Pitfalls in the Diagnostic Evaluation of Pheochromocytomas.

Pheochromocytomas and paragangliomas (PPGLs), rare neuroendocrine tumors arising from chromaffin cells, present a significant diagnostic challenge due to their clinical rarity and polymorphic symptomatology. The clinical cases demonstrate the importance of an integrated approach that combines clinical assessment, biochemical testing, and imaging to distinguish PPGLs from mimicking conditions, such as obstructive sleep apnea and interfering medication effects, which can lead to false-positive biochemical results. Although a rare condition, false-negative metanephrine levels can occur in pheochromocytomas, but imaging findings can give some clues and increase suspicion for a pheochromocytoma diagnosis. This expert endocrine consult underscores the critical role of evaluating preanalytical conditions and pretest probability in the biochemical diagnosis of PPGLs. Moreover, a careful differentiation of PPGLs from similar conditions and careful selection and interpretation of diagnostic tests, with focus on understanding and reducing false positives to enhance diagnostic accuracy and patient outcomes, is crucial.

Identification of Predictors of Metastatic Potential in Paragangliomas to Develop a Prognostic Score (PSPGL).

Context: Paragangliomas (PGLs) are rare tumors in adrenal and extra-adrenal locations. Metastasis are found in approximately 5% to 35% of PGLs, and there are no reliable predictors of metastatic disease. Objective: This work aimed to develop a prognostic score of metastatic potential in PGLs. Methods: A retrospective analysis was conducted of clinical data from a cohort with PGLs and tumor histological assessment. Patients were divided into metastatic PGL (presence of metastasis) and nonmetastatic PGL (absence of metastasis ≥96 months of follow-up) groups. Univariate and multivariable analysis were performed to identify predictors of metastatic potential. A prognostic score was developed based on coefficients of multivariable analysis. Kaplan-Meier curves were generated to estimate disease-specific survival (DSS). Results: Out of 263 patients, 35 patients had metastatic PGL and 110 patients had nonmetastatic PGL. In multivariable analysis, 4 features were independently related to metastatic disease and composed the Prognostic Score of Paragangliomas (PSPGL): presence of central or confluent necrosis (33 points), more than 3 mitosis/10 high-power field (HPF) (28 points), extension into adipose tissue (20 points), and extra-adrenal location (19 points). A PSPGL of 24 or greater showed similar sensitivity with higher specificity than the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP). PSPGL less than or equal to 20 was associated with a risk of metastasis of approximately 10%, whereas a PSPGL of 40 or greater was associated with approximately 80%. The presence of metastasis and Ki-67 of 3% or greater were related to lower DSS. Conclusion: The PSPGL, composed of 4 easy-to-assess parameters, demonstrated good performance in predicting metastatic potential and good ability in estimating metastasis risk.

Intraoperative radiofrequency ablation for unresectable abdominal paraganglioma: a case report.

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

Clinical and Pathological Predictors of Death for Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare and lethal disease with a poor prognosis. This study aims to share our 41-year experience as a referral center, focusing on identifying risk factors associated with ACC mortality. Our retrospective analysis included a cohort of 150 adult patients with ACC in all stage categories, treated between 1981 and 2022. Tumor hormonal hypersecretion was observed in 78.6% of the patients, and the median age of diagnosis was 40 years. The majority presented as European Network for the Study of Adrenal Tumors (ENSAT) III or IV (22.9% and 31.2%, respectively), and the overall mortality rate was 54.6%. Independent predictors of death were elevated secretion of cortisol (HR = 2.0), androstenedione (HR = 2.2), estradiol (HR = 2.8), 17-OH progesterone (HR = 2.0), and 11-deoxycortisol (HR = 5.1), higher Weiss (HR = 4.3), modified Weiss (HR = 4.4), and Helsinki scores (HR = 12.0), advanced ENSAT stage (HR = 27.1), larger tumor size (HR = 2.7), higher Ki-67 percentage (HR = 2.3), and incomplete surgical resection (HR = 2.5). Mitosis greater than 5/50 high-power field (HR = 5.6), atypical mitosis (HR = 2.3), confluent necrosis (HR = 15.4), venous invasion (HR = 2.8), and capsular invasion (HR = 2.4) were also identified as independent predictors of death. Knowing the risk factors for ACC's mortality may help determine the best treatment option.

