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Carotid body tumors (CBTs) are rare neoplasms of the neuroectoderm accounting for 0.6% of head and neck tumors, with a 2%-12.5% risk of malignancy. While surgical resection has been associated with a high rate of neurologic and vascular complications, it remains the mainstay of treatment for malignant CBTs. We present the case of a 40-year-old female with a 5-year history of progressively enlarging right-sided neck mass, with MRI and MRA showing a Shamblin grade III CBT encasement of the internal carotid artery (ICA). Blood flow was absent in the petrous segment of ICA, with great collateralization of brain blood supply, enabling en bloc resection of the tumor with a carotid bulb and ligation of the common carotid artery (CCA) without vascular reconstruction. Further, we describe the characteristics and current management for malignant CBTs, including surgical management, pre-surgical embolization, and adjuvant radiation therapy.

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Pheochromocytomas and paragangliomas are rare neuroendocrine tumors, developed respectively in the adrenal medulla and in extra-adrenal locations. Their malignancy is defined by the presence of distant metastases. Forty percent of them are inherited and can be part of different hereditary syndromes. Their management is ensured in France by the multidisciplinary expert centers of the ENDOCAN-COMETE national network "Cancers of the Adrenal gland", certified by the National Cancer Institute and discussed within multidisciplinary team meetings. The diagnostic and therapeutic work-up must be standardized, based on an expert analysis of clinical symptoms, hormonal biological secretions, genetics, morphological and specific metabolic imaging. In the context of a heterogeneous survival sometimes beyond seven to ten years, therapeutic intervention must be justified. This is multidisciplinary and relies on surgery, interventional radiology, external or internal radiotherapy and medical treatments such as sunitinib or dacarbazine and temodal chemotherapy. The personalized approach based on functional imaging fixation status and genetics is progressing despite the extreme rarity of this disease.

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Malignant middle ear paraganglioma (MEPGL) is an exceedingly rare tumor of the neuroendocrine system. In general, MEPGLs represent as slow growing and hypervascularized benign neoplasms. The genetic basis of MEPGL tumorigenesis has been poorly investigated. We report a case of malignant MEPGL accompanied by the comprehensive genetic analysis of the primary tumor and metastasis. Based on whole-exome sequencing data, the germline pathogenic mutation p.R230H in the SDHB gene, encoding for subunit B of mitochondrial complex II, was found in a patient. Analysis of somatic mutation spectra revealed five novel variants in different genes, including a potentially deleterious variant in UNC13C that was common for the tumor and metastasis. Identified somatic variants clustered into SBS1 and SBS5 mutational signatures. Of note, the primary tumor was characterized by Ki-67 4% and had an elevated mutational load (1.4/Mb); the metastasis' mutational load was about 4.5 times higher (6.4/Mb). In addition, we revealed somatic loss of the wild-type SDHB allele, as well as loss of heterozygosity (LOH) at the 11p locus. Thus, germline mutation in SDHB combined with somatic LOH seem to be drivers that lead to the tumor's initiation and progression. Other somatic changes identified can be additional disease-causing factors. Obtained results expand our understanding of molecular genetic mechanisms associated with the development of this rare tumor.

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Not required for Clinical Vignette.

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Paraganglioma is a neuroendocrine tumor that originates from extraadrenal chromaffin cells. Primary thyroid paraganglioma is an extremely rare neoplasm. In this study, an exceptionally uncommon case of recurrent mediastinal malignant paraganglioma with primary origin from thyroid gland is presented. Median resternotomy, resection of left brachiocephalic vein, and extirpation of the mediastinal tumor were performed successfully. Commonly, it is preoperatively misdiagnosed and has unpredictable biological behavior. Incorrect diagnosis results in disastrous consequences for the patient, and consequently, correct pre- and postoperative diagnoses promise an optimal treatment plan and good prognosis. Long-term follow-up is indicated in all patients due to the risk of recurrence and distant metastases.

