Impact of Lymphadenectomy on the Oncologic Outcome of Patients With Adrenocortical Carcinoma
Joachim Reibetanz, MD,* Christian Jurowich, MD,* Ilknur Erdogan, MD,t Christoph Nies, MD,} Nada Rayes, MD, § Henning Dralle, MD, [ Matthias Behrend, MD, | Bruno Allolio, MD,t and Martin Fassnacht, MDt for the German ACC study group
Objective: Adrenocortical carcinoma (ACC) is a rare malignancy with an unfavorable prognosis. The impact of a locoregional lymph node dissection (LND) has never been defined in this disease. We report the disease-specific outcome of patients treated with or without LND during primary adrenalec- tomy.
Methods: The medical records of patients followed by the German ACC Registry were retrospectively reviewed. Patients with incomplete resection or distant metastases were excluded. Only if the histologic analysis retrieved 5 or more lymph nodes, an intended LND was assumed (LND group). The predefined primary end point of the study was disease-specific survival.
Results: Of 283 included patients, 47 patients (16.6%) were treated with LND, whereas 236 patients (83.4%) underwent surgery without LND. Patients who underwent LND had a larger median tumor size (12.0 cm, range: 2.3-30 cm vs 10.0 cm, range: 4.0-39 cm, P = 0.007) and were more often treated by multivisceral resection (LND: 47.8% vs no-LND: 18.1%; P < 0.001). The other baseline characteristics (age, sex, endocrine activity, Weiss score, Ki-67 index, and adjuvant treatment) did not differ significantly. Median follow-up of all patients still alive was 40 months (range: 6-326). Multivariate analysis adjusted for age, tumor stage, multivisceral resection, adjuvant treatment, and lymph nodes status on preoperative imaging demonstrated a significantly reduced risk for tumor recurrence (hazard ratio: 0.65; 95% confidence interval: 0.43-0.98; P = 0.042) and for disease-related death (hazard ratio: 0.54; 95% confidence interval: 0.29-0.99; P = 0.049) in LND patients when compared with no-LND patients.
Conclusions: Our retrospective data indicate that locoregional LND improves tumor staging and leads to a favorable oncologic outcome in patients with localized ACC.
(Ann Surg 2012;255:363-369)
R adical lymph node dissection (LND), first proposed by Moyni- han et al1 more than a century ago, has become standard practice in the attempted curative surgical treatment of most solid malig- nancies. Lymph node dissection permits refined tumor staging by
From the Departments of *General, Visceral, Vascular, and Pediatric Surgery; +Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany; ¿ Department of General and Visceral Surgery, Marienhospi- tal Osnabrück, Osnabrück, Germany; §Department of General, Visceral, and Transplantation Surgery, University Hospital Charité, Berlin, Germany; TDepartment of General, Visceral, and Vascular Surgery, University Hospital Halle, Halle, Germany; and | Department of Visceral, Thoracic, and Vascular Surgery, Klinikum Deggendorf, Deggendorf, Germany.
Disclosure: Supported by grants of the Deutsche Krebshilfe (grant # 107111 to M.F. and grant # 106080 to B.A. and M.F.) and Deutsche Forschungsgemeinschaft DFG (grant # FA 466/3-1 to M.F).
J.R. and C.J. contributed equally to this study.
Reprints: Martin Fassnacht, MD, Department of Internal Medicine I, University Hospital of Würzburg, Oberdürrbacher Strasse 6, 97080 Würzburg, Germany. E-mail: fassnacht_m@medizin.uni-wuerzburg.de.
