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
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
Downloaded from: https://hdl.handle.net/1887/13397
Note: To cite this publication please use the final published version (if applicable).
Chapter 8
General Discussion and Summary
In this thesis we have evaluated patients with paragangliomas associated with mutations in the succinate dehydrogenase genes, in the Leiden University Medical Center. In the general discussion we will address the following issues:
8.1 Mutations in succinate dehydrogenase genes and paragangliomas
8.2 Clinical aspects of familial paraganglioma syndromes 8.2.1 Genotype-phenotype associations
8.2.2 Quality of life and subjective sleep characteristics in head-and-neck paraganglioma patients
8.2.3 The necessity to screen patients with head-and-neck paragangliomas for catecholamine excess
8.2.4 Malignant paragangliomas
8.3 Developments in diagnostic strategies 8.3.1 Biochemical tests
8.3.2 Imaging
8.4 Treatment strategies of paragangliomas 8.4.1 Head-and-neck paragangliomas
8.4.2 Pheochromocytomas and extra-adrenal paragangliomas
8.5 Summary
8.1 Mutations in succinate dehydrogenase genes and paragangliomas
Different germline mutations in the genes encoding the four subunits of the mitochondrial complex II associated succinate dehydrogenase (SDH) were recently identified as hereditary causes for familial paraganglioma and pheochromocytoma syndromes.
Hereditary patterns in the occurrence of head-and-neck paragangliomas had since long been suspected, but it was van der Mey et al. who for the first time described a gender specific transmission of the disease, called maternal imprinting (1). This so- called maternal imprinting means that only patients who inherited the gene mutation from the father will develop the disease. The evaluation of large Dutch families using linkage analysis led to the discovery of 2 loci: PGL1 on chromosome 11q23 and PGL2 on chromosome 11q13 (2-4). Strong evidence for a common founder in head-and-neck paragangliomas in the Netherlands has been demonstrated (5).
These SDH mutations are believed to cause mitochondrial dysfunction and subsequent accumulation of succinate and other metabolites. Mitochondria are cellular organelles that generate ATP as an intermediate source for energy. The inner mitochondrial membrane bound electron transport (or respiratory) chain and the mitochondrial matrix associated Krebs tri-carboxylic-acid (TCA) cycle are closely related and are necessary for maximal efficiency in ATP (energy) production under aerobic conditions (6). Five mitochondrial complexes participate in the electron transport chain of which complex II is made up of the four components of SDH (subunits A, B, C, and D). Mutations in these SDH genes result in loss of functional or structural integrity of this electron-transferring complex II. In addition to their role in energy metabolism, mitochondria are thought to play a direct role in intracellular oxygen sensing and the regulation of apoptosis (6-8). Mitochondria may serve as an intracellular oxygen sensor due to their close association with cellular respiration (7).
Mutations in these SDH genes may lead to partial assembly or disassembly of complex II and result in alteration in membrane composition with a subsequent change in resistance to apoptosis (6). Furthermore, reduced SDH activity leads to increased levels of reactive oxygen species (ROS), which have been reported to activate the hypoxia-inducible factors (HIF), which could further lead to reduced apoptosis and increased cell proliferation via several mechanisms (9-11). SDH-dysfunction may lead to activation of hypoxia related pathways such as the stabilization of HIF and the expression of Vascular Endothelial Growth Factor (VEGF) in SDHD-associated paraganglioma syndromes (12;13).
Remarkably, the von Hippel Lindau (VHL) syndrome (which is another hereditary pheochromocytoma syndrome) is also associated with HIF- stabilization, because the mutated VHL gene product leads to decreased degradation of HIF-. The normal VHL protein binds to the HIF- in an oxygen dependent manner and targets it for degradation. This binding is regulated by the hydroxylation of two specific prolyl residues and is catalyzed by the HIF--prolyl hydroxylases (PHD). Interestingly, these enzymes are inhibited by the accumulation of succinate associated with a down regulation of SDH activity, like in paragangliomas (Figure 1). Apparently, there is a possible link in pathogenesis between SDH mutation associated paragangliomas and pheochromocytomas related to the VHL syndrome (11).
In general, SDH mutations result in reduced apoptosis, increased ROS formation and activation of a hypoxic proliferative response under normoxic circumstances called pseudo-hypoxia. We believe that this state of chronic pseudo-hypoxia in cells with SDH dysfunction contributes to tumor development in the oxygen sensitive neural crest cell derived tissues. A very important question remains to be answered: why do these germline mutations, present throughout the whole body, selectively lead to paraganglioma syndromes? We believe that certain genes must have a particular type of expression in those tissues derived from neural crest cells that create the specific environment required for paraganglioma development.
Figure 1: Model for a possible link between succinate dehydrogenase (SDH) and the von Hippel Lindau protein (pVHL)
PHD
succinate
Target genes associated with angiogenesis, metastasis, metabolism
pVHL
Adapted from Selak et al.