Renal Function Evolution and Hypoaldosteronism Risk After Unilateral Adrenalectomy for Primary Aldosteronism.

Few studies demonstrated a percentage decrease in the estimated glomerular filtration rate (eGFR) at a single time and the rate of hypoaldosteronism after adrenalectomy for primary aldosteronism (PA). Our aim was to investigate the evolution of renal function and the hypoaldosteronism risk after adrenalectomy for PA. Aldosterone, renin, eGFR, and electrolyte levels were determined before and at 1 week, 1, 3 and 6 months after unilateral adrenalectomy in 94 PA patients (40 men and 54 women). The main outcome was the postoperative eGFR decline using analysis of covariance with the preoperative eGFR as a covariate. eGFR decreased during first postoperative week compared to 3 months before surgery. During the first 6 months, eGFR remained stable at similar levels to the first week after surgery. Age (p=0.001), aldosterone levels (p=0.021) and eGFR 3 months before surgery (p+<+0.0001) had a significant correlation with eGFR during first postoperative week. High aldosterone levels at diagnosis were correlated with decline in renal function in the univariate model (p=0.033). In the multivariate analysis, aldosterone levels at diagnosis had a tendency to be an independent predictor of renal function after surgery (p=0.059). Postoperative biochemical hypoaldosteronism was diagnosed in 48% of the cases after adrenalectomy, but prolonged hyperkalemia occurred in only 4 cases (4.5%). Our findings showed a decrease of eGFR after unilateral adrenalectomy for PA. Additionally, aldosterone levels at diagnosis correlated with postoperative renal function. Postoperative biochemical hypoaldosteronism occurred in almost half of the patients, but prolonged hyperkalemia with fludrocortisone replacement was less frequent.

Three Cases of Carney-Stratakis Syndrome: A Genetically Heterogeneous Disease.

Carney-Stratakis syndrome (CSS) is an autosomal dominant rare syndrome, with incomplete penetrance, characterized by the association of paragangliomas and/or pheochromocytomas and gastrointestinal stromal tumors (GISTs). CSS is caused by germline heterozygous loss-of-function pathogenic variants (PVs) in the succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD), with SDHB and SDHD being the most frequent. To date, only 2 germline SDHC PVs (c.43 C > T; c.405 + 1G > A) have been described in 3 patients with CSS. Three patients with CSS and very distinct clinical presentations are reported here: 1 caused by a germline SDHC large deletion and the others with metastatic GIST and negative genetic investigation for SDHx defects. Two cases (1 and 2) presented with pheochromocytoma (case 1 also with abdominal paraganglioma) and metastatic GIST. Although these 2 cases fulfilled the diagnostic criteria for CSS, the genetic investigation for SDHx PVs by next-generation sequencing and multiplex ligation-dependent probe amplification was negative. Case 3 had a large abdominal paraganglioma and a small low-grade GIST not associated with recurrence or metastasis. This case harbored a germline SDHC exon 3 deletion, not previously reported. In conclusion, CSS is a rare and morbid disease with distinct clinical presentations and genetic heterogeneity, which can contribute to underdiagnosis.

Sudden Cardiac Arrest: A Rare Clinical Presentation of Primary Aldosteronism.

Sudden cardiac arrest (SCA) may be related to reversible causes in up to 50% of cases, such as electrolyte imbalances. Primary aldosteronism (PA) is characterized by excessive autonomic aldosterone production and can present with hypokalemia. We present an uncommon case of a 36-year-old woman who was diagnosed with PA after two episodes of ventricular fibrillation, secondary to severe hypokalemia.

Embryonic stem cell factor FOXD3 (Genesis) defects in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms, believed to originate from the interstitial cells of Cajal (ICC), often caused by overexpression of tyrosine kinase receptors (TKR) KIT or PDGFRA. Here, we present evidence that the embryonic stem cell factor FOXD3, first identified as 'Genesis' and involved in both gastrointestinal and neural crest cell development, is implicated in GIST pathogenesis; its involvement is investigated both in vitro and in zebrafish and a mouse model of FOXD3 deficiency. Samples from a total of 58 patients with wild-type GISTs were used for molecular analyses, including Sanger sequencing, comparative genomic hybridization, and methylation analysis. Immunohistochemistry and western blot evaluation were used to assess FOXD3 expression. Additionally, we conducted in vitro functional studies in tissue samples and in transfected cells to confirm the pathogenicity of the identified genetic variants. Germline partially inactivating FOXD3 sequence variants (p.R54H and p.Ala88_Gly91del) were found in patients with isolated GISTs. Chromosome 1p loss was the most frequent chromosomal abnormality identified in tumors. In vitro experiments demonstrate the impairment of FOXD3 in the presence of those variants. Animal studies showed disruption of the GI neural network and changes in the number and distribution in the ICC. FOXD3 suppresses KIT expression in human cells; its inactivation led to an increase in ICC in zebrafish, as well as mice, providing evidence for a functional link between FOXD3 defects and KIT overexpression leading to GIST formation.

