-
Radiologia 2022Pheochromocytomas are adrenal paragangliomas. Potentially malignant, these tumors have a low incidence but clear importance. They can appear in various hereditary...
Pheochromocytomas are adrenal paragangliomas. Potentially malignant, these tumors have a low incidence but clear importance. They can appear in various hereditary syndromes, especially in von Hippel-Lindau syndrome, multiple endocrine neoplasia-2 (MEN2), and familial paraganglioma syndromes. In sporadic cases, underlying genetic alterations are often found, and these findings are changing our understanding of the disease. Although these tumors can manifest with a characteristic clinical presentation, in 13.1%-57.6% of cases, it is the radiologist who first suggests the diagnosis, indicating analyses for catecholamines or nuclear medicine examinations. Radiologists should suspect a pheochromocytoma on detection of a well-delimited adrenal mass with rapid, intense enhancement that typically shows cystic and hemorrhagic phenomena, high T2 signal intensity, and the absence of macroscopic or microscopic lipids. The behavior in diffusion-weighted imaging usually does not provide very useful information. Approximately one-third of lesions show late washout similar to that seen with adenomas on CT. Percutaneous puncture should be avoided to avoid the risk of unleashing a severe hypertensive crisis.
Topics: Adrenal Gland Neoplasms; Humans; Paraganglioma; Pheochromocytoma; Syndrome; von Hippel-Lindau Disease
PubMed: 36030082
DOI: 10.1016/j.rxeng.2022.07.002 -
The International Journal of... May 2021Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours. So far, over 20 causative genes have been identified, of which the most frequent and strongest... (Review)
Review
Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours. So far, over 20 causative genes have been identified, of which the most frequent and strongest indicator for malignancies are mutations in succinate dehydrogenase subunit B. No curative therapy is available for patients with metastases resulting in poor prognosis. Therapy development has been hindered by lack of suitable model systems. The succinate dehydrogenase complex is located in the inner membrane of the mitochondria and plays a crucial role in the oxidative phosphorylation chain and the tricarboxylic acid-cycle. Succinate dehydrogenase deficiency results in accumulation of the oncometabolite succinate inducing hypoxia inducible factor stabilization, deoxyribonucleic acid and histone methylation inhibition, and impaired production of adenosine triphosphate. It remains unknown which combination of pathways and/or triggers are decisive for metastases development. In this review, the role of mitochondria in malignant succinate dehydrogenase subunit B-associated phaeochromocytomas and paragangliomas and implications for mitochondria as therapeutic target are discussed.
Topics: Adrenal Gland Neoplasms; Animals; Electron Transport Complex II; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Metabolism, Inborn Errors; Mitochondria; Mitochondrial Diseases; Mutation; Paraganglioma; Pheochromocytoma; Reactive Oxygen Species; Succinate Dehydrogenase
PubMed: 33609747
DOI: 10.1016/j.biocel.2021.105949 -
Frontiers in Endocrinology 2020Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic... (Review)
Review
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis including , , , and are more frequently found in PPGLs. Multiple lines of evidence indicate that pseudohypoxia plays a crucial role in the tumorigenesis of PPGLs, and therefore PPGLs are also known as metabolic diseases. However, the interplay between VHL/HIF-mediated pseudohypoxia and metabolic disorder in PPGLs cells is not well-defined. In this review, we will first discuss the VHL/HIF axis and genetic alterations in this axis. Then, we will dissect the underlying mechanisms in VHL/HIF axis-driven PPGL pathogenesis, with special attention paid to the interplay between the VHL/HIF axis and cancer cell metabolism. Finally, we will summarize the currently available compounds/drugs targeting this axis which could be potentially used as PPGLs treatment, as well as their underlying pharmacological mechanisms. The overall goal of this review is to better understand the role of VHL/HIF axis in PPGLs development, to establish more accurate tools in PPGLs diagnosis, and to pave the road toward efficacious therapeutics against metastatic PPGLs.
