phenotype associations
Havekes, B.
Citation
Havekes, B. (2008, December 11). Hereditary paragangliomas : clinical characteristics and genotype-phenotype associations. Retrieved from https://hdl.handle.net/1887/13397
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Chapter 4
High Prevalence of Pheochromocytomas and Extra-adrenal Paragangliomas
Detected by Screening for Catecholamine Excess
in Patients with SDHD-Associated Head-and-Neck Paragangliomas
B. Havekes1, A.A. van der Klaauw1, M.M. Weiss2, J.C. Jansen3, A.G.L. van der Mey3, A.H.J.T. Vriends2, B.A. Bonsing4,J.A. Romijn1, E.P.M. Corssmit1
Leiden University Medical Center, 1Departments of Endocrinology and Metabolic Diseases, 2Center of Human and Clinical Genetics,
3Otorhinolaryngology, and 4Surgery, Leiden, the Netherlands
Submitted for publication
Abstract
Context: Patients with SDHD-associated head-and-neck paragangliomas (HNP) are at risk for developing pheochromocytomas. In recent years biochemical screening at regular intervals for catecholamine excess has been advised in these patients.
Objective: The aim of this study was to assess the clinical, biochemical and radiological outcomes of screening of SDHD-positive patients with HNP for catecholamine excess in a large single-center study and to address the necessity for repetitive follow up.
Design: Prospective study in new and previously known patients.
Patients and Methods: We evaluated 93 consecutive patients with SDHD-related (p.Asp92Tyr, p.Leu139Pro) HNP. Initial screening consisted of measurement of 24-hour urinary excretion of catecholamines in duplicate, which was repeated with intervals of 2 years if initial biochemical screening was negative. In patients with excessive catecholamine excretion imaging studies with MIBG scintigraphy and whole-body MRI and/or CT were performed. Pheochromocytomas and extra-adrenal paragangliomas were treated surgically after appropriate - and ß-blockade.
Results: Median follow up was 4.5 years (range 0.5 - 19.5 years). In 30 of the 93 patients, additional imaging for pheochromocytomas/extra-adrenal paragangliomas was performed. Twenty-nine of these patients had increased urinary catecholamine excretion at some point during follow-up. In 12 patients intra-adrenal pheochromocytomas were found. In 8 patients extra-adrenal paragangliomas located in abdomen, mediastinum or pelvis were discovered. These pheochromocytomas and extra-adrenal paragangliomas were detected during initial screening in 60% of cases, whereas 40% were detected only after repeated biochemical screening. Inadvertently, radiological imaging was performed in one patient without catecholamine excess, who appeared to have a biochemically silent pheochromocytoma.
Conclusions: Repetitive screening at regular intervals is necessary in patients with SDHD (p.Asp92Tyr, p.Leu139Pro) associated HNP, because they have a high prevalence and incidence of pheochromocytomas/extra-adrenal paragangliomas.
Introduction
Paragangliomas are frequently multifocal tumors arising from the neural crest cells associated with the autonomic nervous system. Traditionally, they are divided in head- and-neck paragangliomas (HNP) and paragangliomas located in the thorax and abdomen. Some paragangliomas produce excessive amounts of catecholamines, especially if they are located in the adrenals (pheochromocytoma). Familial paraganglioma syndromes are associated with germ line mutations in the genes encoding subunits of mitochondrial complex II succinate dehydrogenase (SDH): SDHD, SDHC and SDHB (1;1-6). These SDH-genes can behave as tumor suppressor genes and distinct genotype-phenotype relations have been described (1;5;7-9). Among these 3 genes, mutations in SDHD are the most frequent cause of familial HNP in the Netherlands (1;9-11). Although malignant disease is most frequently associated with an SDHB mutation (7;9), we recently described patients with malignant disease associated with the SDHD-c.274G>T (p.Asp92Tyr) mutation (12). Although several studies have investigated genotype-phenotype correlations in SDHD mutation carriers, these were most often multi-center referral based patients with diverse underlying SDHD mutations.
In 2005 we reported that the prevalence of catecholamine excess in our SDHD- linked HNP patients was much higher than previously appreciated (11). At the time of that study, 15 of 40 consecutive patients (37.5%) had elevated urinary catecholamine excretion and a pheochromocytoma / paraganglioma was ultimately identified in 8 of these 15 patients (20%). In patients with SDHD-linked HNP without catecholamine excess we repeat biochemical testing at intervals of 2 years. In recent years we followed 93 consecutive HNP patients associated with a SDHD mutation (p.Asp92Tyr, p.Leu139Pro). This is one of the largest, single-center cohorts with SDHD-linked HNP.
