Andel G. L. van der Mey

Estimation of growth rate in patients with head and neck paragangliomas influences the treatment proposal

Extraadrenal paragangliomas of the head and neck are tumors with variable clinical behavior. Because tumor growth as well as surgery can cause disabling loss of function, knowledge of the natural history of paragangliomas is important for the development of treatment strategies.

Nearly all hereditary paragangliomas in The Netherlands are caused by two founder mutations in the SDHD gene

Hereditary paragangliomas or glomus tumors are usually benign slow‐growing tumors in the head and neck region. The inheritance pattern of hereditary paraganglioma is autosomal dominant with imprinting. Recently, we have identified the SDHD gene encoding subunit D of the mitochondrial respiratory chain complex II as one of the genes involved in hereditary paragangliomas. Here, we demonstrate that two founder mutations, Asp92Tyr and Leu139Pro, are responsible for paragangliomas in 24 and 6 of the 32 independently ascertained Dutch paraganglioma families, respectively. These two mutations were also detected among 20 of 55 isolated patients. Ten of the isolated patients had multiple paragangliomas, and in eight of these SDHD germline mutations were found, indicating that multicentricity is a strong predictive factor for the hereditary nature of the disorder in isolated patients. In addition, we demonstrate that the maternally derived wild‐type SDHD allele is lost in tumors from mutation‐carrying patients, indicating that SDHD functions as a tumor suppressor gene.

Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families

Germline mutations in succinate dehydrogenase subunits B, C and D (SDHB, SDHC and SDHD), genes encoding subunits of mitochondrial complex II, cause hereditary paragangliomas and phaeochromocytomas. In SDHB (1p36)- and SDHC (1q21)-linked families, disease inheritance is autosomal dominant. In SDHD (11q23)-linked families, the disease phenotype is expressed only upon paternal transmission of the mutation, consistent with maternal imprinting. However, SDHD shows biallelic expression in brain, kidney and lymphoid tissues (Baysal et al., 2000). Moreover, consistent loss of the wild-type (wt) maternal allele in SDHD-linked tumours suggests expression of the maternal SDHD allele in normal paraganglia. Here we demonstrate exclusive loss of the entire maternal chromosome 11 in SDHD-linked paragangliomas and phaeochromocytomas, suggesting that combined loss of the wt SDHD allele and maternal 11p region is essential for tumorigenesis. We hypothesize that this is driven by selective loss of one or more imprinted genes in the 11p15 region. In paternally, but not in maternally derived SDHD mutation carriers, this can be achieved by a single event, that is, non-disjunctional loss of the maternal chromosome 11. Thus, the exclusive paternal transmission of the disease can be explained by a somatic genetic mechanism targeting both the SDHD gene on 11q23 and a paternally imprinted gene on 11p15.5, rather than imprinting of SDHD.

Does Intervention Improve the Natural Course of Glomus Tumors? A Series of 108 Patients Seen in a 32-Year Period

To acquire more insight into the results of treatment versus the “natural” course of glomus tumors, we studied the clinical data of 108 patients, in 58 of whom the disease was hereditary. During a period of 32 years (1956 to 1988), 175 tumors were diagnosed: 52 glomus jugulotympanic tumors, 32 vagal body tumors, and 91 carotid body tumors. The results of radical surgical treatment were disappointing for tumors located at the skull base, ie, nonradical in 59% (n = 23) of the cases, but very good for the carotid body tumors, for which 96% (n = 68) radical excision was achieved. Moreover, surgery at the level of the skull base dramatically increased morbidity, since it frequently induced cranial nerve palsy. During the follow-up period (maximal observation time 32 years, mean 13.5 years) none of the patients died of residual or recurrent tumor or developed distant metastases, irrespective of the mode and outcome of treatment. When these results are combined with the results of pedigree analysis, a realistic approximation of the “natural” course of the disease for both hereditary and nonfamilial tumors can be made. The results raise the question of whether this natural behavior is really improved by intervention. We conclude that removal of carotid body tumors and solitary vagal body tumors should be considered in order to prevent future morbidity. However, for skull base and bilateral glomus tumors a more conservative monitored “wait and see” policy can be sensible and should be considered in any proposal for treatment of head and neck paragangliomas. When there is serious progression of cranial nerve palsy or when intracranial growth becomes life-threatening, surgical intervention cannot be avoided. The main goal of glomus tumor treatment should be to reduce morbidity rather than trying to increase survival rates.

