Adrenocortical carcinoma in the United States

Treatment utilization and prognostic factors

Authors

  • Karl Y. Bilimoria MD, MS,

    Corresponding author
    1. Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
    2. Cancer Programs, American College of Surgeons, Chicago, Illinois
    • American College of Surgeons, Cancer Programs, 633 N. St. Clair Street, 22nd Floor, Chicago, IL 60611
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    • Karl Bilimoria is supported by the American College of Surgeons Clinical Scholars in Residence program.

    • Fax: (312) 202-5011

  • Wen T. Shen MD,

    1. Department of Surgery, University of California San Francisco, San Francisco, California
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  • Dina Elaraj MD,

    1. Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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  • David J. Bentrem MD,

    1. Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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    • David Bentrem is supported by the American Cancer Society (ACS IRG 93-037-12).

  • David J. Winchester MD,

    1. Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
    2. Department of Surgery, Evanston Northwestern Healthcare, Evanston, Illinois
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  • Electron Kebebew MD,

    1. Department of Surgery, University of California San Francisco, San Francisco, California
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  • Cord Sturgeon MD, MS

    1. Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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Abstract

BACKGROUND.

Adrenocortical carcinoma (ACC) is a rare tumor with a relatively poor prognosis. The authors' objectives were to examine treatment utilization and factors associated with long-term survival after resection of ACC in a large, national, patient population.

METHODS.

Patients diagnosed with ACC from 1985 to 2005 were identified from the National Cancer Data Base (NCDB). Patient, tumor, treatment, and hospital factors associated with survival after resection were examined.

RESULTS.

For the current study, 3982 patients with ACC were identified. Median age at diagnosis was 55 years. Median tumor size was 13 cm. Of the patients with nodes examined, 26.5% had nodal metastases. Distant metastases were found on presentation in 21.6% of patients. A total of 57.4% of patients underwent surgical resection alone, whereas 16.0% underwent resection with adjuvant chemotherapy or radiation. A total of 19.4% had margin-positive resections. Treatment utilization remained unchanged from 1985 to 2005 (P = .28). Median follow-up was 24 months. Overall 5-year survival for all patients who underwent resection was 38.6% (median survival, 31.9 months). Multivariable analysis demonstrated a higher risk of death with increasing age, poorly differentiated tumors, involved margins, and nodal or distant metastases. Overall survival remained unchanged from 1985 to 2000 (P = .08).

CONCLUSIONS.

ACC carries a poor prognosis for patients commonly presenting with large, locally invasive tumors, involved margins, and metastatic disease. Survival is not affected by size but is diminished with increasing age, poorly differentiated tumors, involved margins, and the presence of regional and distant disease. Identification of novel therapies may help to increase survival, which has remained unchanged over the last 20 years. Cancer 2008. © 2008 American Cancer Society.

Adrenocortical carcinoma (ACC) is a rare tumor with an estimated worldwide annual incidence of 2 per million.1–5 It is responsible for only approximately 0.2% of all cancer deaths in the United States annually, and it is the second most aggressive endocrine malignancy behind anaplastic thyroid cancer.1 Women are more frequently affected than men (1.5:1), and patients present with evidence of adrenocortical hormonal excess in 40% to 60% of cases.2, 3, 5–7 The prognosis of ACC is generally dismal because most patients present with large tumors and advanced disease. Approximately 50% to 70% of patients have extra-adrenal disease at the time of presentation.1–6

Treatment strategies have included resection with or without adjuvant chemotherapy and/or radiation. Complete resection is considered the most important component of therapy with curative intent for both primary and recurrent ACC.3–5, 8 Recurrence occurs in approximately 70% to 80% of patients after resection, and a survival advantage has been demonstrated in some series for patients who undergo resection of recurrent disease.2, 5, 6, 9, 10 Furthermore, resection of recurrent disease can provide palliation of hormonal symptoms of functional ACCs,11 although surgical therapy is controversial for patients presenting with metastatic disease because overall prognosis is poor regardless of treatment modality.1, 3, 5

