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WORLD Journal of SURGERY @ 2004 by the Société Internationale de Chirurgie
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Andrenocortical Carcinomas: Twelve-year Prospective Experience
Libuse Tauchmanovà, M.D., Ph.D.,1 Annamaria Colao, M.D, Ph.D.,1 Luigi Antonio Marzano, M.D.,2 Lucianna Sparano, M.D.,3 Luigi Camera, M.D.,4 Annalisa Rossi, M.D.,1 Giovanna Palmieri, M.D.,1 Ettore Marzano, M.D.,2 Marco Salvatore, M.D., Ph.D.,4 Guido Pettinato, M.D., Ph.D.,3
Gaetano Lombardi, M.D., Ph.D.,1 Riccardo Rossi, M.D.1
1Department of Molecular and Clinical Endocrinology and Oncology, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy
2Department of Molecular and Clinical Endocrinology and Oncology, Section of Endocrine and General Surgery, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy
3Department of Anatomical Pathology and Cytology, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy
4Department of Biomorphological and Functional Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy
Published Online: August 19, 2004
Abstract. Adrenocortical carcinoma (AC) is a rare tumor with poor prog- nosis. Twenty-two patients (14 F, 8 M; age 22 to 59 years; median, 43 years) with AC were evaluated prospectively in a single center: tumor stage was I-II in 12 cases and III-IV in 10. The overall survival in our cohort was 41.6 ± 42 months; 16 subjects are still alive. Curative surgery was followed by longer survival than debulking or no surgery (p < 0.0001). The first relapse was highly predictive for further recurrences. Recurrent ACs were progres- sively more aggressive, and they occurred with variable but ever shorter intervals. At diagnosis, 14 patients (63.5%) presented with features of clear adrenocortical hyperactivity. Despite the absence of clinical signs of hor- monal excess, all other patients presented some abnormalities of steroid secretion. The most common clinical finding was a recent diagnosis of mod- erate-to-severe hypertension (68%), poorly controlled by pharmacological treatment, often associated with multiple cardiovascular risk factors. High mitotic rate and undifferentiated polymorph cellular pattern were associ- ated with worse prognosis. Response to treatments other than surgery (mi- totane chemotherapy) was better in patients treated early after the first surgery. In conclusion, curative surgery was the most effective treatment. Monitoring arterial pressure, endocrine parameters, and metabolic pa- rameters can be helpful for the early detection of AC recurrences.
Adrenocortical carcinoma (AC) is a rare tumor with poor progno- sis for which there is no known effective treatment other than sur- gical resection. The incidence has been estimated at 1.5 to 2 per million persons per year [1-3] with a mean survival of untreated tumors of 2.9 months [4], compared to that of surgically treated of 12 months [5]. In most previous studies, however, the disease was diagnosed at an advanced clinical stage with subsequent early re- currence and metastases after an apparently curative surgical treat- ment [6, 7]. More recently, better survival rates have been reported both in Europe and the USA, with a 5-year overall survival ranging between 38% and 60% [8, 9]. Improvement and more common use of imaging techniques, together with better supportive care may
have positive influence on the natural history of the disease. Fur- thermore, because some ACs are diagnosed incidentally in earlier stages of the disease [3, 10, 11], their possibly better outcome is a matter of debate. A large body of evidences indicates that histologi- cal features, early stage detection, and curative resection have a significant impact on the outcome of the disease [5, 12, 13]. Never- theless, the poor prognosis of AC is explained in part by its relative unresponsiveness to conventional chemotherapy and external irra- diation.
The clinical features of AC consist of either endocrine dysfunc- tion or symptoms related to an abdominal mass [14]. Mixed Cush- ing’s syndrome and virilizing syndrome due to overproduction of glucocorticoids and androgens is the most frequent endocrine manifestation in adults [12], whereas smaller, non-functioning AC may be asymptomatic [10, 15]. The histopathological evaluation of malignant adrenocortical tissue shows a heterogeneous phenotypic expression, suggesting that the difference in tumor behavior can be related to this heterogeneity [16, 17].
Most previous studies on AC have been carried out in a single institution or in very few institutions, and have included a small number of patients. There are a few larger single center or multi- center studies evaluating disease-specific survival and predictive factors [3, 5, 8, 9, 18]. Here we report a 12-year experience in a single university hospital center where the patients were diagnosed and treated by either medical or surgical treatment, or both. Clini- cal, biochemical, and endocrine features were analyzed, together with treatment efficacy and outcome.
