Adrenocortical carcinoma
C. Gicquel,1 E. Baudin,2 Y. Lebouc1 & M. Schlumberger2 1Hôpital Trousseau, Paris; 2 Institut Gustave-Roussy, Villejuif Cedex, France
Key words: adrenocortical carcinoma, chemotherapy, genetic abnormalities, mitotane
Epidemiology
Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Its incidence is 0.6 to 1.67 cases per million people per year [1]. It occurs at all ages and is more frequent after 45 years of age [2, 3].
In children, ACC are uncommon and often manifested by a virilizing syndrome [4, 5], as well as sometimes occurring in the context of a tumor predisposing syn- drome such as Beckwith-Wiedemann [6] or Li-Fraumeni syndrome [7].
Diagnosis
The majority (80%) of patients with ACC present with an endocrine syndrome, usually Cushing’s syndrome, either in isolation or associated with virilizing features. Hyperaldosteronism and feminization syndromes are rare. Approximately half of the ACC produce mainly hormonal precursors with low bioactivity and their diag- nosis is often delayed [2].
Patients with nonhormone-producing ACC present with fever, weight loss, or symptoms related to the presence of an abdominal tumor or rarely to distant metastases [2, 3].
At initial work-up, a high proportion of ACC patients (30% to 40%) have had metastatic disease. Metastatic disease develops in the majority of patients (>80%) with apparently localized disease. Areas involved in- clude liver, lungs, bones, brain, and organs or tissues adjacent to the adrenal gland [2, 3, 8].
In the case of nonfunctioning tumor with an involve- ment of both the adrenal and other sites such as the lungs, the question of the primary tumor may arise. In fact, metastases to the adrenals are frequent, being ob- served in 9% of all malignant tumors and particularly in patients with breast and bronchic carcinoma, whereas nonfunctioning metastatic ACC are rare. Furthermore, distant metastases are rarely the revealing feature of ACC. In these patients, a complete work-up should be performed before any treatment. Ultrastructural studies
and immunohistochemistry may help to differentiate ACC from an adrenal metastasis or a renal carcinoma [9].
The diagnosis of malignancy can be difficult among primary adrenal tumors. A number of histological char- acteristics and hormonal tests have been used to differ- entiate adenomas from carcinomas. In the absence of distant metastasis or regional spread, no single finding can absolutely resolve this issue, but several features may be useful: the large size of malignant tumors, a tumor weight above one hundred grams being usually indicative of malignancy; the combination of histolog- ical features such as high mitotic rate, atypical mitoses, high nuclear grade, low percentage of clear cells, necrosis, diffuse architecture of tumor, capsular or vas- cular invasion [10]. Among them, mitotic rate is strongly associated with patient outcome [11]. The hormonal patterns such as the increased production of steroid precursors or androgens in female patients are indica- tive of malignancy. Recent data suggest that ACC ex- hibit a dysfunction of the aldosterone pathway with hypoaldosteronism and normal or increased levels of aldosterone precursors [12, 13]. It has recently been shown that the class II MHC antigens are expressed in the majority of benign adrenocortical tumors whereas their expression is abrogated in all ACC studied [14]. Finally, the evaluation of molecular abnormalities may help to distinguish malignant from benign adrenal tu- mors.
Genetic abnormalities
The molecular and genetic mechanisms of adrenocorti- cal tumorigenesis are still not well understood. Various oncogenes (as gip2, Ras or p53) have been proposed to be involved in adrenocortical tumorigenesis.
The a subunit of one of the inhibitory regulators of adenyl cyclase, the Gi2 protein, has been reported to occasionally harbour mutations of the Arg179 codon. This protooncogene was initially found to be mutated in 27% of adrenocortical tumors [15]; however, this was not confirmed in subsequent studies [16, 17].
Discordant results concerning Ras mutations were also reported in adrenocortical tumors [18, 19].
