Management of Adrenocortical Carcinoma
Jonathan R. Strosberg, MD;ª Gary D. Hammer, MD;b and Gerard M. Doherty, MD,b Tampa, Florida, and Ann Arbor, Michigan
Key Words
Adrenocortical cancer, adrenal carcinoma, Cushing’s syndrome, mitotane
Abstract
Adrenocortical carcinomas (ACCs) are rare tumors that arise from the cortex of the adrenal gland with an incidence 1 to 2 per mil- lion. The rarity of this tumor translates into a paucity of experience in managing patients in most medical centers. Because clinical se- ries are small and prospective evaluation of treatment strategies is limited, the current state of knowledge is strongly influenced by expert consensus opinion from a few medical centers specializing in ACCs. This article describes the basic diagnostic and prognostic issues in adrenal cancer management, and presents detailed ratio- nales for therapeutic management. (JNCCN 2009;7:752-759)
Medscape: Continuing Medical Education Online
Accreditation Statement
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of MedscapeCME and JNCCN-The Journal of the National Compre- hensive Cancer Network. MedscapeCME is accredited by the Ac- creditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
MedscapeCME designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credits™M. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activ- ity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or com- plete the evaluation at http://www.medscape.com/cme/jnccn; (4) view/print certificate.
Learning Objectives
Upon completion of this activity, participants will be able to:
. Describe the incidence of adrenocortical carcinoma (ACC)
. Identify the most common clinical presentations of ACC
. Describe the most useful diagnostic tests for ACC
· Describe a pathologic assessment for ACC to distinguish it from benign conditions
. Describe surgical approaches to the treatment of ACC
Epidemiology
Adrenocortical carcinomas (ACCs) are rare tumors that arise from the cortex of the adrenal gland with an inci- dence 1 to 2 per million.1-3 This extremely low incidence translates into minimal experience with diagnosing and treating the disease in most medical centers. Moreover,
From the ªH. Lee Moffitt Cancer Center, Tampa, Florida, and ‘University of Michigan School of Medicine, Ann Arbor, Michigan.
Submitted January 5, 2009; accepted for publication April 9, 2009. Correspondence: Gerard M. Doherty, MD, University of Michigan, 2920 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail: gerardd@med.umich.edu
EDITOR
Kerrin G. Robinson, MA, Medical/Scientific Editor, Journal of the National Comprehensive Cancer Network
Disclosure: Kerrin G. Robinson, MA, has disclosed no relevant financial relationships.
AUTHORS AND CREDENTIALS
Jonathan R. Strosberg, MD, H. Lee Moffitt Cancer Center, Tampa, Florida Disclosure: Jonathan R. Strosberg, MD, has disclosed no relevant financial relationships.
Gary D. Hammer, MD, University of Michigan School of Medicine, Ann Arbor, Michigan
Disclosure: Gary D. Hammer, MD, has disclosed no relevant financial relationships.
Gerard M. Doherty, MD, University of Michigan School of Medicine, Ann Arbor, Michigan
Disclosure: Gerard M. Doherty, MD, has disclosed no relevant financial relationships.
CME AUTHOR
Désirée Lie, MD, MSEd, Clinical Professor, Department of Family Medicine, University of California, Irvine; Director, Division of Faculty Development, UCI Medical Center, Irvine, California
Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.
