Guideline sources The following summarized guidelines for the evaluation and management of adrenocortical carcinoma (ACC) are prepared by our editorial team based on guidelines from the Canadian Urological Association (CUA 2023), the American Association of Endocrine Surgeons (AAES 2022), the European Reference Network on Rare Adult Solid Cancers (EURACAN/ESMO 2020), the European Society of Endocrinology (ESE 2018), the European Society of Endocrine Surgeons (ESES/ENSAT 2017), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES 2013). 1 2 3 4 5 6 Calculator Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s TNM class Guidelines 1. Classification and risk stratification https://web.pathway.md/diseases/recuSEdsRdEILoF3w 1/7 6/23/23, 2:10 AM Adrenocortical carcinoma Pathway Risk of malignancy: As per AAES 2022 guidelines, consider using washout characteristics on an adrenal protocol CT to stratify the risk of malignancy for adrenal nodules when the non-contrast HU is > 10 and other clinical risk factors for malignancy are not present. Recognize that adrenal protocol CT does not improve diagnostic accuracy for nodules with non-contrast HU < 10 nor does it improve evaluation for pheochromocytoma. C Show 2 more As per ESES 2017 guidelines, regard adrenal mass to be at increased risk of malignancy in the presence of any of the following: multiple hormonal, steroid precursor, or sex hormone oversecretion intratumoral radiological signs of malignancy and/or a diameter > 6 cm evidence of local invasion, suspected metastatic lymph nodes, distant metastasis, and/or high 18F-FDG-PET uptake. A Staging: As per ESMO 2020 guidelines, use the ENSAT-TNM system for the initial staging of ACC. B As per ESE 2018 guidelines, use the European Network for the Study of Adrenal Tumours staging classification at initial diagnosis of ACC. B Prognosis: Take the following factors into account when assessing prognosis and treatment options at initial diagnosis tumor stage resection status ki67 index (or mitotic count) autonomous cortisol secretion patient's general condition. B Reassess prognosis at each evaluation during follow-up to guide treatment strategy. B 2. Diagnostic investigations Clinical assessment: As per CUA 2023 guidelines, elicit a focused history and perform a physical examination to identify signs/symptoms of adrenal hormone excess, adrenal malignancy, and/or extra-adrenal malignancy in patients with an adrenal incidentaloma. E As per ESMO 2020 guidelines, obtain careful clinical assessment for signs of adrenal hormone excess in all patients with suspected ACC. E Diagnostic imaging: obtain at least abdominal CT or MRI and chest CT (or 18F-FDG-PET/CT) in patients with suspected ACC. B Laboratory tests: https://web.pathway.md/diseases/recuSEdsRdEILoF3w 2/7 6/23/23, 2:10 AM Adrenocortical carcinoma Pathway As per CUA 2023 guidelines, obtain serum testing for excess androgen in patients with suspected ACC. E As per AAES 2022 guidelines: Obtain biochemical testing to identify autonomous cortisol secretion in all patients with an adrenal incidentaloma 1 cm. Obtain biochemical evaluation for primary aldosteronism in patients with hypertension or hypokalemia. B Obtain a directed hormonal evaluation in patients with an adrenal mass regardless of history of extra-adrenal malignancy. B As per ESMO 2020 guidelines, obtain a comprehensive endocrine workup to identify potential autonomous excess of glucocorticoids, sex hormones, mineralocorticoids, and adrenocortical steroid hormone precursors in all patients with suspected ACC. B 3. Diagnostic procedures Biopsy and histopathology: As per AAES 2022 guidelines, consider performing an image-guided biopsy of a radiographically indeterminate mass, only after confirming a lack of hormone excess, if the results will change overall disease management. B As per ESMO 2020 guidelines: Avoid performing biopsies of suspected ACC because they are usually not informative. D Define ACC histopathologically by a Weiss score 3. B Make histological diagnosis by an experienced endocrine pathologist. Assess Ki-67 index to stratify the risk of recurrence. E As per ESE 2018 guidelines, confirm the diagnosis of ACC by histopathology. B Show 5 more 4. Medical management Setting of care: As per AAES 2022 guidelines: Treat patients with clinical and radiographic findings consistent with ACC at high-volume multidisciplinary centers to improve recurrence outcomes. B Perform adrenalectomy preferentially by a high-volume adrenal surgeon to optimize outcomes, including lower rates of morbidity and mortality. B As per ESMO 2020 guidelines, discuss all cases of suspected or proven ACC in a multidisciplinary expert team meeting, at least at the time of initial diagnosis and in case of progressive disease. E As