Extra-adrenal Paragangliomas Research Articles

Metastatic Paraganglioma

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, (18)F-FDA, (18)F-FDOPA, (18)F-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.

Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma

The last 10 years have seen enormous progress in the field of paraganglioma and pheochromocytoma genetics. The identification of the first gene related to paraganglioma, SDHD, encoding a subunit of mitochondrial succinate dehydrogenase (SDH), was quickly followed by the identification of mutations in SDHC and SDHB. Very recently several new SDH-related genes have been discovered. The SDHAF2 gene encodes an SDH co-factor related to the function of the SDHA subunit, and is currently exclusively associated with head and neck paragangliomas. SDHA itself has now also been identified as a paraganglioma gene, with the recent identification of the first mutation in a patient with extra-adrenal paraganglioma. Another SDH-related co-factor, SDHAF1, is not currently known to be a tumor suppressor, but may shed some light on the mechanisms of tumorigenesis. An entirely novel gene associated with adrenal pheochromocytoma, TMEM127, suggests that other new paraganglioma susceptibility genes may await discovery. In addition to these recent discoveries, new techniques related to mutation analysis, including genetic analysis algorithms, SDHB immunohistochemistry, and deletion analysis by MLPA have improved the efficiency and accuracy of genetic analysis. However, many intriguing questions remain, such as the striking differences in the clinical phenotype of genes that encode proteins with an apparently very close functional relationship, and the lack of expression of SDHD and SDHAF2 mutations when inherited via the maternal line. Little is still known of the origins and causes of truly sporadic tumors, and the role of oxygen in the relationships between high-altitude, familial and truly sporadic paragangliomas remains to be elucidated.

Hereditäre und nichthereditäre syndromale gastrointestinale Stromatumoren

The majority of gastrointestinal stromal tumours (GISTs) present as solitary gastrointestinal masses in adults aged 50-70years. A small subset of GISTs (≤5%) occurs in the setting of familial or idiopathic multitumour syndrome. In decreasing order of frequency, neurofibromatosis Recklinghausen (NF-1), Carney triad (gastric GIST, pulmonary chondroma and extra-adrenal paraganglioma), familial GIST syndromes resulting from germline mutations in c-Kit/PDGFRA and the Carney-Stratakis syndrome (hereditary GIST paraganglioma syndrome caused by germline mutations in the mitochondrial tumour suppressor gene pathway involving the succinate dehydrogenase subunits SDHD, SDHC and SDHB) represent the four most important GIST syndromes characterized to date. Since affected patients and their family members require special treatment and/or counseling and follow-up, early diagnosis and precise classification of this likely still underdiagnosed diseases is of the utmost importance. This review summarizes the pertinent clinicopathological and molecular features of the main GIST syndromes to facilitate their diagnosis and distinction from their non-syndromic mimics.

Update on tumours of the adrenal cortex, phaeochromocytoma and extra‐adrenal paraganglioma

This review covers aspects of adrenal cortical tumours, phaeochromocytoma and extra-adrenal paragangliomas. Relevant clinical and epidemiological information is included. It is now known that about 30% of paragangliomas occur in a familial setting and these new aspects of the genetic background are presented. The main diagnostic problem in both groups of tumours is the recognition of malignant potential. The uses and limitations of multifactorial histological assessment in diagnosis and prognosis are discussed. Finally, data on the molecular changes associated with tumorigenesis and tumour progression are highlighted, and how this information may contribute in future to diagnosis and prognosis.

Clinical, Radiologic and Pathologic Characteristics of the Carney Triad: A Case Report and Literature Review

