Paragangliomas (PGs) represent rare tumors of neuroendocrine origin, are comprised of sustenacular and chief cells in an organoid or Zellballen pattern and commonly arise in various locations in the head and neck [1]. Malignant PGs are defined by presence of pathologically confirmed PG cells in lymph nodes or in distant organs, rather than by the histological features of the primary tumor [2]. Only a small percentage of patients ultimately develop metastatic disease, and malignant PGs are believed to represent only 4% to 15% of all head and neck PGs [3–5]. When considering the major classes of PG sub-types, rates of malignancy are believed to be 2 - 4% for jugular-tympanic tumors, 6% for carotid body tumors, and 16 - 19% for vagal tumors [6, 7].

For patients identified with regionally metastatic disease, radiation after primary surgical treatment offers the best prognosis [4]. Patients with metastases to distant organs, most commonly lung and liver, are often treated with systemic therapy [8]. However, due to the rarity of these lesions, optimal treatment strategies have not been defined to date. In particular, most studies of chemotherapy for malignant PG have focused on thoracic and abdominal PG, which have biological behaviors distinct from head and neck PG [9]. Abdominal, pelvic, and thoracic PGs originate in the sympathetic autonomic nervous system ganglia. They are frequently associated with a norepinephrine biochemical phenotype. A significant number of sympathetic PGs are malignant. Conversely, head and neck PGs originate in parasympathetic autonomic nervous system ganglia. Typically, they are hormonally silent and are rarely malignant.

To define the outcomes and optimal treatment strategies of malignant head and neck PG, we reviewed a single institution's 35-year experience with these lesions.

All patients with malignant PG of the head and neck treated at the University of Texas MD Anderson Cancer Center (MDACC) from 1970 to 2005 were reviewed after IRB approval was obtained. Pathology, radiologic imaging, operative reports, and all clinical notes were reviewed. Patients referred to our institution without complete documentation were excluded from our study. A comprehensive review of the literature was also performed.

Due to their rarity, metastatic head and neck PGs remain clinically challenging. Our data reveal that the management and progression of malignant head and neck PGs is complicated and highly variable. These results suggest that young patients (age ≤ 40) are more likely to demonstrate a favorable response to therapy. Additionally, female patients tended to have more favorable responses, though this trend was not statistically significant. While specific regimens cannot be prescribed, the aggressive tumors may be treated with multiple systemic agents, though strict follow-up to assess progression in the absence of treatment also appears appropriate given the outcomes of treatments detailed herein.

Our data reflect the results of a previous study performed at MDACC where, in a group of 13 patients with malignant PGs (only two patients with primary head and neck PGs), 92% achieved at least stable disease on CVAD [10]. This compares to the use of a combination of cyclophosphamide, vincristine, and dacarbazine (CVD) studied in the setting of malignant PGs, where complete response was achieved in only 11% of patients, partial response in 44% of patients, and stable disease in 22% of patients [11]. A newer approach to therapy has been the use of radio-iodinated metaiodobenzylguanidine, a norepinephrine analog that has yielded a 75% 5-year survival with a majority of patients achieving at least a partial response to therapy [12–14].

Historically, external beam radiation has assumed a palliative role in the treatment of spinal and other bone metastasis [15]. None of the 14 patients receiving radiation experienced neurologic sequelae, a recognized complication in the palliative treatment of bone disease. Though not statistically significant, radiation appeared to be more effective in younger patients. These findings are in line with prior studies where radiation has been described for bony metastasis, though no evidence of a benefit to younger patients was found [16].

During the entire follow-up period, 7 patients (41%) were found to have local disease spread either to regional nodes or surrounding structures. This compares to the aforementioned study conducted by Lee et al, which revealed that 69% of patients with malignant PG experienced regional spread [4]. Though only 50% of patients with regional metastasis eventually develop distant spread of disease, these patients typically do not have favorable outcomes. High rates of local spread and poor response to therapy complicate management in these patients.

Based upon data from the National Cancer Database, Lee et al reported on patients with both regional and distant spread from head and neck PG and found a 5-year survival of 11.8% [4]. More recently, a 44% 5-year survival was observed in patients with metastatic PGs undergoing radiation and chemotherapy [12]. In a study performed by Fitzgerald et al, patients with pulmonary metastases experienced significantly shortened survival compared to patients with metastases to other sites. Our series revealed an 84% five-year survival that is likely attributable to the head and neck origin of disease in these patients compared to pheochromocytoma. Additionally, previously reported studies involve clinical trials with patients that were likely to present with more advanced disease than those reported in this series. What requires further study is the impact of germline mutations in the SDH genes on overall outcomes. Genotype-phenotype correlations have identified distinct mutations that pre-dispose to malignant lesions, findings that may offer novel therapies that specifically target these malignant phenotypes [17].

Though the metastatic potential of this tumor remains unclear, distant spread is an extremely rare event [18]. Therefore, regional lymphadenectomy, as well as adjuvant radiation with primary surgical resection for metastatic PG, remains the optimal treatment modality. Data from the National Cancer Database revealed that 34% of patients with regional metastasis received adjuvant radiation, though the distribution of patients receiving radiation increases with time [4]. Due to the inability to detect aggressive disease, surgical resection, radiation therapy, or observation without adjuvant therapy is currently the standard of care for the tumors that do not exhibit aggressive characteristics.

The present management of malignant head and neck PGs are based largely on retrospective data. Due to the rarity of this disease process, prospective data are difficult to obtain. The 35-year interval over which these patients presented complicates the ability to compare the efficacy of any particular management approach and compromises the completeness of the patient records. Additionally, due to the small number of patients presenting with head and neck PGs, some of the trends described here were unable to achieve statistical significance. Based on our observations we have developed a treatment algorithm that guides, at a very high level, the diagnostic and treatment options for patients. However, lacking controlled trial data prevent the recommendation of specific therapeutic modalities or types of therapy within each category. Figure 6 presents this algorithmic overview.

What remains clear is that aggressive treatment of regional and distant disease with radiation therapy and systemic chemotherapy may be a viable option to achieve disease control in a large number of patients. In our study, 33% of patients experienced clinical benefit with aggressive therapy. Therefore, the risks and benefits of treatments should be carefully weighed against the possibility of close follow-up with treatments directed at controlling symptoms. Further investigation will be needed to capture the indolent and complex course these tumors typically experience.