per ESES 2017 guidelines: Manage patients with ACC in referral centers with established multidisciplinary teams consisting of surgeons, endocrinologists, oncologists, radiologists, pathologists, nuclear https://web.pathway.md/diseases/recuSEdsRdEILoF3w 3/7 6/23/23, 2:10 AM Adrenocortical carcinoma Pathway medicine physicians, biologists, and geneticists. B Perform surgeries in patients with ACC by surgeons with expertise in adrenal surgery (open and laparoscopic) and with a volume of > 15 adrenalectomies per year (benign and malignant). B Management of locoregional disease (neoadjuvant chemotherapy): do not use neoadjuvant chemotherapy in patients with resectable ACC. D Management of locoregional disease, surgery: As per CUA 2023 guidelines: Consider performing minimally invasive adrenalectomy in patients with suspected ACCs suitable for safe resection without rupturing the tumor capsule. C Consider performing open adrenalectomy in patients with larger ACCs or presenting with locally advanced tumors, lymph node metastases, or tumor thrombus in the renal vein/IVC. B As per AAES 2022 guidelines, perform resection of the primary tumor in patients with systemic disease if all sites of disease are reasonably amenable to resection or local treatment and if performance status allows. Consider performing surgery also in patients with hormone excess medically refractory to steroidogenic inhibition. B Show 3 more As per EURACAN/ESMO 2020 guidelines, perform complete en bloc resection (by a surgeon experienced in adrenal and oncological surgery) of all adrenal tumors suspected to be ACC as the mainstay of a potentially curative approach. E Show 2 more As per ENSAT/ESES 2017 guidelines, perform complete en bloc resection of the ACC with the peritumoral/periadrenal retroperitoneal fat. Do not perform enucleation and partial adrenal resection in patients with suspected ACC. Avoid causing intraoperative tumor capsule rupture or spillage. B Show 8 more As per SAGES 2013 guidelines, prefer minimally invasive adrenalectomy over open surgery for all non-primary adrenal cancer pathology due to less postoperative pain, shorter hospital stay, earlier recovery, and similar long-term outcomes. B Show 8 more Management of locoregional disease (other therapeutic interventions): avoid using ablation or stereotactic radiation as an alternative to adrenalectomy in patients with adrenal lesions. D Management of locoregional disease, adjuvant chemotherapy: As per EURACAN/ESMO 2020 guidelines: Offer adjuvant mitotane in patients at high risk of recurrence (stage III, or R1-RX resection, and/or Ki-67 index > 10%). B Individualize the decision to offer adjuvant therapy in patients at low risk of recurrence (stage I/II, R0 resection, and Ki-67 index 10%). B As per ESE 2018 guidelines, do not use adjuvant therapy in patients with adrenal tumors with uncertain malignant potential. D https://web.pathway.md/diseases/recuSEdsRdEILoF3w 4/7 6/23/23, 2:10 AM Adrenocortical carcinoma Pathway Show 3 more Management of locoregional disease, adjuvant radiotherapy: As per EURACAN/ESMO 2020 guidelines, consider offering adjuvant radiotherapy only on an individualized basis (in addition to mitotane) in patients with R1 or RX resection or in stage III. C As per ESE 2018 guidelines: Insufficient evidence to recommend adjuvant radiation therapy in patients with ACC. Avoid offering routine radiation therapy in patients with stage I-II and R0 resection. I Initiate adjuvant radiation therapy as soon as clinically possible after surgery, if a decision is made to deliver, at the dose of 50-60 Gy to the previous tumor bed in fractionated doses of approximately 2 Gy each. B Management of advanced/metastatic disease, systemic therapy: As per AAES 2022 guidelines, offer neoadjuvant systemic therapy in patients with advanced ACC if R0 surgical resection is not initially feasible. Perform up-front surgical intervention if R0 resection is possible. B As per EURACAN/ESMO 2020 guidelines: Offer mitotane monotherapy or mitotane plus chemotherapy (EDP-M: mitotane with etoposide, doxorubicin, and cisplatin) as first-line therapy in most patients with metastatic ACC. A Consider offering mitotane monotherapy in selected patients, such as with low tumor burden and/or more indolent disease. E As per ESE 2018 guidelines, offer either mitotane monotherapy or mitotane plus EDP (etoposide, doxorubicin, and cisplatin) depending on prognostic parameters in patients with advanced ACC at the time of diagnosis not qualifying for local treatment. B Management of advanced/metastatic disease, surgery: As per EURACAN/ESMO 2020 guidelines, offer surgery and locoregional therapies in addition to systemic therapy in selected patient populations. E Perforn surgery as the treatment of choice