Ubiquitination is a vital post-translational modification that regulates protein stability and various cellular processes through the addition of ubiquitin molecules. Central to this process are E3 ubiquitin ligases, which determine the specificity of ubiquitination by coordinating the attachment of ubiquitin to target proteins, influencing their degradation, localization, and activity. E3 ubiquitin ligases are involved in numerous cellular pathways, including DNA repair, cell proliferation, and immune responses. Dysregulation of E3 ubiquitin ligases is often associated with cancer, contributing to tumor progression and resistance to therapies. The development of targeted protein degraders, such as proteolysis-targeting chimeras (PROTACs), represents a significant advancement in drug discovery, leveraging the specificity of E3 ubiquitin ligases to selectively eliminate pathogenic proteins. However, challenges remain in translating this knowledge into effective therapies, including issues related to tissue-specific targeting and off-target effects. The limitations also include a limited understanding of ligase-substrate interactions that includes both the identification of novel E3 ligases and their substrates, as well as understanding the dynamic, context-dependent nature of these interactions, which can vary across tissue types or disease states This review emphasizes the therapeutic potential of E3 ubiquitin ligases, exploring their diverse roles in disease, their contribution to targeted degradation strategies while highlighting the need for further research to overcome current limitations and enhance therapeutic efficacy.

Pheochromocytoma (PHEO) is an uncommon neuroendocrine tumor originating from the chromaffin cells of the adrenal medulla. These tumors are capable of producing and releasing substantial amounts of catecholamine (CA) hormones. Individuals with PHEO often experience transient blood pressure fluctuations, headaches, and palpitations, among other symptoms. In extreme cases, they may develop severe complications, including cardiovascular and cerebrovascular incidents, myocardial disorders, and gastrointestinal issues. At the advanced stage, PHEO can affect multiple organs, potentially leading to pheochromocytoma crisis. However, the clinical manifestations of pheochromocytoma may be diverse. Some patients have no typical triad of headache, palpitations, and sweating, and are not accompanied by obvious clinical symptoms or signs. There are only abnormalities in imaging and biochemical indicators, which will pose a challenge for early diagnosis. The primary treatment options for PHEO encompass surgical and non-surgical approaches. In contrast to many other adrenal pathologies, there is currently no consensus on the optimal surgical versus non-surgical management of PHEO. Laparoscopic surgery, as opposed to traditional open surgery, offers numerous benefits. However, whether retroperitoneal or transperitoneal laparoscopic adrenalectomy remains controversial. Da Vinci robot-assisted adrenalectomy has the advantages of highly precise operation and excellent hemostasis capabilities. The day surgery management model for adrenalectomy procedures has proven to be both safe and feasible. However, current research on its long - term effectiveness and wide - scale application still has limitations. Additionally, the application of the Senhance robot in urology, particularly in adrenalectomy, has seen relatively little investigation thus far. In terms of non-surgical treatment for pheochromocytoma, chemotherapy, radionuclide therapy, targeted therapy and immunotherapy, as well as radiofrequency ablation and microwave ablation chemotherapy have all advanced significantly. This article aims to review the latest advancements in the treatment of pheochromocytoma.

Bladder Paraganglioma (BPG) is a rare form of pheochromocytoma and paraganglioma (PPGL) characterized by elevated blood pressure when urinating, headache, dizziness, palpitations, and hematuria. Surgical resection is the most commonly used treatment for BPG. Here, we reporte a man who initially presented with hypogastralgia and hematuria and was diagnosed as BPG at local hospital. The size of mass was too huge to receive partial cystectomy at diagnosis. Then this patient was referred to our medical center. After evaluation, we chose temozolomide as neoadjuvant therapy to reduce the tumor size. Followed by seven cycles of temozolomide, the tumor was decreased and was successfully removed via partial cystectomy.

Paraganglioma (PGL) is a neuroendocrine tumor originating from paraganglia that can occur in various locations, such as the head, neck, chest, abdomen, and pelvis. Retroperitoneal PGLs are rare, and recurrent cases in this area are particularly uncommon, posing considerable surgical complexities. Owing to their neuroendocrine activity, PGLs are capable of secreting hormones like catecholamines, thereby presenting significant challenges in hemodynamic management during the perioperative period.

We report a 64-year-old man with a recurrent retroperitoneal PGL. The patient underwent retroperitoneal mass resection in 2013, with postoperative pathology revealing a PGL. Regular follow-up was not conducted until April 2024, when a computed tomography scan revealed a huge mass in the retroperitoneum, closely adjacent to the abdominal aorta. Laboratory examinations revealed elevated levels of catecholamines in the patient's blood serum. Upon admission, volume expansion and blood pressure (BP) monitoring were carried out for one week, with catecholamine levels reviewed and normalized. Adequate preoperative preparation was conducted, including central venous access, arterial BP monitoring, and the preparation of vasoactive agents. During tumor resection, the patient experienced acute, significant fluctuations in BP. The timely intervention of the anesthesiologist stabilized the BP, facilitating the successful resection of the tumor which was confirmed as a recurrent PGL. Postoperative follow-up revealed no evidence of tumor residual or recurrence.

PGL recurrence is rare but non-negligible. PGLs adjacent to major arteries complicate surgery, and perioperative hemodynamic stability demands meticulous attention.

Pheochromocytoma and paragangliomas (PPGLs) caused refractory hypertension in clinics. The sustained risk of local or metastatic recurrences or new tumor development prompted more research on diagnosis, prognosis prediction, and immunotherapy.

