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Ear, Nose, & Throat Journal Sep 2023Paragangliomas are rare, slow-growing, hypervascular, catecholamine-secreting neuroendocrine tumors arising from the paraganglia. Paragangliomas are rarely found in the...
Paragangliomas are rare, slow-growing, hypervascular, catecholamine-secreting neuroendocrine tumors arising from the paraganglia. Paragangliomas are rarely found in the head and neck and are typically benign, presenting as a painless, slow-growing mass. Surgical extirpation in combination with long-term surveillance has been long regarded as the standard of care; however, the advances in imaging, radiation therapy, and embolization techniques have improved diagnostic and therapeutic modalities. We present a case of an 87-year-old female who had previously undergone resection of a paraganglioma in 1998, with no evidence of disease in 2002. Eighteen years later, the patient presented to the clinic with otogenic complaints. Imaging showed an expansive mass from the jugular foramen with bone destruction and opacification within the ear canal. The patient opted for observation. The patient eventually presented to the emergency room with neurologic manifestations. Imaging showed a cerebellar abscess prompting emergency drainage. Intraoperative cultures grew and , and the patient was started on 6 weeks of IV antibiotic therapy. Debulking of the paraganglioma was performed followed several months by mastoid and ear canal obliteration; however, the patient experienced complications, including dehiscence of the external auditory canal and infection. The patient was eventually treated successfully, marked by a reduction in complaints, a return to baseline activities, and imaging showing no increase in tumor size.
Topics: Female; Humans; Aged, 80 and over; Paraganglioma; Diagnostic Imaging; Head and Neck Neoplasms; Neck; Mastoid
PubMed: 37551648
DOI: 10.1177/01455613231187762 -
Cancers Jun 2022Hypoxia-inducible factors (HIF) 2α and 1α are the major oxygen-sensing molecules in eukaryotic cells. HIF2α has been pathogenically linked to paraganglioma and...
Hypoxia-inducible factors (HIF) 2α and 1α are the major oxygen-sensing molecules in eukaryotic cells. HIF2α has been pathogenically linked to paraganglioma and pheochromocytoma (PPGL) arising in sympathetic paraganglia or the adrenal medulla (AM), respectively. However, its involvement in the pathogenesis of paraganglioma arising in the carotid body (CB) or other parasympathetic ganglia in the head and neck (HNPGL) remains to be defined. Here, we retrospectively analyzed HIF2α by immunohistochemistry in 62 PPGL/HNPGL and human CB and AM, and comprehensively evaluated the HIF-related transcriptome of 202 published PPGL/HNPGL. We report that HIF2α is barely detected in the AM, but accumulates at high levels in PPGL, mostly (but not exclusively) in those with loss-of-function mutations in and genes encoding components of the succinate dehydrogenase (SDH) complex. This is associated with upregulation of and the HIF2α-regulated genes and . In contrast, HIF2α and HIF2α-regulated genes are highly expressed in CB and HNPGL, irrespective of VHL and SDH dysfunctions. We also found that HIF2α and HIF1α protein expressions are not correlated in PPGL nor HNPGL. In addition, HIF1α-target genes are almost exclusively overexpressed in -mutated HNPGL/PPGL. Collectively, the data suggest that involvement of HIF2α in the physiology and tumor pathology of human paraganglia is organ-of-origin-dependent and HIF1α-independent.
PubMed: 35740651
DOI: 10.3390/cancers14122986 -
Gene Jul 2023Pheochromocytoma and paraganglioma (PPGL), are rare neuroendocrine tumors arising from the adrenal medulla and extra-adrenal paraganglia, respectively. Up to about 60%...
Pheochromocytoma and paraganglioma (PPGL), are rare neuroendocrine tumors arising from the adrenal medulla and extra-adrenal paraganglia, respectively. Up to about 60% are explained by germline or somatic mutations in one of the major known susceptibility genes e.g., inNF1,RET,VHL, SDHx,MAXandHRAS. Targeted Next Generation Sequencing was performed in 14 sporadic tumors using a panel including 26 susceptibility genes to characterize the mutation profile. A total of 6 germline and 8 somatic variants were identified. The most frequent somatic mutations were found in NF1(36%), four have not been reported earlier in PCC or PGL. Gene expression profile analysis showed that NF1 mutated tumors are classified into RTK3 subtype, cluster 2, with a high expression of genes associated with chromaffin cell differentiation, and into a RTK2 subtype, cluster 2, as well with overexpression of genes associated with cortisol biosynthesis. On the other hand, by analyzing the entire probe set on the array and TCGA data, ALDOC was found as the most significantly down regulated gene in NF1-mutated tumors compared to NF1-wild-type. Differential gene expression analysis showed a significant difference between Nt - and Ct-NF1 domains in mutated tumors probably engaging different cellular pathways. Notably, we had a metastatic PCC with a Ct-NF1 frameshift mutation and when performing protein docking analysis, Ct-NF1 showed an interaction with Nt-FAK suggesting their involvement in cell adhesion and cell growth. These results show that depending on the location of the NF1-mutation different pathways are activated in PPGLs. Further studies are required to clarify their clinical significance.