The 17p13 region includes the p53 gene (17p13.3) which is the most frequently mutated suppressor gene in carcinomas of various origins. Loss of heterozygosity (LOH) at this locus has been shown in adrenocortical tumors and is associated with the malignant phenotype, occurring in most malignant tumors and in less than 10% of the benign ones [20, 21]. The LOH always in- volves the p53 gene. Discordant results were reported about p53 mutations. About 25% of malignant adreno- cortical tumors, but none of benign tumors in one series showed p53 mutations [22] whereas the majority of the benign tumors from another series were found to have p53 mutations [23]. The discrepancy between the low frequency of p53 mutations and the high frequency of 17p13 LOH in malignant adrenocortical tumors sug- gests that another tumor suppressor gene within the 17p13 region may be involved. HIC-1 was recently iso- lated from this region and was considered as a suppres- sor gene candidate [24].
The expression of the H19 and IGF II genes which both map to the same region on chromosome 11p15 is important for adrenal fetal growth [25] and expression of both H19 and IGF II genes is up-regulated by ACTH in human fetal adrenals [26]. It has been shown that the majority of adrenal carcinomas but less than 10% of benign tumors demonstrated strong IGF II overexpres- sion [21, 27, 28]. Mitogenic activities of IGF II has been clearly established in various models of overgrowth dis- orders (including the Beckwith-Wiedemann syndrome) [29-31] and of tumors [32].
The chromosomal 11p15 region (where the IGF II gene maps) is subject to parental imprinting and the IGF II gene is transcribed from the paternal allele [33]. Adreno- cortical tumors harboring IGF II overexpression also exhibit LOH of 11p15. This LOH invariably involves loss of the maternal allele with duplication of the paternal allele (paternal isodisomy). Duplication of the paternal allele implies that both IGF II copies can be transcribed.
Frequent loss of the maternal allele suggests that a tumor suppressor gene expressed from this allele is involved in tumorigenesis. This 11p15 region contains two other imprinted genes which are expressed from the maternal allele. In vitro experimental data suggest that the H19 gene may have a tumor suppressor activity [34], but the frequent expression of this gene in tumors suggests that it is not involved in tumor progression in vivo. P57KIP2, a potent inhibitor of several Gl cyclin- CDK complexes [35-37], is also expressed from the maternal allele and inactivation by chromosome loss can possibly result in tumorigenesis due to acceleration of the cell cycle.
Abnormalities of the 11p15 region (paternal isodis- omy and IGFII gene overexpression) appear with the transition from the benign to the malignant phenotype. These new molecular markers permit a more accurate diagnosis of malignancy and probably also a better as- sessment of prognosis of adrenocortical tumors.
Prognosis
Prognosis is poor, with a five year survival rate ranging from 16% to 35% [2, 3, 8, 38-41]. In patients with localized disease, the main prognostic factor after initial treatment is the completeness of surgical excision, five year survival rate ranging from 32% to 47% after com- plete excision and only 10% to 30% after incomplete excision or after locoregional relapse.
Even after complete surgical excision, almost 80% of patients developed a locoregional relapse or distant metastases. More than 50% of those who had distant metastases were dead within 12 months.
Sex, tumor weight, and functional status of the tumor had no effect on prognosis.
Treatment
Principles of treatment
Radical surgery should be undertaken, when feasible. It provides disease control for a minority of patients with localized disease and, for this reason, routine mitotane treatment is advocated by several researchers postoper- atively even after complete excision. However, a survival benefit from mitotane has yet to be shown.
Combined radiotherapy and mitotane did not confer any additional benefit over mitotane alone. Radiother- apy should be considered only as palliative treatment for metastatic bone disease.
After incomplete surgery or in patients with metas- tatic disease, therapy has two aims: control of hormonal overproduction and control of tumor growth. The first- line treatment is oral mitotane. In the absence of disease progression, a continuous treatment with mitotane should be given during at least three months before concluding it is inefficient.
In patients with disease that progresses during mito- tane treatment, mitotane is maintained at the same dosage, and chemotherapy with cisplatin-based regimen is given. In patients who achieve a partial response during mitotane treatment or chemotherapy, excision of residual tumor is performed, when feasible. In fact, disease control has been obtained in some metastatic patients with extensive and repeated surgical procedures [8, 38-41].
