Impact of Regional Lymph Node Dissection on Disease Specific Survival in Adrenal Cortical Carcinoma *
Authors
N. Saade1, C. Sadler1, M. Goldfarb2
Affiliations
1 University of Southern California Keck School of Medicine, Los Angeles, USA
2 John Wayne Cancer Institute at Providence St. John’s Health Center, Santa Monica, USA
Key words
adrenal cortical carcinoma (ACC)
· lymph node dissection
· disease specific survival
Abstract
▼
Adrenocortical carcinoma (ACC) is a rare malig- nancy with a poor prognosis. The purpose of this study is to evaluate the impact of a more exten- sive regional lymph node dissection (LND) has on survival in ACC patients in the United States. Patients≥ 15 years of age without distant metas- tases who underwent surgical intervention for primary ACC were identified from the SEER18 registry from 1988-2009. Patients were divided into 2 groups: having a regional LND (≥5 LNs removed) vs. no-LND (0-4 LNs removed). Overall survival (OS) and disease specific survival (DSS) were compared between groups. Of 259 patients with complete data on nodal resection, 243 (93.8%) underwent no-LND and 16 (6.2%) LND. There was no difference in age, sex, metastases,
or ENSAT stage between groups. However, LND patients had larger tumors (p=0.004), and more frequently underwent en-bloc surgery (p=0.002). One- and 3-year OS and DSS did not differ between groups. In a cox regression model, performance of a regional LND did not significantly influence DSS. However, female gender (HR: 1.67, CI: 1.04-2.69, p=0.033) and later stage (stage III-HR: 4.78, CI: 1.14-20.00, p=0.032) or positive LNs (HR: 5.92, CI: 2.05-17.08, p=0.001) were risk factors for worse DSS. Regional LND may not improve DSS or OS in nonmetastatic ACC patients undergoing adrenal- ectomy. It remains controversial as an essential part of the surgical management for ACC and deserves further investigation in a larger, prospec- tive study. However, regional LND should still be considered for staging and prognostic purposes and to standardize surgical care.
received 19.01.2015 accepted 26.03.2015
Bibliography
DOI http://dx.doi.org/ 10.1055/s-0035-1549877 Published online: May 4, 2015 Horm Metab Res 2015; 47: 820-825 @ Georg Thieme Verlag KG Stuttgart . New York ISSN 0018-5043
Correspondence
M. Goldfarb, MD, MS, FACS, FACE
Assistant Professor of Surgery Endocrine Tumor Program John Wayne Cancer Institute at Providence St. John’s Health Center 2200 Santa Monica Blvd Santa Monica CA 90404 USA Tel .: + 1/310/829 8751
Fax: +1/310/315 6113 goldfarbm@jwci.org
Introduction
▼
Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with 5-year survival rates less than 40%. Patients often pre- sent with advanced disease and thus have limited treatment options. For nonmetastatic disease, surgical resection offers the highest likelihood of cure, although recurrence rates are as high as 70-80%. Unfortunately, survival rates and treat- ment methods for ACC have remained essentially unchanged over the past 20 years, reflecting a need for further investigation into novel thera- pies for this disease and standardization of surgi- cal management [1-10].
Open adrenalectomy is the surgical procedure of choice for ACC, often with the addition of a regional lymph node dissection (LND). Although positive LNs are an important determinant of
both prognosis and tumor biology, potentially guiding adjuvant therapy decisions in ACC and other cancers, the extent of LND and its impact on survival in ACC remain controversial [11-19]. Recently, a study through the German ACC regis- try reported a significant decrease in recurrence rates and improved disease specific survival (DSS) for patients who had 5 or more regional LNs removed during surgical resection when compared to patients who did not undergo a complete LND [20]. Therefore, this study will attempt to investigate if a more complete regional LND (more than 5 LNs) confers similar improve- ments in DSS and OS in ACC patients in the United States.
