Adrenocortical Carcinoma
Surgical Progress or Status Quo?
Michael L. Kendrick, MD; Ricardo Lloyd, MD; Lori Erickson, MD; David R. Farley, MD; Clive S. Grant, MD; Geoffrey B. Thompson, MD; Charles Rowland, MS; William F. Young, Jr, MD; Jon A. van Heerden, MD
Hypothesis: Outcome of patients with adrenocortical carcinoma (ACC) has improved with the advent of more widely available and higher quality imaging. Operative management strategies and use of adjuvant therapy have not changed.
Design: Retrospective review of patient histories, im- aging studies, operative data, adjuvant therapy, and out- comes at a single institution. Follow-up was complete for a mean of 53 months. Data was compared with prior in- stitutional experience.
Setting: Tertiary care referral center.
Patients: All patients undergoing operative manage- ment for ACC during the period from 1980 to 1996.
Main Outcome Measures: Determinants of recur- rence, survival, and the effect of adjuvant therapy on over- all outcome.
Results: Fifty-eight patients (30 men, 28 women) with a mean age of 53 years underwent primary operative man- agement for ACC. Functional tumors were identified in 27 patients (47%). Mean tumor size was 12.5 cm. Stage
according to the TNM staging system (AJCC Cancer Stag- ing Manual) at presentation was I (n=0), II (n=30), III (n=7), and IV (n=21). Surgical management included curative resection in 41 (71%), noncurative resection in 14 (24%), and open biopsy in 3 (5%). Perioperative mor- tality was 5%. Recurrence occurred in 30 patients (73%) with a median time to recurrence of 17 months. Five- year survival by the Kaplan-Meier method was 37%. Prognostic factors (P <. 05) included functional status, stage, and chemotherapy in stage III/IV patients. When compared with our prior institutional experience (1960-1980), current patients were more likely to pre- sent with stages I to II (52% vs 34%), have curative resections (71% vs 50%), and have improved 5-year survival (37% vs 16%).
Conclusions: (1) Surgical resection remains the prin- cipal treatment for stage I to III disease. (2) Adjuvant therapy may improve survival in patients with stage III or IV disease. (3) Current patients were more likely to present at an earlier stage, undergo curative resections, and have improved 5-year survival than institutional his- torical comparisons.
Arch Surg. 2001;136:543-549
From the Departments of Surgery (Drs Kendrick, Farley, Grant, Thompson, and van Heerden), Pathology (Drs Lloyd and Erickson), Endocrinology (Dr Young), and Statistics (Mr Rowland), Mayo Clinic, Rochester, Minn.
A DRENOCORTICAL carci- noma (ACC) is a rare en- docrine malignancy typi- cally associated with a poor prognosis. Determination of the optimal treatment of patients with ACC has proven extremely difficult given its infrequent occurrence; thus, good ran- domized prospective trials are lacking. Sur- gical resection improves survival and con- tinues to be the mainstay of treatment. However, many trials of chemotherapy, with varied treatment regimens, have been performed in an attempt to improve out- come. The most commonly utilized che- motherapeutic agent o,p’-DDD (mito- tane) has been at the forefront of adjuvant
and nonsurgical management, yet debate continues whether its use significantly al- ters the outcome of patients with ACC when used in either a palliative or prophy- lactic fashion.1-5 We set out to determine whether the surgical and postoperative (ad- juvant) management of patients with ACC has changed in our practice and whether this change has improved the outcome of patients with this challenging disease. With the more widely available and higher qual- ity imaging, specifically computed tomog- raphy (CT), we speculated that patients might have ACC diagnosed at an earlier stage of the disease and therefore have im- proved outcome when compared with his- torical controls.
METHODS
We retrospectively reviewed all patients diagnosed with ACC who underwent surgical resection at our institu- tion from 1980 to 1996. Additionally, we compared this group with similar patients at our institution treated from 1960 to 1980.6 Data evaluated included presur- gical and postsurgical history; results of serum and urine chemical analyses and endocrine studies; imaging re- sults; findings from pathologic examination; neoadju- vant or adjuvant treatment; and patient outcome.