Management of Adrenocortical Carcinoma
series are small and prospective evaluation of strategies has been limited. Thus, the current state of knowledge is strongly affected by expert consensus opinion from a few centers with dedicated ACC programs.4
A bimodal age distribution shows peak incidences in early childhood and in the fourth to fifth decades of life with a female to male ratio of approximately 1.5 to 1.5,6 Most cases are sporadic; however, ACCs have been observed in association with several hereditary syndromes, including Li-Fraumeni syndrome, Beck- with-Wiedemann syndrome, familial adenomatous polyposis, and multiple endocrine neoplasia type 1.7-11 Although the underlying mechanisms of carcinogen- esis in sporadic ACCs have not been fully elucidated, similar to familial ACC, inactivating mutations of the p53 tumor suppressor gene (chromosome 17p13)12,13 and activating mutations in the Wnt signaling path- way and alterations at the 11p15 locus (site of the IGF-2 gene)14,15 occur with high frequency.16
Clinical Presentation
Patients typically present either asymptomatically or with symptoms caused by hormone excess or mass ef- fect of the tumor. Nonfunctional masses are discovered because of symptoms of local invasion or unrelated symptoms that lead to abdominal imaging. Approxi- mately 60% of patients present with evidence of ad- renal steroid hormone excess. Cushing’s syndrome, with or without virilization, is the most common pre- sentation.2,3,17,18 Signs and symptoms associated with hypersecretion of cortisol include weight gain, weak- ness (primarily in proximal muscles), hypertension, hyperglycemia, and hypokalemia. Patients with rare aldosterone-secreting tumors may present with hyper- tension and pronounced hypokalemia. Androgen-se- creting tumors in women may induce hirsutism, deep- ening of the voice, and oligo- or amenorrhea.3 For men, estrogen-secreting tumors may induce gyneco- mastia and testicular atrophy. Patients whose tumors secrete multiple hormones causing mixed hormonal syndromes almost always have malignant tumors.
Hormonally inactive ACCs can produce symp- toms related to tumor burden, including abdominal pain, back pain, early satiety, and weight loss, lead- ing to abdominal imaging.3,19 Some smaller ACCs are sometimes discovered during imaging for other indications. The challenge with these patients is distinguishing small ACCs from the many benign
incidentally discovered adrenal tumors. Most ACCs discovered through imaging do not present a diagnos- tic challenge because they are large (mean tumor size is 10 cm and 95% are larger than 5 cm at diagnosis) and heterogeneous in internal appearance (Figure 1). However, because all large tumors were initially small tumors, distinguishing small malignant tumors from the multitude of small benign adenomas, although difficult, is of paramount importance.
Incidental Adrenal Masses
Full evaluation of incidental adrenal masses requires investigation for functional syndromes of medullary or cortical origin and risk for malignancy. Simple blood and urine testing together with standard CT scans are usually sufficient to distinguish a functional from a nonfunctional adrenal tumor, and a benign from a malignant mass.
Hormonal Evaluation
A hormonal workup of hypercortisolism and cat- echolamine excess has been considered standard care for all symptomatic and asymptomatic patients because of the morbidity of subclinical Cushing’s syn- drome and the potential for hypertensive emergency in a patient with subclinical pheochromocytoma. Only asymptomatic patients with definitive imag- ing evidence of myelolipoma or an adrenal cyst have been considered by some to be exempt from this eval- uation. Historically, the workup of primary hyperal- dosteronism was only considered to have diagnostic efficacy in hypertensive patients. Because recent data indicate subclinical hyperaldosteronism in as high as 10% of patients with clinically silent incidentally dis- covered adrenal masses, all patients in this cohort are screened for primary hyperaldosteronism.
Plasma or urine free metanephrines are the pre- ferred tests for excluding or confirming the diagnosis of pheochromocytoma. Because of a 99% sensitivity, testing of plasma levels is reserved for patients with a high index of suspicion (i.e., incidental adrenal mass), wherein any value above the normal range is considered diagnostic of a pheochromocytoma; 24- hour urine free metanephrines are usually reserved for patients with a low index of suspicion. Levels 2 to 3 times the upper end of the normal range are consis- tent with a pheochromocytoma.
