Adrenocortical Carcinoma Clinical Outcome at the End of the 20th Century
Rena Vassilopoulou-Sellin, M.D. Pamela N. Schultz, R.N.
Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M.D. Anderson Can- cer Center, Houston, Texas.
The authors thank all the physicians and health professionals who have participated in the care of patients with adrenocortical carcinoma over the years. They also thank Teofila C. Spear for article preparation.
Address for reprints: Rena Vassilopoulou-Sellin, M.D., Department of Endocrine Neoplasia and Hor- monal Disorders, Box 435, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard., Houston, TX 77030.
Received September 20, 2000; revision received April 12, 2001; accepted May 8, 2001.
BACKGROUND. Adrenocortical carcinoma remains a rare and lethal neoplasm. Effective therapies have not emerged in recent decades. However, medical ad- vances have improved diagnostic techniques and supportive measures; these changes may have a beneficial impact on the natural history of the disease. METHODS. The authors retrospectively analyzed the clinical outcomes of patients with adrenocortical carcinoma registered at the University of Texas M.D. Anderson Cancer Center focusing on patients who received their diagnosis since 1980 and comparing data from those patients with earlier reports.
RESULTS. Since 1980, 139 patients have registered at M.D. Anderson Cancer Center with the diagnosis of adrenocortical carcinoma. One-third had evidence of hor- mone hypersecretion, and one-third had localized disease at diagnosis. Men were affected as frequently as women but tended to be older and have larger tumors at diagnosis. The 5-year survival rate was 60% (Kaplan-Meier analysis). The 30 pa- tients with the longest survival (> 5 years) and the 30 patients with the shortest survival (< 11 months) had no significant differences in age, gender, tumor size, or functionality. However, long-term survivors had significantly less extensive dis- ease. A comparison with patients reviewed in earlier reports from the same insti- tution showed no significant differences in gender predilection, tumor function, or extent of disease. Despite these similarities, patients whose disease was diagnosed since 1980 lived much longer than patients observed in earlier decades.
CONCLUSIONS. Despite the lack of significant improvements in early diagnosis and effective therapies, patients with adrenocortical carcinoma are living longer (5-year survival rate, 60%). It is important to revise assumptions regarding the clinical outcomes of patients with this disease. Cancer 2001;92:1113-21. @ 2001 American Cancer Society.
KEYWORDS: adrenal carcinoma, clinical outcome, survival, endocrine neoplasm.
A drenocortical carcinoma represents one of the more rare and aggressive endocrine malignancies. The prognosis of patients, many of whom present with extensive regional or distant disease, is guarded. Less than one-third of patients survive 5 years, remains the majority die of progressive or recurrent disease much sooner.1-7 Bet- ter outcomes have been described for a subset of patients with local- ized tumors that can be resected completely.8,9 In addition, reports, mostly anecdotal, persist of patients with more indolent disease who live for many years.
Because adrenocortical carcinoma is a rare disease, most reviews on the subject include all available cases, combining clinical material from many decades. In earlier cases, a diagnosis of initial, recurrent, or progressive disease usually was made with physical examination, plain abdominal X-ray films, and intravenous pyelograms. More re- cently, continuously improving computer tomography (CT) and mag-
netic resonance imaging have been used for diagnosis for most patients. In addition to the improvements in diagnostic imaging, general medical and supportive care also has changed greatly over time. It is difficult therefore to compare and contrast recurrence and survival data from many published series; further- more, it is difficult to extrapolate from previous stud- ies the prognosis of patients diagnosed and treated today. Accordingly, we studied the clinical outcomes of patients with adrenocortical carcinoma diagnosed within the past 20 years, focusing on clinical features with potential prognostic value and comparing the clinical profiles and outcomes of these patients with that of patients from earlier decades.
PATIENTS AND METHODS
Between 1944 and 1997, 217 patients registered at the University of Texas M.D. Anderson Cancer Center with a confirmed diagnosis of adrenocortical carcinoma. All patients received at least some of their treatment at M.D. Anderson Cancer Center. Their clinical courses have been documented through visits to the M.D. Anderson clinics (including the endocrinology clinic for most cases) and written or telephone communica- tions. For the current report, the patient population was identified through a search of the Tumor Registry database maintained by the Department of Medical Informatics and of the Endocrine Patient Registry maintained by the Department of Endocrinology.