Reported prognostic factors associated with long-term survival have varied. The most consistently cited factors associated with worse outcomes are advanced stage and incomplete surgical resection.3–5, 12 High grade, older age, hormonal hypersecretion, sex, and large tumor size have been found to be associated with poorer prognosis in some studies.2, 3, 5, 12 The era of treatment has also been considered a factor related to prognosis. Some studies have suggested an improved disease-specific mortality when comparing patients with ACC treated in the past 20 years to those treated in the 20 years prior,3, 5, 12 but others have shown no change in stage at presentation or survival over the past 2 decades.4, 12

Thus far, no studies, to our knowledge, have been able to evaluate national treatment practice patterns in the United States for ACC. Prognostic factors are not well defined, largely because of the small sample sizes of studies to date. Furthermore, the improved survival reported by some investigators to be a result of earlier diagnosis of incidentally discovered small adrenal tumors is controversial. Therefore, we examined a large, national, cancer registry to determine treatment utilization in the United States and factors associated with long-term survival after resection of ACC.

MATERIALS AND METHODS

Data Source and Study Population

The National Cancer Data Base (NCDB) is a nationwide cancer registry supported by the American College Surgeons, the Commission on Cancer, and the American Cancer Society.13 The more than 1450 hospitals approved by the Commission on Cancer are required to report all new cancer diagnoses to the NCDB. These hospitals report approximately 1 million new cancer cases to the NCDB each year, which account for approximately 70% of all cancers diagnosed in the United States annually.13

Based on International Classification of Diseases for Oncology (second and third editions), patients with adrenocortical cancers were identified based on site (C74.0-C74.9) and histology codes (8370).14, 15 The NCDB requires reporting of the surgical procedure and any adjuvant therapies administered within the first 6 months after diagnosis. Treatment modalities were defined based on the Commission on Cancer's Registry Operations and Data Standards and Facility Oncology Registry Data Standards (FORDS) coding.16, 17 Patients were excluded when they were younger than 18 years of age at the time of diagnosis.

The Commission on Cancer classifies hospitals into academic and community centers based on case volume and the availability of cancer-related services and specialists.1 Academic centers must be primarily affiliated with a medical school or National Cancer Institute (NCI)-designated Comprehensive Cancer Center. In addition, 24 of 37 NCI-designated Comprehensive Cancer Centers, and 67 of 121 major inpatient Veterans Health Association's (VA) hospitals report to the NCDB. The hospital-type variable compared NCI, other academic (academic but non-NCI), VA, and community hospitals.

Because patient-level socioeconomic data are not collected by cancer registries, median household income and the percentage of patients with a bachelor's degree were ascertained through linkage with 2000 United States Census Bureau data based on the patient's zip code at the time of diagnosis.2

Statistical Analysis

Trends in treatment utilization were examined with the chi-squared test for trend. Survival was calculated in months from the date of surgery to the date of death or last contact. Patients diagnosed from 1985 to 2000 with follow-up reported in 2006 were used in the survival analyses. Five-year survival was estimated by the Kaplan-Meier method, and differences in prognostic factors were compared by using the log-rank test.18 In addition, relative survival was estimated by adjusting the observed survival rates for differences in sex, age, and race/ethnicity by using 2000 United States Census Bureau data.7 The United States population used for standardization has a very small proportion of patients with ACC overall. Because recurrences are challenging to capture, relative survival calculated currently serves as the best estimate of disease-specific survival using data from cancer registries. Cox proportional hazards modeling was used to assess the association of patient, tumor, treatment, and hospital factors on 5-year survival. Factors examined in the Cox model included sex, age (18-35 years, 36-55 years, 56-75 years, >75 years), race/ethnicity (white, black, Asian, Hispanic, other), median household income quartiles, percentage of patients with a bachelor's degree quartiles, tumor size (continuous, and <5 cm, 5-10 cm, 10-15 cm, and >15 cm), nodal status (negative, involved, missing), absence or presence of distant metastases, tumor grade (low vs high grade), margin status (clear, microscopic, macroscopic), tumor laterality (right, left, bilateral, unilateral, not otherwise specified [NOS]), type of resection (resection, resection with contiguous organ, debulking, surgery, NOS), chemotherapy administration, radiation therapy administration, hospital type, and the year of diagnosis (1985-1990, 1991-1995, 1996-2000).19 The Cox model was stratified by the presence or absence of distant metastases, but there was not an appreciable difference in the magnitude or direction of the hazard ratios of the other variables, so the model including distant metastases as a predictor variable is shown. Because of missing data for nodal status, tumor grade, and margin status, indicator variables were used. Hazard ratios (HR) with 95% confidence intervals (CI) were generated. The proportional hazards assumptions were confirmed graphically.