ADRENAL CANCER
SUPERIOR POLE LEFT KIDNEY
Cushing’s syndrome is evaluated using 1 of 3 screening tests: an overnight (1 mg) dexametha- sone suppression test, 24-hour urine free cortisol, or midnight salivary cortisol. After the administration of 1-mg dexamethasone at bedtime, most normal people suppress serum cortisol to less than 2 µg/dL. Lack of suppression is indicative of autonomous pro- duction of cortisol. An adrenocorticotropin (ACTH) that is undetectable is consistent with the presumed adrenal (vs. pituitary) autonomy. An elevated 24- hour urinary free cortisol measurement is equally di- agnostic and can help confirm Cushing’s syndrome in a borderline suppression test. Similarly, a plasma aldosterone concentration of greater than 15 ng/dL with a concomitant aldosterone:renin ratio greater than 20 support autonomous aldosterone production. The measurement of sex steroids can be limited to patients who present with masculinization or femini- zation, because sex steroid excess is rarely an inciden- tal finding. Measurements include follicle stimulating hormone, leuteinizing hormone, dehydroepiandros- terone sulfate, testosterone, and estradiol.3
Radiographic Studies
In surgical series of adrenal incidentalomas, ACCs comprise approximately 2% of tumors smaller than
4 cm, 6% of tumors 4 to 6 cm, and 25% of tumors with a diameter greater than 6 cm. For this reason, radiologic studies include size as a risk factor for ma- lignancy. A high lipid content has proven to be one of the most useful lesion characteristics to confirm the presence of a benign adrenocortical adenoma. For this reason, standard radiologic evaluation now involves a non-contrast CT to determine size and homogenous lipid content of the adrenal mass.
Density measurement of 10 or less Hounsfield units (HU) is consistent with a benign adenoma. Le- sions that are large, poorly circumscribed, more than 10 HU, or heterogeneous in signal are more worrisome. MRI can provide similar diagnostic value, with ACC usually isointense to liver on T1-weighted images but having increased intensity on T2 sequences. Lastly, flu- orodeoxyglucose (FDG)-PET is emerging as a powerful adjuvant in the determination of benign versus malig- nant disease.20-27 FDG-PET scans typically show FDG uptake in malignant tumors, especially high-grade tu- mors, but less frequently in benign adenomas.28,29
Because the lung and liver are the most com- mon sites of metastatic spread, and pelvic metastatic deposits are not uncommon, thoracic, abdominal, and pelvic scans are integral to the staging workup of ACC. MRIs are particularly useful in assessing lo- cal invasion and involvement of the inferior vena cava.30,31 Bone scans may be considered to evaluate bone pain.
Pathologic Assessment
Preoperative pathologic assessment of an adrenal mass is almost never indicated. Image-guided biopsy is only considered useful in patients with a known extra-adrenal primary cancer to determine whether the adrenal mass is a primary adrenal neoplasm ver- sus metastatic disease from the nonadrenal primary. This rationale is predicated on data that indicate that the procedure is dangerous for patients with medullary tumors, in whom biopsy can result in a hypertensive crisis. Moreover, a biopsy is likely to be uninformative for cortical lesions because of the cy- tologic overlap between normal, benign, and malig- nant adrenocortical tissue. Lastly, peritoneal seeding of the ACC after biopsy can impair the opportunity for subsequent curative resection.
In the absence of local invasion or distant metas- tases, the pathologic distinction between a malignant
Management of Adrenocortical Carcinoma
and benign adrenal tumor can be difficult. The most commonly used diagnostic tool is the Weiss score.32,33 This score (0-9) can be determined for each patient, based on the presence or absence of 1) high mitotic rate, 2) atypical mitoses, 3) high nuclear grade, 4) low percentage of clear cells, 5) necrosis, 6) diffuse architecture of tumor, 7) capsular invasion, 8) sinu- soidal invasion, and 9) venous invasion. A Weiss score of 3 or more is considered consistent with a malignant adrenal tumor.