Topics: Adrenal Gland Neoplasms; Animals; Antineoplastic Agents; Apoptosis Regulatory Proteins; Basic Helix-Loop-Helix Transcription Factors; Chromaffin Cells; Germ-Line Mutation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Pheochromocytoma; Protein Kinase Inhibitors; Repressor Proteins; Von Hippel-Lindau Tumor Suppressor Protein
PubMed: 33329393
DOI: 10.3389/fendo.2020.586857 -
Frontiers in Endocrinology 2023Pheochromocytomas and paragangliomas (PCC/PGL) are rare neuroendocrine tumors and can secrete catecholamine. Previous studies have found that SDHB immunohistochemistry...
INTRODUCTION
Pheochromocytomas and paragangliomas (PCC/PGL) are rare neuroendocrine tumors and can secrete catecholamine. Previous studies have found that SDHB immunohistochemistry (IHC) can predict SDHB germline gene mutation, and SDHB mutation is closely associated with tumor progression and metastasis. This study aimed to clarify the potential effect of SDHB IHC as a predictive marker for tumor progression in PCC/PGL patients.
METHODS
We included PCC/PGL patients diagnosed in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from 2002 to 2014 for retrospective analysis and discovered that SDHB (-) staining patients had poorer prognoses. Then we examined SDHB protein expression by IHC on all tumors in the prospective series, which was composed of patients from 2015 to 2020 in our center.
RESULTS
In the retrospective series, the median follow-up was 167 months, and during follow-up, 14.4% (38/264) patients developed metastasis or recurrence, and 8.0% (22/274) patients died. Retrospective analysis revealed that 66.7% (6/9) of participants in the SDHB (-) group and 15.7% (40/255) of those in the SDHB (+) group developed progressive tumors (OR: 10.75, 95% CI: 2.72-52.60, P=0.001), and SDHB (-) was independently associated with poor outcomes after adjusting by other clinicopathological parameters (OR: 11.68, 95% CI: 2.58-64.45, P=0.002). SDHB (-) patients had shorter disease-free survival (DFS) and overall survival (OS) (P<0.001) and SDHB (-) was significantly associated with shorter median DFS (HR: 6.89, 95% CI: 2.41-19.70, P<0.001) in multivariate cox proportional hazard analysis. In the prospective series, the median follow-up was 28 months, 4.7% (10/213) patients developed metastasis or recurrence, and 0.5% (1/217) patient died. For the prospective analysis, 18.8% (3/16) of participants in the SDHB (-) group had progressive tumors compared with 3.6% (7/197) in the SDHB (+) group (RR: 5.28, 95% CI: 1.51-18.47, P=0.009), statistical significance remained (RR: 3.35, 95% CI: 1.20-9.38, P=0.021) after adjusting for other clinicopathological factors.
CONCLUSIONS
Our findings demonstrated patients with SDHB (-) tumors had a higher possibility of poor outcomes, and SDHB IHC can be regarded as an independent biomarker of prognosis in PCC/PGL.
Topics: Humans; Pheochromocytoma; Immunohistochemistry; Retrospective Studies; China; Paraganglioma; Prognosis; Adrenal Gland Neoplasms; Succinate Dehydrogenase
PubMed: 37008946
DOI: 10.3389/fendo.2023.1121397 -
International Journal of Molecular... Aug 2023The purpose of this study is to investigate the expression of the epithelial membrane proteins (EMP) 1, 2, and 3 in adrenal gland neoplasm and to explore the broader...
