Long-Term Survival After Adrenalectomy for Stage I/II Adrenocortical Carcinoma (ACC): A Retrospective Comparative Cohort Study of Laparoscopic Versus Open Approach
Gianluca Donatini1, Robert Caiazzo1, Christine Do Cao2, Sebastien Aubert3, Carlos Zerrweck1, Ziad El-Kathib1, Thomas Gauthier1, Emmanuelle Leteurtre3, Jean-Louis Wemeau2, Marie Christine Vantyghem2, Bruno Carnaille1, and Francois Pattou1,4
1Department of General and Endocrine Surgery, Lille Regional University Hospital, Lille, France; 2Department of Endocrinology, Lille Regional University Hospital, Lille, France; 3Department of Pathology, Lille Regional University Hospital, Lille, France; 4Chirurgie Générale et Endocrinienne, Hôpital Claude Huriez, Lille Regional University Hospital, Lille Cedex, France
ABSTRACT
Background. Laparoscopic adrenalectomy (LA) is the standard treatment for benign adrenal lesions. The laparo- scopic approach has also been increasingly accepted for adrenal metastases but remains controversial for adreno- cortical carcinoma (ACC). In a retrospective cohort study we compared the outcome of LA versus open adrenalec- tomy (OA) in the treatment of stage I and II ACC.
Methods. This was a double cohort study comparing the outcome of patients with stage I/II ACC and a tumor size <10 cm submitted to LA or OA at Lille University Hos- pital referral center from 1985 to 2011. Main outcomes analyzed were: postoperative morbidity, overall survival, and disease-free survival.
Results. Among 111 consecutive patients operated on for ACC, 34 met the inclusion criteria. LA and OA were performed in 13 and 21 patients, respectively. Baseline patient characteristics (gender, age, tumor size, hormonal secretion) were similar between groups. There was no difference in postoperative morbidity, but patients in LA group were discharged earlier (p < 0.02). After a similar follow-up (66 ± 52 for LA and 51 ± 43 months for OA),
Kaplan-Meier estimates of disease-specific survival and disease-free survival were identical in both groups (p = 0.65, p = 0.96, respectively).
Conclusions. LA was associated with a shorter length of stay and did not compromise the long-term oncological outcome of patients operated on for stage I/II ACC ≤ 10 cm ACC. Our results suggest that LA can be safely proposed to patients with potentially malignant adrenal lesions smaller than 10 cm and without evidence of extra-adrenal extension.
Initially described in 1992, laparoscopic adrenalectomy (LA) has rapidly become the gold standard of treatment for benign adrenal tumors.1 The advantages over conventional open adrenalectomy (OA) include a lower complication rate, shorter hospital stay, reduced morbidity within 30 postoperative days, and lower overall costs.2-5 In experi- enced referral centers, LA is now increasingly used for large adrenal lesions and adrenal metastases.3-8 Neverthe- less, the role of LA remains controversial for the treatment of adrenocortical carcinoma (ACC), a rare but highly aggressive neoplasia.9-14 Favorable oncological outcome after LA for ACC has been suggested in several studies, with most cases reporting only a small series of patients with short-term follow-up.15-35 Conversely, many authors have questioned the role of LA for achieving a complete tumor resection (R0), which is the prerequisite for long- term cure of ACC.36-49 In this study, we compared the early surgical outcome and long-term survival of patients treated by LA and OA for ACC tumors less that 10 cm without extra-adrenal invasion.
@ Society of Surgical Oncology 2013
First Received: 8 April 2012;
Published Online: 18 September 2013
F. Pattou
METHODS
Study Design and Patients
We initially analyzed the characteristics of all patients who underwent adrenalectomy in our department for an ACC as confirmed by pathology tests (Weiss score ≥3) between 1982, the year of introduction of CT scan at our institution, and August 2011. Among this cohort of patients, we then selected all in whom LA could be con- sidered, based on our current criteria (lesion smaller than 10 cm, no radiological sign of local invasion). Therefore, we initially excluded patients with extra-adrenal extension of the disease, corresponding to stages 3 and 4 according to the classification of the European Network for the Study of Adrenal Tumours (ENSAT) (Table 1) as well as those with a lesion larger than 10 cm on preoperative CT scan, for whom LA is currently considered as contraindicated by our team. All remaining patients (i.e., those with ENSAT stage 1 or 2 tumors smaller than 10 cm) operated on during the study period were included in the present study. Moreover, we excluded from our retrospective analysis all patients in which an R0 resection was not achieved.
