ANAQUETA
World Journal of Surgery C 1992 by the Société Internationale de Chirurgie
Survival Rates and Prognostic Factors in Adrenocortical Carcinoma
Ph. Icard, M.D., A. Louvel, M.D., and Y. Chapuis, M.D.
Departments of Surgery and Anatomopatholgy, Hospital Cochin, Paris, France
In the last 12 years, 41 patients with adrenocortical carcinoma were operated on at Cochin Hospital. There were 29 females and 12 males having an average age of 42 ± 17 years. Seven of them underwent repeat operation for local recurrence after an average interval of 22 months. Eighty per cent of the tumors had secretory activity while 20% did not. Adrenalectomy and lymphadenectomy were performed on all patients. Thirteen (32%) patients underwent extensive resection because of invasive cancer. The same procedure was performed on 7 patients undergoing re-operation. Operative mortality was 4% (2 of 48 patients). Twenty-four patients died of cancer with an average survival time of 22 months (range 2-86 months) and 15 (37%) patients were still alive, 4 of them with metastases, with an average survival time of 51 months. Curative resection for the 31 patients with local (n = 21) or regional disease (n = 10) allowed a 5 year actuarial survival rate of 45%. The 5 year actuarial survival rate for patients undergoing repeat surgery was 33%. Only 1 of the 10 patients with metastases, and who had an impressive response to OP’DDD, was alive 2 years after the operation. The other 9 patients died within 3-4 months after operation. We found that neither patient characteristics or tumor characteristics were of significant prognostic value. There was no overall prolongation of survival in patients receiving OP’DDD. However 4 patients with metastases occurring in the course of their disease experienced an impressive response with OP’DDD and a relatively long survival.
Adrenocortical carcinoma is a rare malignant tumor with an annual incidence rate estimated at <2 cases per million per year [1, 2]. The malignancy has a poor prognosis and approximately 70% to 85% of patients die within 5 years [3-7]. Because of the rarity of this cancer, extensive experience with its treatment and particularly its surgical resection are exceptional [4, 6-9]. Consequently, the survival rates and the prognostic factors for patients undergoing surgery are not well known. The purpose of this study was to report the survival rates of 41 patients who were treated consecutively and to define prognostic factors.
Patients and Methods
Patient Characteristics
From March 1979 to March 1991, 41 patients with adrenocor- tical carcinoma underwent surgery in Cochin Hospital, Paris. A
Presented at the International Association of Endocrine Surgeons in Stockholm, Sweden, August, 1991.
Reprint requests: Y. Chapuis, M.D., Department of Surgery, Hospi- tal Cochin, 27, rue du Faubourg Saint Jacques, 75014 Paris, France.
total of 48 operations were performed because 7 of these patients underwent repeat operation for local recurrence. There were 29 women and 12 men (sex ratio 2:4) having an average age of 42 ± 17 years (range 17 to 74 years) and the men were, on average, 10 years older than the women. Twenty-nine (71%) patients had a functional syndrome, and based on hormonal studies, 33 (80%) patients had secretory tumors, whereas 8 (20%) patients had non-secretory tumors. The various hor- mones secreted by the carcinoma are shown in Table 1.
An abdominal mass was present in 14 (34%) patients, weight loss, anorexia or fever were present in 9 (22%) patients. The average time interval between initial symptoms and diagnosis was estimated in 25 patients at 10 months (range 2 to 48 months) and no difference was observed between men and women or between secretory or non-secretory tumors. Two tumors were incidentally discovered. In 4 women, adrenal carcinoma was discovered during pregnancy because of Cushing’s syndrome. The sex ratio (female/male) was 3:1 for functional tumors and 1:1 for non-functional tumors. At time of diagnosis and treat- ment, 10 (24%) patients had metastases either in lung, liver or bone, or combinations of the three.
