Abstract
Context
Germline mutations in succinate dehydrogenase (SDH) genes predispose carriers for developing paragangliomas, and studies on their quality of life (QoL) are scarce.
Objectives
The objectives of this study were to assess QoL in patients with paragangliomas (PGL), to evaluate long-term QoL, and to explore potential differences in QoL between SDH mutation carriers and paraganglioma patients without an SDH mutation.
Design
Cross-sectional, case–control study.
Setting
Tertiary referral center.
Subjects
One hundred and seventy four paraganglioma patients were included: 25 SDHB, two SDHC, and 122 SDHD mutation carriers and 25 patients without an SDH mutation. They provided 100 peers as control persons. Furthermore, patients were compared with age-adjusted reference populations.
Main outcome measures
QoL was assessed using three validated health-related QoL questionnaires: the Hospital Anxiety and Depression Scale, the Multidimensional Fatigue Index 20, and the Short Form 36.
Results
Patients reported a significantly impaired QoL compared with their own controls, mainly on fatigue and physical condition subscales. Compared with age-adjusted literature values, patients had significantly impaired scores on physical, psychological, and social subscales. A decreased QoL was mainly related to paraganglioma-associated complaints.
There was no difference in QoL between the various SDH mutation carriers or paraganglioma patients without an SDH mutation. QoL in asymptomatic mutation carriers, i.e. without manifest disease, did not differ from QoL of the general population. Long-term results in 41 patients showed no alteration in QoL besides a reduced level of activity.
Conclusion
QoL is decreased in paraganglioma patients but stable when measured over time.
Introduction
Paragangliomas (PGL) are rare tumors originating from neural crest cells and are strongly associated with the autonomic nervous system. They are divided by region in head and neck paragangliomas (HNPGLs), adrenal paragangliomas (i.e. pheochromocytomas), and extra-adrenal paragangliomas (i.e. paragangliomas in the thorax, abdomen, or pelvis).
Paragangliomas can produce excessive amounts of catecholamines, especially when located in the adrenals. The classic triad of symptoms associated with pheochromocytomas is episodic headache, sweating, and palpitations with often additional persistent hypertension. Pheochromocytomas require surgery and preoperative management with α- and β-blockade to inhibit the effects of released catecholamines, thereby preventing lethal cardiovascular complications (1).
The primary cause of morbidity in HNPGL patients is cranial nerve impairment due to proximity to the tumor. Patients complain about hearing loss, tinnitus, hoarseness, and problems in swallowing. Although surgery is an option in the treatment of HNPGLs, the risk of treatment-related additional loss of nerve function is a matter of consideration (2, 3). Therefore, considering the indolent nature of most HNPGLs, a ‘wait and scan’ policy may be advisable in appropriate cases (4).
Paragangliomas can occur as a consequence of germline mutations in one of the subunits of the mitochondrial complex II succinate dehydrogenase (SDH) gene. Mutations in subunits A, B, C, and D and assembly factor 2 have been identified (5, 6, 7, 8, 9). In The Netherlands, the p.Asp92Tyr founder mutation in SDHD is the most prevalent cause of hereditary paragangliomas (10). Distinct genotype–phenotype associations have been reported. SDHB mutation carriers seem to be at highest risk for developing malignant paragangliomas (11, 12). Possibly, this could result in a reduced quality of life (QoL) in these patients.
In a previous case–control study from our department, Havekes et al. (13) reported an impaired QoL in 82 HNPGL patients with or without (a history of) paragangliomas at other locations. No differences of QoL scores were found between SDHD mutation carriers and paraganglioma patients who were genotyped without finding a mutation or patients who had not been tested. To the best of our knowledge, QoL has never been assessed in SDHB and SDHC mutation carriers, nor has it been compared between different groups of mutation carriers. Considering the classical maternal imprinting related to SDHD transmission, it would also be of interest to compare QoL scores between male and female SDHD mutation carriers.
In addition, no long-term data on QoL in paraganglioma patients are available and we do not know how this is affected by surgical or conservative treatment. This is important to evaluate, as QoL has become an important outcome parameter for patients as well as their treating physicians in discussing the various treatment options (14, 15, 16).
