Utilizing bioinformatics for integrated analysis of multiple genes in the diagnosis and pathogenesis of metastatic pheochromocytoma and paraganglioma

Objective:The aim of the study was to investigate effective diagnostic molecular markers and the specific mechanisms of metastatic pheochromocytomas and paragangliomas(PPGLs).Methods:Data were collected from GEO datasets GSE67066 and GSE60458.The R software and various packages were utilized for the analysis of differentially expressed genes,Gene Ontology analysis,Kyoto Encyclopedia of Genes and Genomes analysis,receiver operating characteristic curve assessment,logistic model construction,and correlation analysis.The NetworkAnalyst tool was used to analyze gene-miRNA interactions and signaling networks.In addition,the TIMER database was used to estimate the immune scores.Results:A total of 203 and 499 differentially expressed genes were identified in GSE67066 and GSE60458,respectively.These genes are implicated in cytokine and cytokine receptor interactions,extracellular matrix–receptor interactions,and platelet activation signaling pathways.Notably,MAMLD1,UST,MATN2,LPL,TWIST1,SFRP4,FRMD6,RBM24,PRIMA1,LYPD1,KCND2,CAMK2N1,SPOCK3,and ALPK3 were identified as the key genes.Among them,MATN2 and TWIST1 were found to be coexpressed with epithelial-mesenchymal transition–linked markers,whereas KCND2 and LPL exhibited associations with immune checkpoint expression and immune cell infiltration.Eight miRNAs were identified as potential regulators of key gene expression,and it was noted that TWIST1 might be regulated by SUZ12.Notably,the area under the curve of the 4-gene model for distinguishing between malignant and benign groups was calculated to be 0.918.Conclusions:The combined gene and mRNA expression model enhances the diagnostic accuracy of assessing PPGL metastatic potential.These findings suggest that multiple genes may play a role in the metastasis of PPGLs through the epithelial-mesenchymal transition and may influence the immune microenvironment.

Extrasurrenal Pheochromocytoma: A Case Report and Review of the Literature

Introduction: Pheochromocytoma is a rare cause of endocrine hypertension. We report the case of an extra-adrenal pheochromocytoma discovered in the setting of an abdominal mass. Observation: The patient was 25-year-old and presented with headaches, excessive sweating and palpitations, followed by a sensation of abdominal weightlessness and diastolic arterial hypertension. Abdominal computed tomography revealed a retroperitoneal, right para-renal extra-adrenal mass. In biology, an increase in urinary methoxylated derivatives at the expense of normetanephrine. Conclusion: Pheochromocytoma is a rare disease, diagnosed by measuring urinary or plasma methoxylated derivatives. Conventional or nuclear imaging allows topographic diagnosis. Genetic studies helps to identify other tumors.

Anesthetic management of bilateral pheochromocytoma resection in Von Hippel-Lindau syndrome:A case report

BACKGROUND Von Hippel-Lindau disease(also known as VHL syndrome),is an autosomal dominant inherited disease.We describe a sporadic case of VHL syndrome where bilateral pheochromocytomas were unexpectedly identified.The patient underwent selective laparoscopic resections of the pheochromocytomas,and the anesthetic management during surgery was complex and challenging.CASE SUMMARY A 22-year-old man presented to our hospital to seek medical advice for infertility without any other complaints.The results of computed tomography and catecholamine levels in blood and urine demonstrated adrenal gland masses which were diagnosed as pheochromocytomas.Further examination confirmed that the patient also had VHL syndrome.After thorough preparation,the patient underwent selective laparoscopic resection of the pheochromocytomas and was discharged 10 d after surgery.We describe the process of perioperative anesthesia management in this patient undergoing pheochromocytoma resection.CONCLUSION This case summaries specific clinical traits and considerations in perioperative anesthesia management for VHL syndrome patients undergoing bilateral pheochromocytoma resection.