The purpose of this study is to investigate the expression of the epithelial membrane proteins (EMP) 1, 2, and 3 in adrenal gland neoplasm and to explore the broader implications of this. Tissue microarrays were constructed for 132 cases of adrenal cortical neoplasms (ACN) (adrenal cortical adenoma (115 cases), and carcinoma (17 cases)) and 189 cases of pheochromocytoma. Immunohistochemical staining was performed to identify EMP 1, 2, and 3, and was compared with clinicopathological parameters. The H-score of EMP 3 ( < 0.001) was higher in pheochromocytoma when compared to that of ACN, and the H-score of EMP 1 ( < 0.001) and EMP 3 ( < 0.001) was higher in adrenal cortical carcinomas when compared to that of adrenal cortical adenomas. A higher EMP 1 H-score was observed in pheochromocytomas with a GAPP score ≥3 ( = 0.018). In univariate analysis, high levels of EMP 1 and EMP 3 expression in ACN were associated with shorter overall survival ( = 0.001). Differences were observed in the expression of EMPs between ACN and pheochromocytoma. EMPs are associated with malignant tumor biology in adrenal cortical neoplasm and pheochromocytoma, suggesting the role of a prognostic and/or predictive factor for EMPs in adrenal tumor.
Topics: Humans; Pheochromocytoma; Adrenal Gland Neoplasms; Adrenocortical Adenoma; Adrenocortical Carcinoma; Adrenal Cortex Neoplasms
PubMed: 37629198
DOI: 10.3390/ijms241613016 -
ELife Feb 2024Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells in the adrenal gland. However, the cellular molecular characteristics and...
Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells in the adrenal gland. However, the cellular molecular characteristics and immune microenvironment of PCCs are incompletely understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 16 tissues from 4 sporadic unclassified PCC patients and 1 hereditary PCC patient with Von Hippel-Lindau (VHL) syndrome. We found that intra-tumoral heterogeneity was less extensive than the inter-individual heterogeneity of PCCs. Further, the unclassified PCC patients were divided into two types, metabolism-type (marked by NDUFA4L2 and COX4I2) and kinase-type (marked by RET and PNMT), validated by immunohistochemical staining. Trajectory analysis of tumor evolution revealed that metabolism-type PCC cells display phenotype of consistently active metabolism and increased metastasis potential, while kinase-type PCC cells showed decreased epinephrine synthesis and neuron-like phenotypes. Cell-cell communication analysis showed activation of the annexin pathway and a strong inflammation reaction in metabolism-type PCCs and activation of FGF signaling in the kinase-type PCC. Although multispectral immunofluorescence staining showed a lack of CD8 T cell infiltration in both metabolism-type and kinase-type PCCs, only the kinase-type PCC exhibited downregulation of molecules that possibly regulated by , suggesting the potential of combined therapy with kinase inhibitors and immunotherapy for kinase-type PCCs; in contrast, the application of immunotherapy to metabolism-type PCCs (with antigen presentation ability) is likely unsuitable. Our study presents a single-cell transcriptomics-based molecular classification and microenvironment characterization of PCCs, providing clues for potential therapeutic strategies to treat PCCs.
Topics: Humans; Pheochromocytoma; Tumor Microenvironment; Adrenal Gland Neoplasms; Antigen Presentation; CD8-Positive T-Lymphocytes
PubMed: 38407266
DOI: 10.7554/eLife.87586 -
BMJ Case Reports Mar 2021A postpartum patient with acute-onset dyspnoea and hypotention, associated with reduced left ventricular function requiring intensive blood pressure control, was...
A postpartum patient with acute-onset dyspnoea and hypotention, associated with reduced left ventricular function requiring intensive blood pressure control, was initially misdiagnosed as having peripartum cardiomyopathy. Her clinical symptoms rapidly resolved. Echocardiography revealed reversible left ventricular dysfunction with apical ballooning and coronary angiography was normal. Based on these findings, we diagnosed takotsubo syndrome. Over the next two months, the patient experienced repeated bouts of elevated sympathetic activity. On workup, we found an adrenal mass and elevated urine metanephrines. After adrenalectomy, histology confirmed pheochromocytoma. Our patient had the rare diagnosis of postpartum pheochromocytoma-induced takotsubo syndrome.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Female; Humans; Pheochromocytoma; Postpartum Period; Takotsubo Cardiomyopathy
PubMed: 33741570
DOI: 10.1136/bcr-2020-240098 -
ELife Dec 2021Ectopic Cushing's syndrome due to ectopic ACTH&CRH-secreting by pheochromocytoma is extremely rare and can be fatal if not properly diagnosed. It remains unclear whether...