The tumor stemness is closely related to the heterogeneous growth of tumor, metastasis, and drug-resistance, and mRNA expression-based stemness indices (mRNAsi) could reflect tumor stemness. This was calculated based on OCLR machine learning algorithm and PPGLs patients' TCGA RNAseq data. The relationship between clinical, molecular, and tumor microenvironment (TME) features and tumor stemness was analyzed through the hub genes that best captured the stem cell characteristics of PPGLs using weighted gene co-expression network analysis (WGCNA), Cox, and LASSO regression analysis.

Our study found that metastatic PPGLs had higher mRNAsi scores, suggesting the degree of tumor stemness could affect metastasis and progression. HRAS, CSDE1, NF1, RET, and VHL-mutant subtypes displayed significant difference in stemness expression. Patients were divided into stemness high-score and low-score subtypes. High-score PPGLs displayed the more unfavorable prognosis compared with low-score, associated with their immune-suppressive features, manifested as low macrophages M1 infiltration and downregulated expression of immune checkpoints. Furthermore, from the viewpoint of stemness features, we established a reliable prognostic for PPGLs, which has the highest AUC value (0.908) in the field so far. And this could stratify PPGLs patients into high-risk and low-risk subtypes, showing the significant differences in prognosis, underlying mechanisms correlated with specific molecular alterations, biological processes activation, and TME. Notably, high immune infiltration and tumor neoantigen in low-risk patients and further resulted in more responsive to immunotherapy.

We indicated that tumor stemness could act as the potential biomarker for metastasis or prognosis of PPGLs, and integrated multi-data sources, analyzed valuable stemness-related genes, developed and verified a novel stemness scoring system to predict prognosis and guide the choice of treatment strategies.

Significant advances have been made in the past few decades in surgical management and outcomes of patients with pheochromocytoma and paraganglioma. Improvements in preoperative hypertensive control with the implementation of alpha- and beta-adrenergic blockade has resulted in better intra-operative blood pressure control and less incidence of hypertensive crises, which had been a large source of morbidity in the past. Emphasis on anesthesia and surgical team communication has also assisted in minimizing intraoperative hypertensive events at critical points of the operation. Shifting away from open resection, the now standard-of-care laparoscopic and minimally invasive adrenalectomy offers less pain, shorter hospitalizations, and quicker recoveries. Patient underlying germline mutations can guide the timing, approach, and extent of surgery. Postoperative outcomes have significantly improved with recent advancements in perioperative care in addition to regimented biochemical and radiographic surveillance. Here, we highlight the recent advancements in surgical approaches and outcomes for patients with pheochromocytoma and paraganglioma.

There are few studies on the efficacy of temozolomide (TMZ) in the treatment of Metastatic pheochromocytoma / paraganglioma (MPP) patients. And it remains unclear which MPP patients may benefit from TMZ treatment.

This was a prospective study. MPP patients were enrolled. Patients were treated with TMZ until disease progression or intolerable toxicities. The primary endpoints were disease control rate (DCR) and objective response rate (ORR). Secondary endpoints included biochemical response rate progression-free survival (PFS) and safety. We compared the difference between effective and ineffective groups, to explore which patients are more suitable for TMZ treatment.

62 patients with MPP were enrolled and tumor response were evaluated in 54 patients. The DCR was 83% (35/42), and the ORR was 24% (10/41) among the progressive patients. PFS was 25.2 ± 3.1 months. The most common adverse event was nausea (41/55). We found that 92.9% (13/14) of patients with MGMT methylation greater than 7% respond to treatment. For the patients with MGMT methylation less than 7%, Ki-67 index could be used to guide the use of TMZ in these patients. Among the patients with Ki-67 index less than 5%, 66% (8/12) patients showed respond to treatment, and only 33% (4/12) patients with Ki-67 index more than 5% showed respond to TMZ.

This study indicated that TMZ is a potential choice for the treatment of MPP with the high ability on disease control and well tolerability. We recommended to MGMT methylation analysis test and Ki-67 index to guide TMZ application.

Pheochromocytomas (PCCs) and paragangliomas (PGLs, together PPGLs) are the most hereditary tumors known. PPGLs were considered benign, but the fourth edition of the World Health Organisation (WHO) classification redefined all PPGLs as malignant neoplasms with variable metastatic potential. The metastatic rate differs based on histopathology, genetic background, size, and location of the tumor. The challenge in predicting metastatic disease lies in the absence of a clear genotype-phenotype correlation among the more than 20 identified genetic driver variants. Recent advances in molecular clustering based on underlying genetic alterations have paved the way for improved cluster-specific personalized treatments. However, despite some clusters demonstrating a higher propensity for metastatic disease, cluster-specific therapies have not yet been widely adopted in clinical practice. Comprehensive genomic profiling and transcriptomic analyses of large PPGL cohorts have identified potential new biomarkers that may influence metastatic potential. It appears that no single biomarker alone can reliably predict metastatic risk; instead, a combination of these biomarkers may be necessary to develop an effective prediction model for metastatic disease. This review evaluates current guidelines and recent genomic and transcriptomic findings, with the aim of accurately identifying novel biomarkers that could contribute to a predictive model for mPPGLs, thereby enhancing patient care and outcomes.

Iodine-123 metaiodobenzylguanidine (I-123 MIBG) is a crucial radiopharmaceutical widely used in nuclear medicine for its diagnostic capabilities in both cardiology and oncology. This review aims to present a comprehensive evaluation of the clinical applications of I-123 MIBG, focusing on its use in diagnosing and managing various diseases. In cardiology, I-123 MIBG has proven invaluable in assessing cardiac sympathetic innervation, particularly in patients with heart failure, where it provides prognostic information that guides treatment strategies. In oncology, I-123 MIBG is primarily utilized for imaging neuroendocrine tumors, such as neuroblastoma and pheochromocytoma, where it offers high specificity and sensitivity in the detection of adrenergic tissue. Additionally, its role in neurology, specifically in differentiating between Parkinson's disease, dementia, and Lewy body dementia, has become increasingly significant due to its ability to identify postganglionic sympathetic dysfunction. Despite its established clinical utility, the use of I-123 MIBG is not without limitations, including variability in imaging protocols and interpretation challenges. This review will explore these issues and discuss emerging alternatives, while also highlighting areas where I-123 MIBG continues to be a gold standard. By synthesizing the current research, this article aims to provide a clear understanding of the strengths, limitations, and prospects of I-123 MIBG in clinical practice.