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BACKGROUND: Paragangliomas and extra-adrenal pheochromocytomas are uncommon neuroendocrine tumors with ubiquitous distribution. Malignant paraganglioma is a relatively rare entity. We report the treatment and pathological characteristics of a patient with malignant paraganglioma, and summarize the latest advances in the treatment of malignant paraganglioma based on a literature review. CASE SUMMARY: A 45-year-old Chinese woman presented to the hospital due to pain in the waist (right side) and right buttock, and was diagnosed as malignant paraganglioma after the placement of ureteral stent, implantation of ileus catheter, and transvaginal removal of the vaginal mass. After relief of intestinal obstruction, the patient received intravenous chemotherapy and peritoneal perfusion chemotherapy. Although her pelvic mass disease was stable, she developed multiple liver metastases and bone metastases. Due to the development of spinal cord compression, she underwent orthopedic surgery, followed by radiotherapy, and molecular targeted therapy with apatinib, but with poor disease control. CONCLUSION: Clinical management of paraganglioma is challenging for endocrinologists and oncologists. Prospective studies are required to develop standardized therapeutic strategies for malignant paragangliomas.

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INTRODUCTION: Paragangliomas are infrequent neuroendocrine tumours whose only criterion for malignancy is presence of metastases; thus, all paragangliomas show malignant potential. Actually, different risk factors have been analyzed to predict metastases but they remain unclear. PURPOSE: To analyze clinical, histological, and genetic factors to predict the occurrence of metastasis. PATIENTS AND METHOD: A multicentre retrospective observational analysis was performed between January 1990 and July 2019. Patients diagnosed with paraganglioma were selected. Clinical, histological, and genetic features were analyzed for the prediction of malignancy. RESULTS: A total of 83 patients diagnosed with paraganglioma were included, of which nine (10.8%) had malignant paraganglioma. Tumour size was greater in malignant tumours than in benign (6 cm vs. 4 cm, respectively; p = 0.027). The most frequent location of malignancy was the thorax-abdomen-pelvis area observed in six cases (p = 0.024). No differences were observed in histological differentiation, age, symptoms, and catecholaminergic production. The most frequent genetic mutation was SDHD followed by SDHB but no differences were observed between benign and malignant tumours. In the univariate analysis for predictive factors for malignancy, location, tumour size, and histological differentiation showed statistical significance (p = 0.025, p = 0.014, and p = 0.046, respectively); however, they were not confirmed as predictive factors for malignancy in the multivariate analysis. CONCLUSION: In this study, no risk factors for malignancy have been established; therefore, we recommend follow-up of all patients diagnosed with paraganglioma.

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Paraganglioma is a neuroendocrine tumor arising from extra-adrenal sites in the peripheral nervous system. Although malignant paraganglioma is known to metastasize to bones, including vertebral bodies, there is little literature on the compressive myelopathy accompanied by sphincter dysfunction; to our knowledge, only 12 cases have been reported. Moreover, neuropathological investigations of the spinal cord in this state have not been well-documented. This autopsy report describes a 55-year-old man with malignant paraganglioma and compression myelopathy caused by vertebral metastasis. The present case showed a gradual numbness and a sudden onset of irreversible paraplegia with sphincter dysfunction, which were not palliated these neurologic dysfunctions despite radiotherapy. Computed tomography (CT) revealed multiple metastases to the bones, lymph nodes, and lungs when he was diagnosed with malignant paraganglioma. At the same time, he had numbness, and magnetic resonance imaging (MRI) showed multiple diffuse metastatic lesions in the vertebral bodies. Following abrupt onset of paralysis, MRI showed fractured third and sixth thoracic vertebral bodies. An autopsy revealed residual vertebral metastases with fractures of the third and sixth thoracic vertebral bodies, resulting in compressive myelopathy at the fourth thoracic segment, which was characterized by complete spinal cord destruction. Destructive spinal cord lesion-induced secondary degeneration was observed in the gracile fasciculus at the rostral side and in the pyramidal tract at the caudal side, which showed Wallerian degeneration. Such pathology was consistent with the presenting neurological symptoms, including paraplegia and somatic sensory loss below the fourth thoracic spinal cord segment. Although it is difficult to identify the pathognomonic morphological changes responsible for the sphincter dysfunction, the present case suggests a supranuclear dysregulation of the somatosensory and central autonomic nervous systems involved in urination and defecation. Based on a review of the literature and the features of the present case, paraganglioma can metastasize aggressively even with a low pathological grading. This case of vertebral metastasis as a result of malignant paraganglioma may not be extraordinary but the autopsy report is rare. This autopsy revealed transverse myelopathy as a result of malignant vertebral metastasis of malignant paraganglioma.