Materials and Methods ▼
Data source and cohort selection
Public use data from 18 SEER registries were uti- lized for this study. The SEER18 currently covers approximately 28% of the total U.S. population
* This paper was presented as a poster at the 99th Annual American College of Surgeons Meeting in Washington, DC, October 2014
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and includes the states of Connecticut, Hawaii, Iowa, New Mex- ico, Kentucky, Louisiana, New Jersey, and Utah; the metropolitan areas of Atlanta, Detroit, and San Francisco-Oakland; Los Ange- les County, the 4-county area of San Jose-Monterey, and greater California; the 13-county area of Seattle-Puget Sound; rural as well as greater Georgia; and the Alaska Native tumor registry. The populations in these areas are generally representative of the United States population as a whole, although they are somewhat more urban and racially diverse. After cancer is diag- nosed by biopsy, medical records are abstracted for patient demographics, primary tumor site, morphology, stage at diag- nosis, and first course of cancer-directed treatment. Since the SEER database is publicly available and all patient information is de-identified, this study was granted an exemption from institu- tional review board approval [21].
All patients with a histologically confirmed primary ACC (ICD- 0-3: 8370, location: C74.0) diagnosed between 1988 and 2009 were identified. Patients were excluded if they did not undergo surgical intervention or had an unknown surgery status, were under 15 years of age, had less than 6 months of follow-up, had Stage IV disease, or did not have the number of LNs removed recorded. The 14 patients with unknown LND status had no sig- nificant difference in demographic or tumor characteristics compared to the LND and no-LND groups. Patients with distant metastases (stage IV) were excluded from the study since only palliative treatment is possible for these patients. Therefore, the influence of any co-variable surgical procedure is not expected to be constant in time or be comparable to that observed in other potentially curable patients. A total of 699 patients were identified by the search for primary site of adrenal cortex, and 259 were included in the final analyses ( Fig. 1).
Clinical covariates and outcome measures
A cohort of 259 patients met the inclusion criteria for the study. Primary outcome measures for this study include both overall (OS) and DSS. Demographic variables included age (continuous variable); gender (male, female); race [white, black, or other (including American Indian, native Alaskan, East Asian, South Asian, Southeast Asian, and Pacific Islander populations)]; and marital status (married vs. not married).
Clinical covariates available in SEER for ACC include tumor size (mm), T-stage (T1: < 5 cm, T2: >5 cm, T3: growth into adjacent in fat or positive lymph nodes: T4: tumor in adrenal fat with posi- tive lymph nodes, tumor invasion of adjacent organs, and/or dis- tance metastases), N-stage (positive or negative), M-stage (distant metastases), laterality (left, right) and Grade (I: well dif- ferentiated through IV: undifferentiated). European Network for the Study of Adrenal Tumors (ENSAT) staging system was derived by defining stage I as ACC measuring ≤5 cm in greatest dimen- sion confined to the adrenal gland, stage II as tumor >5 cm with- out extra-adrenal invasion, stage III by the presence of positive lymph nodes, infiltration of surrounding tissue, and stage IV includes only patients with distant metastases [22]. Treatment variable include surgery (simple/partial adrenalectomy, radical en-bloc surgery), radiation (yes, no), and lymph nodes removed. For this analysis, regional LND is defined as the removal of 5 or more lymph nodes.
Statistical analysis
Nominal categorical variables were compared using Fisher exact test, ordered categorical variables were analyzed using the Man- tel-Haenszel chi-square test, and continuous variables with the
Search for Primary site: Adrenal Cortex C74.0 Age 15+ (n=699)
No histologic confirmation (n=65)
Histologically confirmed ACC (n=634)
No surgical intevention (n=129)
Surgical intervention unknown (n=142)
Adrenal surgery confirmed (n=363)
Follow-up <6 months (n=21)
Stage IV (n=69)
LND Unknown (n=14)
Final Analysis (n=259)
Mann-Whitney U-test to evaluate any demographic, clinical, or treatment differences between LND and no-LND patients. Step- wise forward logistic regression was employed to identify inde- pendent predictors of LND with variables that were statistically significant on univariate analyses at an a level of 0.05. Odds ratios with associated 95% confidence intervals were calculated to evaluate the strength of association between each variable and the performance of an LND. Kaplan-Meier survival analysis with a log-rank test was performed to evaluate difference in sur- vival between patient groups for all variables. Those that were significant (p<0.1), in addition to the performance of a regional LND, were entered into a cox proportional hazard regression model; only those with a p<0.05 were retained in a final multi- variate model. Hazard ratios and 95% confidence intervals were calculated to evaluate the strength of association between each
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variable and survival. Adjustments were made for both lymph node positivity and stage. Data analysis was performed using SPSS Version 21.0 (SPSS Inc, Chicago, IL, USA). All tests were 2-sided, and a p-value of <0.05 was considered to be statistically significant.