This report describes a patient with a gastrointestinal stromal tumor (GIST) and upper gastrointestinal hemorrhage as initial presentations of the Carney triad, a synchronous or metachronous condition involving gastric leiomyosarcoma, extra-adrenal paraganglioma and pulmonary chondroma. A 26-year-old woman presented with dizziness and several episodes of melena over 3 days. Physical examination revealed pale conjunctiva but normal hemodynamic status. Gastroendoscopy showed one antral submucosal tumor with evidence of an associated bleeder (the bleeder over the mucosal surface of the gastric tumor). An abdominal computed tomography scan showed an antral submucosal tumor, two secondary lesions over segment II/V of the liver and a retroperitoneal tumor. Surgical removal of the tumor and subsequent recovery were uneventful. The gastric GIST with liver metastasis and retroperitoneal paraganglioma were confirmed by pathologic study. The patient was treated with imatinib mesylate for the GIST with liver metastasis, and continued follow-up treatment at our hospital. An abdominal computed tomography scan at 32 months after surgery showed no change in the liver metastatic lesions and no evidence of local recurrence. Another follow-up visit at 33 months after surgery confirmed the stable condition. Of nearly 100 cases reported in the literature, this case is the first to be reported in Taiwan. This case highlights the possibility of this rare syndrome occurring in young female patients with one of the three components of the triad and the need for further diagnostic studies for early identification of tumors when curative surgery is still possible.

L157X nonsense mutation of the succinate dehydrogenase subunit B gene in a Japanese patient with right paraaortic paraganglioma

Nuclear genes succinate dehydrogenase B subunit and succinate dehydrogenase D subunit, which encode two mitochondrial complex II subunits, are associated with the development of familial paraganglioma (PGL). Succinate dehydrogenase B subunit gene mutation is highly associated with extraadrenal PGL and subsequent distant metastasis. We describe the case of a 29-year-old Japanese man with a 3-year history of hypertension, headache, and palpitation. Endocrinological examinations showed that the patient had elevated levels of catecholamines, and imaging studies revealed a right paraaortic PGL without distant metastases. The PGL was surgically removed. Genetic analysis of the patient showed a heterozygous thymine deletion at position 470 (c.470delT) in exon 5 of the succinate dehydrogenase B subunit gene complementary DNA. This thymine deletion changed TTG (leucine) to TGA (stop codon) at codon 157 (L157X). It remains unclear whether this mutation was associated with PGL malignancy because the patient has had no metastases for the past 3 years. It has been recently reported that L157X is associated with malignant paraaortic PGL. Thus, strict follow-up is required because this succinate dehydrogenase B subunit gene's nonsense mutation (L157X) may be related to the malignancy.

Composite ganglioneuroma-paraganglioma of the filum terminale

Extraadrenal paragangliomas are most commonly found in the carotid body and are also found with lower frequency in the CNS. These lesions are derived from the sympathoadrenal lineage of neural crest cells. Here, the authors report a rare case of a composite paraganglioma with ganglioneuromatous components found at the filum terminale in a patient who presented with a brief history of low-back pain and paresthesias in the inguinal region. Immunohistochemical analysis of the resected lesion revealed admixed elements of neuroendocrine and neuroblastoma lineages, indicating the presence of divergent differentiation of sympathoadrenal progenitor cells. This case represents a unique opportunity to understand the cell fate of sympathoadrenal progenitor cells. Here, the authors propose that paragangliomas at the filum terminale can revert to a neural crest cell precursor fate, giving rise to divergent neoplastic populations.

Intra-tumoral molecular heterogeneity in benign and malignant pheochromocytomas and extra-adrenal sympathetic paragangliomas

Pheochromocytomas (PCCs) and extra-adrenal sympathetic paragangliomas (sPGLs) are catecholamine-producing tumors occurring in the context of hereditary tumor syndromes, with known germline mutations, and as sporadic tumors. The pathogenesis of sporadic PCC and sPGL is poorly understood, and little is known about intra-tumoral heterogeneity with respect to molecular aberrations. Since knowledge on intra-tumoral heterogeneity is important for understanding the pathogenesis of these tumors, we investigated 12 benign and 8 malignant PCCs and sPGLs for loss of heterozygosity (LOH) on DNA extracted from different regions of each tumor and from metastases. LOH markers were selected on chromosomal regions frequently deleted in PCC, including 1p, 3q, 3p, and 11p. Benign tumors were found to have less intra-tumoral heterogeneity (overall 8%) than malignant tumors (overall 23%), with the highest frequencies for chromosome 1p36 in the benign tumors (17%) and 1p13 and 3q24 in malignant tumors (both 38%). In addition, differences in LOH patterns were detected between paired primary malignant tumors, and their metastases and different LOH patterns were observed in bilateral PCC of a multiple endocrine neoplasia type 2 patient. We demonstrate that malignant PCC and sPGL have more intra-tumoral molecular heterogeneity than benign tumors, which suggests that benign and malignant PCC and sPGL have a different pathogenesis.