Staging and Tumor Grading
The WHO staging system for ACC, which is based on tumor size and invasion (T), regional nodal in- volvement (N), and distant metastases (M), is rou- tinely used to compare disease status at presentation across patients and medical centers and to guide therapy (Table 1).34 The TNM staging is similar to the MacFarlane classification originally proposed in 1958 and then modified.35 However, individual prog- nostication to allow rational planning for therapy and follow-up monitoring requires integration of the information from the staging system and histologic grading. For example, patients whose carcinoma has a high mitotic rate (> 20 mitoses per 50 hpf) have a more limited disease-free interval.36,37
Prognosis largely depends on stage and grade. In one large study, the actuarial 5-year survival rates were 66% for patients with stage I tumors, 58% for stage II, 24% for stage III, and 0% for stage IV.38
Surgical Therapy
Definitive resection should be considered for patients with functional adenomas/carcinomas or apparently localized ACCs. For incidentally identified lesions that may be ACCs, careful surgical judgment must de- termine the operative approach (laparoscopic vs. open exploration).39 Laparoscopic resection is reserved for patients believed to harbor small, benign, functional tumors or those with borderline risk for malignancy.
Any difficulty in the laparoscopic approach de- mands conversion to open resection. Resection in- cludes gross total removal of the tumor and adrenal gland without capsular breach. For patients with stage II or III disease, concomitant resection of adja- cent structures can include the kidney, liver, spleen, pancreas, stomach, colon, or vena cava if needed to
| Table 1 | WHO Staging of Adrenocortical Carcinomas |
| Primary Tumor (T) | |
| T1 | Tumor ≤ 5 cm in greatest dimension, local invasion absent |
| T2 | Tumor > 5 cm in greatest dimension, local invasion absent |
| T3 | Tumor outside adrenal, in fat |
| T4 | Tumor invading adjacent organs |
| Regional Lymph Nodes (N) | |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis |
| Distant Metastasis (M) | |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
| Stage Grouping | |
| Stage I | T1, N0, M0 |
| Stage II | T2, N0, M0 |
| Stage III | T1 or T2, N1, M0 T3, N0, M0 |
| Stage IV | T3 or T4, N1, M0 Any T, any N, M1 |
From DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. World Health Organization Classification of Tumours: Pathology & Genetics of Tumours of Endocrine Organs. Lyon: IARC Press; 2004; with permission.
completely remove direct tumor extension to those structures. En bloc resection of the kidney should be planned for any patient with apparent involvement of the renal capsule or vasculature.
Resection should be considered for recurrent tu- mors in selected patients with excellent performance status and locoregional recurrence, or isolated distant metastases, if complete resection can be achieved. For some patients, a symptomatic recurrence (e.g., from local effects or hormone hypersecretion) can be palliated through operative resection; however, surgical resection is rarely indicated if incomplete resection can be achieved or for patients with unre- sectable, distant, metastatic disease.2-4,38
Adjuvant Treatment
Because ACC is so rare, no randomized, prospective trials of adjuvant therapy have been published. Most retrospective reports have examined the use of adju- vant mitotane, an oral adrenocorticolytic agent.40-42 The largest study retrospectively analyzed 177 pa-
tients with resected ACC (stages I-III) treated in Italy and Germany.43,44 Adjuvant mitotane at doses ranging from 1 to 5 g/d was administered to almost half of patients (47 of 102 patients) in the Italian cohort, compared with none in the German cohort (75 patients). The median duration of treatment was 29 months. In follow-up, the treatment cohort had significantly longer disease-free and overall survival than the control cohorts, suggesting that adjuvant mitotane may be an effective postoperative strategy.
A recommended protocol for mitotane use is as follows:4
· The usual tolerated dose is 3.0 to 4.0 g/d; how- ever, serum levels and patient tolerance should determine optimal dose.
· Adjuvant therapy duration goal is 2 years, but patients should be treated longer if they are do- ing well.
· Treatment should begin with 2 g/d and advance to achieve serum levels of 14 to 20 mg/dL.45 The therapeutic window of mitotane is low and tox- icities increase sharply with blood levels exceed- ing 20 mg/L. Side effects are mainly gastrointes- tinal and neurologic, including nausea, dizziness, and somnolence.46 The target blood level may be unattainable because of side effects, and there- fore the dose should be adjusted to tolerance.
