High-Specific-Activity-131I-MIBG versus 177Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.

Targeted radionuclide therapies (TRT) using 131I-metaiodobenzylguanidine (131I-MIBG) and peptide receptor radionuclide therapy (177Lu or 90Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-131I-MIBG therapy was approved by the FDA and both 177Lu-DOTATATE and 131I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.

Clinical features and outcomes of metastatic pheochromocytoma treated by cytotoxic chemotherapy.

Cytotoxic chemotherapy, including cyclophosphamide, vincristine, and dacarbazine (CVD) therapy, is widely used to treat metastatic pheochromocytoma and paraganglioma. Because these diseases are rare, studies are needed to establish treatment strategies. This was a single-center and retrospective study to analyze the efficacy of chemotherapy for patients with metastatic pheochromocytoma and paraganglioma diagnosed in 1983-2020. Clinical characteristics, tumor volume response, biochemical response based on catecholamine level, overall survival, and progression-free survival were evaluated. Patients with a complete response or partial response in tumor volume or catecholamine level were classified as responders. Sixteen patients were administered chemotherapy for a median of 16.5 cycles (interquartile range, 10-42). The tumor volume response was classified as follows: partial response (N = 4), stable disease (N = 9), and progressive disease (N = 3) (disease control rate = 81%). The biochemical responses were as follows: complete response (N = 2), partial response (N = 5), no change (N = 3), and progressive disease (N = 1) (disease control rate = 91%). The 5-year survival rate was 50% (95% confidence interval [CI], 21-74%) and median overall survival was 4.4 years (95% CI, 2.4 years-not reached). Overall survival and progression-free survival between responders and nonresponders were not statistically different. One patient developed myelodysplastic syndrome during CVD therapy. In conclusion, chemotherapy achieved disease control among more than half of patients, although survival did not differ between responders and nonresponders. Further fundamental research and prospective trials are needed to analyze the efficacy of CVD therapy.

Longest survival by the combination of radiation-therapy and resection in patient with metastatic spinal paragangliomas from primary-neck lesion with succinate dehydrogenase subunit B (SDHB) mutation.

Metastatic paraganglioma (MPG) of the spine is a rare condition, with no established management. Herein, we report the longest survival case of a primary neck tumor that caused spinal MPG with a succinate dehydrogenase subunit B (SDHB) mutation (c.470delT, p.L157X) which could have promoted its malignancy. This male patient initially presented with a left neck PG which was diagnosed by a biopsy when he was 54 years-old. Simultaneously performed additional examinations revealed the spinal metastatic tumors on the T5-7 vertebrae and L3 vertebra-sacrum. These primary neck and metastatic spinal tumors' growths were once suppressed under the radiation therapy. Nineteen years later, he developed acute progressive paraparesis due to a mass located at the T2-3 level, tightly compressing the spinal cord, and protruding into the left thoracic cavity. We resected the maximum possible area of tumor in the spinal canal, confirmed MPG by histological examination, and then, we administered radiation therapy of 40 Gy in 20 fractions. Eventually, the patient was able to walk unaided with no evidential tumor recurrence for 3 years after treatment. Generally, clinical feature of MPG with SDHB mutation from abdominal lesion is thought to be poor prognosis. However, our case suggests the possibility of long-term control of spinal MPG with the adequate combination of radiation therapy and resection if metastatic lesions from primary-neck lesion with an SDHB mutation are remained to spine.

A Durable Response With the Combination of Nivolumab and Cabozantinib in a Patient With Metastatic Paraganglioma: A Case Report and Review of the Current Literature.