PATHOLOGY
Adrenocortical carcinoma was diagnosed using estab- lished criteria.7-10 These included areas of confluent ne- crosis; mitoses, including atypical mitoses; vascular and capsular invasion; and nuclear atypia. Tumors were classified into 4 grades using the criteria given in Table 1. Mitoses were counted using light micros- copy ×400 magnification. Tumors falling into grade 2 through 4 were relatively easy to diagnose. Grade 1 tumors were more difficult to classify because of the low mitotic activity, absence of necrosis, and atypical mitosis. These tumors were usually larger than 5 cm and weighed more than 100 g, but they invariably did not have many mitoses or malignant cytologic fea- tures. Within this group, the potential for an overlap between an “atypical” adenoma and a low-grade car- cinoma exists. All surgical specimens underwent re- evaluation for histological grading at the time of this study, which was reconfirmed by 2 pathologists (R.L. and L.E.). Stage of disease was assigned according to the criteria of MacFarlane11 as modified by Sullivan et al12 (Table 2).
FOLLOW-UP
Data was obtained from the patients by telephone, return visits, or from follow-up generated by their pri- mary physician. Follow-up was complete in all pa- tients until death or completion of the study. Tu- mor endocrine functional status was determined either by serum or urinary endocrine studies and clinically when the medical history and physical examination were consistent with a diagnosis of Cushing syn- drome (hypercortisolism), Conn syndrome (hyper- aldosteronism), virilization, or feminization.
STATISTICAL ANALYSIS
Statistical evaluation was performed using the Wil- coxon rank sum test to assess differences in continu- ous measurements between groups, the x2 test to com- pare categorical variables between groups, and the log-rank test to compare distributions of survival. A multivariate analysis of survival end points was per- formed with the Cox proportional hazards model us- ing a forward stepwise regression procedure.
RESULTS
CLINICAL CHARACTERISTICS
During the period of 1980 to 1996, 58 patients (30 men, 28 women) with a mean age of 53 years (range, 16-77
| Grade | Mitoses | Necrosis | Atypical Mitosis |
|---|---|---|---|
| 1 | <5/50 high-power field | − | − |
| 2 | 5-20/50 high-power field | + | + |
| 3 | 21-50/50 high-power field | + | + |
| 4 | >50/50 high-power field | + | + |
| Stage | TNM Staging Criteria |
|---|---|
| TNM | |
| T1 | Tumor ≤5 cm, no invasion |
| T2 | Tumor >5 cm, no invasion |
| T3 | Tumor any size, locally invading to but not involving adjacent organs |
| T4 | Tumor any size, locally invading adjacent organs |
| N0 | No regional positive nodes |
| N1 | Positive regional nodes |
| M0 | No distant metastatic disease |
| M1 | Distant metastatic disease |
| Tumor | |
| I | T1 N0 M0 |
| II | T2 N0 M0 |
| III | T1 N1 M0, T2 N1 M0, T3 N0 M0 |
| IV | TX NX M1, T3 N1, T4 |
* Stage of disease was assigned according to the criteria of MacFarlane11 as modified by Sullivan et al.12 The TNM classification is according to the AJCC Cancer Staging Manual.
years) underwent surgical management of ACC. Ab- dominal pain was the presenting symptom in 28 pa- tients (48%). Other presenting symptoms or signs in- cluded various manifestations of endocrine syndromes (47%), weight loss (16%), a palpable abdominal mass (7%), or back pain (3%). Functional tumors were iden- tified in 27 patients (47%). Cortisol-secreting tumors were the most common functional tumors, comprising 67%, followed by mixed hormonal-secreting tumors in 15%, sex hormonal excess in 11%, and aldosterone-secreting tumors in 7%. The tumor was located on the right in 31, left in 26, and bilaterally in 1 patient.
SURGICAL MANAGEMENT
Surgical management consisted of curative resection (no gross residual disease) in 41 patients (71%), noncurative resection (gross residual disease) in 14 patients (24%), and open biopsy in 3 patients (5%). At operation the tumor was localized in 31 (53%), regionally metastatic in 10 (17%), and distantly metastatic in 17 (29%). In 11 patients (19%), tumor thrombus was identified in the renal vein or the inferior vena cava; 6 of these patients underwent complete resection with no gross residual disease.
