Metastatic Paraganglioma

doi:10.1053/j.seminoncol.2010.10.017

Seminars in Oncology

Volume 37, Issue 6, December 2010, Pages 627-637

https://doi.org/10.1053/j.seminoncol.2010.10.017 Get rights and content

Paragangliomas (PGLs) are chromaffin cell tumors arising from ganglia; when arising in the adrenal gland they are called pheochromocytomas. In recent years the opinion that metastatic disease is rare in PGL had to be revised, particularly in patients presenting with extra-adrenal PGL, with PGLs exceeding 5 cm in diameter, and/or those carrying an SDHB germline mutation. Metastases are expected to be present at the time of diagnosis in more than 10% of these patients. Measurement of plasma and urinary metanephrine levels is well established in diagnosing PGL. Recently, a dopaminergic phenotype (excess dopamine or methoxytyramine) was recognized as a good indicator of metastatic disease. Vast progress in targeted positron emission tomography (PET) imaging (eg, ¹⁸F-FDA, ¹⁸F-FDOPA, ¹⁸F-FDG) now allows for reliable early detection of metastatic disease. However, once metastases are present, treatment options are limited. Survival of patients with metastatic PGL is variable, and frequently short. Here we review recent advances involving findings about the genetic background, the molecular pathogenesis, new diagnostic indicators, pathologic markers, and emerging treatment options for metastatic PGL.

Section snippets

Rule of Ten Percent Overcome

PGL has long been considered as the disease of 10% (10% metastatic, 10% familial, 10% recurring, 10% extra-adrenal, 10% occurring in children). However, improved diagnostic techniques showed that the rule of 10% does not accurately characterize PGL. Overall, 0% to 36% of PGL patients develop metastatic disease, depending on the type of tumor³ (Table 1). The percentage of PGL with family history has been revised to approximately 30%.4, 5 Extra-adrenal tumors have been reported in 15% to 20% of

Genetic Predispositions

Up to 30% of PGLs appear to present in a hereditary manner.4, 5 To date, eight different germline mutations are associated with PGL (NF1: van Recklinghausen neurofibromatosis type 1; RET: multiple endrocrine neoplasia type 2; VHL: von Hippel-Lindau disease; SDH-B, -C, -D: familial PGL syndrome 4, 3, 1; SDH5⁷ [also referred to as SDHAF1]: familial PGL syndrome 2; TMEM127: familial PGL). However, SDH5/SDHAF1 mutations seems to be rare and should be suspected only in very young patients with HNP

Metastatic Paraganglioma: Does Location Play a Role?

PGL tissue from different locations appears similar microscopically. However, the prognosis is quite different for different tumor locations.

Patients with PHEO rarely develop metastases. Also, metastases secondary to HNP seem to be infrequent.¹⁷ However, development of metastatic disease in patients with eaPGL and/or multiple PGLs has been reported frequently.¹⁸ Patients with SDHB-derived PGL are more prone to developing metastatic disease. However, the primary tumor location most often found

Metastatic Paraganglioma in Children

PGL in children is rare; thus studies including a representative cohort of pediatric patients are sparse and often contradictory. Available studies were recently reviewed by Havekes et al.²²

Pediatric PGL appeared to be related to germline mutation frequently, even in the absence of family history (30%,²³ 39%,²⁴ 59%,²⁵ up to 80% [own unpublished observations]). Mutation of the VHL gene has been reported as predominant in pediatric patients.24, 26 However, in a large group of children and

Insights into the Pathogenesis of Metastatic Paraganglioma

Cell culture experiments suggest that apoptosis resistance in absence of nerve growth factor (NGF) is common to several hereditary forms of PGL.²⁹ Thus, familial PGL may develop due to impaired culling of neural crest cells during the development of chromaffin tissues. NGF is an essential survival factor for developing neuroendocrine cells. Later in development, NGF becomes scarce, leading to neuronal culling. Survival of cultured cells, with impaired NF1, RET, or VHL gene expression, was

Markers for Malignant Paraganglioma

Currently there are no reliable markers for metastatic disease in PGL. The single way to diagnose malignancy is the presence of metastases. Thus, patients with PGL ultimately require follow up because metastatic disease or recurrence can appear even after decades free of disease.