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BACKGROUND: Carotid paragangliomas are rare tumors. They are usually unique, non-secreting, resectable, and benign. However, additional rare cases of complex tumors (bilateral, secretory, nonresectable, or malignant) complicate the management and final outcomes. METHODS: Records of paragangliomas from our hospital are reviewed. Criteria defining complex paragangliomas have been previously defined. These are compared with those of the simple group. RESULTS: Fifty patients, two groups: simple (n = 39) and complex (n = 11). The patients in the complex group were significantly younger (47.7 vs 63.8 years). Postoperative nerve complications (45.4% vs 6.3%) and mortality during follow-up (27.3% vs 0%) were significantly more common in the complex group. Vascular complications (0% vs 3.1%) and early mortality (0%) were similarly in both groups. CONCLUSIONS: Patients with complex carotid paragangliomas are heterogeneous. The former are younger, exhibit a high degree of diagnostic and therapeutic complexity, and have poorer morbidity and mortality. Surgical experience and interdisciplinary collaboration are essential.

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Malignant paragangliomas pose a real challenge for the practitioners. They are rare complex tumors, very heterogeneous in their evolution and prognosis. Given the rarity of this tumor group, there is no consensus on therapeutic management. Through this illustrative case study, we report the case of a 29 year old female patient followed for malignant paraganglioma due to which she initially had surgery. After a six month interval, multifocal recurrence was detected on Octreoscan PET-CT (Positron Emission Tomography- Computer Tomography). The patient underwent monthly injection of Somatuline for one year and then discontinued therapy due to disease progression. Cytoreduction was then performed followed by radiotherapy. After a year, the patient had massive disease progression. Dacarbazine-based chemotherapy was initiated. The patient had an almost complete metabolic response after eight cycles. This study aims to highlight the different therapeutic options in the management of malignant paragangliomas.

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BACKGROUND: Paragangliomas are neuroendocrine neoplasms that arise from the extra-adrenal paraganglia of the autonomic nervous system. Approximately 3% of all paragangliomas occur in the head and neck region. Most reported cases are benign and unilateral. We present a rare case of bilateral malignant paragangliomas. CASE DESCRIPTION: A 28-year-old woman presented with a 10-year history of bilateral neck swelling. Physical examination showed bilateral neck masses with obvious pulsation. Enhanced computed tomography revealed 2 irregular solid nodules, located in the left and right carotid artery bifurcation, respectively. Carotid artery angiography showed compression of the internal and external carotid arteries by the tumors on both sides. On diagnosis of the bilateral carotid body tumors, preoperative embolization was performed. The left-side lesion and lymph nodes were resected and a diagnosis of malignant paraganglioma with lymph node metastasis was made. She was treated with 50-Gy radiotherapy, and computed tomography performed 2 years later showed that the right-side lesion was unchanged. She was symptom-free as of the last follow-up. CONCLUSIONS: The rarity of bilateral malignant paragangliomas makes their management clinically challenging. The primary management of a recognized malignancy should be directed toward complete surgical removal of the primary tumor and regional lymph nodes. Postoperative radiation is beneficial in slowing the progression of residual disease. Genetic studies have shown that familial paragangliomas are associated with germline mutation of SDHD on 11q23.

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Tumors of the carotid body are uncommon neoplasms that originate in the neuroectoderm. These tumors are slow growing but well vascularized and very destructive. Between 5% and 13% of carotid body tumors are malignant, behaving aggressively at the local level, invading the adjacent lymph nodes, and resulting in remote metastases. We present the case of a 60-year-old man who was examined for pain and paresthesias in his arm. Magnetic resonance imaging showed a large tumor in the left carotid space. Histologic study of a biopsy specimen from the tumor revealed that it was a paraganglioma. Further studies to determine the extent of disease detected metastases in bone and lung, confirming the tumor's malignancy.