Surgical Treatment
During the first operation all patients underwent complete removal of the carcinoma with at least adrenalectomy and lymphadenectomy. More extensive resections were performed in 13 (32%) patients because of invasive carcinoma and included 1 partial-pancreatectomy, 4 nephrectomies, 3 right hepatecto- mies, 3 intestinal resections, 1 extraction of tumor thrombus from the inferior vena cava, and 3 lateral resections of the vena cava under clamping. Eleven additional patients underwent nephrectomy although their kidneys were not apparently in- vaded. The nephrectomy was performed to facilitate the re- moval of large tumors and to facilitate complete lymphadenec- tomy with the hope of improving survival of these patients. Finally, 31 (76%) patients underwent curative resection, whereas 10 (24%) patients, despite macroscopically complete resection of their adrenal cancer, underwent a palliative resec- tion because of the presence of distant metastases.
| Hormone | No. of pts. (%) |
|---|---|
| Secretory tumors | 33 (80) |
| Glucocorticosteroids | 10 (30) |
| Glucosteroids + androgens | 13 (39) |
| Androgens | 2 |
| 17 Hydroxyprogesterone | 2 |
| Aldosterone | 1 |
| Glucocorticosteroids + 17 | 1 |
| hydroxyprogesterone | |
| Glucocorticosteroids + 17 hydroxyprogesterone + aldosterone | 2 |
| Glucocorticosteroids + androgens + estradiol | 1 |
| Estradiol | 1 |
| Non-secretory tumors | 8 (20) |
Tumor Characteristics
Twenty-five (61%) carcinomas involved the left adrenal gland and 16 (39%) involved the right gland. The mean weight as recorded in 39 tumors was 937 ± 1123 gm (range 13 to 4750 gm). The mean diameter as recorded in 34 tumors was 12 cm (range 3 to 25 cm). No correlations was found between functional presentation and histologic findings. Our histologic criteria for diagnosis of adrenocortical carcinoma were similar to other reports [10, 11] and included size >5 cm, weight >100-150 gm, lobulation, architectural disorder, tumor cell necrosis, hemor- rhage, fibrosis, calcifications, mitotic activity, nuclear pleomor- phism, lymph node involvement, and capsular or vascular invasion.
Seven of the 41 tumors, because of their small size and weight (range 13 to 75 gm) were classified initially as indeterminate tumors because of the presence of some of the aforementioned criteria of malignancy. Three of these patients died of metasta- ses within 22 to 36 months postoperatively. The smallest metastasizing carcinoma weighing 25 gm. None of the 11 kidneys which were removed to facilitate surgery were found to be microscopically invaded. Microscopic invasion of lymph nodes was rarely observed, being recognized in only 2 of the 41 lymphadenectomy specimens. In these 2 cases the patients had associated distant metastases.
Staging
All patients were staged according to the classification of Mac Farlane [10] reintroduced by Sullivan and associates [12]. A stage I tumor is <5 cm in size, while a stage II tumor is >5 cm. Neither of these stages has lymph node involvement, local invasion, or metastases. Stage III tumors have associated lymph node involvement or local invasion without distant metastases, while stage IV tumors have distant metastases.
Three patients were classed stage I and 18 patients were classed stage II. These two stages define local disease. Ten patients had regional disease and 10 patients had distant metas- tases (stage IV). Right adrenal tumors were more frequently associated with stage IV disease than were left adrenal tumors.
Seven patients underwent repeat surgery for local recurrence an average of 22 months (range 7 to 44 months) postoperatively (Table 2). One of these patients (Patient 4) had intestinal metastases which were removed. Then liver metastases ap- peared in the course of the disease and decreased after admin- istration of OP’DDD. Patient 6 had lung metastases which decreased for several months with OP’DDD treatment. All of the local recurrences were completely removed with resection of contiguous invaded organs including 2 partial pancreatecto- mies, 2 intestinal resections, 2 left nephrectomies, and 1 parietal resection with prosthetic muscular replacement. Three left nephrectomies were also performed although the kidneys were not invaded.
Treatment with OP’DDD
The drug, OP’DDD, was administered without randomization of patients. It was given orally at a dose of 12 gm per day for 3 to 6 weeks before surgery in 14 patients with severe functional syndromes and in 4 patients with very large tumors. Twenty patients received OP’DDD postoperatively at a lower dose of 3 to 4 gm daily with a maximal dose of 6 gm until death or completion of the study. Three patients could not tolerate the drug. Cortisol (30 to 40 gm per day) and 9 alphafluorocortisol (50 gm per day) were given with OP’DDD.
