Laparoscopic Resection is Inappropriate in Patients with Known or Suspected Adrenocortical Carcinoma
B. S. Miller . J. B. Ammori . P. G. Gauger . J. T. Broome . G. D. Hammer . G. M. Doherty
Published online: 7 April 2010 @ Société Internationale de Chirurgie 2010
Abstract
Background Complete surgical resection is the mainstay of treatment for patients with adrenocortical cancer (ACC). Use of laparoscopy has been questioned in patients with ACC. This study compares the outcomes of patients undergoing laparoscopic versus open resection (OR) for ACC.
Methods A retrospective review (2003-2008) of patients with ACC was performed. Data were collected for demo- graphics, operative and pathologic data, adjuvant therapy, and outcome. Chi-square analysis was performed.
Results Eighty-eight patients (66% women; median age, 47 (range, 18-81) years) were identified. Seventeen patients underwent laparoscopic adrenalectomy (LA). Median tumor size of those who underwent LA was 7.0 (range, 4-14) cm versus 12.3 (range, 5-27) cm for OR. Recurrent disease in the laparoscopic group occurred in 63% versus 65% in the open group. Mean time to first recurrence for those who underwent LA was 9.6 months (±14) versus 19.2 months (±37.5) in the open group (p < 0.005). Fifty percent of patients who underwent LA had positive margins or notation of intraoperative tumor spill versus 18% of those who underwent OR (p = 0.01).
Local recurrence occurred in 25% of the laparoscopic group versus 20% in the open group (p = 0.23). Mean follow-up was 36.5 months (±43.6).
Conclusions ACC continues to be a deadly disease, and little to no progress has been made from a treatment standpoint in the past 20 years. Careful and complete surgical resection is of the utmost importance. Although feasible in many cases and tempting, laparoscopic resection should not be attempted in patients with tumors suspicious for or known to be adrenocortical carcinoma.
Introduction
Adrenocortical carcinoma (ACC) is a rare and deadly disease with an annual incidence of approximately two per million population. Careful and complete surgical resection by an open approach has been the mainstay of treatment. Adjuvant therapies have not been successful, and indica- tions for the use of mitotane, other chemotherapy, or external beam radiotherapy are not well defined. Overall 5-year survival rates are generally reported to be 15-20%. A recent study [1] revealed that in the past 20 years no significant progress has been made with regard to the treatment of ACC, and 5-year survival outcomes have remained static as well. Forty-five percent of adrenalecto- mies for ACC are performed in community hospitals, 30% in academic centers, and only 15% in NCI-designated cancer centers [2]. Data from studies reviewed for the NIH consensus statement in 2002 [3] revealed a wide range of recurrence (0-100%), an overall local recurrence rate of 26%, peritoneal recurrence in 32%, and distant metastasis in 29%. No studies have been performed to evaluate dif- ferences in outcome according to hospital size, hospital type, or surgeon ACC volume.
B. S. Miller · J. B. Ammori . P. G. Gauger . G. M. Doherty Division of Endocrine Surgery, University of Michigan, 2920F Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA e-mail: barbram@umich.edu
G. D. Hammer Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
J. T. Broome Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University, Nashville, TN, USA
Controversy surrounds the appropriateness of laparo- scopic resection for patients with ACC. Since the early 1990s when Snow performed the first successful laparo- scopic adrenalectomy (LA) [4] and Gagner et al. [5] reported their initial series of patients undergoing LA, this technique has become the “gold standard” for resection of benign adrenal masses. LA has been shown to have sig- nificantly lower morbidity, pain, shorter hospital stay, and overall time to recovery compared with open resection. On occasion ACCs have been unknowingly resected by using a laparoscopic approach. More recently, some surgeons have begun to advocate for laparoscopic resection of ACCs despite a paucity of data on this topic. Most accounts of laparoscopically resected ACC are included in papers dis- cussing LA in general, comprised of only a few cases, and suffer from a lack of long-term oncologic follow-up. Because effective adjuncts to surgery for the treatment of ACC are extremely limited and uniformly unsuccessful, ensuring a complete, margin-negative tumor resection at the initial operation is critical. Most opponents of LA dispute the ability to achieve negative margins on a routine basis. Furthermore, larger adrenal tumors (as most ACCs are) are more difficult to retract, and laparoscopic instru- ments may abrade the tumor, penetrate the tumor (grossly or microscopically), or tear the capsule of the tumor, allowing spread of tumor cells leading to early local recurrence, peritoneal carcinomatosis, and the potential for distant metastatic spread.
