Metastatic Pheochromocytoma And Paraganglioma Research Articles

Efficacy and Safety of Ablative Therapy in the Treatment of Patients with Metastatic Pheochromocytoma and Paraganglioma.

Metastatic pheochromocytoma and paraganglioma (PPGL) are incurable neuroendocrine tumors. The goals of treatment include palliating symptoms and reducing tumor burden. Little is known about the use of radiofrequency ablation (RFA), cryoablation (CRYO), and percutaneous ethanol injection (PEI) to treat metastatic PPGL. We performed a retrospective study of patients age 17 years and older with metastatic PPGL who were treated with ablative therapy at Mayo Clinic, USA, between June 14, 1999 and November 14, 2017. Our outcomes measures were radiographic response, procedure-related complications, and symptomatic improvement. Thirty-one patients with metastatic PPGL had 123 lesions treated during 42 RFA, 23 CRYO, and 4 PEI procedures. The median duration of follow-up was 60 months (range, 0–163 months) for non-deceased patients. Radiographic local control was achieved in 69/80 (86%) lesions. Improvement in metastasis-related pain or symptoms of catecholamine excess was achieved in 12/13 (92%) procedures. Thirty-three (67%) procedures had no known complications. Clavien-Dindo Grade I, II, IV, and V complications occurred after 7 (14%), 7 (14%), 1 (2%), and 1 (2%) of the procedures, respectively. In patients with metastatic PPGL, ablative therapy can effectively achieve local control and palliate symptoms.

Recent advances in the imaging of pheochromocytomas and paragangliomas

Pheochromocytoma and paraganglioma (PPGL) belong to the family of neural crest cell-derived neoplasms, and can be widely distributed throughout the body. Over the past few years, with respect to these tumors, precision medicine has offered the promise of improved patient care. Through tumor visualization and identification of molecular signatures, nuclear medicine is capable of playing a key role in PPGL precision medicine. 68Ga-labeled somatostatin analogs were found to improve the detection and staging of head and neck paragangliomas, SDHx-related PPGLs and metastatic PPGLs regardless of genetic background. For PPGLs associated with increased kinase signaling or HIF2A mutations, 18F-fluorodihydroxyphenylalanine appears to be the most informative radiopharmaceutical. This review emphasizes the current theranostic approaches and future perspective related to PPGL imaging options.

Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years.

Malignant pheochromocytoma (PHEO) and paraganglioma (PGL) are rare and knowledge of the natural history is limited. We aimed to describe baseline characteristics and outcomes of patients with malignant PHEO and PGL (PPGL) and to identify predictors of shorter survival. Retrospective review of patients with malignant PPGL evaluated from 1960 to 2016. Referral center. The group comprised 272 patients. Baseline description, survival outcomes, and predictors of shorter survival were evaluated in patients with rapidly progressive (n = 29) and indolent disease (n = 188). Malignant PPGL was diagnosed at a median age of 39 years (range, 7 to 83 years), with synchronous metastases in 96 (35%) patients. In 176 (65%) patients, metastases developed at a median of 5.5 years (range, 0.3 to 53.4 years) from the initial diagnosis. Median follow-up was 8.2 years (range, 0.01 to 54.1 years). Median overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Shorter survival correlated with male sex (P = 0.014), older age at the time of primary tumor (P = 0.0011), synchronous metastases (P < 0.0001), larger primary tumor size (P = 0.0039), elevated dopamine (P = 0.0195), and not undergoing primary tumor resection (P < 0.0001). There was no difference in the type of primary tumor or presence of SDHB mutation. The clinical course of patients with malignant PPGL is remarkably variable. Rapid disease progression is associated with male sex, older age at diagnosis, synchronous metastases, larger tumor size, elevated dopamine, and not undergoing resection of primary tumor. An individualized approach to patients with metastatic PPGL is warranted.

DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers. We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic). Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Δβmetastatic-benign = 0.29, P = 0.003; HR, 1.4; 95% confidence interval (CI), 1.1-2.0; P = 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity. This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases.

Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.

The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL). The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines. The Task Force recommends that initial biochemical testing for PPGLs should include measurements of plasma free or urinary fractionated metanephrines. Consideration should be given to preanalytical factors leading to false-positive or false-negative results. All positive results require follow-up. Computed tomography is suggested for initial imaging, but magnetic resonance is a better option in patients with metastatic disease or when radiation exposure must be limited. (123)I-metaiodobenzylguanidine scintigraphy is a useful imaging modality for metastatic PPGLs. We recommend consideration of genetic testing in all patients, with testing by accredited laboratories. Patients with paraganglioma should be tested for SDHx mutations, and those with metastatic disease for SDHB mutations. All patients with functional PPGLs should undergo preoperative blockade to prevent perioperative complications. Preparation should include a high-sodium diet and fluid intake to prevent postoperative hypotension. We recommend minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas. Partial adrenalectomy is an option for selected patients. Lifelong follow-up is suggested to detect recurrent or metastatic disease. We suggest personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.

Abstract 5754: Temozolomide therapy for progressive metastatic paraganglioma/pheochromocytoma: SDHB mutation as a prognosis biomarker for efficacy

Abstract Malignant pheochromocytoma and paraganglioma (PPGLs) are rare diseases with a heterogeneous behaviour. Nowadays systemic therapies, including 131I-MIBG therapy and the cyclophosphamide-dacarbazine-vincristine chemotherapy regimen (CVD), constitute the most popular options in case of aggressive tumors. We have investigated the antitumor effect of temozolomide (TMZ), in patients with metastatic PPGLs. All patients were assessed for TMZ efficacy, with CT scan and PET scan performed every 3 months. Safety and identification for prognosis factors of response were secondary endpoints. Fifteen consecutive patients with progressive (n=14) or symptomatic (n=1) metastatic PPGLs began TMZ therapy at our institution between November 2007 and January 2011. There were 12 men (80%); median age was 43 years, with a functioning tumor in 73% of the cases. Germline mutations were screened: 10 patients harbored SDH B mutation and 5 patients had no mutation among SDH A, SDH C, SDH D, NF1, RET or VHL genes. Primary was located in the adrenal gland for 53% of the patients, thorax for 40 % and neck for 7%. TMZ was given at a dose of 150 mg/m2/d for five days of a 28-days cycle for the first cycle and then at 200 mg/m2 for five days each subsequent cycle. Seven patients received TMZ as first line therapy, 2 patients as second line and 6 patients as third line. Median number of cycle administered was 7, mean dose intensity was 171 mg/m2 (95% CI 160.7-181) for each treatment cycle. TMZ was well tolerated: the most frequent all grade toxicities included asthenia, nausea and anemia. Grade 3 toxicities were lymphopenia (n=2) and hypertension (n=1). According to RECIST 1.1 criteria, 11 patients were evaluable: 4 patients experienced a partial response, 6 a stable disease, 1 patient a progressive disease. With a median follow up of 29 months (range 6.4-37.9), median overall survival was not reached and median progression free survival (PFS) was 9.6 months. Partial response was observed in 4 out of 10 SDHB mutated patients but no sporadic case. Patients with SDH B mutations or with no mutation had a median PFS of 16.7 months or 2.6 months, respectively (log-rank, p=0.013); Patients with SDH B mutations or with no mutation had a 12-month PFS of 60% or 0%, respectively. Expression of Methyl Guanine Methyl Transferase (MGMT) by immunohistochemistry (IHC) was analyzed in 4 patients, including 3 responders and, was found negative. MGMT IHC is ongoing in the remaining patients This study demonstrates for the first time the antitumor efficacy of TMZ in a large series of metastatic PPGLs as well as the potential role for SDH B mutation as a prognosis biomarker of response of response. Loss of MGMT expression in SDH B mutated patients could explain these results. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5754. doi:1538-7445.AM2012-5754