Extra-adrenal Paragangliomas Research Articles

English

INTRODUCTION: Paragangliomas, are rare neuroendocrine neoplasms that are derived from the paraganglia. Extra-adrenal paraganglioma arising within the pancreas is an extremely rare entity. CASE REPORT: Here we present a case of 72 year male patient with the complaints of abdominal distension and ultrasound showing a large multicystic mass measuring 12 x 8.5 cm extending from the tail of the pancreas to the pelvis. DISCUSSION: The diagnosis was made as a rare case of pancreatic paraganglioma on the basis of histological examination and immune

Carotid body tumor presenting as parotid swelling misdiagnosed as pleomorphic adenoma: A rare presentation

Carotid body tumor (CBT) also known as chemodectoma is a rare tumor of neuroendocrine tissue of carotid body and is the most commonly seen jugular paraganglioma. In most cases, it is benign but it can be malignant. Extra adrenal paraganglioma is rare. We present such a rare case where unusual presentation of chemodectoma was seen as a parotid swelling. This swelling was misdiagnosed as a pleomorphic adenoma on clinical examination, ultrasonography, and fine-needle aspiration cytology and superficial parotidectomy was done for the same, but on histopathological examination it was found to be CBT presenting as a parotid swelling.

Paraganglioma Presenting as Postpartum Fever of Unknown Origin.

A young healthy postpartum mother presented with intermittent high fevers and tachycardia. Appropriate testing was done to rule out infectious causes including pan cultures but no identifiable infectious source was found. A CT of the abdomen showed a retroperitoneal mass with two small pulmonary nodules and a bony metastatic lesion. She was found to have stage 4 extra-adrenal paraganglioma with metastases to the lungs and spine. She underwent resection of the mass and is currently undergoing palliative radiation to the spine for pain control. Subsequent genetic testing identified a likely pathogenic variant in SDHB, confirming a diagnosis of Hereditary Paraganglioma-Pheochromocytoma syndrome.

Peptide receptor radionuclide therapy with lutetium-177 DOTATATE in a case of recurrent extradrenal retroperitoneal malignant paraganglioma with nodal and bone metastasis

Extra-adrenal retroperitoneal paragangliomas (PGLs) are rare tumors causing considerable difficulty in both, diagnosis and treatment. They can be unicentric or multicentric, tend to be locally invasive and therefore have a high incidence of local recurrence. PGLs shows somatostatin receptor positivity, which can be imaged with technetium-99m (Tc-99m)-hydrazinonicotinyl-Tyr3-octreotide (HYNIC-TOC) and can be treated with lutetium-177 (Lu-177) DOTATATE. We present a case of recurrent unresectable retroperitoneal PGL with nodal and bone metastases in a 27-year-old male, 6 months postsurgery detected with Tc-99m-HYNIC-TOC and was administered with peptide receptor radionuclide therapy using Lu-177 DOTATATE.

Malignant paraganglioma of the bladder: A case report and review of the literature

Although paragangliomas of the bladder are uncommon, malignant paragangliomas of this anatomic site are exceedingly rare, with a mere 37 previously reported cases. We report the case of a 58-year-old man with a malignant paraganglioma of the bladder who sought care secondary to gross hematuria; however, misdiagnosis of this tumor resulted in hypertensive crisis during cystoprostatectomy. Not only does this case present a unique malignant paraganglioma of the bladder, but also it discusses the clinical ramifications when misdiagnosed. Like pheochromocytomas, extra-adrenal paragangliomas can manifest with similar sympathetic stimulation; this becomes a serious complication for clinicians resecting these tumors in unusual locations without proper histologic diagnosis. Additionally, we discuss the unique clinical and pathologic findings of our patient and comprehensively review the previously published cases comparing clinical and pathologic features. Several interesting findings are identified including average age at diagnosis, gender predilection, presenting symptoms, size at diagnosis, and common sites of metastasis.