Pheochromocytoma and stress cardiomyopathy:Insight into pathogenesis

AIM To investigate the occurrence of cardiomyopathy(CMP)in a cohort of patients with histologically proven pheochromocytoma(pheo),and to determine if catecholamine excess was causative of the left ventricular(LV)dysfunction.METHODS A retrospective chart review spanning years 1998through 2014 was undertaken and patients with a diagnosis of pheo confirmed with histopathologic examination were included.Presenting electrocardiograms and cardiac imaging studies were reviewed.Transthoracic echocardiography(TTE),ventriculography or single positron emission computed tomography imaging was evaluated and if significant abnormalities[left ventricular hypertrophy(LVH)or LV dysfunction]were noted in the pre operative period a follow up post-operative study was also analyzed.Multivariate analysis using logistic regression was used to investigate independent predictors for outcomes of interest,LV dysfunction and LVH.RESULTS We identified 18 patients with diagnosis of pheo confirmed on pathology.Mean age was 54.3±19.3years and 11(61.1%)patients were females.50%of such patients had either resistant hypertension or labile blood pressures during hospitalization,which had raised suspicion for a pheo.Cardiac imaging studies were available for 12(66.7%)patients at the time of inclusion into study and preceding the adrenalectomy.7(58.3%)patients with a TTE available for review had mild or more severe LVH while 3(25%)patients had LV dysfunction of presumably acute onset.In a multivariate analysis,elevated catecholamine levels as assessed by urinary excretion of metabolites was not an independent predictor of development of LV systolic dysfunction or of presence of LVH on TTE.Two female patients with a preceding history of hypertension had marked LV hypertrophy and systolic anterior motion of the mitral valve.Prolongation of the QTc interval was noted in 5(27.8%)patients but no acute arrhythmias were observed in any patient.CONCLUSION This study adds to the growing body of literature on the predilection of patients with pheochromocytomas to develop non-ischemic CMP.Degree of catecholamine excess as measured by urinary secretion of metabolites did not predict the development of CMP but 2 of 3patients developed CMP in the setting of significant acute physiologic stress.Our findings provide support to the proposed etiologic role of elevated catecholamines in TC and other stress induced forms of CMP,however,activation of a brain-neural-cardiac axis from acute stress and local release of catecholamines but not chronic catecholamine elevations are likely to be responsible in pheo related CMP.

Management of bladder pheochromocytoma by transurethral resection

Bladder pheochromocytoma is the most common extra-adrenal genitourinary tumor.Endoscopic management is feared due to the risk of intra-operative hypertensive crisis.We described a case of successful endoscopic management of a bladder pheochromocytoma and discussed its technical aspects.

Robot-Assisted Laparoscopic Resection of Large-Volume Pheochromocytoma through the Surface of the Kidney

Objective: To investigate the clinical application of robot-assisted laparoscopic surgery on the treatment of large-volume pheochromocytoma. Methods: A retrospective analysis of 31 patients with pheochromocytoma disease admitted to the Department of Urology, Affiliated Hospital of Hebei University from May 2020 to August 2021. According to clinical data, the tumor volume was 62.4 ± 29.5 mm, including 16 males and 15 females, aged (35.6 ± 16.1) years old;17 cases on the left side and 14 cases on the right side. All patients underwent anatomical resection through the renal superficial approach, and underwent pheochromocytoma resection through the retroperitoneal approach. The operation time, blood loss, postoperative complications, retention time of drainage tube and postoperative follow-up were observed. Results: All the 31 operations were successful, and there were no obvious postoperative complications. The average operation time, blood loss, and drainage tube retention time were 71 min, 80 mL, and (1.2 ± 0.6) days, respectively. Postoperative pathology was confirmed to be pheochromocytoma. There was no tumor recurrence in the follow-up for 1 - 15 months. Conclusion: Robot-assisted laparoscopic anatomical resection of large-volume pheochromocytoma through the renal surface of the abdominal cavity can provide a larger operating space during the operation, with clear anatomical landmarks of “lipocrasis”, less bleeding, less trauma, intraoperative and postoperative. The advantages of fewer complications, procedural operation, and shorter learning curve can be promoted in clinical practice.

Multivessel coronary artery ectasia and severe calcification in a patient with pheochromocytoma:a case report

Multivessel coronary artery ectasia with severe calcification is rare among patients with coronary artery disease. A 74-year-old Chinese woman suffered from acute myocardial infarction on a background of 50 years of poorly controlled hypertension secondary to pheochromocytoma, which was surgically removed in June 2012 prior to the presentation. Coronary angiography revealed total occlusion of the proximal left anterior descending artery, and multiple ectasias with severe calcification in the left main, circumflex and right coronary artery. After an aspiration thrombectomy and balloon angioplasty, grade 3 coronary flow was restored in the left descending coronary artery. No cardiac events were found in the 12-month follow-up. We conclude that multivessel coronary artery ectasia and severe calcification may be present in patients with a long-standing history of hypertension secondary to pheochromocytoma.

