World Journal of Surgery
ORIGINAL SCIENTIFIC REPORT
Risk of Adrenocortical Carcinoma in Adrenal Tumours Greater than 8 cm
Tarek Ezzat Abdel-Aziz · Parameswaran Rajeev · Greg Sadler . Andrew Weaver . Radu Mihai
@ Société Internationale de Chirurgie 2014
Abstract
Background Adrenocortical cancer (ACC) is a rare malignancy. In the absence of metastatic disease, the suspicion of ACC is based on size and radiological appearance. The aim of this study was to analyse the long-term outcome of patients with large adrenal cortical tumours (>8 cm).
Methods A prospective database recorded clinical, biochemical, operative and histological data on patients operated for cortical adrenal tumours between January 2000 and February 2013. Out of 130 patients operated for cortical adrenal tumours, analysis was restricted to 37 cortical tumours >8 cm.
Results There were 31 (84 %) ACCs and 6 (16 %) benign adenomas (p < 0.01). The most common presentation was that of an abdominal mass [17 (55 %) vs. 3 (50 %), ACC vs. benign, respectively]. There was no difference in size between stage II and stage III-IV tumours; however, there was a trend for tumours to be heavier in advanced stages (920 ± 756 vs. 1,435 ± 1,022 g, p = 0.08, stage II vs. stage III-IV, respectively). No mortality was observed in patients with benign tumours during a median follow-up of 70 months (range 36-99 months). Mortality in the ACC group occurred in 17/31 (55 %) patients. Mitotane was administered in 12 (71 %) patients with stage III-IV ACCs with a 5-year survival rate 25 % compared to 20 % in patients who did not receive Mitotane. In stage II ACC, eight (57 %) patients received Mitotane with a 50 % mortality at 5 years.
Conclusions The high incidence of ACC in cortical tumours >8 cm underlines the need for adequate surgical resection via open surgery aiming to avoid local recurrence. Beyond surgery, the impact of other therapies is not fully characterised and the efficacy of adjuvant Mitotane treatment is yet to be proven.
T. E. Abdel-Aziz ☒ · P. Rajeev · G. Sadler · R. Mihai Department of Endocrine Surgery, Churchill Cancer Centre, Oxford UniversityHospitals NHS Trust, Old Road, Headington, Oxford OX3 7LE, UK
e-mail: t.abdel-aziz@ucl.ac.uk
R. Mihai e-mail: radumihai@doctors.org.uk
T. E. Abdel-Aziz Department of General Surgery, Alexandria University, Alexandria, Egypt
A. Weaver
Department of Oncology, Oxford University Hospitals NHS Trust, Oxford, UK
Introduction
The prevalence of adrenal incidentalomas in scans per- formed for unrelated symptoms ranges between 3-5 % with an increasing frequency in old age [1, 2]. In contrast, adrenocortical cancer (ACC) is a very rare malignancy, with an incidence of 0.5-2/1 million population/year [3]. In the absence of metastatic disease or local invasion, the suspicion of ACC is based on the size and the radiological appearance of the adrenal tumour and current guidelines recommend surgical excision for adrenal incidentalomas larger than 4 cm [4]. An estimated risk of malignancy in
relation to the size of the tumour has been recently reported with a specificity of 95 % and a sensitivity of 77 % for tumours larger than 8 cm [5]. Furthermore, in large clinical series the mean diameter of ACC is 12 cm [6, 7], sug- gesting that the vast majority of patients present with large tumours.
The histological diagnosis of ACC remains challenging in the absence of metastatic disease as many features associated with malignancy can also occur in benign ade- nomas. A list of nine histological characteristics are usually assessed as part of the Weiss score [8], and tumours with a score >6 are considered malignant and those with a score 3-6 are suspicious of malignancy. The limitation of this assessment is that such a score is observer dependent and poorly reproducible [9], hence its use is not uniformly accepted. It results that in many patients histological ana- lysis provides only a suspicion rather than a confirmation of ACC. For such patients, it remains difficult to predict the risk of local or distant recurrence and it is unknown whe- ther such a risk can be minimised by using adjuvant che- motherapy with Mitotane. To address this uncertainty the European Network for the Study of Adrenal Tumours (ENSAT, www.ensat.org) is currently recruiting into an international multicentre randomised trial (ADIUVIO) to determine whether in the absence of metastatic disease adjuvant Mitotane chemotherapy is beneficial for patients with tumours with histological features of malignancy [10].
