Adrenocortical Carcinoma A Clinical Study and Treatment Results of 52 Patients
Anna A. Kasperlik-Zakuska, M.D., Ph.D., Barbara M. Migdalska, M.D., Ph.D., Stefan Zgliczyński, M.D., Ph.D., and Anna M. Makowska, M.D.
Background. Adrenocortical carcinoma is a rare tu- mor with a poor prognosis. This work was aimed at ana- lyzing the clinical outlook and treatment results of 52 pa- tients with this disease.
Methods. This study included patients with adreno- cortical carcinoma referred to the Department of Endo- crinology at the Center of Postgraduate Medical Educa- tion (Warsaw, Poland) during the last 30 years. In 11 pa- tients, the adrenal tumor was found incidentally by ultrasonographic scan. Hormonal examinations made it possible to define the endocrine activity of the tumors, whereas imaging techniques helped to determine their staging. Forty-eight patients underwent surgery, and 36 of them received mitotane. This drug was administered to 26 patients for a range of 10 months to 10 years; 13 pa- tients received mitotane immediately after the operation, and 13 others after a delay. The patients with severe hy- percorticism were pretreated before surgery with amino- glutethimide and mitotane.
Results. The study comprised 10 men and 42 women; hormonally active tumors were diagnosed in 39 of them. Cushing’s syndrome was the most frequent entity. At di- agnosis, 17 cases were classified as localized disease, 15 as regional disease, and 20 as distant disease. Pretreatment with the inhibitors of steroidogenesis improved the sur- vival perspectives in the early postoperative period. As of this writing, there were 12 survivors in the group of 26 patients treated by surgery and long term mitotane ther- apy and only 2 survivors of 7 patients treated with sur- gery only.
Conclusions. Surgery with immediate adjuvant long term mitotane administration was the most effective form of therapy for patients with adrenocortical carcinoma. Cancer 1995; 75:2587-91.
Key words: adrenocortical carcinoma, Cushing’s syn- drome, virilization, mitotane.
In the last 30 years, 105 patients with hormonally active nonmalignant adrenal tumors have been treated at the Department of Endocrinology (Center of Postgraduate Medical Education) in Warsaw. Due to the development of imaging techniques, 130 new incidentally found nonfunctional adrenal tumors were observed in the last 8 years. The results of diagnostic procedures and ther- apy in most patients in both groups have been recently described.1,2 The frequency of detection of adrenocorti- cal carcinomas has increased lately, too. Between 1965 and 1994, 52 patients with adrenocortical carcinoma have been referred to our department, 30 of them de- tected in the last 10 years. The analysis of clinical data and results of treatment are the subject of this paper.
Patients and Methods
The study comprised 42 female patients (81%) age 13- 70 years (mean, 38.2 ± 13.7 years), and 10 male patients age 20-76 years (mean, 53.1 + 18.1 years). The mean age of all the patients was 40.9 ± 15.3 years, and the female/male ratio was 4.2. The children with adreno- cortical carcinoma age 12 years or younger were re- ferred to the Center of Child Health. In 11 cases, the tumor was found incidentally on ultrasonographic ex- amination.3 In two female patients, intensive retroperi- toneal and peritoneal bleeding was the first sign of the disease.
All of the patients underwent clinical, hormonal, and imaging evaluation. Histologic examination con- firmed the diagnosis in each patient (basing on histo- logic criteria described by Hough et al.4).
Hormonal Examinations
Daily urinary 17-hydroxycorticosteroids (17-OHCS) by the Silber and Porter method and 17-ketosteroid excre-
From the Department of Endocrinology, Center of Postgraduate Medical Education, Warsaw, Poland.
This work was supported by a Komitet Badań Naukowych Sci- entific Research Committee Grant 4 1679 91 01.
Address for reprints: Anna A. Kasperlik-Załuska, Department of Endocrinology, Bielański Hospital, Cegłowska, 80, 01-809 Warsaw, Poland.