Since the inception of our multidisciplinary adrenal disorder clinic, which treats patients with all disorders involving the adrenal glands and specializes in the treat- ment of patients with ACC, our group has noticed that patients who undergo laparoscopic resection of ACCs appeared to have earlier local tumor recurrence despite having smaller lower stage tumors. We hypothesized that patients who undergo laparoscopic adrenalectomy experi- ence higher rates of margin-positive resections and develop local recurrence significantly earlier than patients who undergo open adrenalectomy.
Methods
We performed a retrospective review of all patients seen in our multidisciplinary adrenal clinic at University of Michigan from July 2003 through August 2008. Records of patients diagnosed with ACC were identified and analyzed separately. Demographics, imaging results, operative reports, pathology, adjuvant or palliative therapy received, and outcome data were collected and reviewed to compare patients who underwent laparoscopic versus open resection of ACC. The European Network for the Study of Adrenal Tumors (ENSAT) staging system was used to categorize ACC (Table 1). Patients with stage IV disease at diagnosis were excluded because any resection that might have been performed was not for cure. Seventy-nine percent of operations were performed at outside institutions before referral (17/17 laparoscopic, 53/71 open). Although many patients were referred for evaluation after evidence of local recurrence (tumor bed and adjacent organs) or distant metastases, a fair number were referred for consultation just after surgical resection when a definitive diagnosis was initially made, allowing our group to follow these patients closely and make treatment recommendations regarding external beam radiation therapy, mitotane, chemotherapy, and need for further surgery. Results are described using mean (±standard deviation) or median (range). Compari- sons were performed with Chi-square analysis, and p ≤ 0.05 was considered statistically significant.
Results
Of the 309 new patients seen in the clinic for an adrenal disorder during the study period, 88 were identified as having ACC who underwent surgical resection with intent to cure. Patient demographics and general tumor charac- teristics are reviewed in Table 2. Women accounted for 66% of the patients. Median age was 47 (range, 18-80) years. Mean follow-up for the cohort was 36.5 months
| ENSAT Staging System for ACC | 0 | 1 | 2 | 3 | 4 | |
|---|---|---|---|---|---|---|
| T | n/a | ≤5 cm, no local invasion | >5 cm, no local invasion | Local invasion into fat | Invasion of adjacent organs | |
| N | No lymph nodes involved | Lymph nodes involved | ||||
| M | No distant metastases | Distant metastases | ||||
| Stage I: T1, N0, M0; | Stage II: T2, N0, M0; Stage III: T1-2, N1, M0 or T3-4, N1, M0; Stage IV: any T, any N, M1 | |||||
T tumor; N lymph node disease; M distant metastases
| All | Open | Laparoscopic | |
|---|---|---|---|
| Total no. of patients | 88 | 71 (81%) | 17 (19%) |
| Median age, yr (range) | 46.3 (18-81) | 45.9 (18-81) | 48.2 (20-68) |
| Sex (#) | |||
| Male | 31 | 28 | 3 |
| Female | 57 | 43 | 14 |
| Tumor characteristics | |||
| Median size (cm) | |||
| CT (range) | 9.3 | 10.1 (4.2-24) | 6.0 (3.2-13) |
| Final pathology | 11.2 | 12.3 (5-28) | 7.0 (4-14) |
| Tumor grade | |||
| Low | 35% | 35% | 35% |
| Intermediate | 1% | 1% | |
| High | 45% | 43% | 59% |
| Unknown | 19% | 21% | 6% |
(±43.6). Half of patients had functioning tumors, with excess cortisol production being most common. The smallest ACC was 4 cm by pathology, but measured only 3.2 cm in greatest dimension by CT scan. Sixty-five per- cent of patients underwent surgery with a known or pre- sumed diagnosis of ACC. Fourteen patients (16%) had biopsies positive for ACC. The overall incidence of recurrent ACC during the follow-up period was 64%.