Cancer cell, 2005;7:77-85
fumarate SDH
HIF1- HIF1-
HIF1- Degradation Mutant pVHL
VHL syndrome Mitochondria
Cytosol
SDHD/SDHB associated PGL
Legend: Reduced SDH activity in SDH mutation carriers results in accumulation of succinate in the mitochondria and the Cytosol. This inhibits prolyl hydroxylase which is necessary to ‘prime’ HIF1- for degradation by VHL protein (pVHL). In VHL syndrome, the mutated protein is not able to bind properly and reduces the degradation of HIF1-. Thus, both mutations in SDH and VHL may lead to stabilization of HIF1- with a proliferative response as a consequence.
An interesting point is that the carotid body is the most distinct paraganglia in the head- and-neck and normally functions as a chemo-sensor for oxygen. Because all other paraganglioma are derived from the same neural crest cells during the embryologic stages of development, the idea of a possible innate ‘oxygen sensitivity’ in these neural crest cell derived tissues is appealing. Paraganglia may have adapted a very sensitive mitochondrial oxygen sensing system as compared to other cells in the body. In line with this idea are studies that have described paragangliomas to be more prevalent amongst high-altitude dwellers, thus suggesting a role for hypoxia to stimulate tumor formation (14;15). We strongly believe that clinical studies of genotype-phenotype (Chapters 3, 4, 5 and 6) associations can be contributory to the development of new ideas regarding the pathogenesis of paraganglioma syndromes.
8.2 Clinical aspects of familial paraganglioma syndromes 8.2.1 Genotype-phenotype associations
The discovery of the underlying SDH genes has led to a revolution in the way we regard paraganglioma syndromes. Each SDH mutation (SDHB, SDHC, and SDHD) is associated with specific genotype-phenotype associations. Carriers of SDHD mutations most often present with head-and-neck paragangliomas and multifocal disease (16), but they have a small chance of developing malignant disease, reported in this thesis (chapter 5). The SDHB mutation predisposes patients to extra-adrenal localizations and metastatic disease (in up to 30-50% of the patients) (16-19). Most of these studies, however, included patients with different subtypes of mutations within the separate SDH subtypes. In Leiden, the so-called ‘founder effect’ resulted in genetic clustering with an extremely high prevalence of one single SDHD mutation, the SDHD-c.274G>T (p.Asp92Tyr) mutation. Therefore, we were able to study a very large cohort of head- and-neck paraganglioma patients with the identical mutation, thus providing an excellent opportunity to display genotype-phenotype associations in SDHD related paraganglioma syndromes.
8.2.2 QoL and subjective sleep characteristics in head-and-neck paraganglioma patients
Head-and-neck paraganglia have been subjected to research since the first discovery of the carotid body by Albrecht von Haller (1708-1777) in 1742 in Leiden. Several theses have since then been written about head-and-neck paragangliomas at the Leiden University (see end of this thesis for an overview). One of the essential problems in the treatment of head-and-neck paragangliomas is the close proximity of tumors to nerves and vasculature, which results in a thin line between tumor related complaints and the damage that will be inflicted by the surgery itself. Therefore, the focus of surgery should not be tumor removal per se, but must be intended to prevent morbidity, indicated by Jansen in his thesis (20). We favor a watch-and-wait policy in many cases, because of the usually indolent growth pattern and benign behavior of head-and-neck paragangliomas. In this respect it is essential to know which determinants of morbidity have the greatest impact on paraganglioma patients. Quality of Life (QoL) assessment is the method to investigate effects of disease on physical, psychological and social functioning of patients (21). Although there is consensus that a conservative therapeutic strategy has become an important alternative to surgery and the level of expected morbidity is a key determinant, no QoL studies had been performed prior to the present thesis in head-and-neck paraganglioma patients.
Therefore, we evaluated QoL in head-and-neck paraganglioma patients using validated health related questionnaires focusing specifically on QoL (HADS, MFI-20, NHP, SF-36), comparing patient outcomes to control groups (chapter 2). We also added more specific questions focusing on disease related complaints (e.g. dysphonia,
headache, swallowing). We were therefore able to identify those complaints, which had the most effect on the outcome of QoL. The QoL scores in paraganglioma patients were significantly reduced in 12 out of 21 subscales compared to own controls and in 18 out of 21 subscales compared to age and sex adjusted values derived from previous studies.
In the MFI-20 questionnaire patients reported more general fatigue, physical fatigue, mental fatigue and a reduction in activity and motivation. The scores in the NHP showed a difference in energy, emotional reaction and social isolation. General health perception, pain and physical functioning were reported to be worse in paraganglioma patients on the SF-36 scale. Although anxiety and depression did not reveal any significant differences between patients and their own controls, an increased score on both anxiety and depression was seen as compared to the extended control group.
