ORIGINAL ARTICLE - ENDOCRINE TUMORS
Comparative Outcomes of Laparoscopic and Open Adrenalectomy for Adrenocortical Carcinoma: Single, High-Volume Center Experience
Maria C. Mir, MD, PhD1, Joseph C. Klink, MD1, Julien Guillotreau, MD1, Jean-Alexandre Long, MD, PhD1, Ranko Miocinovic, MD1, Jihad H. Kaouk, MD1, Matthew N. Simmons, MD, PhD1, Eric Klein, MD1,
Venkatesh Krishnamurthi, MD1, Steven C. Campbell, MD, PhD1, Amr F. Fergany, MD1, Jordan Reynolds, MD2, Andrew J. Stephenson, MD1, and Georges-Pascal Haber, MD, PhD1
1Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH; 2Pathology Molecular Institute, Cleveland Clinic, Cleveland, OH
ABSTRACT
Purpose. Adrenocortical carcinoma (ACC) is a rare and clinically aggressive cancer. Previous studies reported increased recurrence rates associated with laparoscopic adrenalectomy (LA). We evaluated a single-center expe- rience of LA versus open adrenalectomy (OA) for the management of ACC.
Methods. Between 1993 and 2011, 44 consecutive patients with primary ACC were treated at our institution. Baseline patient characteristics and surgical and patho- logical outcomes were compared between OA and LA groups. Multivariable Cox proportional hazards analysis was used to estimate the association between OA versus LA with recurrence-free and overall survival.
Results. Eighteen and 26 patients underwent LA and OA, respectively. Patients who underwent OA had larger tumors and more advanced clinical stage compared with LA group. During a median follow-up of 22 months, 22 recurrences and 26 deaths were observed. The 2-year, recurrence-free and overall survivals for OA and LA were 60 vs. 39 % (P = 0.7) and 54 vs. 58 % (P= 0.6), respectively. After adjusting for clinical stage, OA was associated with lower risk of recurrence (hazard ratio (HR) 0.4; 95 % confidence interval (CI) 0.2-1.2; P = 0.099) and improved overall survival (HR 0.5; 95 % CI 0.2-1.2;
P = 0.122) compared with LA, although differences were not statistically significant.
Conclusions. A nonstatistically significant increase in recurrence and death was observed among patients under- going LA versus OA after adjusting for clinical stage. The rarity of this disease limits the ability to assess for signif- icant differences in a single-institution series. Patients with suspected ACC should be considered for OA.
Adrenocortical carcinoma (ACC) is a rare endocrine neoplasm with a poor prognosis due to the high rate of recurrence even after complete surgical resection, with the 5-year survival rate ranging from 32 to 45 %. The inci- dence of ACC is estimated to be 2 per million, and it is responsible for 0.2 % of all cancer deaths.1,2 Detection at an early and curable stage is uncommon, thus the majority of cases present with large tumors and high likelihood of invasion of adjacent organs at diagnosis.
Laparoscopic adrenalectomy (LA) is currently accepted as a standard option for treatment of suspected benign adrenal masses. LA is associated with a decreased hospi- talization, reduced pain, and decreased perioperative morbidity.3-5 The efficacy of LA has been reported even for masses up to 12 cm.6
For ACC, complete tumor resection and negative margins have been shown to be primary determinants of survival.7 Radiation and chemotherapy are largely ineffective, and the role of adjuvant mitotane is unproven. The role of LA for the management of ACC remains highly controversial. Early reports on LA for ACC described tumor fragmentation and port-site or peritoneal carcinomatosis recurrences related to technical issues.8,9 A recent multi-institutional analysis
@ Society of Surgical Oncology 2012
First Received: 2 July 2012;
Published Online: 26 November 2012
G .- P. Haber, MD, PhD e-mail: haberg2@ccf.org
showed a 4-year rate of peritoneal carcinomatosis of 67 % for LA and 27 % for open adrenalectomy (OA), although few patients underwent LA in this series.10 Other reports have suggested that the laparoscopic approach should be avoided in cases where ACC is suspected due to an increased risk of positive surgical margins.11 Recently, a review of the German ACC registry recommended tumor size of 10 cm as the upper-most limit of feasibility for LA based on the similar oncologic outcomes of LA versus OA. 12
Laparoscopic surgery has been effectively employed for a myriad of uro-oncologic indications at our institution during the past two decades, including LA.13,14 The pur- pose of our study was to report a single-institution experience of OA versus LA in the management of ACC.