Evaluation after initial therapy included clinical, biochemical, and radiologic surveillance at regular in- tervals for recurrent disease. Although there were vari- ations in the exact approach among patients, CT of the abdomen and chest X-ray were performed in almost all cases, with additional studies conducted to address clinical concerns.
The extent of disease was defined according to the Surveillance, Epidemiology, and End Results classifi- cation.1º Localized disease refers to disease limited to the organ of origin, confirmed at surgery after diag- nostic imaging techniques have failed to show mea- surable disease elsewhere. Regional disease refers to disease that extends beyond the limits of the organ of origin directly into surrounding tissues or lymph nodes. Distant disease refers to distant metastases. Tumor size was categorized as small (> 5 cm), inter- mediate (5-14 cm), or large (> 14 cm).
We focused the current analysis on patients who received their diagnosis after 1980 for two reasons: 1) the use of CT for the diagnosis and follow-up of cancer had become fairly standard by that time; this technol- ogy has since been used extensively for diagnosis, staging, and recurrence surveillance and has signifi- cantly altered our ability to detect disease; and 2)
| Patient and tumor characteristics | No. of patients (%) |
|---|---|
| Gender | |
| Male | 55 (40) |
| Female | 84 (60) |
| Functional tumorª | |
| Yes | 47 (34) |
| No | 92 (66) |
| Disease extent | |
| Local | 46 (33) |
| Regional | 46 (33) |
| Distant | 47 (34) |
| Median tumor size (cm) | 12.0 (range, 1.7-35.0) |
ª Characterized by excess adrenocortical hormone production.
uninterrupted tenure at M.D. Anderson since 1980 has provided the authors the opportunity to care for most of these patients during at least part of their treatment.
Since 1980, 139 patients have registered at M.D. Anderson with the confirmed diagnosis of adrenocor- tical carcinoma. Clinical information regarding their disease was derived through review of information within the databases and review of the medical records.
Quantitative analyses utilized the StatSoft Statis- tica ‘99 edition for the personal computer. Descriptive statistics included frequencies, percentages, chi- square, and measures of central tendency. Inferential statistics included t test for independent samples, analysis of the variance, and Kaplan-Meier survival analysis.
RESULTS
Patient and Tumor Characteristics
Table 1 outlines the characteristics of patients who received their diagnosis after 1980. The mean plus or minus standard deviation age at diagnosis was 45.6 ± 14.4 years (range, 17-79 years). There were 55 males (40%). Forty-seven patients (34%; 9 men and 38 women) presented with signs and symptoms of hor- mone hypersecretion. Sixty-one tumors (44%) were located on the right side. At the time of diagnosis, 46 patients (33%) had localized disease, 46 patients (33%) had regional extension, and 47 patients (34%) pre- sented with distant metastases. Adrenalectomy was performed for 119 patients (86%), and 74 patients (53%) were treated with mitotane. A variety of other systemic chemotherapeutic agents were given to 20% of patients. Radiotherapy was used sparingly, primar- ily to provide symptomatic relief of metastatic disease.