Especially dysphonia was found to be an independent determinant in the reported QoL (chapter 2).
Furthermore, we evaluated systematically complaints in patients that were more specifically related to sleep, because these patients had an increased frequency of reported fatigue, in combination with complaints of disturbed sleep, based on our experience in clinical practice during outpatient consultation (chapter 3). We suspected that carotid body tumors, which are derived from the paraganglia physiologically involved in oxygen sensing, have an impact on sleep physiology and consequently could contribute to the observed reduced QoL. Remarkably, the presence of a carotid body tumor was an independent predictor of increased daytime somnolence compared to patients without such a tumor. Again, we found dysphonia to be a predictor of symptoms, activity, impacts and total scores, thus underscoring the significance of complaints in head-and-neck paraganglioma patients (chapter 2 and 3).
Clinical implications: The results presented in chapter 2 and in chapter 3 underline the growing realization that adequate patient care first necessitates proper investigation and classification of the complaints expressed by the patients themselves.
This is especially true if the decision to treat or to wait-and-see is dependent on the expression of these same complaints, like is the case in head-and-neck paragangliomas.
Nowadays, ‘patient satisfaction scores’ are often used by government, hospitals and media as key issues to reflect ‘quality of patient care’. Furthermore, the awareness of the relation between head-and-neck paragangliomas (especially those of the carotid body) and daytime somnolence, described in chapter 3, could have several clinical implications. Future studies using objective sleep assessments may prove that patients with carotid body tumors need to be evaluated for possible sleep disorders, especially sleep apnea syndrome. This may not only be necessary for good anesthetic care, but it could also be critical in the decision whether or not bilateral carotid bodies should be removed unilaterally or bilaterally. Further detailed polysomnographic studies with arterial blood gas analyses in both pre- and postoperative patients are necessary to further elucidate the pathophysiology.
8.2.3 The necessity to screen patients with head-and-neck paragangliomas for catecholamine excess
Although the association between head-and-neck paragangliomas and pheochromocytoma had been suspected for several years, in 2005 van Houtum et al.
published that the prevalence of catecholamine excess in our SDHD-linked head-and- neck paraganglioma patients was much higher than previously appreciated (22). At the time of that first study, 15 of 40 consecutive patients (37.5%) had elevated rates of urinary catecholamine excretion and a pheochromocytoma / paraganglioma was ultimately identified in 8 of these 15 patients (20%). Importantly, there was no direct relationship between the levels of catecholamine excess and the complaints generally attributed to catecholamine excess (e.g. palpitations, headache, and hypertension).
Therefore, in recent years the multidisciplinary approach in Leiden was extended. It was decided to evaluate all patients consulted by Otorhinolaryngology, the Department of Endocrinology and/or the Department of Clinical Genetics for catecholamine excess on a routine basis, instead of only selective screening of patients with catecholamine excess related complaints. The aim of including all consecutive head-and-neck paraganglioma patients in our Leiden cohort was to further specify the clinical and biochemical characteristics, and outcome of diagnostic imaging in our Leiden cohort. In recent years we have followed more than 150 head-and-neck paraganglioma patients in which we have detected 93 consecutive head-and-neck paraganglioma patients associated with a SDHD mutation. This is the largest, single- center cohort with SDHD-linked head-and-neck paragangliomas. We have described the results in chapter 4. 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 [123I]-MIBG scintigraphy and whole-body MRI and/or CT were performed. In 30 of the 93 patients, additional imaging studies for pheochromocytomas / extra-adrenal paragangliomas were performed. Twenty-nine of these patients had increased levels of urinary catecholamine excretion at some point during follow-up, whereas one patient revealed no catecholamine excess. Intra-adrenal pheochromocytomas were found in 12 patients. In 8 patients extra-adrenal paragangliomas located in abdomen, mediastinum or pelvis were discovered.
Importantly, the identified pheochromocytomas and extra-adrenal paragangliomas were detected during initial screening in 60% of cases, whereas 40% were detected only after repeated biochemical screening. These results 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.
Some patients appear to have ‘non-secreting’ paragangliomas. The clinical implication of this clinical entity is challenging and presently unknown.
Inadvertently, one patient in chapter 4 provided the proof for this entity, by the detection of a pheochromocytoma, even though no urinary catecholamine excess had been found. In other words, this particular pheochromocytoma would not have been discovered, if the protocol had not been violated by imaging studies in a patient with an SDHD mutation without catecholamine excess. It should be emphasized that the protocol of screening in SDHB patients is completely different. These patients require repetitive MRI imaging independent of the results of urine or plasma analysis, because these patients have a much higher incidence of malignant disease than those patients with SDHD mutations, which is the most prevalent genotype in our studies (17).