PATHOLOGY
Surgical pathology was performed on all surgical speci- mens at the time of the original resection. Additionally,
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Time Since Surgery, y
at the time of this study, all specimens were reexamined to confirm the diagnosis and establish tumor grade. Grade 1 tumors were found in 7 patients, grade 2 in 15, grade 3 in 17, and grade 4 in 17. In 2 patients tumor grade could not be determined owing to inadequate material for review. Mean tumor diameter was 12.5 cm (range, 5-23 cm) and mean weight, 604 g (range, 32-3060 g). There were no patients identified with stage I disease. Stage II, III, and IV tumors were identified in 30, 7, and 21 pa- tients, respectively.
ADJUVANT THERAPY
Patients were typically evaluated prior to hospital dis- missal by a medical oncologist. Twenty patients (34%) received adjuvant therapy. In most patients, adjuvant treat- ment was initiated prior to hospital dismissal. Mitotane was initiated using 1 to 2 g per day and was advanced over the next few weeks to months as tolerated up to 10 g per day. The median dose of mitotane was 4.5 g per day (range, 1 to 10 g) for a median duration of 6.5 months (range, 1 to 131 months). Mitotane alone was used in 16 patients; mitotane plus etoposide and/or cisplatin, 1 patient; and a variety of agents excluding mitotane were utilized in 3 patients.
OUTCOME
Thirty-day perioperative mortality occurred in 3 pa- tients (5%). Two patients died of sepsis with multior- gan system failure. One patient died 28 days postopera- tively following hospital dismissal of a pulmonary embolus.
Recurrence occurred in 30 patients (73%) with a me- dian time to recurrence of 17 months (range, 2-90 months). The cumulative probability of recurrence is shown in Figure 1. In 23 patients (74%), multiple sites were involved at the time of documented recurrence. Lo- cal or regional disease was the most common site of re- currence (65%), followed by lung (58%), liver (58%), and bone (29%). Recurrence was confined to local or re- gional involvement in only 4 patients and was distantly metastatic in 26. Thirteen patients with recurrence un- derwent subsequent surgical exploration with complete resection of gross disease. Currently, 4 of these pa- tients-3 with isolated liver and 1 with lung metastases-
100
90
80
70
Survival, %
60
50
40
30
20
10
0
5
10
15
20
Time Since Surgery, y
| Table 3. Predictive Factors of Prognosis | ||||
|---|---|---|---|---|
| Factor | Univariate | Multivariate | ||
| Risk Ratio | P | Risk Ratio | P | |
| Female | 1.09 | .76 | . . . | NSt |
| Age ≥55 y | 1.02 | .96 | . . . | NSt |
| Functional | 1.68 | .08 | 2.70 | .005 |
| Grade 3 or 4 | 2.50 | .006 | . . . | NSt |
| Stage III or IV | 3.62 | <. 001 | 5.25 | <. 001 |
| Thrombus | 2.67 | .008 | . . . | NSt |
| Curative resection | 0.33 | <. 001 | . . . | NSt |
| Chemotherapy | 0.99 | .97 | 0.30± | .004# |
*Ellipses indicate not applicable; NS, not significant. Values in boldface are significant.
t Variable was not selected at .05 significance level in the forward stepwise model.
Patients with stage III or IV disease only.
are alive. Two of these patients are without evidence of disease (90 and 143 months from initial diagnosis), and 2 harbor recurrent ACC (88 and 166 months from ini- tial diagnosis). Patients who underwent resection of recurrent disease had an improved survival over pa- tients who did not, with a median survival of 29 months vs 11 months, respectively (P <. 01), after documented recurrence.
Overall Kaplan-Meier 5-year survival in 58 pa- tients was 37% with a median survival of 33 months (Figure 2). Median survival for curative compared with noncurative resection was 50.6 and 7.6 months, respec- tively.
Factors analyzed as prognostic indicators of sur- vival are given in Table 3. Univariate analysis revealed significant (P <. 05) factors for improved survival as low tumor grade, stage I to II, no tumor thrombus, and curative resection. On multivariate analysis however, only nonfunctional status, low tumor stage, and chemo- therapy (in patients with stage III or IV disease) were predictors of longer survival. Survival by stage is shown in Figure 3. Factors analyzed for predictors of tumor recurrence are given in Table 4. On both uni- variate and multivariate analysis, age younger than 50 years and high tumor stage (III-IV) were predictive of recurrence.
