Adrenocortical Carcinoma: A Single Institution Experience

Adrenocortical carcinoma (ADCC) ranks among the least common malignant endocrine tumors. Surgical resection is considered the most important treatment for this neoplasm. Medical records of patients with the diagnosis of ADCC between 1990 and 2000 were reviewed. Patient and pathologic factors were analyzed with overall survival as the primary endpoint. Statistical analysis was performed by the method of Kaplan-Meier. There were a total of 17 patients, with a mean age of 56 years. Twelve per cent presented as an asymptomatic mass, 41 per cent as a functional tumor, and 47 per cent as a nonfunctioning tumor. Primary treatment was surgical resection in 71 per cent. There was no operative mortality and one complication. Seven patients presented with stage II, five with stage III, four with stage IV, and in one could not be determined. Median follow-up was 12.8 months, median survival 67, 13, and 3 months for stages II, III, and IV, respectively. Older age, distant metastasis, nonoperative management, positive margins, advanced tumor stage, and venous invasion were significantly associated with worse overall actuarial survival. Survival for ADCC is poor. Factors associated with a worse prognosis were stage of disease, nonoperative management, positive surgical margins, vascular invasion, and older age.

ADRENOCORTICAL CARCINOMA (ADCC) is a rare malignant neoplasm. It accounts for about 0.02 per cent of all carcinomas and ranks among the least common malignant endocrine tumors.1 Several genetic alterations have been found in patients with adrenocortical carcinoma and sometimes it develops in conjunction with familial cancer syndromes as Beckwith-Wiedemann syndrome, Li-Fraumeni, and MEN-1 (multiple endocrine neoplasia type 1). Clinical presentation can vary widely from an incidental finding to an endocrine or a compressive syndrome; unfortunately, they rarely present in early stages. Today, surgical resection is considered the single most important treatment for ADCC; mitotane may be useful for advanced disease.2, 3 Here we report the experience of a tertiary care center with the treatment of ADCC.

Patients and Methods

The medical records of patients with the diagnosis of adrenocortical carcinoma in the period 1990 to 2000 were reviewed. Presumed risk factors such as smoking and oral contraceptive use, demographical information, endocrine and compression symptoms were investigated. The workup of all patients included the measurement of serum electrolyte levels to exclude hypokalemia secondary to aldosterone excess. An overnight 1 mg dexamethasone suppression test was performed to rule out Gushing syndrome, and a 24-hour urine collection for 17-ketosteroids if a masculinizing or feminizing adrenal tumor was suspected. A 24-hour urine collection to measure catecholamine and metanephrine concentrations was done if pheochromocytoma was considered. Imaging modalities included CT scan, MRI, and angiography. Metastatic workup consisted on a careful evaluation of the abdominal CT for liver metastases and chest X-ray or chest CT. Patient, tumor, and pathologic factors were analyzed with overall survival as the primary endpoint. Kaplan-Meier curves were used for statistical analysis, comparisons by log-rank test, significance defined as P < 0.05.

Results

Medical records of 17 patients with the diagnosis of adrenocortical carcinoma in the period 1990 to 2000 were reviewed. Age ranged from 33 to 81 years with a median of 57. There were 11 female patients (65%), predominantly white race (87%). Of the described risk factors, only smoking history was frequently present (47%).

Regarding clinical features, 2 patients (12%) presented with an incidentally discovered mass of 8 and 15 cm diameter, respectively. Seven patients (41%) presented with endocrine symptoms: six with Gushing syndrome and one patient with virilizing features. Eight patients (47%) with nonfunctioning tumors presented with flank pain, weight loss, and/or compressive symptoms, including nausea, vomiting, fullness, or even jaundice (Table 1).

Pheochromocytoma was excluded in all patients. In seven patients, cortisol excess was confirmed. One of them had hypokalemia but aldosterone and renin levels were not diagnostic of Conn syndrome. No patient had elevation of 17-ketosteroids. Imaging included CT scan in seven cases, MRI in five, and angiography in three cases. In one case, the CT scan initially was suspicious for a liver tumor, and the MRI defined it as an adrenal mass.