Introduction: Pheochromocytomas and sympathetic paragangliomas (PPGL) are neuroendocrine catecholamine-secreting tumors that are usually localized. Metastatic disease is rare and systemic treatment consists of conventional chemotherapy and high-specific-activity iodine-131-MIBG which was approved by the FDA in 2018. Although chemotherapy combinations still have value in specific settings, the debilitating side effects of treatment with only modest benefit have limited their use. With the introduction of a new generation of targeted therapy and immunotherapy patients with metastatic PPGL may have improved therapeutic options. Areas Covered: The current paper presents a case of a patient with metastatic PPGL who received multiple lines of systemic treatment. Despite progression on previous single agent cabozantinib and single agent pembrolizumab on separate clinical trials, the patient has exhibited a major response to the combination of cabozantinib and nivolumab for the past 22 months. In addition, we will review the available therapies for metastatic PPGL and discuss novel agents under clinical development. Conclusion: Newer targeted therapies and immunotherapy options are under clinical development with promising results for patients with PPGL.

Emerging Treatments for Advanced/Metastatic Pheochromocytoma and Paraganglioma.

OPINION STATEMENT: The incidence of metastatic pheochromocytoma (PHEO) and paraganglioma (PGL) may occur in as many as 35% of patients particularly with PGL and even more frequently in those with specific mutations. Biochemical, morphological, and molecular markers have been investigated for use in the distinction of benign from malignant PHEO/PGL. PHEO/PGL metastasizes via hematogenous or lymphatic routes and shows differences based on mutational status. The most common sites of involvement in patients that have an SDHB mutation are the bone (78%), lungs (45%), lymph nodes (36%), and liver (35%). In patients with sporadic PHEO/PGL, the most common sites of metastasis are the bones (64%), lungs (47%), lymph nodes (36%), and liver (32%). Metastases may be present at presentation or may occur later. Metastases to the liver and lungs are associated with a shorter survival. Overall, the estimated 5-year survival rates are between 34 and 74%. Currently, treatments for metastatic PHEO/PGL are essentially palliative. Surgery is potentially curative; however, tumor dissemination limits the chance for a curative resection. When surgical intervention is not amenable, the therapeutic options include radiolabeled MIBG (Azedra®-iobenguane 131 was recently FDA-approved for patients > 12 years and older with iobenguane scan positive) or systemic chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) with an overall objective response rate (ORR) of less than 40%; however, it is not clear if the administration of CVD impacts overall survival, as nearly all patients develop progressive and ultimately fatal disease. Other treatment modalities under investigation include cytoreductive techniques, novel radiopharmaceuticals, chemotherapy, radiotherapy, immunotherapy, and experimental therapies. Here we are discussing emerging treatment for advanced/metastatic PHEO/PGL.

Paraganglioma of the Spermatic Cord With Spinal Metastasis: A Case Report.

A 40-year-old male with presented to the clinic with the chief complaint of right inguinal pain radiating to his right testicle and right thigh with no history of trauma, fever, chills, dysuria, hematuria, or unprotected sexual activity. Physical exam revealed right testicular tenderness with no palpable abnormality of the bilateral testes or spermatic cords. Scrotal ultrasound was performed and was unremarkable for testicular or other intrascrotal pathology. Concurrently, chronic low back pain had prompted a lumbar CT to be performed, which was indeterminate, but subsequent lumbar MRI performed three months later revealed abnormal signals in the vertebral bodies of T12, L3, and L5, concerning for occult metastatic disease or multiple myeloma. PET-CT was performed revealing hypermetabolic lesions throughout the axial skeleton and, most notably, hypermetabolic lesions in the left inguinal and left upper scrotum. At this time, about 4 months after the original visit, physical exam revealed a palpable mobile mass in the left upper scrotum that was distinct from the left testicle, and another mass palpable near the left inguinal ring.