ß-Catenin-Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer.

Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent ß-catenin-activating mutations. Here, we demonstrated that ACC differentiation is maintained by a balance between nuclear, tissue-specific ß-catenin-containing complexes, and the epigenome. On chromatin, ß-catenin bound master adrenal transcription factor SF1 and hijacked the adrenocortical super-enhancer landscape to maintain differentiation in CIMP-high ACC; off chromatin, ß-catenin bound histone methyltransferase EZH2. SF1/ß-catenin and EZH2/ß-catenin complexes present in normal adrenals persisted through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC expelled SF1/ß-catenin from chromatin and favored EZH2/ß-catenin assembly, erasing differentiation and restraining cancer growth in vitro and in vivo. These studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities. SIGNIFICANCE: Oncogenic ß-catenin can use tissue-specific partners to regulate cellular differentiation programs that can be reversed by epigenetic therapies, identifying epigenetic control of differentiation as a viable target for ß-catenin-driven cancers.

Evidence for a Founder Effect of SDHB Exon 1 Deletion in Brazilian Patients With Paraganglioma.

CONTEXT: Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula. OBJECTIVE: Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs. METHODS: Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint. RESULTS: Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X2 = 29.43; P < 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin. CONCLUSION: The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas.

Retrospective Analysis of Prognostic Factors in Pediatric Patients with Adrenocortical Tumor from Unique Tertiary Center with Long-Term Follow-Up.

Pediatric adrenocortical tumors (PACTs) represent rare causes of malignancies. However, the south/southeast regions of Brazil are known to have a high incidence of PACTs because of the founder effect associated with a germline pathogenic variant of tumor suppressor gene TP53. We aimed to retrospectively analyze the types of variables among hormone production, radiological imaging, tumor staging, histological and genetic features that were associated with the occurrence of malignancy in 95 patients (71% females) with PACTs from a unique center. The worst prognosis was associated with those aged > 3 years (p < 0.05), high serum levels of 11-desoxicortisol (p < 0.001), tumor weight ≥ 200 g (p < 0.001), tumor size ≥ 5 cm (p < 0.05), Weiss score ≥ 5 (p < 0.05), Wieneke index ≥ 3 (p < 0.001) and Ki67 ≥ 15% (p < 0.05). Furthermore, patients with MacFarlane stage IV had an overall survival rate almost two times shorter than patients with other stages (p < 0.001). Additionally, the subtractions of BUB1B-PINK1 (<6.95) expression (p < 0.05) and IGF-IR overexpression (p = 0.0001) were associated with malignant behavior. These results helped identify patients who are likely to have an aggressive course; further multicenter prospective studies are required to confirm our results. In conclusion, PACTs with these patterns of prognostic factors could be treated using an adjuvant approach that may improve the overall survival in such patients.

Pathogenesis of Primary Aldosteronism: Impact on Clinical Outcome.

Primary aldosteronism (PA) is the most common form of secondary arterial hypertension, with a prevalence of approximately 20% in patients with resistant hypertension. In the last decade, somatic pathogenic variants in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 genes, which are involved in maintaining intracellular ionic homeostasis and cell membrane potential, were described in aldosterone-producing adenomas (aldosteronomas). All variants in these genes lead to the activation of calcium signaling, the major trigger for aldosterone production. Genetic causes of familial hyperaldosteronism have been expanded through the report of germline pathogenic variants in KCNJ5, CACNA1H and CLCN2 genes. Moreover, PDE2A and PDE3B variants were associated with bilateral PA and increased the spectrum of genetic etiologies of PA. Of great importance, the genetic investigation of adrenal lesions guided by the CYP11B2 staining strongly changed the landscape of somatic genetic findings of PA. Furthermore, CYP11B2 staining allowed the better characterization of the aldosterone-producing adrenal lesions in unilateral PA. Aldosterone production may occur from multiple sources, such as solitary aldosteronoma or aldosterone-producing nodule (classical histopathology) or clusters of autonomous aldosterone-producing cells without apparent neoplasia denominated aldosterone-producing micronodules (non-classical histopathology). Interestingly, KCNJ5 mutational status and classical histopathology of unilateral PA (aldosteronoma) have emerged as relevant predictors of clinical and biochemical outcome, respectively. In this review, we summarize the most recent advances in the pathogenesis of PA and discuss their impact on clinical outcome.