The aim of this study was to assess the clinical, biochemical and radiological outcomes of screening of SDHD-positive patients with HNP for catecholamine excess in a large single-center study. Furthermore, we address the need for repetitive follow up in these patients.
Patients and methods
Consecutive patients were recruited from the outpatient clinic of the department of Endocrinology in the Leiden University Medical Center, which is a tertiary referral center for HNP.
Associations between glomus tumors, catecholamines and pheochromocytoma had been known for several years (13-15). Therefore, since 1988 patients with HNP have been referred to our outpatient clinic, mostly by the Otorhinolaryngology department to exclude catecholamine secretion by HNP, especially when resection of the HNP was planned. Since the discovery that mutations in the SDHD gene are a cause of HNP in 2000, systematic screening for SDHD mutations was implemented in our
institution in those HNP patients, who agreed upon genetic testing. We also checked the mutation status of the patients who had been previously seen at the endocrinology department and we included those patients who had a SDHD mutation or who had a direct family member in whom a SDHD mutation was ascertained. In those patients, 24- hour urine samples were obtained in twofold and, if positive for catecholamine excess, imaging studies using MIBG, CT and/or MRI, focussed at the adrenals, were performed.
The initial diagnostic protocol in those patients in the period before 2002 was identical with that of the period starting in 2002, with the exception of protocolized follow up each 2 years.
Since 2002, all HNP patients in our center were routinely referred to the department of Endocrinology and prospectively included in our study. Patients that had been referred to the department of Endocrinology since 1988 were included in this protocol and their retrospective data were analyzed for reasons of careful description of the available data. Patients were being followed-up according to a standardized protocol. They were seen at least every two years with repetitive head-and-neck MRI.
Urine was collected over 24 hours in duplicate under strict dietary regulations and after withdrawal of medication for several weeks or changing antihypertensive medication to doxazosine. In case of excessive catecholamine excretion (i.e. any value above the upper reference limit), MIBG scanning and additional whole-body MRI and/or CT imaging were performed to identify the source of catecholamine overproduction.
In 93 of 154 consecutive patients with HNP, a SDHD mutation (p.Asp92Tyr, p.Leu139Pro) was ascertained in the patient or documented to be present in a direct family member. Of these 93 patients, 29 had increased urinary catecholamine excretion at some point during follow-up and underwent further diagnostic imaging. Although one patient revealed no catecholamine excess, imaging studies were performed and a pheochromocytoma was subsequently diagnosed. Therefore, this patient was included in our study. Four additional SDHD patients with catecholamine excess were excluded from this study, because their increased catecholamine levels were found to be a direct result of continued use of tricyclic antidepressants, -blockers and/or cannabis (16-18) prior to urine collection (with normalization after cessation of medication and/or drugs). The clinical presentations, the biochemical phenotypes and outcome of diagnostic imaging of these 30 SDHD (p.Asp92Tyr, p.Leu139Pro) patients are described in this report.
Table1:Patientcharacteristics
Legend: § = Age at first diagnosis of catecholamine excess, M = male, F = female, SDHD = succinate
dehydrogenase type D, HNP = headandneck paraganglioma, HT = hypertension, ¥ = year of
pheochromocytomaorparagangliomadiagnosis,=previouslypublishedbyHavekesetal.(ref.12),# =
second episode of catecholamine excess was due to glomus tumor, $ = imaging for pheochromocytoma
performedwithouthavingcatecholamineexcessatthattime.