Many pathologic markers of malignancy used in other tumors were evaluated for PGL, but to date none could be sufficiently confirmed as a diagnostic or prognostic tool (summarized elsewhere2, 52, 53, 54). Among them were

Diagnosis of Metastatic Paraganglioma

Signs and symptoms of patients bearing metastatic disease cannot be distinguished from those of patients with solitary or multiple PGLs. In some cases, symptoms related to tumor burden of metastases are present. Most often patients with metastatic as well as nonmetastatic PGLs suffer from hypertension caused by the tumor's hypersecretion of catecholamines. As described below, the secretion profile of a tumor can present valuable clues about tumor location and the possibility of multiple lesions

Biochemical Phenotype of Metastatic Paraganglioma

Currently, the diagnostic gold standard for PGL is an elevated plasma and/or urine metanephrine level. When a PGL is present, catecholamine levels also can be elevated in plasma and urine, but due to their lower stability they show a lower sensitivity as a diagnostic tool than metanephrines.⁶³ For reliable results it is recommended to collect samples from relaxed patients. For plasma collection, patients should rest in the supine position without a pillow for at least 20 minutes after insertion

Current Approaches to Detect Metastatic Paraganglioma

Following detection of elevated catecholamines and/or their metabolites or if PGL is otherwise suspected, confirmatory diagnosis and/or localization of PGL and possible metastases is necessary. Tumors can often be localized by computed tomography (CT) and/or magnetic resonance imaging (MRI). Nonspecific functional imaging modalities, such as ¹⁸F-FDG–PET and octreotide scintigraphy are also applied. However, only functional imaging techniques using tracers that are specifically internalized by

Management and Treatment of Malignant Paraganglioma

Once the presence of metastases is verified, there is no reliable cure. Treatment options are: (1) mechanical removal by excision or ablation; (2) targeted pharmaceutics; or (3) chemotherapy. Recently, current treatment options were excellently summarized.79, 80, 81

Conclusion

Tyrosine kinase inhibitors are the most common therapeutic option at present. However, their efficacy may be limited, especially in SDHB-related metastatic PGL. Perhaps some new tyrosine kinase inhibitors, like axitinib, may be of better value. Ultratrace lobenguane ¹³¹I showed the first promising results, but additional studies are needed. While promising based on preliminary studies, patient trials targeting the ST3 (perhaps in combination with dopamine receptor antagonists) and IL-13