only if all tumoral lesions can be removed. B As per ESE 2018 guidelines: Consider performing surgery in patients with limited intra-abdominal metastases at the time of initial diagnosis, if complete resection of all lesions seems feasible. Consider performing adrenal tumor resection in conjunction with therapy aiming at long-term tumor control of other lesions in patients with limited extra-abdominal lesions. Initiate mitotane therapy as soon as clinically possible in all patients. C Avoid performing routine adrenal surgery in patients with widespread metastatic disease at the time of initial diagnosis. D As per ENSAT/ESES 2017 guidelines, consider performing surgical resection of liver and/or pulmonary metastases in patients with metastatic ACC, if R0 resection is achievable and can be performed with low morbidity and mortality rates. Recognize that the best results are observed in highly selected patients with favorable biological behavior (low Ki-67 index and long disease- free interval). C https://web.pathway.md/diseases/recuSEdsRdEILoF3w 5/7 6/23/23, 2:10 AM Adrenocortical carcinoma Pathway Show 2 more Management of advanced/metastatic disease, other therapeutic interventions: As per EURACAN/ESMO 2020 guidelines, offer local therapies (such as radiotherapy, radiofrequency ablation, cryoablation, microwave ablation, and chemoembolization) in patients with advanced ACC on an individualized basis. B As per ESE 2018 guidelines, consider offering other local therapeutic interventions (such as radiotherapy, radiofrequency ablation, cryoablation, microwave ablation, and chemoembolization) in addition to surgery in patients with advanced ACC. Consider individualizing the choice based on the localization of the tumor lesions, local expertise, prognostic factors, and patient's preference. C Management of progressive/relapsed disease: As per ESE 2018 guidelines, perform surgery or alternatively offer other local therapies in patients with recurrent disease and a disease-free interval of at least 12 months, if a complete resection/ablation seems feasible. B Show 3 more As per ESES 2017 guidelines, perform complete resection of locally recurrent ACC when feasible. Recognize that the best results after surgery for recurrent ACC are seen in patients with delayed recurrence (> 12 months), low Ki-67 status, and R0 complete resection. Do not use a laparoscopic approach for resection in patients with recurrent ACC. B 5. Perioperative care Preoperative evaluation: Elicit clinical history and perform a physical examination to assess the following before adrenalectomy for suspected ACC: symptoms related to hormone excess symptoms related to local compression by a large mass detailed family history for familial forms of cancer. B Show 4 more Perioperative corticosteroid replacement: administer perioperative hydrocortisone replacement in all patients with autonomous cortisol secretion. B 6. Follow-up and surveillance Follow-up: As per ESMO 2020 guidelines, obtain radiological imaging every 3 months for 2 years after complete resection, then every 3-6 months for at least another 3 years. B As per ESES 2017 guidelines, obtain clinical and hormonal evaluation, thoracoabdominal CT, and 18F-FDG-PET every 3 months for the first 2 years and every 4-6 months thereafter based on the risk of recurrence. B https://web.pathway.md/diseases/recuSEdsRdEILoF3w 6/7 6/23/23, 2:10 AM Adrenocortical carcinoma Pathway References 1. S Gaujoux, R Mihai, joint working group of ESES and ENSAT. European Society of Endocrine Surgeons ESES and European Network for the Study of Adrenal Tumours ENSAT recommendations for the surgical management of adrenocortical carcinoma. Br J Surg. 2017 Mar;104 4 358 376. Open 2. M Fassnacht, G Assie, E Baudin et al. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Nov;31 11 1476 1490. Open 3. Martin Fassnacht, Olaf Dekkers, Tobias Else 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 Oct 1;179 4 G1 G46. Open 4. Linwah Yip, Quan-Yang Duh, Heather Wachtel et al. American Association of Endocrine Surgeons Guidelines for Adrenalectomy: Executive Summary. JAMA Surg. 2022 Aug 17. Open 5. Neal E Rowe, Ravi M Kumar, Nicola Schieda et al. Canadian Urological Association guideline: Diagnosis, management, and followup of the incidentally discovered adrenal mass. Can Urol Assoc J. 2023 Feb;17 2 12 24. Open 6. Dimitrios Stefanidis, Melanie Goldfarb, Kent W Kercher et al. SAGES guidelines for minimally invasive treatment of adrenal pathology. Surg Endosc. 2013 Nov;27 11 3960 80. Open 7. Expert Panel on Urological Imaging, Rekha N Mody, Erick M Remer et al. ACR Appropriateness Criteria Adrenal Mass Evaluation: 2021 Update. J Am Coll Radiol. 2021 Nov;18 11S S251 S267. Open https://web.pathway.md/diseases/recuSEdsRdEILoF3w 7/7