting paragangliomas may be more likely to be malignant (38%) compared to nonsecreting paraganglioma tumors (less than 10%) [19]. And while other studies have noted similar comparisons, in contrast, Linnoila and colleagues noted that malignant paragangliomas express considerably lower levels of neuropeptides [20, 21].

Several attempts have been made to utilize newer imaging technologies to identify occult tumors, such as somatostatin receptor imaging with ¹¹¹In-octreotide scintigraphy, ¹⁸F-fluorodopamine positron emission tomography-computed tomography (¹⁸F-DOPA), and ¹³¹I and ¹²³I-metaiodobenzylguanidine (MIBG), with varying reliability [14, 21]. Hoegerle and colleagues showed that ¹⁸F-DOPA demonstrated a low sensitivity for detecting metastases, especially in subjects with SDHB mutations, which occur most frequently in head and neck paragangliomas [21, 22].

Prognostically, Brewis et al. found that the rates of persistence or recurrence were 97 and 51% in metastatic and nonmetastatic paragangliomas, respectively, with the mortality rate of 68 and 10% in metastatic and nonmetastatic cases, respectively, both of which were statistically different [11]. In Lee and colleagues’ review of 59 malignant paragangliomas, they found that patients with regional metastasis demonstrated a 76.8% 5-year survival rate, as compared to 11.8% in those with distant metastases [12]. Spetz et al. reviewed 154 patients with pheochromocytomas and paragangliomas and observed that those patients who developed metastases following primary surgery had better prognoses than those patients who presented with locally advanced disease and or distant metastases [23]. Mediouni and colleagues reviewed 11 malignant paragangliomas at a single institution and found that the mean metastasis-free interval was 8 years, ranging from 1 to 25 years [21]. Thus, while malignant paragangliomas carry a poorer prognosis than benign disease, development of malignancy following primary surgery, which can occur between 1 and 25 years later, leads to a better prognosis than those patients who initially present with malignant paragangliomas.

In terms of management of metastases, little data is available. Massey and Wallner performed a single institutional retrospective review of six patients who received chemotherapy or radiation therapy for malignant paragangliomas [24]. Though only four of the patients had disease originating in the head and neck, of four patients who received chemotherapy, none had significant subjective or objective responses to treatment, while three patients who had nine painful metastatic sites radiated reported complete subjective responses to treatment at eight of nine locations [24]. Noting the extremely slow growth rates of paragangliomas, Massey and Wallner were not surprised by the lack of response to single-agent or multiple-agent chemotherapy, suggesting that continuous infusion medications, or chronic low doses, may be more effective [24]. Mediouni and colleagues postulate that surgery is the only curative treatment for metastatic paragangliomas, acknowledging that most metastases involve the bone, most frequently the vertebrae, and thus is not amenable to resection [21]. They recommend surgery for isolated or multiple lymph node metastases, as well as neck, chest, or abdominal metastases, including liver metastases, which can also be treated with radiofrequency ablation [21]. For vertebral metastases, they encourage a combined medical and surgical approach, including analgesics, anti-inflammatory drugs, bisphosphonates, and localized radiotherapy [21].