-
Clinical Epigenetics Dec 2023Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Pathogenic variants have been identified in more than 15 susceptibility genes; associated...
A comprehensive characterisation of phaeochromocytoma and paraganglioma tumours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide.
BACKGROUND
Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Pathogenic variants have been identified in more than 15 susceptibility genes; associated tumours are grouped into three Clusters, reinforced by their transcriptional profiles. Cluster 1A PPGLs have pathogenic variants affecting enzymes of the tricarboxylic acid cycle, including succinate dehydrogenase. Within inherited PPGLs, these are the most common. PPGL tumours are known to undergo epigenetic reprograming, and here, we report on global histone post-translational modifications and DNA methylation levels, alongside clinical phenotypes.
RESULTS
Out of the 25 histone post-translational modifications examined, Cluster 1A PPGLs were distinguished from other tumours by a decrease in hyper-acetylated peptides and an increase in H3K4me2. DNA methylation was compared between tumours from individuals who developed metastatic disease versus those that did not. The majority of differentially methylated sites identified tended to be completely methylated or unmethylated in non-metastatic tumours, with low inter-sample variance. Metastatic tumours by contrast consistently had an intermediate DNA methylation state, including the ephrin receptor EPHA4 and its ligand EFNA3. Gene expression analyses performed to identify genes involved in metastatic tumour behaviour pin-pointed a number of genes previously described as mis-regulated in Cluster 1A tumours, as well as highlighting the tumour suppressor RGS22 and the pituitary tumour-transforming gene PTTG1.
CONCLUSIONS
Combined transcriptomic and DNA methylation analyses revealed aberrant pathways, including ones that could be implicated in metastatic phenotypes and, for the first time, we report a decrease in hyper-acetylated histone marks in Cluster 1 PPGLs.
Topics: Humans; Pheochromocytoma; Histones; DNA Methylation; Paraganglioma; Adrenal Gland Neoplasms; Gene Expression Profiling
PubMed: 38124114
DOI: 10.1186/s13148-023-01598-3 -
BMC Medical Genomics Sep 2020Carotid and vagal paragangliomas (CPGLs and VPGLs) are rare neoplasms that arise from the paraganglia located at the bifurcation of carotid arteries and vagal trunk,...
BACKGROUND
Carotid and vagal paragangliomas (CPGLs and VPGLs) are rare neoplasms that arise from the paraganglia located at the bifurcation of carotid arteries and vagal trunk, respectively. Both tumors can occur jointly as multiple paragangliomas accounting for approximately 10 to 20% of all head and neck paragangliomas. However, molecular and genetic mechanisms underlying the pathogenesis of multiple paragangliomas remain elusive.
CASE PRESENTATION
We report a case of multiple paragangliomas in a patient, manifesting as bilateral CPGL and unilateral VPGL. Tumors were revealed via computed tomography and ultrasound study and were resected in two subsequent surgeries. Both CPGLs and VPGL were subjected to immunostaining for succinate dehydrogenase (SDH) subunits and exome analysis. A likely pathogenic germline variant in the SDHD gene was indicated, while likely pathogenic somatic variants differed among the tumors.
CONCLUSIONS
The identified germline variant in the SDHD gene seems to be a driver in the development of multiple paragangliomas. However, different spectra of somatic variants identified in each tumor indicate individual molecular mechanisms underlying their pathogenesis.
