Pheochromocytoma/Paraganglioma Syndrome Type 1 Presenting with Atypical Symptoms and a Novel Pathogenic Variant in the SDHD Gene: A Case Report.

This case report presents a 10-year-old patient diagnosed with pheochromocytoma/paraganglioma syndrome type 1 (PPGL1), underlined by a novel heterozygous pathogenic variant (c.154_161del, p.ser52Profster14) in the SDHD gene. Initially, the patient manifested symptoms unusual for pheochromocytoma, including polyuria and polydipsia; however, further diagnostic investigations revealed a pheochromocytoma (PCC) tumor in the adrenal gland. Subsequently, whole exome sequencing (WES) test identified a pathogenic frameshift variant in the SDHD gene, strongly suggestive of PPGL1. This study highlights the importance of considering atypical symptoms in diagnosing rare pediatric pheochromocytoma/paraganglioma tumors and underscores the value of genetic testing in identifying underlying genetic causes, thereby facilitating personalized management of the condition.

Cardiac Paraganglioma in a Young Patient Presents with Angina-like Symptoms: A Case Report and Literature Review.

Paragangliomas are rare extra-adrenal neuroendocrine tumors originating from chromaffin tissue that present a diagnostic and therapeutic challenge due to their diverse clinical manifestations and low incidence. While these tumors often manifest as catecholamine-secreting functional tumors, their clinical presentation can vary, leading to delayed diagnosis and challenging management. This study presents the case of a 22-year-old patient with cardiac paraganglioma who initially presented with angina-like symptoms, highlighting the importance of considering this rare condition in young individuals with nonspecific complaints. Diagnostic imaging, including transthoracic echocardiography, CT angiography, and MRI, played a crucial role in identifying the tumor's location and vascularization. Surgical excision, including pulmonary artery graft and CABG, was the primary management approach, which was accompanied by intraoperative complications that later led to CCU admission, followed by postoperative complications, ultimately leading to the patient's death. This case highlights the significance of early recognition and management of complications following a surgical approach to treat paragangliomas.

Paediatric renal hilar paraganglioma.

Retroperitoneal neuroendocrine tumours are exceptionally rare. The excision of tumours located in the renal hilum near the renal vessels can be challenging. We report a case of a paraganglioma located at the renal hilum which was excised successfully in a child who presented with abdominal pain, breathlessness, left varicocele and hypertension.

Metastatic disease and major adverse cardiovascular events preceding diagnosis are the main determinants of disease-specific survival of pheochromocytoma/paraganglioma: long-term follow-up of 303 patients.

Purpose: 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. Methods: 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). Results: 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). Conclusion: 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.

[A case report of giant jugular foramen paraganglioma].

To investigate the clinical experience of glomus jugulare paraganglioma by presenting a case of giant glomus jugulare paraganglioma. The clinical data of 1 case of giant glomus jugulare paraganglioma with unilateral anacousia and pulsatile tinnitus admitted to our department was retrospectively analyzed, and the relevant literature was reviewed to summarize the characteristics of the disease. The tumor tissue in the jugular venous foramen region was completely resected, with complete preservation of the facial nerve during the operation. There was no tumor recurrence during the 2-year postoperative follow-up period. With nonspecific clinical symptoms and a high rate of early misdiagnosis The giant glomus jugulare paraganglioma case only manifested as symptoms of unilateral anacousia and pulsatile tinnitus is clinically rare. The intraoperative safe resection of the tumor, maximum preservation of facial nerve function remains the focus of surgery.

Gangliocytic paraganglioma: A case report.

