CrossMark
Adrenocortical carcinoma surgery-surgical extent and approach
C. Vanbrugghe1 . A. J. Lowery1 . C. Golffier1 . D. Taieb 2 . F. Sebag1
Received: 13 November 2015 / Accepted: 8 June 2016 C Springer-Verlag Berlin Heidelberg 2016 ☐
Abstract
Purpose Adequate tumour resection is the gold standard of care for adrenocortical carcinoma (ACC). However, the optimal surgical strategy remains debatable. In our opinion, the extent of surgery (adequate tumour resection) is the pri- mary concern, rather than the surgical approach (laparoscopic or open). We propose that both surgical approaches have a role in the management of ACC provided the extent of resection is selected based on patient and tumour characteristics and accurate pre-operative investigations.
Methods A review of 25 curative intent resections for ACC between 2002 and 2013 was done. Group A (16 patients- 64 %) included all patients who underwent planned radical adrenalectomy without any other resection and group B (9 patients-36 %) included all patients who underwent a planned extensive resection based on pre-operative investigations.
Results Of 471 adrenalectomies, 25 were performed for ACC with curative intent. Tumours were significantly larger in group B with mean size of 119.6 versus 62.4 mm in group A (p = 0.002). Tumours in group B also had higher WEISS scores (mean score 7 vs 5.2, p = 0.033) and almost always
☒ C. Vanbrugghe charlesvb@wanadoo.fr
1 Department of Endocrine Surgery, La Conception University Hospital, 176, boulevard Baille, 13006 Marseille, France
2 Department of Nuclear Medicine, La Timone University Hospital, 264, rue Saint-Pierre, 13005 Marseille, France
required multi-organ resection. The recurrence rate was 37.5 % (n = 6) for group A and 44.4 % for group B (n = 4), p = 1.00. Poor prognosis was associated with significantly higher WEISS scores (p = 0.016) and a trend towards more advanced ENSAT disease stage (p = 0.06). Estimated overall survival was 74.17 months (group A 67.3 vs group B 70.1, p = 0.244).
Conclusions Accurate pre-operative staging is critical to select a tailored surgical strategy. Multi-organ resection remains the preferred approach for large and potentially inva- sive ACC. Some patients presenting with smaller ACC may benefit from a more extensive resection.
Keywords Adrenocortical carcinoma · Laparoscopic approach · Radical adrenalectomies · Multi-organ resection
Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy. The reported annual incidence is approximately one to two per million [1], and although clini- cal presentation can be heterogeneous and the natural history of the disease can be highly variable, many patients present with large, locally advanced tumours at the time of diagnosis.
As pre-operative biopsy is not recommended, the diag- nosis of ACC is suspected and usually never proven before histological analysis of the resected tumour. Complete surgical excision with curative intent remains the mainstay of treatment for this challenging disease [2]. However, effective’ surgical treatment remains unclear in some situations, especially for some patients in whom the diagnosis of ACC is possible but doubtful (atypical small tumours on imaging studies). Unfortunately, prognosis remains poor with 5-year
survival rates of 32-45 % due to high rates of recurrence even after complete surgical resection [3, 4].
The primary determinant of survival in ACC is com- plete tumour resection with negative margins [5]. Traditionally, an open surgical approach has been the procedure of choice in the management of ACC; however, recently, an increasing number of reports have investigat- ed the requirement for open resection in all cases [6-13], with a number of authors advocating the use of laparo- scopic adrenalectomy (LA) in this setting [6-9, 13].
The fundamental aim of ACC surgery should be to deter- mine the appropriate extent of resection for each individual patient. In fact, depending upon variables such as tumour size and position, functional status and hormone secretion profile and the patient’s anatomy the optimal surgical treatment may vary from a radical adrenalectomy (adrenal gland and all surrounding fatty tissue and negative margins) to a complex multi-organ resection.
We believe that the focus on ‘laparoscopy versus open surgery’ (LA vs OA) does not address the critical issue and in ACC the aim should be to determine the best strategy for adequate margin free resection depending on the individual tumour characteristics. An analogy could be drawn between laparoscopic versus open adrenalectomy and the question of adequate total mesorectal excision and open versus laparo- scopic approach in rectal cancer [14] where it has been clearly shown that it is the extent of resection that determines prog- nosis, not the surgical approach.
