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The Impact of Nodal Dissection on Staging in Adrenocortical Carcinoma
Suraj Panjwani, MBBS1, Maureen D. Moore, MD1, Katherine D. Gray, MD1, Brendan M. Finnerty, MD1, Toni Beninato, MD1, Laurent Brunaud, MD2, Thomas J. Fahey III, MD1, and Rasa Zarnegar, MD1
1Department of Surgery, New York Presbyterian Hospital - Weill Cornell Medicine, New York, NY; 2Digestive, Hepato- Biliary and Endocrine Surgery, CHU Nancy-Hospital Brabois Adultes, University de Lorraine, Nancy, France
ABSTRACT
Background. The role of lymphadenectomy in adreno- cortical carcinoma (ACC) is controversial, and formal lymph node (LN) dissection is not routine. We sought to determine the minimum number of LNs that must be examined to accurately identify a patient as node negative. Methods. The National Cancer Database was used to identify patients diagnosed with ACC from 2004 to 2013 who underwent surgical resection. Patients with distant metastases, multivisceral resection, or missing surgical or lymphadenectomy data were excluded. The primary out- come was overall survival (OS).
Results. LNs were identified on histopathology in 156 patients. Of these, 35 (22%) had at least one positive LN. Positive LNs were associated with positive surgical mar- gins (odds ratio [OR] 5.80, p = 0.002) and increasing LN yield (OR 1.06, p = 0.02). Overall, on Cox regression analysis, LN positivity (hazard ratio [HR] 3.02, p < 0.001) and positive surgical margins (HR 2.06, p = 0.048) inde- pendently predicted poor OS after controlling for other factors that may influence survival. LN(-) disease in patients with one to three LNs examined had poorer overall survival compared with when at least four LNs were examined (p = 0.02). None of the other patient, tumor, and treatment variables had any impact on OS of the LN(-)
cohort. The likelihood of identifying nodal involvement was higher on examination of at least four LNs compared with examination of one to three LNs (30 vs. 16%, p = 0.03).
Conclusions. LN positivity in ACC tumors independently predicts worse 5-year OS and a minimum of four LNs may be required to accurately determine LN negativity.
Adrenocortical cancer (ACC) is a rare malignancy with an incidence of approximately 1-2 per one million person- years.1,2 Surgical resection provides the best outcomes for patients when feasible. However, even after complete resection, the 5-year survival rate is 42-63% for stage 1-3 disease.3 One possible reason for these poor outcomes may be early locoregional spread not detected during resection.
Lymph node (LN) status is incorporated into both the combined American Joint Committee on Cancer (AJCC)/ International Union against Cancer (UICC) and The European Network for the Study of Adrenal Tumors (ENSAT) staging systems.4,5 However, staging lym- phadenectomy during surgical resection of ACC has not been defined, resulting in only selective lymphadenectomy being performed currently. Recent studies have evaluated the impact of lymphadenectomy on ACC disease recur- rence and patient survival; however, conflicting results have emerged from these studies. Some have shown a reduced risk for tumor recurrence and increased disease- specific and overall survival for patients undergoing a lymphadenectomy.6,7 Other studies report no additional benefit of lymphadenectomy on oncological outcomes. 8,9
In other solid-organ malignancies, LN status is not only an important predictor of survival but also is a useful guide for adjuvant therapy.10,11 There have been studies for such cancers that identify a minimum number of LNs that need to be examined for accurate stage assessment. For instance,
Electronic supplementary material The online version of this article (doi: 10.1245/s10434-017-6064-3) contains supplementary material, which is available to authorized users.
@ Society of Surgical Oncology 2017 First Received: 27 March 2017
R. Zarnegar, MD e-mail: Raz2002@med.cornell.edu
the College of American Pathologists advises examination of a minimum of 12 LNs for recognition of true LN status in colorectal carcinoma.12
Hence, the purpose of this study was to investigate, using a national database, whether the number of LNs assessed plays a role in staging and overall survival of patients with ACC.
METHODS
Data Source: National Cancer Database
The National Cancer Database (NCDB), a joint program of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, is a national oncological outcomes database that involves more than 1500 Commission-accredited cancer programs in the Uni- ted States and Puerto Rico. Approximately 70% of all newly diagnosed cases of cancer in the United States are captured by this database.13 This study was exempted from the Institutional Review Board approval at Weill Cornell Medicine due to the de-identified nature of information retrieved from the NCDB Participant User File (PUF).