· Patients should be monitored clinically and by measuring ACTH, urinary free cortisol, and electrolytes.
· The dose of cortisol replacement should be ad- justed to assure adequate glucocorticoid replace- ment. All patients with ACC receiving mitotane require cortisol replacement because mitotane will also destroy any normal adrenocortical tis- sue. Because mitotane stimulates the catabolism of cortisol, patients require supraphysiologic doses of hydrocortisone (30-40 mg/d in divided doses) while on mitotane. Mineralocorticoid re- placement is rarely indicated because glomeru- losa function is often maintained on mitotane.
· Thyroid function, serum testosterone, and lipids should be monitored and corrected as needed.
· Vigorous antiemetics and other symptomatic support should be provided.
Data regarding the efficacy of adjuvant radio- therapy for ACC are limited.47-49 However, evidence suggests that radiotherapy is probably as effective in ACC as it is for other solid tumors. Although in
other solid tumors radiotherapy is routinely recom- mended as a supplemental treatment for local con- trol after marginal resection, its use to limit ACC local recurrence is not specifically proven. The risk:benefit ratio should be individually assessed and account for the grade of the tumor, margins of resec- tion, and likelihood of recurrence.
Treatment of Metastatic Disease
For more than 50 years, the only registered FDA- approved drug for ACC was the adrenolytic drug mitotane, a derivative of the pesticide DDT. The efficacy of mitotane has been evaluated in multiple small, single-arm studies and retrospective series. Although whether treatment with mitotane alone is associated with a survival benefit remains unclear in the absence of randomized prospective studies, objective radiographic response rates have been ob- served in approximately 25% of patients.17,50-52 Mi- totane also palliates symptoms of excess corticoste- roids in the majority of patients by the inhibition of steroidogenic enzymes.
Several small studies evaluating the combination of mitotane with other cytotoxic agents, including cisplatin and etoposide, have shown modest objective responses, albeit in small patient cohorts. A large re- cent study analyzed the combination of mitotane (4 g/d) with cisplatin, etoposide, and doxorubicin (the Italian Protocol), yielding an overall response rate of 49% (according to WHO criteria) and a complete hormonal response in 9 of 16 patients with function- ing tumors.53 In a separate study, the combination of mitotane with streptozotocin yielded a reported objective response rate of 36%.54 Currently, one ran- domized international trial (FIRM-ACT) is compar- ing the effectiveness of mitotane/streptozotocin with mitotane/etoposide/doxorubicin/cisplatin for the treatment of ACC (http://www.firm-act.org/).55
Additional treatment strategies for isolated meta- static deposits may include surgery, radiation therapy, chemoembolization, cryotherapy, or other local thera- peutic options that are routinely reserved for reliev- ing signs or symptoms of hormone excess, pain, or impending organ damage caused by metastatic ACC.
Management of Adrenocortical Carcinoma
Medical Treatment of Corticosteroid Excess
Palliative treatment may be required for patients who experience symptoms secondary to adrenocorti- cal steroid secretion, such as hypertension, hypergly- cemia, hypokalemia, and muscle atrophy. In addition to mitotane, other steroidogenic inhibitors include ketoconazole, metyrapone, aminoglutethimide, and etomidate. Ketoconazole is most commonly used at doses of 400 to 1200 mg/d because of its easy avail- ability and relatively tolerable toxicity profile. Al- though ketoconazole has measurable benefits in low- ering cortisol levels in benign adrenal disease, it does not effectively control the extreme cortisol excess in many patients with ACC. Therefore, current trials are examining the efficacy of glucocorticoid receptor blockade (mifepristone) in Cushing’s syndrome as- sociated with ACC.
