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Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.
CLINICAL RECOGNITION
Adrenocortical cancer (ACC) is a rare disease with an annual incidence of 0.7-2 cases per million per year and two distinct age distribution peaks, the first occurring in early adulthood and the second between 40-50 years with women being more often affected (55-60%). Although the great majority of ACCs are of sporadic origin, they can also develop as part of familial diseases the most common being the Beckwith-Wiedeman syndrome, the Li-Fraumeni syndrome, the Lynch syndrome, the multiple endocrine neoplasia (MEN) 1, and familial adenomatous polyposis (FAP) (Table 1). In recent years several multi-center studies have shed light on the pathogenesis of ACC
but ‘multi-omic’ studies reveal that only a minority of ACC cases harbour pathogenic driver mutations.
Table 1.
Clinical and Genetic Features of Familial Syndromes Associated with ACC
| Genetic disease Gene and chromosomal involvement | Organ involvement |
| Beckwith-Wiedemann syndrome CDKN1C mutation KCNQ10T1, H19 (epigenetic defects) 11p15 locus alterations IGF-2 overexpression | Macrosomia, macroglossia, hemihypertrophy (70%), omphalocele, Wilm’s tumor, ACC (15-20% adrenocortical tumors) |
| Li-Fraumeni syndrome P53(17p13) | Soft tissue sarcoma, breast cancer, brain tumors, leukemia, ACC |
| Multiple Endocrine Neoplasia syndrome 1 Menin (11q13) | Parathyroid, pituitary, pancreatic, bronchial tumors Adrenal cortex tumors (30%, rarely ACC) |
| Familial Adenomatous polyposis APC (5q12-22) | Multiple adenomatous polyps and cancer colon and rectum Periampullary cancer, thyroid tumors, hepatoblastoma, rarely ACC |
| SBLA syndrome | Sarcoma, breast and lung cancer, ACC |
The clinical features of sporadic ACCs are due to hormone hypersecretion and/or tumor mass and spread to surrounding or distant tissues. An increasing number of cases (≈ 10-15%) are increasingly been diagnosed within the group of incidentally discovered adrenal masses (incidentalomas). However, the likelihood of an adrenal incidentaloma being an ACC is rather low. Approximately 50-60% of ACCs exhibit evidence of hormonal hypersecretion, usually that of combined glucocorticoid and androgen secretion (Table 2). Nearly 30-40% of patients with primary ACC present with a mass syndrome as abdominal or dorsal pain, a palpable mass, fever of unknown origin, signs of inferior vena cava (IVC) compression, and signs of left-sided portal hypertension. Rarely, complications as hemorrhage or tumor rupture may also develop. Lately the number of patients that are identified while being investigated for an adrenal incidentaloma is rapidly increasing.
Table 2.
Signs and Symptoms of ACC and Recommended Testing for Confirmation of Hypersecretory Syndromes
| Symptoms/Signs | Hormonal testing (ENSAT 2005) |
| Hypercortisolism Centripetal fat distribution Skin thinning – striae Muscle wasting – myopathy Osteoporosis Increased blood pressure (BP) Diabetes Mellitus Psychiatric disturbance Gonadal dysfunction | Overnight dexamethasone suppression test (1mg) 24-hour free cortisol Basal ACTH (plasma) Basal cortisol (serum) [for diagnosis minimum 3 out of 4 tests) |
| Androgen hypersecretion Hirsutism Menstrual irregularity – infertility Virilization (baldness, deepening of the voice, clitoris hypertrophy) | DHEA-S Androstendione Testosterone 17-OH-progesterone |
| Mineralocorticoid hypersecretion Mineralocorticoid excess with increased BP, hypokalemia | Potassium (serum) Aldosterone to renin ratio |
| Estrogen hypersecretion Gynecomastia (men) Menorrhagia (post-menopausal women) | 17β-estradiol |
| Non-hypersecretory syndrome |
PATHOPHYSIOLOGY
Although studies of hereditary neoplasia syndromes have revealed various chromosomal abnormalities related to ACC development the precise genetic alterations involved are still unknown. The Wnt/β-catenin constitutive activation and insulin growth factor 2 (IGF2 overexpression) are the most important implicated genetic pathways. Germline TP53 mutations and dysregulation of the Gap 2/mitosis transition and the insulin-like growth factor 1 receptor (IGF1R) signalling have also been described. Steroidogenic factor 1 (SF1) plays an important role in adrenal development and is frequently overexpressed in ACC.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
A palpable mass causing abdominal pain in the presence of the inferior vena cava syndrome IVC syndrome is highly suggestive of an ACC. This is substantiated further by the presence of symptoms/signs of combined hormonal secretion (cortisol and androgens), virilizing or rarely feminizing signs confirmed with the use of specific endocrine testing (Table 2). As the majority of ACCs are relatively large (size > 8cm, weight >100g) at diagnosis, specific imaging features are used to distinguish them from other adrenal lesions. If adrenal imaging indicates an indeterminate mass other parameters should be considered including tumor size > 4 cm, combined cortisol/androgen hormone excess, rapidly developing symptoms and/ rapid tumor growth and/or young age (e.g. < 40 years) that might point to an ACC.