Abstract 568: Few Carney's Triad patients have mutations in two subunits of the succinate dehydrogenase enzyme (SDHB, SDHC)

Abstract Carney's triad (CTr) is a non-hereditary condition, primarily seen in young women, characterized by gastrointestinal stromal tumors (GIST), extra-adrenal paragangliomas and pulmonary chondromas. Most CTr patients present with GIST and pulmonary chondroma (incomplete CTr). A marked decrease in the enzymatic activity of succinate dehydrogenase (SDH) has been detected in these tumors, but the presence or absence of SDH mutations in CTr is controversial. A related disease, known as Carney-Stratakis Syndrome (CSS), has no female predisposition and presents with extra-adrenal paragangliomas and GIST tumors, without pulmonary chondromas. In distinction to CTr, CSS is hereditary due to germline SDH mutations in the enzyme's subunits (SDHA, SDHB, SDHC and SDHD) with corresponding decreased SDH activity in associated tumors. We have investigated 64 patients with CTr for germline mutations and/or deletions in the SDH subunit genes; four patients were found to have germline mutations in SDHB or SDHC. All four patients had multifocal gastric GIST and pulmonary chondromas at diagnosis; two subsequently developed paragangliomas, confirmed by biopsy. One of the patients with CTr and a SDHB mutation had a nephew with the same mutation and a neuroblastoma, confirming a previously reported association of neuroblastoma with gist (JMG 2009; 46:215, and AJMG 2010; 152A: 1531). We conclude that few CTr patients maybe more correctly classified as having CSS; the genetic distinction of CTr from CSS needs further study. [S.A.B. and P.X. should be regarded as joint first authors.] Citation Format: Sosipatros A. Boikos, Paraskevi Xekouki, Fabio R. Faucz, Karel Pacak, Margarita Raygada, Karen Adams, Evan Szarek, Evan Ball, Su Young Kim, Elena Fumagalli, Lee J. Helman, J Aidan Carney, Constantine A. Stratakis. Few Carney's Triad patients have mutations in two subunits of the succinate dehydrogenase enzyme (SDHB, SDHC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 568. doi:10.1158/1538-7445.AM2014-568

Genetics and the clinical approach to paragangliomas.

This study analyses new information on gene mutations in paragangliomas and puts them into a clinical context. A suspicion of malignancy is critical to determine the workup and surgical approach in adrenal (A-PGL) and extra-adrenal (E-PGL) paragangliomas (PGLs). Malignancy rates vary with location, family history, and gene tests results. Currently there is no algorithm incorporating the above information for clinical use. A sum of 1,821 articles were retrieved from PubMed using the search terms "paraganglioma genetics". Thirty-seven articles were selected of which 9 were analyzed. It was found that 599/2,487 (24%) patients affected with paragangliomas had a germline mutation. Of these 30.2% were mutations in SDHB, 25% VHL, 19.4% RET, 18.4% SDHD, 5.0% NF1, and 2.0% SDHC genes. A family history was positive in 18.1-64.3% of patients. Adrenal PGLs accounted for 55.1% in mutation (+) and 81.0% in mutation (-) patients (RR 1.2, p < 0.0001). Bilateral A-PGLs accounted for 56.4% in mutation (+) and 3.2% in mutation (-) patients (RR 8.7, p < 0.0001). E-PGL were found in 33.6% of mut+ and 17.3% of mut- (RR 1.7, p < 0.0001). In mutation (+) patients PGLs malignancy varied with location, adrenal (6.4%) thoraco-abdominal E-PGL (38%), H & N E-PGL (10%). Malignancy rates were 8.2% in mutation (-) and lower in mutation (+) PGLs except for SDHB 36.5% and SDHC 8.3%. Exclusion of a mutation lowered the probability of malignancy significantly in E-PGL (RR 0.03 (95% CI 0.1-0.6); p < 0.001). Mutation analysis provides valuable preoperative information to assess the risk of malignancy in A-PG and E-PGLs and should be considered in the work up of all E-PGL lesions.

Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia.

Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (P=0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact tumors. We conclude that TERT promoter mutations occur in ACCs and ea PGLs. In addition, preliminary evidence indicates a potential association with the acquisition of TERT promoter mutations in SDH-deficient tumors.

Paraganglioma retroperitoneal no funcional

Retroperitoneal non-functional paraganglioma: Report of a case from the Cardioinfantil Foundation, Bogotá, Colombia Paragangliomas are tumors derived from chromaffin cells from the neural crest. They are able to secrete catecholamines, hormones and peptides. They can be found in the skull base, neck, thorax and abdomen, and may be functional or not-functional. We report the case of a male patient with non-specific pain in the right hypochondrium. Based on the initial imaginological studies a neuroblastoma was suspected, but it not possible to differentiate it from a paraganglioma, a ganglioneuroblastoma or a neurofibroblastoma. The pathological study of the surgical specimen revealed extensive hemorrhagic areas, consistent with a non-functional extra-adrenal paraganglioma. This is an infrequent neoplasia with difficult surgical treatment

Renaissance of (18)F-FDG positron emission tomography in the imaging of pheochromocytoma/paraganglioma.

