Metastatic Paraganglioma Research Articles

Metastatic Malignant Paraganglioma of Rare Sites Failed on Conventional Treatments Demonstrating Beneficial Response to 177Lu-DOTATATE PRRT

Metastatic Malignant Paraganglioma of Rare Sites Failed on Conventional Treatments Demonstrating Beneficial Response to 177Lu-DOTATATE PRRT

Surgical Treatment and Clinical Evaluation of Calvarial Metastases.

The aim of this study is to explore surgical treatment techniques and clinical attributes associated with calvarial metastases, while providing a comprehensive review of the treatment experiences relevant to this particular type of tumor. This study involves a retrospective analysis of clinical data from 12 patients diagnosed with calvarial metastatic tumors who underwent surgical intervention. Among these patients, 5 had a history of previous malignant tumor resections, while 7 presented with calvarial metastatic tumors as their initial symptom. In all cases, the surgical approach consisted of calvarial tumor resection followed by titanium mesh repair. Following the surgical intervention, all patients underwent a comprehensive course of treatment, encompassing both local radiotherapy and systemic chemotherapy. In 1 instance, a patient presented with multiple tumors located in the central area of the frontal bone and the right temporal bone. The larger tumor situated in the middle of the frontal bone was surgically excised, while the tumor in the right temporal bone was treated using radiotherapy. In 2 cases characterized by multiple metastases within the skull, a comprehensive excision of all tumors was accomplished in a single surgical procedure. In the remaining cases featuring a solitary metastatic growth, the respective tumors were surgically removed. There were 10 instances of dura mater invasion and 3 cases involving the invasion of brain tissue. Pathologic examinations revealed 1 case of metastatic lung adenocarcinoma, 1 case of metastatic paraganglioma, 1 case of metastatic hepatocellular carcinoma, 2 cases of metastatic thyroid carcinoma, and 7 cases of metastatic clear cell renal cell carcinoma. Throughout the follow-up period, spanning from 14 to 90 months, various outcomes were noted. These included three occurrences of in situ recurrence. In addition, 1 patient required 3 distinct surgical interventions, while 2 other patients underwent 2 separate surgical procedures each. Notably, 1 of these cases involved the exposure of the titanium mesh on the scalp, necessitating the removal of the titanium mesh. Regrettably, there have been 9 recorded fatalities among the patients, while 3 individuals have survived. Solitary metastasis of calvarium region is rare, and surgical resection is effective. However, it is necessary to extend the resection range and combine with local radiotherapy to avoid local recurrence. Surgical intervention can significantly enhance the quality of life for affected patients. The prognosis of the patients mainly depends on the treatment of the primary disease and the situation of important organ dissemination and treatment.

6912 Nail Fold Capillary Findings In Patients With Somatic EPAS1 Pathogenic Variants

Abstract Disclosure: H. Alkaissi: None. B. Turturice: None. J.S. Rosenblum: None. A.S. Alzahrani: None. S. Talvacchio: None. A. Derkyi: None. M. Nazari: None. H. Wang: None. I. Pinal Fernandez: None. Z. Zhuang: None. K. Pacak: None. We recently discovered a new syndrome characterized by a triad of pheochromocytoma/paraganglioma, polycythemia, and somatostatinoma (so called Pacak-Zhuang syndrome) caused by somatic gain-of-function pathogenic variants in the EPAS1 gene, encoding hypoxia-inducible factor 2α (HIF-2α). Recently, we have described additional features of this syndrome, including systemic developmental vascular malformations in patients and the mouse model [1]. Here we evaluated vascular changes in the nailfold capillaries by using video capillaroscopy in four patients, three of whom were female and carried the same pathogenic somatic EPAS1 variant allele (EPAS1A530V). The first patient is an 18-year-old female with a history of ventricular septal defect since birth, acrocyanosis, abdominal paraganglioma, left adrenal pheochromocytoma, and polycythemia. The second patient is a 64-year-old female who presented with paraganglioma without polycythemia, in whom we found the EPAS1A530V variant from hair sample, and an additional variant (EPAS1P53[1]A) in a resected paraganglioma, confirming the diagnosis. The third patient is a 33-year-old female had polycythemia, right adrenal pheochromocytoma, abdominal paragangliomas and duodenal somatostatinoma. The fourth patient is a 25-year-old male with PZS bearing a somatic EPAS1M535V pathogenic variant and an additional D536_L542 deletion, with hypoplastic left ventricle and metastatic paraganglioma who never developed polycythemia due to concomitant sickle cell-thalassemia traits. Despite the notable differences in genotype between the first three patients compared to the fourth patient, whose genotype is more complex, nailfold video capillaroscopy of all these patients showed similar phenotype—abnormal capillary structure marked by widespread dilations, megacapillaries, sporadic capillary hemorrhages, and regions with diminished capillary density. While polycythemia has been implicated in megacapillaries phenotype, two of our patients did not have polycythemia at the time of evaluation, further supporting the role of HIF-2a in angiogenesis. In conclusion, we describe nailfold capillary changes on video capillaroscopy as a non-invasive clinical sign in patients with EPAS1 pathogenic variants. Whether this finding is due to circulating angiogenic factors secreted by the tissues harboring HIF-2α mutation, or a direct effect of HIF-2α on angiogenesis remains to be determined.