Copyright @ 2012 by Lippincott Williams & Wilkins ISSN: 0003-4932/12/25502-0363
DOI: 10.1097/SLA.0b013e3182367ac3
histologic examination and in cases of lymph node (LN) involve- ment may guide the use of adjuvant treatment. Whether a locore- gional LND is of prognostic benefit for the individual patient remains controversial.2-8
Adrenocortical carcinoma (ACC) is a rare endocrine neoplasm with a stage-dependent but generally poor prognosis,9,10 mainly be- cause of a high rate of recurrence. For localized disease, complete resection of the primary tumor is the mainstay of therapy and the only treatment that can offer a prospect of cure.11-14 Thus, pa- tient prognosis is highly dependent on radical initial surgery.1 To date, there are no data available on whether or not tumor resec- tion should include locoregional LND to improve disease control. Therefore, we analyzed the diagnostic and therapeutic impact of locoregional LND in patients with complete resection for ACC in Germany.
PATIENTS AND METHODS
Clinical data of all patients included in the German ACC Reg- istry (www.nebennierenkarzinom.de) were retrospectively reviewed. The German ACC Registry is a nationwide database established in 2003.20 The registry obtains detailed information on patient demo- graphics, symptoms at primary diagnosis, tumor characteristics, sur- gical, adjuvant, or palliative treatment modalities, and outcome. The German ACC Registry is approved by the Ethics Committee at the University of Würzburg, Würzburg, Germany, and all patients gave written informed consent.
At the time the database was closed for analysis (December 2009), the German ACC Registry contained data sets of 563 patients. For detailed information on the extent of LND, all surgical protocols and pathology reports were critically reviewed. Tumor staging at primary diagnosis was based on imaging studies and intraoperative findings and is reported according to the European Network for the Study of Adrenal Tumors (ENSAT) classification9: stage I, a tumor diameter of 5 cm or less; stage II, a tumor diameter greater than 5 cm; stage III, a tumor of any size with infiltration into surrounding tissue, invasion into adjacent organs, LN involvement or tumor thrombus in the renal vein or vena cava; and stage IV, metastatic disease. The tumor stage distribution at primary diagnosis was the following: ENSAT stage I, 31 patients (5.5%); ENSAT stage II, 220 patients (39.1%); ENSAT stage III, 147 patients (26.1%); and ENSAT stage IV, 160 patients (28.4%). For 5 patients, there were insufficient data to assess exact tumor stage.
The criteria for patients included in this study were the fol- lowing: ENSAT stage I to III, complete resection (R0 by histology), and a follow-up of at least 6 months (except for tumor-related death within 6 months). Laparoscopic procedures were also included in the analysis. Surgery was performed in more than 100 departments of surgery and urology throughout Germany. Patients with uncertain resection status, incomplete resection (R1, R2), or distant metastases at the time of primary diagnosis, and patients who did not undergo surgery, were excluded (Fig. 1).
Total, n = 563
Insufficient data , n=9 Missing tumor stage, n=5 Others, n=4
ENSAT IV, n=160
ENSAT I-III, n = 394
Incomplete resection, n=99
R1, n = 28
R2, n = 9 Rx, n = 60 No resection, n = 2
ENSAT I-III, RO, n = 295
Follow-up <6 months, n = 12
Included patients, n = 283 (ENSAT I-III, RO, follow-up >6 months)
LND, n = 47
no-LND,n = 236
Definition of Lymph Node Dissection
Because current literature offers no definition of LND in ACC or provides guidance on the “adequate” number of LN to be retrieved, we aimed at a definition that retrospectively allowed, at best, to sep- arate patients in whom LN were excised accidentally from patients with intended LND. This definition was based on the effort of the surgeon to perform an LND (according to the surgical protocol) and on the number of LN excised (according to the pathology report). Re- garding the latter, after extensive discussion within the study group we decided-before any outcome analysis was performed-to choose a threshold of 5 LN, which was also the median number of LN excised (range: 1-53, Fig. 2). Accordingly, patients with at least 5 excised LN were considered as patients with intended LND (LND group), whereas patients with fewer than 5 excised LN were considered as patients without intended LND (no-LND group).
Outcome
The predefined primary end point of the study was disease- specific survival in patients with or without intended LND using multivariate analysis adjusting for potentially prognostic factors. Sec- ondary end points were recurrence-free survival, postoperative hos- pital stay, and 30-day mortality.