Received September 17, 1994; revision received January 17, 1995; accepted January 17, 1995.
tion by the Zimmerman method were measured at base- line and during the dexamethasone suppression test (2 mg daily for 2 days and 8 mg daily for next 2 days). Serum cortisol and testosterone levels were determined by radioimmunologic assay when possible. In one case, serum growth hormone, growth hormone-releasing hormone (GH-RH), and insulin-like growth factor-I concentrations were also measured by radioimmuno- logic assay.
Radiologic studies, ultrasound scan, and computed tomography were performed when available. In the 1960s, the main imaging techniques were radiologic studies, intravenous, pyelography with simultaneous tomography, and arteriography.
Treatment
Forty-eight patients were treated surgically; for four of them a partial hepatectomy was performed. The pa- tients with severe Cushing’s syndrome were pretreated with aminoglutethimide (Orimeten, Ciba-Geigy, Basel, Switzerland), 1.5 g daily and mitotane (o,p’-DDD, i.e., 1,1-dichlorodiphenyldichloroethane) in a dose of 3.0 g daily for about 2 weeks. For four patients, the second operation was performed within 24 months because of the recurrence of cancer. Thirty-six patients received mitotane, including 26 with localized or regional dis- ease (according to the Surveillance, Epidemiology and End Results Classification5). Thirteen among them were given mitotane immediately after the operation, and the other 13 were given mitotane 3-15 months after sur- gery for 2 years or more, for a maximum of approxi- mately 10 years. When the operation appeared unsuc- cessful, the initial daily dose of 3.0 g was quickly in- creased to 8.0-10.0 g for about 2 weeks, and then it was decreased gradually. For long term treatment, a dose of 3.0-5.0 g daily has been used. For patients with local- ized disease, the postoperative dose of mitotane did not exceed 4.0 g daily. Two patients with metastatic disease were treated with mitotane only, 4.0-10.0 g daily. Rou- tine replacement therapy with hydrocortisone or corti- sone and fluorohydrocortisone was instituted for the patients receiving mitotane.
For three patients, cisplatin and etoposide have been administered every 4 weeks. 5-Fluorouracil was added to mitotane therapy for four patients with a large abdominal mass 3-12 months after surgery. Radiother- apy was given to two young women after surgery. Two patients with metastatic disease died just before the sur- gery.
Results
Clinical Evaluation
At the time of diagnosis, 39 patients (75%) presented with features of adrenocortical hyperactivity. The initial
| Feature | No. of patients | % |
|---|---|---|
| Cushing's syndrome | 25 | 48 |
| Virilization and hypertension | 8 | 15 |
| Virilization | 2 | 4 |
| Gynecomastia | 1 | 2 |
| Myasthenia | 1 | 2 |
| Pathologic fractures | 2 | 4 |
| Acromegaly | 1 | 2 |
| Abdominal pain | 4 | 8 |
| Lumbar pain | 4 | 8 |
| Weight loss, weakness, fever | 3 | 6 |
| Abdominal mass | 1 | 2 |
clinical findings are shown in Table 1. Additionally, in two female patients, Cushing’s syndrome appeared about 4 months after surgery. By contrast, in a 22-year- old woman, the endocrine features observed before sur- gery did not appear during the recurrence of the tumor. In the patient with some acromegalic signs, a secondary amenorrhea was the only initial hormonal disturbance, whereas 10 months later, severe hirsutism developed. In a woman with Cushing’s syndrome a coincidental uterine carcinoma was diagnosed. A severe symptom- atic hypoglycemia was observed in the last weeks of the life of two young women with metastatic liver infiltra- tion (both patients were referred to our clinic after ra- diotherapy following surgery).