8639 Clinical characterization and germline DNA methylation analysis of a large cohort of patients with paraganglioma syndrome type 4

Abstract Disclosure: R. Halperin: None. R. Horowitz: None. A. Jabarin: None. A. Tirosh: None. Background: Patients harboring germline pathogenic variant (PV) in the SDHB gene (Paraganglioma syndrome type 4, PPGL4) have a higher risk of developing paragangliomas and pheochromocytomas. PPGL4 is considered a higher-risk syndrome for aggressive and metastatic abdominal-thoracic paragangliomas compared with other paraganglioma syndromes. The penetrance in PPGL4 reaches 65% by the age of 80 years. Aims: To assess possible germline DNA epigenetic alterations in patients harboring the SDHB PV. Materials and Methods: A large cohort of patients with PPGL4 was characterized clinically in our clinic and genetically via germline DNA sequencing for the familial variant (SDHB c.640C>T p.Q214Ter, n=144) and whole genome methylation analysis compared 19 patients vs. 129 healthy controls. The control group consisted of four SDHB PV-negative family members and an additional 125 samples retrieved from a public database (GSE153712). Analysis was performed on Rstudio, using the ChAMP suite for normalization, imputation, differentially methylated probes (DMP), and regions (DMR) analyses. Pathway analysis and visualization were executed using the clusterprofiler and enrichplot packages. Promoter regions were defined by the transcription start site (TSS1500). Results: The cohort includes three kindreds, and each presented independently with an index patient: Index patient in kindred A, a 12-year-old boy, with thoracic paraspinal and testicular paragangliomas, non-secretory, requiring several surgeries due to spinal compression with subsequent improvement of neurological deficit. Index patient in kindred B, a 26-year-old woman with abdominal paraganglioma, metastatic to the lungs and spine. Index patient in kindred C, a 41-year-old man with a locally aggressive abdominal paraganglioma, metastatic to the skull and spine. A total of 114 (44.2% females) patients underwent genetic evaluation (45/50, 16/28, and 25/36 in kindreds A, B and C, respectively). Of those, 50 (58.1%) harbored the familial SDHB PV (68.9%, 56.2%, and 40.0%, respectively). Twenty-six patients underwent at least partial clinical evaluation: Eight had paraganglioma (4/8 had metastatic disease), three had pheochromocytoma, and two patients had neck masses that are currently being evaluated. Pathway analysis revealed enrichment of the germline DNA alterations to the regulation of cell differentiation and development, metabolic processes, and cellular component organization (p<0.03 for all pathways). Conclusions: We report one of the largest cohorts of patients with SDHB PV, showing typical low penetrance and aggressive phenotype. Genomic analysis shows distinct germline DNA methylation in SDHB PV-positive compared with the control group. Future studies may reveal an association between specific epigenetic alterations and penetrance/phenotypic patterns in this rare hereditary syndrome. Presentation: 6/2/2024

Using a combination of bulk and single cell RNA sequencing to identify transcriptomic differences in metastatic vs non-metastatic phaeochromoctyomas and paragangliomas

Using a combination of bulk and single cell RNA sequencing to identify transcriptomic differences in metastatic vs non-metastatic phaeochromoctyomas and paragangliomas