Statistical Analysis
Survival rates were calculated by the actuarial survival method and compared by the log Rank test. Results were considered to be significant if p < 0.5. Except for the operative period, all deaths were attributed to malignancy.
Follow-Up
Follow up was obtained for all patients either until death or the completion of the study (July 1991) with one exception, a patient who was lost to follow-up after 53 months.
Results
Survival
Twenty-six (63%) patients died, two of them in the operative period (operative mortality 4%, 2 of 48 patients) and 24 of them because of malignancy with an average survival time of 22 months (range 2 to 86 months). Fifteen (37%) patients were still alive at the completion of this study in July 1991. Their mean survival time was 51 months (range 4 to 120 months). Eleven patients were free of disease and 4 patients had recurrence of tumor with metastases. Mean survival times of patients with stage I, II, III, IV, tumors were, respectively, 30 months, 47 months, 36 months, and 6 months. The average survival time for the 31 patients who underwent curative resection (i.e., stage I, II, III) was 44 months. The 7 patients who underwent resection of local recurrence had an average survival time of 51 months (25 months on average after the initial operation and 26 months after the reoperation).
| Clinical characteristic | Pt. no. | ||||||
|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | |
| Age (yrs) | 61 | 50 | 40 | 70 | 41 | 24 | 21 |
| Sex | Female | Female | Female | Male | Male | Female | Female |
| Secretory status | S | NS | S | NS | S | S | S |
| Side of tumor | RIGHT | LEFT | LEFT | LEFT | LEFT | LEFT | RIGHT |
| Initial stage | III | II | II | III | III | II | III |
| Local recurrence (mos) | 43 | 27 | 13 | 18 | 27 | 14 | 5 |
| Time re-operation (mos) | 44 | 27 | 14 | 30 | 30 | 26 | 7 |
| Metastases at re-operation | - | - | - | Intestine | - | Lung | - |
| Tumor response to OP'DDD | - | - | - | Yes | - | Yes | - |
| Outcome | DOD | DOD | DOD | DOD | AWM | DOD | DOS |
| Survival since re-operation (mos) | 7 | 21 | 9 | 77 | 39 | 27 | 3 |
| Overall survival (mos) | 51 | 48 | 22 | 107 | 69 | 53 | 10 |
S: Secretory; NS: Non-secretory; DOD: Dead of disease; AWM: Alive with metastasis.
%
- overall patients (n = 41)
100
— curative group (n=31)
**** palliative group (n=IO)
p<0.001
80
- reoperated group (n=7)
60
145% (8)
40
35% (8)
20
33% (2)
10% (1)
0
0
2
3
4
5
6
7
8
9
years
As presented in Figure 1, the 5 year actuarial survival rate for the entire series was 35%. The 5 year actuarial survival rate for the patients undergoing curative resection was 45%, very significantly higher (p <0.0001) than that of the patients under- going palliative resection, 10% actuarial survival at 1 and 2 years. Nine of these 10 patients with stage IV disease died within 2 to 4 months after the operation. The sole patient who was alive at 2 years follow-up underwent an impressive pre- operative reduction of both lung metastases and primary tumor with OP’DDD treatment. The 5 year actuarial survival rate for the patients undergoing repeat surgery was 33%.
Prognostic Factors
We found that the survival rates were independent of sex, age (<40 years versus >40 years), functional status, or tumor weight (<50 gm, 100 gm, versus >100 gm).
With the group of patients undergoing curative resection, there was no statistical difference between the first two stages (Fig. 2), however the difference in 5 year survival rates between patients with stage II disease and those with stage III disease was significant.
Patients with left-sided tumors had better survival rates than patients with right-sided tumors (Fig. 3, p < 0.01). However, there was no difference when the comparison was made be-
%
100
- stage | (n =3)
— stage Il (n = 18)
**** stage III (n=IO)
p = 0.5
80
- stage IV(n=IO)
60
40
20
0
0
2
3
4
5
6
7
8
9
years
%
100
- left tumors (n = 25)
— right tumors (n=16)
80
60
44% (6)
40
31% (2)
20
p<0.01
0
0
2
3
4
5
6
7
years
tween the patients undergoing curative resection, not taking into account the higher incidence of stage IV disease in right- sided tumors (Fig. 4). There was no difference in survival rates between patients with stage I disease and those with stage II disease considering those with or without systematic nephrec- tomy. However, none of the re-operated patients with left-sided tumors had undergone previous nephrectomy at the first oper- ation. In the re-operated patients, the survival rates were independent of the disease free interval before recurrence (<12 months, 24 months, or >24 months).