Hormonal Examinations
Urinary 17-OHCS excretion was elevated in 13 patients (25%), 17-ketosteroids in two women (4%), and both groups of hormones in 24 patients (46%). In one woman without signs of adrenocortical hyperactivity, the chromatographic analysis revealed raised urinary excretion of fetal-type androgens, 16-OH-androstendi- one, and androstendiol. Dexamethasone did not sup- press 17-OHCS and 17-ketosteroids urinary excretion in any patient. Serum cortisol levels were elevated in 36 patients, whereas testosterone levels where higher in 5 of 12 female patients being investigated. Serum GH concentrations in the patient with the acromegalic signs ranged from 42 to 49 ug/1 (normal, 1.0-5.0 µg/l) before the surgery, having been 22 ug/1 2 weeks after the in- complete adrenal tumor resection. However, they rose to 190 µg/1 during the progression of the metastatic dis- ease. The GH-RH plasma levels were 110 pg/ml (nor- mal, 10-70 pg/ml) and insulin-like growth factor-I was 230 ng/ml (normal, 97-381 ng/ml). Somatostatin ana- logue octreotide (Sandostatin; Sandoz, Basel, Switzer-
| Diameter (cm) | 3.2-6.0 | 6.1-10.0 | >10 |
| No. of cases | 10 | 15 | 28 |
land) in a dose of 100 µg subcutaneously every 8 hours decreased GH levels to 82 ug/1, the nadir having been observed 4-6 hours after the injection.
Imaging Diagnostics
The right adrenal gland was involved in 25 patients (48%); the left adrenal gland in 26 patients (50%), and both adrenal glands in 1 patient. In the group with inci- dentally found nonfunctional adrenal tumors, there was a 70-year-old woman with carcinoma of the left adrenal gland found incidentally during echocardiogra- phy 5 years after the resection of the right adrenal ade- noma (the histologic diagnosis was verified after the second operation). The diameter of the adrenal tumors ranged from 3.2 to 20.0 cm (Table 2).
Staging
At the time of diagnosis, 17 cases were classified as lo- calized disease (33%), 15 cases as regional disease (29%), and 20 cases as distant (metastatic) disease (38%). On histologic examination, the most frequent findings were cellular pleomorphism, diffuse growth pattern, vascular invasion, tumor cell necrosis, and cap- sular invasion. The incidentally found adrenocortical carcinomas did not differ significantly in histologic pa- rameters from the remaining tumors. However, in two of them a low cellular differentiation was stated. In the smallest incidentally found adrenocortical carcinoma (3.2 cm diameter), an invasion of blood vessels was found.
Treatment
The results are summarized in Table 3. The best effect of the surgery has been observed in two patients (survival time, 7 and 21 years). One of them, observed for 21 years after the operation, gave birth to two healthy chil- dren during this period.6,7 There are 10 survivors in the group of 13 patients given mitotane immediately after the surgery for a period of 2 to approximately 10 years. Three patients from this group died within 10 years be- cause of metastatic dissemination. In the remaining group of patients not treated immediately after the op- eration with mitotane, only two women survived (both were classified as having localized disease at the time of diagnosis). The patient in whom mitotane therapy was
finished after 10 months died 2.5 years later because of neoplasmatic dissemination. A 22-year-old woman experienced a rapid recurrence when the dose of mito- tane had been lowered from 4.0 to 3.0 daily. The recur- rent tumor was hormonally inactive, whereas the pa- tient had had Cushing’s syndrome at the time of first presentation.
Cisplatin and etoposide given immediately after the operation in a 40-year-old woman resulted in a 20- month remission. In two other cases, these drugs, ad- ministered when the disease severely progressed, caused only a slight improvement. Similarly, 5-fluoro- uracil given during widespread abdominal neoplas- matic infiltration was not curative.
Discussion
Our study was based on material collected for nearly 30 years. The diagnostic procedures have changed over time, particularly with the introduction of new imaging techniques. Therefore, not all hormonal and imaging examinations could have been done for each patient, and the incidence data (e.g., concerning the elevated testosterone levels) are not representative for the entire population in this study. We are not sure whether the increased detection of adrenocortical carcinoma in the last years is due mainly to better imaging methods or whether it represents a true increase in the frequency of these tumors. According to the Third National Cancer Survey of 1975,8 the annual incidence of adrenocortical carcinoma is approximately 0.5-2.0 per million popula- tion in the United States. A new epidemiologic study on the incidence of these neoplasms would be useful. It is noteworthy that 11 tumors in our study were found incidentally by ultrasonographic scan; only one of them caused mild signs of Cushing’s syndrome, which was misinterpreted before the adrenal tumor detection. This problem has not been discussed in the literature be-
| Method | No. of patients | Survival (mo) | No. of survivors |
|---|---|---|---|
| Surgery | 7 (5*) | 1-255 | 2 |
| Surgery + adjuvant | 41 (17*) | ||
| therapy | 4-118 | 14 (5*) | |
| + Mitotane | 32 (10*) | 4-118 | 12 (5*) |
| + Mitotane + 5-FU | 4 (4*) | 10-24 | 0 |
| + Radiation therapy | 2 | 5,12 | 0 |
| + Cisplatin + etoposide | 3 (3*) | 12-20 | 1* |
| Mitotane | 2 (2*) | 6,10 | 0 |
5-FU: 5-fluorouracil.