Study Population
The NCDB PUF was used to identify patients diagnosed with ACC from 2004 to 2013 using the International Classification of Disease codes (ICD-O-3 topographic codes C74.0 and C74.9, and histological code 8370.3). Patients ≥18 years of age in whom ACC was the only lifetime cancer diagnosis and who were managed with a surgical resection were included in the analyses. Those with distant metastasis, staged as T4 (primary tumor invasion into other adjacent organs), or managed with multivisceral resection were excluded. Patients with any incomplete data also were excluded.
Variables
Patient and tumor characteristics, such as age, sex, race, tumor size, and laterality, were analyzed. Tumor extension was classified as “local” if the tumor belonged toT1/T2 stage or “regional” if staged T3. Treatment characteristics, including surgical margins (positive vs. negative), treating facility (nonacademic vs. academic), and administration of adjuvant chemotherapy or radiotherapy, were evaluated. Surgical margins were considered positive if there was any microscopic, macroscopic, or nonspecified residual tumor. Variables defining the total number of LNs examined, and those positive on histopathology were used for analyses. Patients were classified into LN(+) and LN(-) groups
based on the presence or absence of any positive LNs found on histopathology.
Statistical Analysis
Continuous variables are reported as median with interquartile range (IQR), and categorical variables are reported as frequency and percentages. Univariate analysis to evaluate association between each variable and nodal metastasis was performed using Student’s t test/Mann- Whitney U test for continuous variables and Chi square/ Fisher exact test for categorical variables as appropriate. All variables found to be significant on univariate analysis (p < 0.05) were entered into a multivariate logistic regression analysis to identify factors associated with positive LNs.
Survival Analysis
Overall survival (OS) was calculated as number of months from diagnosis to last contact or death. Survival curves were created by the Kaplan-Meier method and were compared using the log-rank test. Covariates found to be significant on univariate survival analysis (p < 0.05) were then considered in the Cox Proportional Hazard Regression Model to identify independent predictors of OS.
LN Cutoff Point Analysis
To determine the minimum number of LNs needed for adequate sampling, we created binary variables comprising patients with number of LNs assessed below and above each sequentially increasing value. Survival curves were then compared within these binary variables for each cutoff value in the LN(-) cohort. The significant cutoff value that resulted in the highest Chi square value between the sur- vival curves was chosen for further analysis.10,14 Additionally, the likelihood of identifying at least one positive LN was compared taking the applicable cutoff value into consideration using a two-sided Chi square test.
All p values are two tailed, and p < 0.05 was considered significant. All analyses were performed using Stata 14 (StataCorp, College Station, TX).
RESULTS
Patient Cohort
The NCDB PUF 2004-2013 identified 2168 patients diagnosed with ACC as their only lifetime cancer diagno- sis. Of these patients, 1537 (71%) underwent surgical resection. After excluding patients with T4 disease, distant
metastases, those undergoing multivisceral resection, and having incomplete data, there remained 827 patients who had information regarding number of LNs examined (Supplementary Fig. 1). In total, 156 patients (19%) had at least one LN examined and 671 (81%) had no LNs examined. This cohort of 156 patients was defined as the study cohort. Among these, 90 (58%) were female, and the median age was 54 (interquartile range [IQR] 44-65) years. Median tumor size was 12 (IQR 9.4-16) cm, 66% of the tumors were staged as T1/T2 (local), and 34% were staged T3 (regional) on the basis of tumor extension. Median number of LNs examined was three (IQR 1-8) per tumor specimen. Forty-six (35%) patients had postoperative chemotherapy, of which 41 (89%) were administered sin- gle-agent chemotherapy and 5 (11%) were administered multiagent chemotherapy. Also, 17 (11%) patients had postoperative radiotherapy.
Differential Characteristics of LN(+) and LN(-) Cohorts
On histopathological diagnosis, 35 (22%) of 156 patients had a positive LN identified. On univariate anal- ysis, the LN(+) group had a higher median number of LNs evaluated compared with the LN(-) group (5 vs. 2, p = 0.01). The LN(+) group also was associated with a higher proportion of tumors associated with positive sur- gical margins (30 vs. 7%, p < 0.001) and T3-staged tumors (52 vs. 30%, p = 0.02; Table 1). These groups were sim- ilar on the basis of age, sex, race, tumor size, laterality, surgical approach, treating facility, and adjuvant therapy. On multivariate analysis, surgical margins (OR 5.80, p = 0.002) and increasing LN count (OR 1.06, p = 0.02) were the only two variables that were associated with increasing odds of nodal metastasis (Table 2).