A Case of Extra-Adrenal Paraganglioma Localized in Retroperitoneum Diagnosed With FDG-PET

Abstract:Paragangliomas are extremely rare chromaffin cell tumors arising from neural crest cells. Extra-adrenal paragangliomas originate from paravertebral and para-aortic paragangliomas distributed from the skull base to the pelvic floor. Here, we report a 57-year-old woman who presented with abdo

Metastatic Extra-Adrenal Sympathetic Paraganglioma in a Horse

Post-mortem examination was performed on a horse that died after exhibiting signs of colic. Gross findings included haemoperitoneum and a large round encapsulated mass located in the sublumbar area cranial to the left kidney. On sectioning the mass was solid red to brown and small nodules of similar tissue were noted at the periphery of the mass. The spleen was firm and three nodules were found in one thyroid gland. Microscopically, the abdominal mass, adjacent nodules, the spleen and one thyroid nodule consisted of clusters and cords of round to oval neoplastic cells, separated by a fine collagen and reticulin fibre network. Immunohistochemically, tumour cells expressed chromogranin A, synaptophysin and neuron-specific enolase, but did not express cytokeratin. The findings were consistent with a metastatic extra-adrenal sympathetic paraganglioma.

A decade of clinical experience with extra-adrenal paragangliomas of retroperitoneum: Report of 67 cases and a literature review

Object:The purpose was to highlight the diagnosis and treatment of extra-adrenal para-gangliomas, which often causes catecholamine hypersecretion and hypertension.Methods:67 cases of extra-adrenal paraganglioma of retroperitoneum proven pathologically from 1999 to 2009 were reviewed and studied after operation. Endocrine secretion examinations, B-US, CT, MRI, 131-MIBG, octreotide and hands microcirculation inspection were used to diagnose the disease.Results:All patients underwent successful surgical resection of the tumors, which proved to be paragangliomas. They were from 3 cm to 25 cm in size. Almost all of them were diffusely positive for cgA, syn, NSE and s-100 by immunohitochemical staining. There were nine cases assayed malignant paraganglioma by the follow-up.Conclusions:131-MIBG and octreotide have high sensitivity and accuracy in diagosing extra-adrenal paraganglioma. Surgical treatment should be carried out on the basis of correct drug preparation of α-receptor blocker, such as prazosin and phenoxybenzamine. Complete surgical excision is the treatment of choice for extra-adrenal paragangliomas as well as recurrent or metastatic disease, which could be resected laparoscopically. Intimate lifelong follow-up is necessary and important.

Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases.

Carney triad, as originally described in 1977, was the association of 3 tumors: gastric epithelioid leiomyosarcoma [later renamed gastrointestinal stromal tumor (GIST)], extra-adrenal paraganglioma, and pulmonary chondroma. The disorder affected mostly young women and was not familial. We studied the clinical and pathologic features of the gastric neoplasm in 104 patients with the syndrome. Most (88%) were young women (mean age, 22 y), and the usual presentation was gastric bleeding. The tumors, commonly antral-based (61%), were multifocal, and ranged from 0.2 to 18.0 cm in dimension. Most (86%) featured round and polygonal (epithelioid) cells. Metastasis occurred in 49 patients (47%): to gastric lymph nodes (29%), liver (25%), and peritoneum (13%). Immunopositivity was detected in the tumors tested as follows: KIT, 100%; CD34, 75%; PKCtheta, 21%; PDGFRA, 90%; and smooth muscle actin, 6%. Fourteen patients (13%) died of metastatic GIST at a mean age of 45 years (range, 30 to 69 y). Estimated 10 and 40-year survivals were 100% and 73%, respectively. Median survival time was 26.5 years (range, 16 to 60 y). There was no correlation between the National Institutes of Health tumor risk classification and the tumor behavior. Compared with sporadic gastric GISTs, the gastric stromal tumor in Carney triad showed distinctive features: female predilection, young patient age, epithelioid cell predominance, multifocality, frequent lymph node metastasis, serial tumor occurrence, and unpredictable behavior. Thus, the Carney triad gastric stromal tumor is different clinically, pathologically, and behaviorally from sporadic gastric GIST.

