World Journal of Surgery
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Does Lymphadenectomy Improve Survival in Patients with Adrenocortical Carcinoma? A Population-Based Study
Naris Nilubol1 . Dhaval Patel1 . Electron Kebebew1
@ Société Internationale de Chirurgie 2015
Abstract
Background A recent study suggested a survival benefit in patients with adrenocortical carcinoma (ACC) who had undergone lymphadenectomy. The objective of this study was to study the effect of lymphadenectomy on the survival rates of patients with ACC.
Methods Data from adult patients with histology-proven ACC from the National Cancer Institute’s Surveillance, Epidemiology, and End Results 18 Registries (1973-2011) were analyzed to assess the impact of lymphadenectomy (≥4 lymph nodes removed) on disease-specific survival (DSS).
Results Of 1525 patients with ACC, 45 % were male. 36, 20, and 44 % of patients presented with localized, regional, and distant metastatic diseases, respectively. 8 % of patients (n = 67/802) underwent lymphadenectomy. We observed a higher rate of lymphadenectomy performed in patients with regional disease [locally advanced tumors (stage T3 and T4) and/or lymph node metastasis] and distant metastasis than in those with localized tumors (12.4 % and 12.0 vs. 5.1, respectively, p < 0.01) and in patients with primary tumor sizes >10 cm (12.4 vs. 4.2 %, p < 0.01). Lymph node metastasis was present in 12.8 % (19.2 % in locally advanced ACC). A lymphadenectomy was not associated with improved DSS on univariate analysis (p = 0.30), regardless of tumor size or staging. Independent prognostic factors included: ages ≥60 years (p <0.01, HR 1.70), lymph node metastasis (p<0.01, HR 1.7), distant metastasis (p < 0.01, HR 5.6), complete resection of tumor (p <0.01, HR 0.47), and debulking surgery (p <0.01, HR 0.49).
Conclusion A lymphadenectomy is not commonly performed in patients with ACC in the U.S. Although we found no survival benefit in this cohort with a low rate of lymphadenectomy, a lymphadenectomy may be considered in patients with locally advanced tumors (T3 and T4) due to a higher rate of lymph node metastasis.
Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy with an annual incidence of 1-2 cases per million. The prognosis of patients with ACC is poor. The five-year survival rate of
☒ Naris Nilubol niluboln@mail.nih.gov
1 Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, 10 Center Drive, Rm. 3-5840, Bethesda, MD 20892, USA
patients with locally advanced and metastatic ACC ranges from 16 to 38 % [1-3]. Little progress has been made in the treatment of ACC, with no improvement in the survival rate of patients with ACC over the past decades. En bloc resection with negative margins (R0 resection) remains the treatment of choice in patients with resectable ACC, but this procedure is not possible in most patients. Although a complete surgical resection may cure some patients with localized ACC, 50-80 % of patients develop recurrent or metastatic disease despite initial R0 resection [4, 5]. Patient prognosis depends on ACC stage, age at diagnosis, tumor grade, and the
completeness of initial surgery [4, 6]. Lymph node involvement is an important prognostic factor and is present in approximately 20 % of patients with ACC [7]. The role of a lymphadenectomy has been established for accurate stag- ing and/or improving the outcome in a number of solid malignancies, such as gastric cancer [8], renal cell carcinoma [9], and testicular cancer [10]. However, the role of lym- phadenectomy in patients with ACC is unclear. A signifi- cantly reduced risk of tumor recurrence and lower disease- specific mortality were observed in patients with ACC from the German ACC Registry who underwent lymphadenec- tomy as compared to those who did not have lym- phadenectomy [11]. The aim of this study was to evaluate the impact of lymphadenectomy on the survival rate of patients with ACC, using a United States (US) population-based cancer registry.
