ONCOLOGY
Oncology 1997:54:490-496
Adrenocortical Carcinoma: Experience in 45 Patients
Luisa Barzona Francesco Falloa Nicoletta Soninoª Otello Danieleb Marco Boscaroa
ª Division of Endocrinology, Institute of Semeiotica Medica. University of Padova and
b Division of Oncology, City Hospital, Padova, Italy
| Key Words | Abstract |
| Adrenocortical carcinoma | Forty-five patients with adrenocortical carcinoma (13 nonfunctioning and 32 |
| Chemotherapy | functioning carcinomas) were retrospectively studied. Five-year survival rate |
| Mitotane | was 29% overall; for patients at stage I-II (n = 15) it was 70%, and for patients at stage III-IV (n = 30) it was 12%. In patients given mitotane + chemotherapy survival rate was similar to that observed in patients given chemotherapy alone, and significantly longer than in patients given mitotane alone (p < 0.05). There were no differences in disease-free interval and survival between adjuvant mitotane and no treatment. Optimization of therapeutic protocols in addition to early recognition may improve prognostic aspects of this type of malignancy for which treatment outcome is still unsatisfactory. |
| Survival |
Introduction
Adrenocortical carcinoma is an extremely rare type of tumor with an annual incidence estimated at 0.5-2 cases per million per year [1-6]. It accounts for 0.2% of cancer- related deaths [3, 7], and represents 0.02% of all cancers [6]. The diagnosis is often difficult and delayed, mainly as a result of nonfunctioning forms, and prognosis is poor, with median survival reported to be less than 2 years [8- 10]. The unresponsiveness of the tumor to most chemo- therapeutic agents adds to the poor overall survival. Because of the low prevalence, information about its nat- ural history, prognostic factors and the effects of therapy is limited. To our knowledge, no extensive studies on these issues have been reported so far from Italy. Thus, we decided to examine retrospectively a relatively large series of patients with adrenocortical carcinoma, all referred to a single center.
Patients and Methods
Fourty-five patients (26 females and 19 males; median age 40 years, range 17-75 years) with adrenocortical carcinomas were referred to the Division of Endocrinology of the University of Pa- dova from 1978 to 1995. Part of the sample was described in a pre- vious review [11]. Patients underwent clinical, radiologic, and hor- monal evaluation. They were considered to have functioning tumors on the basis of the clinical picture and abnormal hormone levels. Staging of the disease was done according to the Surveillance. Epide- miology, and End Results (SEER) classification [12], which we slight- ly modified. Stage I refers to tumor <5 cm in size and stage II to tumor >5 cm in size, confined to the adrenal gland with no evidence of local or distant spread. Stage III refers to direct extension of tumor into adjacent tissues or organs, including regional lymph nodes. Stage IV refers to tumor with distant metastases. Thus, at variance with the SEER classification, local disease was classified in two stages according to tumor size.
Tumor response to treatment was evaluated according to WHO criteria [13]. A complete response was defined as the disappearance of all clinical evidence of tumor for a minimum of 4 weeks. Partial response involved a ≥ 50% reduction of all measurable tumor for a
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minimum of 4 weeks. Stable discase was defined as a >25% but <50% reduction of all measurable tumor for at least 4 weeks. Pro- gressive discase was defined as a ≥ 25% increase in the size of any measured lesion or the appearance of new lesions. Survival periods were calculated from the time of diagnosis to the time of death.
Diagnosis of malignancy was confirmed by histological examina- tion following the criteria reported by Weiss et al. [14].