Presentation, Management, and Outcomes of Urinary Bladder Paraganglioma: Results From a Multicenter Study.

CONTEXT: Urinary bladder paraganglioma (UBPGL) is rare. OBJECTIVE: We aimed to characterize the presentation and outcomes of patients diagnosed with UBPGL. METHODS: We conducted a multicenter study of consecutive patients with pathologically confirmed UBPGL evaluated between 1971 and 2021. Outcomes included repeat bladder surgery, metastases, and disease-specific mortality. RESULTS: Patients (n=110 total; n=56 [51%] women) were diagnosed with UBPGL at a median age of 50 years (interquartile range [IQR], 36-61 years). Median tumor size was 2 cm (IQR, 1-4 cm). UBPGL was diagnosed prior to biopsy in only 37 (34%), and only 69 (63%) patients had evaluation for catecholamine excess. In addition to the initial bladder surgery, 26 (25%) required multiple therapies, including repeat surgery in 10 (9%). Synchronous metastases were present in 9 (8%) patients, and 24 (22%) other patients with UBPGL developed metachronous metastases at a median of 4 years (IQR, 2-10 years) after the initial diagnosis. Development of metachronous metastases was associated with younger age (hazard ratio [HR] 0.97; 95% CI, 0.94-0.99), UBPGL size (HR 1.69; 95% CI, 1.31-2.17), and a higher degree of catecholamine excess (HR 5.48; 95% CI, 1.40-21.39). Disease-specific mortality was higher in patients with synchronous metastases (HR 20.80; 95% CI, 1.30-332.91). Choice of initial surgery, genetic association, sex, or presence of muscular involvement on pathology were not associated with development of metastases or mortality. CONCLUSIONS: Only a minority of patients were diagnosed before biopsy/surgery, reflecting need for better diagnostic strategies. All patients with UBPGL should have lifelong monitoring for development of recurrence and metastases.

Perioperative Management of Pheochromocytomas and Sympathetic Paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia, respectively. PPGLs have the highest degree of heritability among endocrine tumors. Currently, ~40% of individuals with PPGLs have a genetic germline and there are at least 12 different genetic syndromes related to these tumors. Metastatic PPGLs are defined by the presence of distant metastases at sites where chromaffin cells are physiologically absent. Approximately 10% of pheochromocytomas and ~40% of sympathetic paragangliomas are linked to metastases, explaining why complete surgical resection is the first-choice treatment for all PPGL patients. The surgical approach is a high-risk procedure requiring perioperative management by a specialized multidisciplinary team in centers with broad expertise. In this review, we summarize and discuss the most relevant aspects of perioperative management in patients with pheochromocytomas and sympathetic paragangliomas.

Cushing's syndrome due to ectopic adrenocorticotropin secretion by a parotid carcinoma

SUMMARY We report a rare case of Cushing's syndrome in a 37-year-old female who initially presented with localized acinic cell carcinoma of the parotid gland. In January 2014, she underwent a right parotidectomy with facial nerve preservation and adjuvant radiotherapy. In August 2018, she presented a histologically-proven local regional relapse. The patient was considered for salvage surgery with facial nerve sacrifice and remained with no evidence of disease. One year later the patient developed pulmonary dissemination and started to gain weight and developed facial plethora and acne on the face and upper trunk. In a physical examination, the patient presented moon face, buffalo hump, acne and stage 2 hypertension. Biochemical evaluation confirmed ACTH-dependent Cushing's syndrome. IHC for ACTH in the lung biopsy revealed strong positive staining for ACTH confirming a diagnosis of ectopic ACTH secretion by a metastatic parotid acinic cell carcinoma. Ketoconazole (600 mg/d) was started to treat the CS. In addition, as chemotherapy was initiated to treat the metastatic disease. After the fifth cycle of chemotherapy, ketoconazole was suspended and the patient remained in remission of CS for four months, when CS recurred. A unique feature of this case is related to the clinical CS relapse associated with disease progression, which needed prompt treatment with ketoconazole, resulting in a significant improvement in the patient's condition. Although rare, should be attentive for possible CS features in patients with high-grade salivary gland carcinomas, since the diagnosis of ectopic secretion of ACTH may significantly impact their management and outcomes.