Renaissance of (18)F-FDG positron emission tomography in the imaging of pheochromocytoma/paraganglioma.

Protocol for the examination of specimens from patients with pheochromocytomas and extra-adrenal paragangliomas.

During the last decade there have been revolutionary breakthroughs in understanding the biology of pheochromocytomas and extra-adrenal paragangliomas. Discoveries of new susceptibility genes and genotype-phenotype correlations have led to the realization that appropriate patient care requires a complete integration of clinical, genetic, biochemical, imaging, and pathology findings. Clinical practice has in many cases not kept pace with the rate of discovery, underscoring a need for updated procedures for evaluation of patient specimens and reporting of data. We therefore propose a new synoptic reporting approach for pheochromocytomas and extra-adrenal paragangliomas that will provide clear and uniform information to pathologists and clinicians, in order to advance the diagnosis of these neoplasms and optimize patient care.

Le réseau TENpath, réseau d’expertise anatomopathologique des tumeurs neuroendocrines malignes de l’adulte, sporadiques et familiales : premier bilan et premières leçons

TENpath is a network for the expert pathological diagnosis of malignant neuroendocrine tumors of the adult, both familial and sporadic, created by the French National Institute of Cancer in 2010. After 3years of activity, a first evaluation can be made. The perimeter of the network includes all neuroendocrine tumors (except small cell carcinomas of the lung), medullary carcinomas of the thyroid and extra-adrenal paragangliomas. The objectives of the network are not only the pathological review of all newly diagnosed cases of neuroendocrine tumors, but also the epidemiological surveillance, the training of pathologists, the production of recommendations and the initiation of research projects. The organisation of the network includes a database in which all referred cases are declared and a virtual expert system making it possible collegial expertises in line. Twenty-two expert centers are currently participating to TENpath. A total of 1350 cases have been referred in 2011 and 1518 in 2012. Major discrepancies amounted up to 5.9% in 2011 and to 2.9% in 2012. They mainly involved problems of differential diagnosis and wrong evaluations of the differentiation status of the tumor. The lessons to draw from the first years of TENpath are: (a) the long-standing underestimation of the actual number of patients with neuroendocrine tumors in France, (b) a better delineation, based on objective data, of the cases raising actual problems of diagnosis, (c) the existence of cases raising problems of classification even to experts and justifying a particular effort of research. These informations will be important to discuss the future evolution of TENpath.

Checklists, Protocols, and the “Gold Standard” Approach

Checklists (now referred to as case summaries) have been used for educational and quality improvement purposes in surgical pathology reporting of cancer cases for a number of years, with published protocols, checklists, and structured reports developed by many societies such as the Association of Directors of Anatomic and Surgical Pathology, the College of American Pathologists (CAP), and The Royal College of Pathologists of the United Kingdom. The adoption of checklists designed to improve the quality of patient care is also gaining momentum in various clinical settings, including perioperative suites, emergency departments, and intensive care units. 1,2 In pathology, the use of checklists or structured reporting for histopathologic findings in cancer resection cases has been shown to produce sustained improvement in reporting of critical data elements. 3 However, development, maintenance, dissemination, and revision of such checklists can be labor intensive and costly because the documents must be continuously reviewed and updated as medical knowledge and practices change. This review process is especially important when adherence to pathology reporting protocols is included as a standard for accreditation, as by the Commission on Cancer of the American College of Surgeons in the accreditation of cancer programs. The ‘‘Protocol for the Examination of Specimens From Patients With Pheochromocytomas and Extra-adrenal Paragangliomas,’’ 4 published in this issue of the Archives of Pathology & Laboratory Medicine, represents a ‘‘gold standard’’ approach to reporting of these rare neoplasms based on expert opinion from a distinguished international group of pathologists and endocrinologists. However, it is not an official protocol of the CAP. The CAP cancer protocols are developed by the CAP Cancer Committee and multidisciplinary Cancer Protocol Review Panels, which include pathologists from various practice settings (academics, community practice, and large reference laboratories), surgeons, and medical and radiation oncologists. Protocols undergo a stringent review process that includes posting for public comment, followed by review of all comments by the CAP Cancer Committee, with final revisions to the protocol made in response to this feedback. New cancer protocols officially endorsed by the CAP are developed in response to needs from the larger oncology community. Because the protocol portfolio has matured over the years since the publication of the first CAP cancer checklists in 1986 5 , new protocols are often developed in response to changes in the American Joint Committee on Cancer TNM staging manual. For example, at the time of this writing a new CAP cancer protocol for uterine sarcomas is in the final stages of development in response to a separate staging schema for this tumor type as adopted by the F ´ ederation Internationale de Gyn ´