Topics: Humans; Pheochromocytoma; Paraganglioma; Mutation; Adrenal Gland Neoplasms; Gene Expression Profiling
PubMed: 37062455
DOI: 10.1016/j.gene.2023.147432 -
International Journal of Surgery Case... Sep 2021Mediastinal paragangliomas are rare neuroendocrine tumors that originate from extra-adrenal paraganglia, occasionally secreting catecholamines. Nonfunctional mediastinal...
INTRODUCTION AND IMPORTANCE
Mediastinal paragangliomas are rare neuroendocrine tumors that originate from extra-adrenal paraganglia, occasionally secreting catecholamines. Nonfunctional mediastinal paragangliomas present nonspecific clinical and radiological features and represent a diagnostic challenge.
CASE PRESENTATION
A 53-year old woman presented with cough and dyspnea increasing over time. CT-scan and ultrasonography showed a large vascularized cervico-mediastinal mass, consistent with an intrathoracic ectopic goiter. Preoperative angiography showed a blood supply from neck vessels. The lesion was completely removed through a cervical approach. The diagnosis of paraganglioma was a histological surprise. The patient is alive without recurrence 30 months after surgery.
CLINICAL DISCUSSION
When preoperatively diagnosed, the treatment of choice of a mediastinal paraganglioma is surgical excision. However, a preoperative diagnosis of mediastinal paraganglioma is difficult to obtain, especially in cases of nonfunctional lesions. Distinction between an intrathoracic goiter and a nonfunctional paraganglioma can be extremely difficult and, given the rarity of the latter, an ectopic goiter is suspected in first instance. CT-scan and ultrasonography are of little use in the differential diagnosis. However, scintigraphy with I-metaiodobenzylguanidine can be an useful diagnostic tool when a paraganglioma is suspected. In case of vascularized cervico-mediastinal mass, such as paragangliomas or intrathoracic goiter, preoperative angiography should be performed to study the blood supply and orient the surgical approach.
CONCLUSION
Although uncommon, paragangliomas should be considered in the differential diagnosis of mediastinal masses, especially when an ectopic goiter is suspected.
PubMed: 34464842
DOI: 10.1016/j.ijscr.2021.106357 -
Ear, Nose, & Throat Journal Jan 2024Paragangliomas of the thyroid gland are rare and usually they originate from the inferior laryngeal paraganglia. In this case report, we describe the case of a... (Review)
Review
Paragangliomas of the thyroid gland are rare and usually they originate from the inferior laryngeal paraganglia. In this case report, we describe the case of a 78-year-old woman who presented with an incidental finding of thyroid nodule dislocating the trachea. After a systemic and radiological evaluation, right lobo-isthmectomy was performed, and the definitive diagnosis of paraganglioma was reached. Diagnosis of these thyroidal lesions could be difficult due to their rarity, to their specific radiological aspects and the need of employing specific histological staining techniques. Once the definitive diagnosis is reached, patients should undergo a systemic and genetic evaluation. Surgery is the gold standard treatment; radiotherapy should be considered when aggressive behavior is suspected. Regular long-lasting follow-up should be proposed to these patients considering the unpredictable behavior of these lesions.
Topics: Female; Humans; Aged; Thyroid Nodule; Paraganglioma; Thyroidectomy; Trachea
PubMed: 34384034
DOI: 10.1177/01455613211034595 -
International Journal of Molecular... Dec 2022Head and neck paragangliomas (HNPGLs) are rare neuroendocrine neoplasms derived from the parasympathetic paraganglia of the head and neck. At least 30% of HNPGLs are...
