Urologia Internationalis
Urol Int DOI: 10.1159/000345489
Adrenocortical Carcinoma: Clinicopathological Features, Prognostic Factors and Outcome
Serkan Keskin Faruk Taş Sezai Vatansever
Department of Medical Oncology, Institute of Oncology, University of Istanbul, Istanbul, Turkey
Key Words
Adrenocortical carcinoma . Clinicopathological characteristics · Survival rates
Abstract
Objective: The purpose of this study was to investigate the clinicopathological characteristics and treatment outcomes of patients with adrenocortical carcinoma (AC). Methods: Twenty-four patients (10 females and 14 males) diagnosed with AC between 1998 and 2009 were evaluated. Clinical features and outcomes were reviewed. Results: Median age was 46.5 years. One (4%) patient was classified as stage I, 10 (42%) were classified as stage II, 8 (33%) were classified as stage III and 5 (21%) were classified as stage IV. Tumor sizes ranged from 3 to 22 cm with a mean diameter of 11 cm. Five patients were locally inoperable at initial diagnosis. In addi- tion to surgery, 2 of 19 patients were treated with an adju- vant cisplatin plus etoposide regimen. Sixteen patients were treated with chemotherapy after recurrence. Median survival time was 18 months. The 1- and 5-year overall sur- vival estimates were 73 and 48%, respectively. Mean sur- vival times for male and female patients were 58 and 12 months, respectively (p = 0.046). Early T stage (p = 0.04), lymph node negativity (p < 0.001), the absence of distant metastases (p < 0.001) and early stage (p < 0.001) were cor-
related with overall survival. Conclusion: AC is a rare disease with a poor prognosis. There are correlations between gen- der, stage and survival. Copyright @ 2013 S. Karger AG, Basel
Introduction
Adrenocortical carcinoma (AC) is a rare tumor with poor prognosis. The incidence is estimated as 1 case per 1.7 million subjects, accounting for only 0.02% of cancers [1, 2]. Clinical presentation can vary widely from an inci- dental finding to an endocrine or a compressive syn- drome. Most commonly, functional tumors produce cor- tisol, causing Cushing’s syndrome. Unfortunately, they rarely present in early stages. The most common sites of metastases include lung, liver and lymph nodes.
Most of the previous studies on AC have been carried out in a single institution or in very few institutions, and have included a small number of patients. Thus, the ac- cumulation of clinical experience of even a small number of patients with the disease is still needed in order to be able to provide better care for them. This study retrospec- tively reviewed the clinical findings and treatment out- comes in 24 AC patients.
KARGER
Patients and Methods
Between January 1998 and December 2009, 30 patients with AC applied to the Institute of Oncology, Istanbul University. Six patients were excluded from the study because of insufficient records. Data on the remaining 24 patients were analyzed. This retrospective study was approved by the institutional review board of the Institute. All of the patients had a histologically con- firmed diagnosis of AC. Clinical records were reviewed and in- formation on age, gender, pathology and stage as well as treatment details for recurrences were collected.
The stage of the disease was determined according to the mod- ified MacFarlane classification [3]: a stage I tumor is <5 cm in diameter without evidence of regional nodal involvement, local invasion or metastases, a stage II tumor is ≥5 cm without the evidence described for stage I, a stage III tumor is associated with evidence of regional nodal involvement or local invasion but not distant metastases and a stage IV tumor has distant metastases.
Follow-Up
After the completion of therapy, the patients were followed up every 3 months for 2 years, and then biannually for the next 3 years; thereafter, they were followed up annually.
Statistics
The x2 and Mann-Whitney U tests were used for the compar- ison of groups. Overall survival (OS) was calculated from the date of initial diagnosis to the date of death from any cause or since the last follow-up. Survival analysis was performed by the Kaplan- Meier method. All analysis was performed using the SPSS 15.0 statistical software package (Chicago, Ill., USA) program, and p < 0.05 was considered to be significant.
Results
Median age of the 10 (42%) female and 14 (58%) male patients was 46.5 years (range 26-67 years). Hyperal- dosteronism, Cushing’s syndrome and virilization were shown in 1, 3 and 2 patients, respectively. Other patients did not have any clinical evidence of endocrine syn- drome.
One patient (4.2%) was classified as stage I, 10 (41.7%) were stage II, 8 (33.3%) were stage III, and 5 (20.8%) were stage IV. Tumor sizes ranged from 3 to 22 cm with a mean diameter of 11 cm.