Malignant pheochromocytoma:Hepatectomy for liver metastases

Malignant pheochromocytoma accounts for approximately 10% of pheochromocytoma cases. The main site of distant metastasis is the liver. Hypertensive crisis due to catecholamine oversecretion is potentially fatal. We present a case of malignant pheochromocytoma with multiple liver metastases. A 60-year-old female with repeated hypertensive episodes was diagnosed with malignant pheochromocytoma. She underwent a left adrenalectomy and partial hepatectomy with resection of segment 6. Catecholamine levels remained high after surgery and she received repeated cycles of chemotherapy. Four months after surgery, multiple liver metastases were detected. In spite of ongoing chemotherapy, catecholamine levels eventually became uncontrollable. Serum and urine noradrenaline andvanillylmandelic acid levels increased, but adrenaline and dopamine levels stayed within the normal range. Preoperative liver imaging revealed multiple metastases in all segments except segment 4. Percutaneous transhepatic portal vein embolization(PTPE) of the right and lateral branches of the portal vein was performed. The functional liver volume of segment 4 increased after PTPE. Right hepatectomy, lateral segmentectomy and partial resection of segment 1 were performed 10 mo after the initial surgery. Intraoperative ultrasonography detected two small tumors in segment 4, which were treated with intraoperative microwave coagulation therapy. Noradrenaline levels normalized immediately after the second hepatectomy. As there was increased telomerase activity in the resected specimen, she received adjuvant chemotherapy. She remained in good health for 2 years. However, further metastases eventually occurred and she subsequently died due to a brain hemorrhage. Hepatectomy may be a therapeutic option for reduction of tumor mass in pheochromocytoma with liver metastases.

Adenovirus-mediated short hairpin RNA interference against p75 neurotrophin receptor in pheochromocytoma cells

Previous studies have confirmed that motor neuron apoptosis in the anterior horn of the lumbosacral spinal cord is positively correlated with p75 neurotrophin receptor （p75NTR） expression in rat models of cauda equina syndrome. This study used adenovirus to carry a short hairpin RNA （shRNA） for p75NTR gene silencing, to reduce p75NTR expression in the damaged phase and to decrease motor neuron apoptosis. Three p75 siRNA template oligonucleotide segments （shRNA） were designed, and cloned into the 1.0 CMV shuttle vector. HEK293 cells were cotransfected with shuttle vector （carrying shRNA） and an adenovirus vector framework expressing enhanced green fluorescent protein. Thus, this study successfully obtained adenovirus carrying p75shRNA. The obtained viruses were named Ad.shRNA1, Ad.shRNA2, and Ad.shRNA3. The recombinant adenoviruses were separately used to infect cultured pheochromocytoma cells （PC12）. Forty-eight hours later, p75NTR mRNA and total protein were analyzed from the PC12 cells. Compared with the negative controls, RNA interference rates were separately 98.49 ± 0.68%, 95.08 ± 1.79% and 96.60 ± 1.14% at the mRNA level, and 72.89 ± 2.17%, 58.83 ± 1.15% and 59.88 ± 0.44% at the protein level in the Ad.shRNA1, Ad.shRNA2, and Ad.shRNA3 groups, respectively. Thus, recombinant adenovirus shRNA-mediated gene silencing successfully suppressed p75NTR expression.

Composite pheochromocytoma masquerading as solidpseudopapillary neoplasm of pancreas

Pheochromocytoma and ganglioneuroma form rare composite tumours of the adrenal medulla comprising less than 3% of all sympathoadrenal tumours. We present a case of intraoperatively detected adrenal medullary tumour of composite pheochromocytoma and ganglioneuroma diagnosed on histopathology, in a normotensive patient. A 50-year-old male with a past history of chronic obstructive pulmonary disease presented with abdominal pain and significant weight loss since one month. Ultrasound and contrast-enhanced computed tomography abdomen revealed a large lobulated lesion in the distal body and tail of pancreas suggestive of solid and papillary neoplasm of body and tail of pancreas. Intra-operatively, a 15 cm × 10 cm solid lesion with cystic areas was seen arising from the left lower pole of the adrenal gland pushing the pancreas which appeared unremarkable. In our case, exploratory laparotomy with tumour excision was done. Extensive sectioning and microscopic examination of this adrenal tumour confirmed a diagnosis of composite Pheochromocytoma with Ganglioneuroma on histopathology. Immunophenotyping with S-100 further supported the diagnosis. The goal of this report is to increase the awareness of this rare disease and to further identify its variable presentation.