No. Sex,age
(yr)§ SDHD HNP HT
Start
screening
(yr)
Diagnosis
(yr)¥ Comorbidity
1 M,64 c.416T>C + + 1997 2004 sleepapnea,kneeoperation
2 M,35 c.274G>T + 2001 2001
3 F,40 c.274G>T + + 1998 2005 asthma
4 M,61 c.274G>T + + 2006 2006 macroprolactinoma,sleep
apnea
5 M,60 c.416T>C + + 2002 2006 gastricmyoleioblastoma,
migraine
6 F,62 c.274G>T + + 1988 2002
7 M,50 c.274G>T + + 2007 2007 pneumonia
8 M,24 c.274G>T + + 1988 1988
M,39 c.274G>T + 1988 1994#
9 F,48 c.274G>T + + 1988 1988$ diabetestype2
10 M,30 c.274G>T + + 1990 1990
11 M,33 c.274G>T + + 2004 2005 depression,anxietydisorder
M,35 c.274G>T + 2004 2006#
12 F,43 c.274G>T + 2002 2003
13 M,32 c.416T>C + 2007 2007 anxietydisorder
14 M,34 c.274G>T + + 2003 2004
15 M,40 c.274G>T + 2007 2007 eyeoperation
16 M,61 c.274G>T + 2002 2004
17 M,64 c.274G>T + + 1998 2006
18 F,42 c.274G>T + 2005 2006 Graves’disease
19 M,43 c.274G>T + 2003 2006 hypercortisoluria
20 F,67 c.274G>T + + 2005 2005 meningioma,uterusmyoma
21 M,40 c.274G>T + + 2003 hypercholesterolemia
22 M,45 c.274G>T + + 2004
23 M,25 c.274G>T + + 1989
24 F,35 c.274G>T + 2002
25 F,49 c.274G>T + 2000
26 F,64 c.274G>T + + 2003 thromboembolism
27 M,34 c.274G>T + 2005
28 M,47 c.274G>T + 2005 Graves’disease
29 F,52 c.274G>T + + 2006
30 M,62 c.274G>T + + 2007 nephrolithiasis,neckhernia,
bladderpolyps
Laboratory tests
Epinephrine, norepinephrine and dopamine excretion in 24 h urine collections were quantified by reversed high pressure liquid chromatography (HPLC) by an electrochemical detector. Inter- and intra-assay coefficients of variations (CV’s) for epinephrine were 4.3-9.0% ranging from high to low levels. For norepinephrine these data are 2.7-3.6% and for dopamine 3.1-4.8%. Vanillylic mandelic acid (VMA) in urine was measured using HPLC with fluorometric detection with inter- and intra-assay CV’s of 2.4- 9.1%. Since 2005 samples were tested for metanephrine, normetanephrine and 3-methoxytyramine in the University Medical Center Groningen as well (19). Reference ranges were: norepinephrine 0.06-0.47 μmol/24h, epinephrine <0.16 μmol/24h, dopamine 0.46-3.40 μmol/24h, VMA <30 μmol/24h, metanephrine 33-90 μmol per mol creatinine, normetanephrine 64-260 μmol per mol creatinine and 3-methoxytyramine 45-197 μmol per mol creatinine. Prior to germ line mutation testing informed consent was obtained from each patient. SDHD mutation analysis was performed by restriction digestion as described by Taschner et al.(10).
Results
HNP were present in all patients, because the presence of HNP was an inclusion criterion. All except 4 patients (patients 12, 19, 22, and 27) had a positive family history for HNP. The median duration of follow up was 4.5 year (range 0.5 – 19.5 years). Mean age at presentation for first screening was 46.2 ± 12.9 years. Imaging studies for pheochromocytomas and extra-adrenal paragangliomas were performed in 30 of the 93 SDHD mutation carriers. The data of these patients are detailed in Table 1 and 2.
Genetics
Most patients in the Leiden cohort have the SDHD-c.274G>T (p.Asp92Tyr) mutation, both in the included group and those without catecholamine excess that were excluded from this study. Twenty-seven of the 30 SDHD positive patients included in this study had the SDHD-c.274G>T (p.Asp92Tyr) mutation. Patients 1, 5 and 13 had a SDHD- c.416T>C (p.Leu139Pro) mutation.