Five patients had metastases at the time of initial diag- nosis: 2 had lung metastases, 1 had lung and liver metas- tases, 1 had lung and bone metastases and 1 had lung, bone and skin metastases. Twelve patients developed me- tastases during follow-up. Three patients had pulmonary metastases, 2 had hepatic metastases, 3 had extensive in- volvement in the abdomen, 1 had lung and bone metas- tases, 1 had lung and liver metastases, 1 had lung, liver and bone metastases and 1 had skin metastases.
Five patients were locally inoperable at the time of the initial diagnosis. In addition to surgery, 2 out of 19 pa- tients (1 with stage II and 1 with stage III disease) received adjuvant cisplatin plus etoposide treatment. Sixteen pa- tients who had local or systemic relapse were treated with intensive chemotherapy. Regimens used at relapse were cisplatin and etoposide (n = 6), mitotane (n = 1), mitotane and cisplatin (n = 2), paclitaxel and carboplatin (n = 1), cisplatin and adriamycin (n = 2) and cisplatin, adriamy- cin and cyclophosphamide (n = 4). Only 2 patients - 1 treated with cisplatin and etoposide and 1 treated with cisplatin, etoposide and cyclophosphamide - had a par- tial response after chemotherapy; in these cases, unfortu- nately, the disease progressed within a short time.
Median survival time was 18 ± 16 months. During the median follow-up time, 4 patients (17%) showed no evidence of the disease, 11 (46%) were alive, but with the disease and 9 (37%) died. Death was associated with dis- ease progression. The 1- and 5-year OS estimates were 73 and 48%, respectively.
Several clinical features, including age, gender, T stage, lymph node positivity, metastases, disease stage, capsule invasion and vascular invasion were assessed for correla- tion with outcomes (table 1). In the univariate analysis, the following variables indicated a statistically significant effect on the length of survival: gender (female vs. male), T stage (TI-II tumors vs. TIII-IV), node status (positive vs. negative), distant metastases (no vs. yes) and stage. Vas- cular and capsular invasion were observed in 11 and 15 patients, respectively. However, these were not found to be significantly predictive of survival. Multivariate anal- ysis was not applicable for this number of patients.
Discussion
AC is an infrequent malignant tumor with poor prog- nosis. The mainstay of treatment is surgery, and complete resection of the disease is a prerequisite for a better out- come. The overall 5-year survival rates have been report- ed to be 16-60%, depending on the clinical background of the patients in the studies [4-8]. Stage is a strong influ- ential factor for survival in most studies. Despite en bloc resection even in patients without evidence of metastatic disease, the 5-year survival rate is only approximately 50% with complete resection [1]. However, 5-year surviv- al rate for patients with distant metastases ranges from 0 to 11.5% [4, 9, 10]. In our study, the mean survival rate for patients with stage I-II, stage III and stage IV disease was 61, 32 and 5 months, respectively (p < 0.001).
| Feature | Patients, n | Events | Mean survival | 95% CI | p | |
|---|---|---|---|---|---|---|
| n | % | |||||
| Age, years | ||||||
| ≤50 | 15 | 5 | 33 | 38 | 18-59 | |
| >50 | 9 | 4 | 44 | 44 | 10-78 | 0.535 |
| Sex | ||||||
| Male | 14 | 5 | 36 | 58 | 35-81 | |
| Female | 10 | 4 | 40 | 12 | 7-17 | 0.046 |
| T stage | ||||||
| I-II | 11 | 3 | 27 | 61 | 30-93 | |
| III-IV | 13 | 6 | 46 | 20 | 6-34 | 0.04 |
| N stage | ||||||
| 0 | 19 | 5 | 26 | 57 | 34-79 | |
| 1 | 5 | 4 | 80 | 5 | 2-8 | <0.001 |
| Metastasis | ||||||
| 0 | 19 | 5 | 26 | 57 | 34-79 | |
| 1 | 5 | 4 | 80 | 5 | 2-8 | <0.001 |
| Stage | ||||||
| I-II | 11 | 3 | 27 | 61 | 30-92 | |
| III | 8 | 2 | 25 | 32 | 14-51 | |
| IV | 5 | 4 | 80 | 5 | 2-7 | <0.001 |
| Vascular invasion | ||||||
| No | 5 | 1 | 20 | 43 | 28-57 | |
| Yes | 6 | 2 | 33 | 42 | 11-72 | 0.272 |
| Capsular invasion | ||||||
| No | 4 | 3 | 75 | 47 | 4-91 | |
| Yes | 11 | 3 | 27 | 41 | 15-66 | 0.961 |