Factors Associated with Overall Survival
On univariate survival analysis of patients undergoing LN assessment, OS was significantly different based on LN status, surgical margins, and tumor extension (Table 3). The LN(+) group had a 5-year OS of 19% versus 63% for the LN(-) group. Patients with positive surgical margins had a 5-year OS of 16% compared with 58% for those with uninvolved surgical margins. Patients with localized tumors (T1/T2) had a 5-year OS of 62% compared with 43% for those with regional tumors (T3). OS did not differ based on age, sex, race, tumor size, laterality, surgical approach, facility type, or administration of adjuvant therapy. Based on multivariate Cox regression analysis, a positive LN (HR 3.02, p < 0.001) and a positive surgical margin (HR 2.06, p = 0.048) proved to be independent predictors of worse overall survival (Table 2).
LN Cutoff Point Analysis
Looking at serially increasing number of LNs examined in node-negative disease, we found that a threshold of four LNs was able to impact OS (p = 0.02; Table 4). Those patients identified as LN(-) on assessment of one to three LNs had a 5-year OS of 53%, whereas for those who had assessment of four or more LNs, the 5-year OS was 79% (Fig. 1a). None of the other patient, tumor and treatment variables have any impact on OS of the LN(-) cohort (Supplementary Table 1). Additionally, the likelihood of recognizing at least one positive LN was significantly higher for patients with at least four LNs examined (30%) compared with those with one to three LNs examined (16%, p = 0.03; Fig. 1b).
DISCUSSION
Knowledge of LN status is important for accurate stage assessment of a patient with ACC. We found that surgical resection was accompanied by evaluation of LNs in only 19% of the patients between years 2004-2013. However, among these patients, it was confirmed that LN status was an important factor for predicting prognosis. Furthermore, we suggest that examination of a minimum of four LNs was required to ascertain accurately node-negative disease.
Studies have reported that LN assessment accompanies less than 30% of the surgical resections performed for ACC.8,9,15 This finding was consistent for this cohort as well, where only 19% of the patients had at least one LN examined and majority of the patients had three or less LNs examined. LNs were found to be involved in 22% of these patients. Based on univariate survival analysis, these patients suffered a 44% reduction in their 5-year OS compared with those without LN involvement. LN posi- tivity also was identified as an independent predictor of poor survival. Bilimoria et al. have previously studied the treatment utilization and prognostic factors for 3982 patients with ACC identified from a prior iteration of the NCDB (1985-2005) and reported nodal metastasis in 26.5% patients. They also showed that these patients had significantly worse OS compared with those without nodal metastasis (HR 1.56, p < 0.001).15
Tumor recurrence rates range between 60 and 80% even after complete surgical resection.16,17 Adjuvant therapy, such as Mitotane or radiotherapy, has been shown to reduce the risk of tumor relapse.16,18,19 As in other solid organ cancers where nodal staging is regularly used to guide adjuvant therapy, ACC patients with positive LNs also may benefit from adjuvant therapy. Currently, there is a prospective, randomized trial underway to evaluate the usefulness of Mitotane in prolonging recurrence free sur- vival in patients with low-intermediate risk of tumor
| LN(-) | LN(+) | p Value | |
|---|---|---|---|
| Total n =156 | 121 (77.6) | 35 (22.4) | |
| Age, years [median (IQR)] | 54 (42-65) | 55 (49-65) | 0.49 |
| Sex [n (%)] | 0.94 | ||
| Male | 51 (42%) | 15 (43%) | |
| Female | 70 (58%) | 20 (57%) | |
| Race [n (%)] | 0.57 | ||
| White | 108 (89%) | 30 (86%) | |
| Black | 8 (7%) | 2 (6%) | |
| Other | 5 (4%) | 3 (9%) | |
| Tumor size, cm [median (IQR)] | 12.5 (9.5-17) | 12 (8.5-14) | 0.14 |
| Laterality [n (%)] | 0.31 | ||
| Right | 41 (34%) | 15/34 (44%) | |
| Left | 80 (66%) | 19/34 (56%) | |
| No. of LNs examined [median (IQR)] | 2 (1-8) | 5 (2-14) | 0.01 |
| Facility [n (%)] | 0.77 | ||
| Nonacademic | 43/100 (43%) | 12/30 (40%) | |
| Academic | 57/100 (57%) | 18/30 (60%) | |
| Postoperative chemotherapy [n (%)] | 0.52 | ||
| Administered | 33/101 (33%) | 13/32 (41%) | |
| Not administered | 68/101 (67%) | 19/32 (59%) | |