100
Stage II
90
Stage III
80
Stage IV
70
Survival, %
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50
40
30
20
10
P <. 001
0
5
10
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Time Since Surgery, y
| Table 4. Predictive Factors of Recurrence* | ||||
|---|---|---|---|---|
| Factor | Univariate | Multivariate | ||
| Risk Ratio | P | Risk Ratio | P | |
| Age ≥55 y | 0.46 | .05 | 0.35 | .01 |
| Female | 1.0 | .99 | . . . | NSt |
| Functional | 1.74 | .13 | . . . | NSt |
| Grade 3 or 4 | 1.76 | .14 | . . . | NSt |
| Stage III or IV | 2.17 | .05 | 2.82 | .02 |
| Thrombus | 2.24 | .07 | . . . | NSt |
| Chemotherapy | 0.83 | .63 | . . . | NSt |
*Ellipses indicate not applicable; NS, not significant. Values in boldface are significant. Variable was not selected at .05 significance level in the forward stepwise model.
HISTORICAL COMPARISON
Table 5 gives comparative data of the 2 time periods. When compared with our institutional experience from 1960 to 1980,6 current patients were more likely to pre- sent with higher grade yet lower stage tumors. They were also more likely to have a curative resection, but less likely to receive adjuvant chemotherapy. However, the de- creased overall utilization of adjuvant therapy was largely due to less frequent use of non-mitotane chemothera- peutic agents. Overall, patients from the most recent era displayed an improved 5-year survival (37% vs 16%).
COMMENT
Adrenocortical carcinoma is a rare endocrine malig- nancy with an annual incidence of less than 2 cases per million.13,14 Equally rare is the ability to cure a patient with this disease as the overall 5-year survival ranges from 16% to 35% in large series.15,16
There are several intriguing yet unanswered ques- tions pertaining to ACC. (1) Why do we continue to make the diagnosis so late? The mean tumor diameter re- mains greater than 12 cm at the time of diagnosis. (2) Is the surgical experience in the treatment of these pa- tients improving, or are the outcomes status quo? (3) Is adjuvant therapy indicated with either a palliative or a prophylactic intent? If so, which agent or agents? (4) Do
| Variable | Year | P | |
|---|---|---|---|
| 1960-1980+ (n = 62) | 1980-1996 (n = 58) | ||
| Male | 42 | 52 | .36 |
| Functional tumor | 58 | 47 | .21 |
| Mean tumor size, cm | 12.4 | 12.5 | .89 |
| Tumor grade 3-4 | 37 | 58 | .006 |
| Stage at presentation III-IV | 66 | 48 | .05 |
| Curative resection | 50 | 71 | .02 |
| Adjuvant treatment | 58 | 34 | .01± |
| Mitotane | 39 | 29 | 14§ |
| Other | 19 | 5 | . . . |
| Kaplan-Meier 5-year survival analysis | 16 | 37 | .02 |
* Values are given as percentages except where indicated. Ellipses indicate not applicable. Values in boldface are significant. t According to Henley et al.6
Comparing any adjuvant treatment/no adjuvant treatment.
§ Comparing mitotane/other treatment among patients who received adjuvant treatment.
benign adenomas become malignant? (5) Should all in- cidentalomas, regardless of their size, be resected to de- tect the rare (but curable) small ACC? (6) Are all ACCs in fact ACCs, or are some atypical adenomas? This study, which is retrospective and comparative in design, does not and cannot answer any of these important questions with the possible exception of that pertaining to surgi- cal results. We can only hope that answers to the remain- ing questions will be forthcoming.