A multiple logistic regression model was developed to examine patient, tumor, and hospital factors associated with margin-positive resections (microscopic/macroscopic vs clear). Variables were examined in a forward stepwise fashion and included sex, age, race, median income/education, laterality, tumor size, nodal status, distant metastases, and hospital type. Odds ratios (OR) with 95% CI were generated.

The level of statistical significance was set to P < .05. All P-values reported are 2-tailed. Statistical analyses were performed by using SPSS, version 15 (SPSS, Chicago, Ill). This study was approved by the Northwestern University Institutional Review Board.

RESULTS

From the NCDB, 3982 patients with adrenocortical carcinoma diagnosed from 1985 to 2005 were identified (Table 1). The median age at diagnosis was 55 years (interquartile range, 43 years to 67 years). The majority of patients were female (58.2%), white (84.7%), and lived in areas with median incomes and education levels above the national median (67.6% and 70.7%, respectively). Tumors were located in the left adrenal gland in 49.6% of patients, in the right adrenal gland in 41.3%, and bilaterally in 1.1%. (Tumor location was unknown in 8.0%.) The median tumor size was 13 cm (interquartile range, 8 cm to 29 cm). Distant metastases were identified at presentation in 21.6% of patients. From 1985 to 2005, there was not a significant change in tumor size or the proportion of patients presenting with nodal or distant metastases (data not shown). The majority of patients received their care at community hospitals (45.7%) and other academic centers (30.6%), whereas 15.5% were treated at NCI-designated cancer centers and 1.2% at VA hospitals.

Table 1. Characteristics of Patients With Adrenocortical Carcinoma, 1985 to 2005
CharacteristicsNo.%
  1. Missing data on grade (n=767), margin status (n=868), income (n=251), and education (n=251).

Patients3982 
Women231658.2
Median age, y, (interquartile range)55 (43-67) 
Race  
 White337384.7
 Black2787.0
 Asian/Pacific Islander721.8
 Hispanic1694.2
 Other902.3
Median income  
 >$46,000143838.5
 $36,000-45,999108729.1
 $30,000-$35,99971819.2
 <$30,00048813.1
Education (% with college degree)  
 >21%163443.8
 13-20.9%100426.9
 9-12.9%63917.1
 <9%45412.2
Laterality  
 Right164341.3
 Left197649.6
 Bilateral451.1
 Unilateral NOS3188.0
Median tumor size (interquartile range)13 (8-29) cm
Distant metastases86021.6
Hospital type  
 NCI62615.7
 Other Academic121930.6
 VA481.2
 Community182145.7
 Other2686.7

For the majority (57.4%) of patients, surgery was the only treatment modality utilized (Table 2). An additional 16.0% underwent resection with adjuvant therapy. Nonsurgical therapy consisting of chemotherapy or radiation was employed in 9.7% of patients. Of the 2920 patients who underwent resection (with or without adjuvant therapy), 85.2% underwent resection, 3.5% had a debulking procedure, and for 11.3% of patients, the type of operation was not specified. From 1985 to 2005, there was not a significant change in the therapeutic management of adrenocortical carcinoma (P = .28; Fig. 1).