The aim of this study was to characterise the clinical course and final outcome in a cohort of patients with cortical adrenal tumours larger than 8 cm operated in a tertiary referral centre.
Methods
A prospective database recorded clinical, biochemical, operative and histological data on patients operated for adrenal tumours.
All patients underwent full biochemical screening, including cortisol levels after overnight dexamethasone- inhibition test, renin/aldosterone/ratio, DHEAS, 24-h uri- nary metanephrines. All patients had cross-sectional imaging including CT and/or MRI scans. Based on these results, some were deemed to benefit from more detailed endocrinological tests and from preoperative PET scans in case of disease recurrence to confirm the diagnosis. The principle operative procedure for cortical tumours >8 cm was an open adrenalectomy. A multivisceral resection was performed if other organs were involved or for ensuring complete clearance of tumour or for avoiding disruption of tumour capsule during control of renal or splenic vessels. All operations were performed by two consultant surgeons.
Statistical analysis was performed using SPSS 17. Data with normal distribution are presented and mean ± std and data with non-normal distribution are presented as median (range). Comparison between groups was made using parametric and non-parametric tests, as appropriate. For all test, p < 0.05 was considered significant.
Results
Patients characteristics
A total of 130 patients underwent adrenalectomy for cor- tical adrenal tumours between January 2000 and February 2013. Using the threshold of 8 cm, there were 93 (71.5 %) tumours <8 cm and 37 (28.5 %) tumours >8 cm. Further analysis was performed only for patients with tumours >8 cm (M:F = 21:16, age 20-79 years, median age = 57 years).
Based on the histological diagnosis, there were 31 (84 %) ACCs and 6 (16 %) benign cortical adenomas (p < 0.01). Patients’ characteristics were comparable between both groups (Table 1). The most common pre- sentation in tumours >8 cm was that of an abdominal mass [17/31 (55 %) vs. 3/6 (50 %) in ACC vs. benign group, respectively]. In the ACC group, the abdominal mass was associated with anaemia and/or weight loss in eight patients (26 %). More details on ACC patients’ presenta- tion are summarised in Table 2.
Cross-sectional imaging showed no evidence of meta- static disease in 18 patients (6 with benign adenomas and 12 ACCs classified as stage II postoperatively) and locally invasive/metastatic disease in 19 patients. The most com- mon sites for distant metastasis in patients with stage IV
| Malignant (n = 31) | Benign (n = 6) | |
|---|---|---|
| Gender n (%) | ||
| Male | 16 (52) | 5 (83) |
| Female | 15 (48) | 1 (17) |
| Age at presentation (years) | 57 (23-79) | 53 (20-59) |
| Presentation n (%) | ||
| Non-functioning | 19 (61) | 4 (67) |
| Functioning | 12 (39) | 2 (33) |
| Tumour | ||
| Maximum dimension (mm) | 146 ± 44 | 129 ± 37 |
| Laterality n (%) | ||
| Right | 9 (29) | 2 (33) |
| Left | 22 (71) | 3 (50) |
| Bilateral | 0 | 1 (17) |
| ACC-stage II (n = 14) | ACC-stage III-IV (n = 17) | |
|---|---|---|
| Functioning tumours n (%) | 4 (29) | 8 (47) |
| Cortisol secreting | 3 (75) | 5 (63) |
| Mixed-hormone secreting | 0 | 3 (37) |
| Aldosterone secreting | 1 (25) | 0 |
| Abdominal mass | 9 (69) | 8 (44) |
| Anaemia/weight loss | 3 (23) | 5 (28) |
| Asymptomatic | 1 (8) | 1 (6) |
ACCs were the lungs (n = 12), liver (n = 8) and bone (n = 3).
Surgical treatment
Patients with benign disease (n = 6) had laparoscopic adrenalectomy via a lateral transperitoneal approach (n = 3) or an open adrenalectomy (n = 3).
For stage II ACC (n = 14) tumours, open adrenalec- tomy was the procedure of choice, with only two patients (14 %) requiring a multivisceral resection of left-sided tumours.