Metastatic pheochromocytoma and paraganglioma: Integrating tumor biology in clinical practice

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors derived from chromaffin cells in the autonomic nervous system. Depending on their location, these tumors are capable of excessive catecholamine production, which may lead to uncontrolled hypertension and other life-threatening complications. They are associated with a significant risk of metastatic disease and are often caused by an inherited germline mutation.Although surgery can cure localized disease and lead to remission, treatments for metastatic PPGL (mPPGL)—including chemotherapy, radiopharmaceutical agents, multikinase inhibitors, and immunotherapy used alone or in combination— aim to control tumor growth and limit organ damage.Substantial advances have been made in understanding hereditary and somatic molecular signaling pathways that play a role in tumor growth and metastasis. Treatment options for metastatic disease are rapidly evolving, and this paper aims to provide a brief overview of the management of mPPGL with a focus on therapy options.

Management of metastatic pheochromocytomas and paragangliomas: when and what

Recently, the treatment landscape for metastatic pheochromocytomas and paragangliomas (MPPGL) has seen both progress and setbacks. We provide an up-to-date review of the multimodality management of MPPGL and discuss novel opportunities and current challenges in the treatment landscape. Given the unique clinical presentation of MPPGL, we discuss the management of hormone-related clinical sequelae and traditional modalities of therapy. Advances in the understanding of the molecular biology of these diverse tumors have enabled novel strategies such as augmenting DNA damage by targeted delivery of radionuclides such as 131I and 177Lu, abrogating tumor angiogenesis, hypoxia resistance, and DNA damage repair. Despite progress, we address the significant challenges still faced by patients and researchers engaged in efforts to improve outcomes in these rare cancers.

Presentation of metastatic carotid body paraganglioma on F-18 FDG PET/CT: a rare disease

Carotid body paraganglioma is a slow growing tumor of head and neck region. It can rarely be malignant in nature which is characterized by distant metastases on anatomical imaging. We share an interesting presentation of a malignant carotid body on F-18 FDG PET/CT in form of liver and skeletal metastases.

Adverse skeletal related events in patients with bone-metastatic pheochromocytoma/paraganglioma

Metastatic pheochromocytomas and paragangliomas (PPGLs) are frequently associated with skeletal complications.Primary objective: to describe the frequency of adverse skeletal related events (SREs) in PPGL patients with bone metastases (BMs). Secondary objectives: to 1) identify predictive and prognostic factors for SREs and 2) obtain information on the effectiveness of bone resorption inhibitors in reducing SRE risk and improving outcomes in term of survival and SREs time onset.In this retrospective multicenter, multinational study, 294 PPGL patients were enrolled.SREs occurred in 90 patients (31 %). Fifty-five patients (19 %) had bone fractures, 47 (16 %) had spinal cord compression, and 11 (4 %) had hypercalcemia. Twenty-two patients (7 %) had more than one SRE. Sixty-four patients (22 %) underwent surgery, and 136 (46 %) underwent radiotherapy. SREs occurred a median of 4.4 months after diagnosis of BM (range, 0–246.6 months). Independent factors associated with reduced risk of SREs in multivariable analysis were I-131-MIBG radionuclide therapy (hazard ratio [HR], 0.536 [95 % CI, 0.309–0.932]; P = .027) and absence of liver metastases (HR, 0.638 [95 % CI, 0.410–0.992]; P = .046). The median overall survival duration was 5.3 year. In multivariable analysis, age younger than 48 years at PPGL diagnosis (HR, 0.558 [95 % CI, 0.3877–0.806]; P = .002), absence of liver metastases (HR, 0.618 [95 % CI, 0.396–0.965]; P = .034), treatment with bisphosphonates or denosumab (HR, 0.598 [95 % CI, 0.405–0.884]; P = .010), and MIBG radionuclide therapy (HR, 0.444 [95 % CI, 0.274–0.718]; P = .001) were associated with a reduced risk of death.SREs occur frequently and early in bone-metastatic PPGL patients but do not negatively impact survival. MIBG radionuclide therapy and treatment with bone resorption inhibitors are associated with favorable outcome.

Successful delivery in the setting of SDHB metastatic paraganglioma.