Mean tumor size was 11 cm, ranging from 6.5 to 20 cm. Pathologic evaluation was done according to Weiss criteria.

Primary treatment was surgical resection in 12 patients (71%), and no one had preoperative tissue diagnosis. One patient underwent surgical exploration through a thoraco-abdominal incision, and the tumor was deemed unresectable. Another patient had a flank incision with subcostal extension. All other operations were done through a bilateral or unilateral subcostal incision. Five patients underwent en bloc resections of adjacent organs: four nephrectomies and one splenectomy. There was no operative mortality and only one surgical complication: an intraoperative hemorrhage requiring blood transfusion; patient recovery was uneventful. All patients were replaced with stress dose hydrocortisone postoperatively. Mitotane was used in two patients: one preoperatively and the other in the adjuvant setting. Chemotherapy based on cisplatinum, paclitaxel, and mitotane as the only treatment was reserved for three patients with metastatic disease. Another patient with stage IV disease received best supportive care only.

The median follow-up was 12.8 months (range, 1-248 months). No patients were lost to follow-up. According to the modification by Sullivan et al.4 of the MacFarlane staging system,5 seven patients presented with stage II, one with stage III, and eight patients in stage IV disease. There were no patients in stage I. According to Icard system,6 seven patients presented in stage II, five in stage III, and four more in stage IV. The most frequent sites for metastatic disease were the lung and liver. Other sites were bone and pancreas. Median survival was 67, 13, and 3 months for stages II, III, and IV, respectively, using the Icard staging system (P = 0.01) (Fig. 1). The actuarial 1- and 5-year survival for the entire cohort was 37 per cent and 16 per cent, respectively.

TABLE 1. Clinical Presentation

Of the patients with localized disease who were resected (12 patients), seven had a recurrence (58%) with a median disease-free interval of 14 months (range, 3.9-58.7 months). There were six distant and one local recurrence, six patients had additional treatment: three were resected, (one patient had two resections for recurrent disease), two received palliative chemotherapy, and the other had palliative external radiotherapy.

Significantly unfavorable prognostic factors on univariate analysis for overall survival included patients older than 65 years, stage, nonoperative management, positive margins of resection, and venous invasion (Fig. 2). Capsular invasion, atypical mitosis, tumor necrosis, and high mitotic rate were not associated with a worse prognosis. The absence or presence of endocrine function did not have any prognostic significance either, although there were relatively few patients (Table 2).

Discussion

Adrenocortical cancer is an infrequent malignant tumor, the age distribution is bimodal with a peak in children less than 5 years of age and in individuals in the fourth and fifth decades of life.3 In our own series, the average age was higher (56 years). The male:female ratio has a slight trend toward women7; in accordance in this report, 65 per cent were female patients. Associated risk factors suggested to date are smoking and oral contraceptives8, 9; however, only half of our patients were smokers. Oral contraceptive use was rarely reported. Our results demonstrate that adrenocortical carcinoma presents more often in white and female patients.

FIG. 1. Survival by stages (Icard et al.6): 4, stage IV; 3, stage III; 2, stage II. Log-rank P = 0.01.

FIG. 2. Overall survival for surgical treatment versus nonoperative management. Log-rank P < 0.001.

The clinical presentation can be of a functional endocrine tumor (60%), compressive symptoms (30%), or as an incidental finding (10%).10 We had 41 per cent cases of confirmed Gushing syndrome, 47 per cent presented as a mass syndrome without any clinical evidence of hypersecretion, and asymptomatic in 12 per cent of patients. The incidence of primary carcinoma in a series of incidentally discovered adrenal masses has ranged from 0 per cent to 25 per cent11; in a multicentric retrospective study from Italy, the incidence was 13 per cent.12 However, in adrenal masses larger than 6 cm, the incidence of adrenocortical carcinoma has ranged from 35 per cent to 98 per cent.13 We had two asymptomatic patients, of which both had tumors greater than 6 cm in diameter.

