Proposal for modification of the ENSAT staging system for adrenocortical carcinoma using tumor grade
Barbra S. Miller . Paul G. Gauger . Gary D. Hammer . Thomas J. Giordano . Gerard M. Doherty
Received: 19 June 2010 /Accepted: 12 July 2010 /Published online: 9 August 2010 C Springer-Verlag 2010
Abstract
Purpose Various staging systems for adrenocortical carci- noma (ACC) have been proposed. We hypothesized that incorporating tumor grade into the current European Network for the Study of Adrenal Tumors (ENSAT) staging system would improve the ability to more accurately predict time to recurrence and death.
Methods A retrospective review of patients included in the University of Michigan ACC database from 2005 to 2009 was done; and stage, tumor grade, time to recurrence, and death were recorded and analyzed using the Cox regression and Kaplan-Meier survival curves.
Results Ninety one patients had complete information for inclusion. The median follow-up was 24 months while the median time to recurrence was 4.1 months. There were 28 deaths; overall, tumor grade showed a significant differ- ence in time to tumor recurrence (p=0.011) and time to
Presented as an oral presentation at the 2010 ESES meeting. Vienna, Austria.
B. S. Miller . P. G. Gauger . G. M. Doherty Division of Endocrine Surgery, University of Michigan, Ann Arbor, MI, USA
e-mail: barbram@umich.edu
G. D. Hammer
Division of Metabolism, Endocrinology, Nutrition and Diabetes, University of Michigan, Ann Arbor, MI, USA
T. J. Giordano Department of Pathology, University of Michigan, Ann Arbor, MI, USA
B. S. Miller
Department of Surgery, University of Michigan,
2920F Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA
death (p=0.004). Time to death among stage 2 patients separated into those with high- and low-grade tumors reached statistical significance (p=0.05), and notable but not statistically significant differences were identified in all stages. Based on tumor grade and survival curves, modifications to the current ENSAT staging system were made.
Conclusion Tumor grade plays a significant role in the outcome of patients with ACC. High-grade tumors are associated with shorter disease-free intervals and shorter overall survival. The proposed modification of the ENSAT staging system allows for incorporation of tumor grade when predicting overall survival.
Keywords Adrenal cancer . Staging . Endocrine . Adrenocortical carcinoma · Adrenal
Introduction
Adrenocortical carcinoma (ACC) is a rare disease with an estimated annual incidence of one to two per million population [1]. Careful and complete surgical resection has been the mainstay of treatment. Adjuvant therapies have not been particularly successful, and indications for the use of mitotane, other chemotherapy, or external beam radiother- apy are not well defined. Overall 5-year survival rates are generally reported to be 20-35% [1, 2]. A recent study [3] revealed that in the past 20 years no significant progress has been made with regard to the treatment of ACC, and 5-year survival outcomes have remained static.
Various ACC staging systems (Table 1) have been proposed and all have been used at various times which makes comparing ACC studies in the literature difficult especially for a disease as rare as ACC and so poorly
| Stage | Macfarlane | Sullivan | Icard | UICC/WHO | ENSAT |
|---|---|---|---|---|---|
| I | T1, N0, M0 | T1, N0, M0 | T1, N0, M0 | T1, N0, M0 | T1, N0, M0 |
| II | T2, N0, M0 | T2, N0, M0 | T2, N0, M0 | T2, N0, M0 | T2, N0, M0 |
| III | T3, N0, M0 | T3, N0, M0 | T3-4,N0,M0 | T3, N0, M0 | T3-4, NO, M0ª |
| T1-3,N1,M0 | T1-3,N1,M0 | T1-4,N1,M0 | T1-2, N1, M0 | T1-4, N1, M0 | |
| (mobile nodes) | |||||
| IV | Any T, N1 or M1 | T4,N1,M0 | Any M1 | T3, N1, M0 | Any M1 |
| (fixed nodes) | or any M1 | T4, N0-1, M0 Any M1 | |||
ª The Lee staging system is similar to the ENSAT staging but in stage III includes local invasion as evidenced by: adjacent organ invasion, direct tumor extension to the inferior vena cava (IVC), tumor thrombus within IVC or renal vein.