Paragangliomas (PGLs) are rare and encapsulated neuroendocrine tumors (NET), located in the adrenal gland or the extra-adrenal paraganglia. Extra-adrenal PGLs may develop a gangliocytic component with ganglion cells which are called gangliocytic paragangliomas (GPs). The most common location is the duodenum, and they appear with digestive symptoms or as an incidental finding. We described a 43 years old patient, with epigastric pain, nausea and vomiting. The CT-scan reveals a nodular image in the duodenum. An ultrasound-guided FNA was performed and the pathological report revealed neuroendocrine cell groups and neural tissue. Surgery was the chosen treatment. As the patient did not present lymphatic or pancreatic parenchyma invasion, radiotherapy (RT) was not administered. The management of GPs is not well established and multidisciplinary team approach is recommended to lead to therapeutic options. Surgical resection is still key in the treatment, and adjuvant RT may be considered in cases of lymph node invasion.

Hot Trends in Pheochromocytoma and Paraganglioma: Are We Getting Closer to Personalized Dynamic Prognostication?

Pheochromocytoma and abdominal paraganglioma (PPGL) are rare catecholamine-producing, keratin-negative, non-epithelial neuroendocrine neoplasms characterized by a unique association with syndromic diseases caused by constitutional mutations in a wide range of susceptibility genes. While PPGLs are recognized for their malignant potential, the risk of metastatic disease varies depending on several clinical, histological, and genetic factors. Accurate diagnosis and prognosis of these tumors require a multidisciplinary approach, integrating insights from various medical specialties. Pathologists play a crucial role in this complex task, as numerous morphological, immunohistochemical, and genetic findings can be linked to worse outcomes. Therefore, it is vital to stay informed about the latest advancements in PPGL pathology. This brief review provides an overview of the challenges associated with PPGLs and highlights the most recent developments in tumor prognostication.

[Simultaneous occurrence of facial neurinoma in internal auditory canal and middle ear paraganglioma in patient. Unusual combination and difficult surgical task]. / Odnovremennoe vozniknovenie nevrinomy litsevogo nerva vo vnutrennem slukhovom prokhode i paragangliomy srednego ukha u patsientki: neobychnoe sochetanie i neprostaya khirurgicheskaya zadacha.

CLINICAL CASE: The 59-year-old patient complained of hearing loss on the left, ear murmur for a long time, periodic pain and discomfort in the left ear, dizziness for 6 months. She was found to have concurrent vestibular schwannoma in the internal auditory canal and temporal bone paraganglioma. Both tumors were removed in one operation. The schwannoma was removed by translabirinth access due to preoperative deafness, while the glomus tumor was removed during this access. Postoperative biopsy showed the presence of two unrelated diseases: paraganglioma (ICD-0 code 8690/3) and schwannoma (ICD-0 code 9560/0).

[Diagnosis and management of patients with pheochromocytoma/paraganglioma: Consensus of experts of the Russian Medical Society for Arterial Hypertension and the Multidisciplinary Group for the Diagnosis and Treatment of Neuroendocrine Tumors].

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.

A rare association of pheochromocytoma, paraganglioma, and pituitary adenoma (3PA): A case report and literature review.

RATIONALE: 3P association (3PA) is a rare condition with co-occurrence of pituitary adenoma and pheochromocytoma/paraganglioma. There have been less than a hundred documented cases of 3PA, which can be sporadic or related to genetic mutations. The present case report describes the first Iranian patient with 3PA and a 90th case of 3PA in the available literature. PATIENT CONCERNS AND INTERVENTIONS: A 36-year-old Caucasian male was admitted with headache and sudden increase in blood pressure. An abdominal CT scan revealed a retroperitoneal mass posterior to the inferior vena cava, later removed and diagnosed as a pheochromocytoma. Four years later, he noticed occasional mild headaches and a painless mass on the right side of his neck. The ultrasonography evaluations suggested a carotid body tumor, which was surgically removed. About a month after his second surgery, the severity of the patient's headaches worsened, and he developed right homonymous hemianopia. A brain MRI showed a mass in favor of macroadenoma, craniopharyngioma, or meningioma, and elevated prolactin level led to the diagnosis of macroprolactinoma. DIAGNOSES: Based on the provided history, this patient was diagnosed with 3PA, and a genetic study identified a positive succinate-dehydrogenase-complex subunit b mutation, possibly linked to his family history of carotid body tumor. OUTCOMES: He has remained symptom-free during his visits every 3 months. LESSONS: The number of cases diagnosed with 3PA worldwide is increasing. Using clinical and genetic assessments, we can timely diagnose and adequately monitor individuals with or at risk of 3PA.

