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.

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.

Contralateral suppression in adrenal venous sampling predicts clinical and biochemical outcome in primary aldosteronism.

CONTEXT: The role for hormone parameters at adrenal venous sampling (AVS) in predicting clinical and biochemical outcome remains controversial. OBJECTIVE: To investigate the impact of hormone parameters at AVS under cosyntropin stimulation on lateralization and on complete biochemical and clinical outcome. METHODS: We retrospectively evaluated 150 sequential AVS under cosyntropin infusion. Bilateral successful cannulation rate was 83.3% (n = 140), 47.9% bilateral and 52.1% unilateral. The lateralization index (LI), aldosterone/cortisol ratio (A/C) in the dominant adrenal vein (AV), relative aldosterone secretion index (RASI = A/C in AV divided by A/C in inferior vena cava) were assessed. The contralateral suppression (CS) percentage was defined by (1 - nondominant RASI) *100. RESULTS: A nondominant RASI <0.5 (CS >50%) had 86.84% sensitivity and 92.96% specificity to predict contralateral lateralization. An A/C ratio in dominant AV >5.9 (74.67% sensitivity and 80% specificity) and dominant RASI >4.7 (35.21% sensitivity and 88.06% specificity) had a worst performance to predict ipsilateral lateralization. Complete biochemical and clinical cure were significantly more frequent in the patients with CS >50% [98.41% vs. 42.86% (p < 0.001) and 41.94% vs. 0% (p < 0.001)]. CS correlated with high aldosterone at diagnosis (p < 0.001) and low postoperative aldosterone levels at 1 month (p = 0.019). Postoperative biochemical hypoaldosteronism was more frequent in patients with CS >50% (70% vs. 16.67%, p = 0.014). In multivariable analysis, a CS >50% was associated with complete biochemical cure (OR 125, 95%CI 11.904-5,000; p = 0.001) and hypertension remission (OR 12.19, 95%CI 2.074-250; p = 0.023). CONCLUSION: A CS >50% was an independent predictor of complete clinical and biochemical cure. Moreover, it can predict unilateral PA and postoperative biochemical hypoaldosteronism. Our findings underscore the usefulness of CS for clinical decision-making.

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.

Efficacy of Oral Furosemide Test for Primary Aldosteronism Diagnosis.

Context: Confirmatory tests represent a fundamental step in primary aldosteronism (PA) diagnosis, but they are laborious and often require a hospital environment due to the risks involved. Objective: To evaluate the efficacy of oral furosemide as a new confirmatory test for PA diagnosis. Methods: We prospectively evaluated the diagnostic performance of 80 mg of oral furosemide in 64 patients with PA and 22 with primary hypertension (controls). Direct renin concentration (DRC) was measured before, and 2 hours and 3 hours after the oral furosemide. In addition, the oral furosemide test was compared with 2 other confirmatory tests: the furosemide upright test (FUT) and saline infusion test (SIT) or captopril challenge test (CCT) in all patients with PA. Results: The cut-off of 7.6 µU/mL for DRC at 2 hours after oral furosemide had a sensitivity of 92%, specificity of 82%, and accuracy of 90% for PA diagnosis. In 5 out of 6 controls with low-renin hypertension, which might represent a PA spectrum, renin remained suppressed. Excluding these 6 controls with low-renin hypertension, the DRC cut-off of 10 µU/mL at 2 hours after oral furosemide had a sensitivity of 95.3%, specificity of 93.7% and accuracy of 95% for PA diagnosis. DRC after 3 hours of oral furosemide did not improve diagnostic performance. Using the cut-off of 10 µU/mL, the oral furosemide test and the FUT were concordant in 62 out of 64 (97%) patients with PA. Only 4 out of 64 cases with PA (6.4%) ended the oral furosemide test with potassium <3.5 mEq/L. Hypotension was not evidenced in any patient with PA during the test. Conclusion: The oral furosemide test was safe, well-tolerated and represents an effective strategy for PA investigation.

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.

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.

Intra-individual Variability of Serum Aldosterone and Implications for Primary Aldosteronism Screening.