Surgical treatment of large pheochromocytoma(>6 cm):A 10-year single-center experience

Objective:Clinical practice guidelines recommend open adrenalectomy(OA)for large pheochromocytoma(LPCC)>6 cm in size.Although laparoscopic adrenalectomy(LA)for the treatment of LPCC has been reported,its role remains unclear.This study aimed to compare the effectiveness of LA and OA,and summary the surgical treatment experience.Methods:Data concerning LPCC,from January 2010 to June 2019 of a single institution,were retrospectively reviewed.Altogether 82 patients with a tumor larger than 6 cm were included(52 patients in LA group and 30 patients in OA group).Groups were balanced by propensity score matching(PSM)into 15 pairs.Patients’demographics,preoperative characteristics,and prognosis were analyzed.Results:Before PSM,the OA group had larger tumor sizes(median[interquartile range,IQR]:8.9[7.3-10.3]vs.7.2[6.7-8.0]cm;p=0.000)and higher vanillylmandelic acid level(median[IQR]:114.3[67.8-326.4]vs.66.6[37.8-145.8]μmol/24 h;p=0.004)and needed a higher cumulative dose of prazosin(median[IQR]:83.5[37.0-154.0]vs.38.0[21.0-81.0]mg;p=0.028).After PSM,the baseline data showed no significant differences between both groups.The LA group had relatively more stable blood pressure in surgery,with a lower fluctuation of systolic blood pressure(mean±standard deviation[SD]:70.9±25.1 vs.107.4±46.2 mmHg,p=0.012)and a lower percentage of hemodynamic instability(46.7%vs.86.7%,p=0.020).The LA group had shorter postoperative hospital stays(mean±SD:6.4±2.7 vs.10.1±3.4 days;p=0.003)than the OA group.Differences regarding metastasis rate(6.7%vs.0,p=1.000)were not statistically significant between LA and OA groups.The median(IQR)follow-up time of 82 patients was 72.5(47.0-103.5)months.Binary logistic regression showed that right-side tumors or those>8 cm in size were independent risk factors of OA.Conclusion:LA is a safe,minimally invasive procedure for LPCC and has relatively better perioperative characteristics in large medical centers.Patients with tumors on the right side or larger than 8 cm are more likely to undergo OA initially.

Malignant pheochromocytoma in neurofibromatosis; mutation screening of RET proto-oncogene, VHL and SDH gene

AIM: To investigate pathogenic mutations related to malignant pheochromocytoma in neurofibromatosis(NF).METHODS: We present a patient with NF and metastatic pheochromocytoma in whom genetic screening for presence of pathogenic mutations in RET protooncogene, von Hippel-Lindau(VHL) and succinate dehydrogenase complex subunits B(SDHB) genes were investigated. RET proto-oncogene mutation screening for exons 10, 11, 13, 14, 15, 16 were examined by polymerase chain reaction(PCR) and direct DNA sequencing in patient. Mutation screening for exons 1, 2, 3 of VHL gene was carried out. Both forward and reverse strandswere subjected to direct sequencing after PCR amplification. The entire coding sequence of SDHB gene was screened for the presence of pathogenic mutations by PCR-sequencing.RESULTS: A 45-year-old man presented with abdominal pain and hypertension over the previous year. The patient was a known case of neurofibromatosis type 1(NF1) who presented at the age of 15 years with hyperpigmented and hypopigmented lesions. After complete evaluation for hypertension, biochemical tests and imagings indicated a malignant pheochromocytoma of 120 mm × 70 mm in size. The patient underwent left adrenalectomy, nephrectomy and splenectomy. After surgery the symptoms improved and blood pressure was controlled. After 5 years he was admitted again for evaluation of hypertensive crisis. Biochemical tests were again consistent with pheochromocytoma and disease relapse. Imaging studies and liver biopsy confirmed metastatic pheochromocytoma to the liver and para-aortic area. 131 Iodine-metaiodobenzylguanidine therapy was carried out. Genetic screening of VHL(exons 1, 2, 3), RET proto-oncogene(exons 10, 11, 13, 14, 15, 16) and SDH complex subunits revealed no pathogenic mutation. CONCLUSION: We conclude that mutations in the NF1 gene are responsible for the patient's clinical findings. However, would be helpful to further examine somatic mutations for a more precise study of genotypephenotype correlation.