Hormonal Evaluation
Endocrine evaluation consisted of plasma cortisol at 8 a.m. and 6 p.m. in baseline conditions and after low-dose (1 mg overnight and/ or 2 mg/day for 2 days) and high-dose (8 mg/day for 2 days) dexa- methasone suppression tests, plasma ACTH, dehydroepiandroste- rone-sulfate (DHEA-S), 17a-hydroxyprogesterone, testosterone, an- drostenedione, 17ß-estradiol, supine and upright plasma renin activ- ity (PRA) and plasma aldosterone, 24-hour urinary free cortisol, 24- hour urinary aldosterone and 24-hour urinary catecholamines. Plas- ma and urinary cortisol was measured with a radioimmunoassay (RIA) kit from Diagnostic Products (Los Angeles, Calif.). PRA, plas- ma and urinary aldosterone with RIA kits from Sorin (Vercelli, Ita- ly), plasma ACTH with a two-site immunoradiometric assay, sup- plied by Euro-Diagnostic (Amsterdam, The Netherlands), DHEA-S with a kit from BioRad Labs (Milano, Italy), plasma 17a-hydroxy- progesterone, testosterone and 17ß-estradiol with RIA kits from Diagnostic System Laboratories (Webster. Tex.), and androstene- dione with a RIA kit from Medical Systems (Genova, Italy). Urinary catecholamines were measured with HPLC using an electrochemical detector. Intra- and interassay coefficients of variation for all above- mentioned assays were below 8 and 12%, respectively.
Imaging Evaluation
Most patients underwent abdominal sonography and computed tomography (CT) with intravenous contrast medium. Magnetic reso- nance imaging (MRI) was performed in 7 patients. Adrenal scinti- scan with 75Sc-selenomethylnor-cholesterol was performed in 10 patients.
Treatments
Thirty-five of 45 patients (78%) underwent surgical removal of the tumor with at least total adrenalectomy. Complete resection was possible in 18 cases, while in the remaining patients maximal debulk- ing of tumoral mass was pursued. Twenty-seven patients received mitotane (op’-DDD, Lysodren, Bristol Myers Squibb) therapy at doses of 4-8 g daily. The median duration of treatment was 8 months (range: 1-36 months). Cytotoxic chemotherapy, cither as a single agent or as a combination regimen, was given to 22 patients. The following compounds were employed: cisplatin, vincristine. 5-fluoro- uracil, Adriamycin, etoposide, and cyclophosphamide. Twelve out of 22 patients were given mitotane as an additional treatment. Three patients received palliative radiotherapy.
Statistics
Comparisons between variables were carried out with the Pcar- son x2 test and the Kruskal-Wallis test, as appropriate. Cumulative disease-free interval and survival rates were calculated with the Kaplan-Meier method [15] and compared with the Cox-Mantel log- rank test [16]. Relationships were investigated by calculating correla- tion coefficients. A p < 0.05 was considered significant.
Results
Clinical and Hormonal Characteristics of Disease
The distribution of patients according to sex and age showed a prevalence of females with a female:male ratio of 2:1 and a peak of incidence in the 5th decade. The over- all median age at diagnosis was 40 years (range: 17-75 years). The median age tended to be higher in males (44 years; range: 18-75 years) than in females (36 years; range: 17-67 years). Thirteen patients (29%) had a non- functioning tumor, and 32 (71%) had a functioning tumor. Nonfunctioning tumors were more common in males and at older age (median 48 years; range: 18-75 years), while functioning tumors were more frequent in females and in younger subjects (median 39 years; range: 17-63 years). The female/male ratio was 2.6 in patients with functioning tumors, and 0.3 in those with nonfunc- tioning tumors.
Time from initial symptoms to diagnosis was similar in functioning and nonfunctioning tumors, varying from 1 to 13 months (median 5 months). Main symptoms at diagnosis in patients with nonfunctioning carcinomas were abdominal pain (90%) associated with fever and fatigue (30%), profuse sweats (20%), hypertension (20%), and loss of weight (20%). In an asymptomatic patient the tumor was found incidentally during sonography for liver disease. Clinical presentation of the 32 functioning tu- mors was Cushing’s syndrome in 21 cases (66%), Cush- ing’s syndrome and virilization in 5 (16%), virilization in 4 (12%), Cushing’s syndrome and feminization in 1 (3%), and hyperaldosteronism in 1 (3%). Main symptoms at diagnosis were those of the associated clinical syndrome. Patients with Cushing’s syndrome showed elevated levels of plasma and urinary free cortisol, lack of circadian rhythm of plasma cortisol, lack of suppression with high- dose dexamethasone, no response to ACTH or ovine CRH stimulation tests, and low ACTH levels. Androgens were very high in patients with virilizing tumors, and estrogens in the case of feminization. Urinary catechol- amines were normal in all cases. Interestingly, a patient who presented with severe hypertension, hyperaldoste- ronism and suppressed PRA developed over time corti- sol-secreting metastases associated with Cushing’s syn- drome. Six patients had nonfunctioning metastases of a primary functioning tumor.