In patients with a locoregional relapse, surgery is also performed, when feasible. In fact, median survival after complete excision ranged from 2.3 to 4.6 years. When surgical excision was impossible, one-year survival rate was only 10% to 30% [8, 38, 41].
Details of therapy
Mitotane (Op’DDD or 1,1 dichlorodiphenildichloro- ethane) controls endocrine hypersecretion in 75% of patients and provides an objective tumor response rate
of 14% to 38% (mean: 23%). A high percentage of tumor responses have been partial responses (PRS) and tran- sient, but some complete responses (CRS) lasting a few years have reported [42]. Tumor responses are rarely noted before eight weeks of continuous therapy.
Response rate is not related to age, sex, tumor bur- den, hormonal production or histological characteris- tics. The prognostic value of genetic abnormalities is still under study.
In a retrospective study, the only significant prognos- tic factor for tumor response to mitotane was its serum level: tumor response rate was 59% in the 27 patients in whom serum mitotane level could be maintained above 14 mg/l and 0% in the 25 patients in whom serum mitotane remained below this level [43]. Furthermore, a multivariate analysis showed that a serum mitotane level above 14 mg/l was associated with a significantly longer survival (P < 0.01). We are currently conducting a pro- spective trial to confirm these data. The serum level of mitotane cannot be predicted from the daily dose or the morphotype of the patient. Therefore, it has to be meas- ured in the serum at a monthly interval.
Mitotane is given at a daily dose of 10 g for two months and then adapted according to its serum level. The daily dose is given orally in three divided doses. To offset adrenal insufficiency induced by mitotane, 30 to 60 mg oral hydrocortisone and 50 µg oral fludrocor- tisone are administered daily [44], starting after the second week of mitotane treatment, the salt diet being normal.
Side effects requiring a reduction or temporary with- drawal of mitotane therapy may be a gastrointestinal (anorexia, nausea, vomiting) or neurologic (somnolence, lethargy, ataxia, vertigo, speech difficulty) nature. Blood biochemical abnormalities such as hepatic disturban- ces, hypercholesterolemia, and hypouricemia occur fre- quently. These clinical side effects may be avoided by maintaining serum mitotane level below 20 mg/1 [43].
Drugs that block the synthesis of steroids (metyra- pone, aminoglutethimide, ketoconazole) or that block the action of steroids in their target tissue (mifepristone) may control the clinical manifestations induced by hy- persecretory tumors, but do not inhibit tumor growth.
The most tested drug is cisplatin. When used alone, the tumor response rate was 27% (6 of 22 patients). Efficacy seems to be dose dependent [45-47]. Combina- tion of mitotane (4 g/d) and cisplatin (75-100 mg/m2 every three weeks) in 37 patients resulted in 11 objective tumor responses, including 1 CR [48]. This association did not seem to be synergic in terms of response rate (30%) nor in response duration. On the other hand, toxicity was high leading to withdrawal of therapy in 47% of patients.
Combination of cisplatin and adriamycin proved to be effective in two trials: in 11 patients, CAP (cyclophos- phamide 600 mg/m2, adriamycin 40 mg/m2, and cis- platin 50 mg/m2, every three weeks) provided two PRs and six stabilizations [49], and 2) in 13 patients, FAP (5-FU 500 mg/m2/d on days 1-3, adriamycin 60 mg/m2
on day 2 and cisplatin 120 mg/m2 on day 2, every four weeks) provided one CR, 2 PRs, and three stabilizations [50]. Evidence emerged suggesting the absence of cross resistance between mitotane and FAP [50]. These com- binations did not provide higher response rate than cisplatin alone. Furthermore, adriamycin (60 mg/m2 every three weeks) did not induce any response in 15 patients with well differentiated ACC or with poorly differentiated and functioning ACC; it induced three tumor responses including one CR in 16 patients with poorly differentiated and nonfunctioning ACC [51]. It is possible that these responses have occurred in patients with adrenal metastases from another primary tumor, but considered as ACC.
