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WORLD Journal of SURGERY @ 2001 by the Société Internationale de Chirurgie
Adrenocortical Carcinoma: Is Prognosis Different in Nonfunctioning Tumors? Results of Surgical Treatment in 31 Patients
Gennaro Favia, M.D., Franco Lumachi, M.D., Davide F. D’Amico, M.D.
Endocrine Surgery Unit, Department of Surgical and Gastroenterological Sciences, University of Padua, School of Medicine, Via Giustiniani 2, 35128 Padova, Italy
Abstract. From 1980 to 1998 a series of 265 patients with adrenal tumors underwent surgery, with an adrenocortical carcinoma found in 31 (11.7%). Altogether, 17 (54.8%) patients (group A) had Cushing syndrome (n = 15) or virilization (n = 2), and 14 (45.2%) patients (group B) had nonfunctioning adrenal tumors. Tumor staging was as follows: (groups A/B): stage I, n = 5 (3/2), stage II, n = 14 (9/5), stage III, n = 5 (1/4), stage IV, n = 7 (4/3) patients. There were 12 (38.7%) men and 19 (61.3%) women (median age 51 years, range 25-73 years), and the size of the mass ranged from 3.5 to 20.0 cm (median 8.0 cm), with no differences (p = NS) between groups A and B. Two (6.4%) patients (stage IV) did not undergo surgery and received only palliative drug treatment; 6 (19.4%) were treated with debulking surgery; 15 (48.4%) had unilateral adrenalectomy; and 8 (25.8%) had an extended adrenalectomy. Eighteen (58.0%) patients underwent adjuvant postoperative mitotane treatment, and in 8 (25.8%) patients one or more reoperations for recurrence were required. Nine (29.0%) patients are still alive with a mean follow-up of 34 months; 22 (71.0%) died 2 to 60 months (median 20 months) after surgery. The overall 2- and 5-year survival rates were 62.1% and 10.3%, with no difference (p = NS) between groups A and B. The survival rates at the 1- and 3-year follow-ups were 90.3% and 32.3% (stages I and II) and 71.0% and 6.5% (stages III and IV). In conclusion, adrenocortical carcinoma remains a highly malignant tumor, and stage III-IV patients still have a poor prognosis; but nonfunctioning tumors do not seem to be more aggressive.
Adrenocortical carcinomas are rare tumors that account at au- topsy for 2.5 cases per million and represent only 0.2% of the deaths due to cancer [1, 2]. The cases reported are numerically limited; and because of the aggressive nature of the tumor there are few long-term follow-ups by which we can evaluate and com- pare the efficacy of a single treatment. The aim of this retrospec- tive study was to evaluate the results of surgery and adjuvant chemotherapy in patients with functioning and nonfunctioning adrenocortical carcinoma, the latter usually considered to have a poorer prognosis due to the delay in diagnosis.
Materials and Methods
From 1980 to 1998 a total of 307 patients underwent unilateral or bilateral adrenalectomy; among them 265 (86.3%) had adrenal tumors, which were malignant in 36 (13.6%) cases. Altogether, 5 (1.9%) were malignant phenochromocytomas, and 31 (11.7%) were adrenocortical carcinomas, of which 17 (54.8%) were func- tioning (group A) and associated with Cushing syndrome (n = 15) or virilization syndrome (n = 2). In 14 (45.2%) patients the tumor was nonfunctioning (group B), without any clinical or biochemical evidence of hypersecretion. The patient population consisted of 12 (38.7%) men and 19 (61.3%) women with an age ranging from 25 to 73 years (median 51 years). Three (8.3%) patients with Cushing syndrome were observed with a relapse of the disease following adrenalectomy elsewhere 15, 10, and 18 months prior, respectively. Two (6.4%) patients (group A), because of the extent of the tumor and the presence of multiple hepatic and pulmonary metastases, did not undergo surgery and received palliative drugs. Six (19.4%) patients, owing to extension of the tumor, were treated with debulking surgery at our institution (n = 3) or elsewhere (n = 3). In the others we performed 15 (48.4%) adrenal tumor excisions with resection of involved nodes in 6 (19.4%) patients and extended adrenalectomy in 8 (25.8%), of whom 4 also had hepatic resection and 4 had nephrectomy.