Table 2 outlines the tumor characteristics: tumor size was analyzed using analysis of variance to deter-
| Characteristic | Males | Females | P value |
|---|---|---|---|
| Age at diagnosis, yrs (mean) | 48.3 | 42.9 | 0.03 |
| Extent of disease (%) | |||
| Local | 15 (27) | 31 (37) | |
| Regional | 17 (31) | 29 (35) | < 0.001 |
| Distant metastasis | 23 (42) | 24 (29) | |
| Tumor size (cm) | 16.9 | 12.2 | 0.05 |
| Patient characteristics | Improved | Stable | Progressed | P value |
|---|---|---|---|---|
| Mean | ||||
| Age | 52.4 | 39.0 | 44.0 | 0.16 |
| Gender | ||||
| Male | 3 | 2 | 13 | 0.6 |
| Female | 5 | 1 | 19 | |
| Extent disease | ||||
| Local | 3 | 0 | 8 | 0.7 |
| Regional | 2 | 2 | 11 | |
| Distant | 3 | 1 | 13 | |
| Tumor size (cm) | 10.6 | 13.5 | 13.0 | 0.4 |
| Tumor function | ||||
| Functioning | 3 | 0 | 14 | 0.3 |
| Nonfunctioning | 5 | 3 | 18 |
mine if there was an interaction among gender, side of the tumor, and functional status of the tumor. The assumption of homogeneity of variance was met (P = 0.4). There was a main effect for gender (f = 8.33; P < 0.004). The median tumor size was 12.0 cm (range, 1.7-35.0 cm). Males had significantly larger tumors at diagnosis than females (16.9 vs. 12.2 cm; P = 0.05). However, there were no significant interactions be- tween side of the tumor and its functional status. In addition, males were significantly older than females at diagnosis (48.3 vs. 42.9 years; P = 0.03).
Impact of Mitotane
Of the 74 patients who received mitotane, 43 could be evaluated for response. Table 3 summarizes their characteristics. The response to mitotane was not as- sociated with patient gender or age, tumor size or functionality, or extent of disease at the time of diag- nosis. The patients whose disease progressed during mitotane therapy tended to be older than patients whose disease improved or remained stable and to have more disease at presentation, although neither trend was significant. Both the duration of mitotane use and the dose administered over time varied con- siderably and were difficult to analyze quantitatively.
No differences in the mean mitotane dose (usually 4-5 g/day) were apparent. The overall survival time was higher in patients who responded to mitotane than in patients who had disease progression with mitotane (P = 0.01). In addition, patients who took mitotane appeared to have a modest, but not significant (P = 0.07), overall survival advantage; selection bias of the treatment options may have played a role.
Survival
At the time of this analysis, 82 patients (58%) who received their diagnosis of adrenocortical carcinoma since 1980 have died, presumably from this cancer. Seventy-three of these patients (90%) died within the first 5 years; 53 patients (65%) died within the first 2 years.
The 5-year survival rate was 60% (Fig. 1). Accord- ing to the Kaplan-Meier survival analysis, the 25th percentile survival time was 24.0 months, the 50th percentile survival time was 77.2 months, and the 75th percentile survival time was 100.7 months.
Figure 2 depicts the overall survival time accord- ing to gender. Overall survival is not different between males and females; however, the group characteristics are different. These results suggest that gender may be a surrogate for patient age or extent of disease at diagnosis rather than an independent risk factor.
Figures 3 and 4 depict survival relative to tumor size. Males with large tumors did not survive as long as males with intermediate and small tumors (P = 0.002; Fig. 3). Only one male patient had a small tumor. Tumor size did not make a difference in survival for women ( P = 0.22; Fig. 4).
Comparison of Patients with Longest versus Shortest Survival
In this cohort, there were 30 patients known to have survived at least 5 years; we considered them long- term survivors (patients for whom we did not have a minimum follow-up of 5 years were excluded). At the other extreme, there were 30 patients who were known to have died within 11 months of diagnosis. In a further attempt to identify characteristics with prog- nostic value, we compared the clinical profile at the time of diagnosis of the two groups (Table 4). Although there were more women among the long-term survi- vors, there were no significant differences in patient age, gender, tumor size, functionality, and laterality between the short-term survivors and the long-term survivors. However, the long-term survivors had sig- nificantly less disease at presentation than did the short-term survivors; at the time of initial surgery, 18 long-term survivors (but only 2 short-term survivors) were thought to have localized disease (P < 0.001).
Survival Function (Kaplan-Meier) o Complete (57 patients) + Censored (82 patients)
1.2
1.1
1.0
0.9
Cumulative Proportion Surviving
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
-0.1
-0.2
0
50
100
150
200
250
Survival Time in Months
Survival (Kaplan-Meier) Analyzed by Gender o Complete + Censored p = 0.8
1.0
0.8
Cumulative Proportion Surviving
0.6
0.4
0.2
0.0
-0.2
MALE
0
20
40
60
80
100
120
140
160
180
200
220
FEMALE
Time in Months
Among the short-term survivors, 1 26-year-old woman died of severe tumor hypoglycemia 9 months after diagnosis. A 28-year-old woman with severe hypercortisolism died of postoperative com- plications 2 months after diagnosis, and a 22-year- old woman with Cushing disease died 13 months after surgery after a very complicated postoperative course.