Pheochromocytoma and paragangliomas (PPGLs) are rare chromaffin cell tumors arising from neural crest tissue. The majority of these tumors are nonmetastatic, with complete cure achieved through surgical resection. PPGLs have been associated with several hereditary cancer syndromes, including von Hippel-Lindau (VHL). We present the case of a 10-year-old patient with VHL and a history of 2 asynchronous pheochromocytomas requiring bilateral adrenalectomies who presented with a new 1.2 cm × 1.3 cm × 1.5 cm nodular structure between the superior pole of the right kidney and the intrahepatic inferior vena cava. The patient was noted to have hypertension but was otherwise asymptomatic. Positron emission tomography-DOTA-(Tyr)3-octreotate revealed a metabolically active retrocrural lymph node. Based on these imaging findings and laboratory studies showing elevated plasma normetanephrine, clinical suspicion was highest for metastatic pheochromocytoma. The patient underwent surgical resection of multiple abdominal tumors. Pathology ultimately favored a diagnosis of multiple primary paragangliomas rather than metastatic disease. With this shift in diagnosis, the patient was managed with surgery alone. One year later, he has no signs of disease recurrence. Long-term surveillance imaging and screening with fractionated plasma metanephrines is indicated to monitor for new tumors in the setting of VHL and 3 prior endocrine tumors.

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 >0.16 nmol/L, and tumor size >6.0 cm 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.

This continuing education aims to present in a clear and easy-to-understand manner the biology of paragangliomas and pheochromocytomas (PPGLs), the functional imaging studies available for their diagnosis and therapeutic planning, the requirements necessary to administer radioligand therapy (RLT) and the characteristics of these treatments (inclusion criteria, administration protocols, adverse effects and future perspectives). In this pathology we have two RLT options: [131I]MIBG and [177Lu]Lu-DOTA-TATE. The indication for treatment is determined by the expression of its therapeutic target in functional imaging studies, allowing precision and personalized medicine. Although most of the results we have for both treatments have as origin small retrospective series, RLT is presented as a safe and well-tolerated therapeutic option in PPGLs with slow-moderate progression or with uncontrollable symptoms, obtaining high disease control rates.

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.

Carotid body tumors (CBTs) are neoplasms that occur at the bifurcation of the carotid artery and are pathologically classified as paragangliomas. In the 4th edition of the WHO classification, paragangliomas are categorized as neoplasms with malignant potential. Clinically, about 5% of CBTs present with malignant features such as metastasis. Currently, it is challenging to distinguish between tumors with benign courses and those that present malignantly. Recent advances in genetic testing have elucidated the genetic characteristics of paragangliomas, including carotid body tumors. Over 20 genes have been identified as being involved in tumor development. Particularly in head and neck paragangliomas, abnormalities in genes related to succinate dehydrogenase are frequently observed. Research is ongoing to understand the mechanisms by which these genes contribute to tumor development. The definitive treatment for CBTs is surgical resection. These tumors are prone to bleeding and often adhere firmly to the carotid artery, making intraoperative bleeding control challenging. The risk of lower cranial nerve paralysis is relatively high, and there is a risk of stroke because of manipulation of the carotid artery. Preoperative evaluation with angiography is essential, and a multi-disciplinary surgical team approach is necessary. In cases where the tumor is difficult to resect or has metastasized, radiation therapy or chemotherapy are employed. Clinical trials involving targeted molecular therapies and radiopharmaceuticals have recently been conducted, with some applied clinically. The development of various new treatments is anticipated, providing hope for therapeutic options in refractory cases.

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.

For pheochromocytoma and paraganglioma (PPGL), the efficacy of percutaneous ablative therapies in achieving control of metastatic tumors measuring <3 cm had been demonstrated in only few reports, and intraoperative radiofrequency ablation (RFA) of locally invasive primary PPGLs has not been reported. We presented the case of a 31-year-old man who had a 9-cm functioning unresectable PPGL. He was treated with 13 cycles of cytotoxic chemotherapy without objective tumor response, according to the Response Evaluation Criteria in Solid Tumors (RECIST). Subsequently, magnetic resonance imaging revealed a 9.0 × 8.6 × 6.0-cm retroperitoneal mass that extended to the inferior portion of the inferior vena cava, the inferior mesenteric artery, and the infrarenal aorta. Biochemical evaluation demonstrated high level of plasma normetanephrine (20.2 nmol/L, normal range <0.9 nmol/L). Genetic investigation showed the germline pathogenic variant c.1591delC (p. Ser198Alafs*22) in the SDHB gene. I131-metaiodobenzylguanidine scintigraphy was negative and Ga68-dotatate PET-CT scan showed high tumor uptake without distant metastases. On open laparotomy, tumor debulking was not possible. Therefore, intraoperative RFA was performed by a highly experienced team of interventional radiologists. At 12 months after the RFA, the tumor volume decreased from 208 to 45 mL (78%), plasma normetanephrine decreased from 20.2 to 2.6 nmol/L (87%), and the doxazosin dose was reduced from 16 to 8 mg/day. To our best knowledge, this was the first report on intraoperative RFA that markedly reduced the size of a large primary unresectable PPGL, along with clinical and biochemical responses.