The primary objective of this study was to assess QoL in an extended cohort of paraganglioma patients. Secondary objectives were to explore potential differences in QoL between SDHB, SDHC, and SDHD mutation carriers and patients without an SDH mutation, between male and female SDHD mutation carriers, and to assess QoL over time.
Materials and methods
Study protocol
Patients were recruited from the outpatient clinic of the Department of Endocrinology of the Leiden University Medical Center (LUMC), a tertiary referral center for paragangliomas. We included all patients with paragangliomas, as well as asymptomatic SDH mutation carriers. The SDHB, SDHC, and SDHD genes were scanned for the presence of mutations at the laboratory for DNA diagnostics at the LUMC. All exonic and adjacent intronic regions of these genes were tested by direct sequencing using the Sanger method on an ABI 377 Genetic Analyser (Applied Biosystems) and MLPA was carried out with the P226 multiplex ligation-dependent probe amplification (MLPA) Kit (MRC Holland, Amsterdam, The Netherlands) (10).
In February 2012, a total of 302 patients were sent an envelope containing three validated health-related QoL questionnaires: the Hospital Anxiety and Depression Scale (HADS), the Multidimensional Fatigue Index (MFI-20), and the Short Form 36 (SF-36) (17, 18, 19, 20). Furthermore, patients were asked to fill in a questionnaire concerning possible signs and symptoms associated with paragangliomas. This questionnaire had previously been developed at our department in order to relate QoL to clinical data (13). Patients were asked to return these questionnaires in a prepaid envelope.
Non-responders were encouraged by a reminder letter to complete and return questionnaires. All questionnaires received before 1st May were included in our study.
To create a control group with similar socioeconomic status from the same geographical area, all patients received a second envelope containing the HADS, MFI-20, and SF-36 and were requested to provide a control person of similar age and sex. In addition, to compare patients with the general population, we used values derived from the literature. To measure QoL over time, we used results of the study by Havekes et al. (13).
This study protocol was approved by the Medical Ethics Committee of the LUMC. All subjects returning the completed questionnaires gave written consent for participation.
Study parameters
The primary parameters were the outcomes of the three validated health-related QoL questionnaires. The relations between the outcomes and patient characteristics, genetic status, number and location of paragangliomas, signs and symptoms, and treatment characteristics were examined. Longitudinal QoL was assessed.
QoL questionnaires
Hospital Anxiety and Depression Scale
The HADS contains 14 questions related to two subscales: anxiety and depression. Both subscales contain seven items scored on a four-point scale, ranging from 0 to 3. Scores range from 0 to 21 for each subscale and from 0 to 42 for the total score. A higher score indicates a higher level of anxiety and depression (20). Reference values of the Dutch population were derived from Spinhoven et al. (21).
Multidimensional Fatigue Index 20
The MFI-20 consists of 20 statements to assess fatigue (18). Five dimensions of fatigue are measured: i) general fatigue, ii) physical fatigue, iii) reduced activity, iv) reduced motivation, and v) mental fatigue. Items are scored on a five-point scale and subscales range from 4 to 20. Higher scores are associated with a higher feeling of fatigue. General values of the Dutch population were derived from Smets et al. (22).
Short Form 36
The SF-36 questionnaire includes 36 items assessing general well-being/functional status during the previous 30 days (17, 19). The items are formulated as statements or questions to assess eight functional status domains: i) physical functioning, ii) social functioning, iii) limitations in usual role activities because of physical health problems, iv) pain, v) general mental health (psychological distress and well-being), vi) limitations in usual role activities because of emotional problems, vii) vitality (energy and fatigue), and viii) general health perceptions and change in health. Scores are expressed on a 0–100 scale, with higher scores indicating a better QoL. Dutch reference values were derived from the official Dutch manual (23).
Missing data
In case of missing data, patients received the missing questions by mail with a request to complete them. As we were not in possession of postal addresses of control persons provided by our patients, we were not able to send this request to control persons.