Head and neck paragangliomas (HNPGLs) are rare neuroendocrine neoplasms derived from the parasympathetic paraganglia of the head and neck. At least 30% of HNPGLs are linked to germline mutations, predominantly in genes. In this study, we analyzed an extended cohort of Russian patients with HNPGLs using whole-exome sequencing and found a highly frequent missense variant p.H102R in the gene. We determined this variant in 34% of the mutation carriers. This variant was associated with somatic loss of the gene wild-type allele. Data from the B allele frequency method and microsatellite and microdeletion analysis indicated evident LOH at the 11p15.5 region and potential loss of the whole of chromosome 11. We found hypermethylation of H19-DMR in all tumors, whereas differential methylation of KvDMR was mostly retained. These findings do not support the paternal transmission of :p.H102R but are in agreement with the Hensen model. Using targeted sequencing, we also studied the variant frequency in a control cohort; we found :p.H102R in 1.9% of cases, allowing us to classify this variant as pathogenic. The immunohistochemistry of SDHB showed that the :p.H102R mutation, even in combination with wild-type allele loss, does not always lead to SDH deficiency. The obtained results demonstrate the frequent variant associated with HNPGLs in a Russian population and support its pathogenicity. Our findings help with understanding the mechanism of tumorigenesis and are also important for the development of cost-effective genetic screening programs.
Topics: Humans; Succinate Dehydrogenase; Paraganglioma; Head and Neck Neoplasms; Genetic Testing; Alleles; Germ-Line Mutation
PubMed: 36614070
DOI: 10.3390/ijms24010628 -
Cureus Sep 2021Background Glomus jugulare tumors are rare slow-growing hypervascular tumors that arise from the paraganglia of the chemoreceptor system within the jugulare foramen of...
Background Glomus jugulare tumors are rare slow-growing hypervascular tumors that arise from the paraganglia of the chemoreceptor system within the jugulare foramen of the temporal lobe. The historical standard treatment has been surgical resection, but because of their high vascularity and involvement with cranial nerves (CNs), Gamma Knife radiosurgery (GKRS) has been advocated as an alternative. The goal of this study is to update and report long-term results of GKRS to achieve local control and symptomatic improvement and to reduce morbidity and mortality when treating glomus jugulare tumors. Materials and Methods This study retrospectively collected and reviewed clinical and radiographic data of 32 patients with glomus jugulare tumors treated with GKRS at the Miami Neuroscience Center, South Miami, FL, from 1995 to 2019. For the 32 patients, the mean volume treated was 13.9 cc (0.23 to 40.0 cc), with an average of 8.6 isocenters. The median prescription dose was 12.84 Gy ± 2.07 Gy (range: 10-20 Gy). Follow-up data were available for 29 out of 32 patients, with a median clinical follow-up time of 37.3 months (range: 4.3-169.1 months). At follow-up, patients were evaluated for neurological signs and symptoms and radiographic evidence of progression of disease. Results The median age of the cohort treated with GKRS was 60 years (range: 14-83 years). There were three males and 27 females. Presenting symptomatology was available for 30 out of 32 patients. The most common presenting symptom was hearing loss (21/30) and the most common CN deficit was in CN VIII (19/30). Out of 29 of the patients followed up, 28 patients had improvement (20/29) or resolution (8/29) of symptoms. At the most recent evaluation or contact, patients were without symptomatic progression of CN deficits. Radiographic tumor control was achieved in 28 out of 29 patients. One patient had a recurrence seven years after GKRS, which was treated with surgery. There were no complications, radionecrosis, or mortality reported from GKRS. Conclusion These data confirm that GKRS is a reasonable upfront treatment option for glomus jugulare tumors. GKRS should be considered more frequently given its excellent long-term local control with low morbidity and risk of complications.
PubMed: 34692309
DOI: 10.7759/cureus.18095 -
Cell Death & Disease May 2021Pheochromocytoma/paraganglioma (PPGL) is an endocrine tumor of the chromaffin cells in the adrenal medulla or the paraganglia. Currently, about 70% of PPGLs can be...
GIPC2 is an endocrine-specific tumor suppressor gene for both sporadic and hereditary tumors of RET- and SDHB-, but not VHL-associated clusters of pheochromocytoma/paraganglioma.