Twenty-six out of 45 patients (58%) had metastases at diagnosis. The most common sites of tumor dissemina- tion were lung (67%), liver (52%), bone (32%), kidney (27%), caval vein (9%), pancreas (9%), contralateral adre- nal (9%), iliac vein (4%), and psoas (4%).
| Group | Patients | Mean age years | Sex F/M | Size cm | Functioningi non-functioning | Median DFI months | Median survival months |
|---|---|---|---|---|---|---|---|
| Adjuvant mitotane | 7 | 35 ± 4 | 5/2 | 11.2 ± 1.0 | 3/4 | 8 (4-54) | 24 (6-56) |
| No treatment | 11 | 49 ± 4 | 7/4 | 10.1 ± 1.6 | 8/3 | 13 (4-68) | 54 (5-104) |
F = Female: M = male: DFI = discasc-free interval.
| Patients | Mean age years | Sex F/M | Size cm | Functioning' non-functioning | Responses n % | Median survival months | ||
|---|---|---|---|---|---|---|---|---|
| Mitotane | 11 | 40 ± 3 | 10/1 | 11.2 ± 1.3 | 11/0 | 2 | 18 | 14 (2-64) |
| Chemotherapy | 10 | 51 ± 6 | 1/9 | 11.8 ± 1.7 | 0/10 | 0 | 0 | 16.5 (5-108) |
| Chemotherapy + mitotane | 12 | 36 ± 4 | 9/3 | 10.5 ± 1.0 | 12/0 | 2 | 17 | 31 (11-104)* |
F = Female: M = male: * Chemotherapy + mitotane vs. mitotane: p<0.05, by log-rank test.
Morphologic and Morphofunctional Characteristics In 36 of our patients (80%) adrenal disease was found at abdominal sonography. CT scan was performed in all our patients, often as further evaluation after abdominal sonography. Mean tumor size by CT scan was 11.1 ± 0.6 cm (range: 4-21 cm), and was similar in functioning (11.2 ± 0.7 cm; range: 5-21 cm) and nonfunctioning (11 ± 1 cm; range: 4-18 cm) carcinomas. A significant corre- lation between CT and sonography measurements (r = 0.96, p < 0.01) of the diameter of the mass was observed. Magnetic resonance imaging showed a large mass with unhomogeneous intensity on T1-T2-weighted images in 4 cases, and hyperintensity compared to the liver on T2- weighted images in 3 cases. Sixteen carcinomas (36%) involved the left adrenal, 27 (60%) involved the right adrenal, and 2 (4%) involved both adrenal glands.
The adrenal scintiscan demonstrated a lack of bilateral gland visualization in 2 cases of a functioning carcinoma, a prevalent uptake by the tumor with visualization of the contralateral normal gland in 2 functioning tumors, and a decreased or absent radiocholesterol uptake by the af- fected gland with a normal contralateral uptake in 6 non- functioning carcinomas.
CT-guided fine-needle biopsy was performed in 5 pa- tients. It showed a cytologic pattern of adrenocortical neo- plasia in 2 cases and was strongly suggestive of malignan- cy in 3.
Staging
According to the staging system, I patient (2%) at diag- nosis was at stage I, 14 (31%) were at stage II, 4 (9%) at stage III, and 26 (58%) at stage IV. No percentage differ- ence in tumor stages was observed between functioning and nonfunctioning carcinomas at initial presentation.
Histopathology
Tumor size ranged from 4 to 21 cm, with a median of 11 cm, median weight 980 g, range 168-2,200 g. Nuclear grade III-IV was present in 90% of cases. Mitotic rate of >5/50 high power fields was found in 75% of cases, atypi- cal mitoses in 67%, clear cells constituting ≤25% of the tumor in 86%. The architecture was predominantly dif- fuse in 58% of cases, necrosis was present in 89% of cases, venous, sinusoidal or capsular invasion in more than 80%. The immunohistochemical study of 8 carcinomas showed extensive vimentin staining in all cases, but none was keratin-positive. Among neuroendocrine markers, only synaptophysin and neuron-specific enolase were ex- pressed in one carcinoma.
