Data on the incidence of ACC are limited, but there has been no increase in incidence, even though there has been an increase in the number of diagnosed adrenal tumours and the number of adrenal operations. This increase in the early diagnosis and operative treatment of adrenal tumours could in fact be the reason for the slight decrease in the incidence of ACC in Holland over the past 20 years; the incidence has declined from 1.3 to 1.0 per million inhabitants [2].
The gender prevalence in our study corresponds to data from the literature. Women are affected by ACC more often than men, with a ratio of 1.2–1.5:1 [1–4]. Even though most patients are in their fifth or sixth decade of life at the time of diagnosis, with a mean age of 43–56 years, ACC occurs in all age groups, including children [1–4]. The population-based age-standardized incidence rate for patients <20 years of age is 0.2 per million person-years [5].
ACC is rarely diagnosed as stage I. Indeed, in the current study study only 3 % of patients were diagnosed in stage I, compered to 6 % according to the literature [3, 6, 7]. Most patients (approximately 50 %) are diagnosed with stage II ACC, as was the case in the current study and published data [3, 4, 7]. ACC tumours are usually large in size. The mean size of ACC tumours according to published data is ≥ 10 cm [1, 6]. In the current study, the size of ACC tumours ranged from 3.5 to 23 cm (mean, 9.8 cm; standard deviation [SD], 4.0 cm), and the weight ranged from 15 to 2450 g (mean, 323 g; SD, 481 g). Lymphatic metastases are present in 20 % of patients with ACC at the time of diagnosis, while distant metastases occur in nearly 30 % of patients with ACC [1].
The most common sites for distant metastases are in lungs and liver [8]. Even though, lymphatic metastases are often present, locoregional lymph node dissection is not routinely performed, although Reibetanz et al. suggested that locoregional lymph node dessection improves oncologic outcome [9].
The optimal treatment plan for ACC has not been well-defined. The best results have been achieved with surgical treatment, which has the most important role in the treatment of ACC, while additional treatment options are still a matter of discussion [10]. Surgical treatment is relatively safe, considering that the peri-operative mortality is approximately 5 % [3]. A subcostal laparotomy is the most common approach to ACC; a laparoscopic approach was not used at our institution, even though we perform laparoscopic surgery for other indications. Ferreira et al. also reported that a subcostal extended incision is the best approach for ACC and that it can be used even for ACC tumours ≥ 15 cm in size [11]. Laparoscopic adrenalectomy for ACC is associated with higher recurrence rates, particularly peritoneal recurrences. For this reason, open adrenalectomy is a better choice because of the oncologic benefit that surpasses the short-term benefits of minimally invasive surgery [12]. Miller et al. reported the mean size of laparoscopically-removed tumours to be 7 cm, whereas the size of tumours removed through open adrenalectomy was 12 cm. In the same study, positive margins of resection were present in 50 % of laparoscopic operations and ≤ 20 % in open adrenalectomies. Furthermore, there was a shorter interval before recurrence after laparoscopic surgery compared to open surgery (9 months vs. 19 months). For all of these reasons, Miller et al. concluded that laparoscopic surgery should not be attempted for ACC [13].
Open adrenalectomy is superior to laparoscopic adrenalectomy because of a more complete resection of the tumour [14]. Brix et al. after analyzing 35 laparoscopic and 117 open adrenalectomies, concluded that for localized ACC tumours ≤ 10 cm in diameter, laparoscopic adrenalectomy performed by an experienced surgeon is not inferior to open adrenalectomy [15].
ACC is considered a radioresistant tumour, thus radiotherapy is rarely used; except as adjuvant radiotherapy to the tumour bed in patients with incomplete tumour resection or ACC metastases as a palliative measure [16]. Data on the results of the application of adjuvant radiotherapy to the tumour bed in patients with complete resection of the tumour are limited; and the results of the effect of such adjuvant radiotherapy on reducing high rates of local recurrence of ACC are controversial [17, 18].