For 17 patients with stage III/IV ACCs, an isolated open adrenalectomy was performed in three patients (18 %) and a multivisceral resection was performed in 11 (64 %) patients, with the adjacent kidney resected in all cases, the spleen in 5/7 (71 %), and the distal pancreas in 3/7 (43 %) of left-sided tumours. A thoracotomy was indicated in three patients, with the procedure abandoned in one patient due to extensive locally advanced disease which was not identified on previous imaging scans.
The inferior vena cava (IVC) was infiltrated by tumour in four patients, with successful complete extraction of the tumour thrombus in three patients. The fourth patient had extensive liver disease and was deemed inoperable. In addition, the IVC was opened in one patient to extract a tumour thrombus under cardio-pulmonary bypass.
No serious postoperative complications occurred in the benign disease group. Postoperative complications occur- red in four patients with ACC. Two patients required a reoperation for small bowel obstruction and bleeding. Other complications included pancreatitis and iliac vein thrombosis.
Thirty-day perioperative mortality occurred in one patient with severe Cushing syndrome due to a 30-cm left adrenal tumour with extensive thrombus extension into the IVC who developed multiorgan failure and ischemic brain injury.
| Stage II (n = 14) | Stage III-IV (n = 17) | |
|---|---|---|
| Gender n (%) | ||
| Male | 7 (50) | 9 (53) |
| Female | 7 (50) | 8 (47) |
| Age at presentation (years) | 49 (31-79) | 62 (23-75) |
| Tumour size (mm) mean ± SD | 160.29 ± 47 | 133.57 ± 35 |
| Weight (g) mean ± SD | 715.41 ± 45 | 1,584.85 ± 10 |
| Laterality n (%) | ||
| Left | 13 (93) | 9 (53) |
| Right | 1 (7) | 8 (47) |
| Operation n (%) | 13 (100) | 15 (83) |
| Adrenalectomy alone | 12 (86) | 3 (18) |
| Multivisceral resection | 2 (14) | 11 (64) |
| Not operated | 0 | 3 (18) |
| Overall survival (months) | 63 (4-169) | 21 (1-88) |
| With Mitotane | 49 (4-84) | 22 (2-88) |
| Without Mitotane | 95 (9-169) | 17 (1-49) |
No significant statistical differences could be detected between both ACC groups in terms of age and gender. There was a non-significant trend for stage III-IV tumours to be larger than stage II tumours (p = 0.093); however, they were significantly heavier (p = 0.01) (Table 3). Although left-sided tumours were more common than right-sided tumours, all non-resectable tumours (n = 3) were on the right side due to invasion of the liver and the IVC.
Long-term survival
The six patients with benign adenomas showed no signs of local recurrence during a 70-month median follow-up (range 36-99 months).
In patients with stage II ACC, recurrence occurred in 6 (43 %) patients with a median disease-free survival of 32 (range 6-65) months (Table 4). All three patients who had a laparoscopic adrenalectomy developed disease recur- rence after 6 (3-14) months compared to 33 (5-65) months with open surgery with two disease-related mortalities. There was no significant difference between the size of the tumours of patients with stage II ACC who developed recurrence and those who did not (p = 0.7)
Mortality in the ACC group occurred in 19/31 (61 %) patients after a median follow-up of 27 (1-169) months. The 5-year mortality in patients with stage II cancers without recurrence was 25 % which increased to 67 %
| Side | Site of recurrence | DFS (months) | Mitotane Y/N | Response to Mitotane | Current status | OS (months) |
|---|---|---|---|---|---|---|
| L | Epigastrium /liver/paraaortic | 65 | Y | No, stopped at 18 weeks | Deceased | 72 |
| R | Mediastinal/hilar | 14 | Y | Yes, metastases disappeared | Alive | 53 |
| L | Liver | 6 | N | NA | Deceased | 9 |
| L | Local recurrence, splenectomy + excision of mass | 18 | Y | No, stopped after 58 weeks and received radiotherapy | Deceased | 35 |
| L | Lung | 5 | N | NA | Deceased | 11 |
| L | Local | 48 | Y | Yes | Alive | 84 |
NA = Not applicable
No Mitotane Survival Functions Mitotane = . 00
Mitotane Survival Functions
Mitotane = 1.00
1.0
Stage
1.0
Stage
2.00
2.00
0.8
P=0.045*
4.00
4.00
2.00-censored
Stage II
4.00-censored
0.8
P=NS
2.00-censored
4.00-censored
Cum Survival
Cum Survival
0.6
0.6
Stage II
0.4
0.4
Stage III-IV
Stage III-IV
0.2
0.2
0.0
0.0
0.00
24.00
48.00
72.00
96.00
120.00
144.00
168.00
0.00
24.00
48.00
72.00
96.00
Survival
Survival
when patients developed recurrence (Table 4). The mor- tality was 76 % in patients with stage III-IV ACCs. Sur- vival was poor in patients who did not have an operation (p = 0.001), and overall mortality was significantly higher in stage III-IV ACC when compared to stage II ACC (p = 0.011).
