Adrenal GlandsPrognostic Role of Overt Hypercortisolism in Completely Operated Patients with Adrenocortical Cancer
Introduction
Adrenocortical carcinoma (ACC) is a rare tumor characterized by a dismal prognosis with <50% of patients surviving >5 yr after diagnosis [1]. Complete surgical resection of ACC offers the best chance for prolonged survival, particularly in patients diagnosed at an early stage and with low proliferating tumors [1]; however, a significant number of patients without objective and biochemical evidence of residual disease after surgery are destined to relapse [2], [3], [4].
The aggressive behavior and the high recurrence rate of most of the ACC patients provide the rationale for adjuvant therapy. For decades mitotane has been the only approved drug for ACC therapy [5]. In a case-control study involving 177 patients, the outcome in 47 patients treated in Italian reference centers systematically using adjuvant mitotane therapy after radical surgery was significantly improved (in terms of both recurrence-free survival [RFS] and overall survival [OS]) compared with 55 Italian patients and 75 German patients treated at institutions not administering adjuvant mitotane therapy [6].
Although these data cannot be considered conclusive, mitotane is recommended [7] and increasingly prescribed in ACC patients who have undergone a complete resection and are at high risk of recurrence. However, only very few prognostic factors are currently available to identify patients at risk. A few molecules have been proposed as prognostic and predictive markers [8], [9], [10], [11], [12], but none of them are used in clinical practice. Currently only disease stage, completeness of initial resection, and proliferation index are widely accepted prognostic factors [13], [14]. However, they are not sufficiently accurate to predict the outcome of every individual, and risk stratification remains challenging, at least for a subset of patients. Consequently, new prognostic factors are needed.
Two previous reports suggested cortisol secretion as a negative prognostic factor in ACC patients. In a large single-institution French series including 202 patients with different disease stages, cortisol excess was found to be an independent prognostic factor for OS [15]. Similar results were obtained from a series of 72 Italian patients submitted to chemotherapy with etoposide, doxorubicin, and cisplatin plus mitotane [16]. In the French series a significant interaction was found between cortisol overproduction and mitotane therapy, and in a subsequent letter on the same series the authors reported a trend toward improved outcomes for patients with cortisol-overproducing tumors subjected to adjuvant mitotane therapy [17]. Conversely, cortisol excess failed to be associated with prognosis in another series involving metastatic ACC patients [18]. It is not actually known whether or not hypercortisolism has a prognostic role in radically resected patients.
In the current study, the prognostic role of overt cortisol excess at diagnosis was investigated in a large multicenter multinational series of patients who underwent complete resection. A secondary aim of the study was to explore the efficacy of adjuvant mitotane therapy, classifying patients according to their cortisol excess status.
Section snippets
Methods
This retrospective analysis was carried out in five cohorts of patients with ACC collected from several centers in Italy, Germany, and the Netherlands and from two single institutions in France (Gustave Roussy Institute) and the United States (University of Michigan), respectively. All patients had undergone radical surgery. None of the patients included in this study has been included in previous published series [15], [16], [17], [18]. The patients were recruited between 1990 and 2008. Median
Results
A total of 524 patients entered the study. Table 1 shows the patient characteristics. No patient had metastases. Recurrence was documented in 339 patients (64.7%). Death occurred in 204 patients (38.9%). Clinical signs of cortisol plus or minus other hormone excess were observed in 197 patients (37.6%) and clinical hyperandrogenism in 58 patients (11.1%). Seven patients (1.3%) had symptoms and signs of pure mineralocorticoid excess, 9 patients (1.8%) had clinical evidences of estrogen excess,
Discussion
One of the major determinants of the variability in the clinical presentation of ACC is the presence and type of hormone secretion [14]. Hormone-secreting tumors most frequently produce cortisol. In this multinational study we demonstrated for the first time in a large series of radically resected ACC patients that the presence of clinical signs of cortisol excess is prognostically relevant either in terms of RFS or in terms of OS applying a multivariate analysis after adjustment for commonly
Conclusions
The present study demonstrates that overt hypercortisolism is a new prognostic factor in patients with radically resected ACC. The mechanisms underlying the relationship between cortisol secretion and prognosis in this patient subset deserve further elucidation.
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