Prognosis and Follow-up Strategy
Patients who have undergone complete tumor resec- tion should be evaluated for endocrine markers of disease recurrence every 3 months based on the pre- operative hormonal profile. Cross-sectional imaging should be performed at 3-month intervals to identify tumor recurrence and allow subsequent intervention for recurrence. CT scanning is convenient and sensi- tive for detecting disease recurrence in most patients, although MR and FDG-PET scans may be useful in patients with equivocal findings or occult recurrence detected through hormonal elevations.4
For patients with metastatic disease undergoing therapy, follow-up studies should be performed every 3 months or less to assess therapeutic efficacy.
Emerging Therapies
Because current therapeutic regimens have had mod- est results, at best, in treating metastatic ACC, new therapeutic modalities are clearly essential to sig- nificantly impact life expectancy in these patients. Genomic studies have begun to uncover a common set of genetic alterations in ACC. Similar to famil- ial forms of ACC, sporadic ACCs frequently have activation mutations in the insulin-like growth fac- tor and Wnt signaling pathway together with loss of function mutation in p53. Pre- and early clinical studies targeting these pathways have shown prom-
ise, and multi-institutional groups are beginning to enroll patients with ACC in phase II trials involving these and other potential pathways.
References
1. Dackiw AP, Lee JE, Gagel RF, Evans DB. Adrenal cortical carcinoma. World J Surg 2001;25:914-926.
2. Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2006;91:2027-2037.
3. Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 2003;169:5-11.
4. Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer 2005;12:667-680.
5. Crucitti F, Bellantone R, Ferrante A, et al. The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 1996;119:161-170.
6. Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 1993;72:3145-3155.
7. Koch CA, Pacak K, Chrousos GP. The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol Metab 2002;87:5367-5384.
8. Lynch HT, Radford B, Lynch JF. SBLA syndrome revisited. Oncology 1990;47:75-79.
9. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658-5671.
10. Marx S, Spiegel AM, Skarulis MC, et al. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med 1998;129:484-494.
11. Soon PS, McDonald KL, Robinson BG, Sidhu SB. Molecular markers and the pathogenesis of adrenocortical cancer. Oncologist 2008;13:548-561.
12. Reincke M, Karl M, Travis WH, et al. p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies. J Clin Endocrinol Metab 1994;78:790-794.
13. Ohgaki H, Kleihues P, Heitz PU. p53 mutations in sporadic adrenocortical tumors. Int J Cancer 1993;54:408-410.
14. Gicquel C, Bertagna X, Schneid H, et al. Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors. J Clin Endocrinol Metab 1994;78:1444-1453.
15. Gicquel C, Raffin-Sanson ML, Gaston V, et al. Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors. J Clin Endocrinol Metab 1997;82:2559-2565.
16. Barlaskar FM, Hammer GD. The molecular genetics of adrenocortical carcinoma. Rev Endocr Metab Disord 2007;8:343- 348.
17. Luton JP, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 1990;322:1195-1201.
18. Bertagna C, Orth DN. Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med 1981;71:855-875.
Strosberg et al.
19. Kasperlik-Zaluska AA, Migdalska BM, Zgliczynski S, Makowska AM. Adrenocortical carcinoma. A clinical study and treatment results of 52 patients. Cancer 1995;75:2587-2591.
20. NIH state-of-the-science statement on management of the clinically inapparent adrenal mass (“incidentaloma”). NIH Consens State Sci Statements 2002;19:1-25.
21. Korobkin M, Lombardi TJ, Aisen AM, et al. Characterization of adrenal masses with chemical shift and gadolinium-enhanced MR imaging. Radiology 1995;197:411-418.
22. Yun M, Kim W, Alnafisi N, et al. 18F-FDG PET in characterizing adrenal lesions detected on CT or MRI. J Nucl Med 2001;42:1795- 1799.
23. Caoili EM, Korobkin M, Brown RK, et al. Differentiating adrenal adenomas from nonadenomas using (18)F-FDG PET/CT: quantitative and qualitative evaluation. Acad Radiol 2007;14:468- 475.
