Adolescent primary hyperparathyroidism (PHPT) is a rare endocrine disorder bearing distinctions from the adult form. This review examines its unique aspects, focusing on clinical presentation, genetic etiologies, genotype-phenotype correlations, and therapeutic management. Adolescent PHPT often has a genetic basis, whether familial, syndromic, or apparently sporadic, and identifying the underlying genetic cause is important for patient care. The clinical presentation is predominantly symptomatic worldwide. Unique manifestations in this age group include rickets, short stature, and slipped capital femoral epiphysis. Genotype-specific differences are evident in the adolescent PHPT characteristics. Diagnostic evaluation requires careful interpretation of biochemical and dual-energy X-ray absorptiometry findings using age and gender-specific reference ranges, with targeted screening for syndrome-associated neoplasms. Surgery remains the cornerstone of management. Current knowledge gaps in their management include treatment protocols for multiple endocrine neoplasia type 1-associated PHPT, the efficacy and safety of nonsurgical options, and long-term post-surgical outcomes.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours with a strong genetic predisposition, involving over 20 genes and with germline pathogenic variants identified in 40 % of cases. The succinate dehydrogenase (SDHx) genes are the most commonly implicated in hereditary PPGLs, accounting for 20 % of cases, and present unique diagnostic and treatment challenges due to their potential for multiple, recurrent, and aggressive manifestations, often necessitating lifelong follow-up. Over the past two decades, advances in biochemical and imaging assessments, management, and follow-up protocols have significantly improved care for both adult and paediatric patients. These advances include next-generation sequencing, new biochemical tests, cluster-specific functional imaging, and improved surgical and radiotherapy techniques, such as stereotactic surgery and peptide receptor radionuclide therapy (PRRT). International consensus guidelines have been developed to standardise the management of patients with SDHx pathogenic variants, emphasising multidisciplinary approaches and frequent tumour board discussions. These guidelines, summarised below, cover recommendations for initial genetic testing, tumour screening, follow-up care, and management of patients and asymptomatic carriers.

Immunotherapy represents a revolutionary advancement in cancer treatment, which has traditionally focused on T cells; however, the role of B cells in cancer immunotherapy has gained interest because of their role in antigen presentation, antibody production, and cytokine release. In this study, we examined the role of B cells in previously developed intratumoral MBTA therapy (mannan-BAM, TLR ligands, and anti-CD40 antibody) in murine models of MTT pheochromocytoma. The results indicated that B cells significantly enhance the success of MBTA therapy, with wild-type mice exhibiting a lower tumor incidence and smaller tumors compared with B cell-deficient mice. Increased IL-6 and TNF-alpha levels indicated severe inflammation and a potential cytokine storm in B cell-deficient mice. Neutralization of TNF-alpha ameliorated these complications but resulted in increased tumor recurrence. The results highlight the important role of B cells in enhancing the immune response and maintaining immune homeostasis during MBTA therapy. Our findings offer new insights into improving therapeutic outcomes.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumors derived from the paraganglia. These tumors frequently secrete excessive amounts of catecholamines leading to cardiovascular and gastrointestinal complications. While all pheochromocytomas and paragangliomas possess the potential for metastasis, actual metastatic occurrences are observed in approximately one third of cases. The metastases primarily affect the lymph nodes, skeletal system, liver, and lungs. Furthermore, patients often experience a reduced overall survival rate attributed to factors such as tumor size, disease advancement, and excessive catecholamine secretion. For several decades, treatment options for patients diagnosed with metastatic pheochromocytomas and paragangliomas have primarily included combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine, along with Iodine-131-metaiodobenzylguanidine. However, significant advancements in scientific research over the past 25 years have enabled a comprehensive characterization of these tumors from biochemical, molecular, and diagnostic standpoints, resulting in the identification of new therapeutic alternatives for affected patients. In the last decade, we have witnessed the introduction of innovative systemic therapies specifically designed for those with metastatic pheochromocytomas and paragangliomas. In this review, we aim to present findings on the efficacy, safety, and overall activity from prospective clinical trials involving radiopharmaceuticals and tyrosine kinase inhibitors, and we will also outline the prospective advantages of additional novel therapies currently under evaluation.