Pheochromocytoma as a cause of repeated acute myocardial infarctions,heart failure,and transient erythrocytosis:A case report and review of the literature

BACKGROUND Pheochromocytoma is a rare catecholamines-secreting tumor arising from chromaffin cells in the adrenal medulla.It classically presents with paroxysmal hypertension,headaches,palpitations,sweating,and metabolic disorders.Atypical presentations such as acute myocardial infarction,heart failure,cardiomyopathy,stroke,and transient erythrocytosis have been infrequently documented.CASE SUMMARY We describe the case of a 72-year-old man diagnosed with pheochromocytoma presenting with non-ST segment elevation myocardial infarction,heart failure,and transient erythrocytosis with nonobstructed coronary arteries.This was his second heart attack.The patient was previously diagnosed with myocardial infarction,and an immense mass was found on the left adrenal gland 3 years prior.Based on clinical and laboratory findings,a diagnosis of pheochromocytoma was confirmed.His coronary angiogram showed nonobstructed coronary arteries except for a myocardial bridge in the left anterior descending branch.This was a form of type-2 myocardial infarction.The myocardial cell lesions were caused by sudden secretion of catecholamines by the pheochromocytoma.Even more atypically,his hemoglobin level was obviously elevated at admission,but after a few days of treatment with an alpha-adrenergic receptor blocker,it dropped to normal levels without additional treatment.CONCLUSION Pheochromocytoma may be a cause of acute myocardial infarction,heart failure,and transient erythrocytosis.

Malignant pheochromocytoma with cerebral and skull metastasis: A case report and literature review

BACKGROUND Malignant pheochromocytoma with cerebral and skull metastasis is a very rare disease.Combining our case with 16 previously reported cases identified from a PubMed search,an analysis of 17 cases of malignant cerebral pheochromocytoma was conducted.This literature review aimed to provide information on clinical manifestations,radiographic and histopathological features,and treatment strategies of this condition.CASE SUMMARY A 60-year-old man was admitted with a progressive headache and enlarging scalp mass lasting for 3 mo.Radiographic images revealed a left temporal biconvexshaped epidural mass and multiple lytic lesions.The patient underwent a left temporal craniotomy for resection of the temporal tumor.Histopathological analysis led to identification of the mass as malignant pheochromocytoma.The patient’s symptoms were alleviated at the postoperative 3-mo clinical follow-up.However,metastatic pheochromocytoma lesions were found on the right 6th rib and the 6th to 9th thoracic vertebrae on a 1-year clinical follow-up computed tomography scan.CONCLUSION Magnetic resonance spectroscopy and histopathological examination are necessary to make an accurate differential diagnosis between malignant cerebral pheochromocytoma and meningioma.Surgery is regarded as the first choice of treatment.

Pheochromocytoma with abdominal aortic aneurysm presenting as recurrent dyspnea,hemoptysis,and hypotension:A case report

BACKGROUND Pheochromocytomas are rare endocrine tumors with various clinical manifestations,and few of them might present with profound,life-threatening conditions.CASE SUMMARY We report the case of a 65-year-old man who complained of sudden dyspnea and hemoptysis for half a day.There was no obvious cause for the patient to have dyspnea,coughing,or coughing up to approximately 100 mL of fresh blood.Finally,he was diagnosed with pheochromocytoma crisis(PCC),coexisting with an abdominal aortic aneurysm(AAA).CONCLUSION We report a case of pheochromocytoma presenting with recurrent hemoptysis,dyspnea and hypotension coexisting with an AAA.It not only proved the uncommon manifestations of pheochromocytoma but also directed clinicians to consider PCC among the possible diagnoses when meeting similar cases.Moreover,surgical excision is the most beneficial method for the treatment of pheochromocytoma coexisting with AAA when the situation is stable.

Pheochromocytoma in a 49-year-old woman presenting with acute myocardial infarction:A case report