* Patients with metastases and/or regional infiltration at the time of diagnosis.
cause incidentally found nonfunctional adrenal tumors are a new clinical entity.
Our observations of tumors and their function do not differ significantly from recent reports.9-11 In com- parison with these reports, our female/male ratio was significantly higher: 4.2 versus 1.1,9 2.5,10 and 0.6.11 Wooten and King11 reviewed the English literature from 1952 to 1992 and found 1891 cases of the disease. In this group of patients, the female/male ratio was 4:3. Numerous other reports on the malignant adrenocorti- cal neoplasms have been published,12-17 with the distri- bution of epidemiologic data differing slightly from re- port to report. We could not compare the age of our pa- tients with that of other groups of patients, because we did not admit children to our department. The pediatric patients have been diagnosed and treated in the Depart- ment of Endocrinology at the Center of Child Health.
The endocrine activity of the tumors was compara- ble with that observed by Luton et al.10 and with En- glish literature data,11 however, it was evidently higher than in the Venkatesh et al. series.9 The chromato- graphic demonstration of the fetal-type androgens in a 32-year-old woman suggests that this type could be a more frequent phenomenon. Acromegalic signs with concomitantly increased serum GH concentrations in the same patient were a rare finding. A transitory im- provement following the partial adrenocortical tumor resection and elevated GH-RH levels was suggestive of an ectopic neurohormonal secretion of the adrenocorti- cal carcinoma. The presence of synaptophysin and bombesin in tissue specimens was characteristic for the tumors with neuroendocrine activity.18 We did not find any such case in the literature.
In analyzing the clinical picture, we did not con- sider hypoglycemia as an endocrine symptom, because it was caused by a vast metastatic liver infiltration.
Venkatesh et al.9 reported frequently associated malignancies; however, there was only one such case in our material.
We used surgery with adjuvant mitotane admin- istration as the main treatment method.19 Some recent reports20,21 have questioned the efficacy of mitotane ad- ministered to patients treated surgically for adrenocor- tical cancer. We analyzed the results of treatment in our material by comparing the patients treated with mito- tane immediately after the surgery, or even before the operation, with the patients who had not received this drug or received it 3 to 15 months later, after the sur- gery.22 There are 10 survivors in the group of 13 patients treated by surgery and an immediate adjuvant long term mitotane administration versus 2 of 7 patients who received surgery alone and another 2 patients in the se- ries of 13 cases who was given mitotane with a delay of 3-15 months after surgery. The longest survival time in
a patient with regional disease treated with mitotane was approximately 10 years. We did not discuss the re- sults of therapy of four patients treated by surgery with adjuvant mitotane administration in the last year. The main problem in long term mitotane therapy is finding an effective dose and establishing the length of time af- ter surgery that patients with localized disease should be treated.
Recently, cisplatin23,24 and etoposide25 have been tried in patients with adrenocortical carcinoma, and good responses have been noted. In our patients, these cytotoxic drugs were administered to persons with pro- gressive disease and poor prognostic factors, thus cura- tive effects were not expected. Although we did not re- fer any patient for radiotherapy, we observed two young women exposed to such therapy; a rapid meta- static dissemination followed this treatment in both pa- tients. We do not recommend the use of radiotherapy as adjuvant treatment for patients with adrenal malig- nancy.
We have found that surgery with immediate adju- vant long term mitotane administration is the most valuable method of treatment of adrenocortical carci- noma. Routine ultrasonographic abdominal examina- tion could increase early detection of adrenocortical neoplasms and improve the prognosis.
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