Transcriptome Analysis of lncRNAs in Pheochromocytomas and Paragangliomas.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors explained by germline or somatic mutations in about 70% of cases. Patients with SDHB mutations are at high risk of developing metastatic disease, yet no reliable tumor biomarkers are available to predict tumor aggressiveness. OBJECTIVE: We aimed at identifying long noncoding RNAs (lncRNAs) specific for PPGL molecular groups and metastatic progression. DESIGN AND METHODS: To analyze the expression of lncRNAs, we used a mining approach of transcriptome data from a well-characterized series of 187 tumor tissues. Clustering consensus analysis was performed to determine a lncRNA-based classification, and informative transcripts were validated in an independent series of 51 PPGLs. The expression of metastasis-related lncRNAs was confirmed by RT-qPCR. Receiver operating characteristic (ROC) curve analysis was used to estimate the predictive accuracy of potential markers. MAIN OUTCOME MEASURE: Univariate/multivariate and metastasis-free survival (MFS) analyses were carried out for the assessment of risk factors and clinical outcomes. RESULTS: Four lncRNA-based subtypes strongly correlated with mRNA expression clusters (chi-square P-values from 1.38 × 10-32 to 1.07 × 10-67). We identified one putative lncRNA (GenBank: BC063866) that accurately discriminates metastatic from benign tumors in patients with SDHx mutations (area under the curve 0.95; P = 4.59 × 10-05). Moreover, this transcript appeared as an independent risk factor associated with poor clinical outcome of SDHx carriers (log-rank test P = 2.29 × 10-05). CONCLUSION: Our findings extend the spectrum of transcriptional dysregulations in PPGL to lncRNAs and provide a novel biomarker that could be useful to identify potentially metastatic tumors in patients carrying SDHx mutations.

Hepatic metastatic paraganglioma 12 years after retroperitoneal paraganglioma resection: a case report.

BACKGROUND: Paragangliomas, also known as chemodectomas, are rare tumors arise from chemoreceptor tissue, and most commonly locate at the bifurcation of the common carotid, the jugular foramen, aortic arch, and retroperitoneum. Paragangliomas generally are considered to be benign tumors, and rarely produce local or distant metastases. Metastasis to liver is extremely rare. CASE PRESENTATION: We report the case of a 39-year-old woman, who had undergone resection of a retroperitoneal paraganglioma at her local hospital for 12 years. She was referred to our hospital for further evaluation of a hepatic mass, which was misdignosed as hepatocellular carcinoma (HCC) and was treated by transarterial chemoembolization (TACE) in the local hospital 6 years ago. At admission, CT scan revealed a huge hypervascular mass with many feeding arteries, almost the same size as 5 years ago. Ultrasound-guided biopsy of the liver tumor was performed and immunohistochemical examination confirmed the diagnosis of hepatic metastatic paraganglioma. Though liver metastasis failed to achieve complete response or partial response to TACE treatment, it remained stable without progression during the 7-year follow-up. CONCLUSION: Paragangliomas are slow growing tumors and metastasis may develop decades after resection of the primary lesion. Long-term follow-up is necessary, and curative or palliative treatment should be considered to control symptoms, improve life quality, reduce complications and prolong survival.

Paraganglioma of the spine: A twenty-years clinical experience of a high volume tumor center.

Paragangliomas (PGs) are rare tumours with a reported estimated annual incidence of up to 3 per million. Spinal involvement may possible with spinal metastasis and primary extradural localizations. The aim of this paper is to evaluate clinical outcomes of surgical treatment of a rare disease that can involve the spine and that should be considered in the differential diagnosis of spinal injuries. This is a retrospective observational study of the spinal paragangliomas treated at our institute. Five patients have been enrolled: three with metastatic PG and two with extradural PG. Metastatic PGs were treated with intralesional excision plus adjuvant therapies instead, extradural PGs with intralesional excision without adjuvant therapies. Among patients affected by metastastic paraganglioma two patients were Alive with disease (AWD) at the latest follow and one patient died for the spreading of disease at 240 months after surgery. Two patients with extradural paraganglioma of thoracic spine were AWD at the latest follow-up without pain and neurological deficits. Surgical management of spinal localizations can represent a challenge. Surgery has a main role in both diseases where intralesional excision plus adjuvant therapies seems to be able to achieve the local control and a satisfying prognosis in case of undisseminated tumour.

Synchronous Paraganglioma Masquerading as 68Ga-PSMA PET/CT-Avid Metastasis in Carcinoma Prostate-How Specific Is 68Ga-PSMA PET/CT?