Therefore, it is possible that non-secreting paragangliomas are more readily detected in those patients.
Clinical implications: Patients with head-and-neck paragangliomas have an increased risk for development of pheochromocytomas and paragangliomas at other locations.
Undiagnosed catecholamine excess is frequently found and may have disastrous consequences, if not excluded and treated before surgery. Life long, repetitive follow up with protocolized clinical, biochemical and radiological screening is mandatory. The hereditary risk persists during the whole life. Moreover, surgical treatment of head-and- neck or other paragangliomas does not reduce the risk for new tumor development at the same or other locations. Some intra-adrenal paragangliomas are non-secreting, i.e.
they are not detected by biochemical screening. They will be missed using our follow up protocol focused on catecholamine excess. The practical clinical implications of these non-secreting intra-adrenal paragangliomas are currently uncertain. It can not be excluded that during prolonged follow up these become secreting, like is the case in clinical practice in some MEN2A patients.
8.2.4 Malignant paragangliomas
In chapter 5, we report the results of 5 patients with SDHD-related malignant disease.
Malignancy was proven by bone metastases (n=2), intrathoracic paraganglioma with lymph node metastases, locally invasive head-and-neck paraganglioma with destruction of the petrosal bone and locally invasive paraganglioma of the bladder with lymph node metastases, respectively. Four of the 5 patients developed catecholamine excess during follow up due to pheochromocytoma (n=1), extra-adrenal paraganglioma (n=2) and presumed subclinical disease (n=1). This indicates that malignant paragangliomas may occur more frequently in carriers of SDHD mutations, than hitherto recognized.
Moreover, the same SDHD mutation resulted in remarkable variations in clinical presentation of the disease. The first patient was diagnosed with head-and-neck paragangliomas in 1972 and bone metastases were not discovered until 2002. She died 2 years after malignant dedifferentiation. The second patient was first diagnosed with head-and-neck paragangliomas in 1975 and bone metastases were found only in 1993.
She is currently doing well without specific complaints, more than 33 years after the
initial diagnosis. To our knowledge she is one of the longest living patients with a malignant SDHD associated paraganglioma reported in the literature so far. Therefore, this case series indicates that patients with SDHD mutations can develop malignant forms of paraganglioma with extremely divergent clinical phenotypes. We estimate that the prevalence of malignant disease in SDHD mutation carriers is ~2.5%.
In chapter 6 we report mediastinal paragangliomas to be associated with mutations in the succinate dehydrogenase genes (either SDHB or SDHD) and aggressive behavior. All 10 primary mediastinal paraganglioma patients had germline SDHx mutations, 6 in SDHB and 4 in SDHD. Chest or back pain were the most common presenting symptoms (5 patients), and catecholamines and/or their metabolites were elevated in 7 patients (70%; 5 elevated plasma normetanephrines, 2 combined with elevated dopamine, 1 elevated VMA). In addition, 4 patients had head-and-neck paragangliomas, and 2 patients had prior surgery for pheochromocytoma or bladder paraganglioma. Metastatic disease was documented in 6 patients (60%), and a concurrent abdominal mass was found in one patient. One patient (number 8) was diagnosed with a non-secreting malignant paraganglioma. We recommend all patients found to have a mediastinal paraganglioma to be tested for SDH mutations.
Clinical implications: In rare cases SDHD associated disease can be malignant. In patients with SDHD mutations the screening of catecholamine excess is used as the first line of screening. However, the clinician should be well aware that in very rare cases SDHD related paragangliomas may be malignant. The diagnosis of malignant disease was discovered in our cases on clinical and radiological grounds, rather than on biochemical criteria. This supports our protocol of life long, repetitive follow up with protocolized clinical, biochemical and radiological screening. Importantly, in our protocolized approach we have not routinely performed imaging the thoracic cavity and we have found paragangliomas with both extremely divergent clinical behavior and/or
‘non-secreting’ characteristics. Therefore, we believe that the prevalence of mediastinal paragangliomas and ‘non-secreting’ paragangliomas might be higher in SDHD carriers than hitherto appreciated. In SDHB patients all identified tumors need to be removed irrespective of catecholamine levels, because of the high rate of malignancy.