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BACKGROUND: Paragangliomas are generally benign, slow-growing tumors. However, approximately 10%-20% are malignant, characterized by distant metastasis. Recently, a germ line mutation in succinate dehydrogenase B subunit (SDHB) has been shown to be associated with malignant behavior in paraganglioma. Here we present a case of SDHB-negative malignant paraganglioma of the jugular foramen with a pseudohypoxic microenvironment and unique imaging features on [18F]-fluoro-2-deoxy-d-glucose positron emission tomography ([18F]-FDG PET), and discuss the significance of SDHB immunohistochemistry and the potential of [18F]-FDG PET for clinical management. CASE DESCRIPTION: A 55-year-old woman was diagnosed with jugular foramen paraganglioma. Initial surgical resection was performed; however, follow-up [18F]-FDG PET indicated multiple uptake regions throughout the body. Biopsies for multiple recurrent lesions revealed consistent pathological features, suggesting distant metastasis. Immunohistochemical analysis revealed a lack of SDHB immunostaining in all specimens. Pseudohypoxic markers, including hypoxia-inducible factor-1α and downstream glycolysis enzymes, were strongly expressed. [18F]-FDG PET demonstrated increased uptake in the lesions, and the patient died 3 years after initial metastasis. CONCLUSION: In patients with head and neck paraganglioma without SDHB expression, close follow-up should be considered because of the risk for metastasis. In such cases, [18F]-FDG PET might be useful for detecting metastasis due to atypical accumulation from pseudohypoxia-induced glycolysis.

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A 34-year-old man, diagnosed with paraganglioma of the urinary bladder, was referred to our hospital. Computed tomography showed a bladder tumor measuring 64 mm along with right obturator lymphadenopathy. Abnormal uptake was observed on 123I-MIBG scintigraphy. The tumor was, therefore, diagnosed as malignant paraganglioma. We performed cystectomy, pelvic lymph node dissection, and neobladder reconstruction. Pathological examination revealed a malignant paraganglioma of the urinary bladder with right obturator lymph node metastasis. Postoperatively, both the uptake on 123I-MIBG scintigraphy and catecholamine levels in blood and urine normalized. However, 22 months later, positoron emission tomography-computed tomography showed the presence of 2 recurrent tumors in the pelvis. The patient underwent 9 courses of cyclophosphamide, vincristine, and dacarbazine chemotherapy and MIBG radiotherapy twice, following which the tumor size decreased by 35% and catecholamine levels normalized once again. At about 2 years of follow-up, the patient was found to be free of recurrence.

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Metastasis is a rare presentation of non-secretory paraganglioma. Consequently, there is no standard of care for the treatment of metastatic malignant paraganglioma. The most widely used chemotherapy regimen for non-resectable cases includes cyclophosphamide, vincristine, and dacarbazine (CVD). CVD has been previously studied with variable therapeutic response. However, yttrium-90 (Y90) radioembolization has not been previously studied in the treatment of hepatic metastasis in patients diagnosed with malignant paraganglioma. This case report follows the treatment of a patient with stage IV mediastinal paraganglioma with metastasis to the liver. Treatment consisted of the CVD chemotherapy regimen and Y90 radioembolization of the hepatic lesions. After 10 cycles of CVD, the tumor size has decreased from 6.0 × 8.8 to 5.5 × 3.0 × 3.4 cm on computed tomography scan. The prominent metastatic liver lesions responded after Y90 radioembolization of both the right and left hepatic arteries. The prominent right hepatic lobe lesion has decreased in size from 2.6 × 3.4 × 3.0 cm to 2.6 × 2.8 × 2.9 cm. The prominent left hepatic lobe lesion originally measuring 1.6 cm in diameter completely resolved on follow-up imaging studies. After completion of 12 cycles of chemotherapy, the most recent positron emission testing scan determined no evidence of disease regarding both the primary mass and the hepatic lesions. This study demonstrates the first case of combination chemotherapy and Y90 radioembolization with a complete response per response evaluation criteria in solid tumors criteria. The approaches toward diagnosis and treatment corresponding to this case of malignant metastatic paraganglioma are also reviewed in this study.

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PURPOSE OF REVIEW: The purpose of this manuscript is to review the progress in the field of therapeutics for malignant pheochromocytomas and sympathetic paraganglioma (MPPG) over the past 5 years. RECENT FINDINGS: The manuscript will describe the clinical predictors of survivorship and their influence on the first TNM staging classification for pheochromocytomas and sympathetic paragangliomas, the treatment of hormonal complications, and the rationale that supports the resection of the primary tumor and metastases in patients with otherwise incurable disease. Therapeutic options for patients with bone metastasis to the spine will be presented. The manuscript will also review chemotherapy and propose a maintenance regimen with dacarbazine for patients initially treated with cyclophosphamide, vincristine, and dacarbazine. Finally, the manuscript will review preliminary results of several phase 2 clinical trials of novel radiopharmaceutical agents and tyrosine kinase inhibitors. MPPGs are very rare neuroendocrine tumors. MPPGs are usually characterized by a large tumor burden, excessive secretion of catecholamines, and decreased overall survival. Recent discoveries have enhanced our knowledge of the pathogenesis and phenotypes of MPPG. This knowledge is leading to a better understanding of the indications and limitations of the currently available localized and systemic therapies as well as the development of phase 2 clinical trials for novel medications.