Evaluation of Treatment and Survival
Three patients with very advanced disease died within 3 months after surgery. Seven patients with localized or regional disease before surgery (3 functioning and 4 non- functioning tumors), after complete adrenalectomy, were
treated with mitotane as adjuvant: 5 patients were free of disease at last follow-up (range: 5-54 months after sur- gery) and 2 developed metastases (disease-free interval of 4 and 8 months), 1 of whom died 24 months after diagno- sis. Eleven patients who underwent complete adrenalecto- my for localized or regional disease (8 functioning and 3 nonfunctioning) were given no medical treatment: 3 patients were free of disease at last follow-up (range: 4-68 months after surgery) and 8 developed metastases (dis- ease-free interval of 8-40 months), 5 of whom died during follow-up (survival: 15-104 months). Results are summa- rized in table 1. Five patients, including 1 patient pre- viously treated with adjuvant mitotane and 4 never treated before with medical therapy, underwent repeat surgery for local recurrence or metastases on the contra- lateral adrenal gland, liver and lymph nodes. They had an average survival time of 73 months (23 months on aver- age after the initial operation and 50 after reoperation). Thirty-three patients at stage III-IV, including the 10 patients who developed metastases during adjuvant mito- tane or no treatment, underwent medical therapy (ta- ble 2). Eleven of these patients (24%) were treated with mitotane alone, 12 (27%) with mitotane associated with conventional chemotherapy, and 10 (22%) with chemo- therapy alone. None of the treatments was effective in inducing complete regression of disease, but they led to a partial regression in 4 cases. Two of these patients treated with mitotane alone showed tumor regression lasting 12 and 21 months and a survival of 64 and 40 months, respectively. The other 2 patients, treated with mitotane plus etoposide, Adriamycin and cisplatin, were alive at last follow-up (duration of response: 16 and 12 months). Mitotane was effective in the control of clinical and bio- chemical hypercortisolism in all patients with functioning tumors.
At the completion of this study, 32 out of 45 patients (71%) had died, the majority because of complications of metastatic disease, while 13 (29%) patients were still alive: 8 free of disease and 5 with metastases. Their mean survival time was 31 months (range: 4-74 months).
Median survival of patients at stage I-II was 34 months (range: 13-104 months), while at stage III-IV it was 13 months (range: 2-108 months). Overall median survival was 16 months. The 1-year overall survival rate was 71% (93% in stage I-II and 58% in stage III-IV), and 5-year survival rates were 29% overall, 70% in stage I-II patients, and 12% in stage III-IV patients. Survival data analyzed according to stage demonstrated that patients at stage I-II had a significantly longer survival than patients at stage III-IV (p<0.005; fig. la). Among 18 patients who
100
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underwent complete tumor resection, the median disease- free interval was 13 months (range: 4-68 months). The 1-year overall disease-free survival rate was 24%, and the 5-year overall disease-free survival rate was 11% (fig. 1b). Adjuvant mitotane neither influenced disease-free inter- val nor survival of these patients (fig. 2a, b). The distribu- tion of age and tumor size was not significantly different between patients treated with adjuvant mitotane and those not treated (p = 0.42 for age, and p = 0.34 for size, by the Kruskal-Wallis test). Similarly, sex and functional sta- tus distribution between the two treatment groups was not significantly different (p = 0.21, and p = 0.06, respective- ly, by Pearson x2 test). In patients given mitotane + che- motherapy survival rate was similar to that observed in
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patients given chemotherapy alone, and significantly lon- ger than in patients given mitotane alone (p < 0.05, by log-rank test). Sex, age, functional status and mitotic index at histology did not show any influence on recur- rence or survival rates.
Discussion
Clinical characteristics of our patients are similar to those generally reported in the literature [17]. Adrenocor- tical carcinoma was more common in females, with a higher frequency of occurrence in the 5th decade of life. Functioning tumors were more frequent in females of pre-
menopausal age, while nonfunctioning tumors were more frequent in males and occurred 9 years later than in females, suggesting a pathogenetic role of estrogens in functioning tumors [18].