| Postoperative radiotherapy [n (%)] | 1.00 | ||
| Administered | 13/120 (11%) | 4 (11%) | |
| Not administered | 107/120 (89%) | 31 (89%) | |
| Surgical margins [n (%)] | <0.001 | ||
| Positive | 8/116 (7%) | 10/33 (30%) | |
| Negative | 108/116 (93%) | 23/30 (70%) | |
| Tumor extension [n (%)] | 0.02 | ||
| T1/T2 (Localized) | 81/115 (70%) | 15/31 (48%) | |
| T3 (Regional) | 34/115 (30%) | 16/31 (52%) |
LN lymph node, IQR interquartile range
| OR/HR (95% CI) | p Value | |
|---|---|---|
| Logistic regression-positive LNs | ||
| Increasing LN count | 1.06 (1.01-1.11) | 0.02 |
| Positive surgical margin | 5.80 (1.87-17.98) | 0.002 |
| Regional tumor (T3) | 2.17 (0.88-5.34) | 0.092 |
| Cox proportional hazards regression model | ||
| Positive LN | 3.02 (1.72-5.32) | <0.001 |
| Positive surgical margin | 2.06 (1.01-4.19) | 0.048 |
| Regional tumor (T3) | 1.46 (0.85-2.51) | 0.17 |
LN lymph node, HR hazard ratio, OR odds ratio, CI confidence interval
| 5-year OS (%) | Univariate | ||
|---|---|---|---|
| HR (95% CI) | p value | ||
| Age (year) | |||
| ≤55 | 52 | – | |
| >55 | 53 | 1.06 (0.66-1.71) | 0.82 |
| Sex | |||
| Male | 61 | – | |
| Female | 47 | 1.49 (0.90-2.47) | 0.12 |
| Race | |||
| White | 53 | – | |
| Black | 50 | 0.92 (0.33-2.54) | 0.88 |
| Other | 50 | 1.45 (0.53-4.01) | 0.47 |
| Tumor size (cm) | |||
| ≤5 | 71 | – | |
| >5 | 52 | 1.24 (0.39-3.96) | 0.71 |
| Laterality | |||
| Left | 52 | – | |
| Right | 56 | 0.89 (0.54-1.47) | 0.65 |
| Treating facility | |||
| Nonacademic | 59 | – | |
| Academic | 53 | 1.29 (0.74-2.25) | 0.36 |
| Radiation | |||
| Not administered | 55 | – | |
| Administered | 40 | 1.61 (0.79-3.26) | 0.19 |
| Chemotherapy | |||
| Not administered | 57 | – | |
| Administered | 44 | 1.13 (0.65-1.98) | 0.66 |
| LN status | |||
| Negative | 63 | – | |
| Positive | 19 | 3.40 (2.08-5.57) | <0.001 |
| Surgical margins | |||
| Negative | 58 | – | |
| Positive | 16 | 2.84 (1.50-5.35) | 0.001 |
| T stage | |||
| T1/T2 (local) | 62 | – | |
| T3 (regional) | 43 | 1.81 (1.09-3.02) | 0.02 |
OS overall survival, HR hazard ratio, CI confidence interval
recurrence after complete surgical resection of ACC, the results of which will likely assist with answering this question.20 Absence of lymphadenectomy may lead to understaging, which may affect treatment algorithms. This also may reduce the therapeutic advantage of decreasing local recurrences served by adequate tumor clearance. A study performed by Reibetanz and colleagues evaluated the impact of intentional locoregional lym- phadenectomy in ACC. Forty-seven of 283 patients retrieved retrospectively from the German ACC registry
| LN count (number of patients) | Chi square value | p Value |
|---|---|---|
| 1 (49) vs. ≥2 (72) | 0 | 0.96 |
| 1-2 (63) vs. ≥3 (58) | 2.81 | 0.09 |
| 1-3 (70) vs. ≥4 (51) | 5.32 | 0.02 |
| 1-4 (78) vs. ≥5 (43) | 2.31 | 0.13 |
| 1-5 (84) vs. ≥6 (37) | 1.51 | 0.22 |
| 1-6 (89) vs. ≥7 (32) | 0.3 | 0.58 |
| 1-7 (90) vs. ≥8 (31) | 0.13 | 0.72 |
| 1-8 (97) vs. ≥9 (24) | 0.79 | 0.37 |
| 1-9 (100) vs. ≥10 (21) | 0.17 | 0.68 |
| 1-10 (103) vs. ≥11 (18) | 0.01 | 0.91 |
| 1-11 (105) vs. ≥12 (16) | 0.13 | 0.72 |
| 1-12 (107) vs. ≥13 (14) | 0.42 | 0.52 |
| 1-13 (109) vs. ≥14 (12) | 0.4 | 0.53 |
| 1-14 (111) vs. ≥15 (10) | 2.23 | 0.14 |
| 1-15 (111) vs. ≥16 (10) | 2.23 | 0.14 |
LN lymph node
underwent lymphadenectomy that was defined as excision of at least five LNs. The median number of LNs examined in this group was six. It was found that this group of patients demonstrated a considerably lower risk for tumor recurrence (HR 0.65, p = 0.042) and disease-related death (HR 0.54, p = 0.049).6 The positive therapeutic impact of a lymphadenectomy performed in conjunction with adrenalectomy was shown in a recent multi-institutional study performed in the United States; operative reports of the surgeons and the surgical pathology reports were reviewed to decide whether a lymphadenectomy was per- formed. Median number of LNs examined in the lymphadenectomy group was 5.5. It was found that patients undergoing R0 resection and lymphadenectomy had 5-year OS of 76% compared with 59% for those without lym- phadenectomy.7 However, these studies were limited by size and the lack of a stepwise analysis identifying mini- mum number of LNs that need to be examined for accurate recognition of node-negative disease. Interestingly, the number of LNs examined was higher in the LN(+) cohort, and increasing number of LNs examined had higher odds of nodal metastasis, even after accounting for surgical margin status. This may reflect improved recognition of positive LNs following a more complete harvest. Studies evaluating lymphadenectomy in other cancers, such as colorectal, have shown that the proportion of identifying diseased LNs increases as a function of the number of LNs harvested and examined. 21,22