Pheochromocytoma/paraganglioma (PPGL) is an endocrine tumor of the chromaffin cells in the adrenal medulla or the paraganglia. Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including RET, VHL, and SDHB, while for the remaining, mainly sporadic cases, the pathogenesis is still unclear. Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why RET-mutated tumors almost always occur in the adrenal while SDHB-mutated tumors mostly occur extra-adrenal remains a mystery. By analyzing 22 sporadic PPGLs using SNP 6.0 genotyping arrays combined with expression profiling of 4 normal and 4 tumor tissues, we identified GIPC2, a gene located at 1p31.1 with preferential expression in adrenal and inducible by adrenal glucocorticoid, as a novel putative tumor suppressor gene for PPGLs. Copy number deletion and GIPC2 promoter hypermethylation but not GIPC2 mutation, accompanied with reduced GIPC2 expression, were observed in 39 of 55 PPGLs in our cohort. Examination of a published expression database consisting of 188 PPGLs found little GIPC2 expression in Cluster 1A (SDHx-associated) and Cluster 2A (NF1/RET-associated) tumors, but less pronounced reduction of GIPC2 expression in Cluster 1B (VHL-associated) and Cluster 2B/2C tumors. GIPC2 induced p27, suppressed MAPK/ERK and HIF-1ɑ pathways as well as cancer cell proliferation. Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice. We found GIPC2 interacted with the nucleoprotein NONO and both proteins regulated p27 transcription through the same GGCC box on p27 promoter. Significantly, low expression of both GIPC2 and p27 was associated with shorter disease-free survival time of PPGLs patients in the TCGA database. We found that PPGL-causing mutations in RET and in SDHB could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and p27 downregulation, all requiring downregulating GIPC2. Notably, the RET-mutant effect required the presence of dexamethasone while the SDHB-mutant effect required its absence, providing a plausible explanation for the tumor location preference. In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL. Thus, our study raises the importance of cortical hormone in PPGL development, and GIPC2 as a novel tumor suppressor provides a unified molecular mechanism for the tumorigenesis of both sporadic and hereditary tumors of Clusters 1A and 2A concerning SDHB and RET, but not tumors of Cluster 1B concerning VHL and other clusters.
Topics: Adrenal Gland Neoplasms; Carrier Proteins; Genes, Tumor Suppressor; Humans; Pheochromocytoma; Proto-Oncogene Proteins c-ret; Succinate Dehydrogenase; Transfection
PubMed: 33947839
DOI: 10.1038/s41419-021-03731-7 -
Iranian Journal of Otorhinolaryngology Nov 2022Generally, glomus tumors are considered tumors of the autonomic system arising from chromaffin cells of the parasympathetic paraganglia of the skull base and neck....
INTRODUCTION
Generally, glomus tumors are considered tumors of the autonomic system arising from chromaffin cells of the parasympathetic paraganglia of the skull base and neck. Glomus tympanicum is the most common primary tumor of the middle ear cavity and it arises from the paraganglia of the middle ear.
CASE REPORT
We present a case of glomus tympanicum presented in a 70-year-old woman, complicated with facial nerve palsy which at first sight was misdiagnosed as cholesteatoma. Patient presented in our clinic because of otorrhea, pulsatile tinnitus and hearing loss in the right ear. However, facial nerve function was good in the first examination (40 days before the surgery). Eventually, she treated successfully with a canal wall down mastoidectomy. Technique had been chosen because of the mass size and the involvement of external auditory canal, after a discussion with the patient.
CONCLUSIONS
Although histologically benign, glomus tympanicum is slow growing and destructs adjacent tissues potentially. The two most common complaints are hearing loss (conductive) and pulsatile tinnitus. These neoplasms are more common in women and they can be diagnosed by CT or MRI scan. It is of high importance physicians suspect a glomus tumor when patient 's clinical findings are hearing loss and pulsatile tinnitus and use an intravascular agent in imaging so that the differential diagnosis will be supported.
PubMed: 36474487
DOI: 10.22038/IJORL.2022.64737.3217 -
JCEM Case Reports Nov 2023Pheochromocytomas are intra-adrenal sympathetic neuroendocrine tumors that arise from chromaffin cells. Paragangliomas similarly arise from chromaffin cells, although at...
Pheochromocytomas are intra-adrenal sympathetic neuroendocrine tumors that arise from chromaffin cells. Paragangliomas similarly arise from chromaffin cells, although at extra-adrenal sites such as sympathetic paraganglia in the abdomen/thorax, or parasympathetic paraganglia in the head/neck. Collectively, pheochromocytomas and paragangliomas are important to diagnose and resect because they may secrete harmful levels of catecholamines, have mass effects, hemorrhage, and/or metastasize. Anatomic imaging of pheochromocytomas is usually completed with computed tomography or magnetic resonance imaging; however, functional imaging may be used to provide additional localization, staging, and/or biologic information. Accordingly, selection of the proper functional imaging modality can be critical to developing the optimal therapeutic strategy. Gallium- and Copper-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate positron emission tomography computed tomography (Ga- and Cu-DOTATATE) are widely used in evaluating pheochromocytomas and paragangliomas, although data regarding the sensitivity for diagnosing pheochromocytoma are limited. We report 2 cases of pheochromocytoma that showed nondiagnostic Ga-DOTATATE uptake but were subsequently visualized using alternative functional imaging modalities. Additionally, we provide a review of the literature to highlight the underappreciated limitations of functional adrenal imaging with somatostatin-based compounds.
PubMed: 38045868
DOI: 10.1210/jcemcr/luad149