Predictive model of pheochromocytoma based on the imaging features of the adrenal tumours.

The purpose of our study was to develop a predictive model to rule out pheochromocytoma among adrenal tumours, based on unenhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) features. We performed a retrospective multicentre study of 1131 patients presenting with adrenal lesions including 163 subjects with histological confirmation of pheochromocytoma (PHEO), and 968 patients showing no clinical suspicion of pheochromocytoma in whom plasma and/or urinary metanephrines and/or catecholamines were within reference ranges (non-PHEO). We found that tumour size was significantly larger in PHEO than non-PHEO lesions (44.3 ± 33.2 versus 20.6 ± 9.2 mm respectively; P < 0.001). Mean unenhanced CT attenuation was higher in PHEO (52.4 ± 43.1 versus 4.7 ± 17.9HU; P < 0.001). High lipid content in CT was more frequent among non-PHEO (83.6% versus 3.8% respectively; P < 0.001); and this feature alone had 83.6% sensitivity and 96.2% specificity to rule out pheochromocytoma with an area under the receiver operating characteristics curve (AUC-ROC) of 0.899. The combination of high lipid content and tumour size improved the diagnostic accuracy (AUC-ROC 0.961, sensitivity 88.1% and specificity 92.3%). The probability of having a pheochromocytoma was 0.1% for adrenal lesions smaller than 20 mm showing high lipid content in CT. Ninety percent of non-PHEO presented loss of signal in the "out of phase" MRI sequence compared to 39.0% of PHEO (P < 0.001), but the specificity of this feature for the diagnosis of non-PHEO lesions low. In conclusion, our study suggests that sparing biochemical screening for pheochromocytoma might be reasonable in patients with adrenal lesions smaller than 20 mm showing high lipid content in the CT scan, if there are no typical signs and symptoms of pheochromocytoma.

Surgical outcomes in the pheochromocytoma surgery. Results from the PHEO-RISK STUDY.

PURPOSE: To identify presurgical and surgical risk factors for postsurgical complications in the pheochromocytoma surgery. METHODS: A retrospective study of pheochromocytomas submitted to surgery in ten Spanish hospitals between 2011 and 2021. Postoperative complications were classified according to Clavien-Dindo scale. RESULTS: One hundred and sixty-two surgeries (159 patients) were included. Preoperative antihypertensive blockade was performed in 95.1% of the patients, being doxazosin in monotherapy (43.8%) the most frequent regimen. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more frequently (49.4% vs 25.0%, P = 0.003) than patients treated with phenoxybenzamine, but no differences in the rate of intraoperative and postsurgical complications were observed. However, patients treated with phenoxybenzamine had a longer hospital stay (12.2 ± 11.16 vs 6.2 ± 6.82, P < 0.001) than those treated with doxazosin. Hypertension resolution was observed in 78.7% and biochemical cure in 96.6% of the patients. Thirty-one patients (19.1%) had postsurgical complications. Prolonged hypotension was the most common, in 9.9% (n = 16), followed by hypoglycaemia in six patients and acute renal failure in four patients. 13.0% of complications had a score ≥3 in the Clavien-Dindo scale. Postsurgical complications were more common in patients with diabetes, cerebrovascular disease, higher plasma glucose levels, higher urinary free metanephrine and norepinephrine, and with pheochromocytomas larger than 5 cm. CONCLUSION: Preoperative medical treatment and postsurgical monitoring of pheochromocytoma should be especially careful in patients with diabetes, cerebrovascular disease, higher levels of plasma glucose and urine free metanephrine and norepinephrine, and with pheochromocytomas >5 cm, due to the higher risk of postsurgical complications.

Risk factors for intraoperative complications in pheochromocytomas.