We reviewed the surgical management and outcomes of all patients treated with curative intent for ACC at a tertiary referral centre to evaluate our hypothesis that a tailored approach to adequate tumour resection can be safely achieved by either laparoscopic radical adrenalectomy or a more exten- sive resection based on the individual patient and tumour characteristics.
Material and methods
A retrospective review was undertaken of all patients evaluated for a diagnosis of ACC at our institution from January 2002 to June 2013. Patients with metastatic disease at the time of diag- nosis were excluded.
Data collection
Data on patient were extracted from medical records and a prospectively maintained departmental database.
Patient management strategy
All patients referred for ACC were discussed at a pre-operative multidisciplinary meeting. The approach to pre-operative work-
up and management strategy for suspected ACC at our institu- tion is illustrated in Fig. 1. Radical adrenalectomy by laparo- scopic approach was performed for small tumours, without vascular contact or with other organs. A cut off limit of 8 cm was utilized. The European Network for the Study of Adrenal Tumors (ENSAT) [15] stage at presentation was determined to stage all tumours. All patients underwent complete biochemical and hormonal work-up pre-operatively to assess for tumour functionality.
All surgical procedures were performed by one of two senior consultant surgeons. Laparoscopic access was via the transperitoneal lateral approach in case of radical adrenalectomy.
All cases were assessed and classified histopathologically by an expert according to the WEISS criteria [16], with a threshold for the diagnosis of malignancy as a total WEISS score >3.
Markers of malignancy were assessed for all patients.
Statistical analysis
Patient and tumour characteristics and outcome data were compared between group A and group B including demo- graphic, clinical, biological, imaging and pathological data.
Patients’ characteristics were compared with Fisher- exact and x2 tests. Associations between recurrences and ENSAT staging (1 & 2 vs 3), operative modality, mitotic index and Weiss score were analysed with exact test of Fisher.
Disease-free survival was the primary end point and was defined as the period from surgery date and first time of recurrence or the date of last follow-up without recurrence. The overall survival was defined as the period between oper- ation date and the death of the patient or the date of the last follow-up if the patient is still alive. The Kaplan-Meier meth- od was used to analyse the overall and disease-free survival during long-term follow-up.
Results were described using mean (±standard deviation) or median (range). Statistical significance was set at 5 %, and as a tendency from 5 to 20 %.
Results
Patients
Four hundred seventy-one patients who underwent an adrenal resection, between 2002 and 2013, were identified. Of these, 30 patients underwent resection for ACC. Five patients were excluded from the analysis as they presented with metastasis at the time of diagnosis and did not undergo surgery with curative intent. A radical adrenalectomy by a LA was performed in 16 patients (group A) and nine patients
Clinical exam, complete hormonal assessment as recommended by the European Network for The Study of Adrenal Tumours. Glucocorticoid (basal cortisol, basal ACTH and excretion of free urinary cortisol, sexual steroids and steroid precursors (DHEA-S, 17-OH- progesterone, androstenedione, testosterone, 17ß-oestradiol), mineralocorticoid (potassium, aldosterone/renin ratio). Urinary meta- and normetanephrine analysis in order to exclude a pheochromocytoma.
Adrenal computed tomographic scan (CT-scan) and or adrenal magnetic resonance imaging (MRI) Identification of suspicious features suggestive of malignancy
Heterogeneous tumor, irregular aspect, pre-contrast attenuation greater than 10 HU, absence of washout, vascular invasion, organs invasion, suspects nodes or metastasis)
and determination of supposed ENSAT stage
18-FDG PET scan Determination of maximum standardized uptake (MSU) and MSU ratio (adrenal / liver)
At the end of this work up highly suspicious for ACC:
- CT-scan (or MRI) with malignant criteria - high MSU and / or an high ratio (>1.8) +/- hormonal excess
Group A
- tumor supposed ENSAT 1
Group B -tumor supposed ENSAT 2 and size > 8 cm
- tumor supposed ENSAT 2 and size < 8 cm
⇒ RADICAL ADRENALECTOMY ⇒ LAPAROSCOPIC APPROACH
-tumor supposed ENSAT 3.