Impact of mitotane on survival
Mitotane chemotherapy was used in 12 (71 %) patients with stage III-IV ACCs. Five patients with stage III-IV ACCs did not receive Mitotane mostly due to inoperable disease or patient intolerance. Survival rate of this sub- group of patients with advanced metastatic disease treated with Mitotane was 25 % (9/12) compared to 20 % (4/5) in patients who did not receive Mitotane.
In stage II ACC, eight (57 %) patients received Mito- tane with 50 % mortality among those patients. In addition,
patients with stage II ACC who developed recurrence and were started on Mitotane had improved survival when compared to those who did not receive it (p = 0.018) (Table 4). Further sub-analysis showed that stage III-IV ACC patients who did not receive Mitotane had poorer survival when compared to their counterparts in stage II ACC (Fig. 1).
Discussion
This study focused on patients with adrenal cortical tumours greater than 8 cm. Identifying the malignant potential of these tumours is of utmost importance as it impacts on the surgical approach and subsequent clinical management.
According to Hospital Episodes Statistics data, in the UK, adrenalectomy for ACC is commonly done in hospitals
where only one such case is treated annually as two or more such operations were undertaken in only 7 hospitals in 1998 and in 11 hospitals in 2007 [11]. A recent paper described the experience in three large university centres in the UK over a decade with 30 patients [12]. Outside such recognized UK centres for endocrine surgery, the experience remains min- imal since most adrenal surgery in the UK is done by sur- geons who undertake less than five cases per year [13]. The world-wide situation in individual hospitals is likely to be similar. This extremely small number of patients reported from university hospitals is at odds with the data from the International Association of Cancer Registries that records 150 cases diagnosed yearly in the UK. Most patients are therefore either not operated or are operated by surgeons who rarely perform adrenalectomy.
The stratification of tumours greater than 8 cm was derived from the study by Sturgeon et al. on 457 ACCs showing a specificity of 95 % and a likelihood ratio of 16.9 that these tumours were malignant [5]. In our study, a diagnosis of ACC was documented in 84 % of patients with tumours >8 cm. In cortical tumours >8 cm, there was a sixfold increase in malignancy when compared to benign tumours (p <0.01).
With advances in fibreoptics and energy devices, more surgeons are tempted to take on the challenge of removing larger adrenal tumours laparoscopically. The size of adre- nal tumours considered amenable to laparoscopic resection has increased over the years from 5 cm in 2000 to 8 cm between 2008 and 2009 [14-19]. The focus of these studies and many more have been on the safety and cost effec- tiveness of the procedure with less emphasis on disease recurrence and long-term follow-up. From the technical aspect, many surgeons agree that a laparoscopic approach for tumours >8 cm is not a straight forward one and should lie within the domain of well experienced surgeons who would have a low threshold to convert to open surgery if required. It is not uncommon, however, for the procedure to be completed successfully enucleating the tumour without removing the periadrenal fat. Moreover, if con- version is necessary, it is usually due to intraoperative bleeding or tumour capsule disruption making dissection difficult and compromising the oncological principles of resection [20]. The question that arises here is not a fea- sibility one but one related to whether these tumours carry a higher risk of malignancy and hence would need radical local excision to ensure clear surgical margins in order to mitigate the risk of local recurrence (if proven to be malignant). The view of many endocrine surgeons is that laparoscopic adrenalectomy should be discouraged for large tumours with high risk of malignancy.
