The delayed or missed diagnosis of secondary hypertension contributes to the poor blood pressure control worldwide. This study aimed to assess the diagnostic approach to primary aldosteronism (PA) and pheochromocytoma (PHEO) among Italian centers associated to European and Italian Societies of Hypertension.

Between July and December 2023, a 10-items questionnaire was administered to experts from 82 centers of 14 Italian regions and to cardiologists from the ARCA (Associazioni Regionali Cardiologi Ambulatoriali) Piemonte. Results were stratified for geographical area, specialty, and center category (excellence vs. non-excellence centers).

Each center diagnosed an average of 2 cases of PA and 0.2 cases of PHEO annually, with higher figures in excellence centers. PA screening is performed mainly in patients with resistant hypertension (73.2%) or hypertension and spontaneous hypokalemia (84.1%), while only 17.1% and 35.4% of centers screen patients with grade 2-3 hypertension. Screening rate is lower for cardiologists compared to other specialists. The main barriers to wider testing were challenges in interpreting the aldosterone/renin ratio under interfering medications and switching to non-interfering drugs. Clinical scores to predict the likelihood of PA and the definition of Standard Operating Procedures were identified as potential tools to boost screening rates. Testing for PHEO was mostly conducted in patients with typical symptoms (75.6%) and/or hypertensive crisis (74.4%). Only 37.8% of centers screened all patients with adrenal incidentaloma.

This study highlights significant gaps in the screening and diagnosis of PA and PHEO across Italian centers and underscores the need for widespread and standardized diagnostic protocols.

The effects of sex hormones remain largely unexplored in pheochromocytomas and paragangliomas (PPGLs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

We evaluated the effects of estradiol, progesterone, Dehydroepiandrosterone sulfate (DHEAS), and testosterone on human patient-derived PPGL/GEP-NET primary culture cell viability (n = 38/n = 12), performed next-generation sequencing and immunohistochemical hormone receptor analysis in patient-derived PPGL tumor tissues (n = 36).

In PPGLs, estradiol and progesterone (1 µm) demonstrated overall significant antitumor effects with the strongest efficacy in PPGLs with NF1 (cluster 2) pathogenic variants. Estrogen receptor alpha (ERα) positivity was detected in 11/36 PPGLs, including 4/4 head-and-neck paragangliomas (HNPGLs). ERα-positive tumors responded with a significant cell viability decrease to estradiol. DHEAS and testosterone (1 µm) displayed no effects, but higher doses of testosterone (10 µm) demonstrated significant antitumor effects, including a pheochromocytoma lung metastasis with strong androgen receptor positivity (30%). Driven by the antitumor effects of estrogen, we evaluated G-protein-coupled estrogen receptor (GPER) agonist G-1 as a potential therapeutic option for PPGLs and found strong significant antitumor potential, with the strongest efficacy in tumors with NF1 pathogenic variants. Moreover, we detected sex-related differences-tumors from male patients showed significantly stronger responsivity to G-1 compared with tumors from female patients. In GEP-NETs, sex hormones showed overall no effects, especially no tumor growth-promoting effects.

We provide novel data on the effects of elevated sex hormone levels, potentially seen during pregnancy or hormone replacement therapy, on PPGL/GEP-NET tumor growth. G-1 might offer a novel therapeutic approach for some PPGLs depending on patient's sex and the individual tumor's genetic/molecular background. All HNPGLs showed ERα positivity.

Paragangliomas are rare neoplasms arising from extra-adrenal chromaffin cells, with mediastinal paragangliomas representing an exceptionally rare subset. This report details the surgical management of a complex mediastinal paraganglioma case, presenting with refractory hypertension and invasion of critical surrounding structures. A comprehensive review of the current literature is included to underscore existing cases, enhance clinical awareness, and share our insights and experience in the diagnosis and treatment of this challenging condition.

A 16-year-old female presented with recurrent headaches and persistent hypertension lasting over one year. Based on clinical findings and imaging studies, she was preliminarily diagnosed with a mediastinal paraganglioma. The patient underwent comprehensive preoperative management, including oral α- and β-adrenergic blockade, preoperative arterial embolization, and intravenous fluid volume expansion, to optimize endocrine control. Thoracoscopic resection of the mediastinal mass was initially attempted; however, the procedure became complex due to the high risk of uncontrolled hemorrhage and invasion of adjacent vital structures. Following the preoperative surgical plan, the incision was converted to a lateral thoracotomy, and cardiopulmonary bypass was initiated. Meticulous dissection enabled the complete removal of the tumor along with the affected posterior wall of the left atrium, followed by reconstruction of the left atrium and the right pulmonary vein. The surgery was successfully completed, and follow-up assessments showed no signs of tumor recurrence or metastasis.

Functional mediastinal paraganglioma is a rare neuroendocrine tumor, with complete surgical resection being the gold standard treatment. Stringent perioperative management is crucial to mitigate the risk of cardiovascular complications associated with functional tumors. Lifelong surveillance is recommended to detect potential recurrence or metastasis. Effective collaboration within a multidisciplinary team is essential for ensuring accurate diagnosis and delivering optimal, individualized care.