We aimed to identify presurgical and surgical risk factors for intraoperative complications in patients with pheochromocytomas. A retrospective study of patients with pheochromocytomas who underwent surgery in ten Spanish hospitals between 2011 and 2021 was performed. One hundred and sixty-two surgeries performed in 159 patients were included. The mean age was 51.6 ± 16.4 years old and 52.8% were women. Median tumour size was 40 mm (range 10-110). Laparoscopic adrenalectomy was performed in 148 patients and open adrenalectomy in 14 patients. Presurgical alpha- and beta-blockade was performed in 95.1% and 51.9% of the surgeries, respectively. 33.3% of the patients (n = 54) had one or more intraoperative complications. The most common complication was the hypertensive crisis in 21.0%, followed by prolonged hypotension in 20.0%, and hemodynamic instability in 10.5%. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more commonly than patients pre-treated with other antihypertensive drugs (51.1% vs 26.5%, P = 0.002). Intraoperative complications were more common in patients with higher levels of urine metanephrine (OR = 1.01 for each 100 µg/24 h, P = 0.026) and normetanephrine (OR = 1.00 for each 100 µg/24 h, P = 0.025), larger tumours (OR = 1.4 for each 10 mm, P < 0.001), presurgical blood pressure > 130/80 mmHg (OR = 2.25, P = 0.027), pre-treated with doxazosin (OR = 2.20, P = 0.023) and who had not received perioperative hydrocortisone (OR = 3.95, P = 0.008). In conclusion, intraoperative complications in pheochromocytoma surgery are common and can be potentially life-threatening. Higher metanephrine and normetanephrine levels, larger tumour size, insufficient blood pressure control before surgery, pre-treatment with doxazosin, and the lack of treatment with perioperative hydrocortisone are associated with higher risk of intraoperative complications.

Guía práctica sobre la evaluación inicial, seguimiento y tratamiento de los incidentalomas adrenales. Grupo de patología adrenal de la Sociedad Española de Endocrinología y Nutrición / Practical guide on the initial evaluation, follow-up, and treatment of adrenal incidentalomas Adrenal Diseases Group of the Spanish Society of Endocrinology and Nutrition

La evaluación inicial de los incidentalomas adrenales se centra en dos objetivos: descartar malignidad y descartar funcionalidad. Para ello se debe realizar una historia clínica detallada, obtener una valoración radiológica adecuada y un estudio bioquímico-hormonal completo. La entidad que más dudas genera, por la falta de consenso en su definición, es la secreción autónoma de cortisol. Nuestra recomendación es que, salvo para valores de cortisol < 1,8 μg/dl en el test de supresión con dexametasona que descartan secreción autónoma de cortisol, y ≥ 5 μg/dl que establecen el diagnóstico; se debe emplear una definición combinada de test de supresión con dexametasona ≥ 3 μg/dl y al menos uno de los siguientes: cortisol libre urinario elevado, ACTH < 10 pg/ml o cortisol nocturno (sérico y/o salival) elevado para establecer el diagnóstico de secreción autónoma de cortisol. En el seguimiento se debe repetir el test de supresión con dexametasona, generalmente de forma anual, individualizando en función de los resultados de las pruebas previas y de la presencia de comorbilidades potencialmente relacionadas con el hipercortisolismo. La prueba radiológica inicial de elección para la caracterización de los incidentalomas adrenales es la tomografía axial computarizada sin contraste, pero no existe acuerdo unánime sobre el seguimiento posterior. Nuestra recomendación general es repetir la prueba de imagen a los 6-12 meses del diagnóstico (en función de las características radiológicas de la lesión). Si la lesión se mantiene estable y no existen características indeterminadas, no serían necesarios más estudios radiológicos. Consideramos que los pacientes con secreción autónoma de cortisol con comorbilidades potencialmente relacionadas con el hipercortisolismo, especialmente si existe un control deficiente y se trata de pacientes jóvenes, se pueden beneficiar de una suprarrenalectomía unilateral. La indicación de suprarrenalectomía unilateral es clara en pacientes con síndromes hormonales manifiestos o sospecha de malignidad. Como conclusión, los incidentalomas adrenales deben ser valorados de forma integral, teniendo en cuenta las posibles manifestaciones clínicas y comorbilidades relacionadas con síndromes hormonales o malignidad; un estudio hormonal completo (teniendo en cuenta las situaciones que pueden conllevar resultados falsamente positivos y negativos) y radiológico adecuado. En base a los resultados de la evaluación inicial se planificará el seguimiento y/o tratamiento