understood. All ACC staging systems are based on the tumor, node, metastasis (TNM) staging system widely used for other tumors. ACCs were first staged using the Macfarlane system, proposed in 1958 [4] and later modified by Sullivan et al. [5]. Other staging systems followed and included that by Icard et al. [6] and the UICC/WHO classification system. More recently, the Lee staging system [7] and the European Network for the Study of Adrenal Tumors (ENSAT) staging system [8] have been proposed. Both separate patients with advanced loco-regional disease from those with distant metastatic disease. These two more recently proposed staging systems have been found to more accurately predict survival than previous staging systems [9].
Because ACC is rare, limited data exist to study possible prognostic factors that may aid in predicting tumor recurrence and overall survival. Prognostic factors (either from patient demographics or derived from tissue samples) have been found to be particularly useful in other types of malignancies in predicting aggressiveness of disease, ability to cure versus disease progression, and overall survival.
Since the inception of the University of Michigan multidisciplinary adrenal clinic in 2005, which treats patients with all disorders involving the adrenal glands and specializes in the treatment of patients with ACC, our group has noticed a possible association between ACC tumors of different grade (low versus high) and time to tumor recurrence and overall survival. We hypothesized that incorporating tumor grade into the current ENSAT staging system for ACC would further improve the ability to predict time to tumor recurrence and length of survival in patients with ACC.
Methods
A retrospective review of all patients included in the University of Michigan ACC database and seen in the multidisciplinary ACC clinic between January 2005 and November 2009 was undertaken. Patients diagnosed with
ACC and managed surgically or non-surgically within the University of Michigan were combined with patients initially diagnosed and managed at other institutions. Patients were referred from across the United States and from foreign nations. Patients presented for evaluation and management to our clinic at any potential time point during the disease process-at the time of initial diagnosis, after diagnosis and prior to surgery, immediately after surgery and prior to evidence of recurrence, at the time of initial or later recurrence, and within 3 months of death. Decisions for management included assessment of need for and institution of various therapies, including surgery, mitotane, other systemic chemotherapy or trial drugs, and external beam radiotherapy. Demographics, imaging, and pathology reports were reviewed. Tumor staging using the ENSAT staging system was accomplished by review of tumor characteristics from final pathology reports and intraoperative findings as well as radiologic findings immediately before or after initial surgery. Length of time to initial recurrence and time to death or time to last known follow-up visit was recorded. Time to death was identified either from internal documentation or obtained from the Social Security Death Index [10].
Further analysis of time to tumor recurrence and survival was performed by including tumor grade (low and high) in the ENSAT staging system. Tumor blocks and slides are routinely requested prior to a patient’s initial visit if referred from another institution and reviewed by a single pathologist when patients are seen in the multidis- ciplinary adrenal clinic. Confirmation of the diagnosis of adrenocortical carcinoma and determination of tumor grade was determined by a single pathologist (TJG) using a uniform system of reporting and included tumor size, weight, capsular invasion, margin status, presence of necrosis, mitotic rate per high-power field, grade, and extra-adrenal extension status. Immunohistochemistry results were included in reporting if performed. Alpha- inhibin and Melan-A were commonly performed on patients undergoing surgery at the University of Michigan. Tumors were considered high grade based on mitotic
index (>20 mitoses per 50 high-power field) [11]. Results are reported using descriptive methods. Cox regression analysis was used to construct curves identifying time to initial tumor recurrence based on tumor grade and stage. Five-year survival was estimated by the Kaplan-Meier method to analyze patients by stage and tumor grade, and differences in prognostic factors were compared by using the log-rank test. P≤0.05 was considered significant.