Patients and Methods
Clinical Evaluation and Staging
Twenty-two patients with AC (14 women, 8 men 22 to 59 years of age; median age, 43 years) were referred to and followed at the
Department of Molecular and Clinical Endocrinology and Oncol- ogy at the University Federico II in Naples from 1991 to 2002. Only one patient included in this study had received a previous diagnosis of AC (in 1986 by R.R.). The clinical symptoms leading to AC di- agnosis were recorded. Staging of the disease was performed ac- cording to the criteria of McFarlan [4] as modified by Sullivan et al. [19]. Clinical and hormonal evaluations were performed quarterly in disease-free patients, and monthly during progression, whereas imaging studies were performed six-monthly in disease-free pa- tients and quarterly during disease progression. Prognostic factors including anemia, weight loss, and fever were also considered.
Imaging Techniques
Although some adrenal masses were detected by ultrasonography, the diagnosis was always confirmed by abdominal computed tomography (CT) scan. All CT scans were reviewed by a single radiologist (L.C.) to determine the size and radiological features of the tumors. Twelve patients additionally underwent adreno- cortical scintigraphy using [75Se]-6a-methyl-19-nor-cholesterol (Scintadren, Amersham Pharmacia Biotech, Amersham, The Netherlands). Images were obtained by crystal y-camera on days 4 and 7 after radiotracer injection.
Endocrine Evaluation
At diagnosis, the following studies were performed: serum cortisol (F) and plasma ACTH assay at 0800 and 2400 h (mean of at least two samples taken on different days), 24-hour excretion of urinary free cortisol (UFF), low-dose 2-mg DXM suppression test (orally, 0.5 mg four times a day for 2 days with measurement of serum cor- tisol and other steroids at 0800 h the following morning; UFF was also determined). To assess disease activity in the adrenal mass, the ratio of cortisol at 24.00 h vs. 08.00h (F% ratio, normal <50%), which indicates circadian rhythm abnormalities, was calculated as (F at 24.00/F at 08.00) × 100. Reference range for each variable was calculated as means ± 2 SD from 66 healthy controls. Circulating androgens including total testosterone (T), androstenedione (84), dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogester- one (17-OHP), estriol (E1), and 17ß-estradiol (E2) were also de- termined. Excess of 17-OHP alone has not been considered as an- drogen excess. All steroids were assayed by commercial kits that did not change throughout the study: F, T, E2 and DHEA-S, by Immu- lite, solid phase chemoluminescent enzyme immunoassay (DPC, Los Angeles, CA, USA), and 84, 17-OHP by RIA Diagnostic Sys- tems Laboratories (Webster, TX, USA). Normal ranges were as follows: F = 5-20 Mg/dl; 17-OHP = 10-200 ng/dl; 84 = 1-4 ng/ml; DHEA-S: 35-400 Mg/dl; T: 300-1000 ng/dl for men and 30-120 ng/dl for women. Conversion factors to SI units (nmol/l) were as follows: F = 27.6; 17-OHP = 0.0303; 84 = 0.035; DHEA-S = 0.027, and T = 0.0346.
Histopathologic Evaluation
Histopathologic evaluation of all tumor samples was performed in- dependently by two operators (L.S., G.P.). All carcinomas met Weiss’s histologic criteria (Weiss score, >4) [20, 21]. To confirm the origin of neoplastic tissue and discern malignancy, immunohis- tochemical staining was always performed for keratin (Menarini,
| Case no. | Age (year)/ gender | Tumor size (cm) | Staging | Values above the normal range |
|---|---|---|---|---|
| 1 | 59/F | 4 | I | 17OHP |
| 2 | 50/M | 16 | II | F, DHEAS, A4, T, E1, E2 |
| 3 | 41/F | 5 | I | T, A4, 17OHP |
| 4 | 22/M | 9.5 | II | F, 17OHP |
| 5 | 37/F | 15 | IV | F, A4, DHEAS, T |
| 6 | 39/F | 8 | III | F |
| 7 | 36/F | 11 | II | F, 17OHP, DHEAS |
| 8 | 51/F | 5 | III | F, T, DHEAS |
| 9 | 55/F | 12 | IV | F, A4, T, 17OHP |
| 10 | 33/F | 6 | II | F, A4, DHEAS, T |
| 11 | 59/M | 10 | IV | None |
| 12 | 43/M | 23 | IV | None |
| 13 | 52/F | 20 | IV | None |
| 14 | 45/F | 12 | II | F, A4, T, 17OHP |
| 15 | 54/M | 16 | II | None |
| 16 | 26/F | 10 | III | DHEAS, A4, T, E2, 17OHP |
| 17 | 42/F | 13 | II | F, DHEAS, A4, T, 17OHP |
| 18 | 50/M | 15 | III | None |
| 19 | 52/M | 25 | III | None |
| 20 | 32/M | 11 | II | F, DHEAS, T, E2, 17OHP |
| 21 | 44/F | 13 | II | None |
| 22 | 43/F | 10.5 | II | DHEAS, A4, T, E1, E2 |
F: cortisol; 17OHP: 17-hydroxyprogesterone; A4: androstenedione; DHEAS: dehydroepiandrosterone sulfate; T: testosterone; E1: estriol; E2: estradiol.