8.3 Developments in diagnostic strategies 8.3.1 Biochemical tests
The first step in patients with suspected pheochromocytoma or sympathetic extra- adrenal paragangliomas is biochemical testing. Biochemical testing should be performed not only in symptomatic patients and patients with an adrenal incidentaloma, but also as a means of screening in subjects who have a hereditary risk for developing a pheochromocytoma or recurrent disease. In chapter 4 we reported a high prevalence of pheochromocytomas and extra-adrenal paragangliomas supporting
this statement. Traditional biochemical tests consist of measurement of 24-hour urinary and plasma catecholamines (norepinephrine, epinephrine and dopamine), and the degradation product urinary vanillylmandelic acid (VMA). However, the catecholamine metabolites normetanephrine and metanephrine (derived from norepinephrine and epinephrine, respectively) are produced continuously and independently of catecholamine release by intracellular O-methylation after leakage of the parent amines from chromaffin granule stores in the cytoplasm (23). Therefore, these metabolites are more accurate tests to diagnose pheochromocytoma than the conventional catecholamines (24;25). Reference intervals for metanephrines should primarily ensure optimum diagnostic sensitivity, with specificity as a secondary consideration to avoid the deadly consequence of a missed diagnosis (25). Unfortunately, for logistical reasons the metanephrine assay has only been added recently in our center. Although we were not able to show their superiority in our cohort because of the limited number of metanephrine results reported in chapter 4, we have no reason to doubt this superiority.
Interestingly, we have found that the urinary excretion of the O-methylated metabolite of dopamine, 3-methoxytyramine, was increased in 10 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 (26). Interestingly, the elevated levels of 3-methoxytyramine in our study could be a reflection of the fact that we used the presence of head-and-neck paragangliomas as an inclusion criterion, because carotid bodies are known to have dopamine working as a neurotransmitter (27;28). Secondly, although the conversion of the parent catecholamines to their respective metabolites is known to take place in sympathetic paragangliomas, it has not been elucidated whether or not this is the case in the head-and-neck paragangliomas producing catecholamines. We have reported a considerable number of head-and-neck paraganglioma patients with suspected catecholamine production in the head-and-neck area (chapter 4). Up till now, the clinical relevance of these tumors has not been fully elucidated. In addition, the sometimes inoperable tumors and considerable surgery related damage and comorbidity (as was described above), may further complicate deciding which treatment strategy is best in these patients. This further exemplifies the value of a multidisciplinary approach instituted in our center.
8.3.2 Imaging
Head-and-neck paragangliomas are best visualized with MRI scans, as was described in chapter 1. Our protocol includes a 2-yearly MRI of the head-and-neck (chapter 4). In general, localization studies for pheochromocytomas and extra-adrenal paragangliomas should be performed after a conclusive biochemical diagnosis has been made. However, in patients with a hereditary predisposition for pheochromocytoma, even lower or
normal levels of catecholamines may warrant further diagnostic imaging as a means of screening because of a high a-priori chance for developing paraganglioma or malignant disease (25). Since most tumors arise in the abdomen, either in- or outside the adrenals, we recommend starting with a MRI abdomen and pelvis (chapter 4). Although MRI has excellent sensitivity (90-100%) (29), the ability of MRI to specify a pheochromocytoma from other abdominal lesions can be insufficient. Therefore, additional functional imaging using [123I]-MIBG scintigraphy should be performed to confirm the diagnosis and to look for paragangliomas in multiple locations or clues for malignant disease (30).
[123I]-MIBG scintigraphy offers an excellent specificity (95-100%) and reasonable sensitivity for detecting adrenal pheochromocytomas (31;32). It has been reported that malignant paragangliomas lose the ability to accumulate [123I]-MIBG, thus reducing the value of this isotope in metastatic disease. In chapter 4 we reported that the use of [123I]-MIBG in our cohort for detection of intra- and extra-adrenal paragangliomas combined, revealed a sensitivity and specificity of only 80% and 75%, respectively. Our results support the idea that the sensitivity is dependent on tumor localization, with an increase in sensitivity to 92% when investigating (intra-adrenal) pheochromocytomas in our study separately. Furthermore, because our patients were detected using a routine screening protocol, earlier detection of catecholamine excess might have been of influence to sensitivity. Medication use should be checked before [123I]-MIBG imaging, because concurrent use of medications like labetalol or tricyclic antidepressants (TCA) is able to interfere with uptake of the tracer by the tumor (33). In patients with negative [123I]-MIBG imaging other means of imaging like [111ln]-Octreotide scintigraphy, [18F]- FDOPA, [18F]-FDA or [18F]-FDG positron emission tomography (PET) may be of additional value (32;34). Because of its better accuracy and the fact that they are much more patient friendly, we expect [18F]-FDOPA and/or [18F]-FDA to (at least partly) replace MIBG in diagnostic imaging for pheochromocytoma and paraganglioma in the future (chapter 7). Recently, Timmers et al. reported [18F]-FDG PET to be a superior tool in the evaluation of metastatic SDHB-associated adult pheochromocytoma and paraganglioma (35). Future studies will have to take into account the different genotype-phenotype associations with varying imaging performances and provide head-to-head comparisons of imaging methods in these specific subsets of patients (chapter 7).