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Metastatic extra-adrenal paragangliomas are very rare and can represent diagnostic challenges. We report a case of 69-year-old man with a tumor of the right shoulder. Histologic and immunohistochemical examinations confirmed the diagnosis of paraganglioma. Surprisingly, tumor cells were diffusely thyroid transcription factor 1 (TTF-1) positive. Succinate dehydrogenase complex subunit B (SDHB) deficiency has not been detected. Inherited syndromes associated with paragangliomas were ruled out. The primary tumor was identified in the mediastinum. This is the first report of TTF-1 expression in paraganglioma. To avoid misdiagnosis, careful clinical and pathological examination of any tumor with organoid growths pattern is necessary.

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BACKGROUND AND AIMS: Malignant transformation of pheochromocytomas/paragangliomas (PCC/PGL) is a rare occurrence, and predictive factors for the same are not well understood. This study aims to identify the predictors of malignancy in patients with PCC/PGL. MATERIALS AND METHODS: We performed a retrospective analysis of 142 patients with either PCC or PGL registered at our institute between 2000 and 2015. Records were evaluated for clinical parameters like age, gender, familial/syndromic presentation, symptomatic presentation, biochemistry, size, number and location of tumours and presence of metastases and mode of its diagnosis. RESULTS: Twenty patients were found to have metastases; 13 had metastases at diagnosis and seven during follow-up. Metastases were detected by radiology (CT-neck to pelvis) in 11/20 patients (5/13 synchronous and 6/7 metachronous), 131I-metaiodobenzylguanidine in five (2/12 synchronous and 3/6 metachronous) patients and 18F-flurodeoxyglucose PET/CT in 15 (12/12 synchronous and 3/3 metachronous) patients. Malignant tumours were significantly larger than benign tumours (8.3 ± 4.1 cm, range: 3-22 cm vs 5.7 ± 2.3 cm, range: 2-14 cm, P = 0.0001) and less frequently metanephrine secreting. On linear regression analysis, tumour size and lack of metanephrine secretion were the independent predictors of malignancy. CONCLUSIONS: Patients with primary tumour size >5.7 cm and lack of metanephrine secretory status should be evaluated for possible malignancy not only at diagnosis but also in the postoperative period. As compared to CT and 131I-MIBG scan, 18F-flurodeoxyglucose PET/CT analyses are better (sensitivity: 100%) for the diagnosis of metastases in our study.

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There is little evidence to direct the management of malignant paragangliomas (mPGL) beyond initial surgical treatment. Peptide receptor radionuclide therapy (PRRT), using somatostatin analogues, is effective in other neuroendocrine tumours, but data on its efficacy in treating mPGL are scarce. We report safety and efficacy outcomes from a case series of five patients with advanced mPGLs treated with (177)Lu-DOTATATE PRRT. The mean age of our cohort was 34 years (range 16-47); 4 patients were male with bone disease being the most prevalent metastatic site. PRRT scheme varied between 1 and 4 cycles, with premature cessation due to suspected pneumonitis in one case and disease progression in another. Three patients with previously documented progressive disease achieved stabilization following treatment; one had partial response and one was treatment refractory. Median progression-free survival was 17 months (range 0-78 months). 177-Lu-DOTATATE is an effective therapy in mPGLs in this molecularly defined patient cohort, warranting further investigation in larger studies including hereditary and sporadic mPGL.

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Paragangliomas are rare, typically benign neuroendocrine tumors that represent a small portion of head and neck tumors. A small percentage of these are known to have malignant potential. They arise from the carotid body, jugular bulb or vagus nerves. There is limited literature discussing the management of malignant vagal paragangliomas. We present a case of a 25 year old female with a left malignant vagal paraganglioma. The following case presentation will describe the presentation, classic radiologic findings, and management of a malignant vagal paraganglioma along with a review of the literature.

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