Ectopic Cushing's syndrome due to ectopic ACTH&CRH-secreting by pheochromocytoma is extremely rare and can be fatal if not properly diagnosed. It remains unclear whether a unique cell type is responsible for multiple hormones secreting. In this work, we performed single-cell RNA sequencing to three different anatomic tumor tissues and one peritumoral tissue based on a rare case with ectopic ACTH&CRH-secreting pheochromocytoma. And in addition to that, three adrenal tumor specimens from common pheochromocytoma and adrenocortical adenomas were also involved in the comparison of tumor cellular heterogeneity. A total of 16 cell types in the tumor microenvironment were identified by unbiased cell clustering of single-cell transcriptomic profiles from all specimens. Notably, we identified a novel multi-functionally chromaffin-like cell type with high expression of both POMC (the precursor of ACTH) and CRH, called ACTH+&CRH + pheochromocyte. We hypothesized that the molecular mechanism of the rare case harbor Cushing's syndrome is due to the identified novel tumor cell type, that is, the secretion of ACTH had a direct effect on the adrenal gland to produce cortisol, while the secretion of CRH can indirectly stimulate the secretion of ACTH from the anterior pituitary. Besides, a new potential marker (GAL) co-expressed with ACTH and CRH might be involved in the regulation of ACTH secretion. The immunohistochemistry results confirmed its multi-functionally chromaffin-like properties with positive staining for CRH, POMC, ACTH, GAL, TH, and CgA. Our findings also proved to some extent the heterogeneity of endothelial and immune microenvironment in different adrenal tumor subtypes.
Topics: ACTH Syndrome, Ectopic; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Corticotropin-Releasing Hormone; Gene Expression Profiling; Pheochromocytoma; Single-Cell Analysis; Transcriptome
PubMed: 34905486
DOI: 10.7554/eLife.68436 -
Metabolism: Clinical and Experimental Sep 2020Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to...
BACKGROUND
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.
METHODS
Metabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N,N-diethylnorspermine (DENSPM) and N,N- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.
RESULTS
Components of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.
CONCLUSIONS
This study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.
Topics: Adrenal Gland Neoplasms; Animals; Biogenic Polyamines; Cell Line, Tumor; Humans; Male; Metabolomics; Mice; Mutation; Paraganglioma; Pheochromocytoma; Succinate Dehydrogenase; Xenograft Model Antitumor Assays
PubMed: 32562798
DOI: 10.1016/j.metabol.2020.154297 -
Human Pathology Apr 2021The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit to develop evidence-based, internationally agreed-upon standardized data sets for each... (Review)
Review
Data set for the reporting of pheochromocytoma and paraganglioma: explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting.
BACKGROUND AND OBJECTIVES
The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit to develop evidence-based, internationally agreed-upon standardized data sets for each anatomic site, to be used throughout the world. Providing global standardization of pathology tumor classification, staging, and other reporting elements will lead to improved patient management and enhanced epidemiological research.
METHODS
Pheochromocytoma and paraganglioma are uncommon and are frequently overlooked in registry data sets. Malignant criteria have previously been defined only when there was metastatic disease.
RESULTS
With recent recognition of a significant inheritance association and the development of risk stratification tools, this data set was created in order to obtain more meaningful outcomes and management data, using similar criteria across the global pathology community. Issues related to key core and non-core elements, especially clinical hormonal status, familial history, tumor focality, proliferative fraction, adverse or risk stratification features, and ancillary techniques, are discussed in the context of daily application to these types of specimens.
CONCLUSIONS
The ICCR data set, developed by an international panel of endocrine organ specialists, establishes a pathology-standardized reporting guide for pheochromocytoma and paraganglioma.
Topics: Adrenal Gland Neoplasms; Carcinoma; Humans; Paraganglioma; Pathology, Clinical; Pheochromocytoma; Research Design
PubMed: 32407815
DOI: 10.1016/j.humpath.2020.04.012