Cushing's syndrome (CS) refers to the clinical features of prolonged pathological glucocorticoid excess. About 10-20% of individuals with CS have ectopic CS (ECS), that is, an adrenocorticotropin (ACTH)-producing tumour outside the pituitary gland. ACTH-secreting neuroendocrine neoplasia (NENs) can arise from many organs, although bronchial NEN, small cell lung cancer (SCLC), pancreatic NEN, thymic NEN, medullary thyroid cancer (MTC), and pheochromocytoma are the most common. Patients with ECS frequently present with severe hypercortisolism. The risk of life-threatening complications is high in severe cases, unless the hypercortisolism is effectively treated. A good outcome in ECS requires a methodical approach, incorporating prompt diagnosis, tumour localization, control of cortisol excess, and resection of the primary tumour when possible.

Paragangliomas are sympathetic and parasympathetic para-ganglia neuroendocrine tumors of the autonomic nervous system. We analyzed a bifocal paraganglioma case of a 52-year-old patient in December 2013 with hearing loss and right ear pain, headaches, episodes of vomiting, and abdominal pain ten months before her medical consultation. The diagnosis of a right tympano-jugular glomus paraganglioma was based on cerebral magnetic resonance imaging and treated with radiotherapy. In 2016, the patient presented with worsening digestive symptoms; therefore, a second mesocolic localization was suspected by abdominal computed tomography and was histologically confirmed on the resection specimen of the mass. The surgery was the only treatment. After a follow-up of 11 years, the patient remained in good condition. Paraganliomas are rare tumors, their bifocal location in our patient represents an even rarer entity. Given the nonspecific symptomatology, the diagnosis of the retroperitoneal location simultaneously with that of the head and neck was difficult. Our objective is to emphasize the staging workup for paraganglioma, although it is mostly a benign tumor with slow growth.

To develop and validate a rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to detect urinary free metanephrines and methoxytyramine, establishing reference intervals.

Urine samples were diluted with isotope internal standard solution, then analyzed directly using tandem mass spectrometry with multiple reaction monitoring measurement and electrospray ionization source in positive ion mode. Analytical parameters including linearity, lower limit of quantitation, imprecision and accuracy of the method were evaluated. The reference intervals for urinary catecholamine metabolites were established by analyzing 24-h urine samples collected from 81 apparently healthy volunteers.

The analytical times for MN, NMN, and 3-MT were at 2.79, 2.80, and 2.74 min, respectively. The method displayed excellent linearity (r > 0.99) in the range of 1-1000 ng/mL, with lower limits of quantification (LLOQ) at 0.50 ng/mL for MN and NMN, and 0.25 ng/mL for 3-MT. The method's intra-day and inter-day imprecisions were less than 8 %. The method recovery ranged from 96.8% to 105.8 % for MN, 89.7%-106.4 % for NMN, and 93.5%-106.2 % for 3-MT. No carry-over was observed during the analysis of all analytes. The LC-MS/MS method was used to establish reference intervals in 24-h urine samples from 81 apparently healthy volunteers. There was no association of sex with urinary free metabolites.

This study established a novel, fast and sensitive LC-MS/MS method for determining urinary free catecholamine metabolites, which could facilitate screening and diagnosis for catecholamine-related tumors more conveniently and quickly.

Paraganglioma is derived from the paraganglia tissue in the neck, along the sympathetic trunk, and in the pelvis. Paraganglioma has malignant potential and can metastasize to remote organs such as the liver, lungs, and bones. Most metachronous metastases occur within several years after the initial diagnosis of paraganglioma. Here, we report the case of a 71-year-old male patient who developed bony metastasis 52 years after the resection of a large paraganglioma at the aortic bifurcation. The biopsy-proven paraganglioma metastasis to the lesser trochanter of left femur presented as an avulsion fracture. His normetanephrine level was elevated. DOTATATE PET (positron emission tomography) did not find any other metastatic lesions. The bony metastasis was treated with radiation therapy. We believe that the patient had one of the longest gaps ever reported, 52 years, between the initial diagnosis and metastasis of paraganglioma. This case highlights the importance of long-term surveillance of patients with paraganglioma for metastasis.

Pheochromocytoma is an adrenal medullary neuroendocrine tumor that rarely metastasizes to the spine. Currently, its specific treatment methods still present challenges.

A 41-year-old male patient who underwent left total adrenalectomy due to pheochromocytoma 3 years ago presented with lower back pain, accompanied by numbness and decreased muscle strength in both legs, as well as decreased sensation. Abnormal transmittance of the L3 vertebral body could be seen on anterior-posterior and lateral lumbar X-rays, irregular bone destruction of the L3 vertebral body was found on CT, and an MRI scan showed that the tumor was located within the L3 vertebral body, protruding into the spinal canal and compressing the epidural sac. No recurrence was found in the abdomen. Preoperatively, perform local embolization of the blood vessels supplying the tumor. First, the L2-3 intervertebral disc, L3-4 intervertebral disc and L3 vertebral body were removed using an anterior approach, the whole tumor was removed, and some of the vertebrae were taken for pathological examination and replaced with a 3D-printed prosthesis. Then, four pedicle screws were placed in the bilateral pedicles of L2 and L4 using the posterior approach, pre-bent connecting rods were installed to replace the bone cortex of the lamina and articular process followed by bone graft fusion of the interlaminar and facet joints. The postoperative results were satisfactory, and there were no perioperative complications.