Results
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Of the 259 patients with known surgical intervention for ACC, only 51 had one or more lymph nodes removed ( Fig. 2). Of the total study population, 16 (6.2%) were documented as having undergone regional LND and 243 (93.8%) not having a LND. There was no significant difference in age, gender, T-stage, ENSAT stage, grade, or use of radiation therapy between groups (· Table 1). However, patients who underwent regional LND had larger tumors (p=0.004), were more likely to have N1 disease (p<0.001), and more frequently underwent radical surgery with en bloc resection of other organs (p=0.002). No demographic or clinical factors were predictors of having undergone regional LND on multivariate analysis.
Median follow-up was 64.3 (15-100) months for LND patients and 61.8 (6-183) months for no-LND patients (p=0.790). Median OS did not differ between patients that underwent a regional LND vs. no-LND 45 (0-100 months) vs. 44 (0-184 months); p=0.901. One hundred and one (41.6%) patients died from ACC, 94 in the no-LND group and 7 in the LND group, and 33 patients died of other causes (p=0.789). There was no difference in 1-year OS (no-LND: 84.7% vs. LND: 81.3%, p=0.72) or 3-year OS (no-LND: 55.9% vs. LND: 57.1%, p=1.00) between groups. Simi- larly, there was no difference in 1-year DSS (no-LND: 90.1% vs. LND: LND 86.7%, p=0.65) or 3-years DSS (no-LND 62.3% vs. LND 72.7%, p=0.75). When patients with pathologically confirmed positive regional LNs were compared to those without positive regional LNs, both 1-year DSS [+LN: 60.0% vs. (-) LN 92.1%, p=0.027] and 1-year OS [+LN 54.5% vs. (-) LN 92.1%, p=0.009] were significantly worse in patients with positive LNs. However, these differences did not persist at 3 years [DSS: + LN: 33.3% vs. (-) LN 51.9%, p=0.45; OS: +LN 27.3% vs. (-) LN 46.7%, p=0.31]. Kaplan-Meier analysis demonstrated longer DSS for patients with negative LNs, no distant metastases, and early stage tumors ( Table 2). Male patients, those with low-grade tumors, and those that did not receive radiation therapy also trended toward longer DSS, but the results were not statistically significant. In Cox regression modeling using tumor specific variables, female gender, positive LNs, and T3 tumor stage remained independent predictors of worse DSS (· Table 3). In a comparable model using ENSAT disease stage instead of specific tumor variables, female gender and ENSAT stage III were risk factors for lower DSS. Per- formance of a regional LND trended towards, but did not reach significance in predicting DSS ( Fig. 3).
Discussion
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This study seeks to investigate the impact of regional LND on OS and DSS in ACC patients treated in the United States. Experts have recently appealed for the standardization of regional LND for all ACCs to include all first-order draining nodes since at pre- sent, LND is not routinely performed even though the results bear important staging and prognostic significance [10,23]. Due to the low number of patients who received a regional LND and
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| No LND (<4) n=243 | Regional LND (≥5) n=16 | p-Value | |
|---|---|---|---|
| Demographics | |||
| Gender | 0.442 | ||
| Male | 103 (42.4) | 5 (31.3) | |
| Female | 140 (57.6) | 11 (68.8) | |
| Age (median) | 50-54 | 45-49 | 0.202 |
| Race | |||
| White | 215 (88.5) | 14 (87.5) | 0.177 |
| Black | 10 (4.1) | 2 (12.5) | |
| Other | 18 (7.4) | 0 (0) | |
| Marital status | |||
| Unmarried | 74 (30.5) | 5 (31.3) | 0.743 |
| Married | 162 (66.7) | 10 (62.5) | |
| Unknown | 7 (2.9) | 1 (6.3) | |
| Metropolitan | 102 (42.0) | 9 (56.3) | 0.303 |
| Tumor characteristics | |||
| Mean tumor size (mm) | 112.6 | 144.0 | 0.004 |
| Tumor stage | |||
| T1 | 14 (6.3) | 0 (0) | 0.607 |
| T2 | 130 (58.0) | 8 (50.0) | 0.605 |
| T3 | 38 (16.2) | 2 (12.5) | 1.000 |
| T4 | 42 (17.9) | 6 (37.5) | 0.091 |
| N1 | 5 (2.5) | 7 (43.8) | <0.001 |
| ENSAT Disease stage | |||
| Stage I | 13 (6.0) | 0 (0) | 0.608 |
| Stage II | 123 (56.7) | 6 (37.5) | 0.192 |
| Stage III | 81 (35.8) | 10 (62.5) | 0.058 |
| Laterality | 0.309 | ||
| Right | 109 (45.4) | 5 (31.3) | |
| Left | 131 (54.6) | 11 (68.8) | |
| Grade 1 (well differentiated) | 6 (10.3) | 1 (20.0) | 0.457 |
| Adjacent tissue infiltration | 80 (34.0) | 8 (50.0) | 0.278 |
| Treatment variables | |||
| Radiation therapy | 25 (10.5) | 0 (0) | 0.380 |
| Simple/partial adrenalectomy | 160 (67.5) | 6 (37.5) | 0.026 |
| Radical or "En Bloc" surgery | 58 (23.9) | 10 (62.5) | 0.002 |
the retrospective nature of this study, the statistical significance or lack thereof in survival between the LND groups in the pre- sent study should be regarded with caution and suggestive only.