Surgical resection has been the mainstay of treat- ment and improves survival. The world literature is in- undated with retrospective and anecdotal reports regard- ing the role of chemotherapy and the adrenolytic agent o-p’ DDD (mitotane) in patients with ACC. Large retrospec- tive studies exist, which tout of both success and failure of adjuvant therapy in affecting the outcome of these pa- tients.1-4,6,17 However, no randomized prospective trials ex- ist that validate or refute these data, and this debate will likely persist until a prospective randomized study is brought to fruition. Mitotane has been used predomi- nantly as the agent of choice in treating patients with ACC, and one reason adequate studies are lacking is the fre- quently intolerable side effects and resulting compliance issues with this agent. More recently, evaluation of “low- dose” mitotane has surfaced, demonstrating greater pa- tient compliance.4,18 By following serum mitotane levels, the lowest dose is given that achieves a “therapeutic” level of 14 mg/L. This serum level was derived from an obser- vational study by van Slooten et al19 who observed that 7 of 8 patients with tumor regression had mitotane serum levels greater than this level, whereas 19 of 20 patients with- out tumor regression had mitotane serum levels lower than 14 mg/L. It should be noted however that mitotane has still not been definitively proven to improve survival or time to recurrence; thus, a specific serum level has little meaning at present. However, standardization of mito- tane levels at doses that increase compliance will be help- ful when a randomized study of the efficacy of mitotane materializes. Our patients did not have serum levels moni-
A
B
tored but were encouraged to take the highest dose pos- sible with tolerable side effects up to a dose of 10 g per day. The decision to institute adjuvant therapy was some- what arbitrary. Of patients receiving mitotane, 65% were stage III or IV. Mitotane was thus used prophylactically (patients with curative resection) in 60% and with pallia- tive intent in 40%. Adjuvant mitotane did not affect the time to recurrence in this study. Also, we observed no sur- vival advantage with use of mitotane in patients with stage I or II disease. Our observation of an improved survival in patients with stage III or IV disease is similar to other reports.1-4,6,17 Although the numbers are small, this differ- ence was apparent regardless of whether the resection was curative or not.
There is a desperate need for a prospective random- ized trial evaluating the role of mitotane in patients who have undergone resection for cure. Because of the rarity of this disease, all of the current reports in the literature are lim- ited by a small database. In an attempt to overcome this, the American College of Surgeons Oncology Group is currently in the process of preparing an international, prospective, randomized trial evaluating the role of adjuvant mitotane usage in ACC. Specifically, the proposal consists of the fol- lowing: patients with stage I or II disease will be random- ized to receive adjuvant mitotane or placebo. Patients with stage III or IV disease will be randomized to receive either mitotane or standard chemotherapy (cisplatin and etoposide). Finally, patients with stage IV and residual disease will be randomized to receive mitotane or standard chemotherapy. Such a trial is long overdue, and the surgical community anxiously awaits the results of this trial.
The surgical management of ACC has not evolved ap- preciably over time, and wide surgical resection remains the mainstay of treatment. With the advent of laparo- scopic adrenalectomy, the question has risen regarding the appropriateness of laparoscopic resection in patients with known adrenal malignancies.2º Some advocate laparo- scopic adrenalectomy in patients with small noninvasive malignancies21; however, data supporting this are lacking. The pendulum, in our opinion, has swung too far in re- gard to the laparoscopic removal of adrenal tumors. More and more tumors that are subsequently found to be ma- lignant are being removed laparoscopically. In our opin- ion, this is most unwise. The initial operation in patients with ACC is the most important one, and violation of sur-
gical oncologic principles is unacceptable. In particular, the tumor should not be violated or morcellated. The senior author of this manuscript (J.A.V.) has personal experi- ence now with 4 patients who underwent difficult laparo- scopic adrenalectomy for tumors measuring less than 7 cm and who were subsequently found to have abdominal car- cinomatosis secondary to tumor morcellation. Recently, Quan-Yang Duh, MD, and colleagues (unpublished data, 2000) at the University of California San Francisco re- viewed their experience with 133 laparoscopic adrenalec- tomies. In 4 patients, ACC was identified, and all 4 had tu- mor recurrence. They suggested that laparoscopic adrenalectomy for ACC has a high recurrence rate and that this approach for ACC should be reconsidered; we em- phatically agree.
In this study, we were able to identify only nonfunc- tioning tumors, early tumor stage, or use of chemo- therapy treatment in patients with stage III or IV disease as predictive factors of longer survival. Whether resection of renal vein or inferior venocaval tumor thrombus im- proves survival is not known. We identified 11 patients who had either renal vein or inferior venocaval involvement, 7 of whom underwent complete resection of all gross dis- ease. Although these patients clearly had a decreased me- dian survival (18 months vs 33 months for all patients), this study was not designed to address whether a survival advantage exists following resection of tumor thrombus.