Lumbar pheochromocytoma metastasis is rare, difficult to treat, and should be considered in spinal metastases' differential diagnoses so early diagnosis can be made based on medical history and imaging. Preoperative local vascular imaging and embolization of the blood supply vessels were performed. After total en-bloc spondylectomy of the tumor during surgery, a prosthesis was implanted and combined with pedicle screw fixation to reconstruct spinal biomechanical stability, achieving satisfactory results. Therefore, 3D printed artificial vertebral bodies are a good choice for treating adrenal pheochromocytoma lumbar metastasis. The key to successful treatment is close interdisciplinary collaboration in formulating rigorous comprehensive perioperative plans.

Documented symptomatic progression of a paraganglioma (PGL) over many years is unusual. Our objective is to report a young man with such an occurrence.

A 27-year-old male presented with headache, sweating, and palpitation. He had a history of cyanotic congenital heart disease. Five years before presentation, he had 24-hour urine metanephrines 43 mcg/d (25-222), vanillylmandelic acid 3 mg/d (<6), and homovanillic acid 2.4 mg/d (1.6-7.5) levels and a 3.13 cm mass in the upper aortocaval space. Subsequent imaging showed slow growth of the mass. On admission, his blood pressure was 197/134 mm Hg, heart rate was 163 beats per minute, respiratory rate was 25 per minute, and oxygen saturation was 76% on room air. His 24-hour urine normetanephrine level was 2644 mcg/d (81-667) while metanephrine was 405 mcg/d (55-320). Plasma free metanephrine level was 0.92 nmol/L (0-0.49) and normetanephrine was 11.85 nmol/L (0-0.89). DOTATATE positron emission tomography-computed tomography revealed a 4.3 × 3.1 × 4.9 cm mass with activity in the right upper aortocaval space. He was treated with Prazosin. Two months later, he underwent resection of the mass. Pathology diagnosed a 4.9 cm PGL. He had improvement in metanephrine levels.

PGL is diagnosed by documenting excess catecholamines and identifying a lesion on imaging. False negative laboratory testing is rare but can occur. Patients with cyanotic congenital heart disease have a greater risk of developing PGL.

It is crucial to evaluate a patient for PGL if clinical conditions suggest catecholamine excess, especially if a retroperitoneal tumor has grown or the patient has risk factors.

Currently, all pheochromocytoma/paraganglioma (PPGLs) are considered malignant due to metastatic potential. Consequently, PPGLs are divided into «metastatic» and «non-metastatic». Metastatic PPGLs can be with synchronous metastasis (metastases appear simultaneously with the identified primary tumor) or metachronous (metastases develop after removal of the primary tumor). The term metastatic PPGLs is not used in the presence of tumor invasion into surrounding organs and tissues, without the presence of distant metastases of lymphogenic or hematogenic origin. It is generally believed that about 10% of pheochromocytomas and about 40% of sympathetic paragangliomas have metastatic potential. On average, the prevalence of PPGLs with the presence of metastases is 15-20%. Risk factors for metastatic PPGLs are widely discussed in the literature, the most significant of which are groups of clinical, morphological and genetic characteristics. The review presents a discussion of such risk factors for metastatic PPGLs as age, localization and type of hormonal secretion of the tumor, the size and growth pattern of the adrenal lesion, the presence of necrosis and invasion into the vessels, the tumor capsule surrounding adipose tissue, high cellular and mitotic activity, Ki-67 index, expression of chromogranin B and S100 protein, the presence of genetic mutations of three main clusters (pseudohypoxia, kinase signaling and Wnt signaling).Over the past two decades, a number of authors have proposed various predictor factors and scales for assessing a probability of metastatic PPGLs. The review contains detailed description and comparison of sensitivity and specificity of such predictor scales as PASS, GAPP, M-GAPP, ASES and COPPS.

Pheochromocytoma are chromaffin cell-derived tumors that have an exceptionally high genetic predisposition. The presentation of extra-adrenal and pelvic paraganglioma (PGL) in children is uncommon. Due to the relative rarity, PGL tumors' presentation and disease behavior may vary. Genetic testing, imaging, and biochemical investigation are employed to diagnose PGL. Surgical resection with preoperative angioembolization has been practiced in alleviating the burden of torrential intraoperative bleeding.

Phaeochromocytomas (PC) and sympathetic paragangliomas (PGL) are potentially malignant tumours arising from the adrenal medulla (PC) or elsewhere in the sympathetic nervous system (PGL). These tumours usually secrete catecholamines and are associated with significant morbidity and mortality, so accurate and timely diagnosis is essential. The initial diagnosis of phaeochromocytoma/paraganglioma (PPGL) is often dependent on biochemical testing. There is a range of pre-analytical, analytical and post-analytical factors influencing the analytical and diagnostic performance of biochemical tests for PPGL. Pre-analytical factors include patient preparation, sample handling and choice of test. Analytical factors include choice of methodology and the potential for analytical interference from medications and other compounds. Important factors in the post-analytical phase include provision of appropriate reference ranges, an understanding of the potential effects of various medications on metanephrine concentrations in urine and plasma and a consideration of PPGL prevalence in the patient population being tested. This article reviews these pre-analytical, analytical and post-analytical factors that must be understood in order to provide effective laboratory services for biochemical testing in the diagnosis of PPGL.

Pheochromocytomas and paragangliomas (PPGLs) with SDHx pathogenic variants (PVs) are characterized by a higher intratissular succinate/fumarate ratio (RS/F) than non-SDHx-mutated ones. Also, an increase in serum succinate levels has been reported in patients with germline SDHB or SDHD PV.

To assess whether measurement of serum succinate, fumarate levels, and RS/F might aid identification of an SDHx germline PV/likely pathogenic variant (LPV) in patients with PPGL or in asymptomatic relatives; and to guide identification of a PV/LPV among the variants of unknown significance (VUS) identified in SDHx by next-generation sequencing.