Missing data of the SF-36 were computed per subscale by imputation of personal mean scores, in case half or less of questions within the subscale were missing (24). Imputation of personal mean scores per subscale was also used if one item or less was missing per subscale in the HADS and MFI-20. If more questions were missing, the concerning subscale was excluded from our analyses.
Statistical analysis
SPSS for Windows version 17.0 (SPSS, Inc.) was used for data analysis. Data are expressed as mean±s.d., unless otherwise mentioned. To compare patient and control data, the unpaired t-test was used for normally distributed variables and the Mann–Whitney U test for non-normally distributed variables. To compare present QoL results with those of 5 years ago, the paired t-test was used for normally distributed variables and the Wilcoxon signed rank test for non-normally distributed variables. Normal distribution was tested with the Kolmogorov–Smirnov test. We used weighted means from literature reference data according to the age distribution in our cohort (25).
Subgroups of patients were compared using the one-way ANOVA or Kruskal–Wallis test. Using linear regression analysis, we assessed the effect of continuous variables on QoL. These results are expressed as the absolute standardized β of independent predictive values. Post hoc power was calculated using G*Power version 3.1 (Dusseldorf, North Rhine-Westphalia, Germany) (26).
Differences were considered statistically significant at P<0.05.
Results
Patient and treatment characteristics
Out of 302 addressed patients, a total of 174 (58%) returned the completed questionnaires. The mean age of the study population was 52±14 years. The mean time between diagnosis of PGL and this study was 11.3±10.0 years.
No significant difference in age, number, and localization of paragangliomas was found between responders and non-responders, although a significantly higher percentage of women was found in the responder group (60 vs 47%).
The 174 patients who completed the questionnaires provided 100 controls (57%). Mean age in the control group was 49±13 years. There were no significant differences in age and sex between the study population and controls. In the control group, one HADS questionnaire, three MFI-20 questionnaires, and two health change subscales of the SF-36 were discarded because too many questions were missing.
Detailed characteristics of patients are listed in Table 1. Within the patient group, 16% had not been diagnosed with a HNPGL, 25% with one, 27% with two, and 32% had been diagnosed with three or more HNPGLs. A carotid body tumor was the most prevalent HNPGL: 66% of patients had been diagnosed with one or two carotid body tumors. Of these patients, 55 had complete resection of one or two carotid body tumors. Jugulotympanic and vagal body tumors were less frequently found and were also less frequently surgically removed: 6 and 2% respectively. At the time of the study, one participant had a pheochromocytoma in situ and four participants had extra-adrenal paragangliomas in situ, whereas in the past 6% had been operated on a pheochromocytoma and 4% on an extra-adrenal paraganglioma. In patients in whom PGL surgery was performed, the mean time between first operation and this study was 12.4±10.8 years. Six patients were found to have malignant paragangliomas, i.e. metastatic disease. In total, 23 patients (13%) were asymptomatic mutation carriers, i.e. persons without manifest disease, as determined by surveillance for paragangliomas.
Characteristics of patients and controls.