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.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with clinical heterogeneity and a high association with hereditary disease, affecting approximately 30 % of the cases. Differences in the presentation and genetic etiologies of PPGLs have been demonstrated between Chinese and European patients. The frequency of germline genetic diagnosis was remarkably higher in Brazilian patients (∼50 %) compared with other cohorts (Chinese 21 %, European 31 %, and The Cancer Genome Atlas Program cohort 27 %). Interestingly, germline SDHB genetic defects were also more prevalent in Brazilian patients (17 %) with PPGLs when compared with other cohorts (3-9 %). The SDHB exon 1 deletion was responsible for approximately 50 % of the SDHB pathogenic/likely pathogenic variants in Brazilian patients with PPGLs due to a founder effect. The germline SDHB exon 1 deletion represents ∼10 % of the germline drivers in Brazilian patients (and possibly in Latin America). Therefore, a single diagnostic PCR for the SDHB exon 1 deletion might be very useful in clinical practice for genetic testing and counseling of patients with PPGLs in Latin America.

Phaeochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours which arise from chromaffin cells of the adrenal medulla or extra-adrenal autonomic ganglia. PPGL most commonly present in adulthood but can arise in childhood and adolescence with an estimated annual incidence of 0.5 cases per million children per year. There have been significant advances in the diagnosis and management of PPGL over the past 2-3 decades based largely on the study of adult patients. These advances in clinical knowledge can be applied to paediatric patients but like other cancers, paediatric PPGL must be viewed as a distinct subset with their own specific challenges and opportunities for improved clinical care. This review article provides an overview on the diagnosis and management of PPGL in children focusing on recent international guidance.

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.

Phaeochromocytomas (PC) and paragangliomas (PG) are neural crest cancers with high heritability. Recent advances in molecular profiling, including multi-omics and single cell genomics has identified up to seven distinct molecular subtypes. These subtypes are defined by mutations involving hypoxia-inducible factors (HIFs), Krebs cycle, kinase and WNT signalling, but are also defined by chromaffin differentiation states. PCPG have a dominant proangiogenic microenvironment linked to HIF pathway activity and are generally considered "immune cold" tumours with a high number of macrophages. PCPG subtypes can indicate increased metastatic risk but secondary mutations in telomere maintenance genes TERT or ATRX are required to drive the metastatic phenotype. Molecular profiling can identify molecular therapeutic (e.g. RET and EPAS1) and radiopharmaceutical targets while also helping to support variant pathogenicity and familial risk. Molecular profiling and subtyping of PCPG therefore confers the possibility of nuanced prognostication and individual treatment stratification but this still requires large-scale prospective validation.

Head and neck paragangliomas (HNPGLs), rare neuroendocrine tumors that mainly arise from parasympathetic ganglia along the cranial nerves, are challenging due to anatomic origin, tendency to aggressive neurovascular and skull base infiltration, unpredictable metastatic potential, radio-chemoresistance, and risk of multiplicity. Symptoms range from mild to life threatening depending on location/size, but rarely relate to catecholamine excess. Risk factors include female sex and pathogenic germline variants in genes affecting hypoxia signaling (foremost succinate dehydrogenase genes). Diagnostic work-up relies on imaging, measurements of plasma free metanephrines/methoxytyramine, genetic testing, and pathology/immunohistochemistry. Management is tailored to patient/tumor characteristics and encompasses wait-scan, upfront surgery, debulking surgery, and radiotherapy. Presurgical embolization is recommended, except for small tympanic and tympanomastoid tumors. Presurgical stenting is required for internal carotid artery involvement, and two-stage surgery for intradural extension. Current treatments for metastatic/inoperable HNPGL are non-curative, and long-term follow-up should be recommended for all patients to monitor local recurrence and new tumors.

The complexity of omes - the key cellular ensembles (genome and epigenome, transcriptome, proteome, and metabolome) - is becoming increasingly understood in terms of big-data analysis, the omics. Amongst these, proteomics provides a global description of quantitative and qualitative alterations of protein expression (or protein abundance in body fluids) in response to physiologic or pathologic processes while metabolomics offers a functional portrait of the physiological state by quantifying metabolite abundances in biological samples. Here, we summarize how different techniques of proteomic and metabolic analysis can be used to define key biochemical characteristics of pheochromocytomas/paragangliomas (PPGL). The significance of omics in understanding features of PPGL biology that might translate to improved diagnosis and treatment will be highlighted.

Pathogenic variants (PVs) in EPAS1, which encodes hypoxia-inducible factor-2α (HIF-2α), could be the underlying genetic cause of about 3%-6% of pheochromocytoma and paragangliomas (PPGLs). EPAS1-related PPGLs may occur as isolated tumors or as part of Pacak-Zhuang Syndrome (PZS) with two or more of a triad of PPGL, polycythemia, and somatostatinoma. HIF-2α plays a critical role in the regulation of the cellular hypoxia pathway. When a gain-of-function PV is acquired, HIF-2α evades steady-state hydroxylation by the prolyl hydroxylase type 2 (PHD2), which accelerates von Hippel-Lindau (VHL)-mediated proteasomal degradation. In this situation, HIF-2α is stabilized and can translocate to the nucleus, inducing the expression of several genes involved in tumorigenesis. This leads to the development of PPGL and other manifestations of PZS. EPAS1-related PPGLs usually occur in the second or third decade of life, more frequently in females, and are usually multiple, adrenal and extra-adrenal, and norepinephrine-secreting. In addition, these tumors carry an increased metastatic potential and have been reported with metastatic disease in up to 30% of cases. While polycythemia is fairly common in PZS, somatostatinomas are rare. It has been suggested that the character of the acquired PV in EPAS1, which affects its binding to PHD2, correlates with certain phenotypes in PZS. PVs in EPAS1 that have been found in related sporadic PPGLs have also been associated with hypoxic conditions including cyanotic congenital heart disease, hemoglobinopathies and high altitude. Understanding the hypoxia pathway and its role in the pathogenesis of PPGL may open a new avenue for developing effective therapies for these tumors. Indeed, one of these therapies is Belzutifan, a HIF-2α inhibitor that is being tested in the treatment of metastatic PPGLs.

Pheochromocytomas and paragangliomas (PPGLs) represent a unique subset of neuroendocrine neoplasms (NENs) characterized by their genetic diversity and potential for catecholamine secretion. Similar to epithelial NENs, all PPGLs are classified as malignant neoplasms that are associated with a variable risk of metastatic spread. PPGLs arise from neuroendocrine cells of the adrenal medulla (intra-adrenal paraganglia) or extra-adrenal paraganglia. Advances over the past two decades have significantly enhanced our understanding of the biological and genetic underpinnings of these neoplasms, resulting in robust genotype-phenotype (e.g., morphology, anatomic distribution, catecholamine profile, biomarker profile, risk of metastasis) correlations that guide diagnosis and prognostication. The 2022 WHO classification of PPGLs emphasizes a shift away from morphology-only diagnostic approaches by ensuring the integration of morphology with functional, structural and pathogenesis-related biomarker studies into routine pathology practice when assessing PPGLs. This paradigm is critical in distinguishing metastatic disease from multifocal primary tumors, particularly in patients with germline mutations - a hallmark of PPGLs, with germline susceptibility observed in at least 40 % of cases. This review provides practicing pathologists with a concise update on modern diagnostic and risk assessment strategies for PPGLs, focusing on the integration of biomarkers, genetic profiling, and morphological features. It also addresses emerging challenges, such as identifying metastatic potential and distinguishing these from synchronous lesions, to improve multidisciplinary care of these patients.