PATIENTS AND METHODS
After institutional review board (IRB) approval, the records of all patients with a diagnosis of ACC at our institution between 1993 and 2011 were retrospectively reviewed. Patients who underwent adrenalectomy at other institutions or who underwent metastectomy only at our institution were excluded (19 patients). Patients with dis- tant metastasis who underwent resection of both, their primary and synchronous metastatic disease, and those who underwent incomplete resection of their8 primary tumor were included in all analyses, except analysis of failure. OA and LA were performed in a standard manner as pre- viously described.14,15 Lymph node dissection (LND) was performed in selected cases only.
Baseline patient characteristics, signs and symptoms at presentation, clinical evidence of hormone production, radiographic and histopathologic tumor size, operative treatment, patterns of failure, and patient survival were extracted from the medical records. The Clavien system was used to grade postsurgical complications.16
For the purpose of this analysis, recurrent disease was determined on the basis of radiographic (abdominal com- puted tomography and/or chest radiography) and/or clinical findings, and defined as local (operative site), regional nodal (paraaortic for left-side primary tumors or paracaval for right-sided primary tumors), peritoneal cavity (carci- nomatosis), or distant. Tissue confirmation was not required for the diagnosis of recurrent disease.
A blinded genitourinary pathologist reviewed the slides for primary ACC resection. All cases were assessed according to the histopathological criteria of the WRI (Weiss revisited index).17-19 The WRI consists of the fol- lowing parameters: mitotic index, clear cytoplasm <25 %, abnormal mitoses, necrosis and capsular invasion. Each criterion was scored 0 when absent and 1 when present, except for mitotic index and clear cytoplasm <25 % which are scored 2 when present. Thus, each tumor was scored
from 0 to 7 according to the total number of criteria present. The threshold for malignancy in this scoring index was a total score of >3.
Patients’ characteristics between groups were compared with the Fisher exact test, Mann-Whitney test, and x2 test. Survival curves were calculated using the Kaplan-Meier method and comparisons between groups of patients were made using a log-rank test. Multivariate Cox proportional hazard regression analysis was used to assess the associa- tion between OA and LA with recurrence and overall survival for each subgroup adjusting for the clinical stage (I-II, III-IV). Data were analyzed using SPSS v.18.0 (SPSS Inc., Chicago, IL). The alpha level for statistical significance was set at 0.05.
RESULTS
The clinical features and outcomes of the 44 patients included in this analysis are summarized in Table 1. Patients undergoing OA had larger median size of tumors (13 vs. 7 cm; P = 0.001), higher clinical stage (cT3-4 65 vs. 18 %, P = 0.001), and higher rate of metastatic disease at diagnosis (17 vs. 6 %, P = 0.2) compared with LA. Overall, additional procedures were performed in 20 patients (OA 65 vs. LA 17 %, P = 0.002), including nephrectomy (n = 15), liver resection (n = 3), splenec- tomy (n = 3), inferior vena cava resection (n = 1), and cholecystectomy (n = 1). Surgical time, estimated blood loss, and transfusion rates were not significantly different between the two techniques. One patient with ACC and venous involvement died during OA due to tumor throm- bus embolization. The major complication rate (Clavien 3-5) was 20 and 6 % in OA versus LA, respectively, and not statistically significant.