Nonfunctional Pelvic Retroperitoneal Paraganglioma Mimicking Postmenopausal Adnexal Mass

Paraganglioma is a rare tumor originates from paraganglial tissue which is composed of extraadrenal chromaffin cells. The pelvic and retroperitoneal location of this tumor is extremely rare and it can mimic adnexal mass. The diagnosis of paraganglioma in this region is difficult. The exact diagnosis may only be reached after the total excision and histopathologic examination of the tumor. In this report, for the first time, we presented a postmenopausal woman who had nonfunctional retroperitoneal paraganglioma mimicking postmenopausal adnexal mass. This case emphasizes that extraadrenal paraganglioma should be kept in mind in the differential diagnosis in all patients including postmenopausal woman with retroperitoneal mass even in the presence of nonspecific symptoms like abdominal pain.

Bi-Focal Retroperitoneal Paraganglioma in a Young Patient: A Case Report and Review of the Literature

Extra-adrenal paraganglioma of the retroperitoneum are rare neuroendocrine tumors arising from specialized neural crest cells, intimately associated with sympathetic nervous tissue and distributed along the aorta. Here we present a case of multiple extra-adrenal retroperitoneal paraganglioma in a 16-year-old boy. The clinical presentation, imaging characteristics, and surgical pathologic findings were reported. A comprehensive review of the medical literature concerning multiple extra-adrenal paraganglioma in the pediatric and adult population is also discussed.

Role of 18F-DOPA PET/CT in Diagnosis and Follow-up of Adrenal and Extra-adrenal Paragangliomas

The objective of this study was to establish the clinical value of F-DOPA PET/CT in patients with adrenal and extra-adrenal paragangliomas (PGLs). Twenty-six consecutive patients with suspected or recurrent PGL underwent MR (and/or CT) and F-DOPA PET/CT. Histopathology confirmation was obtained in 20 cases. Genetic analysis on known susceptibility genes for PGL (VHL, RET, SDHx, TMEM127) was available in 13 patients. Fourteen patients were affected by PGL (8 with head/neck location, 6 with abdominal/thoracic location), whereas 12 showed masses of other origin. Three patients proved to be SDHD, 1 SDHB, 2 SDHC, and 1 TMEM127 mutation carriers. F-DOPA PET/CT showed pathological uptake in 13 of 26 patients. The procedure identified all PGLs except one with bone metastases (previous malignant adrenal PGL). No uptake was found in patients without proven PGL. Thus, in the whole group, F-DOPA PET/CT sensitivity was 92.8%, and specificity was 100% with positive and negative predictive values of 100% and 92.3%, respectively. Total diagnostic accuracy was 96.2%. In the head/neck subgroup, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were 100%. In the abdominal location, sensitivity was 80% and specificity was 100%, and positive and negative predictive values were 100% and 91.7%, respectively. Abdominal diagnostic accuracy was 93.7%. Radiotracer uptake was superimposable in head/neck PGLs versus abdominal PGLs and in mutated versus wild-type patients. The high diagnostic performance of F-DOPA PET/CT showed this technique to be a useful tool in detecting PGLs, above all those located at the head/neck site, regardless of the genetic pattern.

Cytomorphologic spectrum in aspirates of extra-adrenal paraganglioma.

Background:Paraganglioma is a rare tumor arising from clusters of neuroendocrine cells in association with sympathetic and parasympathetic nervous system. It poses a diagnostic challenge because of its widespread anatomic distribution, subtle clinical manifestations, and a variety of morphologic patterns.Aim:The aim of this study is to have an insight into the diverse morphologic spectrum of extra-adrenal paraganglioma (EAP).Materials and Methods:A retrospective analysis of seven cytologically diagnosed cases of EAP over a period of 10 years was performed. There were five superficial swellings and two deep seated retroperitoneal masses. The superficial swellings were aspirated directly, and the retroperitoneal masses were aspirated under ultrasound guidance using 22-gauge lumbar puncture needle fitted to a 10 mL syringe. Smears were reviewed for cellularity, pattern, cell shape, cytoplasm, nuclear features, and background.Results:The age of patients ranged from 25 to 75 years; four patients were males and three were females. Sites involved were carotid body region (four cases), para-pharyngeal space (one case) and para-aortic region (two cases). All the cases yielded hemorrhagic material on fine-needle aspiration. Smears showed scattered and clusters of cells and loosely cohesive acini of tumor cells. Cells were round to polygonal with pleomorphic nuclei, granular chromatin, inconspicuous nucleoli, and moderate to abundant cytoplasm containing fine pink granules and vacuolations. The cases were confirmed on radiology and histopathology.Conclusion:The cytologic features in EAP along with pertinent clinicoradiologic findings help in making an accurate preoperative diagnosis of an otherwise rare tumor.