Figure 1.

Management of adrenocortical carcinoma from 1985 to 2005 is depicted.

Table 2. Treatment of Adrenocortical Carcinoma and Tumor Characteristics of Patients Who Underwent Resection
Treatment and CharacteristicsNo.%
  • NOS indicates not otherwise specified.

  • *

    716 patients had a pathologic nodal status reported.

  • 2224 patients had a tumor grade reported.

  • 2119 patients had a margin status reported.

Treatment modality  
 Surgery only228457.4
 Surgery and chemotherapy39810.0
 Surgery and radiation1684.2
 Surgery, radiation, and chemotherapy701.8
 Radiation and chemotherapy591.5
 Radiation only782.0
 Chemotherapy only3067.7
 No treatment49412.4
 Unknown1253.1
Surgical procedure  
 Resection167057.2
 Resection with contiguous organ81928.0
 Debulking1013.5
 Surgery NOS33011.3
Tumor characteristics  
 Median size (interquartile range)10 (8-15) cm
 Nodal metastases*19026.5
 Distant metastases33011.3
 Poorly differentiated tumors33815.2
 Involved resection margins41119.4

Of the 2920 patients who underwent resection, the median tumor size was 10 cm (interquartile range, 8 cm to 15 cm; Table 2). Lymph nodes were examined in 17.6% (n = 716) of patients and nodal metastases were found in 26.5% (n = 190) of these patients. Of the resected patients, 15.2% had poorly differentiated tumors. Of the 2117 patients with margin status reported, 19.4% had involved resection margins (microscopic/R1, 9.2%; macroscopic/R2, 10.2%). Of the patients who underwent resection, 11.3% had distant metastases at presentation. Distant metastases were most frequently found in the liver (10.9%), lung (9.0%), and bone (3.1%; Table 3).

Table 3. Site of Distant Metastasis at Presentation
Presentation SiteNo.%
  1. Patients could have more than 1 site of distant metastasis. Overall, 21.6% of patients had at least 1 distant metastasis.

Liver43310.9
Lung3599.0
Bone1243.1
Distant lymph nodes621.6
Peritoneum360.9
CNS280.7
Pleura230.6
Skin100.3

Prognostic factors were examined for patients who underwent resection. The median follow-up was 24 months. Overall 5-year survival for all patients who underwent resection was 38.6% (95% CI, 36.2-40.9%), and median survival was 31.9 months (95% CI, 27.7-36.1 months). Relative 5-year survival was 42.3% (95% CI, 39.6-44.9%). On univariate analysis, survival rates were lower if patients were older than 55 years of age, had high-grade tumors, positive margins, nodal or distant metastases, or underwent surgery with resection of a contiguous organ (Table 4; Fig. 2). Tumor size was not associated with survival when examined as ≥10 cm versus <10 cm or even when comparing tumors <5 cm to those 5-10 cm, 10-15 cm, or ≥15 cm. When examined in a multivariable model, patients had a higher risk of death when they were older than 55 years of age, had high-grade tumors (hazard ratio [HR], 2.26; 95% CI, 1.82-2.82; P < .0001), involved margins (HR, 2.06; 95% CI, 1.74-2.43; P < .0001), nodal metastases (HR, 1.56; 95% CI, 1.23-1.97; P < .0001), distant metastases (HR, 2.20; 95% CI, 1.87-2.55; P < .0001), or underwent surgery with resection of a contiguous organ (HR, 1.23; 95% CI, 1.08-1.40; P = .002; Table 4). Sex, race, income, education, laterality, tumor size, adjuvant treatments, and hospital type were not significantly associated with long-term survival. Prognostic factors were examined separately for right and left adrenal tumors; however, there were no considerable differences in factors associated with survival. In addition, there was not a significant change in survival from 1985 to 2000 (P = .08).