Study Outcomes
In this retrospective comparative double-cohort study, we compared the baseline characteristics and postoperative outcomes of patients submitted to LA (case group) and OA (control group). Study endpoints were tumor rupture during surgery, conversion to laparotomy (LA), postoperative complications, length of hospital stay, recurrence, death, and cause of death. Overall survival and recurrence-free survival status were analyzed until the last follow-up visit available.
Statistical Analysis
Continuous variables were expressed as the mean (SD). Results were compared using the Fisher exact test and Mann-Whitney test, as appropriate. Survival analysis was carried out using the Kaplan-Meier method, and differ- ences between the 2 groups assessed with log-rank
| T | N | M | |
|---|---|---|---|
| Stage 1 | <5 cm | - | - |
| Stage 2 | >5 cm | - | - |
| Stage 3 | Local invasion | - | - |
| Any T | ? | - | |
| Stage 4 | Any T | Any N | ? |
(Mantel-Cox) test. All analyses were performed with GraphPad Prism version 5.00 for Windows (GraphPad Software, San Diego CA, www.graphpad.com). A differ- ence was considered statistically significant when p < 0.05.
Literature Review
A systematic review of available literature was con- ducted to compare these outcomes in our series with those of previous reports of LA for ACC. PubMed database was searched with the keywords “adrenal carcinoma” and “laparoscopic adrenalectomy.” Each identified article was assessed. 15-49
RESULTS
Patients
Figure 1 illustrates the selection of patients who were included in the present study. Among a total of 111 con- secutive patients who underwent adrenalectomy with a final diagnosis of ACC at pathology, 36 had ENSAT stage 3 or 4 lesions and were excluded from this study. All these latter patients were submitted to OA, except 1 75-year old female patient presenting with synchronous liver metastasis, who underwent a palliative laparoscopic adrenalectomy. Among the 75 remaining patients with ENSAT stage 1 or 2 lesions, 41 had an adrenal tumor larger than 10 cm and were there- fore excluded. They were all submitted to OA. The 34 remaining patients had an ENSAT stage 1 or 2 adrenal lesion smaller than 10 cm and were enrolled in the present study. Among them, 13 patients operated on between 1995 and 2011 underwent LA and 21 operated on between 1985 and 2010 underwent OA. The baseline patient characteristics, including median tumor size (Fig. 2) and Weiss score, were similar between the 2 groups (Table 2).
Operation
LA was carried out by classical approach described by Gagner et al.,1 with the patient in flank position, using subcostal approach with 3 trocars for left adrenalectomy and 1 more trocar for liver retraction when facing a right adrenalectomy. No conversion to laparotomy was neces- sary in the LA group. Preoperative rupture of the tumor capsule occurred in 1 patient in the OA group but none in the LA group. One early death occurred at day 7 after OA, in a 78-year-old female with Cushing’s syndrome and severe respiratory insufficiency. Other postoperative com- plications included 1 stroke after LA and 1 wound infection and 1 chylous fistula in the OA group. All 3 patients were
Adrenocortical carcinoma 111
Stage III/IV 36
Stage I/II 75
Stage I/II > 10 cm 41
Stage I/II < 10 cm 34
Open 21
Laparoscopic 13
Size (cm)
Size, median values
P= 0.112
10
8
-
6
4
2
Size lap
Size open
| Patient data | LA group n = 13 | OA group n =21 | p value |
|---|---|---|---|
| Sex, female, n (%) | 11 (85) | 15 (71) | 0.635 |
| Mean age, years, mean (SD) | 46 (14) | 44 (19) | 1.00 |
| Secreting, n (%) | 3 (23) | 8 (38) | 0.588 |
| Median size, mm (range) | 55 (22-80) | 68 (45-90) | 0.112 |
| Median Weiss score (range) | 4.30 (3-7) | 4.32 (3-7) | 0.865 |
SD standard deviation
* No values show to be statistically significant (p < 0.05)
treated medically without reoperation. Overall hospital stay was significantly shorter in the LA group (Table 3); only 1 patient was discharged more than 1 week after LA
compared with 9 after OA (p = 0.035). All patients had an R0 resection of the neoplasia, confirmed by the patholog- ical report.