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| Factor | n | Estimated mean survival (months) | p (log rank) |
|---|---|---|---|
| Gender | 0.084 | ||
| Male | 102 | 104.85 | |
| Female | 141 | 73.94 | |
| Race | |||
| White | 213 | 93.51 | |
| Black | 12 | 92.00 | 0.641 |
| Other | 18 | 86.81 | |
| Marital status | |||
| Unmarried | 76 | 81.93 | |
| Married | 159 | 96.34 | 0.972 |
| Unknown | 8 | 88.75 | |
| Geographic region | |||
| Northeast | 32 | 72.64 | |
| Southeast | 38 | 87.24 | 0.160 |
| West | 131 | 100.85 | |
| Midwest | 42 | 66.86 | |
| Metropolitan | |||
| No | 137 | 85.39 | 0.670 |
| Yes | 106 | 98.71 | |
| N-stage | |||
| N0 | 192 | 82.53 | 0.003 |
| N1 | 12 | 40.20 | |
| T-stage | <0.001 | ||
| T1 | 11 | 112.78 | 0.128 |
| T2 | 132 | 93.78 | 0.002 |
| T3 | 39 | 50.81 | 0.001 |
| T4 | 45 | 85.79 | 0.041 |
| ENSAT stage | 0.001 | ||
| I | 10 | 110.40 | 0.186 |
| II | 123 | 92.79 | 0.002 |
| III | 87 | 78.23 | <0.001 |
| Laterality | |||
| Right | 132 | 81.15 | 0.780 |
| Left | 108 | 92.13 | |
| Grade | |||
| Well differentiated (Grade I) | 7 | 134.71 | 0.090 |
| Poorly/Moderately differentiated (Grade II-IV) | 54 | 68.02 | |
| Adjacent tissue infiltration | |||
| No | 152 | 94.51 | <0.001 |
| Yes | 84 | 77.11 | |
| Lymph node dissection | |||
| <4 LN removed | 228 | 96.77 | 0.725 |
| ≥5 LN removed | 15 | 67.75 | |
| Surgical extent | |||
| Radical/En Bloc surgery | 66 | 80.31 | 0.816 |
| Adrenalectomy-simple/ partial | 153 | 79.31 | 0.591 |
| Radiation | |||
| No | 218 | 80.02 | 0.202 |
| Yes | 22 | 75.31 |
This emphasizes the need for a large, international cancer regis- try for this rare tumor that is inclusive of detailed surgical, path- ological, and adjuvant treatment information. Additionally, the study underscores the need for further investigation into alter- native management strategies and treatments for this rare and aggressive cancer [24,25].