As was described above, in our protocol (chapter 4), MRI imaging was performed only in those cases where catecholamine excess was documented. In most of these cases, the combination of an abdominal MRI and [123I]-MIBG will be sufficient for diagnosis. The possibility of non-secreting and mediastinal paragangliomas (chapter 4 and chapter 6) and the currently unclear consequences of missing one of these tumors in our SDHD-associated population (chapter 5), will have to be considered. Because of high malignant potential, patients with an SDHB mutation are already subjected to repetitive anatomical imaging irrespective of catecholamine levels. Future clinical studies will have to investigate whether or not this needs to be advised in SDHD
carriers. We believe this might eventually lead to future protocols that advocate anatomical imaging studies (e.g. every 5 years) to be performed irrespective of concurrent catecholamines.
8.4 Treatment strategies of paragangliomas 8.4.1 Head-and-neck paragangliomas
The close relation with nerves and vasculature may result in considerable morbidity related to surgery. Radiotherapy has been proposed as a means of treatment as well, but the reported results might be attributed to the general slow growth and long term follow up is mostly lacking. Small carotid body tumors and tympanic tumors may be surgically removed with generally limited complications. However, most new patients present with tumors that are diagnosed in a larger stage. The follow up protocol we have reported in chapter 4 consists of a two-yearly head-and-neck MRI and family members are offered screening for the SDH mutations. Because of increased awareness and family screening, we expect to be able to detect more tumors that are still in a stage where surgery must be considered as an alternative to the general watch-and-scan policy. Furthermore, the use of validated health related questionnaires could help further evaluate the impact of disease and treatment in head-and-neck paraganglioma patients (chapter 2). An important consideration before surgery of bilateral carotid body tumors might be the fact that these tumors arise from cells that may have an important physiological role in breathing (chapter 3). Further studies will investigate this suggested relationship using polysomnographic tests and blood gas analysis.
8.4.2 Pheochromocytomas and extra-adrenal paragangliomas
Treatment of catecholamine-producing pheochromocytomas and extra-adrenal paragangliomas consists of surgery after appropriate blockade of - and -adrenergic receptors. Since these -adrenergic blockade regimes were introduced, surgery related mortality was reduced enormously (36). In the literature, several different protocols have been proposed with -blockade using either doxazosine or phenoxybenzamine (37). Use of the non-competitive -blocker, phenoxybenzamine, has been reported to have advantages over using competitive blockers like doxazosine, which could theoretically be displaced by excessive catecholamine releases during surgery.
However, post-operative hypotension as a side-effect occurs more frequently with phenoxybenzamine. In our view, calcium channel blockers could be useful in situations where the use of -blockade alone is not sufficient to control blood pressure or the extent of side effects outweighs the benefit of -adrenergic blockade. In Leiden, the patients that had been operated for pheochromocytomas or extra-adrenal paragangliomas (chapter 4) were pre-operatively treated with doxazosine started at the outpatient clinics. Five days prior to surgery patients were admitted to the endocrine clinic where they had another physical examination, routine laboratory
investigations and electrocardiogram. Doxazosine dosage was stepwise increased until orthostatic hypotension was found. Blockade of -adrenergic receptors was only added after adequate -blockade had been given and the pulse rate increased above 70 beats per minute. One day prior to surgery isotonic saline is provided to increase plasma volume, in order to prevent peri-operative hypotension. Post-operatively the antihypertensive drugs were stopped and the patients were followed at the intensive care for hypotension and postoperative hypoglycemia. We have had no serious peri- operative complications in the patients reported in the present thesis, using these diagnostic and therapeutic protocols.
As was mentioned above, some intra-adrenal paragangliomas are non-secreting.
The necessity of removal of catecholamine-producing tumors is without doubt, but the indication for resection of non-secreting tumors is not so straightforward. Important determinants are the underlying gene mutations and their associated risk for malignant disease. Therefore, in SDHB patients all identified tumors need to be removed irrespective of catecholamine levels. In chapter 5 and chapter 6 we have reported SDHD-associated tumors with malignant characteristics. Although these tumors had been resected and we found the prevalence of malignant disease in SDHD carriers to be low (estimated 2.5%), some concern has been raised since non-secreting tumors might have been missed in our protocolized approach (chapter 4).
Treatment options in metastasized, surgically incurable situations are limited.
Several studies have reported partial or complete response to have occurred with cyclophosphamide, vincristine and dacarbazine (CVD) chemotherapy. As we have reviewed in chapter 7, we believe therapy with [131I]-MIBG will remain an essential part of the treatment of malignant pheochromocytomas and paragangliomas, but developments in improving uptake and efficiency can be expected. Currently, clinical trials are being conducted with [131I]-MIBG preparations synthesized without the unwanted carrier molecules (cold contaminants). Clinical trials comparing high-dose [131I]-MIBG vs. smaller repeated doses vs. combinations with chemotherapeutic regimens are needed to provide clinicians with solid guidelines.