1/200), vimentin (Menarini, 1/200), epithelial membranous antigen (EMA) (ByoGenex, 1/100), CEA (Menarini, 1/500), and chromo- granin (ByoGenex, 1/50). Any degree of staining was considered “positive.”
Statistical Analysis
The statistical analysis was performed by means of the SPSS Inc. (Chicago, USA) package using nonparametric tests. The Mann Whitney U-test was used for comparing patients and controls. Data are reported as median and range. Statistical significance was set at 5%. Correlation analysis was made by measuring the Spearman co- efficient. Categorical variables were compared using the Pearson’s chi-square test. The Kaplan-Meier method was used to analyze the overall and disease-free survival during long-term follow-up. Over- all and recurrence-free survival was measured from the date of di- agnosis to the date of relapse, and was censored at the date of the last follow-up. The log-rank test was used to compare survival rates.
Results
Clinical Evaluation
Also in our experience, AC was more frequent in women with the F/M ratio of 1.75. Men were slightly older than women (46.7 ± 11 years vs. 42.7 ± 9.7 years, p = 0.4) and had significantly larger tu- mors (15.9 ± 6 vs. 10.4 ± 4.6 cm; p = 0.024). At diagnosis, 14 pa- tients (63.6%) had clear-cut adrenocortical hyperactivity. Non- functioning AC were also slightly but not significantly more frequent in men (62.5% vs. 21.4%, p = 0.15). The initial findings are summarized in Table 1. The most common clinical feature was a recently diagnosed moderate-to-severe hypertension, principally diastolic (68%) (Table 2), and poorly controlled by pharmacologi-
| Patients (n.) | Prevalence (%) | |
|---|---|---|
| Arterial hypertension | 15 | 68.2 |
| Cushing's syndrome | 11 | 50 |
| Virilization | 11 | 50 |
| Hypokalemia | 6 | 27.3 |
| Muscular weakness/myopathy | 5 | 22.7 |
| Recent diabetes mellitus | 3 | 13.6 |
| Pathologic fractures | 2 | 9 |
| Gynecomastiaª | 1 | 12.5 |
| Abdominal or lumbar pain | 13 | 59 |
| Palpable mass | 9 | 40.9 |
ªGynecomastia was considered only in the male population.
cal treatment, as well as Cushing’s syndrome (50%). Virilization was associated with Cushings’ features in eight women (57.1%), whereas three women (21.4%) had virilization without cushingoid habitus. Gynecomastia was associated with Cushing’s syndrome in one man (12.5%). Hypokalemia (serum K, <3.5 mEq/l) was found in six patients (27.3%); moderate hypertension, as the single clini- cal manifestation of AC, occurred in one woman (n.1, Table 1), both at diagnosis and during disease relapses. Abdominal pain was present in 13 patients (59.1%): in two patients tumors were non- functioning; nine patients (40.9%) had a palpable abdominal mass.
After surgical removal of the adrenal mass (either curative or only debulking), clinical symptoms of steroid excess disappeared in all subjects, and arterial hypertension improved or disappeared.
Imaging and Staging
At diagnosis, the right adrenal gland was involved in nine patients (40.9%); the left, in 13 (59.1%). Twelve cases (54.5%) were staged I-II and ten (45.5%) were staged III-IV (Table 1). In three patients (nos. 1, 6, and 21) the diagnosis of AC was made by abdominal ultrasound performed to search out the cause of a moderate hyper- tension (nos. 1 and 6) or the cause of renal colic (no. 21). These patients were included in a cohort of 140 adrenal incidentalomas previously reported [11, 22]. At abdominal CT scan, the diameter of the AC ranged from 4 to 25 cm (median, 11 cm) (Table 1); tumor diameter was ≤ 5 cm in three patients (13.6%), between 5 and 10 cm in five patients (22.7%), and >10 cm in 14 patients (63.7%) (Figure 1). A nonhomogeneous pattern was appreciated in all tu- mors; tumors greater than 5 cm in size had evident necrotic areas (Figure 1 and 2A). At diagnosis, locoregional invasion was present in seven patients (31.8%), and distal metastases (liver, pulmonary, and lymphonodal) were present in three patients (13.6%).
Five patients with hormonally active tumors showed an uptake of the radiotracer at adrenocortical scintigraphy concordant with CT scan (Figure 2B), whereas no concordant uptake was evident in the other seven patients without overt steroid hormone excess.