The diagnosis of adrenocortical carcinoma is difficult and often delayed, when the tumor is at an advanced stage or associated with overt clinical syndromes of hormone hypersecretion. Indeed, a high percentage of our patients (67%) was at stage III-IV at diagnosis. As in other series, the most common clinical presentation in functioning carcinomas was Cushing’s syndrome alone or in associa- tion with virilization in females, while in patients with nonfunctioning tumors the main symptom was abdomi- nal pain. In individual patients with functioning tumors, clinical findings may change during the progression of the disease, reflecting the potential ability of neoplastic cells to vary the secretion of one or more corticosteroids. In fact, several cases had a phenotypical expression of metas- tases different from that of the primary adrenal tumor. In terms of instrumental diagnosis, characterization of ma- lignant adrenal tissue by MRI or adrenal scintigraphy was insufficient, given the high false-negative result rate [19, 20].
At stage I-II, surgery is considered the mainstay of treatment and provides the only chance of cure [9, 21- 25]. In our patients with local disease, surgical removal of the mass was associated with a 5-year actuarial survival rate of 70%, confirming data of others [21-25]. We observed recurrence of disease in 7 of 18 cases (35%) a few months after apparently curative surgery. Thus, mi- crometastases are probably present at early phases of the disease. A surgical approach in patients at stage IV has been reported to accelerate cancer dissemination or in- crease mortality, and is associated with a high periopera- tive mortality [23]. A high percentage of our patients had already metastases at diagnosis, and this did not make surgical treatment with curative aim possible. In spite of the presence of metastases, it appeared, however, useful to remove the primary mass to attenuate symptoms of ste- roid overproduction of functioning tumors and to reduce the mass of neoplastic tissue for subsequent chemothera- py. Repeated surgery of recurrences was performed in few cases, but an aggressive therapeutic approach with exten- sive surgery associated with mitotane and/or convention- al chemotherapy led to a significant improvement of sur- vival in 3 of our 5 patients, a proportion reported by oth- ers [23, 25].
On the whole, the results of drug therapy have been rather disappointing in our series, but in agreement with the literature [9, 10, 17, 26]. No different conventional
chemotherapy led to complete regression of metastases, casting doubt on its truc effectiveness. Only the associa- tion of mitotane with a cisplatin-containing chemothera- py (mitotane plus etoposide, Adriamycin and cisplatin) induced a partial response in 2 cases, with relatively low toxicity [27]. Treatment with mitotane alone was not effective in prolonging overall survival in our cases, con- firming previous data [9, 10, 21, 28-31]. Reports of effica- cy of mitotane in patients at stage III-IV are discordant. While some authors found a reduction of tumor size with an increase in survival and even long-term remission in 20-60% of cases [8, 32-41], other studies failed to docu- ment any improvement in survival [9, 23, 29, 30, 42, 43]. The variable efficacy of mitotane may depend on differ- ent dosages and serum levels of the drug, different stages of the treated patients, and different response criteria used. Two out of our 11 patients (18%) at stage IV, treated with mitotane alone 6-8 g/day for 6 months to 3 years, achieved a partial response with a significant reduction of tumoral mass and a relatively long survival. Moreover, a longer survival of patients given mitotane plus chemo- therapy in comparison with those given mitotane alone was observed. This may provide a clinical confirmation of the mitotane-mediated enhancement of adrenal cytotox- icity by chemotherapeutic agents shown in vitro [44]. The
role of mitotane as adjuvant therapy for adrenocortical carcinoma is controversial [9, 29, 30, 39-41, 46]. Our findings, as those of others [29, 30, 41, 45, 46]. indicate that adjuvant mitotane is not beneficial in terms of either a disease-free interval or survival in patients with local- ized or regional adrenocortical cancer. However, because of the beneficial effect on the control of hormone hyperse- cretion [47]. mitotane may be employed as a tool to con- trol endocrine syndromes of functioning tumors.
In our series. the 1-year survival rate was 71% and the 5-year survival rate was 29%, as in the majority of pre- vious studies with the 5-year survival rate ranging be- tween 20 and 30% [9. 10, 21, 29, 30]. The most important prognostic factor appears to be the tumor stage, which makes diagnosis at an early stage crucial. In addition to early recognition, optimization of treatment protocols and alternative therapeutic strategies are needed to im- prove the prognostic aspects of this disease.
Acknowledgements
This work was supported by Grant No. 568/01/95 from Regione Veneto. Giunta Regionale. Ricerca Sanitaria Finalizzata, Venezia. Italy.
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