Seventeen patients underwent laparoscopic adrenalec- tomy-all performed before referral. Two of these 17 patients had biopsy-proven ACC before operation. Seventy percent of patients who underwent laparoscopic resection versus 51% of patients who underwent open resection had stage 1 or 2 ACC. Median tumor size of those who underwent laparoscopic resection was 7.0 (range, 4-14) cm versus 12.3 (range, 5-27) cm in those who underwent open resection. Data regarding recurrence are shown in Table 3. Overall, recurrent disease (local, peritoneal, and distant) in the laparoscopic group occurred in 63% versus 65% in the open group (p = 0.22). Mean time to first recurrence for those who underwent LA was 9.6 months (±14) versus 19.2 months (±37.5) in the open group (p < 0.005). Fifty
percent of patients who underwent laparoscopic resections had positive margins or notation of intraoperative tumor spill versus 18% of those who underwent open resection (p = 0.01). Margins were noted as “close” in two patients and not commented on in four patients who underwent LA.
Of those who underwent open resection, two were noted to have rupture of the tumor capsule; none had gross tumor remaining. Microscopically positive margins were noted in nine patients. Local invasion of adjacent organs or vascu- lature was present in four of nine patients with positive margins. Local recurrence occurred in 25% of the laparo- scopic group versus 20% of the open group (p = 0.23). Twenty-four percent of patients in the LA group developed distant metastases versus 49% of the open group (p = 0.03). At the time of diagnosis of recurrence, peri- toneal dissemination was noted in 18% of those who underwent LA versus 11% of those who underwent open resection (p = 0.22). Additional resection of local or per- itoneal recurrence was performed in a similar percentage of patients in both groups. Invasion of surrounding structures was identified in one patient (5.8%) in the LA group who underwent concomitant nephrectomy versus 14 patients (19.7%) with local soft tissue invasion or involvement of adjacent organs in the open resection group, suggesting selection of patients with less locally advanced tumors for laparoscopic resection.
Analysis of a subgroup of patients with tumors <6 cm, which many surgeons would consider technically resect- able by a laparoscopic approach, revealed positive margins in four of eight patients (50%) who underwent LA with local recurrence evident by imaging at a mean of 1.14 years. Four were low-grade tumors and four were high-grade. Five have no evidence of disease (NED), two have progressive disease, and one died during attempted resection of a local recurrence. Margins were positive in only one of five patients (20%) who underwent open resection for tumors <6 cm. The one patient with a positive margin had a partial adrenalectomy performed at an outside institution for an unknown reason. Evidence of this per- sistent disease on imaging was detectable at 2.8 years. This was a low-grade tumor. Of the remaining four patients who underwent open resection, one patient had evidence of
| Table 3 Recurrence (initial or late) by type of operative approach | Open (71 patients) | Laparoscopic (17 patients) | |
|---|---|---|---|
| Overall recurrence-any siteª | 65% | 63% | |
| Local/tumor bed | 20% | 25% (p = 0.23) | |
| Peritoneal | 11% | 18% (p=0.22) | |
| Distant | 49% | 24% (p = 0.03) | |
| a Can include patients with multiple sites of recurrence (local/tumor bed ± perito- neal ± distant) | % Positive margins or intraoperative tumor rupture | 18% | 50% (p=0.01) |
| Time to local recurrence (mo) | 19.2 (±37.5) | 9.6 (±14) (p <0.005) | |
| Additional surgery performed for recurrence | 31% | 29.4% |
| Tumor size (cm) | Overall Recurrence | Laparoscopic | Open |
|---|---|---|---|
| <6 | |||
| L/P recurrence | 46% (6/13) | 38% (3/8) | 20%ª (1/5) |
| Margin positive or tumor spill | 38% (5/13) | 50% (4/8) | 20% (1/5) |
| ≥6-10 | |||
| L/P recurrence | 27% (8/30) | 33% (2/6) | 25% (6/24) |
| Margin positive or tumor spill | 33% (9/30) | 50% (3/6) (none locally invasive by pathology report) | 25% (6/24) (66% invasive) |
| >10 | |||
| L/P recurrence | 43% (9/21) | 50% (1/2) | 42% (8/19) |
| Margin positive or Tumor spill | 12% (2/17) | 50% (1/2) | 7% (1/15) |
L/P local or peritoneal; () actual number of patients
a One patient in this group had a partial adrenalectomy for an unknown reason and was excluded from analysis. Some patients did not have data available regarding margin status or intraoperative tumor spill
local recurrence at 2.5 years, one developed distant metastasis but no local recurrence, and two have NED. The patient who developed local recurrence after complete resection underwent reoperation and is currently disease- free 1.5 years later. The patient with distant metastasis had a high-grade tumor. Those with NED had low-grade tumors.