Figure 2.

Five-year overall survival for all patients stratified by (A) tumor size, (B) nodal status, (C) distant metastases, (D) tumor grade, (E) surgery, and (F)margin status is illustrated.

Table 4. Factors Associated With Survival After Resection of Adrenocortical Carcinoma
 Unadjusted 5-Year Observed Survival5-Year Relative SurvivalMedian Survival, moAdjusted Hazard Ratio (95% CI)P
  • Based on patients diagnosed in 1985-2000 with follow-up reported in 2006, as NCDB receives follow-up in 5-year cycles (n=2151).

  • *

    Median survival could not be estimated as the survival rate was higher than 50%.

Age, y     
 18-3544.6%44.8%40.01.0 (Referent) 
 36-5542.1%43.2%39.41.09 (0.90-1.31).37
 56-7535.8%40.9%27.61.51 (1.26-1.81)<.0001
 >7523.7%37.4%14.02.33 (1.81-3.00)<.0001
Tumor grade     
 Well/Moderately differentiated53.3%58.9%*1.0 (Referent) 
 Poorly differentiated21.4%23.6%10.82.26 (1.82-2.82)<.0001
Margin status     
 Uninvolved46.1%50.4%51.21.0 (Referent) 
 Microscopic21.0%23.2%12.61.81 (1.44-2.27)<.0001
 Macroscopic9.9%10.8%7.02.06 (1.74-2.43)<.0001
Nodal metastases     
 Negative38.7%41.8%38.11.0 (Referent) 
 Positive12.6%13.6%8.41.56 (1.23-1.97)<.0001
Distant metastases     
 Absent43.4%55.1%*1.0 (Referent) 
 Present8.0%11.5%9.12.20 (1.87-2.55)<.0001
Type of resection     
 Resection42.8%47.0%38.91.0 (Referent) 
 Resection with continuous organ32.1%35.3%20.11.23 (1.08-1.40).002
 Debulking36.4%40.3%29.51.24 (0.93-1.65).14
 Surgery NOS32.1%36.7%36.01.08 (0.90-1.30).41

Because 19.4% of patients who underwent resection had involved margins, and margin status had a significant impact on prognosis, factors associated with margin involvement were examined. On univariate analysis, patients more frequently had involved margins when they had tumors larger than 10 cm, nodal or distant metastases, high-grade malignancies, bilateral adrenal tumors, or underwent treatment at NCI cancer centers (compared with other academic or community hospitals). On multivariable analysis, only nodal metastases (odds ratio [OR], 3.88; 95% CI, 2.25-6.71; P < .0001), distant metastases (OR, 3.64; 95% CI, 2.59-5.12; P < .0001), and poor tumor differentiation (OR, 1.65; 95% CI, 1.00-2.73; P < .0001) were associated with a higher likelihood of a margin-positive resections.

DISCUSSION

This study demonstrates that despite multiple improvements in the diagnosis and treatment of other types of solid malignancies over the past 2 decades, ACC continues to be a highly lethal malignancy with poor overall survival and few effective treatment options. Our review of 3928 patients with ACC from the NCDB revealed no significant improvement in survival during the time period from 1985 to 2005. The clinical presentation of patients did not change during the study period; tumor size and the proportion of patients with nodal or distant metastases remained stable between 1985 and 2000, suggesting that clinicians who are using radiography or other diagnostic tests are not detecting these tumors earlier. The type of treatment being provided for patients with ACC has also remained unchanged, with the majority of patients undergoing surgery alone, and no other significant changes in the other modalities utilized to treat this disease. These results certainly underscore the pressing need for clinicians to identify better methods of diagnosing and treating this rare, and devastating, malignancy.