Topics: Carotid Artery Diseases; Cranial Nerve Neoplasms; Female; Humans; Middle Aged; Neoplasms, Multiple Primary; Paraganglioma; Succinate Dehydrogenase; Vagus Nerve Diseases; Vascular Neoplasms
PubMed: 32948182
DOI: 10.1186/s12920-020-00789-8 -
Clinics (Sao Paulo, Brazil) 2012Head and neck paragangliomas are tumors arising from specialized neural crest cells. Prominent locations are the carotid body along with the vagal, jugular, and tympanic... (Review)
Review
Head and neck paragangliomas are tumors arising from specialized neural crest cells. Prominent locations are the carotid body along with the vagal, jugular, and tympanic glomus. Head and neck paragangliomas are slowly growing tumors, with some carotid body tumors being reported to exist for many years as a painless lateral mass on the neck. Symptoms depend on the specific locations. In contrast to paraganglial tumors of the adrenals, abdomen and thorax, head and neck paragangliomas seldom release catecholamines and are hence rarely vasoactive. Petrous bone, jugular, and tympanic head and neck paragangliomas may cause hearing loss. The internationally accepted clinical classifications for carotid body tumors are based on the Shamblin Class I-III stages, which correspond to postoperative permanent side effects. For petrous-bone paragangliomas in the head and neck, the Fisch classification is used. Regarding the molecular genetics, head and neck paragangliomas have been associated with nine susceptibility genes: NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127. Hereditary HNPs are mostly caused by mutations of the SDHD gene, but SDHB and SDHC mutations are not uncommon in such patients. Head and neck paragangliomas are rarely associated with mutations of VHL, RET, or NF1. The research on SDHA, SDHAF2 and TMEM127 is ongoing. Multiple head and neck paragangliomas are common in patients with SDHD mutations, while malignant head and neck paraganglioma is mostly seen in patients with SDHB mutations. The treatment of choice is surgical resection. Good postoperative results can be expected in carotid body tumors of Shamblin Class I and II, whereas operations on other carotid body tumors and other head and neck paragangliomas frequently result in deficits of the cranial nerves adjacent to the tumors. Slow growth and the tendency of hereditary head and neck paragangliomas to be multifocal may justify less aggressive treatment strategies.
Topics: Carotid Body Tumor; Genes, Neoplasm; Genetic Predisposition to Disease; Head and Neck Neoplasms; Humans; Neoplasm Staging; Paraganglioma; Skull Base Neoplasms
PubMed: 22584701
DOI: 10.6061/clinics/2012(sup01)05 -
European Annals of Otorhinolaryngology,... Jun 2014The objective of this study was to report 11 cases of malignant head and neck paraganglioma and to compare their epidemiological, clinical, and genetic characteristics,... (Comparative Study)
Comparative Study
BACKGROUND
The objective of this study was to report 11 cases of malignant head and neck paraganglioma and to compare their epidemiological, clinical, and genetic characteristics, their natural history and their treatment with those of a series of 131 benign paragangliomas.
PATIENTS AND METHODS
Retrospective analysis of 142 patients with head and neck paraganglioma managed between 2001 and 2008. Age at the time of diagnosis, gender, primary tumour site, presence of other non-head/neck paragangliomas and/or metastases diagnosed by imaging (CT, MRI, Octreoscan or (18)F-FDG PET), histology, urinary catecholamine and metanephrine levels, family history, and genetic test results were recorded.
RESULTS
This series comprised 131 benign head and neck paragangliomas, mostly observed in women with a mean age at diagnosis of 45 years and a predominance of tympanojugular sites (followed by carotid and vagal sites) with 5% of secreting tumours and 20% of multifocal tumours. Eleven patients (7.7%) with a 1:1 sex ratio presented criteria of malignancy. These patients, with a lower mean age (38 years), predominantly presented carotid lesions with a higher rate of secreting and multifocal tumours, 27% and 46% respectively. The main sites of metastases were bone and lymph nodes. No tympanic paragangliomas were observed.
CONCLUSIONS
Malignant paragangliomas are mainly observed in young patients with multifocal tumours, particularly carotid tumours, and are predominantly related to subunit SDH-B mutation. The work-up in these high-risk patients must include whole body scintigraphy and spine MRI. Malignancy is not necessarily associated with a poor short-term prognosis due to the slow course of the disease.
Topics: Adolescent; Adult; Aged; Bone Neoplasms; Diagnostic Imaging; Female; Genetic Testing; Head and Neck Neoplasms; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Mutation; Neck Dissection; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Paraganglioma; Retrospective Studies; Sex Distribution; Succinate Dehydrogenase; Thyroid Neoplasms; Young Adult
PubMed: 24239180
DOI: 10.1016/j.anorl.2013.05.003 -
The Pan African Medical Journal 2017Non-functional retroperitoneal paragangliomas are rare tumors. They are often asymptomatic and can reach very large sizes. We report the case of a 49-year old woman with...