Other adrenal lesions that need to be considered in the differential diagnosis are myelolipomas, adrenal hemorrhage, lymphoma, adrenal cysts, metastases, and mainly adrenal adenomas, the majority of which have distinctive imaging features. There is no role for biopsy in a patient who is considered suitable for surgery of the adrenal mass.
Computerized Tomography (CT) scanning of the adrenals is the major tool showing a unilateral non-homogenous mass, >5cm in diameter, with irregular margins, necrosis, and occasionally calcifications. Due to the low-fat content X-Ray density is high (>20 Hounsfield Units, HU); in a recent series of 51 ACC none had a density of less than 13 HU. The presence of enlarged aorto-caval lymph nodes, local invasion, or metastatic spread are highly suggestive of ACC. For 3-6 cm size lesions, measuring X-Ray tumoral density before and after contrast administration and estimating washout percentage can be helpful; less than 50% after 15 minutes, is associated with >90% specificity. On Magnetic Resonance Imaging (MRI), ACC appears hypo or isointense to the liver on T1-weighted images, and using gadolinium enhancement and chemical shift techniques the diagnostic accuracy obtained is 85-100%. Recently Positron Emission Tomography (PET-scan) with 18F-fluoro-2deoxy-D-glucose (18FDG) has been proposed as possibly the best second-line test to assess indeterminate masses by unenhanced CT exhibiting 95-100% sensitivity and 91-94% specificity that increases further when fused with CT imaging. Furthermore, 18FDG-PET can also be used as a staging procedure identifying metastatic adrenal disease missed by conventional imaging studies including CT of the chest. With the proper implementation of imaging studies there is no need for adrenal biopsy.
HISTOPATHOLOGICAL DIAGNOSIS
The expression of SF1 is a valid marker to document the adrenal origin (distinction of primary adrenocortical tumors and non-adrenocortical tumors) with a sensitivity of 98% and a specificity of 100%. If this marker is not available, a combination of other markers can be used which should include inhibin-alpha, melan-A, and calretinin. ENSAT has shown that KI67 is the most powerful prognostic marker in both localized and advanced ACC and that higher Ki67 levels are consistently associated with worse prognosis. Weiss system, based on a combination of 9 histological criteria that can be applied on hematoxylin and eosin-stained slides, for the distinction of benign and malignant adrenocortical tumors is the best validated score to distinguish adenomas from ACC although with high inter-observer variability.
PROGNOSIS
As survival depends on stage at presentation several different classification histopathological systems have evolved with the reported 5-year survival using the ENSAT system being 82% for stage I, 61% for stage II, 50% for stage III, and 13% for stage IV (Table 3). Tumor size remains an excellent predictor of malignancy as tumors > 6cm have a 25% chance of being malignant compared to 2% of those with a size < 4cm. As there is no single distinctive histopathological feature indicative of malignancy the Weiss score has been used with a score >3 being suggestive of malignancy and recently ki67 labelling index >10%.
Table 3.
