Special Issue "Pheochromocytoma and Paraganglioma: Research Update"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Cytology".

Deadline for manuscript submissions: closed (30 July 2018).

Special Issue Editor

Dr. Noriko Kimura
E-Mail Website
Guest Editor
Department of Pathology, National Hospital Organization Hakodate Hospital, Hakodate, Hokkaido, Japan
Interests: pheochromocytoma; paraganglioma; GAPP classification; risk stratification; WHO bluebook; adrenal tumor

Special Issue Information

Dear Colleagues,

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors in the adrenal medulla and extra-adrenal paraganglia. Paragangliomas can be divided into parasympathetic PGL (head and neck PGL) and sympathetic PGL. The distinction between “benign” and “malignant” PPGL has been discussed at length for decades. Current thinking is that all PPGL have some metastatic potential and ICD-O code /3 (cancer) was given by the WHO tumor classification 4th ed. 2017. Therefore, the previous categories of benign and malignant PPLGs have been eliminated for an approach based on risk stratification. Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) is a tool for predicting metastasis and patients’ prognosis. However, GAPP cannot be applied for parasympathetic PGL at present. At least 30% of the tumors are now known to be hereditary, and about 19 genes have been determined and genotype–phenotype correlations have been clarified. Of these gene mutations, succinate dehydrogenase genes SDHA, SDHB, SDHC, and SDHD are strongly correlated with extra-adrenal locations, younger age occurrence, multiplicity, metastasis, and poor prognosis. Tumor, Node, Metastasis (TNM) Classification by American Joint Committee on Cancer (AJCC) Cancer Staging Manual (8th edition) was first applied for PPGLs in 2017. Clinical usefulness of GAPP, genetic analysis, and TNM Classification should be comprehensively discussed. Please join us in presenting this Special Issue on the risk stratification on pheochromocytoma and paraganglioma from the point of view of laboratory and clinical medicine.

Dr. Noriko Kimura
Guest Editor

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Keywords

  • Metastasis
  • SDHB
  • Genes
  • Histology
  • GAPP
  • Catecholamine types and levels
  • Imaging
  • Prognosis
  • ICD-O code
  • TNM classification

Published Papers (5 papers)

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Research

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Open AccessArticle
Functioning Mediastinal Paraganglioma Associated with a Germline Mutation of von Hippel-Lindau Gene
J. Clin. Med. 2018, 7(6), 116; https://doi.org/10.3390/jcm7060116 - 23 May 2018
Abstract
We report the case of a 21-year old woman presenting with high blood pressure and raised normetanephrine levels. Indium-111-pentetreotide single photon-emission computed tomography with computed tomography (SPECT/CT) and 2-deoxy-2-[fluorine-18]fluoro-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging showing isolated tracer-uptake by a [...] Read more.
We report the case of a 21-year old woman presenting with high blood pressure and raised normetanephrine levels. Indium-111-pentetreotide single photon-emission computed tomography with computed tomography (SPECT/CT) and 2-deoxy-2-[fluorine-18]fluoro-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging showing isolated tracer-uptake by a 2 cm tumor close to the costovertebral angle of the third thoracic vertebra. Thoracic surgery led to normalization of normetanephrine levels. Histological findings were consistent with the presence of a paraganglioma. Mutations in SDHA, SDHB, SDHC, SDHD, RET, SDHAF2, TMEM127, MAX, NF1, FH, MDH2, and EPAS1 were absent, but a heterozygous missense mutation, c.311G > T, was found in exon 1 of the von Hippel-Lindau gene, VHL, resulting in a glycine to valine substitution in the VHL protein at position 104, p.Gly104Val. This same mutation was found in both the mother and the 17-year old sister in whom a small retinal hemangioblastoma was also found. We diagnose an unusual functional mediastinal paraganglioma in this young patient with a germline VHL gene mutation, a mutation previously described as inducing polycythemia and/or pheochromocytoma but not paraganglioma or retinal hemangioblastoma. Full article
(This article belongs to the Special Issue Pheochromocytoma and Paraganglioma: Research Update)
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Open AccessArticle
Disease and Treatment-Related Sequelae in Patients with Complex Jugulotympanic Paraganglioma
J. Clin. Med. 2018, 7(3), 51; https://doi.org/10.3390/jcm7030051 - 10 Mar 2018
Abstract
Background: Jugulotympanic paraganglioma (JTP) are benign, high-vascularized lesions that frequently invade the jugular foramen, temporal bone, the upper neck, and the posterior fossa cavity, resulting in a wide variety of clinical symptoms. Methods: In this retrospective study, we assess the clinical symptoms and [...] Read more.
Background: Jugulotympanic paraganglioma (JTP) are benign, high-vascularized lesions that frequently invade the jugular foramen, temporal bone, the upper neck, and the posterior fossa cavity, resulting in a wide variety of clinical symptoms. Methods: In this retrospective study, we assess the clinical symptoms and discuss the individual multidisciplinary treatment and outcome of 22 patients with JTP. Results: In 12 patients, a hearing deficit was the presenting symptom, whereas pulsatile tinnitus and otalgia were present in six and four patients respectively. Facial nerve involvement was seen in six patients (three HB Grade 1–2 and three HB Grade 4–6). Four patients presented with lower cranial nerve impairment. Rare symptoms were ataxia caused by brainstem compression and papilledema due to cerebral sinus obstruction. A new or worsening of the preoperative facial nerve or lower cranial nerve function occurred in two and four patients respectively. Conclusion: The treatment strategy and the surgical approach for JTP should be tailored to the tumor extension and the patient’s clinical symptoms. Full article
(This article belongs to the Special Issue Pheochromocytoma and Paraganglioma: Research Update)
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Review