Surgery remains the primary treatment modality and the only chance for cure in these patients [11-13]. How- ever, the role of laparoscopic adrenalectomy (LA) in the treatment of patients with AC is controversial. Since the early 1990s, LA has replaced open adrenalectomy (OA) as the gold standard for addressing adrenal disorders of be- nign origin. In a study from Germany, Brix et al. [14] con- ducted a retrospective analysis of 152 patients with stage I-III AC with a tumor ≤10 cm and they found that LA and OA did not differ with regard to the primary end point using either the matched-pairs approach or multi- variate analysis. Similarly, adjusted recurrence-free sur- vival was not different between LA and OA. Gaujoux and Brennan [15], however, say that the laparoscopic approach for AC should be avoided, at least until such time as a clear standard of operative care has been achieved and established for the open approach. Lastly, Porpiglia et al. [16] recommend that if the following criteria were re- spected and a surgical excision was indicated, LA could
be considered for the following adrenal lesions: (1) inde- terminate small incidentaloma, (2) indeterminate large incidentaloma, without necrosis or evidence of invasion, and (3) likely small ACC.
On the other hand, the role of reoperation has been investigated. Bellantone et al. [17] reported that the mean survival in 20 patients who underwent reoperation was significantly higher than in the cases which were not re- operated. A study by the Memorial Sloan-Kettering Can- cer Center indicated that complete resection for local re- currence and distant metastases were associated with the improved survival [10]. In a review of patients with recur- rent or metastatic ACs, researchers defined that median survival and 5-year survival from the time of the first metastasectomy were 2.5 years and 41%, respectively, and the median survival of patients with a disease-free in- terval <12 months was 1.7 years compared to 6.6 years for patients with a disease-free interval >12 months (p = 0.015). Chemotherapy had no impact on survival in that study [18]. Unfortunately, despite aggressive surgery, 70-85% of patients experienced relapse locally or devel- oped metastases, and patients with incomplete resection had survival <1 year [19].
The age distribution is bimodal with peaks in children <5 years of age as well as in the fourth and fifth decades of life in older individuals. In our own series, the median age was 46.5 years. Until today, it has been reported in most of the studies that the male:female ratio has a slight trend towards women [4, 7, 19]. There have been a few studies indicating an inverse trend towards men [5, 20]. However, the female:male ratios in the studies do vary ac- cording to age. In our own series, the female:male ratio was 3:2 in patients aged 26-40 years (n = 10) and 2:5 in patients aged 46-67 years (n = 14). On the other hand, we detected that gender is a prognostic factor for patients with ACs. In contrast to other studies, male patients had the survival advantage over female patients. OS times for male and female patients were 58 and 12 months, respec- tively (p = 0.046).
Although there is no consensus on the role of adjuvant treatment with mitotane for patients with complete re- section of the primary lesion, some studies have support- ed the benefit of treatment [21, 22]. In a review of 551 cases in the literature, mitotane was reported to induce tumor response in 35% of the patients [23]. In our study, none of the patients was treated with mitotane in an ad- juvant setting. Of the 2 patients whom we treated with adjuvant etoposide plus cisplatin, one had no evidence of disease after 18 months and the other one was alive, but had the disease after 35 months. However, our experience
may not support the use of etoposide plus cisplatin treat- ment in the adjuvant setting. Recently, Fassnacht et al. [24] published a study which investigated the role of two different mitotane-containing regimens for the treat- ment of patients with advanced AC. They reported that response and progression-free survival rates were signif- icantly better with EDP (etoposide, doxorubicin and cis- platin) and mitotane than with streptozocin and mito- tane as a first-line therapy - with similar rates of toxic events, but no significant difference in OS rates.
In conclusion, AC is a rare tumor with poor prognosis. The preoperative staging has an important influence on the survival of the patient. There is no effective systemic therapy for AC and novel therapies are urgently required. Hopefully, with a better understanding of the biological factors influencing AC treatment, the survival rates of these patients will be improved.
Disclosure Statement
The authors declare no conflicts of interest.
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