Endocrine and Biochemical Evaluation
The results of the endocrine evaluation are summarized in Table 3. At diagnosis, nine tumors had a mixed (glucocorticoid, androgen, and estrogen) secretion, one had cortisol and 17-OHP excess, and three induced a hyperandrogenism and one a cortisol excess only. One AC had only 17-OHP increase (Table 1). Steroid secretion abnormalities were also detected in the remaining eight patients,
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none of whom presented clinical signs of hormonal excess. In five patients (nos. 11,12,15,18, and 21) a wide variability of serum cor- tisol and androgen levels and of urinary cortisol excretion was de- tected: the cortisol circadian rhythm, measured as F% ratio, was indeed preserved on some days but absent on others. The DXM test failed to suppress cortisol < 5 ng/dl in all patients but one. Increased 17-OHP values represented the only abnormality in one hypertensive woman (patient no.1) showing 3 locoregional re- lapses.
Disease relapses were characterized by milder clinical evidence of endocrine hyperactivity and by lower serum values of cortisol and androgens. Overproduction became progressively less evident by increasing recurrence number, likely because of an increasing number of defective steroid biosynthesis enzymes, which express progressive cellular undifferentiation with each new recurrence.
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Multiple metabolic abnormalities were seen in more than half of the patients. These were related to a certain extent with clinical evidence of endocrine hyperactivity (Table 3). High levels of total and LDL cholesterol, triglycerides, glucose, and fibrinogen (Table 3) were detected in 14 patients (63.7%), and all measures normal- ized after surgical tumor removal. Metabolic parameters increased again at relapse, more so in patients with apparent steroid excess, but increased were also present in patients without any apparent overproduction.
Histopathological Analysis
All carcinomas weighed > 100 g; the largest weighed > 3.5 kg (me- dian, 730 g). The cut surface showed a variegated pattern; areas of necrosis and hemorrhage were frequent. Invasion of capsule and vessels, aneuploidy, and > 5 mitosis/50 HPF were present in all cases. In 8 cases (36.4%) the capsule was macroscopically infil- trated, and invasion of adjacent tissue was observed. High mitotic rate (>20 mitoses/50 HPF) was present in 11 patients (50%). Mi-
croscopically, tumor cells from four patients (18.2%) closely re- sembled those of normal adrenal cortical cells, whereas others were totally undifferentiated. In eight cases (36.4%), giant cells with bi- zarre and hyperchromatic nuclei and multinucleated cells were found. Five tumors (22.7%) were characterized by a biphasic pat- tern of carcinoma and sarcoma-like components. At immunohisto- chemistry, all ACs were strongly positive for vimentin, faintly posi- tive for keratin, and negative for EMA, CEA, and chromogranin, which confirmed the diagnosis of malignant adrenal tissue. Chro- mogranin negativity confirmed the cortical origin of the lesion [23].
Patients with high mitotic rate had significantly worse survival than those with a low rate of mitosis (relative risk, 12.16; 95% CI, 2.8-56; p < 0.005), and patients with cellular polymorphism and sarcoma-like component within AC had a worse outcome (relative risk, 18.1, 95% CI, 3.4-49; p < 0.001).
Treatment and Outcome
All patients were treated by surgery, except one whose tumor was considered inoperable: in 16 patients (76.2%) surgery was curative; in five (23.8%) only tumor debulking was possible. Surgical treat- ment was performed invariably by anterior laparotomy. Overall survival in our cohort was 41.6 ± 42 months; 16 subjects are still alive at 10-168 months. Patients treated by curative surgery had significantly better overall survival than those who underwent de- bulking or who had no surgery (hazard ratio, 0.06317; 95% CI: 0.0001713-0.03360; p < 0.0001) (Fig. 3). Survival after curative sur- gery was 61.7 ± 47 months; in patients undergoing debulking or no surgery it was 8.6 ± 5.9 months. In fact, the inoperable man (no. 11) and two other patients (nos. 12 and 18) treated by debulking, died 3-6 months after diagnosis. Maximal diameter of residual tumor mass grew from 3-15 cm within 3 weeks after surgery in patient no. 18. The remaining three patients treated by debulking surgery started mitotane (nos. 15 and 17) or mitotane and chemotherapy (no. 13) immediately after surgical healing and are still alive 12-19 months after the diagnosis. Residual masses significantly reduced (no.15 and 17) or disappeared (no.13). In seven survivors, surgery was repeated because of local (n = 15) or isolated distal (n = 3) disease relapses (two pulmonary, one liver); a median of 1.8 inter- ventions/person was performed for a total of 39 treatments (Table 4). In patients with recurrences, the disease-free period was 17.9 ± 18.2 months after the first surgery, 6.5 ± 6.6 months after the first relapse was surgically treated, and 4.2 ± 3.4 thereafter. By the log rank test, the difference between the disease-free period after the first surgery was significantly longer than that after the second and third surgical treatments (p = 0.0047 and p = 0.0011, respectively), whereas the second and the third period did not differ from each other (Fig. 4). Moreover, all patients who were surgically treated for a recurrence after the first curative surgery developed further relapses. This means that patients with one recurrence are very likely to have further relapses of AC.