Materials and methods
Data acquisition
The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute is a US population- based cancer registry where information on patient demo- graphics, incidence, prevalence, tumor characteristics, ini- tial treatment, tumor histopathology, stage at diagnosis, and follow-up vital statistics has been collected since 1973. The data used in this study were derived from 18 SEER registries from various geographic locations throughout the US, rep- resenting 28 % of the US population. This study was exempted from review and approval by the Office of Human Subject Research at the National Institutes of Health because the SEER data contain only deidentified patient information. ACC cases were identified, and detailed information was captured using SEER*Stat software, Release 8.1.5 (March 2014; Surveillance Research Program, Surveillance Systems Branch, National Cancer Institute, Bethesda, MD).
We identified all adult patients (≥20 years of age) who had histologically confirmed ACC between 1973 and 2011. All patients had ACC as their first and primary cancer. We included the following histologic subtypes and their International Classification of Disease codes (ICD-O- 3) [12] for the adrenal gland: carcinoma, not otherwise specified (NOS) (8010); large-cell carcinoma (8012); undifferentiated carcinoma (8020-8021); pleomorphic carcinoma (8022); adenocarcinoma, NOS (81540); oxy- philic adenocarcinoma (8290); adrenocortical carcinoma (8370); and adenocarcinoma with neuroendocrine differ- entiation (8574). Tumors derived from the adrenal medulla were excluded. We defined a lymphadenectomy as having four or more lymph nodes removed because the SEER data-coded patients who had four or more lymph nodes
removed have been placed in a separate category since 2003. We used the same cutoff criterion to categorize patients with information on lymph node removal who had a diagnosis before 2003. Radical surgery was defined as a partial or total removal of the primary tumor, with a resection in continuity with other organs. The variables analyzed were age (<60 and ≥60 years of age); gender; race/ethnicity (white, black, other), according to the stan- dards set by the US Office of Management and Budget for the classification of federal data on race and ethnicity; [13] year of diagnosis (before 1990, 1990-1999, 2000-2011); primary tumor size; T stage; lymph node metastasis; dis- tant metastasis; stage (localized, regional, and distant metastatic disease); surgical treatments (lymphadenec- tomy, surgery of primary and non-primary site[s]); radio- therapy; disease-related mortality; and disease-specific survival (DSS).
Statistical analyses
We defined DSS as the time, in years, from the date of diagnosis to the date of death caused by ACC. Survival rate was censored at the date of the last follow-up if no disease- specific death occurred. We used the Pearson Chi-square test and Fisher’s exact test [14] to evaluate differences in ordinal and nominal categorical variables between patients based on lymphadenectomy status. We chose the age of 60 years and a tumor size of 10 cm because these were approximately the median age and size of tumors in this cohort. The Mann-Whitney U test [15] was used to com- pare continuous variables that were not normally dis- tributed. The Pearson correlation and Spearman’s rho test were used to assess the correlation between normally dis- tributed and non-normally distributed variables, respec- tively. The Kaplan-Meier estimator [16] with a log-rank (Mantel-Cox) test [17] was used to estimate and compare the DSS for patients by demographic, clinical, and patho- logical features, and treatments. Pairwise comparisons were used to determine the differences in survival between subgroups. Multivariate Cox proportional hazards regres- sions [18] were performed to identify variables that were independently associated with DSS. A two-tailed p value of less than 0.05 was considered statistically significant. The primary outcome measure in this study was DSS.
Statistical analysis was performed using SPSS® v16.0 for Windows (SPSS, Inc., Chicago, IL).