Clinical characteristics of the 30 long-term survi- vors are outlined in Table 5. Eleven patients have remained disease free since diagnosis with a median follow-up of 85.0 months (range, 64.0-193.0 months). Among this group, the range of the tumor size was between 5 and 24 cm and of their age between 27 and 65 years. Eight of the 11 patients were women, and 8 of the tumors were considered nonfunctioning. In three
Survival (Kaplan-Meier) Analyzed by Tumor Size o Complete + Censored Males p = 0.002
1.0
Cumulative Proportion Surviving
0.8
0.6
0+
0.4
0.2
0.0
small
-0.2
medium
0
20
40
60
80
100
120
140
160
large
Time in Months
Survival (Kaplan-Meier) Analyzed by Tumor Size o Complete + Censored Females p = 0.22
1.0
Cumulative Proportion Surviving
0.8
0.6
0.4
0.2
0.0
small
-0.2
medium
0
20
40
60
80
100
120
140
160
180
200
220
large
Time in Months
cases, the tumors were considered clinically and pathologically locally invasive. Two additional pa- tients had no evidence of disease at the time of last contact, more than 10 years after they were treated surgically for recurrent disease (regional and lung in one patient and regional only in the other). Seven patients remain alive with progressive though rela-
tively indolent disease 109 ± 15 months after the diagnosis. In several but not all cases, the tumors were described pathologically as “low grade.” However, we cannot discern prognostically useful characteristics with respect to size, gender, age, function, or patho- logic description among the group on long-term sur- vivors and the other cases.
| Characteristic | No. of patients | ||
|---|---|---|---|
| Short survival | Long survival | P value | |
| Mean age, yrs (range) | 47.7 (19-79) | 45.5 (23-65) | 0.55 |
| Mean tumor size, cm (range) | 14.9 (7.0-35.0) | 12.2 (4.0-25.0) | 0.11 |
| Functional tumor (yes/no) | 10/19 | 11/19 | 0.5 |
| Gender (M/F) | 15/15 | 9/21 | 0.1 |
| Extent of disease | |||
| Local | 2 | 18 | < 0.001 |
| Regional | 6 | 9 | |
| Distant | 22 | 3 | |
| Characteristic | No. of patients | DFI, mos (mean ± SEM, median [range]) |
|---|---|---|
| Yes | 19 | 29.7 ± 4.7, 34.0 (0.0-77.0) |
| None | 11 | 95.6 ± 8.0, 85.0 (64.0-147.0) |
| Overall follow-up | 30 | 103.0 ± 6.2, 97.0 (61.0-193.0) |
| Site of recurrence | ||
| Abdomen | 11 | |
| Liver | 2 | |
| Lung | 4 | |
| Disease status at last examination | ||
| Dead of disease | 6 | |
| Dead other cause | 4 | |
| Alive with disease | 7 | |
| No evident disease | 13 |
DFI: disease free interval; SEM: standard error of the mean.