A group of 18 (58.0%) patients (stage I, 2; stage II, 10; stage III, 6)-6 with nonfunctioning cortical carcinomas and 12 with corti- sol- or androgen-secreting neoplasms-were treated with postop- erative (2-12 months after surgery) adjuvant chemotherapy using o,p’-DDD (mitotane) with an average dose of 2 to 5 mg/day, either alone or with cisplatin, doxorubicin, or cyclophosphamide, for a period of 2 to 18 months.
To evaluate statistical significance, the Student t-test was used. Values < 0.05 were considered significant.
Results
There was a significant difference in age between the men and the women (56.8 ± 14.6 vs. 45.5 ± 10.9 years) and between patients with functioning and nonfunctioning tumors (42.9 ± 13.1 vs. 59.3 ± 10.45 years). The size of the tumor ranged from 3.5 to 20.0 cm (median 8.0 cm) with no difference (p = NS) between groups.
This International Association of Endocrine Surgeons (IAES) article was presented at the 38th World Congress of Surgery International Sur- gical Week (ISW99), Vienna, Austria, August 15-20, 1999.
Correspondence to: G. Favia, M.D.
| Diagnosis | I (<5 cm) | II (>5 cm) | III (Locoregional and/or nodal extension) | IV (Distant metastases) | Overall |
|---|---|---|---|---|---|
| Nonfunctioning | 2 | 5 | 4 | 3 | 14 |
| Cushing syndrome | 3 | 7 | 1 | 4 | 15 |
| Virilizing syndrome | 0 | 2 | 0 | 0 | 2 |
| Total | 5 (16.1%) | 14 (45.2%) | 5 (16.1%) | 7 (22.6%) | 31 (100%) |
The staging is according to McFarlane [3] and Sullivan et al. [4].
| Indications for surgery | Type of reoperation | No. of cases | % |
|---|---|---|---|
| Solitary lung metastasis | Pulmonary lobectomy | 1 | 3.2 |
| Local recurrence | Excision | 5 | 16.1 |
| Local recurrence extended to the liver | Excision and liver resection | 3 | 9.7 |
| Hemorrhage | Drainage | 2 | 6.4 |
| Intrahepatic abscess | Drainage | 1 | 3.2 |
| 12ª | 38.6ª |
“Totals.
| Parameter | Pommier and Brennan 1992 [6] | Icard et al. 1992 [5] | Soreide et al 1992 [7] | Barzon et al. 1997 [8] | Khorram-Manesh et al. 1998 [9] | Harrison et al. 1999 [10] | Mean |
|---|---|---|---|---|---|---|---|
| Patients (no.) | 53 | 150 | 61 | 45 | 18 | 46 | 373 |
| Survival rate | 35% | 34% | 16%ª | 29% | 58% | 36% | 32% |
“Six-year survival.
The mass was localized in the right adrenal gland in 16 cases (51.6%) and in the left gland in 15 (48.4%). The staging at the time of the first operation according to MacFarlane [3] and Sullivan et al. [4] is reported in Table 1. None of the patients died during the perioperative period, nor did they undergo radi- ation therapy pre- or postoperatively. Four (6.4%) patients un- derwent one reoperation, and four underwent two reoperations (Table 2).