MANAGEMENT OF CAROTID BODY TUMORS

The carotid body tumor is a rare neoplasm that has generated much literature over the past century, and for which continued controversy exists regarding natural history, biologic behavior, proper technique of excision, and the risk of morbidity and mortality. This article discusses overall management of carotid body tumors.

Conservative treatment of vestibular schwannoma: a follow-up study on clinical and quality-of-life outcome.

Objective: To determine the natural history and long-term quality-of-life (QOL) outcome after conservative treatment for vestibular schwannoma. Study Design: Prospective study conducted in a university-based tertiary referral center. Patients: A total of 70 vestibular schwannoma patients who were initially included in the wait and scan protocol between January 2002 and December 2003 were followed with a mean observation time of 43 months. All patients had small- or medium-sized tumors when they were included in the protocol. QOL was measured at diagnosis and at the end of follow-up in those patients who were still conservatively treated using the Short Form 36 Health Survey (SF-36). The study group was characterized by nongrowing small tumors and relatively stable symptoms over time. Main Outcome Measures: Clinical, audiometric, radiologic, and QOL results. Results: In 44 patients (63%), growth of the tumor was not observed, and 25 (36%) tumors did grow. Of the 70 included patients, 27 patients (39%) required treatment. Forty-one patients (59%) were still conservatively treated at the end of follow-up (mean 47 ± 16 mo). Hearing was preserved in 16 (57%) of the 28 patients with useful hearing at diagnosis. At the end of follow-up, SF-36 scores were only slightly deteriorated for almost all subscales when compared with scores at diagnosis; however, differences were statistically not significant (p > 0.05). There was no significant correlation between the presence of cochleovestibular symptoms and QOL scores (p > 0.05). Conclusion: Conservative observation of small vestibular schwannomas may be regarded as a reasonable management option because most of these tumors do not grow during an initial period of observation. Conservative treatment of this subset of patients with small, nongrowing tumors does not significantly affect life functioning, as reflected in SF-36 survey data. However, hearing loss did progress in this population. Thus, patients should be counseled regarding this risk and generic QOL measures such as the SF-36 should be used with caution in future assessments. This study emphasizes the importance of combining generic and disease-specific QOL measures in future studies of protocols of vestibular schwannoma management.

The respiratory response to carbon dioxide in humans with unilateral and bilateral resections of the carotid bodies.

The acute hypercapnic ventilatory response (AHCVR) arises from both peripheral and central chemoreflexes. In humans, one technique for identifying the separate contributions of these chemoreflexes to AHCVR has been to associate the rapid component of AHCVR with the peripheral chemoreflex and the slow component with the central chemoreflex. Our first aim was to validate this technique further by determining whether a single slow component was sufficient to describe AHCVR in patients with bilateral carotid body resections (BR) for glomus cell tumours. Our second aim was to determine whether the slow component of AHCVR was diminished following carotid body resection as has been suggested by studies in experimental animals. Seven BR subjects were studied together with seven subjects with unilateral resections (UR) and seven healthy controls. A multifrequency binary sequence in end‐tidal PCO2 was employed to stimulate ventilation dynamically under conditions of both euoxia and mild hypoxia. Both two‐ and one‐compartment models of AHCVR were fitted to the data. For BR subjects, the two‐compartment model fitted significantly better on 1 out of 13 occasions compared with 22 out of 28 occasions for the other subjects. Average values for the chemoreflex sensitivity of the slow component of AHCVR differed significantly (P < 0.05) between the groups and were 0.95, 1.38 and 1.50 l min−1 Torr−1 for BR, UR and control subjects, respectively. We conclude that, without the peripheral chemoreflex, AHCVR is adequately described by a single slow component and that BR subjects have sensitivities for the slow component that are lower than those of control subjects.

Surgery for large vestibular schwannoma: residual tumor and outcome.