Pheochromocytomas (PCs) are rare neuroendocrine tumors found in 20-50% of MEN2 patients. MEN2-related PCs are more often bilateral, identified at a younger age and have a low metastatic potential. They secrete epinephrine as the predominant catecholamine, along with its metabolite metanephrine, and lesser amounts of norepinephrine and normetanephrine. The advent of molecular diagnostic tools has enhanced the identification and stratification of these tumors, revealing a strong genotype-phenotype correlation which is crucial for screening and managing patients. Evaluation involves a combination of structural (CT/MRI) and functional imaging. MIBG remains helpful for PC assessment but novel PET ligands (18F-DOPA, 68Ga-DOTATATE, 18F-FDG) aid in the detection of extra-adrenal paragangliomas, recurrence, and metastatic disease. The treatment paradigm has shifted toward personalized medicine, incorporating genetic insights to tailor interventions, particularly surgical approaches and novel therapeutics such as radiolabeling of somatostatin analogs with lutetium and tyrosine kinase inhibitors.

Pheochromocytomas typically arise in the adrenal medulla, whereas ectopic pheochromocytomas/paragangliomas commonly occur near the abdominal aorta, bladder, mediastinum, and head. Diaphragmatic pheochromocytomas are exceedingly rare, and there is limited surgical experience with their treatment.

In Case A, the subject is a 45-year-old male, while in Case B, the subject is a 59-year-old female. Both patients present with a history of paroxysmal hypertension. Computed tomography imaging revealed the presence of diaphragmatic tumors in both patients. The tumor in Case A was observed in the left diaphragm, while the tumor in Case B was located in the right diaphragm.

Two patients were diagnosed with diaphragmatic pheochromocytoma on the basis of disease progression, imaging, endocrinological assessment and postoperative histopathological examination.

Both patients received the same standardized preoperative preparation, which included hypotensive therapy and intravenous rehydration. Subsequently, Case A underwent a transabdominal robotic laparoscopic surgical resection, while Case B underwent a transthoracic thoracoscopic surgical resection.

Both patients demonstrated a favorable recovery trajectory and exhibited stable blood pressure at the 3-month follow-up.

This report serves to remind the reader that the transthoracic approach to diaphragmatic pheochromocytoma may prove to be more advantageous than the transperitoneal approach. Additionally, precise preoperative localization of the tumor and careful intraoperative monitoring and assessment are imperative to achieve favorable outcomes.

Pheochromocytomas and sympathetic paragangliomas (PPGL) are rare neuroendocrine tumors originating from chromaffin tissue of the adrenal medulla and extra-adrenal sympathetic paraganglia. Historically, many of these tumors were diagnosed postmortem, earning pheochromocytomas the moniker "great mimic" due to their diverse clinical manifestations that can resemble various other conditions. Over time, the clinical presentation of PPGL has evolved, with a shift from symptomatic or postmortem diagnoses to more frequent incidental discoveries or diagnoses through screening, with postmortem identification now being rare. The development of a clinical scoring system has improved the identification of patients at increased risk for PPGL. Notably, the proportion of PPGL patients with normal blood pressure ranges from 15 % to 40 %, varying based on the clinical context. Despite the tumor's reputation, PPGL is an exceedingly rare cause of resistant hypertension. Management of a pheochromocytoma crisis has advanced, with several classes of drugs available for treatment. However, PPGL during pregnancy remains a significant concern, associated with substantial maternal and fetal mortality rates. Additionally, PPGL can present as rare disorders, including catecholamine-induced cardiomyopathy, Cushing syndrome, and urinary bladder PGL. Given these varied presentations, heightened awareness and prompt recognition of PPGL are crucial for timely diagnosis and treatment, ultimately improving patient outcomes. In this article, we offer an in-depth analysis of the diverse clinical presentations of PPGL, highlighting their complexity and the associated diagnostic and treatment strategies.

Abdominal pheochromocytomas and paragangliomas (PPGLs) are characterized by the overproduction of catecholamines, which are associated with hemodynamic instability (HDI) during surgery. Therefore, perioperative management to prevent intraoperative HDI is imperative for the surgical treatment of PPGLs. Owing to the rarity and heterogeneous nature of these tumors, pre-surgical prediction of HDI is a clinical dilemma. The reported risk factors for HDI include perioperative preparation, genetic background, tumor conditions, body composition, catecholamine levels, and surgical approach. Additionally, several personalized algorithms or models including these factors have been developed. The first part of this review outlines the prediction models that include clinical features such as tumor size and location, body mass index (BMI), blood glucose level, catecholamine levels, and preoperative management with α-adrenoceptor blockade and crystal/colloid fluid. We then summarize recently reported models that consider additional factors such as genetic background, radiomics, robotic-assisted surgical approach, three-dimensional visualization, and machine-learning models. These findings suggest that a comprehensive model including risk factors is the most likely approach for achieving effective perioperative management.

