Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up

•This updated ESMO Clinical Practice Guideline provides key recommendations on the management of adrenal cancer.•Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe.•Detailed guidance on diagnosis, classification, treatment and follow-up is provided for both adrenocortical carcinoma and malignant phaeochromocytoma.•Recommendations are provided in the text, including levels of evidence and grades of recommendation, where applicable.•Due to the rarity of the adrenocortical carcinoma and malignant phaeochromocytoma, there is a clear recommendation to consult expert centres. Two different primary malignancies can arise from the adrenal gland: adrenocortical carcinoma (ACC) from the adrenal cortex and malignant phaeochromocytoma from the adrenal medulla. Both malignancies are rare. ACC has an estimated incidence of ∼0.5-2 new cases per million people per year.1Kerkhofs T.M. Verhoeven R.H. Van der Zwan J.M. et al.Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993.Eur J Cancer. 2013; 49: 2579-2586Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar,2Kebebew E. Reiff E. Duh Q.Y. et al.Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress?.World J Surg. 2006; 30: 872-878Crossref PubMed Scopus (318) Google Scholar Phaeochromocytomas are catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia. The latter are usually called paraganglioma, leading to the combined term phaeochromocytomas and paragangliomas (PPGLs). The detected incidence of PPGLs is commonly reported at 2-8 per million per year3Pacak K. Eisenhofer G. Ahlman H. et al.Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.Nat Clin Pract Endocrinol Metab. 2007; 3: 92-102Crossref PubMed Scopus (517) Google Scholar (supplementary information, available at https://doi.org/10.1016/j.annonc.2020.08.2099). All patients with suspected and proven ACC or PPGL should be discussed in a multidisciplinary expert team meeting, at least at the time of initial diagnosis (ideally before surgery) and in case of progressive disease. Every patient with (suspected) ACC or PPGL should undergo careful clinical assessment, including case history, clinical examination for symptoms and signs of adrenal hormone excess. For more details on this topic, we refer to more comprehensive guidelines and reviews.3Pacak K. Eisenhofer G. Ahlman H. et al.Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.Nat Clin Pract Endocrinol Metab. 2007; 3: 92-102Crossref PubMed Scopus (517) Google Scholar, 4Fassnacht M. Dekkers O.M. Else T. et al.European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2018; 179: G1-G46Crossref PubMed Scopus (403) Google Scholar, 5Lenders J.W. Duh Q.Y. Eisenhofer G. et al.Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2014; 99: 1915-1942Crossref PubMed Scopus (1471) Google Scholar, 6Amar L. Servais A. Gimenez-Roqueplo A.P. et al.Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma.J Clin Endocrinol Metab. 2005; 90: 2110-2116Crossref PubMed Scopus (283) Google Scholar, 7Fassnacht M. Libe R. Kroiss M. Allolio B. Adrenocortical carcinoma: a clinician's update.Nat Rev Endocrinol. 2011; 7: 323-335Crossref PubMed Scopus (302) Google Scholar, 8Mansmann G. Lau J. Balk E. et al.The clinically inapparent adrenal mass: update in diagnosis and management.Endocr Rev. 2004; 25: 309-340Crossref PubMed Scopus (602) Google Scholar The aims of hormonal evaluation are multiple: (i) hormone assays provide orientation to the nature of the adrenal mass and can be useful to assess presence of malignancy; (ii) a phaeochromocytoma should always be ruled out, because these tumours can induce life-threatening crises, requiring specific management before any intervention; (iii) massive adrenocortical steroid excess can impact short-term survival and quality of life (QoL), requiring specific treatments to block impacts of hormonal excess; (iv) abnormal hormone secretions may serve as biological markers for the follow-up of patients; (v) in case of large bilateral adrenal masses, a systematic assessment of adrenal function is recommended to rule out adrenal insufficiency. Precise hormone assays have been detailed in recent guideline statements,4Fassnacht M. Dekkers O.M. Else T. et al.European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2018; 179: G1-G46Crossref PubMed Scopus (403) Google Scholar,5Lenders J.W. Duh Q.Y. Eisenhofer G. et al.Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2014; 99: 1915-1942Crossref PubMed Scopus (1471) Google Scholar,9Plouin P.F. Amar L. Dekkers O.M. et al.European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.Eur J Endocrinol. 