Novel Germline SDHB Mutation in a 35-Year-Old Male with Malignant Bladder Paraganglioma

ABSTRACT Objective Up to 25% of pheochromocytomas and paragangliomas (PGL) are associated with germline mutations in RET, VHL, NF1, and subunits A, B, C, or D of succinate dehydrogenase (SDH). SDHB mutations are associated with malignant extra-adrenal PGL. Codon specific genotype-phenotype relationships have not been identified. Herein is described a case of malignant bladder paraganglioma from a novel W200R SDHB mutation. The literature is reviewed and clinical management is discussed. Methods Literature review was performed to analyze the relationship between SDHB and PGL, yielding 45 unique articles, which were reviewed and cross-referenced. Results SDHB mutations have a 50% penetrance by age 35, 1/3 of paragangliomas are multifocal, 31 to 48% are malignant, and 50 to 70% of these malignant PGL develop metastases. Conclusion Based on the aggressive nature of the SDHB mutation, we recommend preoperative staging, an aggressive treatment regimen, and intensive screening for recurrence.

Local-regional recurrence of sporadic or syndromic abdominal extra-adrenal paraganglioma: Incidence, characteristics, and outcome

Operative excision of abdominal extra-adrenal paragangliomas (EAPs) does not preclude the late development of local-regional recurrence. We describe the incidence, characteristics, and outcome of this rarely reported feature. Retrospective analysis of local-regional recurrence that occurred during follow-up of 51 consecutive patients operated for a sporadic (n = 26) or hereditary (n = 25) EAP. Seven patients with a sporadic or syndromic EAP (n = 4: von Hippel-Lindau syndrome and SDHB, SDHC, and SDHD gene mutations) underwent reoperation for a local-regional recurrence after a median time of 46 months (interquartile range [IQR], 16-100). The Kaplan-Meier estimated incidence of local-regional recurrence (+/- standard error of the mean) reached 15% +/- 7% at 5 years and 23% +/- 9% after 10 years. Recurrent EAPs were all secreting and 38% provoked clinical symptoms. New lesions were smaller than the primary EAP (P = .01) and more often associated with lymph node metastases (43% vs 4%, P = .01). Operative excision seemed complete in 5 patients. Clinical remission was maintained in 4 patients after a median follow-up of 57 months (IQR, 22-102). Local-regional recurrence of sporadic and syndromic EAPs is frequent and may be delayed beyond 10 years, requiring lifelong follow-up after the initial operation. When technically feasible, operative excision can lead to prolonged remission.

Asymptomatic extra-adrenal paraganglioma masquerading as retroperitoneal sarcoma.

A 41-year-old man without clinical symptoms was referred for treatment of an enlarging retroperitoneal tumor. Enhanced computed tomography showed a well-defined and heterogeneously enhanced tumor, 4cm in size, in the dorsal portion of the pancreas. A low-density nodule was detected in the left adrenal gland, 10mm in diameter. Retroperitoneal sarcoma and nonfunctional left adrenal tumor were suspected, and surgical treatment was performed. During excision of the retroperitoneal tumor, blood pressure was extremely elevated when the tumor was compressed. Blood pressure normalized after excision of the tumor; thus, a diagnosis of paraganglioma was favored over that of retroperitoneal sarcoma. The left adrenal gland was resected together with the adrenal tumor. Microscopically, the tumor cells of the retroperitoneum had round to oval nuclei, and abundant granular amphophilic cytoplasm proliferated in nest-like fashion. Extra-adrenal retroperitoneal paraganglioma was considered, and the adrenal tumor was diagnosed as cortical adenoma. In patients with retroperitoneal tumor, even in the absence of clinical symptoms, we should keep in mind the possibility of extra-adrenal paraganglioma.