| All patients (n=174) | SDHB (n=25) | SDHC (n=2) | SDHD (n=122) | No SDH mutation (n=25) | Own controls (n=100) | |
|---|---|---|---|---|---|---|
| Age (years, mean±s.d.) | 52.2±13.5 | 55.8±14.5 | 48.5±26.2 | 51.1±13.6 | 54.4±11.3 | 49.3±12.9 |
| Sex (M/F) | 70/104 | 10/15 | 0/2 | 54/68 | 6/19 | 38/49a |
| Number of HNPGLsb | ||||||
| 0 | 28 (16%) | 15 (60%) | 0 | 13 (11%) | 0 | |
| 1 | 43 (25%) | 7 (28%) | 2 | 13 (11%) | 21 (84%) | |
| 2 | 47 (27%) | 3 (12%) | 0 | 41 (34%) | 3 (12%) | |
| ≥3 | 56 (32%) | 0 | 0 | 55 (45%) | 1 (4%) | |
| Carotid body tumor | 115 (66%) | 4 (16%) | 1 | 102 (84%) | 8 (32%) | |
| Complete resection | 55 (32%) | 2 (8%) | 0 | 49 (40%) | 4 (16%) | |
| In situ | 91 (52%) | 2 (8%) | 1 | 83 (68%) | 5 (20%) | |
| Jugulotympanic tumor | 52 (30%) | 6 (24%) | 0 | 34 (28%) | 12 (48%) | |
| Complete resection | 11 (6%) | 2 (8%) | 7 (6%) | 2 (8%) | ||
| In situ | 42 (24%) | 4 (16%) | 28 (23%) | 10 (40%) | ||
| Vagal body tumor | 72 (41%) | 1 (4%) | 1 | 63 (52%) | 7 (28%) | |
| Complete resection | 3 (2%) | 0 | 0 | 3 (2%) | 0 | |
| In situ | 70 (34%) | 1 (4%) | 1 | 61 (50%) | 7 (28%) | |
| History intra-adrenal paraganglioma | 10 (6%) | 0 | 0 | 10 (8%) | 0 | |
| History extra-adrenal paraganglioma | 7 (4%) | 2 (8%) | 0 | 5 (4%) | 0 | |
| Intra-adrenal paraganglioma at the time of study | 1 (1%) | 0 | 0 | 1 (1%) | 0 | |
| Extra-adrenal paraganglioma at time of study | 4 (2%) | 0 | 0 | 4 (3%) | 0 | |
| Malignant paraganglioma | 6 (3%) | 1 (4%) | 0 | 4 (3%) | 1 (4%) |
Thirteen control persons did not fill in their sex on the response form.
Head and neck paragangliomas.
The responding patient group consisted of 25 SDHB mutation carriers, two SDHC mutation carriers, and 122 SDHD mutation carriers and 25 patients without an SDH mutation. All SDHD mutation carriers inherited the mutation from their father. The mean time between genetic testing and this study was 4.4±3.2 years. Out of these 174 patients, 11 (6%) had not been molecular genetically tested. Of the untested patients, eight had a positive family history with a proven SDHD mutation and were diagnosed with paragangliomas themselves. Therefore, they were considered to be obligate SDHD mutation carriers. The remaining three patients were diagnosed with a single HNPGL and over the age of 50 years. Considering the fact they did not have multiple paragangliomas or a positive family history, they were regarded as having no SDH mutation.
Forty-one respondents had also participated in the QoL study, which was carried out in our center 5 years earlier (13). Mean age in this group was 54±11 years and 54% were females. One patient carried the SDHB mutation and 36 the SDHD mutation. Thirty-five patients (85%) had a HNPGL in situ, of whom 74% a carotid body tumor, 37% a jugulotympanic tumor, and 54% a vagal body tumor. Six patients had been operated on for a pheochromocytoma in the past and two on an extra-adrenal paraganglioma. One patient had a malignant paraganglioma, i.e. metastatic disease.
QoL in paraganglioma patients compared with controls and age-adjusted reference values
Paraganglioma patients reported a significantly impaired QoL on the HADS, MFI-20, and SF-36 compared with both their own controls and the age-adjusted values derived from the literature (Table 2). Compared with own controls, patients had affected scores on all MFI-20 (i.e. fatigue) subscales. The SF-36 questionnaire demonstrated a decreased score on physical and social functioning, role limitations due to physical problems, mental health, vitality, and general health perception. No differences in anxiety or depression were found between patients and controls (HADS questionnaire).
QoL parameters (HADS, MFI-20, and SF-36) in paraganglioma patients compared to own controls and age-adjusted reference values.
| Questionnaire | Patients (n=174) | Own controls (n=100) | P value | Age-adjusted reference values (21, 22, 23) | P value |
|---|---|---|---|---|---|
| HADS | |||||
| Anxiety | 5.9±3.8 | 5.0±3.2 | NS | 4.9±3.6 | <0.001 |
| Depression | 4.0±3.7 | 3.0±2.7 | NS | 3.6±3.3 | NS |
| Total | 9.9±6.9 | 8.1±5.3 | NS | 8.4±6.3 | <0.005 |
| MFI-20 | |||||
| General fatigue | 11.3±4.8 | 9.3±4.1 | <0.001 | 9.9±5.2 | <0.005 |
| Physical fatigue | 9.9±4.6 | 7.7±3.6 | <0.001 | 8.8±4.9 | <0.02 |
| Reduced activity | 9.3±4.0 | 7.6±3.7 | <0.001 | 8.7±4.6 | NS |
| Reduced motivation | 9.2±4.0 | 7.8±3.4 | <0.005 | 8.2±4.0 | <0.01 |
| Mental fatigue | 10.0±4.3 | 8.9±4.2 | <0.05 | 8.3±4.8 | <0.001 |
| SF-36 | |||||
| Physical functioning | 84.0±18.9 | 89.4±14.3 | <0.05 | 78.4±22.2 | <0.001 |
| Social functioning | 78.0±24.3 | 87.0±17.9 | <0.005 | 86.0±20.9 | <0.001 |
| Role limitations due to physical problems | 68.5±41.0 | 86.5±33.8 | <0.001 | 77.6±36.7 | <0.005 |
| Role limitations due to emotional problems | 79.7±35.4 | 86.3±33.2 | NS | 84.9±31.3 | <0.05 |
| Mental health | 72.0±17.6 | 77.1±15.4 | <0.05 | 76.8±18.5 | <0.001 |
| Vitality | 60.9±20.2 | 66.7±17.5 | <0.05 | 66.8±20.5 | <0.001 |
| Bodily pain | 82.6±21.8 | 87.0±18.6 | NS | 79.0±25.2 | <0.05 |
| General health perception | 62.7±22.9 | 74.5±16.9 | <0.001 | 68.7±22.1 | <0.001 |
| Health change | 50.6±20.3 | 52.0±16.7 | NS | 51.0±18.3 | NS |
NS, not significant; HADS, Hospital Anxiety and Depression Scale; MFI-20, Multidimensional Fatigue Index; SF-36, Short Form 36.
Compared with age-adjusted reference values (21, 22, 23), the anxiety subscale and the total score of the HADS questionnaire were impaired in paraganglioma patients. Patients experienced an increased feeling of fatigue with four out of five subscales of the MFI-20 being increased. In the SF-36 questionnaire, all subscales were significantly decreased in the patient group except for health change (Fig. 1).
QoL in SDH mutation carriers
We aimed to explore potential differences in QoL between SDHB, SDHC, and SDHD mutation carriers and patients without an SDH mutation. As only two subjects carried an SDHC mutation, we excluded these SDHC mutation carriers from our analyses because of a lack of statistical power. Comparing QoL scores of SDHB mutation carriers, SDHD mutation carriers and patients without an SDH mutation revealed no significant differences on the HADS, MFI-20, or the SF-36.
Forty-four percent of the SDHD mutation carriers were men. Comparing QoL scores between male and female SDHD mutation carriers revealed no significant differences except less vitality in female carriers (P=0.039).
Twenty-three SDH mutation carriers (13 SDHB and 10 SDHD mutation carriers) were asymptomatic, i.e. had not displayed manifest disease up to the present. When analyzing this group separately, no significant differences in QoL scores were found compared with self-provided controls and age-adjusted reference values (21, 22, 23). Post hoc power calculations revealed sufficient power (>0.8) to draw these conclusions.
Factors influencing QoL in patients with paragangliomas
Age
The SF-36 subscale physical functioning was negatively affected by age in the patient group (β=−0.377, P=0.000). None of the other variables were affected by age.
Gender
Female paraganglioma patients experienced significantly more general fatigue than male patients (12.1±4.6 vs 10.0±4.8) and a significantly reduced motivation (9.7±3.9 vs 8.5±4.0). On the SF-36, females reported less vitality than males (57.6±19.6 vs 65.9±20.1, P=0.008).
HNPGLs
There was no difference in QoL between patients with HNPGLs and patients without HNPGLs on all 16 dimensions. Surgical removal of HNPGLs was also not related to QoL scores. Post hoc power calculations yielded enough power (>0.8) to draw these conclusions.