Results
Of 1525 adult patients with histologically confirmed ACC reported in the SEER program from 1973 to 2011, lymph node metastasis occurred in 12.8 % (n = 117/916). The
median of lymph nodes removed was 0 (range 0-40) as no lymph nodes were identified in 84 % of patients (n = 942/ 1122). The median of metastatic lymph nodes in patients with ACC who had 1 or more lymph nodes removed was 0 (0-23). 36 % (n = 518/1433), 20 % (n = 282/1433), and 44 % (n = 633/1433) of Patients presented with localized, regional, and distant metastatic diseases, respectively. The median age range at diagnosis was 55-59 years. The mean primary tumor size was 11.5 ± 6.4 cm (±SD). Forty-one percent of patients (402/990) had locally advanced tumors (stage T3 and T4). There was a significantly higher rate of extra-adrenal tumor extension in patients with ACC >10 cm, compared to patients with ACC ≤10 cm (47.7 vs. 34.4 %, p < 0.01). Of 802 patients who had ACC with available data on the number of lymph nodes removed, 8.3 % (n = 67) underwent lymphadenectomies. There was no significant difference in the rate of lymph node metas- tasis by the number of lymph nodes removed (22.9 % in patients with ACC who had 1-3 lymph nodes removed vs. 33.8 % in those with 4 or more lymph nodes removed, p = 0.16). The clinical characteristics of the study cohort are summarized in Table 1.
Factors associated with lymph node metastasis included poorly and undifferentiated ACC (21.4 % in patients with poorly or undifferentiated ACC vs. 6.8 % in patients with well or moderately differentiated ACC, p < 0.01) and locally advanced tumor [19.2 % (stage T3 and T4) vs. 4.8 % (stage T1 and T2), p < 0.01] but did not include tumor size (p = 0.85). There was a higher rate of lym- phadenectomies in black patients [18 vs. 8.1 % (white) vs. 3.6 % (other race/ethnicity), p = 0.02] and in patients with regional disease (locally advanced tumor (stage T3 and T4) and/or lymph node metastasis) and distant metastasis than in those with localized tumor and distant metastasis (12.4 and 12.0 vs. 5.1 %, respectively, p < 0.01) and in patients with primary tumor sizes larger than 10 cm (12.4 vs. 4.2 %, p < 0.01). There was no difference in gender, age, year of diagnosis, histologic differentiation, surgery at other site(s), radiotherapy, disease-related mortality, and duration of follow-up between patients who underwent lymphadenectomy versus patients who did not.
Based on univariate analysis, a lymphadenectomy was not associated with longer DSS (p = 0.30), regardless of age (p = 0.20), race/ethnicity (p=0.36), gender (p = 0.31), tumor differentiation (p = 0.54), overall stage (p = 0.71), tumor size (p = 0.70), locally advanced tumor (stage T3 and T4) (p = 0.82), or distant metastasis (p = 52). Other factors associated with shorter DSS, based on univariate analysis, included ages ≥60 years (p < 0.01), male gender (p < 0.01), diagnosis year before 1990 (p < 0.01), locally advanced tumor (p <0.01), regional ACC (p <0.01), and metastatic ACC (p <0.01). Patients who had no surgery or local tumor destruction had
significantly shorter DSS than those who underwent debulking surgery (p < 0.01) and those who had simple, total, or radical excision of ACC (p < 0.01) (Fig. 1). The results of univariate analysis are summarized in Table 2. Based on multivariate analysis, independent prognostic factors were ages ≥60 years (p <0.01, HR 1.75), regional disease (p <0.01, HR 2.6), distant metastasis (p <0.01, HR 5.5), complete resection of tumor (p < 0.01, HR 0.44), and debulking surgery (p < 0.01, HR 0.46) (Table 3 and Fig. 1).
Discussion
Surgery remains the best treatment option in patients with localized and resectable ACC [19]. Although complete ACC resection is an important prognostic factor, the role of the lymphadenectomy in patients with ACC who are undergoing initial resection remains unclear. We found that the rate of lymph node metastasis was 12.8 %, but only 8.3 % of patients had lymphadenectomy. We found a sig- nificantly higher rate of lymph node metastasis in patients with locally advanced tumors. Lymphadenectomy was performed more commonly in patients with regional dis- ease and larger tumors. However, a lymphadenectomy was not an independent prognostic factor for DSS in patients with ACC. In addition to more advanced tumor stages, we found that patients at ages ≥60 years and those who had no surgery or only local tumor destruction had a shorter DSS. Similar to our results, patient age has been shown to be a significant prognostic factor in patients with ACC in other studies [20, 21]. Incorporating age at the time of diagnosis in the staging system resulted in a significant difference in survival between patients with stages I and II, [20].