Surgical Treatment of Extra-adrenal Abdominal Paragangliomas

Surgical Treatment of Extra-adrenal Abdominal Paragangliomas

Successful outcome after resection of liver metastasis arising from an extraadrenal retroperitoneal paraganglioma that appeared 9 years after surgical excision of the primary lesion

A 54-year-old man underwent surgery for excision of a retroperitoneal tumor that measured 12 cm in diameter, and histopathological examination revealed the tumor was an extraadrenal retroperitoneal paraganglioma. He presented 9 years later with epigastric discomfort. Abdominal ultrasound showed a solitary liver tumor. The diagnosis, based on radiological workup, was metastatic paraganglioma. The tumor was surgically resected and the histological findings resembled those of the primary tumor. The patient has been followed up for 3 years and remains recurrence-free. Surgical resection is an effective treatment approach for primary and secondary paragangliomas, but the resectability of liver metastatic lesions is usually low, although complete resection with a wide surgical margin was possible in this patient. This case suggests that a good prognosis after the resection of hepatic metastasis depends not only on the curative resection of the metastatic lesion but also on the tumor characteristics, such as slow growth or low aggressiveness.

Management of Carotid Body Tumors and Familial Paragangliomas: Review of 30 Years' Experience

Carotid body tumors (CBTs), especially familial paragangliomas, are rare benign neoplasms, accounting for <0.5% of all tumors; and they are the most common extra-adrenal paraganglioma. In this study, CBTs were clinically suspected in 31 patients but diagnosed by histopathology in 28 between 1977 and 2007 at our department. All but one was operated upon. The ages of the 30 surgically treated patients ranged 17-73 years. A mass in the neck was the common symptom in all patients. Two of the 28 patients with CBTs had a familial paraganglioma history of CBT. Twenty-eight of these 30 surgically treated patients had confirmed CBT by histopathology; the diagnoses of other two patients were neurofibroma in one and tuberculosis lymphadenitis in one. These two patients were excluded from the study. CBTs were resected without a shunt procedure. UltraCision was used in five patients for tumor resection; the surgical results of these patients were excellent (easy dissection, minimal hemorrhage and time operation). Twenty patients underwent total resection, six had resection and saphenous vein interposition, one had partial resection, and one had carotid artery ligation with no resultant neurological deficit. One case of hypoglossal paralysis and one benign recurrence were detected. No mortality or malignant course was observed. CBTs are infrequent neoplasms; their surgical treatment is highly dependent on the ability and experience of the surgeon. The diagnostic and therapeutic relevance reside in making a timely diagnosis to propose a surgical treatment aimed at preventing complications and neurological damage. Surgical resection is usually definitive therapy for these lesions.

Primary Pulmonary Paraganglioma with Hodgkin's Lymphoma

Extra-adrenal paragangliomas are uncommon tumors arising from neuroectodermal-derived paraganglionic tissue. There are very few case reports on primary pulmonary paraganglioma in the literature. We present the case of a 21-year-old man who was treated with chemotherapy for Hodgkin's lymphoma. Only a partial response was noted so he underwent additional chemotherapy and involved field radiotherapy. PET-CT showed pathological activity in the lung parenchyma. Subsequent bronchoscopic biopsy showed paraganglioma and the patient underwent a left lower lobectomy.

Paraganglioma: Carotid Body Tumor

Extra-adrenal paragangliomas are neoplasms of the paraganglia located within the paravertebral sympathetic and parasympathetic chains. Thus paragangliomas may arise anywhere along these tracts and common sites of occurrence include abdomen, retroperitoneum, chest and mediastinum and various head and neck locations such as jugulotympanic membrane, orbit, nasopharynx, larynx, vagal body and carotid body. Recent literature suggests a molecular basis for the development of some paragangliomas, i.e. germline mutations. Six genes have been identified and are thought to contribute to the development of pheochromocytoma/paraganglioma. These include RET, VHL, NF1 and SDH subunits SDHB, SDHC, and SDHD. SDHD and SDHB mutations account for a significant percentage of head and neck paragangliomas. It is well know that paragangliomas may be hereditary and may be part of genetic syndromes such as Von Hippel-Lindau syndrome, neurofibromatosis type I (von Recklinghausen disease), MEN 2A and MEN 2B. When features of these more commonly known syndromes are not present, many familial cases, often associated with the above mentioned germline mutations, go unrecognized. In the head and neck region the normal paraganglia are associated with the parasympathetic nervous system and paragangliomas arising from these parasympathetic sites account for up to 70% of extra-adrenal paragangliomas. The most common site is the carotid body. Carotid body paragangliomas arise at the bifurcation of the internal and external carotid arteries and have classic radiographic