Our review uncovered several factors that portend a worse prognosis for patients with ACC who underwent resection; these include an age older than 55 years, positive resection margins, lymph node-positive disease, resection of a contiguous organ, poorly differentiated tumors, and distant metastatic disease. Although some of these prognostic factors such as margin positivity, invasion of adjacent structures, and distant metastases may seem intuitive to the experienced clinician, this is the first study performed in the US and using a national patient population that confirms these empiric observations. The finding that positive resection margins predicted worse prognosis highlights the importance of complete, en-bloc, margin-negative resection of ACC in patients who are fit to undergo surgery. Median survival for patients with margin-negative resection was 51.2 months, whereas those who underwent margin-positive resection had a median survival of only 7.0 months. Although debulking operations have been recommended by some surgeons for palliation in patients with significant hormonal hypersecretion,11 this study was not able to evaluate the effectiveness of surgical debulking in relieving symptoms of hormone excess. We did not find that tumor size was a significant prognostic factor; thus, the size of the lesion should not preclude resection.

Surgical resection still represents the best hope for cure in patients with localized ACC. For those with disseminated or incompletely resected disease, the options for nonoperative therapy remain limited. Mitotane was introduced in the late 1970s and remains the most effective chemotherapeutic agent for ACC despite its significant toxicity and relatively low response rates.20–22 Fewer than half of the patients in this study were reported to have received chemotherapy either alone or in conjunction with surgery or radiation therapy. Radiation therapy has been reserved for patients with brain and bone metastases and those with symptomatic local recurrences who are not amenable to reoperation. The proportion of patients who underwent nonoperative therapy remained the same during the 20 years of the study; this likely reflects the finding that no new treatment agents or changes in surgical approaches achieved widespread use during this time period. The first international, randomized trial on locally advanced and metastatic ACC treatment (FIRM ACT) comparing etoposide, doxorubicin, cisplatin plus mitotane versus streptozotocin plus mitotane (Sz/M) will provide important information on which cytotoxic therapy will benefit patients (http://www.firm-act.org/). There are also several novel therapies that use immunomodulation, tyrosine kinase inhibitors, and gene therapy that are in development and may be clinically beneficial.23

There are several limitations of our study. First, the analyses are limited to the variables available in the NCDB; thus, there may be a missing-variable bias, as we were not able to account for all factors in the model (ie, tumor functional status, extension into adjacent organs, or specific chemotherapy regimen utilized). Approximately 40% to 60% of ACC patients have clinical evidence of hormonal hypersecretion, and the remainder is clinically unapparent until reaching a large size.2, 3, 5–7 Some series have shown that functional status has been associated with worse outcome. Second, the NCDB only requires reporting of “malignant” adrenal tumors. The most widely accepted criterion for malignancy in ACC is the presence of local tumor invasion or metastatic disease. There are no absolute histologic criteria for malignancy. The Weiss histopathologic criteria have been used as an indicator of malignancy when 3 or more features are present.24 However, when there are no absolute indicators of malignancy and the Weiss criteria are not met, the tumor is classified as an “adrenal neoplasm of uncertain malignant potential.” Therefore, there may be a large number of tumors classified as those of “uncertain malignant potential” that have not been included in this analysis. Thus, the tumors included are likely the more aggressive subsets of ACC. Third, the data are reported from more than 1400 hospitals; thus, there is not an opportunity to perform a pathologic review of all specimens. The pathologic variables are related to the quality of analysis at individual hospitals. Despite these limitations, the NCDB offers a large, generalizable sample of patients that can be used to examine practice patterns and outcomes.

Because ACC is so rare and because patients with ACC typically have a poor prognosis and a limited lifespan, previous work in studying ACC has been largely composed of small retrospective series as multi-institutional trials have been logistically difficult to organize and maintain. However, the results of this study highlight the finding that outcomes from this disease have not changed in the past 20 years. Further research is required to understand the molecular biology of ACC, and improvements are needed in the scope and effectiveness of operative and adjuvant treatment modalities for this challenging malignancy.

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