Previous studies have reported that adrenal masses >6cm have a greater than 90% probability of ACC, whereas masses 3-5 cm have a 9% probability. The NCCN guidelines recommend observation for masses ≤4 cm and surgery for ≥6 cm. Currently, there is controversy with regards to the appropriate management for masses 4-6 cm in size. Indications for surgery include (i) functioning tumors (aldosterone, cortisol, pheochromocytoma), (ii) nonfunctioning tumors with risk of malignancy, of which size is the single best indicator of malignancy, and (iii) nonfunctioning tumors 3-6 cm in size require individualized treatment based on patients age/general health, radiographic features, prior history, ie isolated metastases.
Further investigations for adrenal tumors should include radiologic and endocrine evaluation. Patients should have a non-contrast CT abdomen or an MRI +/- contrast; there is no role for percutaneous biopsy unless metastases is suspected and pheochromocytoma has been ruled out. Specifically, there is no role for biopsy in distinguishing adenoma from ACC, however a biopsy may occasionally be indicated for suspicion of metastatic disease to the adrenal gland from a known primary. Additional radiographic workup, according to Dr. Coleman, may include a CT chest or a PET scan. In general, ACC lesions radiographically on CT have >10 HU, are heterogeneous, irregular shape and margins, >5 cm, slow contrast washout, as well as may have invasion, lymph node involvement and/or necrosis. On MRI, ACC lesions are moderately bright on T2 weighted images, significant enhancement with gadolinium, and slower washout than adenoma. PET discrimination between benign vs malignant lesions has a sensitivity of 82-100% and specificity of 73-100%. Furthermore, there may be a role for PET in evaluating 3-5 cm lesions when CT and MRI are indeterminate. The endocrine evaluation should rule out Cushing’s Syndrome, Aldosteronoma, and Pheochromocytoma. This should include a serum cortisol, 24-hour urine (assessing for free cortisol, 17-ketosteroid, 17-hydroxycorticosteroid, catecholamines, metanephrines), serum potassium, and serum catecholamines.
The consensus in treatment for ACC for stage I-III includes complete surgical resection with a negative margin. The Memorial Sloan Kettering Cancer Center experience of 113 patients showed a median DSS of 101 months for stage I-II ACC, compared to stage III/IV with a median DSS of 10 months. The modified Weiss criteria for risk stratification (3 or more criteria associated with malignant potential) includes: (i) mitotic rate >5 per 50 high power fields, (ii) cytoplasm (clear cells comprising 25% or less of the tumor), (iii) abnormal mitoses, (iv) necrosis, and (v) capsular invasion. Unfortunately, in small series’ adjuvant radiotherapy has not been shown to improve local recurrence and has had no effect on CSS or OS. As such, the NCCN guidelines do not support a role for adjuvant radiotherapy. Dr. Coleman recommends close follow-up with a physical exam, biochemical evaluation, chest x-ray and CT scan every 3-4 months for the first two years, every 6 months for years 2-5 and every year for years 5-10. At this point, he feels follow-up beyond 10 years is certainly recommended.
Dr. Coleman highlighted several trials in ACC. The ADIUVO international phase III RCT randomizing patients to adjuvant mitotane vs surveillance following resection of stage I-II ACC at low and intermediate risk. The target accrual is 200 patients in four years, with protected study completion in 2020. The FIRM-ACT is an international phase III RCT for patients with stage III/IV disease (n=304) who were randomized to mitotane + doxorubicin, etoposide and cisplatin (M+DEP) vs mitotane + streptozotocin (M+S) . The median PFS for M+DEP was 5.7 months compared to 2.1 for M+S (HR 0.55, 95%CI 0.42-0.68), and median OS was 14.8 months for M+DEP and 12 for M+S (HR 0.79, 95%CI 0.51-1.02).
Given the advent of minimally invasive techniques, studies assessing open vs laparoscopic adrenalectomy have been reported. The German Adrenocortical Carcinoma Registry Group Compared 35 laparoscopic to 117 open adrenalectomies for stage I-III ACC, with tumors <10 cm . Over a follow-up of 40 months there was no difference recurrence-free survival or OS between the approaches. Dr. Coleman does make a cautionary note with regard to a laparoscopic adrenalectomy for ACC in that small case series at small volume institutions have reported peritoneal recurrence rates of ~1/3, whereas this rate is much lower at higher institutions (~15%). A recent meta-analysis of laparoscopic vs open adrenalectomy for ACC included 9 studies and over 800 patients . The authors concluded that because less complex tumors were being approached laparoscopically with yet a higher peritoneal carcinomatosis risk (RR 2.39, 95%CI 1.41-4.04) compared to open adrenalectomy, that the open approach should still be considered the standard surgical management for ACC. Furthermore, a referral to experienced centers is strongly recommended (>15 cases per year).
Dr. Coleman then shifted gears to briefly discuss pheochromocytoma. These are catecholamine secreting tumors that arise from chromaffin cells of the adrenal medulla or sympathetic ganglia. There is a strong association with familial syndromes, and 10% are malignant, 10% bilateral, and 10% are extra-adrenal. At the NCI, perioperative germline testing identified 47% of operative patients were associated with VHL or other pheochromocytoma-associated syndromes. The biochemical evaluation for suspected pheochromocytoma is plasma catecholamines (diagnostic) and 24-hour urinary catecholamines, metanephrines, and VMA (quantitative). Imaging may include a CT, MRI or I131-MIBG scan. A I131-MIBG scan has a 77-89% sensitivity rate and 88-100% specificity rate for pheochromocytoma. Surgical excision is the only effective treatment for pheochromocytoma, and improved perioperative management has reduced morbidity and mortality, particularly with alpha blockers (phenooxybenzamine, doxazosin, terazosin, prazosin) or calcium channel blocks (nifedipine, nicardipine). Dr. Coleman’s recommendations are for an alpha blocker or calcium-channel block perioperatively, as well as aggressive fluid hydration. Dr. Coleman’s principles of surgery for pheochromocytoma include: (i) complete tumor resection, (ii) minimal tumor manipulation, (iii) control of vascular supply of tumor with early adrenal vein ligation to avoid hypotension, (iv) avoid tumor seeding, and (v) hemostasis. Laparoscopic/robotic approaches have essentially become standard of care at most centers.
Dr. Coleman concluded with several take-home messages:
- Surgery provides the best curative intervention for functional adrenal tumors and adrenal cortical cancers
- Appropriate and thorough work up is imperative to determine functionality and proper surgical planning
- Hormone management includes blockade and peri-operative hormone supplementation
- Resection principles focus on complete and safe resection of all disease (R0)
- Adjuvant therapies with chemotherapy and radiotherapy may be considered in the highest risk patients
- Controversies exist in open vs robotic/laparoscopic approaches, however guidelines recommend open adrenalectomy for suspected ACC
- Pheochromocytomas are often hereditary and germline screening is recommended
Presented by: Jonathan Coleman, MD Memorial Sloan Kettering Cancer Center, New York, NY
Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA
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