Follow-up
Mitotane adjuvant therapy was administered to 8 and 15 patients (62 and 71 %) in the LA and OA groups, respec- tively (p = 0.655). The therapy was usually associated with a higher Weiss Score, although some patients with a score of 3 were equally treated because the size of lesion was >5 cm. Follow-up duration was similar in both groups (Table 3) and exceeded 5 years in 14 patients (7 after LA and 7 after OA). Also, 9 patients (27 %) experienced dis- ease recurrence, 4-48 months after surgery (4 after LA and 5 after OA). Local recurrence at the site of adrenalectomy was observed in 1 patient after LA and 2 patients in the OA group.
No differences in survival were present when comparing patients operated on by LA versus OA and subsequently treated with mitotane (p = 0.436) or when comparing overall number of patients who underwent adjuvant ther- apy independently from the surgical approach (p = 0.123). A total of 6 patients died of disease recurrence 4- 120 months after surgery (2 after LA and 4 after OA), while 2 others died of unrelated causes (melanoma and lymphoma), 101 and 121 months after LA. As summarized in Table 3 and illustrated in Figs. 3 and 4, overall survival and disease-free survival were identical in both groups.
Literature Review
We found 30 studies referenced in PubMed, reporting a total of 150 patients submitted to LA for ACC. Table 4 compares the main outcomes observed in our patients with those reported in the literature. 15 49 Detailed results of this systematic literature review can be found in Table 5.
DISCUSSION
In this single-center series of 34 consecutive patients operated on for an ACC smaller than 10 cm without extra- adrenal extension, LA was associated with a more favor- able early surgical outcome than OA and comparable long- term disease-specific and recurrence-free survivals.
Several authors have previously suggested favorable oncological outcomes of LA for ACC.15-35 In the recent analysis of the German ACC registry, median disease-free survival after LA was 24 months [35]. In a single-center study, Porpiglia et al.34 reported absence of recurrence in 9 of 18 patients submitted to LA for stage I and II ACC for up to 3 years. In the present study, the Kaplan-Meier
| TABLE 3 Results | Patient data | LA group n = 13 | OA group n = 21 | p value |
|---|---|---|---|---|
| Postoperative stay, (mean) days (SD) | 7 (5) 5 (3-23) | 9 (6) 7 (3-26) | <0.02* | |
| Complications, n (%) | 1 (8) | 3 (14) | 0.387 | |
| Type of complication | Postoperative stroke | Tumor rupture | ||
| Chylous fistula | ||||
| Wound infection | ||||
| Median follow-up, months (range) | 80 (1-130) | 57 (0-132) | 0.322 | |
| Overall survival, n (%) | 11 (85) | 17 (81) | 0.634 | |
| SD standard deviation | Recurrence, n (%) | 4 (31) | 5 (24) | 0.655 |
| * Statistically significant (p < 0.05) | Disease-free survival, months (SD) | 46 (27) | 47 (47) | 0.893 |
Survival (%)
Overall survival
P= 0.634
100
80
60
40
LA
OA
20
0
12
24
36
48
60
72
84
96
108
120
Months
Disease-free survival (%)
Disease-free survival
P = 0.960
100
80
60
40
LA
OA
20
0
12 24 36 48 60 72 84 96 108 120 tic
Months
estimate of 5-year disease-free survival was 65 %, including 2 patients who remained disease free 10 years after LA. The overall survival rate reported compares
| Current literature | Present study | |
|---|---|---|
| No. of reports | 30 | – |
| No. of patients | 150 | 13 |
| Mean size of lesion (mm) | 66 | 57 |
| Conversion, n (%) | 21 (14) | – |
| Complications, n (%) | 15 (10) | 1 (8) |
| Mean follow-up, (months) | 34 | 66 |
| Patients with a 5 year follow-up, n (%) | 23 (15) | 7 (54) |
| Recurrence, n (%) | 86 (57) | 4 (31) |
| Deaths, n (%) | 40 (27) | 2 (15) |