%
- left curative group (n=23)
100
== right curative group (n=8)
NS
80
60
53% (2)
40
42% (6)
20
0
0
2
3 4 5
6
7
8
9
years
Efficacy of OP’DDD
Nine (64%) of the 14 patients with a severe functional syndrome who received OP’DDD pre-operatively had a clear favorable response with marked reduction of their functional presentation and biological secretion, and with an improvement of their general condition. None of the disabling effects of OP’DDD were significant enough to stop the drug administration.
Tumoral Response with OP’DDD
The survival rates were found to be independent of the admin- istration of OP’DDD pre-operatively or postoperatively. How- ever, 4 patients with metastases occurring in the course of their disease demonstrated an impressive reduction of their metasta- ses (lung = 2, liver = 2) and also of their primary tumor (n = 1) or recurrent tumor (n = 2). This impressive tumor reduction encouraged us to operate on 3 of the 4 patients with primary or recurrent local tumors, even though initially the extent of the cancer appeared to be too great. Surprisingly, these patients had relatively long survivals. Two died after 53 months and 107 months although their metastases were discovered at an early stage of their disease, respectively, 14 months and 18 months (Table 2, Patients 4 and 6). Two other patients were still alive with disease at 25 months and 48 months postoperatively, their metastases being apparent at the time of the first operation in one patient and at 14 months postoperatively in the other patient.
Discussion
The clinical characteristics of our patients were very similar to those reported in the literature [1, 2, 6, 7, 9, 10, 13] in age, sex, functional status, type of symptoms, and duration of symptoms. Thus, adrenocortical carcinoma is more frequent in females (sex ratio 2:3 in our series) and its maximal frequency of occurence is in the 40th year. We have observed, in agreement with others [6, 7, 9], that functional tumors are about three times more frequent in female patients. The most frequent presentation is Cushing’s syndrome isolated or more often associated with virilizing features [1, 2]. Non-functional tumors are more frequent in men, who are, in our series as in others [7, 9], 10 years older than women.
Metastases at the time of diagnosis were found in 24% of our
patients. In other series metastases occurred in 50% to 70% patients [4, 6, 7, 8, 9]. This could be reflective of an earlier diagnosis in more recent years. Our study shows that curative resection for patients with local or regional disease was asso- ciated with a 5 year actuarial survival rate of 45% and this compares favorably to results of other reports (Table 3). The 35% 5 year survival demonstrated in patients with regional disease is encouraging and could be related to performing extensive complete resection in patients with stage III tumors. Our study confirms [5] that resection of local recurrence sub- stantially improves survival which becomes almost similar to that encountered after a first resection. All of our patients who were operated on for left-sided recurrence did not have system- atic nephrectomy at the first operation. Although we could not demonstrate a prolongation of survival due to nephrectomy, we thought that it might decrease the incidence of recurrence because it facilitates a greater lymphadenectomy and wide en bloc resection of the tumor. Resection of primary tumors in our patients with stage IV disease has been very disappointing (9 out of 10 died within 4 months) and the surgery even seemed to have accelerated the cancer dissemination in some patients. Survival rates from 12 months to 24 months have been reported in patients having simple open biopsy [9] or patients receiving no treatment.
Our search for prognostic factors has not been very decisive. Similar to others series [7, 9], the characteristics of our patients and of their tumors appeared not to be prognostically valuable. However, because of the small number of patients in some groups we must be very careful before reaching definitive conclusions. Although right adrenal tumors were more fre- quently associated with metastases in our study, the survival rate of patients with these lesions among the patients undergo- ing curative resection was not different from that of patients with left adrenal tumors. Although a larger size (>5 cm) and a weight >100 gm [11, 15] or >150 gm [16] are generally consid- ered as the main criteria for malignancy, we have observed very malignant small tumors. The main problem with a small tumor (i.e., <3-5 cm and <30-50 gm) is to recognize its malignancy. Flow cytometric DNA measurement of tumor cells could be helpful [17]. We have not studied the rate of mitoses, which could be a good indicator of poor prognosis for malignant tumors [16, 18].
