Abstract
Purpose
Malignant head and neck paragangliomas (MHNPs) are rare and occur in 6%–19% of all HNPs. We sought to identify predictors of survival and compare efficacy of treatment modalities to inform management of this rare disease.
Materials and methods
We performed a retrospective cohort study of MHNP cases in the National Cancer Institute Surveillance Epidemiology and End Results database (SEER) from 1973 to 2009. We identified 86 patients with MHNP who had documented regional or distant tumor spread with a median follow-up of 74 months. We used Cox proportional hazard models to assess the significance of demographic factors and treatment on five-year overall survival.
Results
The most common treatment was surgery alone (36.0 %), followed by surgery with adjuvant radiation (33.7%). Five-year overall survival was 88.1% for surgery alone and 66.5% for adjuvant radiation (p = 0.2251). In univariate analysis, regional (vs. distant) spread (HR 0.23, p < 0.0001), surgery alone (HR 0.29, p < 0.0001) and primary site in the carotid body (HR 0.32, p = 0.006) conferred significant survival advantage whereas age > 50 (HR 4.04, p < 0.0001) worsened survival. Regional (vs. distant) spread (HR 0.42, p = 0.046) and age > 50 (HR 2.98, p = 0.005) remained significant in multivariate analysis. In patients with regional-only disease, five-year overall survival was 95.4% for surgery alone compared to 75.6% for surgery with radiation ( p = 0.1055).
Conclusions
This is the largest and most contemporary series of MHNP patients. Age and tumor stage are significant factors in predicting survival. Surgical resection significantly improves survival outcomes. From this analysis, the value of adjuvant radiation is not clear.
1
Introduction
Paragangliomas are neuroendocrine tumors that arise from neural crest cells and may occur anywhere along the paraganglia of the autonomic nervous system . Rarely, they develop in the head and neck region, with an estimated incidence of 1 in 30,000 . They have been reported in multiple sites between the skull base and clavicle but are most commonly found within the carotid body (60%), as well as the jugular, tympanic and vagal paraganglia . Clinically, patients may have symptoms caused by the tumor’s compressive effects on surrounding nerves and vessels; however, many are asymptomatic.
Although the majority of head and neck paragangliomas (HNPs) are benign, a small percentage demonstrates malignant behavior . The criteria for malignancy are a source of debate. Histopathological features, including central necrosis, hypervascularity or increased mitotic activity, cannot reliably distinguish benign from malignant tumors . The most widely accepted criterion is evidence of regional or distant metastatic spread to non-endocrine tissue . Using this definition, malignancy has been identified in 6%–19% of all HNPs . Vagal paragangliomas are more likely to demonstrate malignant features (19%) followed by carotid body tumors (CBT) (6%) and lesions from the jugulotympanic paraganglia (2%–4%) . Distant metastases are extremely rare but can occur in the lung, liver, bone and skin . A minority of all patients with paragangliomas has a familial predisposition to these tumors, as a result of a germline mutation in the succinate dehydrogenase (SDH) gene; patients with the SDH subunit B mutation have a significantly higher risk of harboring malignant paragangliomas .
The traditional treatment of malignant HNP (MHNP) is surgery to the primary site and neck dissection to address regional disease. Surgery followed by adjuvant radiation is used less frequently, and chemotherapy is typically reserved for distant disease . The optimal management of patients with MHNP, however, is not well understood. Some studies have supported adjuvant radiation over surgery alone, while other studies have found that radiotherapy does not improve survival outcomes . Prior work has been limited by very small cohorts from single institutions and short survival follow-up. The largest prior series identified 59 patients, but reported survival outcomes on only 35 patients followed for a median of 65.5 months, all of whom were treated before 1991. Using the Surveillance Epidemiology and End Results (SEER) database, which is maintained by the National Cancer Institute, we identified 86 patients diagnosed with MHNP with a median follow-up of 74 months. To our knowledge, this is the largest and most contemporary patient cohort in the literature.
2
Materials and methods
The 18 registries of the SEER database were used to identify patients diagnosed with malignant HNP between 1973 and 2009. Institutional Review Board (IRB) exemption was obtained in advance. SEER includes cancer incidence, prevalence and survival data for approximately 26% of the United States population with over seven million unique cases gathered from population-based cancer registries across the nation. Patient demographics, primary tumor site, tumor morphology and stage, first course treatment of the primary site and long term survival follow up data are included.
Consistent with prior studies, only cases of malignant HNP identified by histologic type (ICD-0 2 codes M8680 and M8693) and documented regional or distant metastatic tumor spread were included in our analysis (N = 86) . The remaining patients (N = 58) were excluded if their tumor was unstaged (N = 23), localized without regional lymph node involvement (N = 23) or if MHNP was not their first cancer diagnosis (N = 12). There is no formal staging system for malignant paragangliomas in the American Joint Committee on Cancer (AJCC) staging manual, therefore the broad staging scheme in SEER, derived from the Collaborative Staging Manual and Coding Instructions, Version 1.0, was used.
Primary tumor site was limited to the head and neck by topographical ICD-O2 codes (C00.0-14.8, C30.0-30.1, C31.0-31.9, C32.0-32.9, C33.9, C41.0-41.9, C47.0, C49.0, C72.2, C73.9, C75.0, C75.2, C75.4-75.9, C76.0, and C77.0) . Documented treatment methods were limited to management of the primary site of disease and included: surgery alone, surgery with adjuvant radiation and radiation alone. Although specific procedural data were not available, metastatic disease was confirmed with formal biopsy or neck dissection. Documentation of metastatic site and treatment for metastatic disease was also unavailable.
Kaplan–Meier method was used to estimate overall survival, with an endpoint of death from any cause, and cause specific survival, with an endpoint of death from disease. Survival trends were compared for patient demographic factors, tumor characteristics, and treatment modality by log-rank test. Hazard ratios were generated using Cox proportional hazard models. Predictors of overall survival in univariate analysis ( p < 0.05) were included in the multivariate model. All analyses were performed using STATA v.11 (StataCorp LP, College Station, TX).
2
Materials and methods
The 18 registries of the SEER database were used to identify patients diagnosed with malignant HNP between 1973 and 2009. Institutional Review Board (IRB) exemption was obtained in advance. SEER includes cancer incidence, prevalence and survival data for approximately 26% of the United States population with over seven million unique cases gathered from population-based cancer registries across the nation. Patient demographics, primary tumor site, tumor morphology and stage, first course treatment of the primary site and long term survival follow up data are included.
Consistent with prior studies, only cases of malignant HNP identified by histologic type (ICD-0 2 codes M8680 and M8693) and documented regional or distant metastatic tumor spread were included in our analysis (N = 86) . The remaining patients (N = 58) were excluded if their tumor was unstaged (N = 23), localized without regional lymph node involvement (N = 23) or if MHNP was not their first cancer diagnosis (N = 12). There is no formal staging system for malignant paragangliomas in the American Joint Committee on Cancer (AJCC) staging manual, therefore the broad staging scheme in SEER, derived from the Collaborative Staging Manual and Coding Instructions, Version 1.0, was used.
Primary tumor site was limited to the head and neck by topographical ICD-O2 codes (C00.0-14.8, C30.0-30.1, C31.0-31.9, C32.0-32.9, C33.9, C41.0-41.9, C47.0, C49.0, C72.2, C73.9, C75.0, C75.2, C75.4-75.9, C76.0, and C77.0) . Documented treatment methods were limited to management of the primary site of disease and included: surgery alone, surgery with adjuvant radiation and radiation alone. Although specific procedural data were not available, metastatic disease was confirmed with formal biopsy or neck dissection. Documentation of metastatic site and treatment for metastatic disease was also unavailable.
Kaplan–Meier method was used to estimate overall survival, with an endpoint of death from any cause, and cause specific survival, with an endpoint of death from disease. Survival trends were compared for patient demographic factors, tumor characteristics, and treatment modality by log-rank test. Hazard ratios were generated using Cox proportional hazard models. Predictors of overall survival in univariate analysis ( p < 0.05) were included in the multivariate model. All analyses were performed using STATA v.11 (StataCorp LP, College Station, TX).