CONTEXT: Primary aldosteronism (PA) screening relies on an elevated aldosterone to renin ratio with a minimum aldosterone level, which varies from 10 to 15 ng/dL (277-415.5 pmol/L) using immunoassay. OBJECTIVE: To evaluate intra-individual coefficient of variation (CV) of aldosterone and aldosterone to direct renin concentration ratio (A/DRC) and its impact on PA screening. METHODS: A total of 671 aldosterone and DRC measurements were performed by the same chemiluminescence assays in a large cohort of 216 patients with confirmed PA and at least 2 screenings. RESULTS: The median intra-individual CV of aldosterone and A/DRC was 26.8% and 26.7%. Almost 40% of the patients had at least one aldosterone level <15 ng/dL, 19.9% had at least 2 aldosterone levels <15 ng/dL, and 16.2% had mean aldosterone levels <15 ng/dL. A lower cutoff of 10 ng/dL was associated with false negative rates for PA screening of 14.3% for a single aldosterone measurement, 4.6% for 2 aldosterone measurements, and only 2.3% for mean aldosterone levels. Considering the minimum aldosterone, true positive rate of aldosterone thresholds was 85.7% for 10 ng/dL and 61.6% for 15 ng/dL. An A/DRC >2 ng/dL/µIU/mL had a true positive rate for PA diagnosis of 94.4% and 98.4% when based on 1 or 2 assessments, respectively. CV of aldosterone and A/DRC were not affected by sex, use of interfering antihypertensive medications, PA lateralization, hypokalemia, age, and number of hormone measurements. CONCLUSION: Aldosterone concentrations had a high CV in PA patients, which results in an elevated rate of false negatives in a single screening for PA. Therefore, PA screening should be based on at least 2 screenings with concomitant aldosterone and renin measurements.

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.

Primary adrenal insufficiency due to bilateral adrenal infarction in COVID-19: a case report.

CONTEXT: Coronavirus disease 2019 (COVID-19) is a proinflammatory and prothrombotic condition, but its impact on adrenal function has not been adequately evaluated. CASE REPORT: A 46-year-old woman presented with abdominal pain, hypotension, skin hyperpigmentation after COVID-19 infection. The patient had hyponatremia, serum cortisol <1.0 ug/dL, ACTH of 807 pg/mL and aldosterone <3 ng/dL. Computed tomography (CT) findings of adrenal enlargement with no parenchymal and minimal peripheral capsular enhancement after contrast were consistent with bilateral adrenal infarction. The patient had autoimmune hepatitis and positive antiphospholipid antibodies, but no previous thrombotic events. The patient was treated with intravenous hydrocortisone, followed by oral hydrocortisone and fludrocortisone. DISCUSSION: Among 115 articles, we identified nine articles, including case reports, of new-onset adrenal insufficiency and/or adrenal hemorrhage/infarction on CT in COVID-19. Adrenal insufficiency was hormonally diagnosed in five cases, but ACTH levels were measured in only three cases (high in one case and normal/low in other two cases). Bilateral adrenal non- or hemorrhagic infarction was identified in five reports (two had adrenal insufficiency, two had normal cortisol levels and one case had no data). Interestingly, the only case with well-characterized new-onset acute primary adrenal insufficiency after COVID-19 had a previous diagnosis of antiphospholipid syndrome. In our case, antiphospholipid syndrome diagnosis was established only after the adrenal infarction triggered by COVID-19. CONCLUSIONS: Our findings support the association between bilateral adrenal infarction and antiphospholipid syndrome triggered by COVID-19. Therefore, patients with positive antiphospholipid antibodies should be closely monitored for symptoms or signs of acute adrenal insufficiency during COVID-19.

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.

New Insights Into Pheochromocytoma Surveillance of Young Patients With VHL Missense Mutations.

CONTEXT: Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by germline mutations in the VHL gene. Guidelines recommend pheochromocytoma (PHEO) biochemical screening should start at age 5 years. OBJECTIVE: Genotype-phenotype correlations in VHL, focusing on PHEO penetrance in children, were studied. DESIGN: We retrospectively evaluated 31 individuals (median age at diagnosis was 26 years) with diagnosed VHL disease. RESULTS: PHEO was diagnosed in six children with VHL. A large PHEO (5 cm) was detected in a 4-year-old boy with p.Gly114Ser mutation. PHEO penetrance was 55% starting at age 4 years. VHL missense mutations were identified in 11 of 22 families (50%), frameshift mutations in four (18.2%), stop codon in three (13.6%), splicing site in two (9.1%), and large gene deletion in two (9.1%). The codon 167 (n = 10) was a hotspot for VHL mutations and was significantly associated with PHEO (90% vs. 38%; P = 0.007). PHEOs and pancreatic neuroendocrine tumors (PNETs) were strongly associated with VHL missense mutations compared with other mutations (89.5% vs. 0% and 73.7% vs. 16.7%; P = 0.0001 and 0.002, respectively). In contrast, pancreatic cysts (91.7% vs. 26.3%; P = 0.0001), renal cysts (66.7% vs. 26.3%; P = 0.027), and central nervous system hemangioblastomas (91.7% vs. 47.3%; P = 0.012) were more frequent in VHL with nonmissense mutations. CONCLUSION: VHL missense mutations were highly associated with PHEO and PNETs. Our data support that in children with VHL harboring missense mutations, biochemical screening for PHEO should be initiated at diagnosis.