Follow-Up
Follow-up data and information on any relevant change in the course of the disease were provided from the participating physicians and the patients themselves at least every 6 months. Usually every 3 months a thoracic and abdominal computed tomography was per- formed. The median follow-up of all patients still alive was 40 months (range: 6-326).
Statistical Analysis
Data were analyzed using the Statistical Package for Social Sciences version 18.0 (SPSS Inc, Chicago, IL). Continuous vari- ables are presented as the median values and range. Characteristics between both patient subgroups were compared by Mann-Whitney U test (continuous variables) and Fisher exact test (categorical vari-
No. of patients
25
20
LND
15
no-LND
10
5
0
1
2
3
4
5
6
7
8
9
10
11
12
>12
No. of lymphnodes excised
ables). Survival analysis was calculated according to the method of Kaplan-Meier, and differences between groups were assessed with log-rank statistics. Recurrence-free survival was defined as the time interval between initial surgery and the date of radiologic evidence of disease relapse. Disease-specific survival was defined as the time in- terval between initial surgery and tumor-related death. Patients alive at the time of the analysis and patients who died unrelated to ACC (n = 7) were censored. The Cox proportional hazards regression model was used for multivariate analysis to adjust for the following presumed prognostic factors: age, ENSAT tumor stage, multivisceral resection, adjuvant treatment, and LN status on preoperative imaging. A P < 0.05 was considered to indicate statistical significance.
RESULTS
Characteristics of the Study Cohort
Of the 563 patients included in the German ACC Registry (December 2009), 283 patients (median age: 47 years, range: 1-87) who had primary surgery between 1981 and 2009 met all inclusion criteria (Fig. 1). Forty-seven of the 283 patients (16.6%) underwent LND during primary tumor resection (≥5 LN excised, LND group). Within this group, the median number of LN taken did not differ between the tumor sites (right: 5.5, range: 5-12 vs left: 6, range: 5-53; P = 0.47) but was significantly higher in patients who had undergone multivisceral resection, when compared with patients after adrenalectomy only (median: 9, range: 5-53 vs median: 5, range 5- 15; P < 0.01). Detailed patient characteristics are given in Table 1. Both groups were comparable with regard to sex and age distribution, Weiss score, the proliferation marker Ki-67, and adjuvant treatment. Patients who underwent LND showed a larger tumor size at primary diagnosis (12.0 cm vs 10.0 cm, P < 0.001), had a higher rate of locally advanced carcinomas (ENSAT stage III, LND: 51.1% vs no LND: 27.1%; P = 0.002), and were more frequently subject to multivisceral resection (LND: 46.8% vs no LND: 17.8%; P < 0.001) (Table 1). Postoperative hospital stay was comparable for patients with and without LND (12 vs 11 days, P = 0.76). Three patients within the no-LND group (1.3%) and none of the LND patients died within 30 days after surgery (P = 1.0).