Staging system for adrenocortical carcinomas proposed by the International Union against cancer (WHO 2004) and the European Network for the study of adrenal tumors (ENSAT).
| Stage | WHO 2004 | ENSAT 2008 |
| I | T1,N0,M0 | T1,N0,M0 |
| II | T2,N0,M0 | T2,N0,M0 |
| III | T1-2,N1,M0 T3,N0,M0 | T1-2,N1,M0 |
| IV | T1-4,N0-1,M1 T3,N1,M0 T4,N0-1,M0 | T1-4,N0-1, M1 |
| M0: No distant metastasis, M1: Presence of distant metastasis, N0: No positive lymph nodes, N1: Positive lymph node(s), T1: Tumor ≤ 5cm, T2: Tumor > 5 cm, T3: Tumor infiltration to surrounding tissue, T4: Tumor invasion into adjacent organs or venous tumor thrombus in vena cava or renal vein. | ||
The median overall survival (OS) of all ACC patients is about 3-4 years. The prognosis is, however, heterogeneous. Complete surgical resection provides the only means of cure. In addition to radical surgery, disease stage, proliferative activity/tumor grade, and cortisol excess are independent prognostic parameters. Five-year survival rate is 60-80% for tumors confined to the adrenal space, 35-50% for locally advanced disease, and significantly lower in case of metastatic disease ranging from 0% to 28%. European Network for the Study of Adrenal Tumors (ENSAT) staging is considered slightly superior to the Union for International Cancer Control (UICC) staging. Additionally, the association between hypercortisolism and mortality was consistent. As Ki67 has been shown to be related with prognosis in both localized and advanced ACC threshold levels of 10% and 20% have been considered for discriminating low from high Ki67 labelling index; however, it is not clear whether any single significant threshold can be determined. Patients with stage I-III disease treated with surgical resection had significantly better median OS (63 vs. 8 months; p= 0.001). In stage IV disease, better median OS occurred in patients treated with surgery (19 vs. 6 months; p=0.001), and postsurgical radiation (29 vs 10 months; p=0.001) or chemotherapy (22 vs. 13 months; p= 0.004). Overall survival varied with increasing age, higher comorbidity index, grade, and stage of ACC at presentation. There was improved survival with surgical resection of the primary tumor, irrespective of disease stage; post-surgical chemotherapy or radiation was of benefit only in stage IV disease.
THERAPY
The management of patients with ACC requires a multidisciplinary approach with initial complete surgical resection in limited disease (stage I, II and occasionally III). Mitotane (1,1-dichloro-2(o-chlorophenyl)-2-(p-chlorophenyl)ethane [o,p’DDD]) is the only currently available adrenolytic medication achieving an overall response of approximately 30%.
Surgery
The aim of surgery is to achieve a complete margin-negative (R0) resection as patients with an R0 resection have a 5-year survival rate of 40-50% compared to the < 1year survival of those with incomplete resection. Patients with stage III tumors and positive lymph nodes can have a 10-year OS rate of up to 40% after complete resection. When a preoperative diagnosis or high level of suspicion of ACC exists, open surgical oncological resection is recommended as locoregional lymph removal might improve diagnostic accuracy and therapeutic outcome. However, the wide range of reported lymph node involvement in ACC (from 4 to 73%) implies that regional lymphadenectomy is neither formally performed by all surgeons nor accurately assessed or reported by all pathologists. Laparoscopic adrenalectomy should be considered for tumors with size up to 6 cm without any evidence of local invasion. Routine locoregional lymphadenectomy should be performed with adrenalectomy for highly suspected or proven ACC and it should include (as a minimum) the peri-adrenal and renal hilum nodes.
Preservation of the tumor capsule is essential whereas involvement of the IVC or renal vein with tumor thrombus is not a contraindication for surgery. However, even following an apparently complete surgical resection, 50-80% of patients develop locoregional or metastatic recurrence. Although such patients may be candidates for aggressive surgical resection, routine debulking is not recommended except for control of hormonal hypersecretion. Ablative therapies particularly targeting hepatic disease are used to decrease tumor load and the hypersecretory syndromes. Individualized treatment decisions are made in cases of tumors with extension into large vessels based on multidisciplinary surgical team. Such tumors should not be regarded ‘un-resectable’ until reviewed in an expert center.
Mitotane
Mitotane has traditionally been used for ACCs obtaining a partial or complete response in 33% of cases mainly by metabolic transformation within the tumor and through oxidative damage. Besides its cytotoxic adrenal action mitotane also inhibits steroidogenesis.