Overall, 17 (38 %) patients had positive surgical mar- gins and no significant differences were observed among those undergoing LA versus OA (39 vs. 38 %; P = 0.5). All patients with positive SM died of their disease within 2 years of surgery. During a median follow-up of 26 months (range, 22-31), 22 recurrences (12 OA vs. 10 LA) and 26 deaths (16 OA vs. 10 LA) were observed. One patient who underwent LA recurred with peritoneal carci- nomatosis at 16 months follow-up. Two of 20 (10 %) patients from the entire cohort had positive lymph nodes at final pathological analysis. Both patients also had positive margins and died within 12 months of surgery.
The 2-year overall and recurrence-free survivals for OA versus LA were 60 vs. 39 % (P = 0.7) and 54 vs. 58 % (P = 0.6), respectively (Fig. 1). After adjusting for clinical stage (hazard ratio (HR) 2.7; 95 % confidence interval (CI) 1.0-7.4; P = 0.048), OA was associated with a 60 % rel- ative risk reduction in recurrence (HR 0.4; 95 % CI
| Variable | Overall (n = 44) | OA (n = 26) | LA (n = 18) | P |
|---|---|---|---|---|
| Baseline characteristic | ||||
| Age (years) | 0.325 | |||
| Mean (SD) | 49 (40-65) | 48 (42-54) | 53 (45-61) | |
| Male gender, n (%) | 22 (50) | 14 (52) | 8 (47) | 0.7 |
| Right side, n (%) | 19 (43) | 11 (44) | 17 (41) | 0.831 |
| Tumor size (cm) | ||||
| Median (SD) | 9 (6.2-15) | 13 (5.8-21.8) | 7 (0.9-18.4) | 0.001 |
| Stage, n (%) | ||||
| I-II | 24 (54) | 9 (35) | 15 (82) | 0.001 |
| III-IV | 20 (46) | 17 (62) | 3 (11) | |
| Metastasis at diagnosis, n (%) | 6 (13) | 5 (17) | 1 (6) | 0.286 |
| Surgical outcomes | ||||
| Adjunctive procedures, n (%) | 20 (45) | 17 (65) | 3 (17) | 0.002 |
| Surgical time (min) | 285 (192.5-356.2) | 272.5 (137.1-407.8) | 297.5 (162.1-432.8) | 0.777 |
| Mean (range) | ||||
| EBL (ml) | 0.064 | |||
| Mean (SD) | 900 (150-1,750) | 1,100 (262-2,375) | 1,500 (300-1,850) | |
| Conversion to open, n (%) | – | na | 5 (24) | – |
| Intraoperative complications, n | 3 | 1 | 2 | 0.325 |
| Intraoperative transfusions, n | 13 | 8 | 5 | 0.536 |
| Postoperative transfusions, n | 6 | 4 | 2 | 0.566 |
| Length of stay, days | 0.69 | |||
| Mean (SD) | 5 (4-7.5) | 6 (5-11.5) | 4 (2.2-7) | |
| Clavien grade, n (%) | ||||
| 1-2 | 37 (86) | 21 (80) | 17 (95) | 0.325 |
| 3-5 | 7 (14) | 5 (20) | 1 (5) | |
| Pathology findings | ||||
| Positive margins, n (%) | 17 (38) | 10 (38) | 7 (39) | 0.5184 |
| Pathology score | ||||
| Weiss score | ||||
| Median (SD) | 7 (6-8) | 7 (6.75-8) | 7 (6-8) | 0.326 |
| Lymph nodes | ||||
| N0 | 40 | 12 | 6 | |
| N1 | 5 | 2 | 0 | 0.3619 |
| Nx | 55 | 13 | 11 | |
| Oncological outcomes | ||||
| Adjuvant mitotane, n (%) | 18 (41) | 9 (33) | 9 (53) | 0.209 |
| Recurrences at 2 years, n | 22 | 12 | 10 | 0.352 |
| Median follow-up (months) | 26 (22-31) | 18 (15-21) | ||
| Mean (SD) | 31 (28-35) | 0.03 | ||
| Time to recurrence (months) | 11.7 (6.8-14.9) | 13.8 (5.8-21.8) | 9.7 (0.9-18.4) | 0.476 |
| Mean (SD) | ||||
| Cancer specific deaths, n (%) | 30 (67) | 20 (73) | 10 (59) | 0.361 |
0.2-1.2; P = 0.099) compared with LA, although the dif- ference was not statistically significant. Likewise, after adjusting for clinical stage (HR 2.6; 95 % CI 1.1-6.0; P = 0.023), OA was associated with a nonstatistically significant 50 % relative risk reduction in mortality (HR 0.5; 95 % CI 0.2-1.2; P = 0.122).