This white paper provides practical guidance for clinicians encountering bilateral adrenal masses.

A case-based approach to the evaluation and management of bilateral adrenal masses. Specific clinical scenarios presented here include cases of bilateral adrenal adenomas, hemorrhage, pheochromocytomas, metastatic disease, myelolipomas, as well as primary bilateral macronodular adrenal hyperplasia.

Bilateral adrenal masses represent approximately 10% to 20% of incidentally discovered adrenal masses. The general approach to the evaluation and management of bilateral adrenal masses follows the same protocol as the evaluation of unilateral adrenal masses, determined based on the patient's clinical history and examination as well as the imaging characteristics of each lesion, whether the lesions could represent a malignancy, demonstrate hormone excess, or possibly represent a familial syndrome. Furthermore, there are features unique to bilateral adrenal masses that must be considered, including the differential diagnosis, the evaluation, and the management depending on the etiology. Therefore, considerations for the optimal imaging modality, treatment (medical vs surgical therapy), and surveillance are included. These recommendations were developed through careful examination of existing published studies as well as expert clinical opinion consensus.

The evaluation and management of bilateral adrenal masses require a comprehensive systematic approach which includes the assessment and interpretation of the patient's clinical history, physical examination, dynamic hormone evaluation, and imaging modalities to determine the key radiographic features of each adrenal nodule. In addition, familial syndromes should be considered. Any final treatment options and approaches should always be considered individually.

Pheochromocytomas and paragangliomas (PPGL) are neuroendocrine tumors which secrete catecholamines, causing cardiovascular compromise. While isolated tumors and locoregional disease can be treated surgically, treatment options for metastatic disease are limited, and no targeted therapies exist. Approximately 25% of PPGL are causatively associated with germline pathogenic variants, which are known risk factors for multifocal and metastatic PPGL. Knowledge of somatic driver mutations continues to evolve. Molecular classification of PPGL has identified three genomic subtypes: Cluster 1 (pseudohypoxia), Cluster 2 (kinase signaling) and Cluster 3 (Wnt-altered). This review summaries recent studies characterizing the tumor microenvironment, genomic drivers of tumorigenesis and progression, and current research on molecular targets for novel diagnostic and therapeutic strategies in PPGL.

The natural history in unselected cohorts of patients with pheochromocytoma/ paraganglioma (PPGL) followed for a period >10 years remains limited. We aimed to describe baseline characteristics and outcome of a large cohort and to identify predictors of shorter survival.

This retrospective single-center study included 303 patients with newly diagnosed PPGL from 1968 to December 31, 2023, in 199 prospectively supplemented since July 2020. Mean follow-up was 11.4 (range 0.3-50) years, germline genetic analyses were available in 92.1%. The main outcome measures were overall (OAS), disease-specific (DSS), recurrence-free (RFS) survival and predictors of shorter survival evaluated in patients with metastases at first diagnosis (n=12), metastatic (n=24) and nonmetastatic (n=33) recurrences and without evidence of PPGL after first surgery (n=234).

Age at study begin was 49.4 ± 16.3 years. There were 72 (23.8%) deaths, 15 (5.0%), 29 (9.6%) and 28 (9.2%) due to PPGL, cardiovascular disease (CVD) and malignant or other diseases, respectively. Median OAS, DSS1 (tumor-related) and DSS2 (DSS1 and death caused by CVD) were 4.8, 5.9 and 5.2 years (patients with metastases at first diagnosis), 21.2, 21.2 and 19.9 years, and 38.0, undefined and 38.0 years (patients with metastatic and with nonmetastatic recurrences, respectively). Major adverse cardiovascular events (MACE) preceded the first diagnosis in 15% (n=44). Shorter DSS2 correlated with older age (P ≤ 0.001), male sex (P ≤ 0.02), MACE (P ≤ 0.01) and primary metastases (P<0.0001, also for DSS1).

The clinical course of unselected patients with PPGL is rather benign. Survival rates remain high for decades, unless there are MACE before diagnosis or metastatic disease.

Pheochromocytomas and paragangliomas are distinctive neuroendocrine tumors which frequently produce excess catecholamines with resultant cardiovascular morbidity. These tumors have a strong genetic component, with up to 40% linked to hereditary pathogenic variants; therefore, germline genetic testing is recommended for all patients. Surgical resection offers the only potential cure in the case of localized disease. Given the potential for catecholaminergic crises, appropriate perioperative management is crucial, and all patients should undergo alpha-adrenergic blockade before resection. Therapeutic options for metastatic disease are limited and include surgical debulking, radiopharmaceutical therapies, and conventional chemotherapy.