The most frequent sites of metastasis were liver and lungs; in one patient (no. 7) gastric infiltration occurred, causing gastrin hyper- secretion (600 mg/dl; normal < 18) and melena. In another patient (no. 8) the spinal medulla was infiltrated by a locoregional metas- tasis that caused neurological symptoms. A total of 16 patients were treated by mitotane, and 10 received chemotherapy. In particular, one patient (no. 13) was treated by mitotane plus chemotherapy (epirubicin and VP16) immediately after the first debulking sur- gery; she is still disease-free at 3 years of follow-up. Mitotane alone
| Patients | Controls (n = 66) | ||
|---|---|---|---|
| Hormonally active carcinomas (n = 14) | Apparently nonfunctioning carcinomas (n = 8) | ||
| Serum cortisol levels 8.00 a.m. (ug/dl) | 243.5 (214-281)* | 135 (67-180) | 160 (88-202) |
| Cortisol 24.00/08.00 ratio (%) | 50 (25-70)* | 39 (23-60)* | 25 (22-48) |
| Urinary cortisol excretion (ug/24 h) | 568 (278-2250) ** | 148 (124-199)* | 85 (56-128) |
| Serum cortisol levels post-DXM (ug/dl) | 153 (96-531) ** | 133 (59-131) ** | 12.5 (7-35) |
| Serum 17-hydroxyprogesterone (ng/dl) | 1200 (230-1680) ** | 200 (130-1370)* | 80 (30-250) |
| Serum androstenedione (ng/ml) | 8.6 (1.8-24.5) ** | 1.6 (0.8-2.4)* | 1.4 (1.0-2.4) |
| Serum dehydroepiandrosterone sulfate (ug/dl) | 509 (95-3651) ** | 319 (7.5-420)* | 216 (103-520) |
| Serum testosterone levels in women (ng/dl) | 310 (150-1500) ** | 50 (30-100) | 40 (10-100) |
| Serum testosterone levels in men (ng/dl) | 950 (700-1020)* | 650 (400-860) | 610 (350-900) |
| Blood fasting glucose levels (mg/dl) | 102 (62-174)* | 93 (84-109) | 82 (74-95) |
| Serum total cholesterol levels (mg/dl) | 224 (148-360)* | 200 (138-280)* | 176 (120-211) |
| Serum triglycerides levels (mg/dl) | 200 (110-302)* | 185 (90-293)* | 120 (87-156) |
| Serum fibrinogen levels (mg/dl) | 480 (270-700) ** | 390 (230-460)* | 288 (250-334) |
| Systolic blood pressure (mm Hg) | 160 (130-212) ** | 150 (121-200) ** | 135 (110-142) |
| Diastolic blood pressure (mm Hg) | 110 (85-22) ** | 105 (83-114) ** | 84 (75-87) |
The data are expressed as median and range, given in parentheses.
DXM: Liddle’s 2-mg dexamethasone inhibition test.
*p < 0.05; ** p < 0.001 vs. controls.
was administered as adjuvant therapy for 16 ± 2.7 months in 11 patients with biochemical evidence of disease; in some of them che- motherapy was added later. The maximal mitotane dose ranged from 1 to 7.5 g/day, and all patients developed adrenocortical in- sufficiency. One woman (no. 6) had received adjuvant mitotane ad- ministration after the breakage of a tumor capsule during surgery; she is still disease-free after more than 168 months. Five patients (nos. 1, 4 15, 17, and 19) are continuing mitotane treatment. Con- sidering all our patients treated by mitotane alone, the response rate was 36% (4/11); but the response increased consistently when only patients treated after the first surgery were considered (4/5; 80%), however, this difference was not significant (4/11 vs. 4/5; p = 0.27).
Ten patients received different combinations of chemotherapy plus mitotane to manage the advanced stages of the disease (Table 4). Only two patients in whom chemotherapy has been initiated after the first surgery achieved disease remission (nos. 13 and 14). In the other eight patients, chemotherapy was administered during the AC relapses and was associated with significant toxicity and short overall survival. Only one patient had stabilization of the dis- ease; all others progressed or died from the side effects. In particu- lar, aplastic crises caused death in 2 patients (nos. 10 and 12) (Table 4), one during the fourth disease relapse and one during the second disease relapse. Given the small number of patients treated, no sta- tistical analysis was performed for outcomes of various treatments or different timing of chemotherapy.
Six patients who died were in good condition until the late stage of the disease, and death was caused by disease progression and dissemination or by chemotherapy-related toxicity. Fever was pres- ent in three patients in late stage due to infections likely related to chemotherapy. Weight loss was present only in the final stage of the disease.