DISCUSSION
Complete resection with negative margins and intact adrenal capsule represent a requisite for disease-free sur- vival in patients undergoing surgical treatment for ACC. Local recurrence has been associated with inadequate
a
Overall survival
1.0
Laparoscopic adrenalectomy
Open adrenalectomy
0.8
0.6
0.4
0.2
0
24
48
72
96
120
144
Months
b
Recurrence free survival
1.0
Laparoscopic adrenalectomy
Open adrenalectomy
0.8
0.6
0.4
0.2
0
24
48
72
96
120
144
Months
| Authors | Institution | Study period | Stage | Technique | No. of cases | Recurrence rate (%) | Local recurrence, n | Distant recurrence, n | Follow-up (months) |
|---|---|---|---|---|---|---|---|---|---|
| Gonzalez et al.10 | MD Anderson | 1991-2004 | I-IV | Open | 133 | 86 | 45 | 11 | 28 |
| Lap | 6 | 100 | 3 | 5 | |||||
| Porpiglia et al.22 | University of Turin | 2002-2008 | I-II | Open | 25 | 64 | 6 | 10 | 38 |
| Lap | 18 | 50 | 6 | 4 | 30 | ||||
| Miller et al.11 | Ann Arbor | 2003-2008 | I-III | Open | 71 | 65 | 17 | 35 | 36.5 |
| Lap | 17 | 63 | 3 | 4 | |||||
| Brix et al.12 | GACRG | 1996-2009 | I-III | Open | 117 | 61 | – | 4 | 32 |
| Lap | 35 | 54 | – | 1 | 64 | ||||
| Mir et al. (this study) | CCF | 1993-2011 | I-IV | Open | 26 | 27 | 12 | 15 | 22 |
| Lap | 18 | 22 | 10 | 11 |
GACRG German Adrenocortical Carcinoma Registry Group, CCF Cleveland Clinic Foundation
primary operation, and radiation and chemotherapy have not been proven to be effective treatments for this dis- ease.20,21 As a result, surgery remains the mainstay treatment of ACC. Very few studies have provided a comparative analysis of the outcomes between OA versus LA for this specific entity, and previous findings from these studies have been conflicting (Table 2). In a single-center experience with substantial expertise in the open and minimally invasive management of adrenal masses, a nonstatistically significant increase in recurrence and death was observed among patients undergoing LA after adjust- ing for clinical stage. The rarity of this disease limits the ability to assess for significant differences in a single- institution series. Patients with suspected ACC should be considered for OA.
In the present study, we reviewed an almost 20-year experience at our tertiary care institution with the surgical treatment of ACC. Our findings mirror those from other
series published to date in that smaller tumors were usually removed laparoscopically. We did not identify an associ- ation of LA with shorter length of stay or lower rate of postoperative major complications. We reported a com- parison of complications according to a standardized grading system, which represented a limitation of previous studies. In terms of recurrence and survival, we were unable to identify any statistically significant differences based on treatment type, in part, because of the relative rarity of this disease and the small patient numbers. However, we believe the 60 and 50 % relative risk reduction in recurrence and mortality associated with OA are clinically meaningful. Based on the 95 % confidence interval estimates for these endpoints, OA is associated with a benefit of up to 80 % at best and a 20 % greater risk of recurrence and death at worst. As such, we believe the available evidence from this study suggests patients with suspected ACC should be strongly considered for OA.