A higher number of HNPGLs positively affected the HADS subscale depression (β=0.489, P=0.030), indicating that a higher number of HNPGLs is associated with more feelings of depression. Furthermore, a higher number of HNPGLs had a negative effect on physical functioning (β=−2.445, P=0.035) and general health perception (β=−3.834, P=0.006). Patients reporting HNPGL-associated complaints (e.g. tinnitus, dysphonia, and aspiration) reported a significantly worse QoL than HNPGL patients without complaints (Table 3). When analyzing this latter group separately, no decreased QoL was found compared with self-provided controls and age-adjusted reference values (21, 22, 23). Post hoc power calculation revealed sufficient power (>0.8) to detect differences between groups.
QoL parameters: patients with HNPGL in situ with associated complaints vs patients with HNPGL in situ without any complaints.
| Questionnaire | Complaints (n=108) | No complaints (n=18) | P value |
|---|---|---|---|
| HADS | |||
| Anxiety | 6.5±3.8 | 3.9±2.5 | <0.05 |
| Depression | 4.5±3.9 | 2.1±2.6 | <0.05 |
| Total | 11.0±6.9 | 6.0±4.4 | <0.05 |
| MFI-20 | |||
| General fatigue | 12.4±4.7 | 7.7±3.7 | <0.001 |
| Physical fatigue | 10.9±4.8 | 6.9±2.8 | <0.001 |
| Reduced activity | 9.6±4.2 | 7.8±2.9 | NS |
| Reduced motivation | 9.7±4.1 | 8.1±3.2 | NS |
| Mental fatigue | 10.4±4.3 | 7.2±4.1 | <0.05 |
| SF-36 | |||
| Physical functioning | 80.7±19.5 | 92.9±9.2 | <0.05 |
| Social functioning | 73.3±25.9 | 93.1±13.0 | <0.05 |
| Role limitations due to physical problems | 64.4±42.3 | 81.9±30.7 | NS |
| Role limitations due to emotional problems | 75.9±38.6 | 92.6±21.6 | NS |
| Mental health | 69.8±18.2 | 82.0±10.8 | <0.05 |
| Vitality | 56.9±20.4 | 73.9±11.8 | <0.001 |
| Bodily pain | 80.7±21.8 | 91.6±14.6 | <0.05 |
| General health perception | 56.1±22.8 | 81.4±12.5 | <0.001 |
| Health change | 49.2±19.9 | 58.3±19.2 | NS |
NS, not significant; HADS, Hospital Anxiety and Depression Scale; MFI-20, Multidimensional Fatigue Index; SF-36, Short Form 36.
Pheochromocytomas and extra-adrenal paragangliomas
The patient group with pheochromocytomas or extra-adrenal paragangliomas in situ was of insufficient size for separate analysis. Patients with a history of surgically treated pheochromocytomas or extra-adrenal paragangliomas were not found to have an altered QoL compared with the rest of the patient group (post hoc analysis power of >0.8).
Patients experiencing complaints associated with excessive production of catecholamines (i.e. vertigo, palpitations, perspiration, pallor, panic attacks, and headaches) did have significantly increased scores on the HADS and MFI-20 and impaired scores on SF-36 on more than eight out of 16 subscales.
Malignancy
Patients with malignant paraganglioma reported significantly more mental fatigue (13.8±2.4 vs 9.9±4.3) and had a reduced score on the general health perception subscale (35.8±21.8 vs 63.6±22.5). All other subscales were not affected.
Long-term QoL
We were able to compare present QoL scores with those of 5 years ago on the HADS and MFI-20 in 41 patients. Results are displayed in Table 4. Patients reported a significantly increased score on the MFI-20 subscale relating to reduced activity. No significant alterations were found on the other subscales.