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Open AccessReview
The Diagnosis and Clinical Significance of Paragangliomas in Unusual Locations
J. Clin. Med. 2018, 7(9), 280; https://doi.org/10.3390/jcm7090280 - 13 Sep 2018
Cited by 8
Abstract
Paragangliomas are neuroendocrine neoplasms, derived from paraganglia of the sympathetic and parasympathetic nervous systems. They are most commonly identified in the head and neck, being most frequent in the carotid body, followed by jugulotympanic paraganglia, vagal nerve and ganglion nodosum, as well as [...] Read more.
Paragangliomas are neuroendocrine neoplasms, derived from paraganglia of the sympathetic and parasympathetic nervous systems. They are most commonly identified in the head and neck, being most frequent in the carotid body, followed by jugulotympanic paraganglia, vagal nerve and ganglion nodosum, as well as laryngeal paraganglia. Abdominal sites include the well-known urinary bladder tumors that originate in the Organ of Zuckerkandl. However, other unusual sites of origin include peri-adrenal, para-aortic, inter-aortocaval, and paracaval retroperitoneal sites, as well as tumors in organs where they may not be expected in the differential diagnosis of neuroendocrine neoplasms, such as thyroid, parathyroid, pituitary, gut, pancreas, liver, mesentery, lung, heart and mediastinum. The distinction of these lesions from epithelial neuroendocrine neoplasms is critical for several reasons. Firstly, the determination of clinical and biochemical features is different from that used for epithelial neuroendocrine tumors. Secondly, the genetic implications are different, since paragangliomas/pheochromocytomas have the highest rate of germline susceptibility at almost 40%. Finally, the characterization of metastatic disease is unique in these highly syndromic lesions. In this review, we summarize updated concepts by outlining the spectrum of anatomic locations of paragangliomas, the importance of morphology in establishing the correct diagnosis, the clinical implications for management, and the impact of genetics on the distinction between multifocal primary tumors compared with malignant disease. Full article
(This article belongs to the Special Issue Pheochromocytoma and Paraganglioma: Research Update)
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Open AccessReview
Risk Stratification on Pheochromocytoma and Paraganglioma from Laboratory and Clinical Medicine
J. Clin. Med. 2018, 7(9), 242; https://doi.org/10.3390/jcm7090242 - 27 Aug 2018
Cited by 6
Abstract
Pheochromocytoma (PCC) and sympathetic paraganglioma (PGL) are rare neuroendocrine tumors characterized by catecholamine production in the adrenal medulla and extra-adrenal paraganglia. PCC and PGL (PPGL) with metastasis was termed malignant PPGL. However, the distinction between “benign” and “malignant” PPGLs has been debated. Currently, [...] Read more.
Pheochromocytoma (PCC) and sympathetic paraganglioma (PGL) are rare neuroendocrine tumors characterized by catecholamine production in the adrenal medulla and extra-adrenal paraganglia. PCC and PGL (PPGL) with metastasis was termed malignant PPGL. However, the distinction between “benign” and “malignant” PPGLs has been debated. Currently, all PPGLs are believed to have some metastatic potential and are assigned malignant tumors (ICD-O/3) by the WHO Classification of Endocrine Organs (2017, 4th edition). Therefore, the previous categories benign and malignant PPGL have been eliminated in favor of risk stratification approach. The Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) is a tool for risk stratification for predicting metastasis and the prognosis of patients. At least 30% of PPGLs are hereditary, with 20 genes identified and genotype-phenotype correlations clarified. Of these genes, VHL, RET and NF1 have been well investigated and are the primary cause of bilateral PCC. In addition, mutation of succinate dehydrogenase gene subunits SDHB and SDHD are strongly correlated with extra-adrenal location, younger age, multiple tumors, metastasis and poor prognosis. Disease stratification by catecholamine phenotype and molecular profiling correlates with histological grading by GAPP. PPGLs should be understood comprehensively based on clinical, biochemical, molecular and pathological data for patient care. A flow chart for pathological diagnosis is included. Full article
(This article belongs to the Special Issue Pheochromocytoma and Paraganglioma: Research Update)
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Other

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Open AccessCase Report
Facial Nerve Paralysis after Onyx Embolization of a Jugular Paraganglioma: A Case Report with a Long-Term Follow Up
J. Clin. Med. 2018, 7(3), 48; https://doi.org/10.3390/jcm7030048 - 07 Mar 2018
Abstract
Jugular paragangliomas are slow growing highly vascular tumors arising from jugular paraganglia. The gold standard of treatment is complete surgical resection. Pre-operative embolization of these highly vascular tumors is essential to reduce intra-operative bleeding, allow safe dissection, and decrease operative time and post-operative [...] Read more.
Jugular paragangliomas are slow growing highly vascular tumors arising from jugular paraganglia. The gold standard of treatment is complete surgical resection. Pre-operative embolization of these highly vascular tumors is essential to reduce intra-operative bleeding, allow safe dissection, and decrease operative time and post-operative complications. Onyx (ethylene-vinyl alcohol copolymer) has been widely used as permanent occluding material for vascular tumors of skull base because of its unique physical properties. We present the case of a 33-year-old woman who had left-sided facial nerve paralysis after Onyx embolization of jugular paraganglioma. The tumor was resected on the next day of embolization. The patient was followed up for 30 months with serial imaging studies and facial nerve assessment. The facial verve function improved from House–Brackmann grade V to grade II at the last visit. Full article
(This article belongs to the Special Issue Pheochromocytoma and Paraganglioma: Research Update)
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