BACKGROUND Pheochromocytoma is a rare endocrine tumor arising from chromaffin cells and having extensive and profound effects on the cardiovascular system by continuously or intermittently releasing catecholamines.The clinical manifestations of pheochromocytoma are diverse,and the typical triad,including episodic headache,palpitations,and sweating,only occurs in 24%of pheochromocytoma patients,which often misleads clinicians into making an incorrect diagnosis.We herein report the case of a patient with intermittent chest pain and elevated myocardial enzymes for 2 years who was diagnosed with pheochromocytoma.CASE SUMMARY A 49-year-old woman presented with intermittent chest pain for 2 years.Two years ago,the patient experienced chest pain and was diagnosed with acute myocardial infarction,with 25%stenosis in the left circumflex.The patient still had intermittent chest pain after discharge.Two hours before admission to our hospital,the patient experienced chest pain with nausea and vomiting,lasting for 20 min.Troponin I and urinary norepinephrine and catecholamine levels were elevated.An electrocardiogram indicated QT prolongation and ST-segment depression in leads II,III,aVF,and V3-V6.A coronary computed tomography angiogram revealed no evidence of coronary artery disease.Echocardiography showed left ventricular enlargement and a decreased posterior inferior wall motion amplitude.Contrast-enhanced computed tomography demonstrated an inhomogeneous right adrenal mass.The patient successfully underwent laparoscopic right adrenalectomy,and histopathology confirmed adrenal pheochromocytoma.During the first-year follow-up visits,the patient was asymptomatic.The abnormal changes on echocardiography and electro-cardiogram disappeared.CONCLUSION Clinicians should be aware of pheochromocytoma.A timely and accurate diagnosis of pheochromocytoma is essential for alleviating serious cardiac complications.

Pheochromocytoma with delayed tumor thrombus detection in renal vein: A case report

BACKGROUND Pheochromocytomas with inferior vena cava(IVC)or renal vein tumor thrombus are rare.Surgical management is the first choice.CASE SUMMARY We presented a 42-year-old man with adrenal pheochromocytoma and delayed tumor thrombus detection in the renal vein at the entrance of the IVC three months after adrenalectomy.We performed laparoscopic adrenalectomy during the first surgery and robot-assisted laparoscopic nephrectomy and resection of tumor thrombus during the second surgery.CONCLUSION We report the surgical management of a patient with adrenal pheochromocytoma with tumor thrombus at the entrance of the IVC.Robot-assisted laparoscopic surgery is safe and efficient.

Peri-operative Treatment for Pheochromocytoma

The perioperative management of 81 cases with pheochromocytoma was reviewed including blood pressure and arrhythmia control, blood volume expansion, patient′s general condition improvement and vital signs monitoring. It was stressed that pre and intra operative management was of prime importance in the treatment of pheochromocytoma.

Severe Ectopic Cushing’s Syndrome Due to ACTH-Secreting Pheochromocytoma

We report a new case of ectopic Cushing’s syndrome caused by an ACTH-producing pheochromocytoma. A 55-year-old woman presented with a history of severe proximal muscle weakness, polyuria, progressive virilization, anxiety, dyspnea on exercise, difficult to treat hypertension, and type 2 diabetes mellitus since 4 months. The laboratory data demonstrated ACTH-dependent hypercortisolism. The abdominal computed tomography scan showed a 30 mm well-defined mass in the left adrenal gland suggestive for pheochromocytoma. The adrenal veins were sampled, with intraprocedural cortisol measurement, to dosing selective ACTH and cathecolamines. The results established clearly the left adrenal gland as the source of ACTH overproduction. A left sided adrenalectomy was performed with subsequent resolution of Cushing’s syndrome. The patient was discharged in good clinical condition.

Current trend in the diagnosis and management of malignant pheochromocytoma:Clinical and prognostic factors

Pheochromocytomas are tumors arising from the chromaffin cell of the adrenal gland and paragangliomas as tumors from extra-adrenal sympathetic chromaffin cells.The combined yearly incidence of pheochromocytoma and paraganglioma(PPGL)is approximately 0.8 per 100000 person/year.Malignant pheochromocytoma is defined only by the presence of metastasis,as there is no confirmatory histology or biomarkers.The most common metastatic sites of these chromaffin tumors are the lymph node,bone,lungs,and liver.This review focuses on relevant clinical and immunohistological factors that are predictive of malignant PPGL or metastasis and determinants of prognosis.Findings showed that the risk of malignant PPGL,along with disease survival,is closely associated with age,primary tumor size,gender,synchronous metastasis,and absence of surgical excision.Other essential biomarkers or immunohistology investigated were galectin-3,COX-2,nm-23,microRNA-210,ERBB-2 overexpression and succinate dehydrogenase subunit mutation,which were predictive of malignancy as well as disease prognosis.Curative resection is possible but most metastatic diseases are amenable to radiopharmaceuticals and chemotherapy due to late presentation.Other therapeutic options,like molecular-targeted therapy,are still undergoing clinical trials.