24. Al-Hawary MM, Francis IR, Korobkin M. Non-invasive evaluation of the incidentally detected indeterminate adrenal mass. Best Pract Res Clin Endocrinol Metab 2005;19:277-292.
25. Szolar DH, Korobkin M, Reittner P, et al. Adrenocortical carcinomas and adrenal pheochromocytomas: mass and enhancement loss evaluation at delayed contrast-enhanced CT [see comment]. Radiology 2005;234:479-485.
26. Hussain HK, Korobkin M. MR imaging of the adrenal glands. Magn Reson Imaging Clin N Am 2004;12:515-544.
27. Israel GM, Korobkin M, Wang C, et al. Comparison of unenhanced CT and chemical shift MRI in evaluating lipid-rich adrenal adenomas. AJR Am J Roentgenol 2004;183:215-219.
28. Becherer A, Vierhapper H, Potzi C, et al. FDG-PET in adrenocortical carcinoma. Cancer Biother Radiopharm 2001;16:289-295.
29. Leboulleux S, Dromain C, Bonniaud G, et al. Diagnostic and prognostic value of 18-fluorodeoxyglucose positron emission tomography in adrenocortical carcinoma: a prospective comparison with computed tomography. J Clin Endocrinol Metab 2006;91:920- 925.
30. Schultz CL, Haaga JR, Fletcher BD, et al. Magnetic resonance imaging of the adrenal glands: a comparison with computed tomography. AJR Am J Roentgenol 1984;143:1235-1240.
31. Chang A, Glazer HS, Lee JK, et al. Adrenal gland: MR imaging. Radiology 1987;163:123-128.
32. Weiss LM, Medeiros LJ, Vickery AL. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202-206.
33. Aubert S, Wacrenier A, Leroy X, et al. Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol 2002;26:1612-1619.
34. DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. World Health Organization Classification of Tumours: Pathology & Genetics of Tumours of Endocrine Organs. Lyon: IARC Press; 2004.
35. Macfarlane DA. Cancer of the adrenal cortex. Ann R Coll Surg 1958;23:155-186.
36. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163-169.
37. Assie G, Antoni G, Tissier F, et al. Prognostic parameters of metastatic adrenocortical carcinoma. J Clin Endocrinol Metab 2007;92:148-154.
38. Icard P, Goudet P, Charpenay C, et al. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 2001;25:891-897.
39. Saunders BD, Doherty GM. Laparoscopic adrenalectomy for malignant disease. Lancet Oncol 2004;5:718-726.
40. Dickstein G, Shechner C, Arad E, et al. Is there a role for low doses of mitotane (o,p’-DDD) as adjuvant therapy in adrenocortical carcinoma? J Clin Endocrinol Metab 1998;83:3100-3103.
41. Khorram-Manesh A, Ahlman H, Jansson S, et al. Adrenocortical carcinoma: surgery and mitotane for treatment and steroid profiles for follow-up. World J Surg 1998;22:605-611; discussion 611-612.
42. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al. Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 1993;71:3119-3123.
43. Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007;356:2372-2380.
44. Schteingart DE. Adjuvant mitotane therapy of adrenal cancer- use and controversy [see comment]. N Engl J Med 2007;356:2415- 2418.
45. Haak HR, Hermans J, van de Velde CJ, et al. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 1994;69:947-951.
46. Hutter AM Jr, Kayhoe DE. Adrenal cortical carcinoma. Results of treatment with o,p’DDD in 138 patients. Am J Med 1966;41:581- 592.
47. Magee BJ, Gattamaneni HR, Pearson D. Adrenal cortical carcinoma: survival after radiotherapy. Clin Radiol 1987;38:587- 588.