Comparisons with Earlier Reports
In the current report, we have focused our analyses on patients who received their diagnosis after 1980; pre- vious reports from our institution have analyzed the clinical profiles of patients with adrenocortical carci- noma diagnosed in earlier years. Table 6 depicts sim- ilarities and differences relative to two earlier groups of patients. It may appear that the three series from this institution were cumulative, but this was not the case. Patients diagnosed at autopsy and patients who died in the immediate postoperative period were ex- cluded. Most patients in the fist two series were not included in this latest series. There is a nonsignificant trend of more diagnoses in women but no differences in the ages of patients at diagnosis. Although func- tional tumors were identified in approximately one- third of patients in each series, the relative proportion of women with functional tumors appears to be higher in the most recent series. This may be because of our improved ability to detect subtle hormonal changes using biochemical methods. Tumor size is not quan-
| Characteristic | No. of patients by study | ||
|---|---|---|---|
| Nader et al.22 | Venkatesh et al.23 | Current study | |
| Yrs diagnosed | 1950-1981 | 1944-1987 | 1980-1997 |
| No. of Patients | 77 | 110 | 139 |
| Mean age at diagnosis, yrs (range) | |||
| Female | 37 (0.5-75) | 38 ± 18 | 44 (18-79) |
| Male | 48 (25-71) | 49 ± 14 | 48 (17-71) |
| Gender (%) | |||
| Female | 39 (50) | 58 (53) | 84 (60) |
| Male | 38 (50) | 52 (47) | 55 (40) |
| Functional tumor | |||
| Yes/no (%) | 26/51 (33) | 39/71 (35) | 47/92 (34) |
| Percentage women | 69 | 74 | 81 |
| Disease extent at | |||
| diagnosis (%) | |||
| Local | NA | 28 (26) | 46 (33) |
| Regional | NA | 30 (27) | 46 (33) |
| Distant | 26 (34) | 42 (38) | 47 (34) |
| Not known | NA | 10 (9) | NA |
| Survival rate (%) | |||
| Alive at 2 yrs | 50 | 40 | 61 |
| Alive at 5 yrs | 30 | 23 | 47 |
| Alive at 10 yrs | 10 | 10 | 41 |
tified in the earlier reports, though the authors com- ment that many patients presented with palpable ab- dominal masses. Large tumor size certainly persists in the current group of patients. The availability of CT since 1980 has allowed the identification of asymp- tomatic, incidental adrenal masses, some of which have proved malignant. It is noteworthy though dis- appointing therefore that there has been only a very modest, nonsignificant reduction in the number of patients who present with metastatic disease.
We also have reanalyzed the aggregate informa- tion available for all 217 patients in our database (Ta- ble 7). The recent group of patients were somewhat older at diagnosis than those whose disease was diag- nosed before 1980. There are no significant differences with respect to gender, extent of disease, and tumor functional status. Information on tumor size was available for only 8 patients whose disease was diag- nosed before 1980.
Despite the similarities in patient and tumor char- acteristics, however, the duration of survival was longer in patients whose disease was diagnosed since 1980. Only 10% of patients remained alive after 10 years in both previous series; in contrast, 41% of pa- tients in the current series are living at least 10 years after initial diagnosis. Because there have been no striking improvements in either stage at diagnosis or
| Characteristic | No. of patients | ||
|---|---|---|---|
| Before 1980 | Since 1980 | P value | |
| Mean age (yrs) | 41.7 | 45.8 | 0.05 |
| Gender (%) | |||
| Male | 34 (44) | 55 (39) | 0.5 |
| Female | 44 (56) | 84 (61) | |
| Extent of disease (%) | |||
| Local | 21 (27) | 46 (33) | 0.4 |
| Regional | 23 (29) | 46 (33) | |
| Distant | 34 (44) | 47 (34) | |
| Functional tumor (%) | 26 (33) | 47 (34) | 0.9 |
| Mean/follow-up (mos) | 48 + 6 | 34 + 3 | 0.06 |
curative therapies, we have to suggest that improved survival must be related to better general and support- ive medical care.
DISCUSSION
Review of the clinical profiles of patients in our insti- tution with adrenocortical carcinoma diagnosed dur- ing the past 20 years indicates that this disease con- tinues to be an aggressive and lethal endocrine neoplasm. Although earlier detection and improved therapies have changed significantly, the presentation and clinical course of disease in patients with other malignancies is not apparent with adrenocortical car- cinoma. At the time of initial diagnosis, many patients already have very large tumors, with distant metasta- ses in one-third of the cases. Although many, if not most, patients have disease progression while receiv- ing available therapy, it is important to recognize that some patients may have a curative initial resection and that a few patients may have a prolonged, indo- lent course despite persistent or slowly progressive disease. Most important, patients appear to be living longer after initial diagnosis.