Re-resection for patients with recurrent disease has been reported to improve survival over patients forgo- ing an additional operation.22 Our study similarly con- firmed a survival advantage to those patients with recur- rence that underwent repeated resection (median of 29 vs 11 months, P <. 01).
With the more widespread use of CT, the manage- ment of incidentalomas is an increasing dilemma for the surgeon. Recommendations for the size at which inciden- talomas should be resected ranges from 3 to 6 cm.5,23,24 We previously addressed the likelihood of a malignancy in an incidentally found adrenal mass by evaluating 231 pa- tients with incidentalomas who were treated nonsurgi- cally and observed for a mean of 7 years.23 No patient in this group subsequently developed a hyperfunctioning tu- mor or adrenal malignancy. We continue to support the concept that most nonfunctioning adrenal incidentalo- mas can be observed safely. For tumors larger than 4 cm,
those with a suspicious imaging phenotype, evidence of en- docrine hyperfunction, or those demonstrating increas- ing interval size, we strongly support adrenalectomy.
One additional area of concern regards a simple but valid question: are all ACCs really ACCs? Pathologic analysis of adrenal neoplasms in the absence of meta- static disease is an inexact science, especially when tu- mors are small (<7 cm) and are low grade (Figure 4). Although mitosis and malignant cytologic features may be sparse, a tumor that is larger than 5 cm and greater than 100 g is generally classified as ACC. Thus, are some of the long-term survivors patients with atypical adeno- mas rather than ACC?
With the improved availability and quality of imag- ing such as CT and magnetic resonance imaging, inciden- talomas are more commonly identified. One might as- sume that this would also lead to earlier detection of “incidental” ACC. When comparing the 2 time periods at our institution however, we observed no difference in the size of adrenal carcinoma at the time of resection (Table 5). An intriguing question then, even in these 2 relatively small groups, is why are current patients more likely to pre- sent at an earlier stage, have an improved chance of cura- tive resection, and have longer survival than the previous 2 decades of patients with similar-sized tumors? We can- not definitively explain this observation. It is possible that with greater awareness and improved imaging and func- tional studies that we are finding these tumors at an ear- lier stage, which may not be as closely related to size as pre- viously thought. Another possibility is that our observations are owing to a referral bias in that patients with seemingly advanced stages may not be referred for surgical resec- tion. However, we have not observed a decline in the num- ber of patients with ACC undergoing resection.
Adrenocortical carcinoma remains a frustrating and challenging malignancy in terms of optimal treatment and patient survival. We support the call for a prospective trial regarding the role of adjuvant therapy to identify and op- timize the management of what is currently a predomi- nantly surgically treated disease.
Presented in part at the 108th Scientific Session of the West- ern Surgical Association, Dana Point, Calif, November 14, 2000.
Corresponding author and reprints: Jon A. van Heerden, MD, Department of Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
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2. Vassilopoulou-Sellin R, Guinee VF, Klein JM, et al. Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer. 1993;7: 3119-3123.
3. Schtiengart DE, Motazedi A, Noonan PA, Thompson NW. Treatment of adrenal carcinomas. Arch Surg. 1982;117:1142-1146.
4. Dickstein G, Shechner C, Arad E, Best L, Nativ O. Is there a role for low doses of mitotane (o,p’-DDD) as adjuvant therapy in adrenocortical carcinoma? J Clin En- docrinol Metab. 1998;83:3100-3103.
5. Prinz RA, Brooks MH, Churchill R, et al. Incidental asymptomatic adrenal masses detected by computed tomographic scanning: is operation required? JAMA. 1982; 248:701-704.
6. Henley DJ, van Heerden JA, Grant CS, Carney A, Carpenter PC. Adrenal cortical carcinoma: a continuing challenge. Surgery. 1983;4:926-931.
7. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetasta- sizing adrenocortical tumors. Am J Surg Pathol. 1984;8:163-169.
8. van Slooten H, Schaberg A, Smeenk D, Moolenaar AJ. Morphologic character- istics of benign and malignant adrenocortical tumors. Cancer. 1985;55:766- 773.
9. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic sig- nificance in adrenocortical carcinoma. Am J Surg Pathol. 1989;13:202-206.