48. Percarpio B, Knowlton AH. Radiation therapy of adrenal cortical carcinoma. Acta Rad Ther Phys Biol 1976;15:288.
49. Fassnacht M, Hahner S, Polat B, et al. Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma [see comment]. J Clin Endocrinol Metab 2006;91:4501- 4504.
50. Hahner S, Fassnacht M. Mitotane for adrenocortical carcinoma treatment. Curr Opin Investig Drugs 2005;6:386-394.
51. Lubitz JA, Freeman L, Okun R. Mitotane use in inoperable adrenal cortical carcinoma. JAMA 1973;223:1109-1112.
52. Venkatesh S, Hickey RC, Sellin RV, et al. Adrenal cortical carcinoma. Cancer 1989;64:765-769.
53. Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer 2005;12:657-666.
54. Khan TS, Imam H, Juhlin C, et al. Streptozocin and o,p’DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann Oncol 2000;11:1281-1287.
55. Koschker AC, Fassnacht M, Hahner S, et al. Adrenocortical carcinoma-improving patient care by establishing new structures. Exp Clin Endocrinol Diabetes 2006;114:45-51.
Management of Adrenocortical Carcinoma
Adrenocortical Carcinoma
To obtain credit, you should first read the journal ar- ticle. After reading the article, you should be able to answer the following, related, multiple-choice ques- tions. To complete the questions and earn continu- ing medical education (CME) credit, please go to http://www.medscape.com/cme/jnccn.
Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers. You must be a registered user on Medscape.com. If you are not registered on Medscape.com, please click on the New Users: Free Registration link on the left hand side of the website to register.
Only one answer is correct for each question. Once you successfully answer all post-test questions you will be able to view and/or print your certificate. For ques-
tions regarding the content of this activity, contact the accredited provider, CME@medscape.net. For techni- cal assistance, contact CME@webmd.net.
American Medical Association’s Physician’s Rec- ognition Award (AMA PRA) credits are accepted in the US as evidence of participation in CME activities. For further information on this award, please refer to http://www.ama-assn.org/ama/pub/category/2922.html. The AMA has determined that physicians not licensed in the US who participate in this CME activity are eligible for AMA PRA Category 1 Credits™M. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit is acceptable as evidence of participation in CME activities. If you are not licensed in the U.S. and want to obtain an AMA PRA CME credit, please complete the questions on- line, print the certificate and present it to your national medical association.
1. Which of the following best describes the peak inci- dence of adrenocortical carcinoma (ACC)?
A. Fourth to fifth decades of life
B. Childhood and young adulthood
C. Over 50 years
D. Early childhood and fourth to fifth decades of life
2. Which of the following is the most common clinical presentation of ACC?
A. Incidental finding
B. Weight loss
C. Cushing’s syndrome
D. Abdominal pain
3. A 45-year-old man presents with early satiety, weight loss, and abdominal pain. Which of the following is least helpful as a diagnostic test to rule out ACC?
A. Noncontrast CT scan
B. Dexamethasone suppression test
C. Image-guided adrenal biopsy
D. Urine free cortisol
4. An adrenal specimen shows a high rate of atypical mitosis with a low percentage of clear cells and necro- sis. Which of the following is the most likely Weiss score for the specimen? A. 2
B. 3
C. 4
D. 5
5. In which of the following situations is surgery least likely to be recommended for patients with adrenal tumors?
A. Metastatic disease
B. Extension to renal capsule
C. Benign functional tumor
D. Localized ACC
Activity Evaluation
1. The activity supported the learning objectives. Strongly Disagree
1
2
3
4 Strongly Agree 5
2. The material was organized clearly for learning to occur. Strongly Disagree Strongly Agree
1
2
3
4 5
3. The content learned from this activity will impact my practice. Strongly Disagree 1 3 Strongly Agree 5
2
4
4. The activity was presented objectively and free of commercial bias. Strongly Disagree Strongly Agree 1 2 3
4 5
To obtain credit, visit Medscape online at www.medscape.com/cme/jnccn.