@ 2012 Lippincott Williams & Wilkins
| no-LND (<5 Excised LN) | LND (≥5 Excised LN) | P | |
|---|---|---|---|
| Total | 236 | 47 | |
| Male, n (%) | 85 (36.0) | 21 (44.7) | 0.32 |
| Female, n (%) | 151 (64.0) | 26 (55.3) | |
| Median age, years (range) | 47 (1-87) | 45 (1-84) | 0.69 |
| Median tumor size, cm (range) | 10.0 (2.3-30.0) | 12.0 (4.0-39.0) | 0.007 |
| Tumor stage, ENSAT | |||
| Stage I, n (%) | 21 (8.9) | 2 (4.2) | 0.39 |
| Stage II, n (%) | 151 (64.0) | 21 (44.6) | 0.02 |
| Stage III, n (%) | 64 (27.1) | 24 (51.1) | 0.0018 |
| Positive LN* | 13/64 (20.3) | 12/24 (50.0) | |
| Adjacent tissue infiltration* | 48/64 (75.0) | 16/24 (66.7) | |
| Venous tumor thrombus | 12/64 (18.8) | 3/24 (12.5) | |
| Weiss score (range)} | 5 (2-9) | 5 (4-8) | 0.73 |
| Ki-67, % (range)} | 10 (1-70) | 10 (1-60) | 0.81 |
| Functional tumor status | 0.66§ | ||
| Secreting tumors, n (%) | 111 (47.0) | 17 (36.1) | |
| Glucocorticoid | 78 (33.1) | 13 (27.6) | |
| Sex hormones | 60 (25.4) | 5 (10.6) | |
| Mineralocorticoid | 10 (4.2) | 4 (8.5) | |
| Nonsecreting tumors, n (%) | 53 (22.4) | 10 (21.2) | |
| Missing data, n (%) | 72 (30.5) | 20 (42.5) | |
| Surgery | <0.001₸ | ||
| Adrenalectomy only, n (%) | 194 (82.2) | 25 (53.2) | |
| Laparoscopic | 25 (10.6) | 0 | |
| Converted | 6 (2.5) | 0 | |
| Multivisceral resection, n (%) | 42 (17.8) | 22 (46.8) | |
| Nephrectomy | 21 (8.9) | 16 (34.0) | |
| Splenectomy | 11 (4.7) | 6 (12.7) | |
| Liver resection | 6 (2.5) | 1 (2.1) | |
| Others | 12 (5.1) | 7 (14.9) | |
| Lymph nodes | |||
| Patients with suspect LN on Preoperative imaging, n (%) | 14 (5.9) | 7 (14.9) | 0.06 |
| LN per patient identified by histology, median, n (range) | 0 (0-4) | 6 (5-53) | <0.001 |
| Patients with LN metastases proven by histology, n (%) | 13 (5.5) | 12 (25.5) | <0.001 |
| Adjuvant treatment | |||
| Mitotane, n (%) | 46 (19.5) | 12 (25.5) | 0.33 |
| Tumorbed irradiation, n (%) | 20 (8.5) | 3 (6.4) | 0.78 |
| Recurrence at the time of registration (%) | 108/143 (75.5) | 23/32 (71.9) | 0.66 |
| Postoperative hospital stay, days (range) | 11 (4-39) | 12 (6-70) | 0.76 |
| Mortality within 30 days, n (%) | 3 (1.3) | 0 | 1.0 |
*Percentages exceeding 100% due to multiple risk factors in some patients.
+Weiss score is available for 39% of LND patients and 48% of no-LND patients.
¿Ki-67 available for 59% of LND patients and 55% of no-LND patients.
§Secreting versus nonsecreting tumors.
TAdrenalectomy versus multivisceral resection.
Follow-Up and Oncologic Outcome
The median follow-up time was 59 months (range, 8-273) for LND patients and 39 months (range, 6-326) for no-LND patients (P = 0.026). During follow-up, recurrence was documented in 32 of 47 LND patients (68.1%) and in 143 of 236 no-LND patients (60.6%). For patients with disease relapse, median time to first recurrence was 14.2 months: 20.1 months for LND patients and 12.8 months for no- LND patients (P = 0.36). Eighty-six patients had died from ACC: 14 patients (29.8%) in the LND group and 72 patients (30.5%) in the no-LND group. Seven patients had died of other causes. One hundred one patients were free of recurrence at the time of last follow-up: 14 patients (29.8%) in the LND group and 87 patients (36.8%) in the no-LND group.
For patients with tumor relapse, treatment for recurrent disease in LND and no-LND patients included surgery (68.7% vs 55.2%, P=
0.17), mitotane and/or cytotoxic chemotherapy (53.1% vs 61.5%, P= 0.42), or radiotherapy (9.4% vs 7.7%, P= 0.72). Treatment modalities were often used in combination. Eight patients with recurrent disease received no specific treatment.