Initial evaluation of adrenal incidentalomas should be aimed at ruling out malignancy and functionality. For this, a detailed clinical history should be taken, and an adequate radiographic assessment and a complete blood chemistry and hormone study should be performed. The most controversial condition, because of the lack of consensus in its definition, is autonomous cortisol secretion. Our recommendation is that, except when cortisol levels < 1.8 μg/dL in the dexamethasone suppression test rule out diagnosis and levels ≥ 5 μg/dL establish the presence of autonomous cortisol secretion, diagnosis should be based on a combined definition of dexamethasone suppression test ≥ 3 μg/dL and at least one of the following: elevated urinary free cortisol, ACTH level < 10 pg/mL, or elevated nocturnal cortisol (in serum and/or saliva). During follow-up, dexamethasone suppression test should be repeated, usually every year, on an individual basis depending on the results of prior tests and the presence of comorbidities potentially related to hypercortisolism. The initial radiographic test of choice for characterization of adrenal incidentalomas is a computed tomography scan without contrast, but there is no unanimous agreement on subsequent monitoring. Our general recommendation is a repeat imaging test 6-12 months after diagnosis (based on the radiographic characteristics of the lesion). If the lesion remains stable and there are no indeterminate characteristics, no additional radiographic studies would be needed. We think that patients with autonomous cortisol secretion with comorbidities potentially related to hypercortisolism, particularly if they are young and there is a poor control, may benefit from unilateral adrenalectomy. The indication for unilateral adrenalectomy is clear in patients with overt hormonal syndromes or suspected malignancy. In conclusion, adrenal incidentalomas require a comprehensive evaluation that takes into account the possible clinical signs and comorbidities related to hormonal syndromes or malignancy; a complete hormone profile (taking into account the conditions that may lead to falsely positive and negative results); and an adequate radiographic study. Monitoring and/or treatment will be decided based on the results of the initial evaluation

Practical guide on the initial evaluation, follow-up, and treatment of adrenal incidentalomas Adrenal Diseases Group of the Spanish Society of Endocrinology and Nutrition. / Guía práctica sobre la evaluación inicial, seguimiento y tratamiento de los incidentalomas adrenales. Grupo de patología adrenal de la Sociedad Española de Endocrinología y Nutrición.

Initial evaluation of adrenal incidentalomas should be aimed at ruling out malignancy and functionality. For this, a detailed clinical history should be taken, and an adequate radiographic assessment and a complete blood chemistry and hormone study should be performed. The most controversial condition, because of the lack of consensus in its definition, is autonomous cortisol secretion. Our recommendation is that, except when cortisol levels <1.8µg/dL in the dexamethasone suppression test rule out diagnosis and levels ≥5µg/dL establish the presence of autonomous cortisol secretion, diagnosis should be based on a combined definition of dexamethasone suppression test ≥3µg/dL and at least one of the following: elevated urinary free cortisol, ACTH level <10 pg/mL, or elevated nocturnal cortisol (in serum and/or saliva). During follow-up, dexamethasone suppression test should be repeated, usually every year, on an individual basis depending on the results of prior tests and the presence of comorbidities potentially related to hypercortisolism. The initial radiographic test of choice for characterization of adrenal incidentalomas is a computed tomography scan without contrast, but there is no unanimous agreement on subsequent monitoring. Our general recommendation is a repeat imaging test 6-12 months after diagnosis (based on the radiographic characteristics of the lesion). If the lesion remains stable and there are no indeterminate characteristics, no additional radiographic studies would be needed. We think that patients with autonomous cortisol secretion with comorbidities potentially related to hypercortisolism, particularly if they are young and there is a poor control, may benefit from unilateral adrenalectomy. The indication for unilateral adrenalectomy is clear in patients with overt hormonal syndromes or suspected malignancy. In conclusion, adrenal incidentalomas require a comprehensive evaluation that takes into account the possible clinical signs and comorbidities related to hormonal syndromes or malignancy; a complete hormone profile (taking into account the conditions that may lead to falsely positive and negative results); and an adequate radiographic study. Monitoring and/or treatment will be decided based on the results of the initial evaluation.

Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients.

BACKGROUND: Nowadays, 65-80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source. METHODS: The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL, the SDH genes, TMEM127, MAX and FH. 99 tumours from patients negative for germline screening were available and tested for RET, VHL, HRAS, EPAS1, MAX and SDHB. RESULTS: Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p=6.62×10(-10)). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p=0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p=2.0×10(-4) and p=0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS. CONCLUSIONS: We recommend prioritising testing for germline mutations in patients with HN-PGLs and T-PGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.