Adjuvant mitotane treatment is proposed in those patients without macroscopic residual tumor after surgery but who have a perceived high risk of recurrence (stage III, KI-67%>10%). However, for patients at low/moderate risk of recurrence (stage I-II, R0 resection, and Ki67 ≤ 10%) treatment with adjunct mitotane is still under investigation (results from ADIUVO trial are pending). When indicated mitotane should be initiated within six weeks and not later than 3 months. Adjuvant mitotane should be administrated for at least 2 years, but no longer than 5 years.
The tolerability of mitotane may be limited by its side effects mainly nausea, vomiting, neurological (ataxia, lethargy), hepatic and rarely hematological toxicity. Measurement of serum mitotane levels, targeting a range of 14-20 mg/l, seems to correlate with a therapeutic response while minimizing toxicity using variable dosing regimens. Mitotane causes hyperlipidemia and increased hepatic production of hormone binding globulins (cortisol, sex hormone, thyroid and vitamin D) increasing total hormone concentration while impairing free hormone bioavailability. The induction of hepatic P450-enzymes by mitotane induces the metabolism of steroid compounds requiring high dose glucocorticoid and mineralocorticoid replacement.
Hormonal excess causes significant morbidity in ACC patients. Although mitotane reduces steroidogenesis it has a slow onset of action necessitating the use of other adrenostatic medications (ketoconazole, metyrapone, aminoglutathemide, and etomidate). As adrenal insufficiency may occur close supervision is required to titrate adrenal hormonal replacement therapy.
Cytotoxic Chemotherapy
Although cisplatin containing regimens have shown some responses most studies lack power and comparisons between different regimens. The most encouraging results originate from the combinations of etoposide, doxorubicin and cisplatin with mitotane (EDP-M) achieving an overall response of 49% of 18 months duration (FIRMA-CT study). This regimen was equally effective as first line treatment or after failing of the combination of streptozotocin with mitotane and is the currently the preferred scheme. In patients who progress under mitotane monotherapy, EDP treatment is also recommended. The combination of gemcitabine with capecitabine is used for patients failing EDP- and for not responding patients targeted therapies with tyrosine kinase inhibitors (mainly sunitinib) could be used. Although initially promising treatment with IGF-1R antagonists did not prove to be efficacious suggesting that combination of therapies may be the way forward.
Radiation Therapy
Radiotherapy has a role in symptomatic metastatic disease particularly bone disease with positive responses in up to 50% - 90% of cancer patients.
Evolving Therapies
Targeting mTOR pathway alone using everolimus did not produce significant responses. An extended phase I study of the anti-IGF-1R monoclonal antibody cixutumumab with an mTOR inhibitor showed a partial but short-lived response. The use of the multikinase inhibitors sorafenib and sunitinib have also shown partial responses leading to a number of phase II studies whereas angiogenesis inhibitors have not been successful (http://www.clinicaltrials.gov). Other potential targets are antagonists of β-catenin and Wnt signaling pathway and SF-1 inverse agonists. The application of radionuclide therapy using 131I-metomidate has recently been explored. However, despite recent advances in dysregulated molecular pathways in ACCs, these findings have not yet been translated into meaningful clinical benefits. Lately immunotherapy (pembrolizumab) in phase II studies is under investigation.
FOLLOW-UP
Patients who have undergone an apparently curative resection should be followed up regularly using endocrine markers and abdominal imaging. After complete resection, radiological imaging every 3 months for 2 years and then every 3-6 months for a further 3 years is proposed. 18FDG-PET should be performed at regular intervals to detect recurrent disease at high risk patients. Patients on mitotane therapy should be regularly monitored measuring serum mitotane levels ensuring adequate replacement therapy. In case of recurrence not amenable to surgical excision patients should be enrolled in prospective clinical trials.
GUIDELINES
- Fassnacht M, Dekkers O, Else T, Baudin E, Berruti A, de Krijger RR, Haak HR, Mihai R, Assie G, Terzolo M. 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 Jul 24; [PubMed: 30299884]
- Berruti A, Baudin E, Gelderblom H, Haak HR, Porpiglia F, Fassnacht M, Pentheroudakis G. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2012;23:131–138. [PubMed: 22997446]
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