In the current study, the 1-, 3-, 5-, and 10-year survivals in patients with ACC were 52.5 %, 48.2 %, 41.1 %, and 16.4 %, respectively; the median survival was 36 months and the mean survival was 61.5 months. Bilimoria et al. reported a median survival of 32 months and a 5-year survival of 38 % in patients with ACC, with no evident change in survival rates between 1985 and 2000 [1]. Tritos et al. reported a median survival of 17 months in patients with ACC [19]. Tauchmanova et al. found an overall survival of 41 months in patients with ACC [4]. Schulick et al. showed a median survival of 38 months and a 5-year survival of 37 % for patients with ACC [20]. According to Keskin et al. the median survival for patients with ACC was 18 months, while the 1-year survival was 73 % and the 5-year survival was 48 % [6]. In the current study, the presence of lymphatic metastasis was a negative prognostic factor, while post-operative therapy with mitotane was a positive prognostic factor of survival for patients with ACC. Keskin et al. reported that the absence of lymphatic metastasis was a favourable prognostic factor for patients with ACC [6]. Also, Keskin et al. showed that the absence of distant metastases and an early stage of the disease were favourable prognostic factors. Additionally, Keskin et al. found gender to be a favourable prognostic factor, because survival length was five times longer in men than women (58 months vs. 12 months). Based on a multivariate analysis, Bilimoria et al. demonstrated a high risk of death with an increase in age, involved margins, and nodal or distant metastasis [1]. The presence of lymphatic metastases in patients with ACC is stage III disease. The higher the stage of disease, the worse the survival rates. Kerkhofs et al. reported, a mean survival in patients with ACC of 159 months for stage I and II disease, 26 months for stage III disease, and 5 months for stage IV disease [2]. Gomez Rivera et al. reported a mean survival in patients with ACC of 67 months for stage II disease, 13 months for stage III disease, and 3 months for stage IV disease [21]. Furthermore, Gomez Rivera at al. concluded that prognostic factors that worsen survival are older age, distant metastases, non-surgical treatment and a locally invasive tumour that involves large veins. Even in stage IV disease, better survival is expected if an ACC is resected in toto (R0), but the question that arises is whether or not there are really negative resection margins in stage IV disease [8, 22]. Dong et al. do not recommend surgical treatment for stage IV ACCbecause the prognosis is not affected; in contrast, surgical treatment in stage I and II ACC are most effective, but surgery is also recommended for stage III ACC [7].
The worst prognosis is expected when the tumour invades large veins (inferior vena cava and renal veins), which shorten disease-free interval and survival six-fold compared to patients in whom invasion of veins is not present [23]. Peri-operative mortality is 13 % when the inferior vena cava is infiltrated, but experienced surgeons should aim for a radical operation even in these cases [24]. We did not show that the extent of surgery influenced the survival outcome, even though this is considered the most important factor with respect to survival of patients with ACC. Because most of our patients had complete resection of the tumour, it was not possible to statistically prove that surgery influenced survival outcome. Based on the results of regression analysis, Tritos et al. showed that the absence of metastases at the time of diagnosis, patients ≤ 54 years of age, and complete surgical resection are independent prognostic factors for improved survival in patients with ACC [19]. Resection for cure is reported in 50–75 % of patients with ACC [3, 7]. The outcome of ACC patients is influenced by the expertise of the surgeons and number of patients at the institution where the patients undergo surgery. For this reason, Hermsen et al. emphasize the relevance of national cooperation and centralized surgery for ACC [25]. Furthermore, Lombardi et al. classified institutions into high and low-volume centres [26]. High-volume centres annually perform more than ten adrenalectomies for ACC, and the outcomes are better in such centres. The survival benefit is not only the consequence of expert surgical treatment, but also the result of a multidisciplinary approach to ACC which is practiced in these specialized centres [27]. We could not statistically analyse this parameter, because all patients underwent surgery at the same centre, which is in fact the centre where most patients with ACC are surgically treated in our country.
The use of mitotane is still under debate, although mitotane is used in greater than one-half of patients with ACC [3]. Mitotane is usually used as monotherapy, at a high-dose, which is favourable [28]. Terzolo et al. reported that the application of mitotane extends the recurrence-free interval in radically-resected ACC patients [29]. Icard et al. concluded that mitotane is only beneficial for ACC patients who undergo complete resection of the tumour [3]. In contrast, Grubbs et al. reported that the recurrence-free interval is nearly the same for patients with ACC who underwent surgery and received mitotane and patients who did not receive mitotane [30]. The hormonal activity of the tumour also influences the outcome of patients with ACC. According to Berruti et al. hypercortisolism is a prognostic factor in completely resected ACC with respect to overall survival and recurrence-free survival [31]. Icard et al. reported that precursor-secreting tumours influenced outcome [3].
ACC has a high recurrence rate. Analysing 101 re-operations for ACC, Erdogan et al. reported prolonged survival for R0 resection, even if > 1 year elapsed between the primary operation and recurrence of the disease [32].
The reported responses to conventional treatment of ACC have not been favourable. Additionally, an alternative approach, such as a wide array of chromosomal, genetic, molecular, and immunohistochemical markers, has been tested in ACC to identify reliable diagnostic and prognostic factors [33–35]. Therefore, certain molecular markers, such as the IGF system, the Wnt pathway, and p53, may be considered as potential targets for treatment and available therapeutic options [33].
There were several limitations to the present study. It would be useful if this study could be conducted as a multicentric study with a higher number of patients, because it would allow better analysis of variables with low occurrences. Additionally, there were missing data for some variables. In our study histopathological and immunochemical parameters were not included, and which will be presented in forthcoming publication.