The extensive use of CT in the past 20 years or so has, inadvertently, caused the identification of “inci- dentalomas,” unexpected and asymptomatic lesions that necessitate a clinical decision. In the adrenal area, incidental masses, some of which turn out to be ma- lignant, are found in a small percentage of patients undergoing abdominal CT scans for other reasons.11,12 One might hope therefore to begin identifying smaller and more localized adrenocortical carcinomas. Unfor- tunately, patients are still presenting with large tumors (average 16.9 cm in men and 12.2 cm in women) that have spread to distant sites in one-third of cases. Endocrine function was recognized more frequently in
tumors found in women; although all tumors in women were generally smaller than those found in men, as has been reported previously,13 the functional tumors were the same size as the nonfunctional le- sions.
The identification of prognostic factors at the time of diagnosis has been the subject of several publica- tions, which generally focused on pathologic14-18 or clinical19-21 criteria. In the current report, we also analyzed separately the 30 patients who lived at least 5 years (long-term survivors) and the 30 patients who survived the shortest time (short-term survivors); we compared and contrasted their clinical profiles hoping to discern additional prognostic features. In addition, we compared and contrasted disease characteristics of patients examined at M .D. Anderson since 1980 with results from earlier cohorts presented in prior publi- cations from our institution.22,23
Most authors conclude that it is difficult to de- velop robust prognostic criteria for adrenocortical car- cinoma. From a pathologic standpoint, a low mitotic rate is considered a favorable feature. From a clinical standpoint, complete resectability is encouraging. Some authors suggest that for selected patients, a second operation also may confer a survival advan- tage.24 Our findings are in agreement with the prevail- ing opinions of these investigators. Most long-term survivors had successful resection of a primary tumor that was described as low-grade and had not spread to distant sites. In addition, two of the long-term survi- vors had surgical excision of isolated distant or re- gional recurrences and have remained disease free for many years. Conversely, many of the short-term sur- vivors also were thought to have localized, completely resected tumors at first, whereas three long-term sur- vivors had invasive disease at diagnosis.
With respect to therapy, complete initial surgical resection appears to offer the best hope for durable control or cure. This concept has been reiterated for many years9,20,24 and currently remains valid . Among our patients, 11 underwent apparently curative initial surgery and had had no measurable disease for at least 5 years despite the variability of their clinical profiles (age, size of tumors, etc.). When surgery is unsuccess- ful or insufficient, mitotane appears modestly helpful for some patients, as previously concluded by our group22,23,25 and other investigators.26-28 Chemother- apy alone29,30 or in combination with mitotane27,28,31 or surgery32 remains an important area of investiga- tion and further development.
Most discussions regarding adrenocortical carci- noma emphasize the seriousness of the disease and the “dismal” survival rate. In most series, less than 20% of patients are reported alive after 5 years; the
same expectation was reflected in the previous reports from our own institution.22,23 In the current analysis, 30 patients lived for at least 5 years after diagnosis (excluding the patients for whom we do not have sufficient follow-up but who contributed to the overall survival rate of 60% for the group whose disease was diagnosed since 1980). Furthermore, 7 patients are known to be alive with persistent or slowly progressive disease 5-13 years after diagnosis, suggesting that the disease may follow an indolent course in some pa- tients. We cannot, at this time, predict the biology of the disease for individual patients. We cannot at- tribute longer survival to early detection or improved oncologic therapy because the clinical and radiologic characteristics of the disease at presentation reported during the past 20 years are not clearly more favorable than those reported in earlier periods. Although diffi- cult to document, it is possible that improved out- come may be related to advances in surgical tech- nique (e.g., more extended lymphadenectomies or greater precautions to avoid tumor spillage). It is also possible that patients may be living longer because of improvements in general medical supportive mea- sures and a gradual change in medical attitudes about the care of patients with “terminal” cancer.
Adrenocortical carcinoma remains a rare and lethal endocrine malignancy, with relatively few in- roads regarding advances in early diagnosis or ef- fective therapies. Clearly, both avenues should be explored to improve patient outcomes. Given the rarity of the disease, multicenter efforts will be re- quired. It is important to emphasize, however, that a few patients may live for many years with this disease regardless of the presence of apparently un- favorable prognostic factors (regional invasiveness or distant metastases).
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