In contrast to a previous report from a German ACC cohort with a higher rate of lymphadenectomy in patients with larger tumors and who had undergone multi-organ resection [11], we did not find an association between tumor size and patients undergoing lymphadenectomy and none of the patients who underwent radical resections had also undergone lymphadenectomy. The rate of lym- phadenectomy in the current study was lower in this cohort (8.3 vs. 16.6 %), but both studies found low rates of lymph node metastasis (12.8 % in the SEER data and 8.8 % in the German ACC cohort). The discrepancy in the rate of lymph node involvement and the rate of lymphadenectomy is likely explained by patients with less than three lymph nodes removed, which were excluded as having a lym- phadenectomy in our analysis but found to have lymph node metastases. The low rate of lymph node involvement in this cohort can be attributed to low lymph node count in the periadrenal area [22] and/or a low rate of lym- phadenectomy performed. Because we observed a
| Patient characteristics | Entire cohort | Lymphadenectomyª | p valueb | |||
|---|---|---|---|---|---|---|
| N (%) | Total | Yes | No | Total | ||
| Number of patients (%) | 1525 | 67 (8.4) | 735 (91.6) | 802 | ||
| Gender | 1525 | 802 | 0.53 | |||
| Male | 693 (45.4) | 26 (38.8) | 288 (39.2) | 314 (39.2) | ||
| Female | 832 (54.6) | 41 (61.2) | 447 (60.8) | 488 (60.8) | ||
| Age (Years) | 1525 | 802 | 0.19 | |||
| <60 | 898 (58.9) | 48 (71.6) | 464 (63.1) | 512 (63.8) | ||
| ≥60 | 627 (41.1) | 19 (28.4) | 271 (36.9) | 290 (36.2) | ||
| Race/ethnicity [13] | 1519 | 798 | 0.02 | |||
| White | 1316 (86) | 56 (83.6) | 637 (87.1) | 693 (86.8) | ||
| Black | 113 (7.4) | 9 (13.4) | 41 (5.6) | 50 (6.3) | ||
| Other | 100 (6.6) | 2 (3.0) | 53 (7.3) | 55 (6.9) | ||
| Years of diagnosis | 1525 | 802 | 0.2 | |||
| Before 1990 | 363 (23.8) | 1 (1.5) | 21 (2.9) | 22 (2.7) | ||
| 1990-1999 | 313 (20.5) | 12 (17.9) | 198 (26.9) | 210 (26.2) | ||
| 2000-2011 | 849 (56.7) | 54 (80.6) | 516 (70.2) | 570 (71.1) | ||
| Tumor differentiation status | 379 | 201 | 0.8 | |||
| Well and moderately differentiated | 115 (0.3) | 7 (38.9) | 63 (34.4) | 70 (34.8) | ||
| Poorly differentiated and undifferentiated | 264 (69.7) | 11 (61.1) | 120 (65.6) | 131 (65.2) | ||
| Tumor size | 1074 | 744 | <0.01 | |||
| <5 cm | 105 (9.8) | 2 (3.1) | 59 (8.7) | 61 (8.2) | ||
| 5-10 cm | 433 (40.3) | 12 (18.5) | 259 (38.1) | 271 (36.4) | ||
| >10 cm | 536 (49.9) | 51 (78.4) | 361 (53.2) | 142 (55.4) | ||
| Locally advanced tumor (T3 and T4) | 990 | 707 | <0.01 | |||
| No | 402 (40.6) | 24 (39.3) | 406 (62.8) | 430 (60.8) | ||