The outcome was worse for patients with histologic proven LN metastases (n = 25), when compared with patients with unin- volved nodes (n = 258) (median time to recurrence: 12.5 months vs 31.3 months, P = 0.002; median disease-specific survival: 86.4 months vs 135 months, P = 0.058). Within the group of patients with LN metastases (n = 25), the patients who underwent in- tended LND (n = 12) had a superior median recurrence-free sur- vival (20.4 vs 9.9 months, P = 0.086) and disease-specific survival (>86 months [median not yet reached] vs 26.2, P = 0.06), when compared with node-positive patients who had not undergone LND (n = 13).
Because important prognostic parameters like tumor size, tu- mor stage, and frequency of suspected LN involvement on preop- erative imaging were not equally distributed between the groups, a predefined multivariate analysis was performed, adjusting for age, ENSAT tumor stage, multivisceral resection, adjuvant treatment, and LN status on preoperative imaging as covariates. This analysis re- vealed a significant reduction in both the risk of recurrence (hazard ratio: 0.65; 95% confidence interval [CI], 0.43-0.98; P = 0.042) and disease-related death (hazard ratio: 0.54; 95% CI, 0.29-0.99; P = 0.049) for LND patients when compared with no-LND patients (Fig. 3, Table 2). Results were the same when only patients at a higher risk of tumor recurrence (ENSAT stage III: LND, n = 24; no-LND, n = 64) were included in this multivariate model. Again, for LND pa- tients, a considerable reduced risk of recurrence (hazard ratio: 0.57; 95% CI, 0.32-1.01; P = 0.05) and for disease-related death (haz- ard ratio: 0.37; 95% CI, 0.16-0.87; P = 0.02) was observed (Fig. 4, Table 3).
DISCUSSION
This is the first study analyzing on the impact of LND in ACC. Our results suggest a clinical benefit of LND in patients undergoing curative intended surgery for localized disease. This finding is of clinical importance, considering the high rate of tumor recurrence even after seemingly complete resection.13 Lymph node dissection was associated with a reduction of the risk of recurrence by 35% and for tumor-related death by 46%. This prognostic benefit of LND was apparent when analyzing both the whole study cohort and the subgroup of patients with high risk of tumor recurrence (ENSAT stage III).
Only few series have reported on the rate of LND in ACC patients and typically revealed a low-lymphadenectomy rate between 17% and 30%.11,17 This contradicts surgical principles of other solid malignancies. It further highlights a yet undefined role of LND in the surgical treatment of ACC, although patients’ LN status is an inherent component of all past and currently used staging systems for ACC.9,21-23
The majority of patients who underwent LND had stage III tumors, whereas for no-LND patients ENSAT II was the dominating tumor stage. A stage migration phenomenon is a reasonable expla- nation for this observation. Without LND, nodal status is beyond evaluation and a stage III carcinoma (due to LN involvement) can easily be missed. Thus, beside a prognostic benefit, LND in ACC patients permits a refined tumor staging and is therefore an impor- tant diagnostic tool. This “contamination” of stage II with locally
advanced cancers may also explain the variable outcome that has been reported for stage II patients in different series.9,15,17,19,24
Because the frequency of multivisceral resections was higher in the LND group, it is likely that the surgical approach influenced on the number of excised LN. However, as all included patients experienced margin-free resection (R0), the imbalance in the extent of surgery (multivisceral resection vs adrenalectomy only) per se is unlikely to explain the different outcome. Indeed, the multivariate analysis confirmed that a more radical surgical approach would have rather favored an inferior outcome (Table 2). Similarly, Bilimoria et al11 reported a worse prognosis for ACC patients undergoing resection of adjacent organs.
In our series, LN were histologically tumor affected in about 26% of LND patients, which largely resembles the incidence of LN metastases of previous reports.11,25 It remains speculative whether LND facilitates complete tumor clearance in these patients. However, without LND, nodal staging might be incorrect. Even worse, residual tumor might have been left in situ implicating a high risk of local recurrence. Our data suggest that this scenario relates to up to every fourth patient.