Table 4 shows the incidence of local and peritoneal recurrence based on tumor size after LA or open resection. All but one tumor resected laparoscopically was noninva- sive, whereas 66% of tumors ≥6 cm to 10 cm and 54% of tumors >10 cm resected via an open approach had specific mention of invasion of adjacent structures requiring addi- tional resection. Although the local and peritoneal recur- rence rates (33% LA vs. 25% open) appear similar (p = 0.33; Table 4) for the intermediate size group (≥6 to 10 cm), the margin positive or tumor spill rate was 50% (3/6) for the LA group (0% invasive) versus 25% (6/24) for the open resection group (66% invasive to adjacent organs requiring resection). The margin positive or tumor spill rate for tumors >10 cm resected laparoscopically was 50% (1/2) versus 7% (1/15) in those resected by an open approach.
Discussion
The data presented in this study support the hypothesis that patients who undergo laparoscopic adrenalectomy experi- ence higher rates of margin-positive resections and develop local recurrence significantly earlier than patients who undergo open adrenalectomy. This persists even when examining outcomes in patients with relatively small tumors (<6 cm), which one would think would be easier to remove. Because the median follow-up is relatively short (36 months), it would be premature to comment on the
effect on overall survival. Tumor biology also may play a role in recurrence, because it seems that low-grade tumors are less aggressive, tend to recur later, and metastasize to distant sites at longer intervals than high-grade tumors.
Limitations of this study include the retrospective nat- ure, small sample size, and referral/selection bias. Because the size difference of ACCs in patients who undergo LA versus open resection is significantly different, it is difficult to compare local and peritoneal recurrence. Although the incidence of local recurrence seems only to approach a significant difference, one must remember to account for the significantly smaller size of laparoscopically resected tumors. As presented in the “Results” section and shown in Table 4, smaller tumors are able to be resected more effectively when performed by an open approach.
It is imperative that surgeons carefully review preoper- ative imaging studies and adrenal size and imaging char- acteristics to choose an appropriate surgical approach. Of concern in this study is that five of six adrenal tumors resected laparoscopically measuring between 4 and 6 cm had heterogeneity, necrosis, or irregularity that should have caused concern for possible malignancy (in addition to meeting size criteria for concern of malignancy). One tumor <4 cm had evidence of small calcifications and had contrast washout of just under 50% (University of Michi- gan criteria require washout >60% to suggest a benign adenoma assuming no other concerning characteristics). In addition, 16% of all patients underwent preoperative biopsy of the adrenal mass despite literature that indicates only very rare circumstances appropriate for biopsy of the adrenal gland. Biopsy with penetration of the tumor cap- sule can lead to unnecessary tumor spread no matter how well the subsequent operation is performed.
Whereas some centers perform open adrenalectomy for all suspected or known ACCs [6], others perform
laparoscopy initially to assess for evidence of intraperito- neal metastasis or invasion of the adrenal gland into other organs. Intraoperative laparoscopic ultrasound has been found to be helpful to evaluate for evidence of invasion. Some surgeons recommend removal of noninvasive ACCs laparoscopically, whereas the majority of surgeons prefer to convert to an open procedure if there is any indication that the tumor is malignant. The difficulty is knowing when to convert and doing so before penetrating the capsule of the adrenal gland or spreading tumor throughout the abdomen while applying traction/countertraction to the gland surface during the initial stages of the operation. Although tumors metastatic to the adrenal gland do not tend to invade beyond the capsule of the adrenal gland, ACCs do invade through the capsule. Perhaps because the tumor may be at the surface of the gland in ACC, appli- cation of laparoscopic instruments to the tumor can shed malignant cells that are undetectable to the operating sur- geon. Tactile sensation is limited with laparoscopy com- pared with an open approach and is nonexistent with robotically performed procedures [7]. Some groups have tried to use colorectal cancer data to support their practice of resection of ACCs by a laparoscopic approach. We believe that this thought process is flawed, because the tumor biology characteristics of ACC are substantially different and usually much more aggressive than colorectal cancer. Just because initially high rates of locoregional recurrence (laparoscopic and port site) of colorectal can- cers operations performed laparoscopically were decreased as techniques changed does not mean that this benefit will ultimately be realized in similarly treated patients with ACC.