2016; 174: G1-G10Crossref PubMed Scopus (251) Google Scholar,10Fassnacht M. Arlt W. Bancos I. et al.Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2016; 175: G1-G34Crossref PubMed Scopus (853) Google Scholar and are summarised in Table 1.Table 1Diagnostic work-up of (suspected) adrenal- or paraganglioma-related malignanciesSpecific questionAssaysIndication(Suspected) ACC Exclusion of glucocorticoid excess?1 mg dexamethasone suppression testAll adrenal masses with no overt Cushing (clinically) Characterisation of glucocorticoid excess?1 mg dexamethasone suppression testFree cortisol in 24-h urineBasal ACTH (plasma)Adrenal masses with clinical signs of Cushing or pathological 1 mg dexamethasone test Sex steroids and steroid precursors excess?DHEA-S17-OH progesteroneAndrostenedioneTestosterone (only in women)17-beta-oestradiol (only in men and postmenopausal women)11-deoxycortisol (if available)Any adrenal mass suspected to be an ACC Mineralocorticoid excess?PotassiumAldosterone/renin ratioAny adrenal masses with hypertension and/or hypokalaemia Extension of the adrenal tumour and evidence for metastases?CT or MRI of abdomen, pelvis and chest (or FDG-PET/CT including full-dose CT)All suspected ACCs Evidence of cerebral metastases?Cerebral MRTOnly if cerebral metastases are suspected Evidence of bone metastasesFDG-PET/CT, bone scan, bone CT or bone MRIOnly if skeletal metastases are suspected(Suspected) PPGL Catecholamine excess?Fractionated metanephrines in 24-h urine or plasma-free metanephrines and methoxytyramineAll adrenal masses and all paraganglioma Extension of the adrenal tumour?CT or MRI of abdomenAll biochemically confirmed phaeochromocytoma Evidence of thoracic metastases?Chest CT (or PET/CT including full-dose CT)All PPGL patients with a 'high risk of metastases'aThe authors suggest being at a 'high risk of metastases' applies to all patients who fulfil one or more of the following criteria: adrenal phaeochromocytoma ≥5 cm or any extra-adrenal paraganglioma or known SDHB germline mutation or plasma methoxytyramine more than threefold above the upper reference limit. Evidence of cerebral metastases?Cerebral MRTOnly if cerebral metastases are suspected Evidence of bone metastasesFDG-PET/CT, DOTATATE-PET/CT, bone scan, bone CT or bone MRIOnly if skeletal metastases are suspectedbSome authors are in favour of carrying out functional imaging to detect bone metastases in all PPGL patients. Additional functional imaging?At least one functional whole-body imaging (i.e. FDG-PET, DOTATATE-PET, MIBG scintigraphy)In all PPGL patients with a 'high risk of metastases'aThe authors suggest being at a 'high risk of metastases' applies to all patients who fulfil one or more of the following criteria: adrenal phaeochromocytoma ≥5 cm or any extra-adrenal paraganglioma or known SDHB germline mutation or plasma methoxytyramine more than threefold above the upper reference limit. Radionuclide therapy possible?MIBG scintigraphy and somatostatin-based imaging (e.g. DOTATATE-PET/CT)In all PPGL patients with evidence for metastases17-OH, 17-hydroxy; ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; CT, computed tomography; DHEA-S, dehydroepiandrosterone sulfate; FDG-PET, 2-fluoro-2-deoxy-d-glucose-positron electron tomography; MIBG, meta-iodobenzylguanidine; MRI, magnetic resonance imaging; MRT, magnetic resonance tomography; PPGL, phaeochromocytoma and paraganglioma; SDHB, succinate dehydrogenase complex iron sulfur subunit B.a The authors suggest being at a 'high risk of metastases' applies to all patients who fulfil one or more of the following criteria: adrenal phaeochromocytoma ≥5 cm or any extra-adrenal paraganglioma or known SDHB germline mutation or plasma methoxytyramine more than threefold above the upper reference limit.b Some authors are in favour of carrying out functional imaging to detect bone metastases in all PPGL patients. Open table in a new tab 17-OH, 17-hydroxy; ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; CT, computed tomography; DHEA-S, dehydroepiandrosterone sulfate; FDG-PET, 2-fluoro-2-deoxy-d-glucose-positron electron tomography; MIBG, meta-iodobenzylguanidine; MRI, magnetic resonance imaging; MRT, magnetic resonance tomography; PPGL, phaeochromocytoma and paraganglioma; SDHB, succinate dehydrogenase complex iron sulfur subunit B. For all adrenal masses, the diagnosis of phaeochromocytoma should be systematically assessed by measuring plasma-free or urinary-fractionated metanephrines [V, A].5Lenders J.W. Duh Q.Y. Eisenhofer G. et al.Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2014; 99: 1915-1942Crossref PubMed Scopus (1471) Google Scholar,10Fassnacht M. Arlt W. Bancos I. et al.Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2016; 175: G1-G34Crossref PubMed Scopus (853) Google Scholar Additional measurements of plasma methoxytyramine, a biomarker now increasingly available, provide useful information to assess the likelihood of malignancy.11Eisenhofer G. Lenders J.W. Siegert G. et al.Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status.Eur J Cancer. 2012; 48: 1739-1749Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar In cases of suspected ACC, an extensive steroid hormone work-up is recommended, assessing gluco-, mineralo-, sex- and precursor-steroids ([V, B] (Table 1)).12Arlt W. Biehl M. Taylor A.E. et al.Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors.J Clin Endocrinol Metab. 2011; 96: 3775-3784Crossref PubMed Scopus (305) Google Scholar, 13Taylor D.R. Ghataore L. Couchman L. et al.A 13-steroid serum panel based on LC-MS/MS: use in detection of adrenocortical carcinoma.Clin Chem. 2017; 63: 1836-1846Crossref PubMed Scopus (66) Google Scholar, 14Hines J.M. Bancos I. Bancos C. et al.High-resolution, accurate-mass (HRAM) mass spectrometry urine steroid profiling in the diagnosis of adrenal disorders.Clin Chem. 2017; 63: 1824-1835Crossref PubMed Scopus (63) Google Scholar, 15Schweitzer S. Kunz M. Kurlbaum M. et al.Plasma steroid metabolome profiling for the diagnosis of adrenocortical carcinoma.Eur J Endocrinol. 2018; 180: 117-125Crossref Scopus (40) Google Scholar, 16Kerkhofs T.M. Kerstens M.N. Kema I.P. et al.Diagnostic value of urinary steroid profiling in the evaluation of adrenal tumors.Horm Cancer. 2015; 6: 168-175Crossref PubMed Scopus (65) Google Scholar For best patient care, adequate visualisation of the tumour and potential metastases is essential. For differential diagnosis of an adrenal mass, computed tomography (CT) and magnetic resonance imaging (MRI) are both effective [IV, A]. Although these methods cannot determine the exact entity of the mass, both are able to correctly diagnose a subset of benign tumours—at least when carried out according to state-of-the-art criteria. The single best criterion to diagnose a benign tumour (e.g. adenoma) remains Hounsfield units ≤10 in an unenhanced CT.17Dinnes J. Bancos I. Ferrante di Ruffano L. et al.Management of endocrine disease: imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis.Eur J Endocrinol. 2016; 175: R51-R64Crossref PubMed Scopus (113) Google Scholar However, other imaging criteria, such as rapid washout in 10- or 15-min delayed contrast-enhanced CT, signal intensity loss using opposed-phase MRI, and low 2-fluorine-18 [18F]fluoro-2-deoxy-d-glucose (FDG) uptake in [18F]FDG-positron electron tomography (PET)/CT are also suggestive of a benign tumour. Most ACCs show an inhomogeneous appearance in CT or MRI with irregular margins and irregular enhancement of solid components after intravenous injection of contrasted agent. Detection of local invasion or tumour extension into the inferior vena cava, as well as lymph node or other metastases—including lung and liver—is mandatory before planning any surgery. Therefore, cross-sectional imaging of the chest, abdomen and pelvis is required preoperatively [V, A]. For PPGLs, conventional radiological imaging can be important to determine the presence of metastases. However, neither CT nor MRI can be used to determine whether PPGLs are benign or malignant. Malignancy can only be determined from the presence of metastatic lesions at sites where chromaffin cells are normally absent. Without such evidence, all PPGLs should be considered potentially malignant, with risk dependent on several factors as outlined below. There are a number of functional imaging modalities available for patients with PPGLs (supplementary File, available at https://doi.org/10.1016/j.annonc.2020.08.2099). The indication is twofold: (i) best tumour staging in patients with suspected metastases (e.g. by conventional imaging) or with presumably high risk for metastases; (ii) to evaluate the option of a radionuclide-based therapy in patients with nonresectable PPGL. For assessments of metastatic risk for the first indication the authors suggest the presence of one or more of the following criteria:•tumour size ≥5 cm;•any extra-adrenal paraganglioma;•known succinate dehydrogenase complex iron sulfur subunit B (SDHB) germline mutation; or•plasma