Objective: To evaluate clinical outcome with regard to the amount of residual tumor after surgery for large vestibular schwannoma. Patients: Between January 2000 and December 2005, 51 large vestibular schwannoma tumors with extrameatal diameter of 2.6 cm or greater (mean, 32 mm; median, 30 mm; range, 26-50 mm) were operated using the translabyrinthine approach. The extent of the resection was intraoperatively estimated as complete, near, and subtotal. The amount of residual tumor was measured, and the shape and localization was scored on gadolinium-enhanced magnetic resonance imaging (MRI). Correlation between intraoperative and MRI assessment was performed using the Fishers exact test. Potential growth of residual tumor was documented with frequent MRI follow-up. Postoperative facial nerve function was classified according to the House-Brackmann classification. Results: Complete resection was performed in 26% of the patients, near-total resection in 58%, and subtotal resection in 16%. Magnetic resonance imaging showed residual tumor in 46% of patients (mean, 16.7 mm; SD, ±8, range, 5-36 mm). Postoperative facial nerve function was House-Brackmann Grades I to II in 78% of the patients. The intraoperative assessment of near-total resection did not correlate with postoperative MRI (p = 0.25). Postoperative MRI showed either no residual tumor or residue that should actually have been classified as a subtotal resection. After a follow-up of 4 years (49 mo; mean, 48 mo), 94% of patients did not show changes on MRI. Conclusion: Tumor control with good facial nerve function could be obtained in most patients. Intraoperative assessment did not correlate with the amount of residual tumor on postoperative MRI. Objective documentation with postoperative MRI to measure the extent of removal is therefore mandatory.

Illness perceptions, coping, and quality of life in vestibular schwannoma patients at diagnosis.

Objective: To evaluate illness perceptions, coping behavior, and quality of life (QOL) in patients with vestibular schwannoma (VS) at diagnosis. Study Design: Prospective patient analysis. Setting: University Teaching Hospital, tertiary care clinic. Patients: Consecutive patients with VS (n = 80) completed a set of questionnaires at diagnosis to assess psychological characteristics and QOL. Intervention: Diagnostic and rehabilitative. Main Outcome Measures: Psychological characteristics and QOL, measured via questionnaires focusing on illness perceptions (Illness Perception Questionnaire Revised), coping (Utrecht Coping List), and QOL (Medical Outcomes Study 36-Item Short Form Health Survey), were compared with normative data for the general Dutch population and to data concerning patients with other illnesses. Results: The 36-Item Short Form Health Survey scores of VS patients at diagnosis were significantly decreased when compared with healthy controls, patients with head and neck cancer, benign prostate hypertrophy, chronic obstructive pulmonary disease, and deaf patients. Scores for illness perceptions were in between those of patients with acute pain and chronic pain for most subscales except illness identity, emotional representations, and illness coherence. In their coping behavior, VS patients scored lower on the subscale active coping, sought less social support, and expressed their emotions less, but also showed less passive coping compared with reference values. Conclusion: Vestibular schwannoma patients experience impaired QOL compared with healthy controls and reference groups. Their illness perceptions are in between those of patients with acute and chronic pain, and their coping behavior is less active in general. This may have implications for clinical decision making and for optimizing interaction with patients. Changing illness perceptions and coping by means of an intervention and encouraging social support by means of patient support groups may improve QOL in VS patients.

Founder Effect at PGL1 in Hereditary Head and Neck Paraganglioma Families from The Netherlands

PGL1, a gene responsible for hereditary paragangliomas of the head and neck, recently was mapped to a 2-cM interval on chromosome 11q22-q23, by linkage and haplotype-sharing analysis of a large multibranch Dutch family. We determined the disease-linked haplotype, as defined by 13 markers encompassing a large interval on 11q21-q23, in 10 additional families ascertained from the same geographical locale. Alleles were identical for six contiguous markers, spanning a genetic distance of 6 cM and containing PGL1. Despite this strong indication of a common ancestor, no kinships between the families could be demonstrated through genealogical surveys going back to 1800 a.d. We conclude that a single ancestral mutation is responsible for most, if not all, hereditary paragangliomas, in this region of The Netherlands, and that strong founder effects may exist at the PGL1 locus.