favorably with previous experiences in literature using LA for ACC (Table 4). A strict patient selection likely con- tributed to limiting the risk of tumor capsule rupture as illustrated by the absence of any conversion to laparotomy in 13 consecutive patients. The feasibility of LA for large and potentially malignant adrenal lesions has been reported 19-22,25-29,32,33 by many authors. We decided to reserve LA for lesions smaller than 10 cm. This threshold is not stated by all authors who favor LA for ACC, but we believe LA increases the risk of tumor spillage and local recurrence for bigger lesions even if technically feasible.15-35 Like other authors, we also contraindicated LA as soon as extra- adrenal extension of disease was suspected, either preop- eratively.19-23,25-35 Conversely, 4 of 35 patients (11 %) submitted to LA reported in the German registry had stage 3 ACC. This may explain the higher rates of conversions (11 %), tumor recurrences (77 %), and disease-specific deaths (37 %), reported in this series.35 Our results stress the paramount importance of stringent selection criteria. Coupled with appropriate indications (size and extension of disease), there is a general agreement in literature to reserve LA for potentially malignant adrenal lesions to an experienced laparoscopist, thus reducing the risk of excessive manipulation and capsule rupture to OA.15-35 An anterior approach for LA was used in all our patients, as in
| Study | No. of patients | Conversion (%) | Complications | Follow-up (months) | Recurrence (%) | Mean recovery time (months) | Survival (%) | Alive with disease |
|---|---|---|---|---|---|---|---|---|
| Ushiyama et al.36 | 1 | 14 | 1 | 14 | 0 | |||
| Hofle et al.37 | 1 | 4 | 1 | 4 | 0 | |||
| Hamoir et al. 38 | 1 | 1 | Tumor rupture | 6 | 1 | 6 | 0 | |
| Heniford et al.39 | 1 | 1ª | 8.3 | 1 | 1 | 1 | ||
| Deckers et al.40 | 1 | R1 resection | 6 | 1 | 10 | 0 | ||
| Foxius et al.41 | 1 | 6 | 1 | 6 | 0 | |||
| Henry et al.20 | 6 | 47 | 1 | 6 | 5 | 0 | ||
| Valeri et al.42 | 3 | 22.7 | 1 | 8 | 2 | |||
| Kebebew et al.43 | 6 | 1 | Pulmonary embolism | 39.6 | 5 | 5 | 4 | |
| MacGillivray et al.21 | 1 | 42 | 1 | 18 | 1 | 1 | ||
| Zeh and Udelsman® | 4 | 22.5 | 1 | 18 | 4 | 1 | ||
| Prager et al.22 | 2 | 43.5 | 2 | 2 | ||||
| Moizandeh and Gills23 | 6 | 1 | 26 | 3 | 3 | 1 | ||
| Gonzalez et al.45 | 6 | 1 | Rumor rupture (1) | 28 | 6 | 2 | 2 | |
| Corcione et al.24 | 2 | 13.6 | 2 | 6 | 2 | 1 | ||
| Liao et al.25 | 4 | 39 | 3 | 10 | 2 | 1 | ||
| Palazzo et al.26 | 3 | 34 | 1 | 2 | 0 | |||
| Lombardi et al.27 | 4 | 1 | 23 | 2 | 3 | 1 | ||
| Nocca et al.28 | 4 | 34 | 1 | 3 | 0 | |||
| Schlamp et al.46 | 1 | 21 | 1 | 10 | 0 | |||
| Ramacciato et al.29 | 2 | 1 | Spleen injury | 45 | 2 | 0 | ||
| Eto et al.30 | 1 | 1 | Massive bleeding | 106 | 1 | 74 | 1 | 1 |
| Kirshtein et al.31 | 5 | 5 | 0 | |||||
| Zafar and Abaza32 | 1 | 3 | 1 | 0 | ||||
| Kazaryan et al.33 | 1 | 25 | 1 | 0 | ||||
| Leboulleuux et al.47 | 6 | Hemorrhage (1) | 35 | 4 | 20 | 2 | 0 | |
| Villar et al.48 | 6 | 1 | ns | |||||
| Miller et al.49 | 17 | 11 | 9.6 | 16 | 11 | |||
| Porpiglia et al.34 | 18 | 30 | 9 | 23 | 17b | 9 | ||
| Brix et al.35 | 35 | 12 | Capsule break (4) | 64 | 27 | 22 | 14 | |
| Current study | 13 | 0 | Postoperative stroke | 80℃ | 4 | 45.8 | 11ª | 2 |
a Second operation
b Dead unrelated to the pathology
Median value
d Two died for unrelated pathologies
almost all the studies presented in literature.20 49 A pos- terior approach is described, however, and is possible for small lesions.35 The choice is up to the surgeon, but again, technical feasibility must not be considered as the only criterion to deal with ACC.
