Keywords
paraganglioma - hereditary - SDHA - SDHB - SDHD - screening
Introduction
Head and neck paragangliomas are rare, slow-growing, and usually benign neuroendocrine
tumors related to the parasympathetic nervous system. The most common type is the
carotid body tumor located in the carotid bifurcation, followed by the vagal tumors
arising along the vagal nerve, and the jugulotympanic tumor arising from the jugular
bulb or on the middle ear promotory.[1]
[2] Since head and neck paragangliomas rarely produce catecholamines (<4%), most symptoms
are caused by tumor mass.[3]
[4] The most frequently observed sign is an indolent mass that in the ear is accompanied
by pulsatile tinnitus and hearing loss. Occasionally, cranial nerve palsy (VII–XII)
is the presenting sign of a paraganglioma.[5]
In the Netherlands, 90% of the patients with head and neck paraganglioma have a pathogenic
variant in the SDH gene encoding for the SDHA, SDHB, SDHC, SDHD, or SDHAF2 subunits.[6] SDHD and SDHAF2 have a parent-specific penetrance; paragangliomas are only present
after paternal transmission.[7] The most common pathogenic variants are found in SDHD and SDHB. SDHD variant carriers
have the highest risk of developing a paraganglioma, almost invariably developing
a paraganglioma during their lifetime.[8]
[9] The lifetime penetrance of paragangliomas in SDHB variant carriers is approximately
40%, whereas the SDHA variant shows the lowest penetrance of all major PGL predisposition
genes: approximately 10%.[10]
The Dutch guideline for head and neck paraganglioma recommends radiological follow-up
with a frequency of 2 to 5 years in case of a proven paraganglioma. In asymptomatic
patients with a pathogenic variant in one of the SDH genes, a lifelong screening is
recommended as well, but without recommendation about the frequency of screening.[11] Thus, there is no clear approach for screening for head and neck paraganglioma in
asymptomatic SDHx variant carriers. Our policy in the Leiden University Medical Centre
(LUMC) is to screen these mutation carriers every 2 to 3 years. If the first screenings
are negative, a longer interval will be applied.
We previously showed that the prevalence of occult paragangliomas in asymptomatic
carriers of SDHD is high (60%), compared with SDHB gene variants (12%).[12] However, this study was limited to the first radiological screening of the patient
group and did not explore the risk of developing paragangliomas after the initial
screening. A similar study in France from 2021 screened a large cohort of asymptomatic
SDHx pathogenic variant carriers and did include more than one follow-up.[13] A total of 124 patients had at least one additional screening and 8% of them developed
head and neck paraganglioma or sympathetic paraganglioma during a median period of
5 (1–13) years. Tufton et al reviewed all published recommendations regarding the
follow-up and noted that there is little guidance on the frequency.[14] They concluded that the differences in phenotype and penetrance should be taken
into account during follow-up and suggested a whole-body magnetic resonance imaging
(MRI) only for carriers of the SDHB pathogenic variant with a 3-year interval. Finally,
in the recently published international consensus statement a recommendation for all
SDHx pathogenic variant carriers was made. This included a head and neck MRI every
2 to 3 years for all SDHx pathogenic variants, based on the authority of the participating
experts.[15]
To fill the knowledge gap that prevents the data-driven development of guidelines,
our current study aims to determine the risk of developing head and neck paraganglioma
in SDHx pathogenic variant carriers after a negative initial screening.
Materials and Methods
Study Design
We performed a retrospective single-center cohort study at the LUMC, where we retrospectively
collected a dataset of patients with a SDHx pathogenic variant and a negative initial
radiological screening for head and neck paraganglioma.
Ethical Approval
The Medical Research Involving Human Subjects Act (Dutch abbreviation: WMO) does not
apply to the current mentioned study. Therefore, it was exempt from review by the
Medical Ethics Review Committee. The non-WMO Review Committee declared to have no
objections to the study.
Data Collection
The database of the Laboratory for Diagnostic Genome Analysis of the LUMC was used
to identify SDHx carriers from 2000 to 2022. Only patients without a tumor during
their initial workup and at least one radiological follow-up were included in this
study. Asymptomatic SDHD variant carriers through maternal transmission were excluded.
Subsequently, information about the remaining patients and their screening outcomes
were extracted from the patient files. All data were collected in Castor (Castor EDC).
Data Analysis
All data were analyzed using SPSS Statistics (IBM). Qualitative variables were expressed
as numbers and percentages and the quantitative variables as median and range. We
used the Kruskal–Wallis and chi-square tests to compare the different variant groups.
Kaplan–Meier curves were used to present the annual risks regarding developing paragangliomas
and symptoms. To compare the risk between the different types of variants, a log-rank
test was performed. Hazard ratios were calculated through a Cox regression model to
identify possible risk factors and confounders, such as age and gender.
Results
Population
As seen in [Fig. 1], a total of 49 subjects with a negative initial screening for paragangliomas and
at least one follow-up were identified at the LUMC; 2 SDHA, 24 SDHB, and 23 paternally
inherited SDHD variant carriers. All cases had a family member with paraganglioma.
Two of the SDHB variants where classified as having an unknown significance.
Fig. 1 Inclusion flow chart.