methoxytyramine more than threefold above the upper cut-offs of reference intervals. For imaging-based diagnosis of metastatic PPGLs, it is important to avoid confusing metastases with multiple primary tumours that often occur in patients with hereditary PPGL syndromes. Additionally, local recurrences should not be misdiagnosed as metastases. Biopsy of adrenal tumours is usually contraindicated because of the risk of tumour spillage, poor diagnostic power to discriminate benign from malignant adrenocortical tumours and risk of hypertensive crises in phaeochromocytoma. However, a biopsy might be indicated in an adrenal mass without any hormone excess in patients with a history of extra-adrenal cancers to exclude or prove an adrenal metastasis of an extra-adrenal malignancy, and in patients in whom tumour sequencing is desired. The pathological differential diagnosis of adrenal neoplasias in both biopsied and resected specimens is primarily based on morphological features requiring an experienced pathologist [IV, A]. Preferably, a panel of immunohistochemical markers should be applied to aid diagnosis; for example, steroidogenesis factor 1 (SF1) or, alternatively, inhibin-alpha, calretinin and melan-A for identification of adrenocortical tumours and chromogranin A for identification of PPGL [IV, A]. Staining for tyrosine hydroxylase and synaptophysin may also be helpful to highlight PPGL, but positive results for synaptophysin are also possible in adrenocortical tumours. The differential diagnosis between ACC and adenoma may be challenging as no single marker indicates malignancy. The most widely used diagnostic score has been introduced by Weiss18Weiss L.M. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors.Am J Surg Pathol. 1984; 8: 163-169Crossref PubMed Scopus (768) Google Scholar,19Weiss L.M. Medeiros L.J. Vickery Jr., A.L. Pathologic features of prognostic significance in adrenocortical carcinoma.Am J Surg Pathol. 1989; 13: 202-206Crossref PubMed Scopus (653) Google Scholar and includes nine parameters (supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.08.2099) [IV, A]. A score of ≥3 suggests malignancy. In addition, the Ki-67 labelling index, as a marker of proliferative activity, may be useful and is very helpful for prognostic purposes (supplementary Tables S2 and S3, available at https://doi.org/10.1016/j.annonc.2020.08.2099). For phaeochromocytomas, the situation is similarly demanding. Tumour size, SDHB mutation status, extra-adrenal location and plasma methoxytyramine may all be used to indicate risk of metastasis. However, there is no single histological or immunohistochemical parameter that can predict the clinical behaviour of PPGL. Nevertheless, several histological scoring systems have been developed.20Thompson L.D. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases.Am J Surg Pathol. 2002; 26: 551-566Crossref PubMed Scopus (494) Google Scholar, 21Kimura N. Takayanagi R. Takizawa N. et al.Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma.Endocr Relat Cancer. 2014; 21: 405-414Crossref PubMed Scopus (193) Google Scholar, 22Koh J.M. Ahn S.H. Kim H. et al.Validation of pathological grading systems for predicting metastatic potential in pheochromocytoma and paraganglioma.PLoS One. 2017; 12: e0187398Crossref PubMed Scopus (45) Google Scholar, 23Pierre C. Agopiantz M. Brunaud L. et al.COPPS, a composite score integrating pathological features, PS100 and SDHB losses, predicts the risk of metastasis and progression-free survival in pheochromocytomas/paragangliomas.Virchows Arch. 2019; 474: 721-734Crossref PubMed Scopus (19) Google Scholar All these scores have value but none of them has reached general acceptance. Therefore, according to the current World Health Organization (WHO) classification, all PPGLs should be considered to have some malignant potential.24Lloyd R.V. Osamura R.Y. Klöppel G. Rosai J. WHO Classification of Tumours of Endocrine Organs. IARC, Lyon, France2017Google Scholar A definitive diagnosis of malignancy can only be made by the presence of metastases at sites where chromaffin tissue is normally absent (e.g. liver, bone, lungs or lymph nodes), assessed by pathology or imaging, in particular functional imaging. Molecular characterisation of ACC (supplementary File, available at https://doi.org/10.1016/j.annonc.2020.08.2099) and PPGL is an active area of ongoing research. The gene encoding subunit B of the SDHB complex is by far the most important molecular contributor to malignant PPGL, with at least 40% of all cases of metastatic PPGLs carrying mutations of this gene.25Brouwers F.M. Eisenhofer G. Tao J.J. et al.High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing.J Clin Endocrinol Metab. 