This prospective monocentric study included 93 patients attending an endocrine oncogenetic unit for genetic testing. Succinate and fumarate were measured in serum by gas chromatography coupled to mass spectrometry. The RS/F was calculated to assess SDH enzymatic function. Diagnostic performance was assessed by receiver operating characteristic analysis.

RS/F had a higher discriminant power than succinate alone to identify an SDHx PV/LPV in patients with PPGL. However, SDHD PVs/LPVs are frequently missed. Only RS/F differed between asymptomatic SDHB/SDHD PV/LPV carriers and SDHB/SDHD-linked patients with PPGL. Finally RS/F could be helpful to easily evaluate the functional impact of VUS in SDHx.

Measurement of serum RS/F in patients with PPGL and in asymptomatic relatives is a valuable initial workup tool to detect those carrying a germline PV/LPV in SDHx. Its discriminative power is equal or superior to those of succinate measured alone. SDHD PVs/LPVs are less frequently identified by these biochemical tools. Use of RS/F for SDHx VUS reclassification needs to be evaluated further.

A 30-year-old man with pheochromocytoma was hospitalized for hemoptysis without inducement. CT revealed a mass in the left lung, and biopsy pathology under the bronchoscope suggested that it was a pheochromocytoma metastasis. To further identify the location of the metastatic lesions, the patient was enrolled in a clinical trial and underwent 18 F-FDOPA and 18 F-MFBG PET/CT. Images from both examinations showed similar lesions. However, the lesions differed in that the uptake of some lesions was significantly higher with 18 F-FDOPA than with 18 F-MFBG, whereas the para-aortic lesion was active in 18 F-MFBG but not in 18 F-FDOPA.

Pheochromocytomas (PCCs) are rare neuroendocrine tumors derived from the chromaffin cells of the adrenal medulla. When these tumors have an extra-adrenal location, they are called paragangliomas (PGLs) and arise from sympathetic and parasympathetic ganglia, particularly of the para-aortic location. Up to 25% of PCCs/PGLs are associated with inherited genetic disorders. The majority of PCCs/PGLs exhibit indolent behavior. However, according to their affiliation to molecular clusters based on underlying genetic aberrations, their tumorigenesis, location, clinical symptomatology, and potential to metastasize are heterogenous. Thus, PCCs/PGLs are often associated with diagnostic difficulties. In recent years, extensive research revealed a broad genetic background and multiple signaling pathways leading to tumor development. Along with this, the diagnostic and therapeutic options were also expanded. In this review, we focus on the current knowledge and recent advancements in the diagnosis and treatment of PCCs/PGLs with respect to the underlying gene alterations while also discussing future perspectives in this field.

Pheochromocytoma and abdominal paraganglioma (PPGL) are rare neuroendocrine tumors originating from chromaffin cells. Even though only 10-15% of the tumors metastasize, all PPGLs are considered potentially malignant. Topoisomerase 2A (TOP2A) is a protein involved in cell proliferation and has been found to be over-expressed in metastatic PPGL. To provide support whether TOP2A could serve as a prognostic marker, 88 PPGLs (of which 8 metastatic/relapsing) and 10 normal adrenal gland samples were assessed for TOP2A mRNA expression using quantitative real-time PCR (qRT-PCR) and TOP2A immunohistochemistry. Comparisons to clinical parameters connected to metastatic behavior were made, and The Cancer Genome Atlas was used for validation of the results. A significant association between high TOP2A mRNA expression in primary PPGL and subsequent metastatic events (p = 0.008) was found, as well as to specific histological features and clinical parameters connected to metastatic behavior and mutations in SDHB. TOP2A immunoreactivity was calculated as an index of positive nuclei divided by the total amount of nuclei, and this index associated with TOP2A mRNA levels (p = 0.023) as well as the Ki-67 labeling index (p = 0.001). To conclude, TOP2A is a potential prognostic marker as it is frequently elevated in PPGL displaying subsequent metastatic disease, and future studies in larger cohorts are warranted to determine if a TOP2A index as assessed by immunohistochemistry could be a marker of poor outcome. Additionally, elevated levels of TOP2A could indicate a potential actionable event, and future studies with topoisomerase inhibitors would be of interest.

Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE and 90Y-DOTATOC showed efficacy in the metastatic setting of pheocromocytomas (PCCs) and paragangliomas (PGLs) where no standard therapies have been established.

A search of peer-reviewed and English articles reporting on 177Lu-DOTATATE and 90Y-DOTATOC efficacy was performed through Medline and Scopus. A subsequent meta-analysis was performed to evaluate the pooled effect size on disease control rate (DCR) with PRRT. Secondary endpoints were description of patients' genetic characteristics, hematologic toxicity, and time-to-outcome. The pooled effect was estimated with both a mixed-effects model and a random-effects model.

Twelve studies met the criteria for this meta-analysis: ten with 177Lu- and two with 90Y-PRRTs (213 patients). The largest one included 46 patients. Median ages ranged from 32.5 to 60.4 years. When reported, mutations of SDHB were the most frequent genetic alterations. The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for 177Lu- and 90Y-PRRT, respectively. The pooled DCR for PRRT was 0.81 (95% CI: 0.74-0.87).

We report an updated and solid estimate of DCR achieved with 177Lu- and 90Y-PRRT in PCCs and PGLs, showing that these therapies can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy.

Metastatic pheochromocytomas and paragangliomas are rare neuroendocrine tumors with a poor prognosis. Bladder paraganglioma concomitant with urothelial papilloma is even rarer. However, the rate of tumor response to cyclophosphamide-vincristine-dacarbazine (CVD) chemotherapy and 5-year overall survival for patients with metastatic PPGLs remained lower. We described, for the first time, a case of a patient with multiple metastatic bladder PGL who received octreotide LAR combined with CVD chemotherapy after urological surgery and then octreotide therapy was continued during follow-up.