In a similar study [6], in which the patient population was referred after the initial operation for evaluation and management of newly diagnosed ACC or recurrent ACC, the MD Anderson group reported overall recurrence rates of 86% in their open resection group (154 patients) and 100% in their LA group (6 patients). In the open approach group, 35% had local recurrence and 8% peritoneal recurrence. In the LA group, 50% had local recurrence as a component of initial failure and 83% (p = 0.0001) had peritoneal carcinomatosis. There were no port site recur- rences. A subset of patients with relatively small ACCs that would have been technically amenable to LA (≤6 cm) but who underwent open resections did relatively well. Four of six were without disease at 21 months in contrast to the uniformly poor outcome of the LA group. They also noted that those with isolated local recurrence after open resec- tion who underwent reoperation experienced a relatively long overall survival duration (median 70 months), sug- gesting that local recurrence may be more related to inadequate primary operation than to particularly aggres- sive tumor biology. This likely has something to do with
tumor biology, but the authors did not comment on tumor grade or Weiss score in their article.
Two studies from the United States have examined treatment and survival of ACC for relatively long-term periods of time. In one study [8], which used the SEER database to examine a 15-year period, there was no change in survival and no change in treatment utilization for patients with ACC. The second study [1], which examined a 20-year period using the National Cancer Database, also noted no change in survival or treatment utilization. Despite increased utilization of imaging studies, ACC is not being identified at earlier stages across the United States as a whole; however, at select quarternary referral centers, it does appear that some progress is being made [9, 10].
The majority of patients with ACC present with stage III or IV disease. Interestingly, the performance of adrenal- ectomy, especially laparoscopic adrenalectomy for “inci- dentalomas”, has increased [11]. Despite this increase in the number of adrenalectomies performed, those with ACC still do not present until late in the disease process. Perhaps with time, a shift may occur toward identification of ACC at lower stages. It may be that the time between stage II and stage III/IV disease is quite short (less than the time to an interval CT/MRI). Much of this is likely dependent on individual tumor biology.
A recommendation will eventually be made regarding the appropriateness of laparoscopic versus open resection for suspected or known ACC. Unfortunately, most of the current literature regarding LA for ACC is case reports involving a single patient, or small case series with an average of less than ten patients [12-18]. Most of these small case series are missing some aspect of important data, such as adequate follow-up time, comparison of laparoscopic to open resections, discussion of margin sta- tus, tumor grade or differentiation between local, regional, and distant metastasis. The question that needs to be answered with regard to LA for ACC is whether time to local recurrence, need for further surgery, and time to death is equivalent in those patients undergoing open resection. Such a study would need to match and compare patients in open and laparoscopic groups for age, size, grade, stage, use of mitotane, XRT, and chemotherapy. At this time, based on the somewhat alarming data generated from this study, we contend that laparoscopic resection should not be performed for suspected or known ACC. We agree with the statement by Dackiw et al. [19] that “In such an aggressive malignancy, any potential benefit from a minimally inva- sive procedure or a smaller incision is insignificant com- pared with the risk of tumor recurrence resulting from an incomplete resection”. Some will argue that in “expert” hands, laparoscopic resection is appropriate. Without a consensus definition of adequate expertise-in technical or
experiential terms-this is not adequate justification. Gu- errieri et al. [20] reported that the learning curve to perform the laparoscopic adrenalectomy procedure requires 30-40 cases. Importantly, resections for ACC are complex and can be far more difficult than a standard LA for benign disease. Guidelines should be directed to those practicing as general surgeons and urologists, not just to those who truly are experts in a small subspecialty field, as we have already discussed that the majority of adrenal cancers are resected by general surgeons and general urologists and not by subspecialists having a particular interest and significant expertise in treating ACC. Because ACC is so rare most physicians only see one or two patients with ACC in a career.
Conclusions
Adrenocortical carcinoma continues to be a deadly disease, and little to no progress has been made from a treatment standpoint in the past 20 years. Careful and complete surgical resection is of the utmost importance. Surgeons must carefully consider tumor size and imaging charac- teristics when choosing a surgical approach for adrenal- ectomy. Although feasible in many cases and tempting, laparoscopic resection should not be attempted in patients with tumors suspicious for or known to be adrenocortical carcinoma.
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