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Stereotactic radiotherapy (SRT) is an effective treatment for head & neck (H&N) paragangliomas. Nevertheless, the timeline for achieving a tumor-volume-reduction (TVR) remains unclear.
Sixty-three cases with H&N paragangliomas received definitive SRT and were evaluated retrospectively. Statistical Package for the Social Sciences (SPSS) v23.0 (IBM, Armonk, NY, USA) was used for statistics.
Sixty-eight lesions were irradiated, with glomus jugulotympanicum being the most common location (44 %). Median tumor diameter and volume were 3 cm (range, 1–7.6 cm) and 15.4 cm³ (range,1–185 cm³), respectively. Median dose was 25 Gy (range, 12–37.5 Gy) in 5 fractions (range, 1–5 fractions). Median follow-up was 40 months (range, 3–184 months). Treatment response, evaluated at a median 4.6 months post-SRT (range: 3–11 months), revealed TVR in 26 cases (41 %). During follow-up, 13 additional cases showed TVR, resulting in an overall TVR rate of 62 %. The median duration for attaining TVR was 9 months (range, 3–36 months) after SRT, and TVR occurred ≥ 12 months in 42 % of cases. Patients without prior surgery (p = 0.03) and with a longer follow-up (p = 0.04) demonstrated a higher rate of TVR. The likelihood of TVR tends to increase as the SRT dose increases (p = 0.06). Overall local control (LC) rate was 100 %. No ≥ grade 3 acute or late toxicities were observed.
While SRT demonstrates an excellent LC rate for H&N paragangliomas, it's important to note that the response to treatment may require time. TVR may last beyond the initial year of treatment in a substantial proportion of patients.
Mediastinal Paraganglioma: A retrospective analysis of 51 cases
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Paragangliomas are rarely found in the mediastinum, where they account for a small proportion of mediastinal masses. This study aimed to better characterize the presenting features and relevant aspects in optimizing the diagnosis and treatment of mediastinal paragangliomas.
A computer-assisted search of electronic health records was performed to identify adult patients (≥18 years) who underwent evaluation for a primary mediastinal paraganglioma at Mayo Clinic between January 2000 and April 2022. Medical charts, laboratory tests and radiology images were reviewed to collect data.
The study included 51 patients, each with a single mediastinal paraganglioma. The median age was 47 years (IQR: 39–67), 67% females. Symptoms of catecholamine excess were manifest in 39% of patients, and 14% presented with mass effect, while the remaining 47% had no paraganglioma-related symptoms. Genetic testing was performed in 35 patients; 66% harbored a pathogenic variant in the succinate dehydrogenase enzyme complex. Most paragangliomas (71%) were in the middle mediastinum and showed uptake of intravenous contrast on chest imaging. Biopsies were performed in 30 (59%) patients; 27% were inconclusive and 10% resulted in major complications. Surgical resection occurred in 75%, primarily for relief of symptoms (50%) followed by proximity to critical structures (45%). Perioperative complications were common (66%), but there were no cases of local tumor recurrence during the follow-up period (median 8 years; IQR: 4–13).
Mediastinal paragangliomas are most located in the middle mediastinum and can often be diagnosed noninvasively using a combination of clinical, biochemical, and radiological features.
A rare presentation of head and neck Paragangliomas in parotid gland: A case report
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Paragangliomas (PGLs) are masses that originate from the neural crest. Carotid bifurcation, jugular foramen, and along vagal nerve course are common sites for PGLs. Meanwhile, the head and neck are unusual places that PGLs arise. This article reported a 54-year-old man with an uncommon PGL from the parotid gland. We also described his signs, symptoms, laboratory data, imaging studies, and pathology. The external carotid was embolized, followed by a successful resection of the right parotid gland's superficial lobe and the tumor mass.
As far as our consideration, this is the second case of PGL of the parotid gland in the literature. In addition, we reviewed and compared the information of the previously reported case. As a result, PGLs should be considered as a differential diagnosis for parotid gland masses in highly suspected patients.
Management of SHDB positive patient with metastatic bilateral giant retroperitoneal paragangliomas
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Citation Excerpt :
Metastatic PGL is rare, with an estimated incidence of 93 cases per 400 million persons, in the United States.3 The most common sites of PGL metastasis are lymph nodes, bone, liver, and lungs.4 The development of metastasis in PGL cannot be predicted reliably by any histologic or pathologic marker, however presence of somatic mutations and primary tumor size appear to be two critical clinical factors.5
Paragangliomas are rare neuroendocrine tumors that can vary in size and metabolic activity. We report a case of giant bilateral malignant retroperitoneal paragangliomas (PGL) in a patient with germline succinate dehydrogenase B (SDHB) mutation. This patient, who presented in an emaciated and debilitated state, was managed with adrenergic blockade followed by radical primary surgery. After being metabolically and radiographically disease free for 4 years, he underwent salvage resection for recurrent retroperitoneal disease and palliative radiation to a site of solidary vertebral metastasis. We review incidence and prognosis of metastatic PGL.
PET/CT Variants and Pitfalls in Head and Neck Cancers Including Thyroid Cancer
2021, Seminars in Nuclear Medicine
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They are usually nonfunctioning and benign, demonstrating only local invasion.172,173 There are no histopathological criteria to accurately define a malignant paraganglioma and therefore malignancy is defined by the presence of metastases.174 Less than 5% of paragangliomas of the head and neck metastasize and this number is even lower for carotid body lesions.170
PET/CT imaging is a dual-modality diagnostic technology that merges metabolic and structural imaging. There are several currently available radiotracers, but ¹⁸F-FDG is the most commonly utilized due to its widespread availability. ¹⁸F-FDG PET/CT is a cornerstone of head and neck squamous cell carcinoma imaging. ⁶⁸Ga-DOTA-TOC is another widely used radiotracer. It allows for whole-body imaging of cellular somatostatin receptors, commonly expressed by neuroendocrine tumors and is the standard of reference for the characterization and staging of neuroendocrine tumors.
The normal biodistribution of these PET radiotracers as well as the technical aspects of image acquisition and inadequate patient preparation affect the quality of PET/CT imaging. In addition, normal variants, artifacts and incidental findings may impede accurate image interpretation and can potentially lead to misdiagnosis. In order to correctly interpret PET/CT imaging, it is necessary to have a comprehensive knowledge of the normal anatomy of the head and neck and to be cognizant of potential imaging pitfalls. The interpreter must be familiar with benign conditions which may accumulate radiotracer potentially mimicking neoplastic processes and also be aware of malignancies which can demonstrate low radiotracer uptake.
Appropriate use of structural imaging with either CT, MR or ultrasound can serve a complimentary role in several head and neck pathologies including local tumor staging, detection of bone marrow involvement or perineural spread, and classification of thyroid nodules. It is important to be aware of the role of these complementary modalities to maximize diagnostic accuracy and patient outcomes.
The purpose of this article is to outline the basic principles of PET/CT imaging, with a focus on ¹⁸F-FDG PET/CT and ⁶⁸Ga-DOTA PET/CT. Basic physiology, variant imaging appearances and potential pitfalls of image interpretation are presented within the context of common use cases of PET technology in patients with head and neck cancers and other pathologies, benign and malignant.
MITOCHONDRIA: Succinate dehydrogenase subunit B-associated phaeochromocytoma and paraganglioma
2021, International Journal of Biochemistry and Cell Biology
Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours. So far, over 20 causative genes have been identified, of which the most frequent and strongest indicator for malignancies are mutations in succinate dehydrogenase subunit B. No curative therapy is available for patients with metastases resulting in poor prognosis. Therapy development has been hindered by lack of suitable model systems. The succinate dehydrogenase complex is located in the inner membrane of the mitochondria and plays a crucial role in the oxidative phosphorylation chain and the tricarboxylic acid-cycle. Succinate dehydrogenase deficiency results in accumulation of the oncometabolite succinate inducing hypoxia inducible factor stabilization, deoxyribonucleic acid and histone methylation inhibition, and impaired production of adenosine triphosphate. It remains unknown which combination of pathways and/or triggers are decisive for metastases development. In this review, the role of mitochondria in malignant succinate dehydrogenase subunit B-associated phaeochromocytomas and paragangliomas and implications for mitochondria as therapeutic target are discussed.