The understanding of the nature of catecholamine-secreting tumors has changed significantly in recent years, affecting terminology and classification. Phaeochromocytoma/paraganglioma (PCC/PG) is a rare neuroendocrine tumor from chromaffin tissue that produces and secretes catecholamines. The incidence of PCC/PG is relatively low, with 2-8 cases per 1 million population per year; among patients with arterial hypertension, their prevalence is 0.2-0.6%. However, delayed diagnosis of PCC/PG is associated with a high risk of cardiovascular complications and a high mortality rate. The consensus presents the clinical manifestations of the disease with an emphasis on the course of arterial hypertension as the most common symptom in PCC/PG; modern ideas about the features of diagnosis, aspects of preoperative preparation, treatment, and follow-up of patients with PCC/PG are considered.

Phaeochromocytomas and paragangliomas are rare catecholamine-producing neuroendocrine tumours which can potentially cause catastrophic crises with high morbidity and mortality. This best practice article considers the causes and presentation of such tumours, screening and diagnostic tests, management of these patients and consideration of family members at risk.

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.

Pheochromocytoma can recur years after curative surgical resection. Rarely, it may reoccur as metastasis. Here, we present a case of metastatic pheochromocytoma to the bones in a patient with neurofibromatosis type 1 (NF1), 8 years after initial resection of primary bilateral adrenal pheochromocytomas without metastases.

A 44-year-old woman presented with diffuse body pain and palpitations. Her past medical history included NF1 and hypertension. Eight years prior to her current presentation, she had undergone a bilateral adrenalectomy for the management of bilateral adrenal pheochromocytomas. Her plasma metanephrines normalized after surgery and remained normal at her 1-year postoperative visit. She was subsequently lost to follow-up until her current presentation. Our evaluation revealed significantly elevated urine and plasma metanephrines as well as innumerable DOTATATE avid lesions along the axial and perpendicular spine compatible with a metastatic neuroendocrine tumor. She was started on doxazosin and metoprolol and discharged home with a plan to be seen by Oncology to discuss systemic therapy.

Predicting malignant disease in patients with primary tumors without metastases is challenging. There is no single factor that can reliably predict tumor behavior. It is unknown if individuals with NF1, who have a genetic predisposition for developing pheochromocytomas, are at an increased risk of malignant disease.

Due to a lack of accurate predictors, annual biochemical testing is recommended after primary tumor resection and in patients with a genetic predisposition. Strict lifelong follow-up should be strongly considered due to a possible higher risk of malignant disease.

Pheochromocytomas and paragangliomas (PPGLs) have emerged as one of the most common endocrine tumors. It epitomizes fascinating crossroads of genetic, metabolic, and endocrine oncology, providing a canvas to explore the molecular intricacies of tumor biology. Predominantly rooted in the aberration of metabolic pathways, particularly the Krebs cycle and related enzymatic functionalities, PPGLs manifest an intriguing metabolic profile, highlighting elevated levels of oncometabolites like succinate and fumarate, and furthering cellular malignancy and genomic instability. This comprehensive review aims to delineate the multifaceted aspects of tumor metabolism in PPGLs, encapsulating genetic factors, oncometabolites, and potential therapeutic avenues, thereby providing a cohesive understanding of metabolic disturbances and their ramifications in tumorigenesis and disease progression. Initial investigations into PPGLs metabolomics unveiled a stark correlation between specific genetic mutations, notably in the succinate dehydrogenase complex (SDHx) genes, and the accumulation of oncometabolites, establishing a pivotal role in epigenetic alterations and hypoxia-inducible pathways. By scrutinizing voluminous metabolic studies and exploiting technologies, novel insights into the metabolic and genetic aspects of PPGLs are perpetually being gathered elucidating complex interactions and molecular machinations. Additionally, the exploration of therapeutic strategies targeting metabolic abnormalities has burgeoned harboring potential for innovative and efficacious treatment modalities. This review encapsulates the profound metabolic complexities of PPGLs, aiming to foster an enriched understanding and pave the way for future investigations and therapeutic innovations in managing these metabolically unique tumors.

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 evaluate the rate of recurrence among patients with pheochromocytomas and sympathetic paragangliomas (PGLs; together PPGLs) and to identify predictors of recurrence (local recurrence and/or metastatic disease).

This retrospective multicenter study included information of 303 patients with PPGLs in follow-up in 19 Spanish tertiary hospitals. Recurrent disease was defined by the development of local recurrence and/or metastatic disease after initial complete surgical resection.

A total of 303 patients with PPGLs that underwent 311 resections were included (288 pheochromocytomas and 15 sympathetic PGLs). After a median follow-up of 4.8 years (range 1-19), 24 patients (7.9%) had recurrent disease (3 local recurrence, 17 metastatic disease and 4 local recurrence followed by metastatic disease). The median time from the diagnosis of the PPGL to the recurrence was of 11.2 months (range 0.5-174) and recurrent disease cases distributed uniformly during the follow-up period. The presence of a pathogenic variant in SDHB gene (hazard ratio [HR] 13.3, 95% CI 4.20-41.92), higher urinary normetanephrine levels (HR 1.02 per each increase in standard deviation, 95% CI 1.01-1.03) and a larger tumor size (HR 1.01 per each increase in mm, 95% CI 1.00-1.02) were independently associated with disease recurrence.

The recurrence of PPGLs occurred more frequently in patients with SDHB mutations, with larger tumors and with higher urinary normetanephrine levels. Since PPGL recurrence may occur at any time after the initial PPGL diagnosis is performed, we recommend performing a strict follow-up in all patients with PPGLs, especially in those patients with a higher risk of recurrent disease.

Hypertension (HTN) affects more than 30% of adults worldwide. It is the most frequent modifiable cardiovascular (CV) risk factor, and is responsible for more than 10 million death every year. Among patients with HTN, we usually distinguish secondary HTN, that is HTN due to an identified cause, and primary HTN, in which no underlying cause has been found. It is estimated that secondary hypertension represents between 5 and 15% of hypertensive patients [1]. Therefore, routine screening of patients for secondary HTN would be too costly and is not recommended. In addition to the presence of signs suggesting a specific secondary cause, screening is based on specific criteria. Identifying secondary HTN can be beneficial for patients in certain situations, because it may lead to specific treatments, and allow better control of blood pressure and sometimes even a cure. Besides, it is now known that secondary HTN are more associated with morbidity and mortality than primary HTN. The main causes of secondary HTN are endocrine and renovascular (mainly due to renal arteries abnormalities). The most frequent endocrine cause is primary aldosteronism, which diagnosis can lead to specific therapies. Pheochromocytoma and Cushing syndrome also are important causes, and can have serious complications. Other causes are less frequent and can be suspected on specific situations. In this article, we will describe the endocrine causes of HTN and discuss their treatments.

Paragangliomas are rare neuroendocrine tumors that arise from the extra-adrenal autonomic paraganglia, i.e., small organs consisting mainly of neuroendocrine cells that are derived from the embryonic neural crest and have the ability to secrete catecholamines. Paragangliomas can derive from either parasympathetic or sympathetic paraganglia. Most of the parasympathetic ganglia-derived paragangliomas are nonfunctional, and symptoms result from mass effect. Conversely, the sympathetic paragangliomas are functional and produce catecholamine. Although such patients could have symptoms similar to pheochromocytoma, mass effect symptoms, or non-specific symptoms, being benign tumors, they can also present with anemia, specifically iron-deficiency anemia. Considering that neoplastic pathology is chronically accompanied by moderate, normochromic, normocytic anemia, association between paragangliomas that are mostly benign but with a potential degree of malignancy and anemia is not as frequent as expected, with only 12 cases reported in the literature. We report a case of a 54-year-old female patient diagnosed with a paraganglioma of the carotid glomus accompanied by severe normochromic, normocytic anemia, which reached normal limits after excision of the paraganglioma.

Immortalized cell lines originating from tumors and cultured in monolayers in vitro display consistent behavior and response, and generate reproducible results across laboratories. However, for certain endpoints, these cell lines behave quite differently from the original solid tumors. Thereby, the homogeneity of immortalized cell lines and two-dimensionality of monolayer cultures deters from the development of new therapies and translatability of results to the more complex situation in vivo. Organoids originating from tissue biopsies and spheroids from cell lines mimic the heterogeneous and multidimensional characteristics of tumor cells in 3D structures in vitro. Thus, they have the advantage of recapitulating the more complex tissue architecture of solid tumors. In this review, we discuss recent efforts in basic and preclinical cancer research to establish methods to generate organoids/spheroids and living biobanks from endocrine tissues and target organs under endocrine control while striving to achieve solutions in personalized medicine.

Paraganglioma is a less prevalent disease, and paraganglioma with only secreting interleukin-6 (IL-6) has not been previously reported. A 64-year-old male patient came to the hospital with the chief complaints of fever and palpitations. The peak body temperature was 38.7°C (101.66°F). Heart rate was 110 bpm, while blood pressure was in the normal range. Antibiotics and antiviral therapies were ineffective. The levels of blood IL-6, C-reactive protein (CRP), alkaline phosphatase (ALP), platelets (PLT), glutamyltransferase (GGT), fibrinogen, and D-dimer were all elevated. Infectious diseases, auto-immune diseases, and hematological malignancy were all excluded. Nearly 10 years ago, a large retroperitoneal mass of the patient was detected by accident. Fortunately, there have been no special symptoms for the past 10 years after regular follow-up. After admission this time, PET-CT was performed. A large confounding density mass at the upper part of the abdominal and retroperitoneal area was seen, and the possibility of paraganglioma was considered. However, biochemical assays for blood and urine catecholamine and their metabolites including adrenaline, norepinephrine, 3-methoxytyramine, methoxyepinephrine, methoxynorepinephrine, and vanillylmandelic acid were all in normal range in spite of mild elevated dopamine with no significance. The whole-exome capture and sequencing of the genomic DNA of the patient showed a heterozygous mutation in the coding site of KIF1B gene (Coding: NM_015047.3:c.4660G>C, Mutation: p.Val1554Leu; chromosomal location was chr1: 10428570). The mutation at this locus of KIF1B has not been reported previously. The patient refused the surgical treatment. Because the mass burdens several important organs including the pancreas, the risk of surgery was high. Doxazosin was then administered to the patient. After taking doxazosin, the symptoms disappeared rapidly. Body temperature returned to normal range in 3 days. Heart rate decreased to approximately 90 bpm. In the following days, the levels of IL-6, CPR, ALP, platelets, GGT fibrinogen, and D-dimer continued to decrease. After 63 days of taking doxazosin, IL-6 level was completely normal. After 190 days of medication, hemoglobin (Hb) and GGT levels also returned to the normal range. After 1 year onset, the patient again underwent a blood test. Almost all blood indexes were in the normal range including IL-6.

Intraoperative hemodynamic instability (HI) deteriorates surgical outcomes of patients with normotensive pheochromocytoma (NP).

To characterize the hemodynamics of NP and develop and externally validate a prediction model for intraoperative HI.

Data on 117 patients with NP (derivation cohort) and 40 patients with normotensive adrenal myelolipoma (NAM) who underwent laparoscopic adrenalectomy from January 2011 to November 2021 were retrospectively collected. Data on 22 patients with NP (independent validation cohort) were collected from another hospital during the same period. The hemodynamic characteristics of patients with NP and NAM were compared. Machine learning models were used to identify risk factors associated with HI. The final model was visualized via a nomogram.

Forty-eight (41%) out of 117 patients experienced HI, which was significantly more than that for NAM. A multivariate logistic regression including age, tumor size, fasting plasma glucose, and preoperative systolic blood pressure showed good discrimination measured by area under curve (0.8286; 95% CI 0.6875-0.9696 and 0.7667; 95% CI 0.5386-0.9947) for predicting HI in internal and independent validation cohorts, respectively. The sensitivities and positive predictive values were 0.6667 and 0.7692 for the internal and 0.9167 and 0.6111 for the independent validations, respectively. The final model was visualized via a nomogram and yielded net benefits across a wide range of risk thresholds in decision curve analysis.

Patients with NP experienced HI during laparoscopic adrenalectomy. The nomogram can be used for individualized prediction of intraoperative HI in patients with NP.

Takotsubo cardiomyopathy (TTC), also known as stress cardiomyopathy or broken heart syndrome, is a condition characterized by transient left ventricular dysfunction resembling myocardial infarction but without obstructive coronary artery disease. We present a rare case of a 59-year-old patient with cardiogenic shock (CS) caused by reverse TTC triggered by an undiagnosed right adrenal pheochromocytoma tumor. The patient initially presented with chronic headaches and difficulty breathing, and their condition rapidly deteriorated, necessitating intubation and inotropic support. Diagnostic tests confirmed the diagnosis of reverse TTC, and further investigation revealed an actively growing adrenal mass suggestive of a pheochromocytoma. The patient responded well to treatments, including the use of intra-aortic balloon pump support and subsequent weaning. A right adrenalectomy confirmed the presence of a pheochromocytoma. This case highlights the association between pheochromocytoma and reverse TTC, emphasizing the need to consider this rare etiology in patients presenting with CS. Long-term monitoring is crucial due to the risk of recurrence, even after tumor removal.

The prognosis of pheochromocytoma and sympathetic paraganglioma (PHEO/sPGL) is difficult to predict at the time of diagnosis and long-term follow-up data are scarce, especially for apparently benign and sporadic variants. The aim of the study was to analyze the long-term outcomes in PHEO/sPGL patients.

A monocentric series of 170 patients who underwent surgery for PHEO/sPGL was analyzed.

The study cohort included 91 female and 79 males with a median age of 48 years (range 6-83). The majority of PHEO/sPGL cases were considered apparently benign at the time of diagnosis; evident malignant behavior was found in 5% of cases. The overall 10-year risk of recurrence was 13%, but it rose up to 33% at 30 years. The risk of new tumor recurrence was higher in patients with hereditary tumors, but the risk was still significant in patients with apparently sporadic variants (20-year risk: 38% vs. 6.5%, respectively; p < 0.0001). The risk of metastatic recurrence was higher in patients with locally aggressive tumors at diagnosis, but the risk was present also in apparently benign variants (5-year risk: 100% vs. 1%, respectively; p < 0.0001).

Lifelong follow-up is required not only for hereditary PHEO/sPGL but also for apparently benign and sporadic tumors at diagnosis because of the risk of long-term recurrent disease.

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.

Hypertension (HT) is a major cardiovascular risk factor that affects 10% to 40% of the general population in an age-dependent manner. Detection of secondary forms of HT is particularly important because it allows the targeted management of the underlying disease. Among hypertensive patients, the prevalence of endocrine HT reaches up to 10%. Adrenal diseases are the most frequent cause of endocrine HT and are associated with excess production of mineralocorticoids (mainly primary aldosteronism), glucocorticoids (Cushing syndrome), and catecholamines (pheochromocytoma). In addition, a few rare diseases directly affecting the action of mineralocorticoids and glucocorticoids in the kidney also lead to endocrine HT. Over the past years, genomic and genetic studies have allowed improving our knowledge on the molecular mechanisms of endocrine HT. Those discoveries have opened new opportunities to transfer knowledge to clinical practice for better diagnosis and specific treatment of affected subjects. In this review, we describe the physiology of adrenal hormone biosynthesis and action, the clinical and biochemical characteristics of different forms of endocrine HT, and their underlying genetic defects. We discuss the impact of these discoveries on diagnosis and management of patients, as well as new perspectives related to the use of new biomarkers for improved patient care.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours, often associated with germline mutations that influence the disease biology and clinical course. We aimed to describe the genotypic and phenotypic characteristics of a consecutive series of PPGL patients and correlate mutation status with clinical outcomes.

We performed a retrospective cohort study of all PPGL patients who presented to a tertiary referral centre between March 2005 and February 2022. Genotypic, phenotypic and follow-up data were analysed.

A total of 140 patients were included. Of these, 94 (67%) patients underwent genetic testing and a mutation was detected in 36 (38%) patients. Mutation presence was associated with younger age, smaller tumour size and bilateral adrenal tumours. Disease recurrence occurred at a median time of 5.4 (IQR 2.8-11.0) years after treatment in 21 (15%) patients, of which 14 (67%) had a mutation in a susceptibility gene. Recurrence pattern was influenced by mutation type; higher local recurrence risk for SDHA, SDHB, and MEN2B disease, and higher metastatic risk for SDHB, VHL and MEN2A disease. Recurrence occurred in three (3%) patients with mutation absence. Multivariate analysis revealed that age  ≤40 years and mutation presence were associated with increased risk of disease recurrence.

Genotypic characteristics strongly influence disease presentation and recurrence risk, which may occur more than 5 years after initial treatment. Routine genetic testing of PPGL patients is warranted given the high prevalence of mutations, allowing for prognostication and tailored follow-up. In the presence of germline mutations, follow-up should be life-long.

Pheochromocytoma is often diagnosed prior to pregnancy. Sometimes, the disease may be diagnosed for the first-time during pregnancy masking itself as a hypertensive disease in pregnancy. Early diagnosis and timely, appropriate management reduce possible maternal and fetal complications. We identified a case of pheochromocytoma during pregnancy misdiagnosed as preeclampsia.

The objective of this study is to present the complete biomarker response dataset from a pivotal trial evaluating the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine in patients with advanced pheochromocytoma or paraganglioma. Biomarker status was assessed and post-treatment responses were analyzed for catecholamines, metanephrines, and serum chromogranin A. Complete biomarker response (normalization) or partial response, defined as at least 50% reduction from baseline if above the normal range, was evaluated at specified time points over a 12-month period. These results were correlated with two other study objectives: blood pressure control and objective tumor response as per RECIST 1.0. In this open-label, single-arm study, 68 patients received at least one therapeutic dose (~18.5 GBq (~500 mCi)) of high-specific-activity I-131 meta-iodobenzylguanidine. Of the patients, 79% and 72% had tumors associated with elevated total plasma free metanephrines and serum chromogranin A levels, respectively. Best overall biomarker responses (complete or partial response) for total plasma free metanephrines and chromogranin A were observed in 69% (37/54) and 80% (39/49) of patients, respectively. The best response for individual biomarkers was observed 6-12 months following the first administration of high-specific-activity I-131 meta-iodobenzylguanidine. Biochemical tumor marker response was significantly associated with both reduction in antihypertensive medication use (correlation coefficient 0.35; P = 0.006) as well as objective tumor response (correlation coefficient 0.36; P = 0.007). Treatment with high-specific-activity I-131 meta-iodobenzylguanidine resulted in long-lasting biomarker responses in patients with advanced pheochromocytoma or paraganglioma that correlated with blood pressure control and objective response rate. ClinicalTrials.gov number: NCT00874614.

The co-existence of pheochromocytoma and pregnancy is rare, with poor maternal and foetal outcomes. This is a case report of a young Ghanaian woman with a pre-existing diagnosis of recurrent pheochromocytoma who became pregnant and experienced elevated blood pressure in the third trimester with proteinuria and abnormal liver function. She was managed as an in-patient and delivered a live baby via caesarean section at 34 weeks after detecting intra-uterine growth restriction. Management of such cases by a multidisciplinary team is recommended for optimal outcomes.