Metastatic LN involvement is associated with both a higher likelihood of incomplete resection and an inferior outcome.9,11 There- fore, accuracy of surgical LN staging is indispensable for determining patient prognosis and may further guide the use of adjuvant mi- totane treatment.26 Although there is evidence that adjuvant mitotane treatment is able to reduce the risk of recurrence,27 the final an- swer concerning the efficacy of this therapy28-31 awaits the results of a prospective randomized trial (www.adiuvo-trial.org). In addition, adjuvant radiotherapy might prolong recurrence-free survival in se- lected patients,32,33 and radiotherapy in patients with LN metastases might be a reasonable approach.34
Tumor relapse in ACC patients is common,16,18,32,35 and in- adequate surgical treatment of the primary tumor without its lym- phatic drainage might be a possible explanation for this phenomenon. The favorable outcome of LND patients in our series with a 5-year disease-specific survival rate of more than 70% strongly argues for an aggressive surgical approach including LND, and a close follow-up by specialized centers. On the basis of the lymphatic drainage of the adrenal gland36 and a recent analysis of the patterns of recurrence in ACC patients,34 we would propose excision of the connective tis- sue as shown in Figure 5. Ideally, such an operative approach would be tested in a prospective, randomized study. However, it is rather unlikely that such a trial will be launched in the near future. There- fore, a first step toward a better evidence could be a prospective trial
A
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@ 2012 Lippincott Williams & Wilkins
| Recurrence-Free Survival | Disease-Specific Survival | |||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Surgical modality no-LND (n = 236)" | ||||
| LND (n = 47) | 0.65 (0.43-0.98) | 0.042 | 0.54 (0.29-0.99) | 0.049 |
| Tumor stage | ||||
| ENSAT I* | ||||
| ENSAT II | 1.32 (0.70-2.49) | 0.39 | 3.56 (0.86-14.77) | 0.08 |
| ENSAT III | 2.00 (1.01-3.98) | 0.04 | 7.21 (1.69-30.69) | 0.008 |
| Multivisceral resection | ||||
| No (n = 219)* | ||||
| Yes (n = 64) | 1.61 (1.09-2.38) | 0.016 | 1.26 (0.73-2.16) | 0.41 |
| Adjuvant treatment | ||||
| No (n = 202)* | ||||
| Yes (n = 81) | 0.99 (0.68-1.44) | 0.96 | 0.92 (0.53-1.59) | 0.77 |
| LN status on preoperative imaging No suspicion of LN metastases (n = 262)* Suspicion of LN metastases (n = 21) | 0.77 (0.76-2.20) | 0.73 | ||
| 0.34 | 1.15 (0.39-1.93) | |||
| Aget | 1.01 (1.00-1.03) | 0.02 | 1.01 (1.00-1.02) | 0.016 |
*Respective reference group.
¡Continuous variable.
HR indicates hazard ratio.
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P = 0.02
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without randomization using standardized preoperative imaging, sur- gical therapy (including predefined clearance of the lymphatic bearing tissue), and histologic workup by experienced pathologists.
Our study raises the question if a secondary surgery is indi- cated in patients with an ACC on final histology, initially operated for a suspected adenoma. We are very cautious to (generally) recommend secondary LND in such cases on the basis of our retrospective analy- sis, not only because final histology is often available not before 10 to 14 days after surgery, which is a period not suitable for reoperation.
Minimally invasive surgery for ACC is currently a matter of debate.37-39 As in our series, none of the LND patients were treated by laparoscopy, the oncologic significance of laparoscopic LND remains unanswered. However, laparoscopic retroperitoneal LND is feasible40 and therefore an intended LND would not a priori preclude minimally invasive surgery in a patient who otherwise could qualify for such an approach.
Although we did not address the issue of perioperative mor- bidity in details, the comparable postoperative hospital stay of both
patient groups suggests that LND in ACC patients is not a major source of an increased complication rate.