3
Results
3.1
Demographics
Between 1973 and 2009, 144 patients were diagnosed with malignant HNP in the SEER database. Of these, 86 patients satisfied the criteria for malignancy – documented regional or distant tumor spread – and were included in our analysis. The median age at diagnosis was 44 years. A higher proportion of patients with MHNP were male (57%). The year of diagnosis ranged from 1973 to 2009. The majority of patients (61 patients, 71.0%) were diagnosed after 1990. Among patients with regional disease who were treated with surgery and adjuvant radiation, the majority (21 patients, 72.4%) were treated after 1990. Median follow up time was 74 months (range 5–430 months). Follow up was greatest for patients who underwent radiation alone (119 months, range 22–430) compared to those who received surgery followed by adjuvant radiation (89 months, range 5–338), surgery alone (76 months, range 7–298) or no treatment (17 months, range 16–66). Demographic findings are summarized in Table 1 .
| Characteristic | All patients (N = 86) |
|---|---|
| Age | |
| 15–19, No. (%) | 4 (4.7) |
| 20–39, No. (%) | 27 (31.4) |
| 40–59, No. (%) | 34 (39.5) |
| 60–79, No. (%) | 16 (18.6) |
| 80–100, No. (%) | 5 (5.8) |
| Age, median, y | 44 |
| Age, mean (SD), y | 46.95 (17.1) |
| Gender | |
| Male, No. (%) | 49 (57.0) |
| Female, No. (%) | 37 (43.0) |
| Race | |
| American Indian/Alaska Native, No. (%) | 1 (1.2) |
| Asian or Pacific Islander, No. (%) | 4 (4.7) |
| Black, No. (%) | 3 (3.5) |
| White, No. (%) | 78 (90.7) |
| Primary Site | |
| Oropharynx, No. (%) | 1 (1.2) |
| Pharynx, No. (%) | 1 (1.2) |
| Ethmoid sinus, No. (%) | 1 (1.2) |
| Overlapping lesion of larynx, No. (%) | 1 (1.2) |
| Pituitary gland, No. (%) | 1 (1.2) |
| Carotid body, No. (%) | 37 (43.0) |
| Other, No. (%) | 44 (51.2) |
| Stage | |
| Distant, No. (%) | 39 (45.3) |
| Regional, No. (%) | 47 (54.7) |
| Treatment | |
| No treatment, No. (%) | 13 (15.1) |
| Surgery alone, No. (%) | 31 (36.0) |
| Radiation alone, No. (%) | 13 (15.1) |
| Surgery + Radiation, No. (%) | 29 (33.7) |
| Year of Diagnosis | |
| 1973–1980, No. (%) | 10 (11.6) |
| 1981–1990, No. (%) | 15 (17.4) |
| 1991–2000, No. (%) | 20 (23.3) |
| 2001–2009, No. (%) | 41 (47.7) |
| Median follow up time (months) | |
| All, No. (range) | 74 (5–430) |
| Surgery alone, No. (range) | 76 (7–298) |
| Surgery with adjuvant radiation, No. (range) | 89 (5-338 |
| Radiation alone, No. (range) | 119 (7–298) |
| No treatment, No. (range) | 17 (16–66) |
3.2
Tumor characteristics
MHNPs were found in multiple primary sites throughout the head and neck, most commonly the carotid body (37 patients, 43.0%). Overall, 47 patients (54.7%) demonstrated spread to the regional lymph nodes only, while 39 patients (45.3%) were found to have distant metastases.
3.3
Treatment
Sixty of the 86 total patients (69.8%) underwent surgical resection of the primary tumor — 31 were treated with surgery alone and 29 received surgery followed by adjuvant radiation. Of the 26 nonsurgical patients, 13 were treated with radiation alone and 13 received no treatment.
Patient demographics and tumor characteristics were compared between treatment groups ( Table 2 ). A nearly equal proportion of patients with disease confined to the regional lymph nodes were treated with surgery alone and surgery and adjuvant radiation (71.0% in surgery alone and 69.0% in surgery with adjuvant radiation). Treatment protocols were also equally distributed for patients with distant metastases—9 patients (23.1%) underwent surgery alone vs. 9 patients (23.1%) treated with surgery followed by radiation therapy. Of the patients who received only radiotherapy, four had only regional lymph node involvement, while nine patients demonstrated distant metastatic involvement. When separated by tumor location, a greater number of patients with CBT were treated with surgery and adjuvant radiation when compared to tumors at other sites (20 patients (69.0%) vs. 9 patients (31.%), respectively).