Results
Of 133 patients with ACC seen between 2005 and 2009, 91 patients (67 female; median age, 46.2 years, range, 14-72.6 years) had complete information required for staging based on initial presentation and had tissue specimens reviewed with the determination of tumor grade. Patients varied with regard to adjuvant and palliative therapy received in the form of mitotane, other chemotherapy, and external beam radiotherapy. The overall median time of follow-up was 24 months (range, 2-124 months). Median time to initial tumor recurrence was 4.1 months (range, 1-59 months).
Twenty eight patients included in the study died during the follow-up period. The median time to death for these 28 patients (all stages and grades) was 17.5 months (6-117 months). The median time to initial tumor recurrence and death according to stage and grade is shown in Table 2. Overall, time to recurrence (Fig. 1) was significantly different when comparing those with low- and high-grade tumors (p=0.011). Overall survival (Fig. 2) was also significantly different when comparing those with low versus high-grade tumors (p=0.004). When the entire cohort was broken down according to stage, all Kaplan-Meier curves showed visible differences in time to chosen endpoint despite the relatively short time of follow-up.
Four patients were found to have stage 1 disease at the time of diagnosis. The median time of follow-up was 56 months (7-124 months). One patient with a low-grade
tumor had initial tumor recurrence after laparoscopic resection at an outside institution 3 months after surgery and died 9 months later. Although the tumor was low grade by mitotic count (12/50 high-power field), there was evidence of microscopic capsular and vascular invasion. One other patient recurred at 48 months, underwent a second resection, and has been without evidence of disease recurrence since that time. Differences in survival in these stage 1 patients cannot be shown due to the small number of patients in this group.
Stage 2 disease was diagnosed in 46 patients. The median time of follow-up was 33 months (2-119 months). The median time to initial tumor recurrence was 13 months (1-59 months). Those with low-grade tumors tended to recur later (median, 19 months) than those with high- grade disease (median, 12 months). Ten of 46 patients have died at a median of 30 months (6-117 months) after initial diagnosis. The median time to death for those with high-grade tumors was 18 months (6-51 months) com- pared to 55 months (11-117 months) for those patients with low-grade disease. The Kaplan-Meier survival curve (Fig. 3) shows a significant difference in these patients when grade is considered (p=0.05).
Twenty six patients were diagnosed with stage 3 disease. The median follow-up time was 16 months (5-101 months). Four patients have no evidence of disease. The median time to recurrence was 5 months (1-17 months). Twelve patients are deceased after a median follow-up time of 16 months (7-36 months). Median time to death for patients with low-grade tumors was 17 months (15-33 months) and 12 months (7-36 months) for those with high-grade tumors. Differences in survival according to grade were apparent but not significant at this point in time (p=0.23). Presumably, this is because patients already have nodal disease and microscopic amounts of tumor that have escaped into the distant circulation but have not advanced to stage 4 by imaging criteria. Significance of grade further decreased when removing patients with intra- operative tumor rupture or positive margins by pathology (p=0.49). Fifteen patients were diagnosed with stage 4
| ENSAT staging system | I (4) | II (46) | III (26) | IV (15) |
|---|---|---|---|---|
| Overall | ||||
| Recurrence | 26.4 (12-49) | 13 (1-59) | 5 (1-17) | N/A |
| Death | 12 (12) | 30 (6-117) | 16 (7-36) | 12 (6-36) |
| Low-grade tumors | ||||
| Recurrence | 26 (3-48) | 19 (2-119) | 5.5 (2-16) | N/A |
| Death | 7 (7) | 55 (11-117) | 17 (15-33) | 24 (12-36) |
| High-grade tumors | ||||
| Recurrence | N/A | 12 | 5 (1-17) | N/A |
| Death | N/A | 18 (6-51) | 12 (7-36) | 8 (6-30) |
N/A not applicable
1.0-
Low Grade - 53%
High Grade - 47%
0.8
Cum Recurrence
0.6
p=0.011
0.4-
0.2
0.0
0.00
10.00
20.00
30.00
40.00
50.00
60.00
Time to Effect
disease and had tissue available for examination; five patients are deceased. The median follow-up was 12 months (4-36 months) and median time to death overall was 12 months, with three low-grade patients surviving longer [24 months (12-36 months)] than two high-grade patients [8 months (6-30 months)].