Combination of cisplatin (100 mg/m2 on day 1 or 40 mg/m2/d on days 1-3) and VP16 (100 mg/m2/d on days 1-3) every three weeks induced nine tumor responses including two CRs in 21 patients (43%) [52, M. Schlum- berger, unpublished results]. At the present time, this association is considered as the reference combination. It has been shown in vitro that mitotane may reverse the mdr phenotype [53, 54]. Therefore, in patients treated with VP16, mitotane treatment should be maintained.
Also, in some patients with isolated or proeminent liver metastases, chemoembolisation with cisplatin has provided remarkable responses (M. Schlumberger, un- published results).
Other drugs have been used only in isolated cases and none proved to be efficient. Clearly, there is a need for trials using other drug combinations. Due to the rarity of this disease, these trials should be done on a multi- centric basis.
Suramin may prove useful against ACC. Responses to suramin have been reported in a few patients with metastatic ACC, some of whom had received previous chemotherapy with mitotane or other agents. However, its high toxicity limits actually its use [55-57].
References
1. Ross N, Aron D. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990; 323: 1401-5.
2. Luton JP, Cerdas S, Billaud L et al. Clinical features of adreno- cortical carcinoma, prognostic factors and the effect of mitotane therapy. N Engl J Med 1990; 322: 1195-1202.
3. Venkatesh S, Hickey R, Sellin R et al. Adrenal cortical carcino- ma. Cancer 1989; 64: 765-9.
4. Sabagga C, Avilla S, Schulz C et al. Adrenocortical carcinoma in children: Clinical aspects and prognosis. J Pediatr Surg 1993; 28: 841-3.
5. Teinturier C, Brugières L, Lemerle J et al. Corticosurénalomes de l’enfant: Analyse rétrospective de 54 cas. Arch Pédiatrie 1996; 3: 235-40.
6. Sotelo-Avila C, Gonzalez-Crussi F, Fowler J. Complete and incomplete forms of Beckwith-Wiedemann syndrome: Their oncogenic potential. J Pediatr 1980; 96: 47-50.
7. Malkin D, Li F, Strong L et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neo- plasms. Science 1990; 250: 1233-8.
8. Jensen J, Pass H, Sindelar W, Norton J. Recurrent or metastatic
disease in selected patients with adrenocortical carcinoma. Arch Surg 1991; 126: 457-61.
9. Tartour E, Caillou B, Tenenbaum F et al. Immunohistochemical study of adrenocortical carcinoma: Predictive value of the DI1 monoclonal antibody. Cancer 1993; 72: 3296-303.
10. Weiss L. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984; 8: 163-9.
11. Weiss L, Medeiros J, Vickey A. Pathologic features of prognostic significance in adrenocortical carcinomas. Am J Surg Pathol 1989; 13: 202-6.
12. Aupetit-Faisant B, Battaglia C, Emeric-Blanchouin N, Legrand J. Hypo-aldosteronism accompanied by normal or elevated miner- alocorticosteroid pathway steroid: A marker of adrenal carci- noma. J Clin Endocrinol Metab 1993; 76: 38-43.
13. Aupetit-Faisant B, Blanchouin-Emeric N, Tenenbaum F et al. Plasma levels of aldosterone versus aldosterone precursors: A french retrospective multicentric study. J Clin Endocrinol Metab 1995; 80: 2715-21.
14. Marx C, Wolkersdörfer G et al. MHC class II expression. A new tool to assess dignity in adrenocortical tumours. J Clin Endocri- nol Metab 1996; 81: 4488-91
15. Lyons J, Landis C, Harsh G et al. Two G protein oncogenes in human endocrine tumors. Science 1990; 249: 655-9.
16. Reincke M, Karl M, Travis W, Chrousos G. No evidence for oncogenic mutations in guanine nucleotide-binding proteins of human adrenocortical neoplasms. J Clin Endocrinol Metab 1993; 77: 1419-22.