It is important in any cancer to assess the number of LNs that minimizes the risk of false negatives while accurately capturing all true positives. In this analysis, we have found
a
1.00
b
Kaplan Meier Survival Estimates
Log rank p=0.02
100
0.75
Lymph Node (LN) status (% Patients)
16%
30%
75
0.50
84%
70%
LN (+)
0.25
50
LN (-)
0.00
25
0
50
Months
100
150
Number at risk
Four or more LNs 45
22
3
0
1-3 LNs
64
24
5
0
0-
1-3
Atleast 4
1-3 LNs assessed
Four or more LNs assessed
Number of LNs examined
that LN(-) patients who had one to three LNs examined had a worse OS than those who had at least four or more LNs examined. This could be explained potentially by inadequate evaluation of LNs, resulting from failure to harvest and identify one or more relevant positive LNs. This suggests that some of those tumors designated as Stage II were in reality Stage III tumors and is supportive of the concept of stage migration. This may in fact be one explanation for the similar survival observed for Stage II and III ACC tumors in several studies.23,24 In fact, sub- optimal LN dissection (<12 LNs) in colorectal cancer is considered to be a nidus for future recurrences/metastasis and is an indication for adjuvant therapy.12 Furthermore, the likelihood of identifying at least one positive LN increased significantly when four or more LNs were examined.
Our study has several limitations inherent in data col- lection from a large-scale, multi-institutional database. The NCDB does not provide data about recurrence or disease- specific survival. Pertinent to our objectives, information about which LN basins were included in each nodal assessment are not captured by the NCDB. This may have helped to understand existing lymphadenectomy practices and possible future recommendations. Data regarding Ki67 index-the single best prognostic factor in localized ACC-Weiss score, and functional status was not available for any patients.25 Also, grade was documented only for a quarter of the patients in the cohort. As a result, the mul- tivariate analysis must be interpreted with caution as these factors could not be accounted for. Additionally, in many instances, the LNs assessed may not have been part of an intentional lymphadenectomy and may have been found on pathology alone. Lastly, this was a retrospective observa- tional study, and there may be potential confounders inherent to such a study.
LNs draining the adrenal gland may span the region between the celiac trunk and the origin of the iliac vessels. It has been suggested that the main collecting LNs are the ipsilateral celiac, para-aortic, para-caval, and renal hilum LNs. However, the large average size of the lesion (>10 cm on diagnosis) may result in involvement of mul- tiple lymphatic pathways. Also, tumor invasion may obstruct the usual lymphatic pathway, thus making it dif- ficult to decipher the extent of LN dissection for ACC lesions. Currently, there is limited data regarding local- ization of involved LNs, and future studies are warranted to investigate the adequate extent of LN assessment.
Future directions should also involve identification of tumor markers predicting aggressive disease that will result in locoregional spread, in addition to prospective, large, multicenter studies to establish the true effect of consid- ering a lymphadenectomy defined by harvesting and examining a minimum of four LNs.
CONCLUSIONS
This study confirmed that LN dissection is infrequently performed for patients with ACC. However, among those who had any LN assessment, LN status was an independent predictor of OS and at least four LNs should be examined per specimen to accurately classify a patient as having node-negative disease.
ACKNOWLEDGMENT None.
DISCLOSURE The CoC’s NCDB and the hospitals participating in the CoC NCDB are the source of the de-identified data used. They have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.
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