[Review and prospect of the diagnosis and treatment of head and neck paragangliomas].

ead and neck paraganglioma（HNPGL） often originates from the parasympathetic ganglia and is a highly invasive benign tumor. The diagnosis and treatment of this disease with strong heterogeneity is still a challenge. In the future, deep exploration is needed in genetic typing, grading diagnosis and treatment decisions, protection of cranial nerves and new drug treatments to better treat this disease.

[New progress in the diagnosis and treatment of jugular paragangliomas].

Jugular paraganglioma is the most common neoplasms in the jugular foramen. It is a slow-growing wiht abundant blood supply, and is intimately associated with critical neurovascular structures at the skull base. In this paper, the latest advance in pathophysiology, surgical treatment, radiotherapy were reviewed based on previous literature, providing reference for clinical diagnosis, treatment and future research.

Pheochromocytoma/paraganglioma type 5 syndrome as a cause of secondary hypertension in a Colombian patient: case report / Síndrome de feocromocitoma-paraganglioma de tipo 5 como causa de hipertensión arterial en una paciente colombiana: reporte de caso

Pheochromocytoma is a tumor derived from neural crest cells able to produce sympathomimetic substances and, hence, a particular clinical picture. It is responsible for less than 1% of high blood pressure cases, with an estimated incidence between 0.4 and 0.6 cases per 100,000 people each year, and an average survival of seven years. Pheochromocytoma is a solid tumor with a high genetic component, as heritability can reach 40%. Once diagnosed, its treatment and prognosis are partly conditioned by the associated pathogenic variants that can be documented, especially those related to RET, SDHx, VHL, and NF1 genes. We present the case of a young woman with abdominal pain and high blood pressure, who was found to have a pheochromocytoma. Genetic testing detected a rare and recently discovered pathogenic variant: the SDHA:c.1A>C (p.Met1Leu). The patient responded adequately to the surgical treatment and continued the follow-up without documented recurrences. The diagnostic approach for pheochromocytoma patients must start with a clinical suspicion, followed by metabolite measurement in blood and urine, and finally, imaging. Currently, technology development allows precision medicine applicability. In this case of pheochromocytoma, recent developments in precision medicine resulted in the detection of associated genetic components involving the patient and her family. Adequate screening of the index patient is required for documenting pathogenic variants and better characterizing the disease.

El feocromocitoma es un tumor derivado de las células de la cresta neural con la capacidad de producir sustancias simpaticomiméticas y, por ende, un cuadro clínico particular. Causa menos del 1 % de los casos de hipertensión arterial sistémica y su incidencia se estima entre 0,4 y 0,6 casos por 100.000 personas cada año, con una supervivencia media de siete años. De todos los tumores sólidos, el feocromocitoma tiene un mayor componente genético, que puede heredarse hasta en el 40 % de los casos. Una vez diagnosticada la enfermedad, se debe definir el tratamiento y el pronóstico, en parte condicionados por las variantes genéticas asociadas, en especial RET, SDHx, VHL y NF1. Se presenta el caso de una mujer joven con dolor abdominal e hipertensión arterial sistémica, a quien se le diagnosticó feocromocitoma. Al secuenciar el exoma, se identificó una variante patogénica extremadamente rara y de reciente descubrimiento: SDHA: c.1A>C (p.Met1Leu). La paciente respondió adecuadamente al tratamiento quirúrgico y continuó en seguimiento sin recurrencias. El abordaje diagnóstico de los pacientes con feocromocitoma comienza con la sospecha clínica, seguida de la medición de determinados metabolitos en sangre y orina, y, finalmente, los estudios de imagenología. Los desarrollos tecnológicos actuales permiten la aplicación de la medicina de precisión en este campo. En este caso de feocromocitoma, se identificó un componente genético importante que no solo afecta al paciente, sino también, a sus familiares. La tamización adecuada del caso índice permite identificar mutaciones y caracterizar mejor la enfermedad.