| Yes | 588 (59.4) | 37 (60.7) | 240 (37.2) | 277 (39.2) | ||
| Lymph node metastasis | 916 | 632 | <0.01 | |||
| No | 799 (87.2) | 43 (66.2) | 535 (94.4) | 578 (91.5) | ||
| Yes | 117 (12.8) | 22 (33.8) | 32 (5.6) | 54 (8.5) | ||
| Staging | 1433 | 787 | <0.01 | |||
| Localized | 518 (36.1) | 20 (29.9) | 382 (53.1) | 402 (51.1) | ||
| Regional | 282 (19.7) | 26 (38.8) | 184 (25.6) | 210 (26.7) | ||
| Metastasis | 633 (44.2) | 21 (31.3) | 154 (21.4) | 175 (22.2) | ||
| Surgery of primary tumor | 1217 | 802 | <0.01 | |||
| No surgery or local destruction | 339 (22.2) | NA | NA | NA | ||
| Simple excision | 250 (16.4) | 5 (7.5) | 238 (32.4) | 243 (30.3) | ||
| Total or radical excision | 338 (22.2) | 21 (31.3)℃ | 307 (41.8) | 328 (40.9) | ||
| Debulking | 239 (15.7) | 41 (61.2) | 190 (25.9) | 231 (28.8) | ||
| Surgery at other site(s) | 904 | 0.28 | ||||
| No | 823 (91.0) | 46 | 495 (89.4) | 541 (88.8) | ||
| (83.6) | ||||||
| Yes | 81 (9.0) | 9 (16.4) | 59 (10.6) | 68 (11.2) | ||
| Radiotherapy | 1525 | 802 | 0.28 | |||
| No | 1336 (87.6) | 58 (86.6) | 667 (90.7) | 725 (90.4) | ||
| Yes | 189 (12.4) | 9 (13.4) | 68 (9.3) | 77 (9.6) | ||
| Disease-related mortality | 1525 | 802 | 0.37 | |||
| No | 567 (37.2) | 29 (43.3) | 364 (49.5) | 393 (49.0) | ||
| Yes | 958 (62.8) | 38 (56.7) | 371 (50.5) | 409 (51.0) | ||
| Patient characteristics | Entire cohort | Lymphadenectomyª | p valueb | |||
|---|---|---|---|---|---|---|
| N (%) | Total | Yes | No | Total | ||
| Median follow-up (months, range | 13 (0-461) | 1500 | 29 (0-252) | 25 (0-286) | 802 | 0.48 |
a Four or more lymph nodes removed
b Bold p values indicates statistically significance
” None of the patients who underwent radical excision had a lymphadenectomy
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Survival in months
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No surgery or local destruction
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+ Age <60-censored
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Fig. 1 Survival plots, estimated by the Kaplan-Meier method, comparing patients with ACC by independent prognostic factors
| Patient characteristics | Disease-specific survival (months) | p |
|---|---|---|
| Age at diagnosis, months | <0.01 | |
| <60 | 145.1 ± 8.1 | |
| ≥60 | 57.4 ± 4.5 | |
| Gender | <0.01 | |
| Female | 138.8 ± 8.8 | |
| Male | 100.3 ± 8.4 | |
| Race/ethnicity | 0.94 to <0.01ª | |
| White | 122.4 ± 6.7 | |
| Black | 82.8 ± 15.3 | |
| Other | 107.0 ± 17.1 | |
| Year of diagnosis | 0.76 to <0.01b | |
| Before 1990 | 75.3 ± 8.7 | |
| 1990-1999 | 89.7 ± 6.5 | |
| 2000-2011 | 58.5 ± 2.4 | |
| Tumor size >10 cm | 0.4 | |
| No | 126.7 ± 8.0 | |
| Yes | 91.0 ± 6.1 | |
| Locally advanced tumor (T3 and T4) | <0.01 | |
| No | 212 ± 11.9 | |
| Yes | 99.8 ± 0.22 | |
| Regional lymph node metastasis | 167.1 ± 10.2 | <0.01 |
| No | 13.6 ± 3.7 | |
| Yes | ||
| Staging | <0.01 | |
| Localized | 233.8 ± 12.7 | |
| Regional | 119.3 ± 13.4 | |
| Metastasis | 22.7 ± 3.1 | |
| Surgery of primary tumor | 0.37 to < 0.01℃ | |
| No surgery or local destruction | 27.7 ± 4.1 | |
| Simple excision | 124.4 ± 8.6 | |
| Total or radical excision | 87.9 ± 4.4 | |
| Debulking | 85.6 ± 8.5 | |
| Lymphadenectomy at initial surgery | 0.3 | |
| No | 121.9 ± 5.6 | |
| Yes | 94.5 ± 14.8 | |
| Surgery at other site | 0.02 | |
| No | 65.6 ± 2.8 | |
| Yes | 42.5 ± 6.5 | |
| Radiotherapy | <0.01 | |
| No | 132.3 ± 6.9 | |
| Yes | 53.8 ± 10.4 |
Kaplan-Meier estimator with log-rank (Mantel-Cox) test was used
a When estimated, the DSS of the white category was compared to that of the other category, p ≤ 0.01. Other pairwise comparisons were not statistically significant
b The estimated DSS of patients diagnosed before 1990 was significantly shorter than other groups (p < 0.01). There was no significant difference when the estimated DSS of patients who were diagnosed between 1990 and 1999 was compared to the estimated DSS of those diagnosed after 2000 (p = 0.76)
” When the estimated DSS of the simple excision category was compared to that of the total or radical excision category, p = 0.36. Other pairwise comparisons were statistically significant, p < 0.01
| Patient characteristics | Hazard ratio | 95.0 % CI for Exp(B) | p | |
|---|---|---|---|---|
| Lower | Upper | |||
| Age ≥ 60 years* | 1.75 | 1.37 | 2.23 | <0.01 |
| Female | 1.01 | 0.8 | 1.29 | 0.9 |
| Surgery of primary tumor | ||||
| No surgery or local destruction (reference) | 0.59 | 0.38 | 0.91 | <0.01 |
| Simple excision | 0.44 | 0.31 | 0.63 | 0.02 |
| Total or radical excision | 0.46 | 0.32 | 0.66 | <0.01 |
| Debulking | <0.01 | |||
| Locally advanced tumors (stage T3 and T4) | 1.19 | 0.83 | 1.71 | 0.93 |
| Regional lymph node metastasis* | 1.7 | 1.23 | 2.36 | <0.01 |
| Staging | ||||
| Localized (reference) | 2.59 | 1.91 | 3.82 | <0.01 |
| Regional* | 5.49 | 3.89 | 7.74 | <0.01 |
| Metastasis* | <0.01 | |||
| Surgery at other site | 1.09 | 0.75 | 1.59 | 0.64 |
| Radiotherapy | 0.94 | 0.65 | 1.37 | 0.76 |
* Significant independent prognostic factors
significantly higher rate of lymph node metastasis in patients with locally advanced tumors (T3 and T4), a regional lymphadenectomy should be considered in this group of patients.
The survival benefit of lymphadenectomy in patients with advanced (stage III and IV) ACC has previously been shown only in univariate analysis [23]. The benefit was likely due to a more complete resection in patients with advanced stages. However, lymphadenectomy was not an independent prognostic factor in this study [23] or in the current study. Our study included patients in earlier stages who would likely be candidates for surgery, but we did not find a lymphadenectomy to be an independent factor for DSS. However, because of a higher rate of lymph node metastasis in those with locally advanced tumors, potential benefits of lymphadenectomy in this subgroup of patients with ACC may include a lower rate of locoregional recurrence [11] and more accurate cancer staging. The study from German ACC registry included patient who had R0 resection for stage I to III ACC [11], while the current study included all stages and performed a subgroup anal- ysis by tumor stages and types of procedures performed. The discrepancy in the results may be due to a selection bias. Unfortunately, tumor recurrence is not captured in the SEER to specifically analyze the association of lym- phadenectomy and recurrence. The role of lymphadenec- tomy has been studied in patients with ACC using the SEER database [24]. Because ACC has a number of his- tologic variants and various degrees of differentiation [25], we included these subtypes in the current study, which was not included in the other studies. In addition, we included
patients with a diagnosis of ACC whose tumors originated from an unspecified area in the adrenal gland, based on AYA/ICD-O-3/WHO 2008 coding systems. Thus, the sample size in the current study was larger (802 vs. 259 patients), and we found that gender was not an independent prognostic factor, as was recently shown in a cohort that excluded patients with stage IV ACC [24]. Because our study included patients in all stages of ACC, the prognostic factors identified in our multivariate analysis are more likely to be applicable to all patients with ACC. A sum- mary of studies that examined the role of a lymphadenec- tomy in patients with ACC is listed in Table 4.
We demonstrated that patients who were selected to undergo either surgery with curative intent or a debulking procedure had longer DSS than those who had no surgery or only local tumor destruction. Our results were consistent with a cohort from the California Cancer Registry that showed surgery was associated with improved survival, even in patients with metastatic ACC [26]. Similar to other retrospective cohorts, the results in this study suggest that patient selection based on disease presentation and tumor biology may influence the observed longer survival time. It is likely that those who did not have surgery or only underwent local tumor destruction had more advanced disease and/or had higher perioperative risk factors. One important disease characteristic that was not available in the SEER data was functional status of ACC. Palliative surgery to debulk ACC that is causing medical refractory Cushing’s syndrome may be one of the factors used in selecting patients for the debulking procedure in order to control hypercortisolism.
| Authors | Year published | Sample size (% lymphadenectomy) | Benefit | Comment | |
|---|---|---|---|---|---|
| Survival | Recurrence | ||||
| Reibetanz et al. [11] | 2012 | 283 (16.6) | Yes (HR 0.5, p = 0.049) | Yes (HR = 0.65, p = 0.04) | Stage IV was excluded. Only patients with R0 resection were included |
| Tran et al. [23] | 2013 | 320 (26) | Yes (univariate only, p = 0.044) | NA | Only stage III and IV patients were included |
| Saade et al. [24] | 2015 | 259 (6.2) | No (HR 0.36, p = 0.06) | NA | Stage IV was excluded |
| Current study | 2015 | 802 (8.3) | No (p= 0.30) | NA | All stages were included |
There are several inherent shortcomings of the SEER database. Many important clinical parameters, such as functional status of ACC, disease recurrence, and additional systemic treatment (mitotane or cytotoxic chemotherapy) are not available. Although the data from the SEER program represents a global picture of cancer at the population level, patient selection and preferred treatment options may vary among various institutions. As a result of selection bias, patients with similar conditions may receive different treat- ments. In addition, it is difficult to determine the indica- tion(s) or clinical characteristics that influence the surgeons to perform lymphadenectomy because only 67 patients (8.4 %) underwent lymphadenectomy. Despite these limi- tations, the SEER data are useful for studying rare cancers, such as ACC, which cannot be well studied in most single- center studies because of a low volume of patients.
In summary, we demonstrated a low rate of lym- phadenectomies performed in patients with ACC in the US. Patients with regional or metastatic disease, or those with larger tumors, were more likely to undergo lymphadenec- tomy. A regional lymphadenectomy was not an independent prognostic factor for DSS. However, it should be considered in patients with locally advanced ACC because these factors are associated with a higher rate of lymph node metastasis.
Compliance with ethical standards
Disclosure The authors have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
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