In our series, three patients with cortical adrenal tumours >8 cm had a laparoscopic adrenalectomy performed early in the time interval analysed. Subsequently, all patients with large
cortical tumours had an open adrenalectomy. In 2004, Saun- ders et al. reviewed 14 studies with 28 ACCs treated laparo- scopically having an average tumour size 5.3 ± 1.3 cm. Loco- regional disease recurrence occurred in nine patients 32 % with an overall disease-free survival of 19 months [20]. Keb- ebew et al. reported six ACCs who had LA with an average tumour size 6.6 cm with 50 % of patients developing recur- rence [21]. There seems to be great variability between dif- ferent groups regarding recurrence rates after LA, and it is difficult to ascertain whether this is solely due to the laparo- scopic approach due to the rarity of the disease and the diffi- culty of conducting prospective studies [22, 23]. Suzuki et al. concluded that adrenal tumours >8 cm should be operated via an open approach partly due to operative difficulty and partly due to increased malignant potential. The authors also men- tioned other criteria which might be of aid in predicting ACC in the absence of radiological evidence. This included rapid onset of virilisation, feminization or CS, in addition to multiple elaborated hormones. This was present in only 40 % of our patients which is lower than the 60-80 % incidence of func- tioning tumours in ACCs suggested by Suzuki et al. [6] and more comparable to the 47 % figure reported by another study on 58 patients with ACC [4]. Although Laurell et al. suggested a correlation between ACC diagnosis, hormonally active tumours and genetic expression profiles, in our series of patients there was no difference in survival outcomes between ACC patients based on hormonal profiles.
Stage III/IV of ACC represent an advanced form of disease and are predictors of recurrence and poorer survival [4]. We therefore subdivided our patients into stage II representing early ACC and stage III-IV representing locally advanced or metastatic ACC [4, 22]. Currently recommendation of sur- gery in stage IV ACC should be discussed within a multi- disciplinary team approach and should aim to reduce excess hormone secretion or debulk the tumour for better palliative control. Our data show that patients who were inoperable had lower survival when compared to either adrenalectomy alone or in combination with multivisceral resection which was a prophylactic measure considered reasonable at the time by the operating surgeon. This is an area of practice that is not evidence based and for which a joint working group estab- lished by ENSAT and European Society of Endocrine Sur- geons is trying to reach a more uniform approach between different centres. Inoperable tumours were mainly right-sided ones due to infiltration of the liver, diaphragm and IVC. Invasion of the IVC per second was not a contraindication to surgery as we successfully resected three ACCs with IVC tumour thrombus extension. We have previously reported in a larger European study the favourable outcomes of such resections which are possible with comparable morbidity and mortality rates [24] but such procedures should be restricted to centres with multidisciplinary teams able to undertake complex resection on cardio-pulmonary bypass.
In this retrospective review, Mitotane has been used in 65 % of patients with ACC, a figure identical with the one reported in a study conducted on 30 patients with ACC in three UK centres [12]. When Mitotane treatment was taken into account, the difference in survival between stage II and stage II/IV was less significant, highlighting the possible role Mitotane plays as a palliative measure in advanced ACC. In addition, patients with recurrent stage II ACC who received Mitotane had a better overall survival compared to patients who did not receive it. These data confirm the established role of Mitotane in advanced/metastatic/recur- rent ACC [25]. Its role, however, in stage II ACC following an adequate resection with no evidence of residual or recurrent disease is a subject of debate. Most of this con- troversy relates to the patients’ intolerance to the medica- tion due to its side effects. Due to poor patient compliance, rarity of the disease and the lack of randomised trials, it is difficult to establish its benefit in less aggressive tumours. These limitations and questions are being addressed in an ongoing randomised trial (ADIUVIO) [10].
In conclusion, the very high incidence of ACC in cor- tical tumours >8 cm underlines the need for adequate surgical clearance via radical open surgery with the aim of avoiding local recurrence. Beyond surgery, the impact of other therapies is not fully characterised and the efficacy of adjuvant Mitotane treatment efficacy is yet to be proven. This highlights the importance of referral and treatment of these tumours in centres with a specialized endocrine multidisciplinary team in an attempt to improve results for a disease with such poor prognosis. The relatively low volume of personal experience accumulated even in ter- tiary centres is yet another proof that future progress can only be achieved through multicentre collaborations, such as projects coordinated through the ENSAT.
Conflict of interest None.
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