View all citing articles on Scopus

: Disclosure statement: the authors have nothing to disclose.

: Funding was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

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Endocrine cancerMetastatic Paraganglioma

Section snippets

Rule of Ten Percent Overcome

Genetic Predispositions

Metastatic Paraganglioma: Does Location Play a Role?

Metastatic Paraganglioma in Children

Insights into the Pathogenesis of Metastatic Paraganglioma

Markers for Malignant Paraganglioma

Diagnosis of Metastatic Paraganglioma

Biochemical Phenotype of Metastatic Paraganglioma

Current Approaches to Detect Metastatic Paraganglioma

Management and Treatment of Malignant Paraganglioma

Conclusion

Lancet

Lancet Oncol

Otolaryngol Head Neck Surg

J Pediatr Surg

J Pediatr Surg

Cancer Cell

Cancer Cell

Cancer Cell

Mitochondrion

Mod Pathol

Lancet Oncol

Pharmacol Ther

Pharmacol Ther

J Vasc Interv Radiol

Surgery

Ein Fall von doppelseitigem, völlig latent verlaufenen Nebennierentumor und gleichzeitiger Nephritis mit Veränderungen am Circulationsapparat und Retinitis

Virchows Arch

Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005

Nat Clin Pract Endocrinol Metab

Clinical spectrum and outcome of functional extraadrenal paraganglioma

World J Surg

Familial nonsyndromic pheochromocytoma

Ann N Y Acad Sci

Pheochromocytoma: the expanding genetic differential diagnosis

J Natl Cancer Inst

SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma

Science

Germline mutations in TMEM127 confer susceptibility to pheochromocytoma

Nat Genet

Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas

J Clin Endocrinol Metab

PHD2 mutation and congenital erythrocytosis with paraganglioma

N Engl J Med

Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas

J Clin Endocrinol Metab

Genetic testing in pheochromocytoma or functional paraganglioma

J Clin Oncol

Phaeochromocytoma, new genes and screening strategies

Clin Endocrinol (Oxf)

Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas

Cancer Res

Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with SDHB-associated pheochromocytomas and paragangliomas

J Clin Endocrinol Metab

The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas

J Clin Endocrinol Metab

High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing

J Clin Endocrinol Metab

Management of malignant pheochromocytoma

Endocrinologist

Malignant pheochromocytoma

Front Horm Res

Update on pediatric pheochromocytoma

Pediatr Nephrol

Pheochromocytoma and paraganglioma in children: a review of medical and surgical management at a tertiary care center

Pediatrics

Characteristics of pheochromocytoma in a 4- to 20-year-old population

Ann N Y Acad Sci

Germ-line mutations in nonsyndromic pheochromocytoma

N Engl J Med

Pheochromocytoma in children and adolescents

Indian J Pediatr

Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations

Hum Mol Genet

A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas

PLoS Genet

Novel pheochromocytoma susceptibility loci identified by integrative genomics

Cancer Res

Endocrine cancer
Metastatic Paraganglioma