Pregnancy in the setting of metastatic paraganglioma is challenging, particularly in the context of tyrosine kinase use. We describe a 26-year-old female with a background of metastatic paraganglioma harboring a pathogenic SDHB variant, requiring sunitinib, which was withheld to facilitate the safe conception and delivery of a healthy baby. She required no alpha- or beta-blockade during her pregnancy and exhibited no signs of tumor progression or symptoms throughout this period. Historically, higher rates of fetal and maternal morbidity and mortality have been experienced in the setting of pregnancy. Although limited data exist on the management of metastatic paraganglioma in pregnant patients, this case suggests that careful treatment modifications, such as temporary tyrosine kinase therapy cessation and vigilant monitoring, can result in successful pregnancies without compromising maternal or fetal well-being. Paraganglioma in pregnancy has been associated with poor fetal and maternal morbidity and mortality. Many of the treatment modalities for metastatic paraganglioma, including tyrosine kinase inhibitors, can affect fertility or cannot be utilized in pregnancy, necessitating the temporary suspension of these treatments. This case exemplifies that careful clinical and biochemical monitoring during pregnancy is required to avoid maternal and fetal harm while balancing the risk of disease progression off treatment.

Evaluating the diagnostic efficacy of whole-body MRI versus 123I-mIBG/131I-mIBG imaging in metastatic pheochromocytoma and paraganglioma

This study aimed to compare tumor lesion detectability and diagnostic accuracy of whole-body magnetic resonance imaging (WB-MRI) and radioiodine-labeled meta-iodo-benzylguanidine (mIBG) imaging techniques in patients with metastatic pheochromocytoma and paraganglioma (PPGL). This retrospective study included 13 patients had pheochromocytoma and 5 had paraganglioma, who were all suspected of having metastatic tumors. Each patient underwent WB-MRI and 123I-mIBG as a pretreatment screening for 131I-mIBG therapy. Two expert reviewers evaluated WB-MRI, 123I-mIBG images, and post-therapy 131I-mIBG images for the presence of metastatic lesions in the lungs, bones, liver, lymph nodes, and other organs. Diagnostic measures for detecting metastatic lesions, including sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristics (ROC)—area under the curve (AUC), were calculated for each imaging technique. We analyzed WB-MRI images for detecting metastatic lesions, which demonstrated sensitivity, specificity, accuracy, PPV, NPV, and AUC of 82%, 97%, 90%, 96%, 86%, and 0.92, respectively. These values were 83%, 95%, 89%, 94%, 86%, and 0.90 in 123I-mIBG images and 85%, 92%, 89%, 91%, 87%, and 0.91 in post-therapy 131I-mIBG images, respectively. Our results reveal the comparable diagnostic accuracy of WB-MRI to one of the mIBG images.

Immunohistochemical Profiling of SSTR2 and HIF-2α with the Tumor Microenvironment in Pheochromocytoma and Paraganglioma.

Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare endocrine malignancies with limited effective treatment options. The association between the tumor microenvironment (TME) with somatostatin receptor 2 (SSTR2) and hypoxia-induced factor-2α (HIF-2α) in PPGLs, critical for optimizing combination therapeutic strategies with immunotherapy, remains largely unexplored. To evaluate the association of SSTR2 and HIF-2α immunoreactivity with the TME in patients with PPGLs, we analyzed the expression of SSTR2A, HIF-2α, and TME components, including tumor-infiltrating lymphocytes (CD4 and CD8), tumor-associated macrophages (CD68 and CD163), and PD-L1, using immunohistochemistry in patients with PPGLs. The primary outcome was to determine the association of the immune profiles with SSTR2A and HIF-2α expression. Among 45 patients with PPGLs, SSTR2A and HIF2α were positively expressed in 21 (46.7%) and 14 (31.1%) patients, respectively. The median PD-L1 immunohistochemical score (IHS) was 2.0 (interquartile range: 0-30.0). Positive correlations were observed between CD4, CD8, CD68, and CD163 levels. A negative correlation was found between the CD163/CD68 ratio (an indicator of M2 polarization) and SSTR2A expression (r = -0.385, p = 0.006). HIF-2α expression showed a positive correlation with PD-L1 IHS (r = 0.348, p = 0.013). The co-expression of PD-L1 (HIS > 10) and HIF-2α was found in seven patients (15.6%). No associations were observed between SDHB staining results and the CD163/CD68 ratio, PD-L1, or SSTR2A expression. Our data suggest the potential of combination therapy with immunotherapy and peptide receptor radionuclide therapy or HIF-2α inhibitors as a treatment option in selected PPGL populations.