Parathyroid carcinoma (PC) is a rare malignancy, comprising 1 % of all cases of primary hyperparathyroidism (PHPT). This narrative review explores recent advances in PC management, with a focus on molecular insights, diagnostic advancements, surgical innovations, and emerging targeted therapies. Manuscripts published between 2023 and 2024 were obtained from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). The review highlights advances in biochemical markers, such as circulating tumour cells (CTCs), and imaging modalities such as F-FDG PET/CT and 4D-CT, which are improving diagnostic accuracy. Surgical resection remains central to localised and metastatic disease management. For patients with widespread metastatic or unresectable disease, newer targeted approaches such as tyrosine kinase inhibitors (TKIs), temozolomide, and immune checkpoint inhibitors (ICIs) may offer clinical benefit to specific patient cohorts. This review identifies future research areas to improve outcomes and recommends that patients with advanced PC continue to be managed in centres of excellence.

Primary hyperparathyroidism is the main cause of hypercalcemia, resulting predominantly from parathyroid adenomas followed by hyperplasia. Diagnosis relies on clinical and biochemical parameters. Accurate pre-operative localization is mandatory for better surgical outcome. Various non-invasive imaging modalities includes cervical ultrasound, radionuclide scintigraphy with Tc-Methoxyisobutyl isonitrile combined with SPECT/CT, 4DCT, MRI and F-Choline PET/CT. Functional imaging has shown higher accuracy in localization especially in ectopic parathyroid adenomas and persistent or recurrent hyperparathyroidism. Combined ultrasound and Tc-MIBI has shown high sensitivity and specificity than individual imaging modality. F-Choline PET/CT has better diagnostic performance in identifying parathyroid hyperplasia and multiple adenomas. In patients with equivocal findings and concurrent thyroid nodular diseases, F-Choline PET/MRI and 4DCT helps in better characterization of lesion. Intraoperative probe guided surgery facilitates targeted and minimally invasive surgery resulting in better surgical outcome. More specific radiopharmaceuticals for parathyroid imaging need to be developed to reduce false positive results.

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.

Gender incongruence and the number of people seeking gender affirming hormone treatment has dramatically risen in the last two decades. In the UK, transgender women and non-binary transfeminine individuals are typically treated with simultaneous suppression of endogenous testosterone production through anti-androgens and exogenous oestradiol replacement. Oestrogen replacement comes in different forms and is primarily given as transdermal (gel or patch) or oral preparations in the UK. Decisions around preparation choice are based on a combination of individual preference and/or mitigating the chance of complications based on individual risk profiles. Time frames to achieve female physical changes are largely predictable and managing expectations of individuals prior to commencing treatment is highly important. Common complications include venous thromboembolism, liver dysfunction and effects on fertility, thus individuals should be thoroughly counselled prior to commencing treatment. This article provides an overview of the management and considerations of gender-affirming hormone treatment in transgender women and non-binary transfeminine individuals.

Detransition, the process of reverting to one's gender assigned at birth after a period of transition, or moving away from the original transition goal, presents unique challenges in healthcare. This paper introduces the clinical issue and provides a comprehensive overview of the ethical, psychological, legal, surgical, and endocrinological considerations involved in supporting individuals who choose to detransition. It emphasises the importance of patient-centred care, informed consent, and the need for expanded research to address the specific needs of this population. The paper highlights the complexities of endocrine management, surgical reversals, and the necessity for comprehensive support systems. Key psychotherapeutic interventions, including trauma-focused Cognitive Behavioural Therapy (CBT), Eye Movement Desensitization and Reprocessing (EMDR), and third-wave approaches like Compassion-Focused Therapy (CFT), are recommended to manage associated trauma and shame. By adopting a holistic approach, healthcare providers can better assist individuals navigating the complexities of detransition.