⇒ PREDICTING MULTIVISCERAL RESECTION
⇒ OPEN APPROACH
underwent an open approach for a pre-operatively planned extensive resection (group B). Clinical and pathologic features of the groups are outlined in Table 1. The median age at diagnosis was 46.6 years (range 22-77), 28 % (7/25 patients) presented with hormonal oversecretion, and the majority of tumours treated in group A (62 %) were incidentalomas. Tumours in group A were predominantly ENSAT stage I and II (87 %) and were significantly smaller than in group B (me- dian tumour size 62.5 mm for LA vs 116.3 mm for OA, p = 0.023). Additionally, tumours resected in group A had lower scores (mean score 5.3 for group A vs 7 for group B, p = 0.013). Most of the patients in group A had a peripheral venous invasion. It was the only significant factor of Weiss score. (p = 0,002).
Multi-organ resection (adrenal gland and at least one other organ) was required in eight of nine patients who underwent OA (group B); this consisted of a nephrectomy in five patients and a splenectomy and partial pancreatec- tomy in three patients. R0 margins were achieved in all nine patients in group B.
No patient who underwent a radical adrenalectomy by LA (group A) required conversion to an open procedure, and all patients underwent complete adrenalectomy with resection of surrounding tissue and preservation of the adrenal capsule during dissection. R0 resection was achieved in 12/16 patients. Four (25 %) patients had an R1 positive resection margin in group A. The four tumours that were designated as R1 status on pathological examination were classified as such due to microscopic tumour extension through the adrenal capsule, or microscopic invasion of the periadrenal fat, indi- cating a potential for residual disease.
Follow-up and recurrence
The median follow-up was 36.4 months for group A (range 9.9-93.8) and 52.9 months for group B (range 19.9-76.8).
There were 10 cases of disease recurrence (6 group A vs 4 group B, p = 1.000, x-2 test) and 6 deaths (5 group A vs 1 group B, p = 0.364, x-2 test). In group A, there were 2 cases of isolated local recurrence, 2 cases of local recurrence with
| Group A Radical adrenalectomy by LA N = 16 (64 %) | Group B Extensive resection by OA N = 9 (36 %) | P value | |
|---|---|---|---|
| Sex, n (%) | 0.691 | ||
| Man | 7 (44) | 3 (33.3) | |
| Women | 9 (56) | 6 (66.7) | |
| Age (year) | 0.418 | ||
| Mean | 48.9 | 44.31 | |
| Range | 22-77 | 27-55 | |
| Incidentaloma, n (%) | 10 (62.5) | 4 (44.4) | 0.434 |
| Symptoms n (%) | 6 (37.5) | 5 (55.5) | 0.434 |
| Hormonal excess n (%) | 4 (25) | 3 (33.3) | 0.673 |
| Median tumour size | 0.023 | ||
| Mm | 62.5 | 116.3 | |
| Range | 38-80 | 12-200 | |
| SUV max | 0.095 | ||
| Median (range) | 5.6 (3.4-50) | 9 (5.8-21.8) | |
| Ratio | 0.095 | ||
| Median (range) | 2.6 (1.3-17.7) | 4.5 (2-10.23) | |
| ENSAT 1 | 3 | 0 | 0.263 |
| ENSAT 2 | 11 | 4 | |
| ENSAT 3 | 2 | 5 | |
| Weiss score | 0.013 | ||
| Mean (range) | 5.3 (3-8) | 7 (5-8) | |
| Resection | 0.260 | ||
| R0 (%) | 12 (75) | 9 (100) | |
| R1 (%) | 4 (25) | 0 (0) |
subsequent distant metastases, 1 case of peritoneal carcinoma- tosis with synchronous distant metastases and 1 case of metastatic recurrence. Four of the six patients in group A who experienced recurrence had an R1 resection (cf supra). In group B, the site of recurrence was local (tumour bed) in one patient and distant (metastases) in three patients, all of whom had an R0 resection margin (Table 2).
Survival
The mean estimated overall survival for all patients was 74.17 months. The overall and recurrence free-survivals for group B versus group A were 88.9 versus 68.8 % (p = 0.364) and 55.6 versus 62.5 % (p = 1.000), respectively (Figs. 2, 3).