These favorable oncological results are in sharp contrast with several papers that in fact advise against LA. 11,13,14,36-49 In the early case reports, in which LA was used for ACC, a peritoneal carcinomatosis almost always developed.36 41 Two reported case series analyzed the recurrence rate after LA and claimed a higher risk for early
recurrence using LA for ACC.45,49 Gonzalez et al.,45 in a retrospective analysis, reported recurrence in 6 patients who had LA in other hospitals, but the study did not clarify if the initial operation was performed by an experienced surgeon or in the preoperative stage of disease. Miller et al.49 published a retrospective study on 88 ACC patients, 17 of whom underwent LA and reported an early mean recurrence time of 9.6 months (vs 19.2 months for OA group; p < 0.005). Data of surgery showed that tumor spillage during LA or positive margins (R1 resection) on pathology specimens were present in 50 % of these
patients, while in OA these events were present in 18 %. Although these authors are against LA their report, in fact, confirms the necessity of a strict patient selection and technical skills when dealing with ACC.
The results of our retrospective comparative cohort study suggests that, as in adrenal surgery for benign lesions, when correctly managed, LA provides a more favorable early outcome for patients with potentially malignant adrenal lesions, with faster recovery and a low morbidity rate.
Adjuvant therapy with mitotane, which could have favorably influenced overall survival and disease-free sur- vival, was similarly administered in the 2 groups.50 Currently our policy is to administer adjuvant therapy to all patients in which pathologist reported a Weiss score ≥4. It usually consists of the administration of mitotane targeting a therapeutic window of 14-20 mg/L.50 If the treatment with mitotane is accepted by the patient and well tolerated (no neurological nor digestive symptoms), it is continued for up to 5 years, as recurrence rate is higher within the first 3 years. For patients with Weiss equal to 3, mitotane treatment is considered when molecular analysis (allelic lost 17p13, higher expression of IGF-1, BUB1, PINK1 and DLG7) is in favor of an aggressive form. However, a clinical study has been initiated to evaluate whether this treatment is still beneficial in low-grade ACC [https:// www.epiclin.it/adiuvo]. In case of recurrence, guidelines give clinicians the options of local treatment for low tumor load (repeated surgical resection, liver or pulmonary radiofrequency ablation, external radiotherapy, liver chemoembolization) or systemic treatment combining mitotane and chemotherapy. Recommended schedules are the etoposide-doxorubicin-platinum regimen for the first- line treatment and the streptozocine for the second-line treatment.51,52 These became available in the last 5 years.
As in any retrospective study there are some limitations. First, a selection bias cannot be eliminated. To minimize this risk, we chose to include all patients operated on for ACC since 1985 (when CT scan was available) who met our current criteria for proposing LA. The laparoscopic route has, however, only been progressively implemented since 1995, following increasing expertise. It is noteworthy that patient and tumor baseline characteristics were strictly similar in both study groups. This was possible for our stringent selection criteria, which may have reduced a little bit the number of our cohort, but considerably reduced the possible biases because of a lack of imaging and the pathological criteria to classify an adrenal lesion as malignant (the Weiss Score was introduced after 1984).
A second issue that may be considered and also may affect a retrospective study is represented by the Weiss classification.53 Although pathological criteria allows a diagnosis of ACC when a score ≥3 is reported, patients in
both groups presented a heterogeneous behavior of disease. Some of them were cured and were healthy after 10 years, while some other experienced local recurrence. We believe that the Weiss system has a “gray zone” for tumor of score 3, which may contain both adrenocortical adenoma and ACC.53
Lastly although our findings are statistically significant (and comparable to those of Brix in the German registry), the statistical power of our analysis may be influenced by the small overall number of patients.35 Nevertheless, our extended follow-up strengthens these findings. Ideally, a wide prospective randomized trial, enrolling 100 patients per arm, should be carried out to unequivocally confirm the similar oncological outcomes of LA and OA for ACC. Because of the rarity of the malignancy, however, this type of study appears unlikely. Clinical practice must therefore often rely on a lower level of evidence than the one provided here.
In conclusion, our results suggest that LA can be safely proposed in expert referral centers to patients with poten- tially malignant adrenal tumors with a size under 10 cm and no evidence of extra-adrenal extension. However, three conditions appear mandatory: a stringent preoperative patient selection, a meticulous operative technique, and early deliberate conversion to laparotomy in order to avoid any risk of tumor capsule rupture.
CONFLICT OF INTEREST None.
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