Catecholamine excess and cause
Details are shown in Table 2-A and 2-B. In 29 patients there was excessive urinary excretion of catecholamines. In one female patient (number 9) additional radiological studies were ordered by her attending physician, though she did not reveal any catecholamine excess at repeated testing. Nonetheless, MRI imaging resulted in the detection of an (unexpected) pheochromocytoma, which was confirmed by pathological examination after surgical removal. In total, intra-adrenal paragangliomas (pheochromocytomas) were identified in 12 of the 30 patients, of which 11 were treated surgically after appropriate -(and -) blockade with subsequent histological confirmation (in 1 patient surgery is pending). Patient 7 is diagnosed with a (small)
pheochromocytoma and is awaiting further treatment. In 6 patients with catecholamine excess extra-adrenal paragangliomas in abdomen or pelvis were found and surgically treated after appropriate blockade. Two patients (patients 19 and 20) were diagnosed with mediastinal paragangliomas, which was operated in patient 20. In patient 29, the resected extra-adrenal lesion suspect for paraganglioma was diagnosed as schwannoma after histological investigation. In patient 30 the definite diagnosis is currently uncertain, but a subclinical pheochromocytoma is suspected. Ultimately, in 11 cases of excessive catecholamine excretion no pheochromocytoma or extra-adrenal paraganglioma could be identified. Per exclusionem their catecholamine excess was attributed to the presence of glomus tumors (patients 8, 11, 21, 22, 23, 24, 25, 26, 27, 28, and 29). Uptake of 123MIBG in the glomus tumor was found in 7 of these patients.
Patients 11 and 27 were operated for these glomus tumors, which resulted in normalization of excessive catecholamine excretion. Patients 8 and 11 had been previously treated for a pheochromocytoma and were later diagnosed with a catecholamine-producing glomus tumor as well.
Signs and symptoms
Palpitations were mentioned in 10 of the 30 patients. Seven of these patients were later diagnosed with either a pheochromocytoma or an extra-adrenal paraganglioma.
Hypertension was found in 19 of the 30 patients included in this study (63%). Eight patients reported excessive transpiration of which 5 had a pheochromocytoma or extra- adrenal paraganglioma. Headaches were only mentioned by 2 patients, both with a pheochromocytoma. Furthermore, HNP patients frequently reported hearing loss (34%), tinnitus (28%) and dysphonia (13%). Anxiety disorders were reported in 4 patients, obstructive sleep apnea in two patients, Graves’ disease in two patients and one patient (number 4) was treated for a macro-prolactinoma.
Biochemical profile of urinary catecholamines
The predominant biochemical profile of urinary catecholamines in our patients is shown in Table 3. Norepinephrine, VMA and, if tested, normetanephrine were most frequently elevated, whereas elevation of epinephrine was only detected in 2 patients of which one had a malignant bladder paraganglioma (number 18). However, metanephrines were negative in these 2 patients, indicating epinephrine could have been falsely elevated. As expected, the O-methylated metabolite normetanephrine was elevated in most patients with elevated norepinephrine. One patient (patient 25) had elevated excretion of normetanephrine, whereas the excretion of norepinephrine was normal. Patients 29 and 30 had elevated excretion of metanephrine with normal values for epinephrine. Excretion of 3-methoxytyramine was increased in 11 of the 30 patients with excessive catecholamine excretion with either pheochromocytomas, extra-adrenal paragangliomas, malignant disease or patients with producing glomus tumors.
Table 2-A: Cause of catecholamine excess, anatomical imaging and histopathology
No. Focus MRI CT-scan Histopathology Meta
1 Adrenal Pheo L Np Pheo (1.8 cm)
2 Adrenal Pheo R Np Pheo (2.5x3.0 cm)
3 Adrenal Pheo L Np Pheo (2.2 cm)
4 Adrenal Pheo R Np Pheo (1.3 cm)
5 Adrenal Pheo L Np Pheo (1.9 cm)
6 Adrenal Np Mass adrenal L Pheo (2 cm) +
7 Adrenal Small nodule adrenal L Np Pending
8 Adrenal Pheo L Mass adrenal L Pheo (4.5 x 2.7 cm)
Glomus # Neg Neg
9 Adrenal $ Pheo L $ Mass adrenal L $ Pheo (1.5 cm)
10 Adrenal Pheo R Np Pheo (4.5 cm)
11 Adrenal Pheo L Np Pheo (1.6 cm)
Glomus # * Neg Np PGL
12 Adrenal Irregular enlarged adrenal L,
Pheo L Np
Pheo (1 cm) and cortical adenoma (1.5 cm)
13 Extra-adrenal PGL medial to adrenal R Np PGL 14 Extra-adrenal Extra-adrenal PGL pancreas
/ adrenal L / aorta Np PGL
15 Extra-adrenal Extra-adrenal PGL, pars
horizontale duodenum Np PGL
16 Extra-adrenal Extra-adrenal PGL
paraaortal L No lesions PGL
17 Extra-adrenal Mass right of inferior VC Np PGL (3.3 cm) +
18 Bladder Np (at first presentation) Tumor bladder Malignant PGL (8
cm) +
19 Mediastinal Neg Mediastinum Watch-and-wait
20 Mediastinal Np Pulmonary mass PGL (Thymus +
lymph nodes) +
21 Glomus Neg Np
22 Glomus Neg Np
23 Glomus Neg Np
24 Glomus Neg Np
25 Glomus Neg Np
26 Glomus Neg Np
27 Glomus * Neg Np PGL
28 Glomus Neg Neg
29
Glomus; no extra-adrenal PGL
Paravertebral mass
bifurcation Inf. VC, Dd/ PGL Np Schwannoma
30 Uncertain No pheo. LN (1.5 cm)
pulmonary hilus R. Np Follow-up
Legend: L = Left, R = Right, Pheo = Pheochromocytoma, PGL = Paraganglioma, # = secondary catecholamine production in glomus, $ = imaging performed although no catecholamine excess present,
* = normalization catecholamine excess after removal glomus tumor, Np = not performed, Neg = negative, LN = lymph node, = previously published by Havekes et al. (ref. 12).