Paragangliomas located in the mediastinum may challenge surgeons with respect to operability. In patient 9 described in chapter 6, a wait-and-see policy was advocated.
It was thought that because of the relatively low risk of malignant disease, in combination with only minor catecholamine elevations, the expected benefits of surgery did not outweigh the risks.
Furthermore, because we have started screening for catecholamine excess on a routine basis, we expect to discover some patients with borderline catecholamine excess in whom the tumor is still too small for detection. This was exemplified by patient 30 in chapter 4, who is suspected of having a subclinical pheochromocytoma.
The consequent question, of course, is what the therapeutic strategy must be in these cases and in those patients with a very small, but just detectable lesion. To further complicate these matters, we have also reported catecholamine-producing head-and-
neck paragangliomas (chapter 4) providing a differential diagnosis in these cases with its own therapeutic decisions that might be even more difficult. Future clinical studies will provide with necessary data.
8.5 Summary
The findings of the present thesis can be summarized in the following conclusions:
1. In Leiden, the so-called ‘founder effect’ resulted in genetic clustering with an extremely high prevalence of one single SDHD mutation, the SDHD-c.274G>T (p.Asp92Tyr) mutation.
2. Patients with head-and-neck paragangliomas have a considerable impairment of quality of life.
3. Patients with head-and-neck paragangliomas have serious subjective sleep complaints.
4. Patients with SDHD-associated head-and-neck paragangliomas have an increased risk for development of pheochromocytomas and paragangliomas at other locations and life long, repetitive follow up with protocolized clinical, biochemical and radiological screening is therefore mandatory.
5. The use of [123I]-MIBG for detection of intra- and extra-adrenal paragangliomas combined, revealed a sensitivity and specificity of only 80% and 75%, respectively.
The sensitivity is dependent on tumor localization and tumor behavior, with an increase in sensitivity to 92% if (intra-adrenal) pheochromocytomas are investigated separately.
6. The practical clinical implications of non-secreting intra-adrenal paragangliomas are currently uncertain.
7. Patients with SDHD mutations have malignant disease in at least ~2.5% of the cases.
8. Mediastinal paragangliomas are associated with mutations in the succinate dehydrogenase genes (either SDHB or SDHD) and aggressive behavior and might be more prevalent than hitherto appreciated.
9. Although the consequences of missing non-secreting and mediastinal paragangliomas in an SDHD-associated population are currently unclear, their possible presence should be taken into consideration in the development of future screening protocols.
10. In the future, [18F]-FDOPA and/or [18F]-FDA are expected to (at least partly) replace MIBG in diagnostic imaging for pheochromocytoma and paraganglioma.
References
1. van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, Schmidt PH, van de Kamp JJ 1989 Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory.
Lancet 2:1291-1294
2. Heutink P, van der Mey AG, Sandkuijl LA, van Gils AP, Bardoel A, Breedveld GJ, van VM, van Ommen GJ, Cornelisse CJ, Oostra BA 1992 A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter. Hum Mol Genet 1:7-10
3. Heutink P, van Schothorst EM, van der Mey AG, Bardoel A, Breedveld G, Pertijs J, Sandkuijl LA, van Ommen GJ, Cornelisse CJ, Oostra BA 1994 Further localization of the gene for hereditary paragangliomas and evidence for linkage in unrelated families. Eur J Hum Genet 2:148-158
4. Mariman EC, van Beersum SE, Cremers CW, van Baars FM, Ropers HH 1993 Analysis of a second family with hereditary non-chromaffin paragangliomas locates the underlying gene at the proximal region of chromosome 11q. Hum Genet 91:357-361
5. van Schothorst EM, Jansen JC, Grooters E, Prins DE, Wiersinga JJ, van der Mey AG, van Ommen GJ, Devilee P, Cornelisse CJ 1998 Founder effect at PGL1 in hereditary head and neck paraganglioma families from the Netherlands. Am J Hum Genet 63:468-473
6. Eng C, Kiuru M, Fernandez MJ, Aaltonen LA 2003 A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 3:193-202
7. Chandel NS, Schumacker PT 2000 Cellular oxygen sensing by mitochondria: old questions, new insight. J Appl Physiol 88:1880-1889
8. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT 2000 Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 275:25130-25138