The mean time to recurrence was 40.45 months in group B and 61.17 months in group A (p = 0.7).
Patients who experienced disease recurrence had signifi- cantly higher WEISS scores on histopathological analysis (p = 0.016), and a trend towards more advanced ENSAT dis- ease stage was also observed in these cases (p = 0.06). After adjusting for WEISS score (hazard ratio (HR) 1.4, 95 % CI 0.87-2.33, p = 0.15), radical adrenalectomy by LA (group A)
was associated with an increased relative risk of recurrence (HR 2.4, 95 % CI 1.33-4.48, p = 0.004) and mortality (HR 2.58, 95 % CI 1.17-5.69, p = 0.018) compared to group B. Additionally, after adjusting for ENSAT stage, there was an increased relative risk of recurrence in group A (HR 7.640, 95 % CI 1.5-38.8, p = 0.014).
Status of resection (R0 vs R1) significantly affected risk of recurrence in both groups (HR 7.335, 95 % CI 1.3-40.3, p = 0.022).
| Group A | Group B | P value | |
|---|---|---|---|
| Recurrence (%) | 6 (37.5) | 4 (44.4) | 0.9 |
| Local (%) | 2 (12.5) | 0 | 0.74 |
| Metastases (%) | 1 (6.25) | 3 (33.3) | 0.2 |
| Local then metastases (%) | 2 (12.5) | 1 (11.1) | 0.59 |
| Carcinomatosis then metastases (%) | 1 (6.25) | 0 | 0.76 |
| Mean time of recurrence (months) | 61.17 | 40.45 | 0.7 |
| Deaths (%) | 5 (31.25) | 1 (11.1) | 0.364 |
1,0
Group B
Group A
Group B censored
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60,00
Discussion
The oncologic outcome of surgery for ACC is dependent on a complete resection, maintaining tumour capsule integrity and negative margins [17]; thus, it is imperative that the surgical technique facilitates adequate resection to provide optimal outcomes.
It is our belief that strict patient selection for radical adre- nalectomy by laparoscopy is critical to the feasibility of this approach for ACC. Capsular disruption is less likely with smaller tumours, and the excellent magnified view afforded by laparoscopy enables fine dissection and minimal manipu- lation of the adrenal gland. Complete resection can be achieved laparoscopically if intra-operative findings support the pre-operative clinical and radiological findings i.e. no local invasion, no gross lymphadenopathy, no venous thrombosis. We advocate that other tumour and patient features should
also be considered when planning operative strategy, includ- ing the tumour position (the proximity of renal pedicle), predicted ENSAT stage based on pre-operative imaging, anat- omy of the patient and amount of fatty tissue surrounding the tumour.
It is imperative that all patients undergo a comprehensive pre-operative work-up in a tertiary referral centre, as selection for the appropriate surgical approach is dependent on our abil- ity to accurately diagnose and stage ACC pre-operatively. 18 FDG PET is increasingly used as a diagnostic tool in patients with suspicious adrenal tumours and has been reported to have a negative predictive value of 94 % and a positive predictive value of 97 % for tumours requiring surgical treatment [18].
Despite advances in pre-operative diagnostics, the determination of disease extent remains challenging; approximately 25 % of stage III ACC are only diagnosed post-operatively by the presence of microscopic extension
1,0
Group B Group A
Group B censored
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DFS-months
through the adrenal capsule [18]. This was the case with two patients in our group A. Microscopic capsular inva- sion is unlikely to be recognized intra-operatively so it is important that the surgical technique systematically in- cludes resection of all surrounding periadrenal fat and soft tissue. Four patients in our group A had a R1 resection, and all of these patients went on to have disease recur- rence. Notably, all had a tumour size greater than 7 cm (the median for group A was 6.25 cm) and 2 had a final ENSAT stage of III, highlighting the importance of strict patient selection for radical adrenalectomy, giving partic- ular consideration to tumour size and pre-operative deter- mination of stage. Although radical adrenalectomy is technically feasible by LA for large adrenal tumours, when selecting the surgical approach for ACC, we advo- cate a lower size threshold (6 cm) for consideration of extensive resection than with other adrenal tumours using the European recommendations.