Table 2-B: Cause of catecholamine excess, functional imaging
No. Focus MIBG scintigraphy Octreotide scintigraphy
1 Adrenal Uptake adrenal L Uptake glomus
2 Adrenal Increased uptake glomus R and adrenal R Neg
3 Adrenal Neg Np
4 Adrenal Increased uptake adrenal R Np
5 Adrenal Uptake adrenal L Np
6 Adrenal Uptake adrenal L Uptake glomus and cranially of bladder
7 Adrenal Uptake glomus and adrenal region L Np
8 Adrenal Uptake adrenal L Np
Glomus # Neg Np
9 Adrenal $ Uptake left adrenal and glomus $ Uptake glomus $
10 Adrenal Uptake right adrenal Np
11 Adrenal Uptake left adrenal Np
Glomus # * Np Np
12 Adrenal Uptake right adrenal Np
13 Extra-adrenal Uptake adrenal R Np 14 Extra-adrenal Uptake adrenal region L Np 15 Extra-adrenal Uptake in abdominal center Np
16 Extra-adrenal Uptake paraaortal L Uptake glomus 17 Extra-adrenal Uptake right adrenal region and head-and-
neck Np
18 Bladder Neg Uptake glomus
19 Mediastinal Neg Uptake glomus
20 Mediastinal Uptake glomus Uptake orbitameningioma
21 Glomus Uptake glomus Np
22 Glomus Neg Np
23 Glomus Neg Uptake glomus
24 Glomus Uptake glomus Uptake glomus
25 Glomus Uptake glomus and minor increase in
uptake adrenal R Np
26 Glomus Uptake glomus Np
27 Glomus * Uptake glomus and adrenal L Np
28 Glomus Uptake glomus, subtle uptake adrenal L Uptake glomus 29
Glomus; no extra-adrenal PGL
Uptake glomus, no uptake abdomen Uptake glomus 30 Uncertain Slightly increased uptake adrenal L Np
Legend: L = Left, R = Right, Pheo = Pheochromocytoma, PGL = Paraganglioma, # = secondary catecholamine production in glomus, $ = imaging performed although no catecholamine excess present,
* = normalization catecholamine excess after removal glomus tumor, Np = not performed, Neg = negative, LN = lymph node, = previously published by Havekes et al. (ref. 12).
Imaging
No patients with negative imaging on whole-body MRI and/or CT had been eventually diagnosed with a pheochromocytoma or an extra-adrenal paraganglioma. MRI revealed one false-positive result in our series (patient 29), in whom the extra-adrenal lesion proved to be a schwannoma instead of a paraganglioma. In patients with pheochromocytomas and extra-adrenal paragangliomas combined, sensitivity and specificity of [123I]-MIBG were 80% and 75%, respectively. Positive and negative predictive values for pheochromocytoma and extra-adrenal lesions combined were 84% and 69%, respectively. MIBG revealed false-negative results in 4 patients, of which 3 cases had malignant and/or mediastinal disease. Furthermore, subtle or more intense MIBG uptake in HNP was frequently found (12 patients), either combined with abdominal uptake or not. In 12 patients an octreotide scintigraphy had been performed, in 11 out of these 12 the HNP showed increased uptake.