9. Lopez-Barneo J, Pardal R, Ortega-Saenz P 2001 Cellular mechanism of oxygen sensing.
Annu Rev Physiol 63:259-287
10. Dang CV, Kim JW, Gao P, Yustein J 2008 The interplay between MYC and HIF in cancer.
Nat Rev Cancer 8:51-56
11. Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E 2005 Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77-85
12. Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rotig A, Jeunemaitre X 2001 The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 69:1186-1197
13. Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP 2005 Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14:2231-2239
14. Saldana MJ, Salem LE, Travezan R 1973 High altitude hypoxia and chemodectomas. Hum Pathol 4:251-263
15. Astrom K, Cohen JE, Willett-Brozick JE, Aston CE, Baysal BE 2003 Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen- sensing defect. Hum Genet 113:228-237
16. Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M, Gimm O, Henley D, Herman P, Murday V, Niccoli-Sire P, Pasieka JL, Rohmer V, Tucker K, Jeunemaitre X, Marsh DJ, Plouin PF, Robinson BG 2006 Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab 91:827-836
17. Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams KT, Solis D, Lenders JW, Pacak K 2007 Clinical Presentations, Biochemical Phenotypes, and Genotype-Phenotype Correlations in Patients with Succinate Dehydrogenase Subunit B-Associated Pheochromocytomas and Paragangliomas. J Clin Endocrinol Metab 92:779-786
18. Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER 2001 Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69:49-54
19. Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C 2004 Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292:943-951
20. Jansen JC 2001 Paragangliomas of the Head and Neck, Clinical Implications of Growth Rate and Genetics. Leiden University Medical Center
21. Testa MA, Simonson DC 1996 Assesment of quality-of-life outcomes. N Engl J Med 334:835-840
22. van Houtum WH, Corssmit EP, Douwes Dekker PB, Jansen JC, van der Mey AG, Brocker- Vriends AH, Taschner PE, Losekoot M, Frolich M, Stokkel MP, Cornelisse CJ, Romijn JA 2005 Increased prevalence of catecholamine excess and phaeochromocytomas in a well- defined Dutch population with SDHD-linked head and neck paragangliomas. Eur J Endocrinol 152:87-94
23. Eisenhofer G, Keiser H, Friberg P, Mezey E, Huynh TT, Hiremagalur B, Ellingson T, Duddempudi S, Eijsbouts A, Lenders JW 1998 Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors. J Clin Endocrinol Metab 83:2175-2185
24. Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, Keiser HR, Goldstein DS, Eisenhofer G 2002 Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287:1427-1434
25. Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM, Tischler AS 2007 Pheochromocytoma:
recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 3:92-102
26. Eisenhofer G, Goldstein DS, Sullivan P, Csako G, Brouwers FM, Lai EW, Adams KT, Pacak K 2005 Biochemical and clinical manifestations of dopamine-producing paragangliomas:
utility of plasma methoxytyramine. J Clin Endocrinol Metab 90:2068-2075
27. Minguez-Castellanos A, Escamilla-Sevilla F, Hotton GR, Toledo-Aral JJ, Ortega-Moreno A, Mendez-Ferrer S, Martin-Linares JM, Katati MJ, Mir P, Villadiego J, Meersmans M, Perez-
Garcia M, Brooks DJ, Arjona V, Lopez-Barneo J 2007 Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study. J Neurol Neurosurg Psychiatry 78:825-831
28. Jeffery J, Devendra D, Farrugia J, Gardner D, Murphy MJ, Williams R, Ayling RM, Wilkin TJ 2006 Increased urinary dopamine excretion in association with bilateral carotid body tumours-- clinical, biochemical and genetic findings. Ann Clin Biochem 43:156-160 29. Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS 2001 Recent advances in
genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 134:315-329
30. Pacak K, Ilias I, Adams KT, Eisenhofer G 2005 Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med 257:60-68
31. Nielsen JT, Nielsen BV, Rehling M 1996 Location of adrenal medullary pheochromocytoma by I-123 metaiodobenzylguanidine SPECT. Clin Nucl Med 21:695- 699
32. van der Harst E, de Herder WW, Bruining HA, Bonjer HJ, de Krijger RR, Lamberts SW, van de Meiracker AH, Boomsma F, Stijnen T, Krenning EP, Bosman FT, Kwekkeboom DJ 2001 [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in benign and malignant pheochromocytomas. J Clin Endocrinol Metab 86:685-693
33. Solanki KK, Bomanji J, Moyes J, Mather SJ, Trainer PJ, Britton KE 1992 A pharmacological guide to medicines which interfere with the biodistribution of radiolabelled meta- iodobenzylguanidine (MIBG). Nucl Med Commun 13:513-521
34. Ilias I, Pacak K 2004 Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 89:479-491
35. Timmers HJ, Kozupa A, Chen CC, Carrasquillo JA, Ling A, Eisenhofer G, Adams KT, Solis D, Lenders JW, Pacak K 2007 Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. J Clin Oncol 25:2262-2269 36. Goldstein RE, O'Neill JA, Jr., Holcomb GW, III, Morgan WM, III, Neblett WW, III, Oates JA,
Brown N, Nadeau J, Smith B, Page DL, Abumrad NN, Scott HW, Jr. 1999 Clinical experience over 48 years with pheochromocytoma. Ann Surg 229:755-764
37. Pacak K 2007 Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab 92:4069-4079