Our study has certain limitations. First, the retrospective study design could have influenced the results by unknown confounders. Second, our definition of LND is somewhat arbitrary, but currently there is no specific recommendation for locoregional LND in ACC we could have referred to. Third, the accurateness of the local pathologist in examining the excised LN may have affected our results. Finally, the performance and extent of LND might be a representative of a more experienced surgical treatment and may therefore have confounded the oncologic outcome.
Beside the large number of included patients, another strength of our study is the well-performed patient selection, including only patients with a margin-free resection (R0 by histology). We believe that this is mandatory to uncover delicate prognostic parameters, as patients with incomplete tumor resection will suffer an unfavor- able prognosis.41 However, this selection obviously contributes to the better-clinical outcome of our cohort in comparison to most published
C 2012 Lippincott Williams & Wilkins
| Recurrence-Free Survival | Disease-Specific Survival | |||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Surgical modality no-LND (n = 64)" | ||||
| LND (n =24) | 0.57 (0.32-1.01) | 0.05 | 0.37 (0.16-0.87) | 0.02 |
| Multivisceral resection No (n = 47) Yes (n = 41) | ||||
| 0.71 (0.42-1.20) | 0.21 | 0.79 (0.40-1.56) | 0.50 | |
| Adjuvant treatment No (n = 61)* | ||||
| Yes (n = 27) | 1.18 (0.65-2.14) | 0.59 | 0.93 (0.45-1.89) | 0.83 |
| LN status on preoperative imaging | ||||
| No suspicion of LN metastases (n = 74)* | ||||
| Suspicion of LN | 0.58 (0.30-1.12) | 0.11 | 1.37 (0.52-3.63) | 0.53 |
| metastases (n = 14) | ||||
| Aget | 1.01 (0.99-1.02) | 0.49 | 1.01 (0.99-1.03) | 0.58 |
| *Respective reference group. +Continuous variable. | ||||
LND right
LND left
IVC
Ao
series that included a relevant number of patients with incomplete or uncertain resection. Baseline and tumor characteristics were evenly distributed between both groups. Furthermore, both patients groups were highly comparable regarding the presence of recurrence at the time of registration in the registry, as this has been shown to be of major prognostic relevance in retrospective series.42 Finally, the participation of more than 100 surgical and urologic departments throughout Germany makes the results of this study generalizable.
In conclusion, our data suggest that locoregional LND con- tributes to a refined tumor staging and improves the prognosis in pa- tients with localized ACC. Lymph node dissection should therefore be considered as part of the surgical treatment in patients undergoing surgery for ACC. We are aware that a final recommendation for such an approach needs the results of a prospective randomized trial. How- ever, the results of this study are the most accurate level of evidence on this issue available at present.
ACKNOWLEDGMENTS
This study was part of the German adrenal network GANIMED (German Adrenal Network Improving Treatment and Medical Edu- cation) and the European Network for the Study of Adrenal Tumors (ENSAT). The authors appreciate the support of Dr. Uwe Maeder (Comprehensive Cancer Center Mainfranken, Würzburg) in estab- lishing the German ACC Registry database and are thankful to Michaela Haaf for documentation. The authors thank all colleagues who provided clinical data for the German ACC Registry.
The following colleagues provided clinical data of 3 or more patients to the study cohort. They also served as scientific advi- sors and/or critically reviewed the manuscript. Ayman Agha (Re- gensburg), Felix Beuschlein (München), Wiebke Fenske (Würzburg), Martin Gasser (Würzburg), Christoph-Thomas Germer (Würzburg), Peter Goretzki (Neuss), Stefanie Hahner (Würzburg), Robert Koburg (Schweinfurt), Matthias Kroiss (Würzburg), Peter Langer (Marburg), Thomas Mussack (München), Jürgen Schiemann (Würzburg), Mar- tin Spahn (Würzburg), Markus Quinkler (Berlin), Holger Willenberg (Düsseldorf).
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