10. O’Hare MJ, Monaghan P, Neville AM. The pathology of adrenocortical neopla- sia: a correlated structural and functional approach to the diagnosis of malig- nant disease. Hum Pathol. 1979;10:137-154.
11. MacFarlane DA. Cancer of the adrenal cortex: the natural history, prognosis and treatment in a study of fifty-five cases. Ann R Coll Surg Engl. 1958;23:155-186.
12. Sullivan M, Boileau M, Hodges CV. Adrenal cortical carcinoma. J Urol. 1978; 120:660-665.
13. Brennan MF. Adrenocortical carcinoma. Cancer. 1987;37:348-365.
14. National Cancer Institute. Third National Cancer Survey Incidence Data. Bethesda, Md: National Cancer Institute; 1975:785-787.
15. Soreide JA, Brabrand K, Thoresen SO. Adrenal cortical carcinoma in Norway. World J Surg. 1992;16:663-668.
16. Pommier RG, Brennan MF. An eleven-year experience with adrenocortical car- cinoma. Surgery. 1992;112:963-971.
17. Haak HR, Hermans J, van de Velde CJH, et al. Optimal treatment of adrenocor- tical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer. 1994;69:947-951.
18. Terzolo M, Pia A, Berruti A, et al. Low-dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocor- tical cancer. J Clin Endocrinol Metab. 2000;85:2234-2238.
19. van Slooten H, Moolenaar AJ, van Seters AP, Smeenk D. The treatment of ad- renocortical carcinoma with o,p’-DDD: prognostic implications of serum level monitoring. Eur J Clin Oncol. 1984;20:47-53.
20. Smith CD, Weber CJ, Amerson JR. Laparoscopic adrenalectomy: new gold stan- dard. World J Surg. 1999;23:389-396.
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DISCUSSION
Richard A. Prinz, MD, Chicago, Ill: I want to congratulate the authors for reviewing one of the largest single-institution ex- periences with adrenocortical carcinoma. Has there been any surgical progress made in this intervening time period? They do report an improved survival of 37% vs 16% in their earlier report, but is this just due to the presence of more favorable lesions in their current series? Stage for stage, has there been any change in the survival outcome of these patients? They have touched on the issue of whether some of these tumors are re- ally adrenocortical carcinomas and not large atypical adeno- mas, which obviously are benign. Presumably, the latter would be grade 1 tumors. Did any of your 7 grade 1 tumors behave malignantly, or did these grade 1 lesions account for a sub- stantial number of your long-term survivals? Only 20 patients in the series received adjuvant chemotherapy, even though you point to this improving survival. How was the decision made on who was to receive adjuvant chemotherapy, and how was the choice of agents that were used made? Local or regional disease was the most common site of recurrence. Have you used or considered using postoperative radiation therapy as an ad- junct to your resection, especially for high-grade and locally invasive tumors? Eleven patients had tumor thrombus in the renal vein or inferior vena cava. How did your approach to these patients differ, and what techniques did you use to prevent tu- mor embolus? Thirteen of your patients had recurrence of dis- ease and underwent subsequent resection of all gross disease. How did you decide that these patients had localized disease,
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and what would make a second resection reasonable in them? Have you used PET [positron-emission tomography] scanning or some other modality to do this? I appreciate your pointing out the challenges that still remain in this unusual cancer.
Donald L. Kaminski, MD, St Louis, Mo: I wonder if the authors could give us some insight into the opposite spectrum of this disease, for example, what percentage of these tumors were under 5 cm? Are there any patients in this series who might have been inappropriately observed with smaller tumors? Ad- ditionally, do they have any suggestions for us with regard to the management of incidental adrenal lesions that are found on CT scan? Should tumors under 5 cm be observed, or should they be removed?
Norman W. Thompson, MD, Ann Arbor, Mich: There are 2 issues that were not addressed. One was the use of fine-needle biopsy in adrenocortical lesions or in adrenal incidentalomas. How many of their patients had actually had a needle put into such a tumor, particularly a type 2, potentially curable tumor. It’s been our experience that far too many patients have had inappropri- ate needle biopsies that may obviate the chance for cure by im- planting carcinoma cells outside the tumor capsule.