Discussion
This large, single-center study evaluated the outcomes of repetitive testing for catecholamine excess in 93 consecutive, SDHD-associated (p.Asp92Tyr, p.Leu139Pro) HNP patients using a standardized protocol. This study confirms the high prevalence of both pheochromocytomas and extra-adrenal paragangliomas in SDHD (p.Asp92Tyr, p.Leu139Pro) mutation carriers (11). In 31% of the patients excessive urinary catecholamine excretion was documented. Ultimately, in 22% of all patients pheochromocytomas or extra-adrenal paragangliomas were identified in addition to the HNP. Forty percent of these pheochromocytomas or extra-adrenal paragangliomas were identified only after repeated screening for excessive catecholamine excretion after normal initial biochemical screening. These results document the relevance of repetitive testing for catecholamine excess in these patients.
In accordance with our previous publication in a smaller subset of patients (11), there was no clear correlation between clinical symptoms and the final diagnosis of either pheochromocytoma or extra-adrenal paraganglioma. Remarkably, in 11 cases (12%) the glomus tumor itself was identified as the presumptive cause of catecholamine excess after extensive investigations to exclude other paraganglioma locations. In contrast to adrenal and extra-adrenal sympathetic paragangliomas, paragangliomas arising from parasympathetic tissue (mainly in the head-and-neck) rarely produce significant amounts of catecholamines (20-22). Unfortunately, because not all patients suspected of having catecholamine-producing HNP were accessible for surgical removal, false-positive results cannot be ruled out. However, in the 2 patients that could be operated, catecholamine levels returned to normal after surgery. In addition, in 7 of these 11 cases MIBG uptake was present in HNP. Our results suggest that catecholamine excess in SDHD mutation carriers might result from HNP more frequently than previously reported in HNP patients in general.
Table 3: Biochemical phenotype
Legend: NE = norepinephrine, E = epinephrine, DA = dopamine, VMA = Vanillylic Mandelic Acid, NMN = normetanephrine, MN = metanephrine, 3-MT = 3-methoxytyramine, PGL = paraganglioma, HNP = head- and-neck pgl, & = one out of two samples elevated, o = not performed, $ = imaging performed without the presence of catecholamine excess, º = representing persistent malignant disease after 2005, previously described in ref 12, # = Patients 8 and 11 were later diagnosed with catecholamine-producing glomus as well, * = normalization catecholamine levels after removal glomus tumor. ^ = No definitive diagnosis, follow up.
Cause Patient NE E DA VMA NMN MN 3MT
Pheo
Extra- adren.
PGL
HNP
1 + - + + o o o +
2 + - - + o o o + 3 + - - + o o o +
4 - - - + +
5 - - - + - - + + 6 + - - + +º -º +º + 7 + - - - + + 8 + - - + o o o + +#
9 $ - - - - o o o +
10 + - + + o o o +
11 + - - + o o o + +# * 12 + - + - o o o + 13 + - - + + - - + 14 + - - + o o o +
15 + - + + + - + +
16 + - - + o o o + 17 + - - + o o o +
18 + + + + + - + +
19 - - - + - - - + 20 + - - + + - - + 21 -/+& - - - o o o + 22 - - - + + 23 + - - - + - - +
24 + - + + + - + +
25 - - - + + - + + 26 - - + - o o o + 27 + - - + o o o +*
28 + + - + + - + +
29 + - + + + + + +
30 + - - + + + -
Follow
up ^
SDHD mutation carriers are at risk for developing catecholamine excess due to pheochromocytomas and/or extra-adrenal paragangliomas. Van Houtum et al. reported increased prevalence of pheochromocytoma (20%) in SDHD-linked familial HNP patients in our center (11). Therefore, in recent years patients have been subjected to repeated urinary catecholamine screening with subsequent further imaging if levels of catecholamines were elevated. In this study we included those patients with catecholamine excess and a SDHD mutation. Elevations of norepinephrine, normetanephrine and VMA excretion were most frequently found. Recently, evaluation of the biochemical phenotype of SDHB associated malignant paragangliomas revealed hypersecretion of norepinephrine, normetanephrine and dopamine (7). The reason for a different prevalence of dopamine excess in our study concerning SDHD associated patients might not only be related to fewer cases of malignant disease, but also to the insensitive and nonspecific nature of measuring urinary dopamine levels (23).