Cushing's syndrome due to ectopic adrenocorticotropin secretion by a parotid carcinoma.

We report a rare case of Cushing's syndrome in a 37-year-old female who initially presented with localized acinic cell carcinoma of the parotid gland. In January 2014, she underwent a right parotidectomy with facial nerve preservation and adjuvant radiotherapy. In August 2018, she presented a histologically-proven local regional relapse. The patient was considered for salvage surgery with facial nerve sacrifice and remained with no evidence of disease. One year later the patient developed pulmonary dissemination and started to gain weight and developed facial plethora and acne on the face and upper trunk. In a physical examination, the patient presented moon face, buffalo hump, acne and stage 2 hypertension. Biochemical evaluation confirmed ACTH-dependent Cushing's syndrome. IHC for ACTH in the lung biopsy revealed strong positive staining for ACTH confirming a diagnosis of ectopic ACTH secretion by a metastatic parotid acinic cell carcinoma. Ketoconazole (600 mg/d) was started to treat the CS. In addition, as chemotherapy was initiated to treat the metastatic disease. After the fifth cycle of chemotherapy, ketoconazole was suspended and the patient remained in remission of CS for four months, when CS recurred. A unique feature of this case is related to the clinical CS relapse associated with disease progression, which needed prompt treatment with ketoconazole, resulting in a significant improvement in the patient's condition. Although rare, should be attentive for possible CS features in patients with high-grade salivary gland carcinomas, since the diagnosis of ectopic secretion of ACTH may significantly impact their management and outcomes.

Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients' Survival.

CONTEXT: The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood. OBJECTIVE: To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC. DESIGN AND SETTING: We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance collaborative research group. PATIENTS: Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019. INTERVENTION: Performance (or not) of cytoreductive surgery of the primary tumor. MAIN OUTCOME AND MEASURES: A propensity score match was done using age and the number of organs with metastasis (≤2 or >2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients. RESULTS: Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (hazard ratio [HR] = 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65). CONCLUSION: Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.

Genetic and clinical aspects of paediatric pheochromocytomas and paragangliomas.

OBJECTIVE: Few and conflicting reports have characterized the genetics of paediatric pheochromocytomas and paragangliomas (PPGLs). This study aimed to investigate the clinical and genetic features of Brazilian children with PPGL. PATIENTS AND METHODS: This study included 25 children (52% girls) with PPGL. The median age at diagnosis was 15 years (4-19). The median time of follow-up was 145 months. The genetic investigation was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification and/or target next-generation sequencing panel. RESULTS: Of the 25 children with PPGL, 11 (44%), 4 (16%), 2 (8%), 1 (4%) and 7 (28%) had germline VHL pathogenic variants, SDHB, SDHD, RET and negative genetic investigation, respectively. Children with germline VHL missense pathogenic variants were younger than those with SDHB or SDHD genetic defects [median (range), 12 (4-16) vs. 15.5 (14-19) years; P = .027]. Moreover, 10 of 11 cases with VHL pathogenic variants had bilateral pheochromocytoma (six asynchronous and four synchronous). All children with germline SDHB pathogenic variants presented with abdominal paraganglioma (one of them malignant). The two cases with SDHD pathogenic variants presented with head and neck paraganglioma. Among the cases without a genetic diagnosis, 6 and 2 had pheochromocytoma and paraganglioma, respectively. Furthermore, metastatic PPGL was diagnosed in four (16%) of 25 PPGL. CONCLUSIONS: Most of the paediatric PPGL were hereditary and multifocal. The majority of the affected genes belong to pseudohypoxic cluster 1, with VHL being the most frequently mutated. Therefore, our findings impact surgical management and surveillance of children with PPGL.