A 43-year-old male patient was admitted to the urology department for frequent micturition syncope concomitant with malignant hypertension. Preoperative findings were elevated levels of normetanephrine in 24-h urine or plasma. CT and MRI indicated diagnosis of suspicious bladder paraganglioma. Transurethral resection of bladder tumor combined with laparoscopic partial cystectomy was performed successfully after preoperative phenoxybenzamine with aggressive volume repletion for 7 days. The result of postoperative pathology was immediate-risk functional bladder paraganglioma (T2N0M0, Stage II) concomitant with urothelial papilloma, and the immunohistochemistry results of PPGL were positive for Ki-67 (15%), SDHB, CgA, and SSTR2. The patient achieved enhanced recovery with normal urination and no syncope after surgery. However, the results of ¹⁸F-FDG and ¹⁸F-DOTATATE PET/CT found that the metastatic localizations of bladder PGLs were in the liver, lung, and bones at the 8th month after surgery. The patient received octreotide long-acting repeatable plus six courses of CVD chemotherapy for 6 months, and then octreotide therapy was continued every 3 months until now. Metastatic localizations were stable in CT scans, and vanillylmandelic acid in 24-h urine was maintained at lower levels during follow-up.

Octreotide long-acting repeatable plus CVD chemotherapy after surgery could achieve stable disease in the case with multiple metastatic bladder PGLs, and the following octreotide therapy could maintain a state of stable disease during the period of 6-month follow-up.

To evaluate the elasticity of carotid body tumors (CBTs) by two-dimensional shear wave elastography (SWE).

22 pathologically or clinically confirmed CBTs in 16 patients were scanned by SWE. The maximum elasticity value (Emax) and its standard deviation (SDmax) in kPa and m/s for CBTs were obtained by placing a round ROI (2-3 mm) on the stiffest region of the CBTs. Elasticity value was compared between hard and soft groups at manual palpation, benign and malignant groups and among three Shamblin types. The area under the receiver operating characteristic curve (AUC) analysis was performed to evaluate the performance of SWE in the malignancy prediction of CBTs. Sensitivity, specificity and accuracy were calculated. The cut-off value was obtained by using the Youden index.

There were 19 benign CBTs and 3 malignant CBTs. Emax (kPa and m/s) and SDmax (kPa) were significantly higher in the hard group than in the soft group at manual palpation (P<0.05); The distribution of Emax in kPa and m/s and SDmax in kPa were different in the three Shamblin types (P<0.05), Emax (kPa and m/s)increased from shambling I to Shambling II and Shambling III; Emax (kPa and m/s) were significantly higher in the malignant CBTs than in the benign ones (P<0.05). Emax in kPa and m/s had the similar AUC value (AUC=0.947, P=1.0000) for the prediction of malignant CBTs. Emax in kPa with the cut-off 124.9kPa showed a sensitivity of 100.0%, specificity of 94.7%, and an accuracy of 95.5% (Z=8.500, P<0.0001); Emax in m/s with the cut-off 5.9m/s showed a sensitivity of 100.0%, specificity of 89.5% and an accuracy of 90.9% for the prediction of malignant CBTs (Z=9.143, P<0.0001).

Quantitative analysis of SWE obtained the good performance in the elasticity assessment of CBTs.

Background: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors arising from chromaffin cells in the adrenal medulla and extra-adrenal ganglia, respectively. The study was aimed to investigate the clinical and genetic characteristics of 22 individuals from six families. Methods: The medical records of six PPGL probands who presented to our hospital between 2016 and 2021 were retrospectively studied. DNA isolated from the probands was analyzed using whole exome sequencing. The identified genetic variants were confirmed by Sanger sequencing and undergone bioinformatic analysis. Results: Six different genetic variants in the six probands were identified, respectively, of which three were novel. A novel von Hippel-Lindau (VHL) variant, c.602T>C (p.L201P), in exon 3 was found. Two novel genetic variants in SDHB (succinate dehydrogenases subunit B), c.423 + 1 G>T and c.662A>G (p.D221G), were identified. Two recurrent genetic variants of VHL, c.C284G (p.P95R) and c.558_560AGAdel (p.186Edel), and one in RET (ret proto-oncogene), c.1901G>A (p.C634Y), were also found. The ClinVar accession number for the present variants are SCV002028348, and SCV002028352 to SCV002028361. Conclusion: Genetic variants in VHL, SDHB and RET were identified in Chinese PPGL patients, which contributed to the knowledge of the genetic etiology and clinical outcome of these tumors.

Adrenal paraganglioma (or "pheochromocytoma") and extra-adrenal paraganglioma, collectively abbreviated PPGL, are rare but spectacular nonepithelial neuroendocrine neoplasms. These are the most inheritable neoplasia of all, with a metastatic potential in a varying degree. As of such, these lesions demand careful histologic, immunohistochemical, and genetic characterization to provide the clinical team with a detailed report taking into account the anticipated prognosis and risk of syndromic/inherited disease. While no histologic algorithm, immunohistochemical biomarker, or molecular aberration single-handedly can identify potentially lethal cases upfront, the combined analysis of various risk parameters may stratify PPGL patients more stringently than previously. Moreover, the novel 2022 WHO Classification of Endocrine and Neuroendocrine Tumors also brings some new concepts into play, not least the reclassification of special neuroendocrine neoplasms (cauda equina neuroendocrine tumor and composite gangliocytoma/neuroma-neuroendocrine tumor) previously thought to belong to the spectrum of PPGL. This review focuses on updated key diagnostic and prognostic concepts that will aid when facing this rather enigmatic tumor entity in clinical practice.