The present study identified only 16 patients (6.2% of all patients, 31.4% of patients with ≥1 LN removed) who met the
| Using individual tumor variables | |||
|---|---|---|---|
| HR | CI (95%) | p-Value | |
| Regional LND | 0.36 | 0.13-1.03 | 0.057 |
| Age | 1.06 | 0.98-1.15 | 0.164 |
| T1 * | 0.001 | ||
| T2 | 1.64 | 0.39-6.86 | 0.497 |
| T3 | 4.58 | 1.05-19.98 | 0.043 |
| T4 | 3.83 | 0.85-17.13 | 0.079 |
| N1 | 5.92 | 2.05-17.08 | 0.001 |
| Received radiation | 1.01 | 0.50-2.28 | 0.863 |
| Female gender | 1.67 | 1.04-2.69 | 0.033 |
| Using ENSAT staging | |||
| Regional LND | 0.85 | 0.39-1.87 | 0.686 |
| Stage 1 * | <0.001 | ||
| Stage 2 | 1.98 | 0.48-8.19 | 0.347 |
| Stage 3 | 4.78 | 1.14-20.00 | 0.032 |
| Age | 1.05 | 0.98-1.13 | 0.178 |
| Received radiation | 1.13 | 0.61-2.10 | 0.694 |
| Female gender | 1.95 | 1.25-3.04 | 0.003 |
* reference group
1.0
⇐ 4 LND
5+ LND
0.8
HR: 0.85, CI: 0.39-1.87, p=0.69
Cumulative Survival
0.6
0.4
0.2
0.0
0
25
50
75
100
125
Survival time (months)
criteria for regional LND, which is within the range of regional LND rates in the sparse literature, though the definition of LND varies [1,26]. A regional LND for ACC would consist of an en bloc resection of all nodes in the quadrant superior to the renal hilum that follow the adrenal blood supply, including the origin of the celiac and mesenteric arteries; however, surgeon comfort level with the procedure and ease of the lymphadectomy should be taken into consideration. In the current study, the number of nodes examined may be underreported in the database or due to less thorough LN examination by some pathologists. Many times involved lymph nodes are “matted” and are therefore counted as single positive node. Additionally, institutional series are gener-
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ally from cancer centers with an expertise in adrenal cancer and likely ensure their pathologists do a complete search for nodes in the removed specimen.
Not surprisingly, larger tumors and those that underwent radi- cal, en-bloc surgery with resection of other organs were more likely to undergo a regional LND, although the performance of a regional LND did not differ by tumor or disease stage. This may simply reflect a pattern of operative management unique to spe- cific surgeons or centers that cannot be discerned from SEER data. There is no information provided on the expertise of the treating center or surgeon volume, which has been shown to influence survival [22,27,28].
Overall disease stage and the presence of distant metastases predicted worse outcomes. This corroborates prior findings showing that prognosis in ACC is stage dependent.[11, 12,27,29]. Female gender was an independent predictor of worse DSS in the model that included stage, which until recently had not been reported [27,29-31]. Treatment factors such as radical surgery and radiation therapy did not impact OS or DSS in the current study. This may corroborate previous reports that show post- surgical radiation therapy may offer equivalent benefit to a com- plete regional LND, though radiation data may be underreported in the SEER database [32-34]. However, it may contrast with other reports in the literature regarding radical surgery [1,27]. Importantly, information on adjuvant medical therapy was not available.
There are several limitations to the current study. The SEER database covers less than a third of the US population, and for such a rare malignancy, even a large database has small num- bers. Thus, the sample size is likely too small to show signifi- cance and therefore the conclusions should not be regarded as decisive, but rather as suggestive. LN information, especially the numbers harvested, is known to be potentially underreported not only in the database, but also in general, again potentially underestimating the regional LND group and thus affecting the significance. Additionally, the number of patients stated as N0 but ultimately having positive nodes was not available. Lym- phatic and vascular invasion, important indicators of tumor biology and thus tumor aggressiveness, are not available. Nor is the study able to account for impact of re-resections, functional tumor status, laparoscopic vs. open surgical technique, surgical margins, or the use of adjuvant therapy, all of which may influ- ence both OS and DSS. Lastly, using the same arbitrary cutoff point of 5 LNs removed to define regional LND as the German ACC registry may not be the most optimal number of LNs to demonstrate a significant effect on survival.
Conclusion
▼
Regional LND may not improve DSS or OS in ACC patients under- going adrenalectomy. It remains controversial as an essential part of the surgical management for ACC and deserves further investigation in a larger, prospective study. However, regional LND should still be considered for staging and prognostic pur- poses and to standardize surgical care.
Conflict of Interest
▼
The authors declare no conflict of interest.
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