The MD Anderson group reported an overall recurrence rate of 86 and 100 % in OA versus LA group, respectively. Interestingly, the OA patients had local recurrence rate of 35 % with peritoneal carcinomatosis observed in 8 %, whereas the LA group had a 50 % local recurrence with 83 % peritoneal carcinomatosis. Miller et al.11 presented a retrospective review of 17 LA patients and observed a dra- matic difference between the groups (OA/LA) once the tumor reached a certain size. They found that in patients with tumors >10 cm, recurrence was observed in 7 and 50 % in OA versus LA techniques, respectively, time to recurrence was 19.2 vs. 9.6 months, respectively, and positive margins rate was 18 vs. 50 % (P = 0.01), respectively. However, no difference in survival was observed between the two groups. These authors as a result strongly discourage the use of minimally invasive approach for treatment of suspected ACC. Similarly, Porpiglia et al.22 reviewed only patients with stage I and II ACC and found no differences in recur- rence-free survival. Importantly, only 28 % of the study population had undergone treatment at the reporting insti- tution, so the experience of the surgeons is unknown. Finally, the German Adrenocortical Carcinoma Registry Group reported the results of their multicenter OA versus LA series for localized disease and tumors <10 cm.12 Because no differences were found in disease-specific or recurrence- free survival, they concluded that LA approach was acceptable for stage I and II ACC.
In general, the most recent reports include series of patients with less aggressive disease, smaller tumors, and lower stage. Nevertheless, ACC mostly presents as an advanced disease infiltrating surrounding organs. Thus, studies incorporating outcomes for all stages may be more pertinent and less biased. Likewise, in our series 63 % of the patients (n = 28) presented with a tumor >10 cm and only 13 % (n = 4) had a tumor < 5 cm of diameter. Notably, our analysis incorporates advanced ACC cases, which reflects our status of referral center. Whereas a learning curve of 30-40 LA has been proposed for adrenal incidentalomas, it is anticipated that larger numbers are needed to achieve proficiency at LA for ACC.23 Outside of highly specialized referral practices, it is unlikely that a surgeon would acquire sufficient experience with LA for ACC during his/her surgical career.
There also has been controversy regarding the extent and need for LND in ACC. The German ACC study group published the results of 283 patients, including 47 with LND and 236 without LND with a median follow-up of 59 and 39 months, respectively.24 After multivariate analysis, a significant reduction in risk of tumor recurrence and disease related-death was found in the LND group, sug- gesting an improvement in terms of oncologic outcomes in patients undergoing a wide local resection of ACC. Because tumor relapse is common in ACC patients, these
results may explain the disparity in results between OA versus LA series, where LND may not be a common practice in LA. Thus, this group of patients may not only benefit from better staging with standardized LND, but there may be a potential long-term survival benefit. In our series, only 2 of 20 patients who underwent LND were found to have metastatic LN disease, and as a result we could not draw any conclusions on this issue.
The major limitations of our study include small sample size, retrospective nature of the analysis, variability in the surgical technique (inconsistent use of LND), selection bias (large tumors, more locally advanced cases in the open group) as well as differences in the length of follow-up. A pooled analysis from multiple institutions would be required to achieve adequate statistical power to evaluate benefits of LND and implications of tumor size when deciding between an open versus laparoscopic approach. Until new systemic therapy regimens are discovered, sur- gery will remain the only hope for patients with ACC. The approach that provides patients with minimal risk of positive surgical margins and lowest risk of recurrence should be undertaken.
CONCLUSIONS
Given the aggressiveness of the disease and the high likelihood of progression in case of recurrence, a wide resection and debulking surgical approach should be per- formed during the adrenalectomy for ACC. The main goal should focus on obtaining tumor-free resection margins. Thus, the surgical approach should be tailored according to patient presentation and surgeon’s experience to optimize the outcomes. Although LA is technically feasible, and recognizing that relatively small number of patients were analyzed in a nonrandomized fashion, the available evi- dence suggests superiority for OA in the management of ACC.
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