Surgery is the single most important treatment for ADCC. Icard et al. reviewed a total of 253 patients with a diagnosis of ADCC from France.6 Seventy-two per cent underwent resection for cure, and 41 per cent had extensive resection because of metastat\ic disease. They had a 5.5 per cent operative mortality rate. Our own resectability rate was 70 per cent, and 41 per cent underwent en bloc resections. We had one complication (intraoperative hemorrhage) and no mortality in this series.

TABLE 2. Prognostic Factors

The role of surgery for resectable recurrent disease has been evaluated elsewhere. A series from Memorial Sloan-Kettering Cancer Center (MSKCC) composed of 113 patients had 83 repeat resections for local recurrence or metastatic disease with a 3.6 per cent mortality rate. They concluded that complete resection for recurrence and distant metastasis also was associated with an improved survival (57% 5-year survival).14 The recurrence rate in this series was also high (41%), and time to recurrence was 14 months. We had four reresections in three patients with no morbidity or mortality.

The histological differentiation between benign and malignant tumors is often difficult; in our hospital, most of the time two different pathologists reviewed the slides based on Weiss criteria.15 At present, there are no prospective data to support the use of mitotane in an adjuvant setting; in retrospective studies results have been contradictory.16-21 No conclusions can be drawn from our patients, as only two had mitotane and surgery. Chemotherapy has had poor results in ADCC, and this may be related to the strong expression of multidrug resistance gene (MDR-1), facilitating the efflux of cytotoxic agents. For this reason, some trials have been conducted with multiple agent chemotherapy in association with mitotane, with better results. 22-25 As mentioned, median survival for patients who had chemotherapy as primary treatment (stage IV) was 3 months.

We found age greater than 65 years, stage, surgical resection and margins free of tumor associated with a longer overall survival on univariate analysis. A multivariate analysis is not useful for this number of patients. Our analysis did not find nonfunctional tumors, capsular invasion, high mitotic rate, tumor necrosis, or nucleolar atypia, associated with a worse survival as others have found. Gender, race, and size were not prognostic factors.

Different staging systems have been used for ADCC; more used are the Sullivan modification of the McFarlane system (SMS) and the Icard system (IS). For both classifications, stage I is a T1 (tumor 5 cm or less in maximum diameter), N0, M0, and stage II is a T2 (tumor more than 5 cm but confined to the adrenal gland), N0, M0. Stage III in SMS is a T3 (local invasion without adjacent organ involvement), N0, M0 or T1-2, N1 (node involvement), M0. In IS, stage III is a T3, N0, M0 or any T, N1, M0. Stage IV in the SMS classification is a T4, N0, M0 or T3, N1, M0 or any T, any N, M1. In IS, stage IV is any T, any N, M1.4, 6 Using the Sullivan staging system, we only had one stage III patient who was alive in follow- up. On the other hand, when we used the Icard staging system, we had five patients in stage III that allowed a better comparison between groups. This difference may be the result of the low number of patients.

Surgical resection of localized primary or metastatic disease remains the most important prognostic factor associated with prolonged survival. The role of additional therapy remains controversial, and new agents should continually be evaluated for efficacy. It is unlikely that prospective randomized trials to further evaluate these questions in this uncommon tumor will be forthcoming, and therefore complete surgical resection should be attempted whenever safe.

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FERNANDO GOMEZ-RIVERA, M.D.,* HERIBERTO MEDINA-FRANCO, M.D.,[dagger] JORGE E. ARCH-FERRER, M.D.,* MARTIN J. HESLIN, M.D.*

From the * Section of Surgical Oncology, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama; and [dagger] Division of Surgery, Institute Nacional de Ciencias Mdicas y Nutritin “Salvador Zubirn,” Mexico City, Mexico

Address correspondence and reprint requests to Martin J. Heslin, M.D., University of Alabama at Birmingham, Department of Surgery, Section of Surgical Oncology, 321 Kracke Building, 1922 7th Avenue South, Birmingham, AL 35294.

Copyright The Southeastern Surgical Congress Jan 2005