Genetic and Molecular Biomarkers in Aggressive Pheochromocytomas and Paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neoplasms producing catecholamines that occur as hereditary syndromes in 25-40% of cases. To date, PPGLs are no longer classified as benign and malignant tumors since any lesion could theoretically metastasize, even if it occurs only in a minority of cases (approximately 10-30%). Over the last decades, several attempts were made to develop a scoring system able to predict the risk of aggressive behavior at diagnosis, including the risk of metastases and disease recurrence; unfortunately, none of the available scores is able to accurately predict the risk of aggressive behavior, even including clinical, biochemical, and histopathological features. Thus, life-long follow-up is required in PPGL patients. Some recent studies focusing on genetic and molecular markers (involved in hypoxia regulation, gene transcription, cellular growth, differentiation, signaling pathways, and apoptosis) seem to indicate they are promising prognostic factors, even though their clinical significance needs to be further evaluated. The most involved pathways in PPGLs with aggressive behavior are represented by Krebs cycle alterations caused by succinate dehydrogenase subunits (SDHx), especially when caused by SDHB mutations, and by fumarate hydratase mutations that lead to the activation of hypoxia pathways and DNA hypermethylation, suggesting a common pathway in tumorigenesis. Conversely, PPGLs showing mutations in the kinase cascade (cluster 2) tend to display less aggressive behavior. Finally, establishing pathways of tumorigenesis is also fundamental to developing new drugs targeted to specific pathways and improving the survival of patients with metastatic disease. Unfortunately, the rarity of these tumors and the scarce number of cases enrolled in the available studies represents an obstacle to validating the role of molecular markers as reliable predictors of aggressiveness.

Head and Neck Paraganglioma (HNPGL) Registry: A study protocol for prospective data collection in patients with Head and Neck Paragangliomas.

INTRODUCTION: There is a lack of comprehensive and uniform data on head and neck paragangliomas (HNPGLs), and research is challenging due to its rarity and the involvement of multiple medical specialties. To improve current research data collection, we initiated the Head and Neck Paraganglioma Registry (HNPGL Registry). The aim of the HNPGL Registry is to a) collect extensive data on all HNPGL patients through a predefined protocol, b) give insight in the long term outcomes using patient reported outcome measures (PROMs), c) create uniformity in the diagnostic and clinical management of these conditions, and thereby d) help provide content for future (randomized) research. METHODS AND ANALYSIS: The HNPGL Registry is designed as a prospective longitudinal observational registry for data collection on HNPGL patients and carriers of (likely) pathogenic variants causative of HNPGLs. All patients, regardless of the received treatment modality, can be included in the registry after informed consent is obtained. All relevant data regarding the initial presentation, diagnostics, treatment, and follow-up will be collected prospectively in an electronic case report form. In addition a survey containing the EuroQol 5D-5L (EQ-5D-5L), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), Modified Fatigue Impact Scale (MFIS), Short QUestionnaire to Assess Health-enhancing physical activity (SQUASH), Cancer Worry Scale (CWS) and Hospital Anxiety and Depression Scale (HADS) will be sent periodically. The registry protocol was approved by the Medical Ethical Review Board of the University Medical Center Utrecht. CONCLUSION: The HNPGL Registry data will be used to further establish the optimal management for HNPGL patients and lay the foundation for guideline recommendations and the outline of future research.

Clinical and molecular markers guide the genetics of pheochromocytoma and paraganglioma.

Over the past two decades, research into the genetic susceptibility behind pheochromocytoma and paraganglioma (PPGL) has surged, ranking them among the most heritable tumors. Massive sequencing combined with careful patient selection has so far identified more than twenty susceptibility genes, leading to an over-detection of variants of unknown significance (VUS) that require precise molecular markers to determine their pathogenic role. Moreover, some PPGL patients remain undiagnosed, possibly due to mutations in regulatory regions of already known genes or mutations in undiscovered genes. Accurate classification of VUS and identification of new genes require well-defined clinical and molecular markers that allow effective genetic diagnosis of most PPGLs.

