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.

Metastatic Pheochromocytomas and Abdominal Paragangliomas.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are believed to harbor malignant potential; about 10% to 15% of pheochromocytomas and up to 50% of abdominal paragangliomas will exhibit metastatic behavior. EVIDENCE ACQUISITION: Extensive searches in the PubMed database with various combinations of the key words pheochromocytoma, paraganglioma, metastatic, malignant, diagnosis, pathology, genetic, and treatment were the basis for the present review. DATA SYNTHESIS: To pinpoint metastatic potential in PPGLs is difficult, but nevertheless crucial for the individual patient to receive tailor-made follow-up and adjuvant treatment following primary surgery. A combination of histological workup and molecular predictive markers can possibly aid the clinicians in this aspect. Most patients with PPGLs have localized disease and may be cured by surgery. Plasma metanephrines are the main biochemical tests. Genetic testing is important, both for counseling and prognostic estimation. Apart from computed tomography and magnetic resonance imaging, molecular imaging using 68Ga-DOTATOC/DOTATATE should be performed. 123I-MIBG scintigraphy may be performed to determine whether 131I-MIBG therapy is a possible option. As first-line treatment in patients with metastatic disease, 177Lu-DOTATATE or 131I-MIBG is recommended, depending on which shows best expression. In patients with very low proliferative activity, watch-and-wait or primary treatment with long-acting somatostatin analogues may be considered. As second-line treatment, or first-line in patients with high proliferative rate, chemotherapy with temozolomide or cyclophosphamide + vincristine + dacarbazine is the therapy of choice. Other therapies, including sunitinib, cabozantinib, everolimus, and PD-1/PDL-1 inhibitors, have shown modest effect. CONCLUSIONS: Metastatic PPGLs need individualized management and should always be discussed in specialized and interdisciplinary tumor boards. Further studies and newer treatment modalities are urgently needed.

Resection of Cardiac Pheochromocytoma With Cardiopulmonary Bypass.

We report a case of a 21-year-old man with a cardiac pheochromocytoma involving the right atrium and extending to the right ventricular inflow tract, which was diagnosed by somatostatin receptor scintigraphy. For the preoperative evaluation, we chose multiple methods of imaging to accurately describe the anatomic extent and location of the tumor and its surrounding tissues, which showed that no major coronary artery ran through the tumor. The tumor was resected with disease-free margins effectively and safely with the use of cardiopulmonary bypass and with cardiac arrest. The patient remained asymptomatic at the 3-month follow-up.

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.

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.

Orbital Pheochromocytoma Metastasis in 2 Patients With Known Pheochromocytoma.

Two patients with previously diagnosed pheochromocytoma presented with facial pain and ptosis. Imaging revealed orbital lesions. Both patients were referred for surgical evaluation of the orbital mass. Surgical excision was performed for both. Pathology confirmed metastatic pheochromocytoma. Pheochromocytomas commonly metastasize to bone, liver, and other tissues. Five cases of metastasis to orbital bone have been previously described. These 2 cases are unique in that the metastases were not hormonally active, presented soon after initial diagnosis, and were treated palliatively with surgical excision. Previous treatment of orbital bony metastasis used radiotherapy. These cases demonstrate that surgical resection is a viable treatment option in these situations. Orbital metastasis of pheochromocytomas should be considered with the appropriate clinical presentation. These are the first documented cases of intraorbital metastasis, separate from the bony walls. Previously, orbital bony wall metastases were treated with radiation. Surgical excision is a viable option for treatment of such metastases.Orbital involvement should be considered in patients with systemic disease presenting with new ocular findings.

Thoracic spine metastasis presenting 18 years after complete resection of a phaeochromocytoma.

Phaeochromocytomas are rare neuroendocrine tumours (NET) with malignant behaviour in about 10% of cases. The median time from the diagnosis of primary tumour and bone metastasis is 3.4 years. We report a case of a 66-year-old woman presenting with a hypertensive crisis and back pain. She has a history of a phaeochromocytoma completely resected 18 years before. MRI showed a neoplastic mass on the 10th thoracic vertebra (T10), with fracture and spinal cord compression. The CT-guided biopsy was consistent with metastasis of a NET. Therefore, she was treated with phenoxybenzamine and external beam radiotherapy. However, clinical (dorsal pain) and biochemical (ie, elevated chromogranin A) signs suggested persistent disease and the patient was treated with iodine-131 metaiodobenzylguanidine and T10 kyphoplasty. After 8 years, she remains clinically stable. This case demonstrates that phaeochromocytomas may reveal malignant behaviour several years after diagnosis, and therefore patients should be maintained under long term surveillance.

Brain Metastasis of Pheochromocytoma: Diagnostic and Therapeutic Challenge.