Subject Characteristics
The characteristics of the asymptomatic SDHx variant carriers are shown in [Table 1]. The SDHB group was first screened at the median age of 43 years compared with 30
years in the SDHD group and 25 years in the SDHA group. However, this difference did
not reach statistical significance.
Table 1
Characteristics of asymptomatic SDHx mutation carriers
|
SDHA (N = 2)
|
SDHB (N = 24)
|
SDHD (N = 23)
|
|
Gender (%)
|
|
Female
|
2 (100)
|
19 (79.2)
|
11 (45.8)
|
|
Age at initial negative screening (median, range)
|
25.00 y
(16–34)
|
43.00 y
(12–75)
|
30.00 y
(16–64)
|
|
Tumor at MRI (%)
|
0 (0)
|
0 (0)
|
9 (39.1)
|
|
Age at discovery tumor (median, range)
|
–
|
–
|
39.00 y (24–69)
|
|
Tumors (%)
|
|
|
13
|
|
Carotid
|
–
|
–
|
8 (61.5)
|
|
Vagal
|
–
|
–
|
4 (30.8)
|
|
Jugular
|
–
|
–
|
1 (7.7)
|
|
Symptoms (%)
|
0 (0)
|
0 (0)
|
1 (11.0)
|
|
Death
|
0 (0)
|
0 (0)
|
0 (0)
|
|
Follow-up (median, range)
|
4.09 y (3.00–5.17)
|
5.92 y (2.33–13.33)
|
4.83 y
(1.08–17.17)
|
Clinical Outcomes
As presented in [Table 1], nine subjects, exclusively from the SDHD group, developed at least one tumor at
a median age of 39 years (24–69). The median time interval between the negative initial
screening and the discovery of a tumor was 6.08 years with a minimum and maximum of
4.17 and 14.08 years, respectively. In these patients, the median time between their
initial and second screening was 4.83 years (0.92–7.75), whereas the overall median
time interval between the initial and second screening was 4.58 years (0.92–17.17).
Most of the tumors were carotid body tumors (61.5%), followed by vagal (30.8%) and
jugulotympanic paraganglioma (7.7%). Only one of the patients developed symptoms related
to their tumor, 3.25 years after the discovery of the paraganglioma. The overall median
follow-up period of the subjects without a tumor was 5.54 years (1.08–17.7); 4.09
years (3.00–5.17) for SDHA, 5.92 years (2.33–13.33) for SDHB, and 4.83 years (1.08–17.17)
for SDHD variant carriers.
Annual Risk
Among the SDHD variant carriers, the risk of developing a head and neck paraganglioma
was 17.5% (confidence interval [CI]: 15.9–19.1) after 5 years, 62.9% (CI: 33.5–92.3)
after 10 years, and 82.4% (CI: 52.8–112.0) after 15 years ([Fig. 2]).
Fig. 2 Inverted Kaplan–Meier curve presenting the annual risk of developing a paraganglioma
for SDHD variant carriers (family cases).
Discussion
Asymptomatic carriers of pathogenic SDHx variants are advised lifelong screening for
paragangliomas. As expected, our study showed a significantly higher risk of developing
head and neck paragangliomas in SDHD variant carriers compared with other SDHx genes.
In fact, no paragangliomas occurred at all during the follow-up of the SDHA and SDHB
group. Of the total study population, 18% developed a paraganglioma, which is higher
than the prevalence in the similar study from France (8%).[13] This difference in prevalence is probably due to the high proportion of SDHD variant
carriers in the Netherlands.
In the SDHD group, the calculated 5-year risk for developing a paraganglioma was 17.5%
and the first paraganglioma was discovered 4.17 years after their initial screening.
In addition, the development of symptoms after radiological diagnosis will typically
last several years, if any symptoms occur at all, as shown in our results. Hence,
we consider MRI screening with an interval of 5 years sufficient for this group. Since
the SDHB group did not develop paraganglioma during a median follow-up time of 5.92
years, the screening interval could be longer. However, to prevent loss of follow-up
it may be advisable to have a similar 5-year screening interval. Although there were
only two patients in the SDHA group, it is unlikely that the risk exceeds that of
SDHB given the fact that the overall penetrance of SDHA is estimated to be only 10%,
compared with 42% in SDHB.[10]
[16]
In our study, the patients developed a tumor at the maximum age of 69 years, which
accords with a larger study at the LUMC from 2011, presenting a maximum risk of 87%
at the age of 70 in SDHD pathogenic variant carriers.[17] This could argue for reducing the screening frequency or even discontinuing the
screening in older patients. In addition, a negative correlation between age and the
development of new symptoms has already been demonstrated.[18] Therefore, in older patients, the benefits of early detection could no longer outweigh
the burdens of screening or treatment. Future studies determining the risk of developing
paraganglioma specifically in elderly patients are needed to assess these assumptions.
The major limitation of this study is the small sample size. Only patients who were
screened and treated in the LUMC were included in this study. By including more medical
centers, a larger study population could be provided. This will increase the power
of the study and strengthen our conclusions.
Conclusion
Given the fact that paraganglioma syndromes have an age-dependent, incomplete penetrance
and that the tumors have slow growth rates, we propose that frequent radiological
follow-up of the head and neck region is an unnecessary burden to the healthy carriers
of an SDHx pathogenic variant. MRI screening every 5 years seems to be a safe interval
for these patients.