QoL at baseline compared with QoL 5 years later in 41patients.
| Questionnaire | Patients at baseline | Patients at 5 years | P value |
|---|---|---|---|
| HADS | |||
| Anxiety | 5.7±3.7 | 6.7±4.4 | 0.167 |
| Depression | 3.5±3.4 | 4.1±4.4 | 0.359 |
| Total | 9.2±6.6 | 10.8±8.1 | 0.210 |
| MFI-20 | |||
| General fatigue | 10.6±5.2 | 11.6±4.9 | 0.117 |
| Physical fatigue | 9.6±4.3 | 10.1±4.8 | 0.480 |
| Reduced activity | 8.1±3.6 | 9.6±4.1 | 0.005 |
| Reduced motivation | 8.2±3.5 | 9.2±4.2 | 0.104 |
| Mental fatigue | 10.3±4.5 | 10.1±4.4 | 0.810 |
HADS, Hospital Anxiety and Depression Scale; MFI-20, Multidimensional Fatigue Index.
Seven patients (17%) were operated on their HNPGLs in these 5 years. It concerned four carotid body tumors, two jugulotympanic tumors, and one tumor localized in between the thyroid gland and right internal jugular vein. In addition, in one patient, an extra-adrenal paraganglioma was surgically removed. In none of these patients, postoperative morbidity was noted.
There were no significant differences in alteration of QoL between patients who were operated on and patients who were conservatively treated, although post hoc power calculation revealed insufficient power (0.5) to detect differences between groups.
Discussion
In this study, we assessed QoL in an extended cohort of paraganglioma patients and compared QoL in the various SDH mutation groups. Our study compared patients with ‘own controls’ as well as with age-adjusted literature values. The advantage of using own controls is the same distribution of sex, age, and geographical area in the control group as in the patient group (27). However, a potential problem of these controls is positive selection bias, i.e. the tendency of patients to choose controls with a good health status (28). Therefore, in addition to own controls, we used age-adjusted literary values that are not subject to this bias. The use of two control groups produces more reliable results if outcomes are consistent (27). Our study showed similar results for patients compared with own controls and compared with reference values derived from the literature.
Our results show that the study cohort as a whole had a significantly decreased QoL relating to fatigue and physical condition compared with own controls. Compared with age-adjusted literature values, patients were found to have decreased QoL scores on physical as well as psychological and social subscales. These results are in line with a previous study conducted in our department (13); however, in this study, the cohort was extended and included SDHB and SDHC mutation carriers.
When we attempt to put our results in perspective and compare the whole study group to patients with a similar condition, i.e. vestibular schwannoma, a similar benign tumor in the head-and-neck area primarily leading to hearing loss, paraganglioma patients seem to have less impairment of QoL on SF-36 scores (29). Comparing our results with other patients suffering from a chronic disease, i.e. diabetes type 2 patients, paraganglioma patients had similar QoL scores on the SF-36, except for better physical functioning and less bodily pain (30).
Assessment of determinants influencing QoL revealed that age negatively influenced physical functioning on the SF-36 subscale. This is not surprising, as it is known that scores on all subscales of the SF-36 decrease with increasing age (23). More importantly, the presence of HNPGL-associated complaints significantly reduced QoL. Interestingly, HNPGL patients without associated complaints were not found to have a decreased QoL compared with the general population (i.e. own controls and values derived from the literature). Apparently, it is not the presence of a HNPGL per se that causes a decreased QoL but it is the associated signs and symptoms that do.
In our study, we aimed to explore potential differences in QoL between SDHB, SDHC, and SDHD mutation carriers and patients without an SDH mutation. Owing to the limited number of patients harboring an SDHC mutation in our cohort, we were not able to analyze these patients separately. However, no differences in QoL between the various SDH mutation carriers were found, reducing the potential weakness in our study of the very low number of patients with SDHC mutations.
Equal scores in QoL between the various SDH mutation carriers are rather remarkable because it is known that patients harboring an SDHB mutation are at increased risk for developing malignant paragangliomas (11, 12). To make SDHB mutation carriers aware of this risk, in our medical center, this is highlighted in a consult and a patient letter. One possible explanation for equal scores in QoL could be that a large proportion of SDHB mutation carriers in our cohort are asymptomatic, which is probably due to the reduced penetrance of the SDHB mutation in our cohort (31). A separate analysis of the group of asymptomatic mutation carriers showed that they do not display an alteration in QoL compared with the general population. These results are in concordance with results of studies exploring psychological well-being after presymptomatic genetic testing in other diseases, e.g. in mutation carriers of the gene predisposing for Huntington's disease and of spinocerebellar ataxia (32, 33). Apparently, mutation carriers of several genetic diseases display psychological resilience after receiving a positive test result for a genetic test.