Non-functional retroperitoneal paragangliomas are rare tumors. They are often asymptomatic and can reach very large sizes. We report the case of a 49-year old woman with retroperitoneal tumor detected during CT scan examination performed to find the cause of non-specific abdominal pain. Malignant forms, more frequent than benign forms, show locoregional invasion and are characterized by delayed-onset metastases. The treatment of these tumors is based on the most complete degree of surgical resection, since prognosis depends on it. There is no consensus on the usefulness of complementary therapies which may nevertheless constitute a supportive treatment.
Topics: Abdominal Pain; Female; Humans; Middle Aged; Paraganglioma; Prognosis; Retroperitoneal Neoplasms; Tomography, X-Ray Computed
PubMed: 28533842
DOI: 10.11604/pamj.2017.26.119.8572 -
Lakartidningen Nov 2022Paragangliomas of the head and neck are rare tumours arising from extraadrenal ganglia. They are highly vascular lesions and are normally benign and not hormone...
Paragangliomas of the head and neck are rare tumours arising from extraadrenal ganglia. They are highly vascular lesions and are normally benign and not hormone secreting. Symptoms are usually discreet and the tumours often present as a lump in the neck or are diagnosed incidentally. Evaluation of paragangliomas of the head and neck, and surgery when indicated, is highly specialized care to be performed at two hospitals nationwide (in Region Uppsala and Region Skåne). Historically, treatment has mainly been surgical. However, with a multidisciplinary evaluation of each case recommendations can be individualized and treatment options may include surgery, radiotherapy or watchful waiting (wait-and-scan). When surgery is recommended for paragangliomas of the neck, it is best performed in collaboration between head-neck surgeons and vascular surgeons. Follow up in benign cases is mainly done through imaging.
Topics: Humans; Glomus Tumor; Head and Neck Neoplasms; Paraganglioma; Diagnostic Imaging
PubMed: 36382609
DOI: No ID Found -
Endocrine-related Cancer Jun 2009Paragangliomas (PGLs) derive from either sympathetic chromaffin tissue in adrenal and extra-adrenal abdominal or thoracic locations, or from parasympathetic tissue of... (Review)
Review
Paragangliomas (PGLs) derive from either sympathetic chromaffin tissue in adrenal and extra-adrenal abdominal or thoracic locations, or from parasympathetic tissue of the head and neck. Mutations of nuclear genes encoding subunits B, C, and D of the mitochondrial enzyme succinate dehydrogenase (SDHB 1p35-p36.1, SDHC 1q21, SDHD 11q23) give rise to hereditary PGL syndromes PGL4, PGL3, and PGL1 respectively. The susceptibility gene for PGL2 on 11q13.1 remains unidentified. Mitochondrial dysfunction due to SDHx mutations have been linked to tumorigenesis by upregulation of hypoxic and angiogenesis pathways, apoptosis resistance and developmental culling of neuronal precursor cells. SDHB-, SDHC-, and SDHD-associated PGLs give rise to more or less distinct clinical phenotypes. SDHB mutations mainly predispose to extra-adrenal, and to a lesser extent, adrenal PGLs, with a high malignant potential, but also head and neck paragangliomas (HNPGL). SDHD mutations are typically associated with multifocal HNPGL and usually benign adrenal and extra-adrenal PGLs. SDHC mutations are a rare cause of mainly HNPGL. Most abdominal and thoracic SDHB-PGLs hypersecrete either norepinephrine or norepinephrine and dopamine. However, only some hypersecrete dopamine, are biochemically silent. The biochemical phenotype of SDHD-PGL has not been systematically studied. For the localization of PGL, several positron emission tomography (PET) tracers are available. Metastatic SDHB-PGL is the best localized by [(18)F]-fluorodeoxyglucose PET. The identification of SDHx mutations in patients with PGL is warranted for a tailor-made approach to the biochemical diagnosis, imaging, treatment, follow-up, and family screening.