2006; 91: 4505-4509Crossref PubMed Scopus (256) Google Scholar Inactivation of SDHB reduces function of the succinate dehydrogenase complex, leading to activation of the hypoxia-inducible pathway and a pseudohypoxic state characterised by increased angiogenesis, growth and expression of mitogenic factors,26Jochmanova I. Yang C. Zhuang Z. Pacak K. Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction.J Natl Cancer Inst. 2013; 105: 1270-1283Crossref PubMed Scopus (126) Google Scholar but also to DNA hypermethylation, which is believed to provide a further drive to metastatic progression.27Letouze E. Martinelli C. Loriot C. et al.SDH mutations establish a hypermethylator phenotype in paraganglioma.Cancer Cell. 2013; 23: 739-752Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar At least 35% of PPGLs result from germline mutations of over 18 tumour-susceptibility genes identified to date,28Dahia P.L. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity.Nat Rev Cancer. 2014; 14: 108-119Crossref PubMed Scopus (353) Google Scholar, 29Neumann H.P. Young Jr., W.F. Krauss T. et al.65 years of the double helix: genetics informs precision practice in the diagnosis and management of pheochromocytoma.Endocr Relat Cancer. 2018; 25: T201-T219Crossref PubMed Scopus (39) Google Scholar, 30Crona J. Taieb D. Pacak K. New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification.Endocr Rev. 2017; 38: 489-515Crossref PubMed Scopus (177) Google Scholar, 31Toledo R.A. Burnichon N. Cascon A. et al.Consensus statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas.Nat Rev Endocrinol. 2017; 13: 233-247Crossref PubMed Scopus (149) Google Scholar, 32Oudijk L. Gaal J. Koopman K. de Krijger R.R. An update on the histology of pheochromocytomas: how does it relate to genetics?.Horm Metab Res. 2019; 51: 403-413Crossref PubMed Scopus (5) Google Scholar, 33Crona J. Lamarca A. Ghosal S. et al.Genotype-phenotype correlations in pheochromocytoma and paraganglioma.Endocr Relat Cancer. 2019; 26: 539-550Crossref PubMed Scopus (63) Google Scholar with those resulting in stabilisation of hypoxia-inducible factors 1α and 2α (HIF1α and HIF2α) carrying a higher risk of metastatic disease than those due to other mutations (supplementary Table S4, available at https://doi.org/10.1016/j.annonc.2020.08.2099). Risk is particularly high, reaching 70% in patients with PPGL due to mutations in the SDHB gene.34Amar L. Bertherat J. Baudin E. et al.Genetic testing in pheochromocytoma or functional paraganglioma.J Clin Oncol. 2005; 23: 8812-8818Crossref PubMed Scopus (554) Google Scholar The vast majority of all metastatic PPGLs, including disease due to SDHB mutations, develop from noradrenergic or dopaminergic PPGLs with poorly developed secretory pathways. Nevertheless, a small minority of about 10% of metastatic PPGLs develop from adrenal adrenergic tumours that are characterised by production of epinephrine, as manifested by increased plasma or urinary metanephrine.35Sue M. Martucci V. Frey F. et al.Lack of utility of SDHB mutation testing in adrenergic metastatic phaeochromocytoma.Eur J Endocrinol. 2015; 172: 89-95Crossref PubMed Scopus (14) Google Scholar Of note, metastatic disease may only become apparent many years after the primary tumour is resected. This and later development in some patients of locally recurrent disease underscore the importance of recommendations for follow-up of all patients with previously resected PPGLs.9Plouin P.F. Amar L. Dekkers O.M. et al.European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.Eur J Endocrinol. 2016; 174: G1-G10Crossref PubMed Scopus (251) Google Scholar •All patients with an adrenal tumour suspected to be an ACC or a phaeochromocytoma should undergo careful clinical assessment for signs of adrenal hormone excess.•All patients with suspected and proven ACC or PPGL should be discussed in a multidisciplinary expert team meeting, at least at the time of initial diagnosis and in case of progressive disease.•All patients with suspected ACC require a comprehensive endocrine work-up to identify potential autonomous excess of glucocorticoids, sex hormones, mineralocorticoids and adrenocortical steroid hormone precursors [IV, A].•Standard imaging for patients with suspected ACC includes at least abdominal CT or MRI and chest CT (or [18F]FDG-PET/CT) [IV, A].•Biopsies of suspected ACC are usually not informative and should be avoided.