Secondly, I wonder if any of their patients had had lapa- roscopic procedures done for their adrenocortical cancers. This raises the issue of the incidentaloma and what size they are will- ing at the Mayo Clinic to say this is potentially a malignancy and therefore not a candidate for procedure. We think that ei- ther needle biopsy or laparoscopic procedure should abso- lutely be avoided in patients with adrenocortical carcinoma. Their pathologist, Rick Lloyd, when at the University of Michi- gan, stated that a cytologist could make the diagnosis based on the needle aspiration. The problem is many physicians are get- ting needle biopsies to differentiate benign from malignant ad- renal cortical tumors when it can’t be done to begin with. This needlessly breaks into a tumor and potentially loses the chance for cure as far as I’m concerned.
Mitchel P. Byrne, MD, Evanston, Ill: I wonder if the ear- lier presentation of these patients since your series in 1980 has anything to do with the type of testing such as ultrasound and CT being done for some other diagnosis much as we pick up aneurysms now on incidental scans being done for gallblad- der problems and that type of thing.
Dr Farley: Dr Prinz asked about the surgical progress that we’ve made specifically per patient and in the operating room. Two differences in this study vs our historical controls: (1) There was lower mortality in the current study. We had 3 periopera- tive deaths from 1980 to 1996, and we had 6 patients die, 2 of them intraoperatively from blood loss, from 1960 to 1980. This lower operative mortality is important when we’re talking about small numbers of patients. Also, in the historical study, 23 pa- tients developed recurrent disease; none of them went back for re-resection. It’s a tribute to Clive and John and others who have operated at Mayo on patients with adrenocortical carcinomas from 1980 to 1996. When 11 underwent re-resection and did well, they
did far better than those that didn’t. Reexploration of an imaged lesion that looks resectable is valid and important. The second question related to patients with low-grade tumors. These tu- mors are bad actors whether they’re grade 1 or grade 4, and grade did not seem to make any difference in this newer study.
Dr Prinz also asked about when to use adjuvant therapy, mitotane or otherwise. We still don’t know the answer to that. We’re delighted that the American College of Surgeons Oncol- ogy Group has made it a priority to study this and will be forth- coming with an international study that’s randomized and pro- spective of adrenocortical carcinomas randomizing placebo and mitotane in stage I and II resectable lesions and then stage III and stage IV looking at mitotane and cisplatin and etoposide. We look forward to these results.
Dr Prinz asked about whether we used radiation therapy. It has not been a major portion of our practice. The historical group (1960-1980) had 10 patients who underwent radiation therapy, and only 1 of those patients showed a response. It would be nice to pull out all the guns, but not all the guns work with this disease.
Dr Prinz asked about surgical technique for tumor throm- bus. Typical vascular control is necessary, but we have put a couple of people on veno-veno bypass when the clot does go up into the atrium. It’s clearly a challenging operation, to say the least. We have not used PET scanner in our 13 recur- rences. We continue to use CT and MRI and have been happy with that at this point, but certainly would welcome the op- portunity to look at that with the PET scanner.
Dr Kaminski asked if any of these lesions were under 5 cm in size, and indeed they were not. The smallest was 5.5 cm. The indication at the Mayo Clinic for removing an inciden- taloma remains pretty much the same as it does elsewhere I think in the United States, (1) if it’s a functional tumor, no matter what size it is, it needs to come out. (2) If it’s greater than 4 cm in size and the patient is fit for general anesthesia, it’s impor- tant to take that tumor out. (3) With high-resolution CT or MRI, if there’s a suspicion or a hint that this is potentially a malig- nant problem, then it should come out.
Dr Thompson asked about fine-needle aspiration, and we did have 8 patients of our 58 who had fine-needle aspiration. We do not recommend this. Five of the patients came to us by a referral with percutaneous needle biopsy, and 3 of our own patients before surgical consultation was obtained had needle biopsy. Again, the outcome was no different, but we clearly do not recommend fine-needle aspiration in these patients. None of these patients underwent a laparoscopic exploration, and again, when in doubt the laparoscope should be put on the back table and an open celiotomy performed.
Dr Byrne asked about the use of CAT [computed axial to- mography] scan and ultrasonography. Both were really not avail- able for most portions of the study from 1960 to 1980, and we thought perhaps that we would have better survival because we found tumors earlier in this study. Size for size, tumors were exactly the same over the last 40 years.