Recurrent malignant pheochromocytoma with unusual omental metastasis: (68)Ga-DOTANOC PET/CT and (131)I-MIBG SPECT/CT scintigraphy findings.

Pheochromocytomas are rare catecholamine-secreting tumors derived from the sympathetic nervous system. The most common sites of metastasis for pheochromocytoma or extra-adrenal paraganglioma are lymph nodes, bones, lungs, and liver. Patients with known or suspected malignancy should undergo staging with computed tomography (CT) or magnetic resonance imaging as well as functional imaging (e.g. with 123I/131I-MIBG (131I-metaiodobenzylguanidine) and 68Ga-DOTANOC (68Ga-labeled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI3-octreotide) positron emission tomography (PET)/CT) to determine the extent and location of disease. We present a case of recurrent malignant pheochromocytoma with unusual site of metastasis in omentum, which was positive on 68Ga-DOTANOC PET/CT and 131I-MIBG single-photon emission computed tomography (SPECT/)/CT scintigraphy.

Pulmonary paraganglioma: A case report

Extra-adrenal paragangliomas are uncommon tumors arising from neuroectodermal-derived paraganglion tissue. These tumors are usually located in the carotid body, the jugulotympanic body or the mediastinum. A limited number of primary pulmonary paragangliomas have been reported previously. We present a case of a 63-year-old lady with a 12-pack-year smoking history and shortness of breath. Radiological investigations revealed a single right middle lobe pulmonary mass with homogenous density and lobulated borders on CT scan. The mass showed high fluorodeoxyglucose avidity on PET scan. A right middle lobectomy of the lung was performed. Macroscopic examination showed a well-defined yellow to cream mass measuring 28mm in maximum dimension. Histologically, the mass was composed of alveolar pattern of spindle cells with granular cytoplasm. No lymph node metastasis was identified. Immunohistochemical stains performed showed that the tumour is positive for chromogranin, synaptophysin, TTF-1, but negative for CK7. S-100 stained the sustentacular cells in the tumour. While approximately 20% of carcinoid tumours are reported to be negative for keratins, the overall histological and radiological features are those of a paraganglioma. The case report describes the radiological and histopathological characteristics of this exceedingly rare tumour, thereby improving its understanding and helping in the differential diagnosis of pulmonary tumours.

Mapping of Succinate Dehydrogenase Losses in 2258 Epithelial Neoplasms

Losses in the succinate dehydrogenase (SDH) complex characterize 20% to 30% of extra-adrenal paragangliomas and 7% to 8% of gastric GISTs, and rare renal cell carcinomas. This loss is reflected as lack of the normally ubiquitous immunohistochemical expression of the SDH subunit B (SDHB). In paragangliomas, SDHB loss correlates with homozygous loss of any of the SDH subunits, typically by loss-of-function mutations. The occurrence of SDHB losses in other epithelial malignancies is unknown. In this study, we immunohistochemically examined 2258 epithelial, mostly malignant neoplasms including common carcinomas of all sites. Among renal cell carcinomas, SDHB loss was observed in 4 of 711 cases (0.6%), including a patient with an SDHB-deficient GIST. Histologically, the SDHB-negative renal carcinomas varied. There was 1 clear cell carcinoma with a high nuclear grade, 1 papillary carcinoma type 2, 1 unclassified carcinoma with a glandular pattern, and 1 oncocytoid low-grade carcinoma as previously described for SDHB-negative renal carcinoma. None of these patients was known to have paragangliomas or had loss of SDHA expression in the tumor. Three of these patients had metastases at presentation (2 in the adrenal, 1 in the retroperitoneal lymph nodes). There were no cases with SDHB loss among 64 renal oncocytomas. SDHB losses were not seen in other carcinomas, except in 1 prostatic adenocarcinoma (1/57), 1 lymphoepithelial carcinoma of the stomach, and 1 (1/40) seminoma. On the basis of this study, SDHB losses occur in 0.6% of renal cell carcinomas and extremely rarely in other carcinomas. Some of these renal carcinomas may be clinically aggressive. The clinical significance and molecular genetics of these SDHB-negative tumors requires further study.