Complications included cardiovascular disease, including recent coronary heart disease in two patients (nos. 7 and 8), two episodes of deep vein thrombosis of the left leg coinciding with disease re- currence in one patient (no.1); left ventricular hypertrophy at ECG was found in eight patients and was associated with atrial fibrilla- tion in two (nos. 5 and 20).
No difference was found in survival and recurrence rates regard- ing gender, age at diagnosis, and initial endocrine activity.
Discussion
The overall survival in our population of adult patients with ACwas 41.6 + 42 months, similar to that reported in recent studies [8, 9]; 16 patients (72.7%) are still alive. Adrenocortical carcinoma was more frequent in women, with the female/male ratio of 1.75 in our series in accordance with the range of previous reports, 1.3 to 4.2 [8, 24- 26]. Mean patient age was 44.2 yr, slightly younger than that ob- served in most adult populations described in the literature [3,5, 7, 8]. In our series, steroid excess occurred in 63.6%; a similar preva- lence of secreting SC has been reported by other reports [5, 8, 13, 26]. No other malignancy was found in our patients.
In line with existing data [8, 15], the most common endocrine syndromes associated with AC were virilization and Cushing’s syn- drome. However, it should be pointed out that a distinction be- tween functional and nonfunctional AC depends on the accuracy and completeness of the hormonal evaluation. A mild degree of endocrine overproduction-or production of steroid precursors- can be revealed in tumors lacking a clear-cut clinical syndrome. In fact, adrenocortical carcinomas often have several defective steroid biosynthesis enzymes, causing elevated levels of steroid precursors [26, 27]. An abnormal cortisol circadian rhythm and incomplete suppressibility by DXM occurred in the vast majority of the pa- tients, regardless of their baseline steroid values. Similar results were obtained by Bertagna and Ort [13] in 34 patients with AC. Because steroid secretion in AC displays a large variability, mul- tiple sampling or combined determination of serum steroids and their urinary excretion, or both are necessary to detect endocrine abnormalities. This complex endocrine work-up can be simplified by use of low-dose DXM, which has been shown to possess a high positive predictive value for the determination of an autonomous adrenal endocrine activity [28]. Adrenal steroids assay can be suc- cessfully used as the equivalent of tumor markers for the early de- tection of tumor recurrence. Furthermore, arterial hypertension and metabolic alterations including increased fibrinogen, glucose,
100
overall survival (%)
75
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72
96
120
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100
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75
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50
*
25
0
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12
24
36
48
60
72
84
96
108
120
132
144
months
and lipids have been frequently associated with AC at diagnosis and during recurrence, and should be monitored during follow-up. Re- cent studies on incidentally discovered adrenal adenomas have shown that even subclinical adrenal steroid excess may be associ- ated with important alterations in arterial pressure and metabolic parameters, increasing the cardiovascular risk [20, 29, 30]. In fact, arterial hypertension was the most frequent symptom related to AC in our series (68%), regardless hormonal excess, and it was ac- companied by low potassium levels in six patients with clinical evi- dence of Cushing’s syndrome. Abnormal metabolic and coagula- tion parameters were found in patients harboring AC with cortisol and androgen excess, but they were mildly increased also in cases with “nonfunctioning AC”. In fact, thrombosis was described as pre- senting syndrome and cause of death related to surgery for AC [5]. A high operative mortality (5.5%) was present also in a recent study [8]. Both cortisol and androgen excess confer an increased risk of cardiovascular events that may worsen in the presence of multiple steroid excess. This evidence should be considered before surgery.
Uptake of radiocholesterol was present in 33.3% of patients; consequently, absence of uptake at adrenocortical scintigraphy was not a helpful marker of malignancy of the adrenal mass in our population. Similar findings have recently been described by Bar- zon et al. [31], who reported increased tracer uptake in 30% of hypersecreting AC, regardless of the biochemical and histological features of the tumor.
Surgical removal has been widely reported as the only effective treatment for AC, particularly if the diagnosis is made at stages I or II [32]. Resection of recurrent tumor or isolated metastases has been documented to prolong survival by some but not all studies [7, 13]. In our experience, the first recurrence was likely followed by other relapses, and the disease-free period progressively shortened with upcoming AC recurrences being characterized by an increas- ingly aggressive tumor behavior. Tumor resectability during the first surgery was associated with a better overall survival, in line with previous evidence. Spillage of tumor cells during surgery may be the cause of recurrence; however, in our experience and in that of another group [33], breakage of the tumor capsule did not shorten survival. One of our patients (no. 6) started mitotane treat- ment immediately after surgery, which caused irreversible adreno- cortical insufficiency. She is disease-free after >14 years since di- agnosis.
Although AC relapse most frequently at the locoregional level, pulmonary, liver, and bone metastases were also observed. Local recurrences and metastases led to variable symptoms in- cluding compression of the lumbar spinal medulla and gastric bleeding.