We present a case of biopsy-proven prostatic adenocarcinoma with a tracer-avid left paravertebral location at D4 to D5 vertebrae, suggestive of metastasis. However, in view of uncommon location of single-site metastasis at paravertebral region with no tracer-avid regional lymphadenopathy, image-guided biopsy was done, which was suggestive of paraganglioma. Ga-PSMA is known to have variable tracer avidity in multiple nonprostatic benign as well as malignant lesions, and our case adds to the list of nonspecific uptake by this once considered "specific" to prostate PET radiotracer.

Malignant paraganglioma presenting as a mandibular metastasis.

BACKGROUND: Metastatic paragangliomas are rare neuroendocrine tumors. Bony metastases most commonly occur in the ribs, vertebrae, and pelvis. Few cases of mandibular metastases have been reported. METHODS: A 75-year-old female presented with a 6-month history of an enlarging mandibular mass. A biopsy was consistent with a paraganglioma. RESULTS: Staging workup with 18 F-fluorodeoxyglucose positron emission tomography demonstrated 2 hypermetabolic intra-abdominal lesions adjacent to the inferior vena cava. These were confirmed as paraganglioma by biopsy and presumed as the primary lesions. The patient underwent left segmental mandibulectomy and neck dissection with osteocutaneous fibula free tissue reconstruction. CONCLUSION: A rare case of malignant paraganglioma presenting as a mandibular metastasis is described. Nuclear medicine studies for paraganglioma are reviewed.

Preoperative 18F-FDG PET/CT in Pheochromocytomas and Paragangliomas Allows for Precision Surgery.

BACKGROUND: Fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) imaging is recommended in patients with metastatic pheochromocytoma (PC) and paraganglioma (PGL). There are no data on whether routine preoperative F-FDG PET/CT in all patients with PC/PGL impacts surgical management. OBJECTIVE: The aim of this study was to determine whether routine preoperative F-FDG PET/CT imaging affects the surgical management of patients with PC/PGLs. METHODS: We analyzed clinical, biochemical, genetic, and anatomic imaging data in 93 consecutive patients with PC/PGL who collectively underwent a total of 100 operations and who had preoperative F-FDG PET/CT imaging. RESULTS: Of 100 operations, preoperative F-FDG PET/CT showed additional lesions compared to anatomic imaging in 15 cases. These patients were more likely to undergo an open surgical approach (P < 0.05). Presence of genetic mutation, redo operations, sex, age, or tumor size had no significant association with finding additional lesions on F-FDG PET/CT. CONCLUSIONS: Additional lesions detected on preoperative F-FDG-PET/CT imaging have an impact on the surgical approach in patients with PC/PGLs. Therefore, surgeons should routinely obtain F-FDG-PET/CT imaging in patients with PC/PGL to allow for a more precise surgical intervention.

Malignant carotid paraganglioma: a case report. / Paraganglioma carotídeo maligno. A propósito de un caso.

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.

Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas.

Comprehensive genetic analyses have identified germline SDHB and FH gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an SDHx-like molecular profile in the absence of SDHx or FH mutations and identified a germline mutation in the SLC25A11 gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline SLC25A11 mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that SLC25A11 acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in SDHx- and FH-related tumors were observed both in tumors with mutated SLC25A11 and in Slc25a11Δ/Δ immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that SLC25A11 is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation.Significance: A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. Cancer Res; 78(8); 1914-22. ©2018 AACR.

Paraganglioma as a risk factor for bone metastasis.