Furthermore, as a consequence of the reduced penetrance, SDHB mutation carriers in our cohort are being confronted with severely affected family members to a lesser extent. Consequently, SDHB mutation carriers may worry less about developing (malignant) paragangliomas, as the experiences of other family members can be modifiers of how mutation carriers conceptualize their own risk (34). Interestingly, also no differences in QoL scores were found between female and male SDHD mutation carriers, the latter at risk to transmit the disease. In future research, it would be of interest to investigate how SDH mutation carriers conceptualize beliefs and representations about their disease, i.e. illness perceptions, and how they try to deal with it, i.e. coping strategies, as these determinants may affect QoL (35, 36).
We assessed long-term QoL in paraganglioma patients by comparing present results of patients with QoL scores they reported 5 years earlier. QoL is stable over time in paraganglioma patients, with the exception of patients reporting a reduced level of activity on the MFI-20. This latter might be due to older age; age-associated increases in mean scores in reduced activity have been reported earlier (37).
Our results imply that the generally applied ‘wait and scan’ policy does not negatively impact QoL over time, which is in concordance with QoL results in conservative treatment for vestibular schwannomas (38). This is very important information for both clinicians and paraganglioma patients when discussing different treatment options.
Although our power may have been limited by the small sample size, surgical management of paragangliomas did not seem to influence alteration in QoL. The fact that QoL did not decrease may partly be explained by the fact that none of the patients experienced postoperative morbidity; however, interestingly, surgical removal of paragangliomas did not increase QoL either. Two studies previously assessed postoperative QoL in paraganglioma patients. Kollert et al. (39) found no difference in depressive feelings of patients after HNPGL surgery compared with those of the general population. Briner et al. (40) reported that 75% of patients regained their preoperative QoL 1–2 years after surgery, but this information was self-reported by patients and not assessed by validated questionnaires. Both studies did not assess QoL preoperatively. We are the first to compare QoL scores in paraganglioma patients at two different moments in time. However, prospective, comparative research is needed to confirm our assumptions.
A potential limitation of our study may be the possibility of non-response bias influencing our results, as 42% of the 302 addressed patients did not return the questionnaires. However, the significance of this potential bias is unclear. Possibly, the most distressed persons were more likely to respond, which could have overestimated our results. On the other hand, people who are mentally or physically unwell might be less likely to participate, which could have led to an underestimation of our results. Nonetheless, besides a significantly higher percentage of women in the responder group, no significant difference in age, number, and localization of paragangliomas was found between responders and non-responders. Moreover, the differences in QoL between paraganglioma patients and control groups were very large, clearly indicating that the presence of symptomatic paragangliomas negatively influences QoL and general well-being.
In conclusion, our study confirms previous research stating QoL is decreased in paraganglioma patients but demonstrates that it is stable when measured over time. The impairment in QoL is significantly associated with the presence of HNPGL-associated complaints. A difference in QoL between the various SDH mutation carriers was not found.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
L T van Hulsteijn was involved in the conception and design of the study, the acquisition, analysis, and interpretation of data, drafted the submitted manuscript, and approved the final version to be published. A Louisse was involved in the acquisition, analysis, and interpretation of data, drafted the submitted manuscript, and approved the final version to be published. B Havekes was involved in the design of the study, revised the manuscript critically, and approved the final version to be published. A A Kaptein and J W A Smit were involved in the conception and design of the study, the interpretation of data, revised the manuscript critically, and approved the final version to be published. J C Jansen was involved in the interpretation of data, revised the manuscript critically, and approved the final version to be published. F J Hes revised the manuscript critically and approved the final version to be published. E P M Corssmit was involved in the conception and design of the study, the analysis, and interpretation of data, drafted the submitted manuscript, and approved the final version to be published.
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