Although, as in others reports [3, 14, 24], there was no clear overall prolongation of survival in patients receiving OP’DDD. However, in our study 4 patients with metastases demonstrated an impressive decrease in tumor size and long survivals, ranging from 25 months to 61 months, after occurrence of metastases. These rare observations have also been found in other reported cases [19-23]. Luton and associates [24] have reported that among 59 patients receiving OP’DDD, 8 patients demonstrated an impressive reduction of their metastases with long survivals up to 96 months. Van Slooten and coworkers [25] suggested that response of metastases to OP’DDD was related to the serum level of OP’DDD. In case of non-response to OP’DDD, other chemotherapy must be attempted as some favorable results have been reported with cisplatinum [26, 27] and recently with suramin [28]. Like Luton and associates [24], we believe that because of our inability to predict patient response it is advised to try adjuvant chemotherapy systemat-
| Author/year/(reference) | No. of pts. | No. undergoing curative resection | Mean survival (mos) | Actuarial 5 year survival (%) Curative Overall resection | |||
|---|---|---|---|---|---|---|---|
| Overall | Curative resection | Non- curative resection | |||||
| Greenberg 1978 (8) | 23 | 10 | - | - | - | - | 50 |
| Didolkar 1981 (4) | 42 | 16 | 30.5 | 71 | 8-11 | 24 | 62 |
| Nader 1983 (6) | 77 | 35 | - | - | - | 30 | - |
| Henley 1983 (7) | 62 | 31 | - | 25-28 | 12 | 16 | 32 |
| Cohn 1986 (9) | 47 | 13 | - | 60 | 27 | - | - |
| Chapuis 1991 | 41 | 31 | 20.6 | 44 | 6 | 35 | 45 |
ically either pre-operatively or postoperatively in large con- trolled trials.
Résumé
Au cours des douze dernières années, 41 patients (29 femmes et 12 hommes) d’un âge moyen de 42 ± 17 ans, porteurs d’un cortico-surrénalome malin ont été opérés à l’Hôpital Cochin. 7 d’entre eux ont été réopérés pour une récidive locale après un intervalle moyen de 22 mois. 80% de ces tumeurs étaient sécrétantes et 20% non sécrétantes. Une adrénalectomie et une cellulo-lymphadénectomie ont été réalisées chez tous les pa- tients. En outre, 13 patients (32%) ont subi une résection élargie en raison d’une extension néoplasique, ce qui a été également le cas des 7 patients réopérés. La mortalité opératoire a été de 4% (2 sur 48 interventions). 24 patients sont décédés de leur cancer dans un délai moyen de survie de 22 mois (extrèmes 2 et 86 mois) et 35 patients (35%) sont encore vivants, 4 d’entre eux avec des métastases, avec un délai moyen de survie de 51 mois. L’exérèse jugée curative chez 31 patients, que la tumeur soit localisée (n = 21) ou régionale (n = 10) correspond à une survie actuarielle à 5 ans de 45%. La survie actuarielle à 5 ans pour les patients réopérés d’une récidive a été de 33%. Un seul des 10 patients porteurs de métastases et dont les métastases avaient régressé sous l’effet de l’OP’DDD est vivant 2 ans après l’opération. Les 9 autres patients sont décédés 3 à 4 mois plus tard, comme si la résection avait accéléré le processus évolutif. Nous avons noté que les caractéristiques des patients et de la tumeur n’influençaient pas significativement le pronostic. Toutefois bien qu’il n’y ait pas eu de prolongation significative de la survie chez les patients traités par l’OP’DDD, 4 patients porteurs de métastases survenant dans l’évolution de leur maladie, ont toutefois montré une réduction tumorale significa- tive sous l’effet de l’administration d’OP’DDD, et correlative- ment une prolongation du délai de survie. Ces patients répon- dant à l’OP’DDD sont essentiels à reconnaître et à étudier.