17. Gicquel C, Dib A, Bertagna X et al. Oncogenic mutations of a Gi2 protein are not determinant for human adrenocortical tu- mourigenesis. Eur J Endocrinol 1995; 133: 166-72.
18. Moul J, Bishoff J, Theune S, Chang E. Absent ras gene mutations in human adrenal cortical neoplasms and pheochromocytomas. J Urol 1993; 149. 1389-94.
19. Yashiro T, Hara H, Fulton N et al. Point mutations of RAS genes in human adrenocortical tumors. Absence in adrenocortical hy- perplasia World J Surg 1994; 18: 455-61.
20. Yano T, Linehan M, Anglard P et al. Genetic changes in human adrenocortical carcinomas. J Natl Cancer Inst 1989; 81: 518-23.
21. Gicquel C, Bertagna X, Le Bouc Y. Recent advances in the pathogenesis of adrenocortical tumours. Eur J Endocrinol 1995; 133: 133-44.
22. Reincke M, Karl M, Travis W et al. p53 mutations in human adrenocortical neoplasms: Immunohistochemical and molecular studies. J Clin Endocrinol Metab 1994; 78: 790-4.
23. Lin S, Lee Y, Tsai J. Mutations of the p53 gene in human func- tional adrenal neoplasms. J Clin Endocrinol Metab 1994; 78: 483-91.
24. Makos Wales M, Biel M, El Deiry W et al. p53 activates expres- sion of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nature Med 1995; 1: 570-7.
25. Goshen R, Rachmilewitz J, Schneider T et al. The expression of the H-19 and IGF-2 genes during human embryogenesis and placental development. Mol Reprod Dev 1993; 34: 374-9.
26. Voutilainen R, Ilvesmaki V, Ariel I et al. Parallel regulation of parentally imprinted H19 and insulin-like growth factor II genes in cultured human fetal adrenal cells. J Clin Endocrinol Metab 1994; 134: 2051-6.
27. Ilvesmäki V, Kahri A, Miettinen P, Voutilainen R. Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: High IGF-II expression in functional adrenocortical carcinomas. J Clin Endocrinol Metab 1993; 77: 852-8.
28. Gicquel C, Bertagna X, Schneid H et al. Rearrangements at 11p15 locus and overexpression of insulin like growth factor-II gene in sporadic adrenocortical tumors. J Clin Endocrinol Metab 1994; 78: 1444-53.
29. Coppes M, Haber D, Grundy P. Genetic events in the develop- ment of Wilms’ tumor. N Engl J Med 1994; 331: 586-90.
30. Hastie N. The genetics of Wilms’ tumor. A case of disrupted development. Ann Rev Genet 1994; 28: 523-58.
31. Morison I, Becroft D, Taniguchi T et al. Somatic overgrowth associated with overexpression of insulin-like growth factor II. Nature Med 1996; 2. 311-6.
32. Le Roith D. Insulin-like growth factors and cancer. Ann Intern Med 1995; 122: 54-9.
33. De Chiara T, Robertson E, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 1991; 64: 849-59.
34. Hao Y, Crenshaw T, Moulton T et al. Tumour-suppressor activity of H19 RNA. Nature 1993; 365: 764-7.
35. Matsuoka S, Edwards M, Bai C et al. p57 KIP2, a structurally distinct member of the p21CIP2 Cdk inhibitor family, is a candi- date tumor suppressor gene. Genes Dev 1995; 9: 650-62.
36 Mong-Hong L, Reynisdottir I, Massagué J. Cloning of p57 KIP2, a cyclin dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev 1995; 9: 639-49.
37. Overall M, Spencer J, Bakker M et al. p57KIP2 is expressed in Wilm’s tumor with LOH of 11p15.5. Genes Chrom Cancer 1996; 17: 56-9.
38. Bodie B, Novick AC, Pontes JE et al. The Cleveland clinic experi- ence with adrenal cortical carcinoma. J Urol 1989; 141: 257-60
39. Henley DJ, Van Heerden JA, Grant CS et al Adrenal cortical carcinoma. A continuing challenge. Surgery 1983; 94: 926-31.