The six patients who died were in good condition until the late stage of the disease; death was caused either by disease progression and dissemination or by chemotherapy treatment toxicity. These patients experienced no weight loss or psychological distress typical of other neoplasms in a similar disease stage, probably because of some mild steroid hyperactivity until the late disease stage. Mito- tane was well tolerated and patient compliance was high, as indi- cated by adrenal insufficiency in all patients treated. As side effects of mitotane are largely dose related [15], monitoring serum mito- tane concentration is recommended to provide long-term treat- ment with fewer side effects [34, 35]. Mitotane alone was effective in 33% of patients, but most data derive from patients in the ad- vanced stages of the disease [36]. Our better (although statistically not significant) results with mitotane use immediately after the first surgery (80% vs. 33% of all cases treated) could be related to an earlier stage of the disease, given the relationship between adreno- lytic activity and the tumor’s ability to metabolize the drug. Anti- blastic therapy was always associated with mitotane, because this drug’s ability to suppress the expression of a multidrug resistant gene has been proven in adrenocortical cells [37]. Multiple anti- blastic agents were employed, because previous experience with single agent chemotherapy has shown a low response rates (<30%). Furthermore, the administration of multidrug chemo- therapy was associated with severe toxicity, causing death in two patients. Given the long duration of this study, different drug com- binations were used. Only recently did we use the combination of etoposide, doxorubicin, and cisplatin, previously shown to achieve the best results (response rate of 54%) in association with mitotane [38]. Considering the cumulative results of combined chemo- therapy, disease remission occurred in only one woman and stabi- lization occurred in two; the disease progressed in all of the remain- ing seven patients.
| Case no. | Surgery (no.) | Surgical approach | Metastasis | Mitotane maximum dose (g/day) | Chemotherapy | Overall survival (months) |
|---|---|---|---|---|---|---|
| 1 | 3 | A | LY | 2 | Carboplatinum/farmarubocin/VP16 | 96b |
| 2 | 1 | A, S | None | None | None | 43b |
| 3 | 1 | A | None | None | None | 60b |
| 4 | 3 | A (1); liver and (2); lung resection (3) | LU, LI | 3 | Etoposide/adriamicin/cisplatinum | 42b |
| 5 | 1 | A | LIª, LUª | 3 | Etoposide/doxorubicin/cisplatinum | 8 |
| 6 | 1 | A | LU, LI | 3.5 | None | 168b |
| 7 | 2 | A (1); S (2) | LY, LU, LI, GA | 2.5 | Cisplatinum/VP16 | 70 |
| 8 | 4 | A (1); kidney (2) and liver resection (4) | LY, LU, LI | 6 | Doxorubicin/etoposide/cisplatinum | 36b |
| 9 | 1 | A, kidney and liver resection | LU, LI | 1 | Bleiomicin/etoposide/cisplatinum | 132b |
| 10 | 5 | A (1); S (2); kidney and lymph node (3) resection | LY, LI, LU | 2 | Bleiomicin/etoposide/cisplatinum | 39 |
| 11 | 0 | None | LYª | 1.5 | None | 3 |
| 12 | 1 | A, S, distal pancreas resection | LUª, LIª | 2 | Carboplatinum/farmarubocin/VP16 | 4 |
| 13 | 1 | A | None | 2 | Epirubicin/cisplatinum | 36b |
| 14 | 1 | A | BO | 6 | Cisplatinum/VP16 | 120b |
| 15 | 1 | A, kidney and distal pancreas resection | None | 7.5 | None | 19b |
| 16 | 1 | A | None | None | None | 12b |
| 17 | 2 | A, S (1); phrenic resection (2) | None | 1 | None | 10b |
| 18 | 1 | A, kidney resection | None | None | None | 6 |
| 19 | 1 | A | None | 1.5 | None | 36b |
| 20 | 1 | A, liver resection | None | 2 | None | 21b |
| 21 | 1 | A | None | None | None | 29b |
| 22 | 1 | A | None | None | None | 25b |
A: adrenalectomy; S: splenectomy; (1), (2), (3), (4) refer to progressive number of surgical intervention; when not indicated, local recurrence was resected.
Sites of metastasis: LI: liver, LU: lung, LY: lymph nodes, BO: bone, GA: gastric. “Metastasis present at diagnosis.
bPatients still alive.
At present, it is difficult to predict AC behavior in individual pa- tients. Some patients experienced an indolent course despite the apparent dissemination of tumor cells caused by capsule damage or by incomplete surgical treatment. Other patients with completely resected AC relapsed after months to years, with recurrences show- ing a less differentiated cellular pattern. In our experience, high mitotic rate and presence of sarcoma-like components were asso- ciated with much more aggressive tumor behavior. Also other authors [39, 40] found that survival time varied with AC differen- tiation. Low mitotic rate and surgical resectability remain encour- aging prognostic criteria, although, other important factors, prob- ably at the molecular level, influence the outcome of patients, and subsequent mutations can likely affect the follow-up course. The important clinical variability perhaps reflects the molecular hetero- geneity previously described [35, 41].