Resumen
En los últimos 12 años se operaron 41 pacientes (29 mujeres y 12 hombres) con edad promedio de 42 ± 17 años con carcinoma adrenocortical en el Hospital Cochin de París. Siete fueron reoperados por recurrencia local después de un intervalo de 22 meses. Ochenta por ciento de los tumores exhibió actividad secretora y 20% no presentó tal actividad. Se realizó adrena- lectomía y linfadenectomía en la totalidad de los pacientes. Trece (32%) fueron sometidos a resección extensa debido a
cáncer invasivo; el mismo procedimiento fue mortalidad oper- atoria fue 4% (2/48). Veinticuatro pacientes murieron de cáncer con una sobrevida promedio de 22 meses (2-86 meses) y 15 pacientes (37%) estaban todavía vivos, 4 de ellos con metásta- sis, con un período promedio de sobrevida de 51 meses. La resección curativa para los 31 pacientes con enfermedad local (n = 21) o regional (n = 10) dió como resultado una tasa actuarial de sobrevida a 5 años de 45%. La tasa actuarial de sobrevida a 5 años para los pacientes reoperados fue 33%. Sólo uno de los 10 pacientes con metástasis, quien exhibió respuesta impresionante a OP’DDD (Mitotane), estaba vivo 2 años después de efectuada la operación. Los otros 9 pacientes murieron dentro de los 3-4 mese siguientes a la operación. Desde el punto de vista de pronóstico no encontramos carac- terísticas del paciente ni del tumor con valor significativo. No se demostró prolongación significativa de la sobrevida en los pacientes que recibieron OP’DDD. Sin embargo, 4 pacientes con metástasis aparecidas en el curso de su enfermedad exper- imentaron una respuesta impresionante con OP’DDD y una sobrevidad relativamente larga.
Acknowledgment
We thank Professor J.P. Luton for his assistance and for the medical care he has provided for many patients presented in this report.
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Invited Commentary
Jon A. van Heerden, M.D.
Department of Surgery, Mayo Clinic, Rochester, Minnesota, U.S.A.
Adrenocortical carcinoma (ACC) remains a relatively rare (41 patients treated over a 12-year period) tumor, with a continuing poor long-term prognosis. In the author’s experience, patients undergoing resection for localized/regional disease survived for an average of 44 months. Icard and colleagues share with us the frustration of the surgical community when faced with a patient with ACC. Although their data reiterates much of what is well known regarding this malignancy, they provide for all of us some data worthy of note and worthy of analysis of current practice in the management of ACC. The most striking of these data are:
1. They report a patient with a 3.0 cm in diameter tumor which is the smallest ACC I am aware of. This has important implications in the management of patients with incidentally discovered adrenocortical tumors.
2. Our French colleagues are seemingly more aggressive in the extent of operation for these patients. Fifteen of the 41 patients underwent nephrectomy, although the kidney was invaded by tumor in only 4 of the 15 patients. This approach, the authors suggest, allows for a more extensive regional lymphadenectomy. In addition, to facilitate tumor removal, a number of patients underwent partial pancreatectomies, hepatic
lobectomies, intestinal resections, and lateral resections of the inferior vena cava. Although this aggressive stance is not universally accepted currently, the authors’ actuarial 5-year survival rate of 45% for patients with stage I, II, and III disease is admirable.
3. Ten of their patients underwent adrenalectomy depsite the pre-operative knowledge of stage IV disease. Operating on such patients is, by and large, of minimal benefit as evidenced by the death of 9 of the 10 patients within 2 months of operation.
4. Adjuvant therapy with mitotane (OP’DDD) did not im- prove patient survival. It is becoming increasingly apparent that despite earlier, somewhat more optimistic reports, the efficacy of this adjuvant modality needs to be seriously questioned today. This has certainly been our institutional experience.
5. The authors operated upon 7 patients for recurrent disease. In this small group of patients, the actuarial 5-year survival was 33%. With the current lack of effective chemotherapy, this aggressive surgical approach is particularly noteworthy.
6. As in most other reports on this subject, the only prognos- tic factor of any significance was the presence of stage IV disease. Patient survival was unrelated to patient age or sex, function, size, or site of the tumor. All patient deaths were due to recurrent disease.
This is an honest appraisal of the surgical treatment of ACC in the year 1992. For the future, we need to concentrate on methods of earlier diagnosis and on the evaluation of newer adjuvant modalities such as cis-platinum and suramin, which need to be employed in larger series of patients.