Although in contrast to the high rates of peritoneal carcinomatosis reported by Miller et al. [18] and Cooper et al. [11], our findings are similar to those of Mir et al. [12] who analysed 44 patients treated surgically for ACC at a tertiary referral centre, excluding those who underwent adrenalectomy at an outside institution; they also report only one incidence of peritoneal carcinomato- sis following radical adrenalectomy by LA.
The overall survival in our cohort was 76 %, which com- pares favourably with previously reported rates of between 35 and 66 % [19, 20], and there was no significant difference in unadjusted disease-free and overall survival between groups A and B. Again, these findings are similar to those of Mir et al. [12]. However, when ENSAT stage and WEISS score were accounted for, controlling for larger, more aggressive tumours in group B, there was an increased risk of recurrence and mortality in group A. This finding leads us to question wheth- er we should expand our indications for extensive resection. This may result in ‘overtreatment’ of some patients in cases of uncertain pre-operative diagnosis, with the inevitable increased risk of morbidity associated with a more extensive resection.
The impact of WEISS score on patient outcomes is a reflection of aggressive tumour biology; in our series, the patients who experienced distant/metastatic recur- rence tended to have higher WEISS scores (>8 in 3 of 5 patients who developed metastases as the first site of recurrence). The mean Weiss score for patients with metastatic disease was 7. These vascular and lymphatic borne metastatic recurrences are unlikely to be influ- enced by surgical technique, and as WEISS score can only be determined histologically following tumour resection, it cannot be used to inform pre-operative planning. Conversely, the impact of ENSAT stage on outcomes is a factor that is likely to be modifiable by
meticulous pre-operative work-up to inform surgical planning; in our series, the metastatic recurrences all occurred in patients who had an R0 resection, reinforc- ing the fact that these recurrences cannot be controlled by surgical approach.
There were 5 cases of local recurrence as the first site of recurrence, 4 of which had an R1 resection; while all of these patients underwent a radical adrenalectomy by LA, this approach may not have been optimal for these specific cases considering that three of them had a tumour larger than the median for our group A (>7.0 cm) and two were finally ENSAT stage III. In these cases, a more extensive resection should have been performed either by laparoscopy or by a conversion to an open approach (laparotomy). It is imperative that the operating surgeon maintains a low threshold for con- version to an open approach in cases of difficult laparoscopic resection or any doubt about the ability to maintain capsule integrity and attain clear margins using a minimally invasive approach.
In group A, one patient presenting with a 49-mm tu- mour, with a Weiss score of 8, underwent an R1 resection with local recurrence and subsequent distant metastasis. This was an exceptional case in which the tumour was located medial to the left kidney. It would have been nec- essary to perform an en-bloc kidney resection to ensure an R0 resection. Regarding this specific case, we consider that the position of the tumour should be also considered when planning an operative strategy to achieve R0 resection.
There were no cases of local recurrence in our group A patients who had an R0 resection. Considering the document- ed benefits of LA [21-25], previously reported series and our experience suggest there may be no difference in oncologic outcome for properly selected patients (ENSAT I and II, smaller tumours, high volume centre) [13, 26-28] treated rad- ically with LA. We propose that this approach is reasonable for tumours of limited size (<6 cm), with no evidence of invasiveness and favourable patient and tumour anatomy to facilitate adequate resection.
This study is limited despite the prospective adrenal data- base established in our department by its partial retrospective nature and the differences in tumour characteristics between groups A and B.
In conclusion, the data presented supports our hy- pothesis that the most important component of the sur- gical approach to ACC is to ensure adequate resection margins. This goal can be achieved by both laparoscop- ic and open surgical approaches depending on patient and tumour characteristics; radical adrenalectomy by a laparoscopic approach may be sufficient in highly se- lected patients with no evidence of invasive disease on pre-operative investigation, while we accept that large en-bloc resection is mandatory in some cases. The
benefit of systematic large en-bloc resection for small tumours is questionable.
The critical aspect is that each patient undergoes an exten- sive and accurate pre-operative work-up upon which surgical strategy is selected and tailored for each case individually.
Compliance with ethical standards The authors declare that they have no conflict of interest.
For this type of study, formal consent is not required.
This article does not contain any studies with human participants or animals performed by any of the authors.
No funding to declare.
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