40. Icard P, Chapuis Y, Andreassian B et al. Adrenocortical carcino- ma in surgically treated patients: A retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 1992; 112: 972-80.
41. Pommier RF, Brennan MF. An eleven-year experience with adre- nocortical carcinoma. Surgery 1992; 112: 963-71.
42. Boven E, Vermorken JB, Van Slooten H, Pinedo HM. Complete response of metastasized adrenal cortical carcinoma with Op’- DDD. Cancer 1984; 3: 26-9.
43. Haak HR, Hermans J, Van de Velde CJH et al. Optimal treatment of adrenocortical carcinoma with mitotane: Results in a consec- utive series of 96 patients. Br J Cancer 1994; 69: 947-51.
44. Robinson BG, Hales IB, Henniker AJ et al. The effect of Op’DDD on adrenal steroid replacement therapy requirements. Clin Endo- crinol 1987; 27: 437-44.
45. Chun HG, Yogoda A, Kemeny N. Cisplatinum for adrenal cort- ical carcinoma. Cancer Treat Rep 1983; 76: 513-4.
46. Hesketh PJ, Mc Caffrey RP, Finkel HE et al. Cisplatin-based treatment of adrenocortical carcinoma. Cancer Treat Rep 1987; 71: 222-4.
47. Tattersall MHN, Lander H, Bain B et al. Cisplatinum treatment of metastatic adrenal carcinoma. Med J Aust 1980, 1: 419-21.
48. Bukowski RM, Wolfe M, Levine HS et al. Phase 11 trial of mitotane and cisplatin in patients with adrenal carcinoma: A Southwest Oncology Group Study. J Clin Oncol 1993; 11: 161-5.
49. Van Slooten H, Van Oosterom AT. CAP (Cyclophosphamide, Doxorubicin and Cisplatinum) Regimen in adrenal cortical carci- noma. Cancer Treat Rep 1983; 67: 377-9.
50. Schlumberger M, Brugieres L, Gicquel C et al. Fluorouracil, Doxorubicin and Cisplatin as treatment for adrenal cortical carci- noma. Cancer 1991; 67: 2997-3000.
51. Decker RA, Elson P, Hogan TF et al. for the Eastern Cooperative Oncology Group. Eastern Cooperative Oncology Group Study 1879: Mitotane and adriamycin in patients with advanced adre- nocortical carcinoma. Surgery 1991; 110: 1006-13.
52. Burgess MA, Legha SS, Sellin RV. Chemotherapy with cis-plati- num and etoposide (VP16) for patients with advanced adrenal cortical carcinoma (ACC). Proc ASCO, J Clin Oncol 1993; 12: 188.
53. Bates SE, Shich CY, Mickley LA et al. Mitotane enhances cyto- toxicity of chemotherapy in cell lines expressing a multidrug resistance gene (MDR-1/P-Glycoprotein) which is also expressed by adrenocortical carcinoma. J Clin Endocrinol Metab 1991; 73: 18-29.
54. Flynn SD, Murren JR, Kirby WM et al. P-glycoprotein expres- sion and multidrug resistance in adrenocortical carcinoma. Sur- gery 1992; 112: 981-6.
55. La Rocca RV, Stein CA, Danesi R et al. Suramin in adrenal cancer. Modulation of steroid hormone production, cytotoxicity in vitro, and clinical antitumor effect. J Clin Endocrinol Metab 1990; 71: 497-504.
56. Arlt W, Reincke M, Siekmann L et al. Suramin in adrenocortical cancer: Limited efficacy and serious toxicity. Clin Endocrinol 1994: 41: 299-307.
57. Dorfinger K, Niederle B, Vierhapper H et al. Suramin and the human adrenocortex: Results of experimental and clinical stud- ies. Surgery 1991: 100: 1100-5.
Received 4 April 1997; accepted 7 April 1997.
Correspondence to: Prof. M. Schlumberger Institut Gustave-Roussy 39, rue Camille-Desmoulins 94805 Villejuif Cedex France