•Histopathologically, ACC is defined by a Weiss score ≥3 [IV, A]. Histological diagnosis should be carried out by an experienced endocrine pathologist. Ki-67 index helps to stratify the risk of recurrence.•All patients with suspected PPGL require the measurement of plasma or urinary metanephrines [V, A]. Suspicion of disease is primarily based on (i) the presence of signs, symptoms or other manifestations of presumed catecholamine excess; (ii) incidental adrenal mass; or (iii) routine screening due to high risk associated with hereditary predisposition or history of PPGLs.•In all patients with 'high risk of metastases' (see definition above), a chest CT and at least one functional whole-body imaging [e.g. FDG-PET, DOTATATE-PET, iodine-123 meta-iodobenzylguanidine ([123I]MIBG) scintigraphy] is recommended in addition to abdominal imaging.•Biopsies of suspected PPGL are contraindicated in most circumstances.•Malignant PPGLs are defined by the presence of metastasis. However, all PPGLs are considered to have some malignant potential. In the assessment of disease stage, the authors recommend the tumour, node, metastasis (TNM) classification proposed by the European Network for the Study of Adrenal Tumours (ENSAT) (supplementary Table S5, available at https://doi.org/10.1016/j.annonc.2020.08.2099) [IV, A],36Fassnacht M. Johanssen S. Quinkler M. et al.Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a revised TNM classification.Cancer. 2009; 115: 243-250Crossref PubMed Scopus (503) Google Scholar because this system seems to be superior to other staging systems and is adapted by the Union for International Cancer Control (UICC) and WHO.24Lloyd R.V. Osamura R.Y. Klöppel G. Rosai J. WHO Classification of Tumours of Endocrine Organs. IARC, Lyon, France2017Google Scholar As indicated above for correct staging, at least a CT of the chest, abdomen and pelvis (or FDG-PET/CT including full-dose CT) is required. Recent data suggest that lymph node involvement correlates with stage IV rather than stage III behaviour.37Libe R. Borget I. Ronchi C.L. et al.Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study.Ann Oncol. 2015; 26: 2119-2125Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Overall, the prognosis of ACC is limited. However, prospective data suggest that in patients with complete resection of a localised stage II tumour 5-year overall survival (OS) can be as high as 90%.38Fassnacht M. Johanssen S. Fenske W. et al.Improved survival in patients with stage II adrenocortical carcinoma followed up prospectively by specialized centers.J Clin Endocrinol Metab. 2010; 95: 4925-4932Crossref PubMed Scopus (122) Google Scholar In metastatic ACC, median survival is about 15 months. However, even in this group, there is a subgroup of patients with long-term survival.36Fassnacht M. Johanssen S. Quinkler M. et al.Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a revised TNM classification.Cancer. 2009; 115: 243-250Crossref PubMed Scopus (503) Google Scholar,37Libe R. Borget I. Ronchi C.L. et al.Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study.Ann Oncol. 2015; 26: 2119-2125Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar It is well established that disease stage and margin-free resection are currently the most important prognostic factors in ACC. For the European Society of Endocrinology (ESE)–ENSAT guidelines, a comprehensive literature search for prognostic factors has been carried out and only the proliferation marker Ki-67 and glucocorticoid excess showed a robust association with prognosis [IV, A] (supplementary Table S2, available at https://doi.org/10.1016/j.annonc.2020.08.2099).4Fassnacht M. Dekkers O.M. Else T. et al.European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2018; 179: G1-G46Crossref PubMed Scopus (403) Google Scholar,39Vanbrabant T. Fassnacht M. Assie G. Dekkers O.M. Influence of hormonal functional status on survival in adrenocortical carcinoma: systematic review and meta-analysis.Eur J Endocrinol. 2018; 179: 429-436Crossref PubMed Scopus (39) Google Scholar Many other (molecular) markers for aggressiveness and survival have been recently proposed, but their clinical use requires validation. In 2017, the WHO proposed a tumour staging system for PPGL (supplementary Table S6, available at https://doi.org/10.1016/j.annonc.2020.08.2099).24Lloyd R.V. Osamura R.Y. Klöppel G. Rosai J. WHO Classification of Tumours of Endocrine Organs. IARC, Lyon, France2017Google Scholar Although this staging classification remains to be validated, the authors