Basaloid squamous cell carcinoma clinically and radiologically masquerading as a head and neck paraganglioma: a case report and review of the literature.

BACKGROUND: This paper reports the first case of basaloid squamous cell carcinoma clinically and radiologically masquerading as a head and neck paraganglioma. CASE PRESENTATION: A 66-year-old Sinhalese male with unilateral hearing impairment and 7th-12th (excluding 11th) cranial nerve palsies was diagnosed radiologically with a head and neck paraganglioma by magnetic resonance imaging of the brain, which revealed a hypointense and hyperintense punctate mass centered at the jugular fossa with intracranial extension. The ascending pharyngeal artery, recognized as the major feeder, was embolized by percutaneous embolization following digital subtraction angiography. Gross total resection of the tumor was followed by an uneventful postoperative recovery. Combined immunohistochemistry and histopathological morphology revealed a basaloid squamous cell carcinoma, following which the patient completed radiotherapy and is at 3-month follow-up currently. CONCLUSION: This case report discusses the diagnostic pitfalls and management challenges of this rare entity on the basis of prior evidence, as well as a literature review and clinical and surgical analysis.

[Paragangliomas of the head and neck]. / Paragangliome im Kopf-Hals-Bereich.

Paragangliomas represent a heterogeneous group of rare neuroendocrine tumors with marked variability in symptoms and disease course. Due to the close proximity to neurovascular structures, paragangliomas of the head and neck region can cause a variety of symptoms. To this day, there are no reliable prognostic factors that can predict a potentially malignant course. All patients with newly diagnosed paragangliomas should undergo an early diagnostic workup and regular follow-up examinations in specialized centers. While radical resection was previously regarded as standard treatment for paragangliomas, radiotherapy and active surveillance (watch-and-scan strategy) have become equally important over the years. Low-threshold techniques for molecular pathology analysis of the mutation-specific behavior of paragangliomas are nowadays available.

Paragangliomas of the Head and Neck: A Review of the Latest Diagnostic and Treatment Methods.

Background and objectives: Paragangliomas of the head and neck are rare, slow-growing neuroendocrine tumors, benign in their vast majority, but with a possibility of developing distant metastases. They show great inheritable character, and their behavior has proven to be unpredictable; therefore, they are considered malignant. Material and methods: This article aims to offer a more comprehensive presentation of the pathogenesis, epidemiology, diagnostic methods, imaging development, and treatment guidelines. We tried to bring together all the necessary data that, in our opinion, a head and neck practitioner should know when managing this type of tumor. Our main focus is on the most recent studies, with the purpose of a homogenous presentation of all current guidelines and approaches to this pathology. Results: Paragangliomas of the head and neck are still a disputed topic. One of the main reasons for that is their low incidence of 0.3 to 1 per 100,000 every year. The most frequent locations are the carotid body, the temporal bone, the jugular and mastoid foramen, and the vagal nerve. Their clinical presentation usually involves a painless lateral mass associated with symptoms such as hoarseness, hearing loss, tinnitus, and cranial nerve deficits. Up to 40% of them are inherited, mostly linked with mutations of succinate dehydrogenase complex. Imaging evaluation consists of CT and MRI, and new functional explorations such as 18F-FDA and 18F-FDG PET/CT, 18F-DOPA PET, 123I-MIBG, and 68Ga-DOTATE PET/CT. Measuring the catecholamine levels in the plasma and urine is mandatory, even though paragangliomas of the head and neck rarely display secretory behavior. Treatment mainly consists of surgery, with different approaches and techniques, but conservative management methods such as wait and scan, radiotherapy, proton therapy, and chemotherapy have proven their efficiency. The therapeutical decision lacks consensus, and current studies tend to recommend an individualized approach. Guidelines regarding long-term follow-up are still a matter of debate.

Management of Pheochromocytomas and Paragangliomas.

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.