Molecular targeted therapy plays an increasingly important role in the treatment of metastatic pheochromocytomas and paragangliomas (PPGLs), which are rare tumors but remain difficult to treat. This mini-review provides an overview of established molecular targeted therapies in present use, and perspectives on those currently under development and evaluation in clinical trials. Recently published research articles, guidelines, and expert views on molecular targeted therapies in PPGLs are systematically reviewed and summarized. Some tyrosine kinase inhibitors (sunitinib, cabozantinib) are already in clinical use with some promising results, but without formal approval for the treatment of PPGLs. Sunitinib is the only therapeutic option which has been investigated in a randomized placebo-controlled clinical trial. It is clinically used as a first-, second-, or third-line therapeutic option for the treatment of progressive metastatic PPGLs. Some other promising molecular targeted therapies (hypoxia-inducible factor 2 alpha [HIF2α] inhibitors, tumor vaccination together with checkpoint inhibitors, antiangiogenic therapies, kinase signaling inhibitors) are under evaluation in clinical trials. The HIF2α inhibitor belzutifan may prove to be particularly interesting for cluster 1B-/VHL/EPAS1-related PPGLs, whereas antiangiogenic therapies seem to be primarily effective in cluster 1A-/SDHx-related PPGLs. Some combination therapies currently being evaluated in clinical trials, such as temozolomide/olaparib, temozolomide/talazoparib, or cabozantinib/atezolizumab, will provide data for novel therapy for metastatic PPGLs. It is likely that advances in such molecular targeted therapies will play an essential role in the future treatment of these tumors, with more personalized therapy options paving the way towards improved therapeutic outcomes.

Pheochromocytoma is a rare tumor frequently overlooked mainly due to the wide range of its clinical presentation, which may vary from entirely untypical signs and symptoms to life-threatening complications.

The present study aims to present a case series recently treated in our center, with emphasis placed on patients' specific characteristics, clinical presentation and diagnostic evaluation. Relevant literature and current guidelines are being briefly reviewed to summarize screening for pheochromocytoma and appropriate diagnostic procedures.

While the classic symptoms include headache, palpitations and sweating with permanent or paroxysmal hypertension, a wide range of clinical manifestations may be attributed to pheochromocytoma. The initial screening test is measurement of plasma or 24-hour urine metanephrine levels. Abdominal computerized tomography with intravenous contrast infusion is suggested as the imaging examination of choice, whereas magnetic resonance imaging should be preferred over CT in exceptional cases. 123I-metaiodobenzylguanidine scintigraphy is particularly useful for establishing the diagnosis of pheochromocytoma and should be further applied to detect or exclude possible metastatic lesions.

Early diagnosis of pheochromocytoma is of great significance not only because it represents a curable form of secondary hypertension, but also because it is often related to familial syndromes, malignancy or metastatic disease. Physicians need to be familiar with relevant clinical manifestations and diagnostic steps to raise clinical suspiction of pheochromocytoma and establish a timely diagnosis.

Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours with malignant potential and a hereditary basis in almost 40% of patients. Germline genetic testing has transformed the management of PPGL enabling stratification of surveillance approaches, earlier diagnosis and predictive testing of at-risk family members. Recent studies have identified somatic mutations in a further subset of patients, indicating that molecular drivers at either a germline or tumour level can be identified in up to 80% of PPGL cases. The aim of this study was to investigate the clinical utility of somatic sequencing in a large cohort of patients with PPGL in the United Kingdom.

Prospectively collected matched germline and tumour samples (development cohort) and retrospectively collected tumour samples (validation cohort) of patients with PPGL were investigated.

Clinical characteristics of patients were assessed and tumour and germline DNA was analysed using a next-generation sequencing strategy. A screen for variants within 'mutation hotspots' in 68 human cancer genes was performed.

Of 141 included patients, 45 (32%) had a germline mutation. In 37 (26%) patients one or more driver somatic variants were identified including 26 likely pathogenic or pathogenic variants and 19 variants of uncertain significance. Pathogenic somatic variants, observed in 25 (18%) patients, were most commonly identified in the VHL, NF1, HRAS and RET genes. Pathogenic somatic variants were almost exclusively identified in patients without a germline mutation (all but one), suggesting that somatic sequencing is likely to be most informative for those patients with negative germline genetic test results.

Somatic sequencing may further stratify surveillance approaches for patients without a germline genetic driver and may also inform targeted therapeutic strategies for patients with metastatic disease.

Cardiac paragangliomas are exceedingly rare. Herein, we describe a patient with a large dopaminesecreting cardiac paraganglioma who had a history of pheochromocytoma after right adrenalectomy. The cardiac surgery was uneventful and without blood pressure fluctuations.The measurement of plasma-free metanephrines or urinary fractionated metanephrines is used as an initial screening test for pheochromocytoma or paraganglioma detection. However, these results must be combined with those of a plasma 3-methoxytyramine test to accurately establish the rare dopaminergic phenotype of pheochromocytomas or paragangliomas, if suspected. F-FDOPA (6-[18F]-L-fluoro-L-3, 4-dihydroxyphenylalanine)-based positron emission tomography (PET) and PET-computed tomography are relatively sensitive and specific; therefore, these techniques are recommended for patients with pheochromocytomas or paragangliomas before operation or during postoperative follow-up.