Primary pancreatic paragangliomas are rare. They are mainly non-functional tumours that lack typical clinical manifestations. Definite diagnosis relies on histopathology and immunohistochemistry, and the main treatment is surgery. We report here a case of primary, non-functional, pancreatic paraganglioma in a 49-year-old woman. The tumour was approximately 5.0 × 3.2 ×4.7 cm in size and located in the pancreatic neck and body. We undertook 3D laparoscopic complete resection of the tumour. The patient developed a pancreatic fistula (biochemical leak) post-surgery, but she recovered and was discharged from hospital 11 days after surgery. We describe this case study and briefly summarize previous related reports.

Due to fewer adverse events, faster onset of action, and longer durable responses compared to chemotherapy, immunotherapy has been widely used to treat advanced solid tumors. Moreover, immunotherapy can improve the autoimmune status, thus allowing patients to benefit from the treatment in the long term. The immune microenvironment status is closely associated with the response to chemotherapies. Here, we analyzed the characteristics of the immune microenvironment in pheochromocytoma and paraganglioma (PPGL). Immunohistochemistry showed that PD-L1 is sparely expressed in PPGL with low positive rates and low expression levels, an expression pattern, that is, not correlated with tumor malignancy. Moreover, the level of intratumoral CD4⁺ and CD8⁺ lymphocyte infiltration in PPGL is low, suggesting that the immune microenvironment in PPGL may be in "immune desertification" or "immune rejection" states in which CD4⁺ and CD8⁺ lymphocyte infiltration is prevented, rendering immunotherapy less effective. In sum, our results indicate that PPGL is a microsatellite-stable tumor with low tumor mutational burden (TMB) levels, weak neoantigen production, and poor tumor antigenicity, hinting at a poor response of PPGL to chemotherapies.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumors. Pheochromocytomas are derived from chromaffin cells of the adrenal medulla, while paragangliomas arise from the extra-adrenal autonomic paraganglia. Paragangliomas can derive from either parasympathetic or sympathetic paraganglia. The majority of parasympathetic ganglia-derived paragangliomas are nonfunctional and symptoms arise from mass effect, while sympathetic paragangliomas are frequently functional and present with symptoms that result from catecholamine hypersecretion. Here, we present the case of a 19-year-old female with hypertension whose biochemical tests revealed elevated plasma and urinary levels of norepinephrine and normetanephrine. Imaging studies showed a left paravertebral mass which was surgically removed. Histopathology confirmed a paraganglioma. Total surgical resection remains the gold-standard treatment and a cure can be achieved; however, all tumors may harbor malignant potential, and a long-term biochemical and imaging follow-up is required in all patients. Screening for genetic germline mutations may be helpful in identifying patients with a higher risk of recurrence or of developing other primary tumors.

There is increasing evidence to support the use of temozolomide therapy for the treatment of metastatic phaeochromocytoma/paraganglioma (PPGL) in adults, particularly in patients with SDHx mutations. In children however, very little data is available. In this report, we present the case of a 12-year-old female with a SDHB-related metastatic paraganglioma treated with surgery followed by temozolomide therapy. The patient presented with symptoms of palpitations, sweating, flushing and hypertension and was diagnosed with a paraganglioma. The primary mass was surgically resected six weeks later after appropriate alpha- and beta-blockade. During the surgery extensive nodal disease was identified that had been masked by the larger paraganglioma. Histological review confirmed a diagnosis of a metastatic SDHB-deficient paraganglioma with nodal involvement. Post-operatively, these nodal lesions demonstrated tracer uptake on 18F-FDG PET-CT. Due to poor tumour tracer uptake on 68Ga-DOTATATE and 123I-MIBG functional imaging studies radionuclide therapy was not undertaken as a potential therapeutic option for this patient. Due to the low tumour burden and lack of clinical symptoms, the multi-disciplinary team opted for close surveillance for the first year, during which time the patient continued to thrive and progress through puberty. 13 months after surgery, evidence of radiological and biochemical progression prompted the decision to start systemic monotherapy using temozolomide. The patient has now completed ten cycles of therapy with limited adverse effects and has benefited from a partial radiological and biochemical response.

Adrenal masses are a frequent finding in clinical practice. Many of them are incidentally discovered with a prevalence of 4% in patients undergoing abdominal anatomic imaging and require a differential diagnosis. Biochemical tests, evaluating hormonal production of both adrenal cortex and medulla (in particular, mineralocorticoids, glucocorticoids and catecholamines), have a primary importance in distinguishing functional or non-functional lesions. Conventional imaging techniques, in particular computerized tomography (CT) and magnetic resonance imaging (MRI), are required to differentiate between benign and malignant lesions according to their appearance (size stability, contrast enhanced CT and/or chemical shift on MRI). In selected patients, functional imaging is a non-invasive tool able to explore the metabolic pathways involved thus providing additional diagnostic information. Several single photon emission tomography (SPET) and positron emission tomography (PET) radiopharmaceuticals have been developed and are available, each of them suitable for studying specific pathological conditions. In functional masses causing hypersecreting diseases (mainly adrenal hypercortisolism, primary hyperaldosteronism and pheochromocytoma), functional imaging can lateralize the involvement and guide the therapeutic strategy in both unilateral and bilateral lesions. In non-functioning adrenal masses with inconclusive imaging findings at CT/MR, [¹⁸F]-FDG evaluation of tumor metabolism can be helpful to characterize them by distinguishing between benign nodules and primary malignant adrenal disease (mainly adrenocortical carcinoma), thus modulating the surgical approach. In oncologic patients, [¹⁸F]-FDG uptake can differentiate between benign nodule and adrenal metastasis from extra-adrenal primary malignancies.