Moreover, in this respect it is relevant to note that tumors can change their hormonal profile during the course of disease and that the hormonal production and secretion can be different in mature or less differentiated tissue (5). The urinary excretion of the O- methylated metabolite of dopamine, 3-methoxytyramine, was increased in 11 of the 30 patients, but could be present in a variety of patients with or without pheochromocytomas, extra-adrenal paragangliomas, malignant disease and producing glomus tumors. Therefore, the clinical relevance of the measurement of 3- methoxytyramine remains to be further evaluated (23). Interestingly, the elevated levels of 3-methoxytyramine in our study could be a reflection of the fact that we used the presence of HNP as a inclusion criterion, because carotid bodies are known to have dopamine working as a neurotransmitter (22;24;25).
Furthermore, our cases have the p.Asp92Tyr or p.Leu139Pro mutations. These are frequently occurring founder mutations in the Netherlands, whereas other reports described patients with other mutations in the SDHD gene. So far, it has not been reported that there are different clinical phenotypes associated with the different mutations within the SDHD gene. However, we can not exclude the possibility that the reported phenotype may be related to these specific Dutch founder mutations and/or to unknown gene-environment interactions in the Netherlands.
MIBG scanning is reported to have a sensitivity of 83-100% in the detection of benign pheochromocytomas in case finding studies, but this sensitivity is considerably reduced in extra-adrenal or malignant paragangliomas (26-29). In our study, use of MIBG for detection of intra- and extra-adrenal paragangliomas combined, revealed a sensitivity and specificity of only 80% and 75%, respectively. Reduced sensitivity of MIBG in familial paraganglioma syndromes, malignant disease and extra-adrenal paragangliomas has been described (26). Our results support these findings, with an increase in sensitivity to 92% when investigating (intra-adrenal) pheochromocytomas separately. Furthermore, because our patients were detected using a routine screening protocol, earlier detection of catecholamine excess might have been of influence to
sensitivity. Even so, we found the combination of MRI and MIBG to be sufficient in most cases. The superiority of [18F]-fluorodeoxyglucose positron emission tomography ([18F]- FDG-PET) in the evaluation of metastatic paraganglioma was recently reported by Timmers et al.(30). However, because in our patients paragangliomas were mostly benign, one might argue that in our cohort the use of [18F]-fluorodopamine-PET would be more appropriate after negative MIBG imaging (31-34).
In our study, the more sensitive and specific metanephrine and normetanephrine measurements were introduced for screening of urine collections only in the last few years. The measurement of these metabolites in both plasma and urine would be more sensitive for diagnosis of pheochromocytoma than measurements of the other catecholamines (21;35-37). Although in our study most patients had concordant results between the excretion of catecholamines, VMA and their O-methylated metabolites, the relatively small number of (nor)metanephrine assays performed in our study limits the reliability of a comparison between those measurements. However, patients 25, 29 and 30 had elevated levels of the O-methylated compounds, whereas their respective parent catecholamines were still within reference ranges, thus exemplifying their superior sensitivity. On the other hand, patient 7 had elevations in norepinephrine but not in its metabolite normetanephrine. Although the later introduction of (nor)metanephrine analyses in our study may have theoretically resulted in a underestimation of catecholamine excess, and thus of the presence of paragangliomas/pheochromocytomas in the first period of the present study, this does not invalidate our conclusions with respect to the relevance of repetitive testing for catecholamine excess in these patients.
More challenging is the concept of the ‘non-secreting paragangliomas’, which might not always be detected using our current standard approach starting with urine analysis. Inadvertently, patient 9 provided the proof for this hypothesis, by the finding of a pheochromocytoma, even though no urinary catecholamine excess had been found.
On the other hand, except for the possibility of malignant dedifferentiation, no one knows the clinical relevance of these ‘non-secreting paragangliomas’. Therefore, patients with SDHB mutations with a much higher incidence of malignant disease, are already subjected to repetitive MRI imaging independent of the results of urine analysis (7).
The results of the present study emphasize the need to screen SDHD mutation carriers for catecholamine excess on a regular basis. If this protocolized approach would not have been instituted, 8 out of the 20 patients, who were diagnosed with pheochromocytomas or extra-adrenal paragangliomas in our report, would have been discharged from follow up, or not have been subjected to screening at all. Furthermore, the possibility of undetected ‘non-secreting’ paragangliomas might lead to future guidelines with imaging studies as primary investigation.
References
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