In conclusion, curative surgical treatment was the most effective form of treatment. However, given the high relapse incidence and progressive tumor undifferentiation, the usefulness of adjuvant treatment in relapsing tumors and those with high aggressiveness at histopathological examination can be the subject of speculation, re- gardless of the evidence of disease persistence after surgery. Keep- ing in mind the complex manifestation of AC, surgical treatment should be performed after adequate treatment of associated hyper- tension and other metabolic alterations in order to reduce surgical risk. Moreover, monitoring the patients’ clinical conditions, includ- ing arterial pressure and metabolic parameters with or without the determination of adrenal steroids can be helpful to detect recur- rences. Finally, a multidisciplinary (endocrinology, surgery, oncol- ogy) approach can improve the quality of care provided to these patients during follow-up.
Résumé. Le carcinome de la corticosurrénale (CCS) est une tumeur rare avec un pronostic sévère. Vingt-deux patients (14 femmes, et 8 hommes, d’âge allant de 22 à 59 ans, médiane 43) porteurs de CCS ont été évalués prospectivement dans un seul centre: le stade tumoral étaient I-II chez 12 et III-IV chez 10. La survie globale dans notre cohorte a été de 41.6 ± 42 mois. Sieze patients sont toujours en vie. La chirurgie à visée curatrice a été suivie d’une survie plus longue qu’en cas de chirurgie de réduction tumorale ou en cas d’absence de chirurgie (p < 0.0001). Une première récidive a été hautement prédictive d’autres récidives. Le CCS récidivant était plus agressif et la récidive était apparente dans des intervalles variables mais courts. Au moment du diagnostic, 14 (63.5%) patients présentaient des caractères claires d’hyperactivité corticale. En dépit de l’absence de signes cliniques d’excès hormonal, tous les autres patients ont présenté quelques anomalies de leurs sécrétions corticostéroïdes. La donnée clinique la plus fréquente a été un diagnostic récent d’hypertension modérée à sévère (68%), non contrôlée pharmacologiquement, souvent associée à des facteurs de risque cardiovasculaires multiples. Un taux élevé de mitose et un polymorphisme cellulaire non différencié étaient associés à un plus mauvais pronostic. La réponse au traitement autre que la chirurgie (mitotane, chimiothérapie) était meilleure chez les patients traités précocement après chirurgie initiale. En conclusion, la chirurgie à visée curative est le traitement le plus efficace. Le monitorage des paramètres endocrine, métabolique et de la pression artérielle, peut être utile pour la détection précoce de récidive.
Resumen. El carcinoma adrenocortical (CA) es un tumor raro que se asocia con pronóstico sombrío. Veintidós pacientes (14F, 8M; edades 22-59 años; mediana 43) con CA fueron evaluados preoperatoriamente en un centro médico único: estado tumoral I-II en 12 casos, III-IV en 10. La supervivencia global de nuestra cohorte fue 41.6 ± 42 meses; 16 pacientes se encuentran vivos. La cirugía curativa mostró una mejor supervivencia que la cirugía de debultamiento (p < 0.0001) o la no cirugía. El primer relapso mostró ser altamente predecible de otras recurrencias. Los CAS recurrentes demostraron ser progresivamente más agresivos y se presentaron a intervalos variables pero siempre más cortos. En el momento del diagnóstico 14 (63.5%) pacientes presentaban clara hiperactividad
adrenocortical. A pesar de la ausencia de signos clínicos de exceso hormonal, todos los demás pacientes presentaron alguna anormalidad en la secreción de esteroides. El signo clínico más común fue el diagnóstico reciente de hipertensión moderada a severa (68%), tratamiento farmacológico pobremente controlado, con frecuencia asociada con múltiples factores de riesgo cardiovascular. Una alta rata de mitosis y un patrón celular polimorfo indiferenciado aparecieron asociados con peor pronóstico. La respuesta a otras terapias diferentes a la cirugía (mitotano, quimioterapia) fue mejor en aquellos pacientes tratados precozmente luego de la primera cirugía. En conclusión, la cirugía curativa representó la modalidad más efectiva de tratamiento. La monitoría de la presión arterial, así como parámetros endocrinos y metabólicos pueden ser de ayuda en la detección de recurrencias del CA.
Acknowledgments
The authors thank the many health professionals who cared for the patients with adrenocortical carcinoma over these years. They are also indebted to Dr Melania Pulcrano for organizing the database, Prof. Fimmanò, and Dr. Nicola Gennarelli for their help in the sur- gical care of some patients, and Mr. Angelo Di Francia for his skilled technical support.
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