BACKGROUND: Pheochromocytoma brain metastasis is extremely rare. Few cases have been reported in the literature. Therefore, diagnosis and effective treatment of these lesions are difficult. CASE DESCRIPTION: Here, we report the case of 29-year-old woman, who was operated on for a right adrenal pheochromocytoma. Fourteen months later, a posterior fossa tumor was diagnosed. Radiologic findings mimicked an extra-axial lesion. The radiologic differential diagnosis was difficult even using magnetic resonance imaging spectroscopy. The patient was operated on through a retrosigmoid approach. Local recurrence occurred 6 months after first surgery. The patient died 1 month later, despite a second operation. CONCLUSIONS: Although the occurrence of brain metastases in pheochromocytoma is not prevalent, patients presenting with suggestive features need to be carefully considered. Magnetic resonance imaging can help in differential diagnosis with a primary brain tumor. There are no established guidelines for the treatment of pheochromocytoma brain metastasis, for which the prognosis remains dismal, despite effective surgery.

Tumor-to-tumor metastasis: a rare case of breast carcinoma metastasizing to a pheochromocytoma, and a literature review.

BACKGROUND: Tumor-to-tumor metastasis is a well-recognized but uncommon entity. Breast carcinoma is one of the most common metastatic donors. Breast carcinoma metastasizes commonly to adrenal glands. However, the co-existence of a metastatic lesion with an existing adrenal tumor is a rare finding. CASE PRESENTATION: A 35-year-old woman was diagnosed with pheochromocytoma using computed tomography and ultrasound examinations. The tumor was surgically removed. Histological and immunohistochemical staining suggested that there were two components in the tumor: pheochromocytoma and metastatic cancer. CONCLUSION: This is the second published case of pheochromocytoma with tumor-to-tumor metastasis from an invasive ductal carcinoma of the breast. Furthermore, we highlight the importance of awareness of tumor-to-tumor metastasis in pathological diagnosis.

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.

Soporte con membrana de oxigenación extracorpórea en paciente con miocardiopatía de estrés secundaria a feocromocitoma / Extracorporeal membrane oxygenation support in a patient with pheochromocytoma stress myocardyopathy

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A clinical prediction model to estimate the metastatic potential of pheochromocytoma/paraganglioma: ASES score.

BACKGROUND: Malignant pheochromocytoma and paraganglioma can be defined only after the development of metastases in nonchromaffin tissues. There is no single clinical parameter that is sufficiently reliable to predict metastatic potential, so our goal was to develop a prediction model based on multiple clinical parameters. METHODS: The baseline age, size, extra-adrenal location, secretory type score was calculated in a retrospective cohort study comprising 333 patients with pheochromocytoma and paraganglioma. In each patient, each variable for age ≤35 years, tumor size ≥ 6.0 cm, extra-adrenal, and norepinephrine-secretory type was coded as 1 point (otherwise 0 point); these points were summed to yield age, size, extra-adrenal location, secretory type score. RESULTS: Metastases occurred in 23 of 333 patients (6.9%). Metastatic pheochromocytoma and paraganglioma was associated with age ≤35 years (hazard ratio [HR] 2.74, 95% confidence interval [95% CI] 1.19-6.35), tumor size ≥6.0 cm (HR 2.43, 95% CI 1.06-5.56), extra-adrenal location (HR 2.73, 95% confidence interval 1.10-7.40), and tumor producing only norepinephrine (HR 2.96, 95% CI 1.30-6.76). The area under the curve of the age, size, extra-adrenal location, secretory type score was 0.735. There was a significant difference in metastasis-free survival between participants with age, size, extra-adrenal location, secretory type score ≥2 and score <2 (P < .0001 by the log rank test). The negative predictive value of this system was 96.5% for a cutoff point of 2. CONCLUSION: We developed a new prediction model, the age, size, extra-adrenal location, secretory type score, based on multiple clinical parameters to assess the metastatic potential of pheochromocytoma and paraganglioma.

Metastatic Pheochromocytoma in an Asymptomatic 12-Year-Old With von Hippel-Lindau Disease.

Pheochromocytoma is a rare chromaffin cell tumor that may be associated with a genetic predisposition, such as von Hippel-Lindau (VHL) disease. VHL is an autosomal dominant disorder that is characterized by a predisposition to multiple tumors, including retinal and central nervous system hemangioblastomas, renal cell carcinoma, and pheochromocytomas. The classic presentation of pheochromocytoma is episodic hypertension, headaches, palpitations, and diaphoresis. In the pediatric population, 40% of pheochromocytomas have a hereditary basis. We present a case of metastatic pheochromocytoma in a child with VHL and discuss the relevant current medical literature.

[Delayed recurrence of a phaechromocytoma with metastasis as a cause of severe hypertension in a woman with a surgically intervened retroperitoneal tumour]. / Recidiva tardía de feocromocitoma con metástasis como causa de hipertensión arterial severa en mujer intervenida quirúrgicamente de tumor retroperitoneal.

We present the case of a woman with a previous history of hypertension and retroperitoneal tumour. The histology was reported as a paraganglioma. There was no clinical follow-up. Years later, there was a recurrence of the phaeochromocytoma after presenting with a difficult to control hypertension, along with elevation of urinary catecholamines. The case aims to highlight the importance of performing a clinical follow-up in these patients, due to the risk of recurrence.

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.