Nine patients (29.0%) (three from group B, six from group A) are still alive after an average follow-up of 34 months (range 6-66 months); 22 (71.0%) died after 2 to 60 months (median 20 months) following operation. The 2- and 5-year overall survival rates for patients who underwent surgery (n = 29) were 62.1% and 10.3%, respectively, with no significant difference between groups A and B (27.47 ± 17.80 vs. 24.07 ± 11.16 months; p = 0.567) or between men and women (25.28 ± 18.63 vs. 27.82 ± 12.77 months; p = 0.657). Survival duration for patients treated with adjuvant chemotherapy after surgery (stages I, 2; II, 10; III, 4; IV, 2) with respect to those who underwent surgery alone (stages I, 3; II, 4; III, 1; IV, 5) were 27.65 ± 17.64 vs. 21.0 ± 61 months (p = 0.332). The average survival of patients treated with extended adrenalectomy (20.75 ± 11.19 months) was less than for other operations (30.43 ± 14.63 months), but the difference was not statistically significant (p = 0.093), although in six cases the tumor was stage III or IV. The prognosis of patients with stage I and II disease was significantly better (p < 0.05) than that for patients in stage III or IV disease, with survival rates at 1, 2, and 3 years of 90.3%, 74.2%, and 32.35% (stages I and II) and 71.0, 29.0%, 6.5% (stages III and IV), respectively.
Discussion
Adrenocortical carcinomas are rare, highly aggressive tumors; and although they may produce hormones, in more than half of the cases they are asymptomatic. Some patients report weight loss, flank pain, or fever; but these nonspecific signs are described by fewer than 30% of patients and are directly related to the mass of the tumor [5].
No more than one-third of patients treated surgically for adre- nocortical carcinoma survive 5 years (Table 3), and survival is influenced by tumor size, the stage of the disease, and the extent of the excision [5, 6, 10]. In our experience patients treated by adrenal tumor excision alone did not have significantly longer survival than those treated by extensive surgery; and it should be noted that the latter all had stage III and IV lesions with a greater risk of recurrence. It seems that survival varies from 22% to 53% in patients with tumors >12 cm and <12 cm, respectively, even if other parameters (e.g., hemorrhage within the mass or mitotic activity) influenced the prognosis [10]. For others, the size and weight of the mass and the endocrine potential of the tumor are not significant prognostic factors [5]. The median survival of the women (28 months, range 6-60 months) was longer than that of the mean (24.5 months, range 4-66 months), but the difference was not significant (p = NS).
Surgical excision of the tumor is always the first step of treat- ment, with the exception of some patients with stage IV lesions for whom the treatment is palliative [10]. Not everyone agrees on the usefulness of chemotherapy with or without mitotane, stating that such treatment does not modify the duration of the disease-free
period [6, 11]. In fact, it seems that only 20% to 25% of the patients respond to mitotane, and careful titration of the drug is necessary to establish the most effective dosage [8]. For others, the use of mitotane as adjuvant therapy after extended adrenalectomy represents a particularly useful and in some cases absolutely necessary therapeutic regimen to the point of prescribing contin- uous administration because it can lead to long-term survival even in patients with stage IV disease [2, 9, 11].
All adjacent invaded organs should be resected while ensuring a functioning kidney on the contralateral side [2]. In the presence of hepatic and pulmonary metastases, extended adrenalectomy with liver or pulmonary resection may be performed, whereas extension to the inferior vena cava without thrombus requires segmental caval resection [2, 13-15].
Conclusion
Adrenocortical carcinomas seem to have variable biologic behav- ior, possibly depending on: (1) their histologic differentiation; (2) their size; (3) local invasiveness; (4) the extent of surgical excision; and (5) the efficacy of adjuvant chemotherapy. We did not observe any difference in aggressiveness between functioning and non- functioning tumors as we might have expected given the delay in the diagnosis of nonfunctioning ones. Indeed, it is difficult to establish the duration of the disease in patients with nonfunction- ing tumors also because these lesions are most frequently diag- nosed in stage III and IV. Despite the improved diagnostic ap- proach to the study of adrenal incidentalomas, it does not seem, at least in our experience, that this has allowed an earlier diagnosis of adrenocortical carcinoma.