Malignant pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGL) are frequently associated with bone metastasis. Bone metastasis requires long-term management and may lead to skeletal-related events (SREs) that remarkably reduce patients' quality of life (QOL). The aim of this study was to elucidate the risk factors for developing bone metastasis in patients with PPGL. The medical records of 40 consecutive adult patients with malignant PPGL at the National Hospital Organization Kyoto Medical Center between 2006 and 2016 were reviewed. SREs were defined as pathologic fracture, spinal cord compression, and the need for bone irradiation and/or surgery. PHEO (20/40) and PGL (20/40) were each present in 50% of the patients. Bone was the most frequent site of metastasis, detected in 60% (24/40). Bone metastasis was more frequent in patients with PGL (16/20, 80%) than in patients with PHEO (8/20, 40%) (p = 0.02). Half (12/24) of the patients with bone metastasis had at least one SRE. Extra-skeletal invasion of the spine, defined as local infiltration to the surrounding tissue beyond the cortical bone, was more frequently observed in patients with bone metastasis associated with SREs than without them (p = 0.001). Careful follow-up and management are warranted especially in patients with PGL as a risk factor for bone metastasis and with extra-skeletal invasion of the spine as risk factor of SREs.

Treatment and outcome of metastatic paraganglioma of the spine.

BACKGROUND: Spinal metastatic paraganglioma (MPG) is rare and only reported in individual case reports. The low incidence makes it difficult to define appropriate therapy and prognosis. Our study illustrated the largest series to discuss the possible treatment and outcomes of patients with spinal MPG. METHODS: A retrospective study of 15 patients with spinal MPG who were surgically treated between 2005 and 2014 was performed. Three surgical modalities were applied, and radiotherapy and chemotherapy were utilized as adjuvant therapy. RESULTS: The mean patients age was 40.9 (range 23-58) years. The period between primary surgery and spinal metastasis averaged 8.2 (0.5-15) years. Lesions were mainly located in cervical spine (2), thoracic spine (8), lumbar spine (3), and sacrum (2). The mean follow-up period was 35.0 months. Lesion progression was detected in nine patients, whereas five patients (33.3%) passed away. For solitary spine, multiple bone and both bone and nonosseous metastasis cases, the mean progression-free survival was 41 (range 9-56), 22.5 (range 12-38) and 8.3 (range 3-18) months, respectively. CONCLUSIONS: The cases presented in the current study highlight the crucial role of surgery. Total en bloc for solitary spinal MPG could result in a satisfying prognosis and piecemeal total resection with postoperative radiotherapy could be an alternative therapy. Radiotherapy and chemotherapy were advocated, especially for the multiple metastasis.

Raynaud's Phenomenon: Revisiting a Rare Sign of Pheochromocytoma and Paraganglioma.

Paraganglioma (PGL) are rare tumors arising from extra-adrenal chromaffin cells and occasionally secret catecholamines. The patient commonly presents with headache, palpitation, anxiety, diaphoresis, and episodic or sustained hypertension. Rarely patient can present with Raynaud's phenomenon. We present a case of adolescent girl who presented with isolated Raynaud's phenomenon as only manifestation of metastasis of PGL 3 years after undergoing surgical excision of normetanephrine secreting abdominal PGL.

Leptomeningeal dissemination of a low-grade lumbar paraganglioma: case report.

Leptomeningeal dissemination of paraganglioma is rare, with only 2 prior cases in the literature. The authors present the case of a metastatic low-grade lumbar paraganglioma via leptomeningeal dissemination. This report emphasizes the utility of 3,4-dihydroxy-6-18F-fluoro-l-phenylalanine (18F-FDOPA) PET scanning for diagnosis, as well as the combination of radiation therapy and alkylating chemotherapeutic agents for the treatment of this rare phenomenon. The patient was a 61-year-old woman who presented with low-back pain and was found to have an isolated L-3 intrathecal tumor on MRI. Sixteen months after gross-total en bloc resection of the paraganglioma, the patient again became symptomatic with new neurological symptoms. MRI findings revealed enhancing leptomeningeal nodules throughout the spine. 18F-FDOPA PET/CT scanning was used to confirm the diagnosis of disseminated paraganglioma. Intrathecal thiotepa, radiation therapy, and systemic therapy with capecitabine and temozolomide have been used sequentially over a 2-year period, with each able to stabilize tumor growth for several months. The authors also summarize the 2 other reports of leptomeningeal dissemination of paragangliomas in the literature and compare the course and management of the 3 cases.