Identification of Predictors of Metastatic Potential in Paragangliomas to Develop a Prognostic Score (PSPGL).

Paragangliomas (PGLs) are rare tumors in adrenal and extra-adrenal locations. Metastasis are found in approximately 5% to 35% of PGLs, and there are no reliable predictors of metastatic disease. This work aimed to develop a prognostic score of metastatic potential in PGLs. A retrospective analysis was conducted of clinical data from a cohort with PGLs and tumor histological assessment. Patients were divided into metastatic PGL (presence of metastasis) and nonmetastatic PGL (absence of metastasis ≥96 months of follow-up) groups. Univariate and multivariable analysis were performed to identify predictors of metastatic potential. A prognostic score was developed based on coefficients of multivariable analysis. Kaplan-Meier curves were generated to estimate disease-specific survival (DSS). Out of 263 patients, 35 patients had metastatic PGL and 110 patients had nonmetastatic PGL. In multivariable analysis, 4 features were independently related to metastatic disease and composed the Prognostic Score of Paragangliomas (PSPGL): presence of central or confluent necrosis (33 points), more than 3 mitosis/10 high-power field (HPF) (28 points), extension into adipose tissue (20 points), and extra-adrenal location (19 points). A PSPGL of 24 or greater showed similar sensitivity with higher specificity than the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP). PSPGL less than or equal to 20 was associated with a risk of metastasis of approximately 10%, whereas a PSPGL of 40 or greater was associated with approximately 80%. The presence of metastasis and Ki-67 of 3% or greater were related to lower DSS. The PSPGL, composed of 4 easy-to-assess parameters, demonstrated good performance in predicting metastatic potential and good ability in estimating metastasis risk.

Immunohistochemical profiling of HIF-2[alpha] and SSTR2 with the tumor microenvironment in metastatic pheochromocytoma and paraganglioma

Immunohistochemical profiling of HIF-2[alpha] and SSTR2 with the tumor microenvironment in metastatic pheochromocytoma and paraganglioma

Preoperative prediction of metastatic pheochromocytoma and paraganglioma using clinical, genetic, and biochemical markers: A cohort study.

The prevalence of metastatic pheochromocytoma and paraganglioma (PPGL) is approximately 15%-20%. Although there are indicators to assess metastatic risks, none of them predict metastasis reliably. Therefore, we aimed to develop and validate a scoring system using clinical, genetic, and biochemical risk factors to preoperatively predict the metastatic risk of PPGL. In the cross-sectional cohort (n=180), clinical, genetic, and biochemical risk factors for metastasis were identified using multivariate logistic regression analysis, and a novel scoring system was developed. The scoring system was validated and compared with the age, size of tumor, extra-adrenal location, and secretory type (ASES) score in the longitudinal cohort (n=114). In the cross-sectional cohort, pseudohypoxia group-related gene variants (SDHB, SDHD, or VHL), methoxytyramine >0.16nmol/L, and tumor size >6.0cm were independently associated with metastasis after multivariate logistic regression. Using them, the gene variant, methoxytyramine, and size of tumor (GMS) score were developed. In the longitudinal cohort, Harrell's concordance index of the GMS score (0.873, 95% confidence interval [CI]: 0.738-0.941) was higher than that of the ASES score (0.713, 95% CI: 0.567-0.814, p=0.007). In the longitudinal cohort, a GMS score ≥2 was significantly associated with a higher risk of metastasis (hazard ratio=25.07, 95% CI: 5.65-111.20). A GMS score ≥2 (p<0.001), but not ASES score ≥2 (p=0.090), was associated with shorter progression-free survival. The GMS scoring system, which integrates gene variant, methoxytyramine level, and tumor size, provides a valuable preoperative approach to assess metastatic risk in PPGL.

Approach to the Patient: Concept and Application of Targeted Radiotherapy in the Paraganglioma Patient.

Paragangliomas can metastasize, posing potential challenges both in symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and 177Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma-targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. Perspectives in radiotherapies of paraganglioma patients are outlined since they hold promising approaches in the near future that can improve patient outcomes.

Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma (the Natalie Trial): a single-arm, phase 2 trial

Metastatic phaeochromocytomas and paragangliomas (MPPGs) are orphan diseases. Up to 50% of MPPGs are associated with germline pathogenic variants of the SDHB gene. These tumours and many non-familial MPPGs exhibit a phenotype that is characterised by abnormal angiogenesis. We aimed to assess the activity and safety of cabozantinib, an antiangiogenic multi-tyrosine kinase inhibitor, in patients with MPPGs. The Natalie Trial is a single-arm, phase 2 clinical trial being conducted at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 18 years or older with histologically confirmed, progressive, and unresectable MPPGs, with an Eastern Cooperative Oncology Group performance status of 0-2, were treated with oral cabozantinib 60 mg/day. The primary endpoint was the investigator-assessed overall response rate per the Response Evaluation Criteria in Solid Tumours version 1.1 criteria. All outcomes were assessed in all evaluable participants who received any amount of study treatment. The trial is registered with ClinicalTrials.gov (NCT02302833) and is active but not recruiting. From March 10, 2015, to May 11, 2021, 17 patients (13 male participants and four female participants) were enrolled. The median follow-up was 25 months (IQR 18-49). The overall response rate was 25·0% (95% CI 7·3-52·4; four of 16 patients). Seven grade 3 adverse events were reported in six patients, including single cases of hand-and-foot syndrome, hypertension, rectal fistula, QT prolongation, and asymptomatic hypomagnesaemia, and two cases of asymptomatic elevations of amylase and lipase. There were no grade 4 adverse events and no patient died on-study. Cabozantinib shows promising activity in patients with MPPGs. Team NAT Foundation, Margaret Cazalot, and Clarence P Cazalot.

Effects of Peptide Receptor Radiotherapy in Patients with Advanced Paraganglioma and Pheochromocytoma: A Nation-Wide Cohort Study.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence. In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with 177Lu-Dotatate or 90Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8-14-week intervals. We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15-76) years. The median follow-up time was 31 (IQR 17-37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations (p = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment (p = 0.083). The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to 131I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group.

Hand2 Immunohistochemistry in the Diagnosis of Paragangliomas and Other Neuroendocrine Neoplasms.

Hand2 is a core transcription factor responsible for chromaffin cell differentiation. However, its potential utility in surgical pathology has not been studied. Thus, we aimed to investigate its expression in paragangliomas, other neuroendocrine neoplasms (NENs), and additional non-neuroendocrine tumors. We calibrated Hand2 immunohistochemistry on adrenal medulla cells and analyzed H-scores in 46 paragangliomas (PGs), 9 metastatic PGs, 21 cauda equina neuroendocrine tumors (CENETs), 48 neuroendocrine carcinomas (NECs), 8 olfactory neuroblastomas (ONBs), 110 well-differentiated NETs (WDNETs), 10 adrenal cortical carcinomas, 29 adrenal cortical adenomas, 8 melanomas, 41 different carcinomas, and 10 gastrointestinal stromal tumors (GISTs). Both tissue microarrays (TMAs) and whole sections (WSs) were studied. In 171 NENs, previously published data on Phox2B and GATA3 were correlated with Hand2. Hand2 was positive in 98.1% (54/55) PGs, but only rarely in WDNETs (9.6%, 10/104), CENETs (9.5%, 2/21), NECs (4.2%, 2/48), or ONBs (12.5%, 1/8). Any Hand2 positivity was 98.1% sensitive and 91.7% specific for the diagnosis of PG. The Hand2 H-score was significantly higher in primary PGs compared to Hand2-positive WDNETs (median 166.3 vs. 7.5; p < 0.0001). Metastatic PGs were positive in 88.9% (8/9). No Hand2 positivity was observed in any adrenal cortical neoplasm or other non-neuroendocrine tumors, with exception of 8/10 GISTs. Parasympathetic PGs showed a higher Hand2 H-score compared to sympathetic PGs (median H-scores 280 vs. 104, p < 0.0001). Hand2 positivity in NENs serves as a reliable marker of primary and metastatic PG, since other NENs only rarely exhibit limited Hand2 positivity.

Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial

No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment. From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock. This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant.