Surgical Management of Advanced Adrenocortical Carcinoma: A 21-year Population-based Analysis
THUY B. TRAN, M.D., DOUGLAS LIOU, M.D., VIJAY G. MENON, M.D., NICHOLAS N. NISSEN, M.D. From Hepatobiliary Surgery and Liver Transplantation, Cedars-Sinai Medical Center, Los Angeles, California
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis. When diagnosed in advanced stages of the disease, the outcomes of surgical resection are not well un- derstood. The objective of this study is to determine the impact of surgery in patients with ad- vanced ACC. Using the Surveillance, Epidemiology and End Results database, we identified patients diagnosed with Stage III and IV ACC between 1988 and 2009. A total of 320 patients with Stage III and IV disease were included in our analysis. In patients treated with surgical resection, the Stage III 1- and 5-year survival rates were 77 and 40 per cent, respectively, whereas the Stage IV 1- and 5-year survival rates were 54 and 27.6 per cent, respectively. Patients treated without surgery had poor survival at 1 year for both Stage III (13%) and Stage IV (16%) (P < 0.01 compared with the surgical groups). Lymph node dissection was performed in 26 per cent of the patients with advanced ACC and was associated with improved survival in univariate analysis of Stage IV patients. Overall, our results indicate that favorable survival outcomes can be achieved even in patients with Stage III and IV disease and surgery should be considered in patients with advanced ACC.
A DRENOCORTICAL CARCINOMA (ACC) is a rare endo- crine malignancy with an annual incidence of two cases per million.1 Despite a generally poor prognosis, little progress has been made in our understanding and treatment of both early and advanced disease. Surgery continues to be the most promising therapy for ACC. Despite early reports that adjuvant therapy such as mitotane may have survival benefits, complete resection (R0) remains the only curative treatment.2, 3 However, the survival benefits of surgery for advanced ACC are not well understood.
Unfortunately, the majority of patients diagnosed with ACC will present with advanced disease, mani- festing as regional or distant spread to the liver, kidney, and inferior vena cava. Only approximately one-fifth of cases will have tumors localized to the adrenal gland.1, 4, 5 The liver is the most common site of metastasis and recurrence.2, 6, 7 Small cohort studies and case series have suggested that resection of regional and meta- static disease can be associated with acceptable long- term survival.3, 5 However, there is still a paucity of data in the literature on the benefits of surgical treat- ment for advanced ACC. The purpose of this study is to
use a large population-based database to determine the impact of surgery on advanced ACC.
Methods
The Surveillance, Epidemiology and End Results (SEER) database consists of 13 population-based cancer registries that represent approximately 28 per cent of patients with cancer in the United States. The SEER database was queried for patients diagnosed with Stage III and IV ACC between 1988 and 2009. Based on the International Classification of Disease, patients with ACC were identified based on site (C74.0 to 74.9) and histologic subtype code (8370). Clinical stage was de- termined using the 7th edition of the American Joint Committee on Cancer Staging Manual.8 Stage III dis- ease was defined as T3 N0/NX M0 and T1 to 2 N1 M0. Stage IV was defined as T3N1M0 and T4 N0/NX M0. Patients with distant metastases were excluded. Survival rates were calculated using the Kaplan-Meier method. Univariate associations between variables and outcomes were determined by log-rank test. Pearson x2 test was used to compare categorical variables. Multivariate analysis was performed using a Cox proportional hazard model and forward stepwise method to determine pre- dictors of survival. In both univariate and multivariate analyses, independent statistical significance was de- termined by a P value ≤ 0.05. Statistical analysis was performed using SPSS software Version 19.0 (IBM, Chicago, IL).
Presented at the 24th Annual Scientific Meeting of the Southern California Chapter of the American College of Surgeons, January 18-20, 2013, in Santa Barbara, California.
Address correspondence and reprint requests to Nicholas N. Nissen, M.D., Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, 8635 W. 3rd Street., 590W, Los Angeles, CA 90048. E-mail: Nicholas.nissen@cshs.org.
Results
Patient and Clinical Characteristics
A total of 320 patients with Stage III (n = 151) and Stage IV (n = 169) ACC were identified from the SEER database between 1988 and 2009. The patient population with advanced ACC consisted of more females (53%, n = 169) than males (47%, n = 151). Demographic and clinical characteristics are shown in Table 1. The majority of patients (88%) were white. The mean age at diagnosis was 52 years (median, 53 years). In recent years, the number of patients reported with the diagnosis of advanced ACC has steadily increased.
The median tumor size was 12.0 cm (mean, 12.3 cm) and the majority of patients presented with tumor size greater than 10 cm. Among cases of advanced ACC with tumor size greater than 5 cm, patients were evenly split between Stage III (48%) and Stage IV (52%) dis- ease. Slightly more patients had left-sided (52%) than right-sided tumors (46%). The majority of patients with Stage III and IV ACC received cancer-directed surgery (81 and 95%, respectively). Only 12 per cent of patients with advanced ACC did not undergo cancer-directed surgery. Furthermore, only 26 per cent of patients with advanced ACC underwent lymphadenectomy. Among patients who underwent lymphadenectomy, 35 per cent were found to have metastatic lymph node involvement. Stage IV patients were more likely to have high-grade tumors compared with Stage III patients (63 vs 37%, P = 0.039).
Survival Analysis
Survival analysis using the Kaplan-Meier method shows that surgery is associated with improved survival in both Stage III and IV compared with patients treated without surgery (mean survival 73 vs 35 months, P = 0.007). Patients with Stage III ACC treated with surgery had a 1- and 5-year survival rate of 77 and 40 per cent, respectively, compared with 1- and 5-year survival rates of 47 and 17 per cent, respectively (P = 0.013) in Stage III ACC treated without surgery (Fig. 1). Similarly, in Stage IV patients treated with surgical therapy, the 1- and 5-year survival rates were 58.9 and 24.9 per cent, respectively. Stage IV patients who did not have cancer-directed surgery had much lower and gener- ally dismal 1- and 5-year survival rates of 16.7 and 0 per cent, respectively (P < 0.001) (Fig. 2).
Analysis of lymph node dissection data showed that across both Stage III and IV ACC, the presence of positive lymph nodes is associated with worse overall survival. Survival in patients with lymph node metas- tases was 40 per cent at 5 years compared with 25 per cent in those with negative lymph nodes (P = 0.021). When evaluating the impact of lymph node dissection by tumor (T) stage, we found that performing lymph
| Characteristic | No. |
|---|---|
| Age (years) | |
| Mean | 52 |
| Median | 53 |
| Sex | |
| Male | 151 (47%) |
| Female | 169 (53%) |
| Race | |
| White | 282 (88%) |
| Black | 22 (6.9%) |
| Other | 15 (5) |
| Tumor size | |
| < 5 cm | 25 (7.8%) |
| 5-10 cm | 97 (30.2%) |
| > 10 cm | 174 (54%) |
| T stage | |
| T1 | — |
| T2 | 11 (3.4%) |
| T3 | 151 (47%) |
| T4 | 158 (49%) |
| N stage | |
| N0 | 57 |
| N1 | 36 |
| NX | 227 |
| Stage | |
| III | 150 (47%) |
| IV | 170 (53%) |
| Surgery | |
| Yes | 280 (88%) |
| No | 39 (12%) |
1.0
p = 0.013
0.8
5-Year Overall Survival
0.6
Surgery
0.4
No Surgery
0.2
0.0
0
20
40
60
Survival (months)
node dissection was associated with improved cancer- specific survival in patients with T4 tumors (P = 0.044).
To determine the predictors of survival, multivariate analysis using a Cox regression model was performed.
Adjusting for demographic factors, multivariate sur- vival analysis demonstrated that the absence of cancer- directed surgery (hazard ratio [HR], 3.341; confidence interval [CI], 1.168 to 9.557) and high tumor grade (HR, 2.797; CI, 1.343 to 5.826) were negative prog- nostic factors of survival (Table 2).
Discussion
In patients with advanced ACC, surgery provides the only potential for achieving long-term survival, because radiotherapy and chemotherapy remain ineffective.2 However, the role of surgery for regionally advanced and metastatic ACC has not been well established. In this study we demonstrated that surgery provides
1.0
p < 0.001
0.8-
5-Year Overall Survival
0.6
0.4-
Surgery
0.2-
No surgery
0.0
0
12
24
36
48
60
Survival (months)
| Variable | HR (95% CI) | P Value |
|---|---|---|
| Age | NS | |
| Race | NS | |
| Tumor size | NS | |
| Sex | Reference | 0.027 |
| Male | ||
| Female | 0.499 (0.270-0.922) | |
| Surgery | ||
| Yes | Reference | 0.025 |
| No | 3.341 (1.168-9.557) | |
| Tumor grade | Reference | 0.006 |
| Low grade | ||
| High grade | 2.797 (1.343-5.826) |
HR, hazard ratio; CI, confidence interval; NS, not significant.
acceptable 5-year survival rates for patients with Stage III and IV disease. This justifies radical surgical re- section in patients with advanced ACC.
The reported survival estimates for advanced ACC in the literature are somewhat variable. Icard et al.9 reported Stage III and IV 5-year survival rates of 24 and 0 per cent, respectively. However, Ohwada et al.5 reported 5-year survival rates of 20 and 40 per cent for Stage III and IV, respectively. Our study, which used the SEER database, revealed encouraging survival rates after surgical intervention for advanced ACC. Other studies have looked at individual tumor factors associ- ated with survival and have suggested that greater tumor size, the presence of necrosis, and the presence of mitotic figures are poor prognostic factors.10-12 Cur- rent knowledge of ACC tumor biology is insufficient and in general progress has been hampered by low incidence and an overall poor prognosis.
There is significant controversy regarding the role of surgery in patients with Stage IV ACC. Although Allolio et al.2 suggested that Stage IV ACC is not amenable to surgery, other studies proposed that mul- timodality therapy (including radical surgery in com- bination with adjuvant chemotherapy) can result in favorable long-term survival outcomes.10, 11 Recent reports demonstrated that resection for metastatic ACC can be associated with long-term survival if negative margins can be achieved.9, 13, 14 Resection of hepatic metastases, regardless of number of metastatic lesions, can be associated with long-term control of disease.14 In our study, patients with Stage IV who did not re- ceive any surgical intervention had dismal 12-month survival rates (16.7%) compared with those who had surgical intervention (58.9%). Our multivariate sur- vival analysis confirmed that nonsurgical therapy is a strong predictor of mortality (HR, 3.341; CI, 1.168 to 9.557; P = 0.025).
Ripley et al.15 reported a 5-year survival rate of nearly 30 per cent and improved disease-free interval after resection in a cohort of 27 patients who underwent liver resection or radiofrequency ablation for ACC. Our study does not address the factors determining how patients were selected for surgery. Clearly per- formance status and general physiologic parameters will have tremendous bearing on surgical decision- making in these patients.
Our study also sheds some light on the current prac- tice of lymphadenectomy in management of advanced ACC. Our data showed that lymphadenectomy was only performed in 26 per cent of all cases of advanced ACC. Unknown nodal status can lead to understaging of ACC, because T3Nx tumors are considered Stage III, whereas T3N1 tumors are considered Stage IV. We noted that the majority of patients (52%) without nodal status were T4NXM0 patients, and it is possible that the tendency
to forego lymph node dissection in these patients re- flects a sense of futility for lymph node retrieval when dealing with large-scale primary tumors. There remains the possibility, however, that lymphadenectomy has important clinical benefit. A recent study analyzing the impact of locoregional lymphadenectomy in patients with ACC in fact concluded that lymphadenectomy not only improves tumor staging, but also leads to improved oncologic outcomes.16 Although the association between extent of lymph node retrieval and survival remains controversial, we advocate routine lymphadenectomy in patients undergoing surgical resection for advanced ACC. Further investigation is warranted to determine the extent of lymph node dissection necessary to im- prove survival in patients with advanced ACC.
SEER reflects the overall U.S. cancer population and provides strong clinical insights on survival outcomes of rare malignancies such as ACC. However, there are several limitations in this study. Information on lym- phovascular invasion and other tumor markers is not available for all malignancies in the SEER database. Margin status has been known to greatly impact survival, but information on complete resection (R0) or margin- positive resection (R1) is not available. Furthermore, specific details on the extent of surgery are unknown in the SEER database. Lastly, although reporting prob- lems may be an inherent problem in these large data- bases, SEER audits medical records at participating institutions and states thereby upholding the highest quality data.
Conclusion
This is the largest population-based study on the survival outcomes of patients with advanced ACC. The management of advanced ACC remains chal- lenging in light of the dismal prognosis and limited medical options. We demonstrated that acceptable long-term survival could be achieved with surgical resection. Until effective chemotherapy or alternate therapies become available, aggressive surgical in- tervention remains justified for advanced ACC. When undertaken, surgical resection should include lymphadenectomy.
REFERENCES
1. Lafemina J, Brennan MF. Adrenocortical carcinoma: past, present, and future. J Surg Oncol 2012;106:586-94.
2. Allolio B, Hahner S, Weismann D, Fassnacht M. Manage- ment of adrenocortical carcinoma. Clin Endocrinol (Oxf) 2004;60: 273-87.
3. Schulick RD, Brennan MF. Long-term survival after com- plete resection and repeat resection in patients with adrenocortical carcinoma. Ann Surg Oncol 1999;6:719-26.
4. Luton JP, Cerdas S, Billaud L, et al. Clinical features of ad- renocortical carcinoma, prognostic factors, and the effect of mito- tane therapy. N Engl J Med 1990;322:1195-201.
5. Ohwada S, Izumi M, Kawate S, et al. Surgical outcome of stage III and IV adrenocortical carcinoma. Jpn J Clin Oncol 2007;37:108-13.
6. Crucitti F, Bellantone R, Ferrante A, et al. The Italian Reg- istry for Adrenal Cortical Carcinoma: analysis of a multiinstitu- tional series of 129 patients. The ACC Italian Registry Study Group. Surgery 1996;119:161-70.
7. Favia G, Lumachi F, Carraro P, D’Amico DF. Adrenocortical carcinoma. Our experience. Minerva Endocrinol 1995;20:95-9.
8. Edge SB, and American Joint Committee on Cancer. AJCC Cancer Staging Manual. New York, NY: Springer; 2010:xiv.
9. Icard P, Goudet P, Charpenay C, et al. Adrenocortical carci- nomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 2001;25:891-7.
10. Harrison LE, Gaudin PB, Brennan MF. Pathologic features of prognostic significance for adrenocortical carcinoma after cu- rative resection. Arch Surg 1999;134:181-5.
11. Stojadinovic A, Ghossein RA, Hoos A, et al. Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 2002;20:941-50.
12. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202-6.
13. Kendrick ML, Lloyd R, Erickson L, et al. Adrenocortical carcinoma: surgical progress or status quo? Arch Surg 2001;136: 543-9.
14. Khorram-Manesh A, Ahlman H, Jansson S, et al. Adreno- cortical carcinoma: surgery and mitotane for treatment and steroid profiles for follow-up. World J Surg 1998;22:605-611; discussion 611-2.
15. Ripley RT, Kemp CD, Davis JL, et al. Liver resection and ablation for metastatic adrenocortical carcinoma. Ann Surg Oncol 2011;18:1972-9.
16. Reibetanz J, Jurowich C, Erdogan I, et al. Impact of lym- phadenectomy on the oncologic outcome of patients with adre- nocortical carcinoma. Ann Surg 2012;255:363-9.