Résumé
Entre 1980 et 1998, 31 des 265 patients (11.7%) opérés d’une tumeur de la surrénale avait en fait un cancer. Dix-sept (54.8%) patients (Groupe A) avaient un syndrome de Cushing (n = 15) ou de virilisation (n = 2) alors que 14 (45.2%) patients (Groupe B) avaient une tumeur de la surrénale non fonctionnelle. Le nombre de patients dans chaque catégorie de staging (Groupes A/B) a été comme suit: stade I = 5 (3/2), stade II = 14 (9/5), stade III = 5 (1/4), stade IV = 7 (4/3) patients. Il y avait 12 (38.7%) hommes et 19 (61.3%) femmes (médiane d’âge 51 ans, extrêmes 25-73) et la taille de la masse allait de 3.5 à 20 cm (médiane: 8 cm), avec aucune différence statistiquement significative (p = NS) entre les groupes A et B. Deux (6.4%) patients (Stade IV) n’ont pas été opérés et n’ont reçu qu’un traitement médical à titre palliatif, alors que six (19.4%) ont été traités par une chirurgie de réduction tumorale, 15 (48.4%) par surrénalectomie unilatérale et huit (25.8%) par une surrénalectomie étendue. Dix huit (58.0%) patients ont eu un traitement postopératoire adjuvant par du Mitotane et chez huit (25.8%) patients, une ou plusieurs reopérations pour récidives ont été nécessaires. Neuf (29.0%) patients sont toujours en vie avec un suivi moyen de 34 mois, alors que 22 (71.0%) sont décédés 2 à 60 mois (médiane 20 mois) après chirurgie. La survie globale à 2 et à 5 ans a été de 62.1% et de 10.3%, avec aucune différence significative (p = NS) entre les deux groupes A et B. Le taux de survie à l et à 3 ans a été de 90.3% et de 32.3% (Stades I et II) et de 71.0% et de 6.5% (Stades III et IV). En conclusion, le cancer de la surrénale reste une tumeur hautement maligne; le pronostic des patients de Stades III-IV est
mauvais, mais les tumeurs non fonctionnelles ne semblent pas être plus aggressives.
Resumen
En el periodo entre 1980 y 1998 se operaron 265 pacientes con tumores suprarrenales, entre los cuales 31 (11.7%) presentaron carcinoma adrenocortical. Diecisiete (54.8%) pacientes grupo A tenían Síndrome de Cushing (n = 15) o virilización (n = 2), en tanto que 14 (45.2%) pacientes (grupo B) tenían tumores no funcionantes. La estadificación tumoral fue la siguiente (grupos A/B): Estado I = 5 (3/2), Estado II = 14 (9/5), Estado III = 5 (1/4), Estado IV = 7 (4/3). Doce pacientes (38.7%) eran hombres y 19 (61.3%) mujeres (edad promedio 51 años, rango 25-73) y el tamaño de la masa tumoral osciló entre 3.5 y 20 cm (media 8 cm), sin diferencies (p = NS) entre el grupo A y el B. Dos pacientes (6.4%) en estado IV no fueron sometidos a cirugía y sólo recibieron drogas paliativas, 6 (19.4%) fueron tratados con cirugía de debultamiento, 15 (48.4%) con adrenalectomía unilateral y en 8 (25.8%) se practicó adrenalectomía ampliada. Dieciocho (58.0%) recibieron terapia adyuvante con Mitotane y en 8 (25.8%) se requirió una o más reoperaciones por recurrencia. Nueve (29.0%) pacientes están vivos, con un seguimiento promedio de 34 meses, y 22 (71.0%) murieron a los 2-60 meses (media de 20 meses) luego de la cirugía. Las tasas globales de supervivencia a 2 y 5 años fueron 62.1% y 10.3%, sin diferencia entre los grupos A y B. La supervivencia en el seguimiento de l y 3 años fue de 90.3% y 32.3% en los Estados I y II y de 6.5% en los Estados III y IV. En conclusión, el carcinoma adrenocortical sigue siendo un tumor de alta malignidad, los pacientes en estados III-IV todavía tienen un mal pronóstico y los tumores no funcionantes no parecen ser más agresivos.
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