Because notable differences in survival were evident across all stages and patients presenting with stage 2 ACC were found to have significantly different overall survival based on tumor grade, we set out to incorporate this new knowledge into the current ENSAT staging system. Because a significant difference between patients with low and high-grade tumors was identified in stage 2, high-
grade stage 2 patients were compared with low-grade stage 3 patients. No significant difference was identified (p=0.85), and stage 2 patients were then combined with low-grade stage 3 patients. Previously published literature (ENSAT) has suggested that stage 1 and stage 2 patients be combined due to the paucity of stage 1 patients and questionable stage 1 data. Low-grade stage 2 patients were down-staged and combined with stage 1 patients. Analysis of high-grade stage 3 patients compared with low-grade stage 4 patients showed a significant difference (p=0.05) and were therefore kept in separate stages. A proposed modification of the current ENSAT staging system is depicted in Table 3. A significant difference is identified
1.0-
Low Grade
High Grade
0.8
Cum Survival
0.6-
p=0.007
0.4-
0.2
0.0
0.00
20.00
40.00
60.00
80.00
100.00
120.00
Time to Effect
1.0-
Grade
Low Grade
High Grade
Low Grade-censored
0.8
High Grade-censored
Cum Survival
0.6
P =. 05
0.4-
0.2
0.0
0.00
25.00
50.00
75.00
100.00
125.00
Time to Effect
between the newly proposed stages 1 and 2 (p=0.001), stages 2 and 3 (p=0.02), and stages 3 and 4 (p=0.05) (Fig. 4).
Discussion
The data presented in this study suggests that close scrutiny of ACC tissue by expert pathologists to differen- tiate low-grade from high-grade tumors and predict tumor aggressiveness predisposing to metastasis and shorter survival is an important factor that can be incorporated into the changing staging system for adrenocortical carcinomas. By separating low-grade tumors from high- grade tumors, a significant difference is shown in stage 2 tumors with regard to time to recurrence and overall survival and clinically significant, but not statistically significant differences are noted across all stages. With increased time of follow-up and greater numbers of patients, significance may be established.
Statistically significant differences in stages 3 and 4 are not seen, likely because the disease is already quite advanced, and follow-up is limited to 36 months at this point in time. Some patients with stages 3 disease likely underwent surgery when hepatic or pulmonary metastases
were present but too small to be able to be detected and characterized appropriately. Stage at time of diagnosis is difficult to define in patients with lung or hepatic nodules too small to characterize. One can retrospectively go back and assign an appropriate stage after the patient has been followed with serial imaging studies. PET imaging can also be a potentially useful modality to answer these questions early on for indeterminate nodules or lymph nodes other than being limited by size of the nodule or other pathology leading to increased SUV determinations (benign inflammatory response).
Limitations of this study include the retrospective nature, small sample size, and limited time of follow-up, especially with regard to stages 3 and 4 patients, referral and selection bias. In addition, there may be some stage-dependent treatment biases in that advanced stage and higher-grade tumors are more likely to be treated with systemic chemotherapy or adjuvant radiotherapy. However, the fact that stage-dependent differences in time to recurrence or survival still exist indicate how ineffective current therapies are. This analysis provides a broad overview as a beginning to investigate other potentially confounding variables. Multivariate analyses will be performed in future studies as our database continues to increase and follow-up time increases.
| ENSAT | Ann Arbor modification of ENSAT | |
|---|---|---|
| Stage 1 | T1, N0, M0 | Stage 1+low-grade stage 2 |
| Stage 2 | T2, N0, M0 | High-grade stage 2+Low-grade stage 3 |
| Stage 3 | T3-4, N0, M0 T1-4, N1, M0 | High-grade stage 3 |
| Stage 4 | Any M1 | Stage 4 |
1.0
Stage I
0.8
Stage II
Stage III
Cum Survival
0.6
Stage IV
0.4
Stage I vs. Il: P =. 001 Stage II vs. Ill: p =. 02 Stage III vs. IV: p =. 05
0.2
0.0
0.00
25.00
50.00
75.00
100.00
125.00
Time to Effect
A multivariate analysis has not been performed in this analysis, but based on previous data using a combined large database system to evaluate different staging systems, factors found to independently predict a poorer survival on multivariate analysis were advanced age, advanced stage at presentation (III or IV), not undergoing surgery or having an incomplete resection associated with debulking surgery [9, 12].