Topics: Adrenal Gland Neoplasms; Humans; Mutation; Paraganglioma; Pheochromocytoma; Succinate Dehydrogenase
PubMed: 19190077
DOI: 10.1677/ERC-08-0284 -
Orphanet Journal of Rare Diseases Dec 2006Catecholamine-producing tumors may arise in the adrenal medulla (pheochromocytomas) or in extraadrenal chromaffin cells (secreting paragangliomas). Their prevalence is... (Review)
Review
Catecholamine-producing tumors may arise in the adrenal medulla (pheochromocytomas) or in extraadrenal chromaffin cells (secreting paragangliomas). Their prevalence is about 0.1% in patients with hypertension and 4% in patients with a fortuitously discovered adrenal mass. An increase in the production of catecholamines causes symptoms (mainly headaches, palpitations and excess sweating) and signs (mainly hypertension, weight loss and diabetes) reflecting the effects of epinephrine and norepinephrine on alpha- and beta-adrenergic receptors. Catecholamine-producing tumors mimic paroxysmal conditions with hypertension and/or cardiac rhythm disorders, including panic attacks, in which sympathetic activation linked to anxiety reproduces the same signs and symptoms. These tumors may be sporadic or part of any of several genetic diseases: familial pheochromocytoma-paraganglioma syndromes, multiple endocrine neoplasia type 2, neurofibromatosis 1 and von Hippel-Lindau disease. Familial cases are diagnosed earlier and are more frequently bilateral and recurring than sporadic cases. The most specific and sensitive diagnostic test for the tumor is the determination of plasma or urinary metanephrines. The tumor can be located by computed tomography, magnetic resonance imaging and metaiodobenzylguanidine scintigraphy. Treatment requires resection of the tumor, generally by laparoscopic surgery. About 10% of tumors are malignant either at first operation or during follow-up, malignancy being diagnosed by the presence of lymph node, visceral or bone metastases. Recurrences and malignancy are more frequent in cases with large or extraadrenal tumors. Patients, especially those with familial or extraadrenal tumors, should be followed-up indefinitely.
Topics: Adrenal Gland Diseases; Adrenal Gland Neoplasms; Catecholamines; Diagnosis, Differential; Genetic Testing; Humans; Hypertension; Paraganglioma, Extra-Adrenal; Pheochromocytoma; Prognosis; Proto-Oncogene Proteins c-ret
PubMed: 17156452
DOI: 10.1186/1750-1172-1-49 -
International Journal of Molecular... Jan 2022Pheochromocytomas and paragangliomas are the most heritable endocrine tumors. In addition to the inherited mutation other driver mutations have also been identified in... (Review)
Review
Pheochromocytomas and paragangliomas are the most heritable endocrine tumors. In addition to the inherited mutation other driver mutations have also been identified in tumor tissues. All these genetic alterations are clustered in distinct groups which determine the pathomechanisms. Most of these tumors are benign and their surgical removal will resolve patient management. However, 5-15% of them are malignant and therapeutical possibilities for them are limited. This review provides a brief insight about the tumorigenesis associated with pheochromocytomas/paragangliomas in order to present them as potential therapeutical targets.
Topics: Adrenal Gland Neoplasms; Carcinogenesis; Genetic Predisposition to Disease; Humans; Mosaicism; Mutation; Paraganglioma; Pheochromocytoma
PubMed: 35163370
DOI: 10.3390/ijms23031450 -
Turkish Neurosurgery 2024Vagal paragangliomas (VPs) are rare tumors arising from paraganglionic tissue within the vagal nerve's perineurium. Usually, benign vascular tumors, VPs tend to invade...
Vagal paragangliomas (VPs) are rare tumors arising from paraganglionic tissue within the vagal nerve's perineurium. Usually, benign vascular tumors, VPs tend to invade the surrounding structures. Herein, we report the case of a VP presenting as a neck mass, which was evaluated as a glomus caroticum tumor preoperatively. A 65-year-old female complaining of a left-sided neck mass and intermittent hoarseness was assessed and operated on for possible glomus caroticum tumor. During the tumor excision, the vagal nerve was also involved, and hence, sacrificed. Histopathological examination revealed an encapsulated tumor associated with a nerve and ganglion and immunohistochemical staining tested positive for succinate dehydrogenase, confirming the diagnosis of VP. Postoperative residual hoarseness was corrected by vocal rehabilitation. While evaluating a retropharyngeal prestyloid neck mass, a VP should always be considered. Surgical excision involving vagal scarification, followed by vocal rehabilitation may be the appropriate treatment strategy.
Topics: Female; Humans; Aged; Hoarseness; Paraganglioma, Extra-Adrenal; Vagus Nerve; Immunohistochemistry; Paraganglioma
PubMed: 37846532
DOI: 10.5137/1019-5149.JTN.40702-22.2