Larger collaborative studies and analysis of other variables will be needed to validate this proposed modifi- cation of the current ENSAT staging system. Previously published data from our group found that gene expression data contains independent prognostic information even when mitotic rate and stage data are included in the multivariate analysis. Twenty four patients with ACC were studied; patients with high-grade tumors had worse out- comes and the use of grade was found to be significantly associated with survival [13]. Other studies have also commented on the importance of mitotic rate grading [14- 17]. If effective, targeted therapies for ACC are developed then the results of our previous study suggest that DNA microarray analysis can be used in several ways: to confirm the diagnosis of ACC, determine prognosis, and assist in the selection of appropriate therapy. While it was suggested that data based on transcriptome profiling was likely too detailed to incorporate in a broader staging system, the data suggested that tumor grade could likely be substituted as a marker of disease aggressiveness and outcome.
Some gene sets, particularly those related to cell cycle regulation, have been associated with high-grade ACC and a poor prognosis [18-22]. IGF-1R has been identified as a possible therapeutic target and several phase II trials, including two at the University of Michigan, using
monoclonal antibodies are in progress in patients with ACC.
The purpose of a staging system is to accomplish several goals: (1) distil large quantities of information into a manageable aliquot to facilitate communication, (2) exchange information, and (3) allow accurate prognosti- cation of disease outcome for a single patient [23]. The most accurate staging systems would incorporate as much information and as many variables as possible that have been shown to be significant on a univariate and multivariate analysis. These variables may be different for every disease process and therefore would become quite complicated. For widespread acceptance, only the most important and commonly collected variables would be able to be included. Even within the commonly used TNM staging systems, there is a considerable variation between cancer types. Some, such as lymphoma or breast cancer utilize additional information from the patient history (A and B symptoms) or receptor status (estrogen, progesterone, and Her2/neu status). Both clinical and pathologic factors can be important for the staging system dependent on the tumor type. Until now, staging for ACC has solely relied on the TNM staging system. Comparison of outcomes from a particular disease process requires that procedures performed, both diagnostic and therapeutic, should be as similar as possible to avoid bias. This is a significant problem in studying patients with ACC, as there is a wide range of diagnostic and therapeutic approaches to the treatment of patients with ACC. Quality of surgical resection [12, 24], including operative ap- proach [25, 26], is extremely important but varies widely. The use of mitotane varies in when it is started, how long it is prescribed for, and the concentration it reaches in the
blood stream. Use of other chemotherapeutic options and external beam radiotherapy also varies widely.
A concerted effort by a number of groups to study ACC in a coordinated fashion has occurred within the past decade, but even this has limitations, as the time point at which patients are referred to these quaternary referral centers varies from those patients referred at the time at initial diagnosis to those just after surgery, at the time of recurrence or metastasis and those nearing death. Collaboration between groups is extremely important in a disease as rare as ACC, and education of the greater medical field with regard to centers with a significant experience managing patients with this disease will be important to ensure uniform management. The latter is a daunting but necessary task to advance the knowledge about ACC and other rare diseases. Similar prospective databases must be maintained in order to accomplish this task to facilitate combined studies which will allow for an appropriately powered study.
Conclusion
Tumor grade is significant for staging patients with ACC and predicting survival. Stage 2 patients will most likely be affected by this change in staging. Visible differences are seen in other stages of ACC, and with continued patient accrual, these differences may become significant. High- grade tumors are associated with shorter disease-free intervals and shorter survival times. This proposed modifi- cation of the ENSAT staging system allows for incorpora- tion of tumor grade when predicting overall survival.
Conflicts of interest None.
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