Department of Pediatrics, Division of Pediatric Endocrinology, Clinics Hospital, Federal University of Parana (R.S., L.D.L.), Curitiba, Parana, Brazil; and the Department of Hematology-Oncology (R.C.R.) and the International Outreach Program (R.C.R., R.S.), St. Jude Childrens Research Hospital; and the Department of Pediatrics, University of Tennessee College of Medicine (R.C.R.), Memphis, Tennessee 38105
Address all correspondence and requests for reprints to: Dr. Romolo Sandrini, Department of Pediatrics, Division of Endocrinology, Rua General Carneiro 181, Curitiba, Pr. Brazil 80060900.
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The problem |
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Industrial pollutants, a major contributor to increased rates of solid tumor development, cannot be accorded more than a minor role in the Parana cases due to the slow pace of industrial expansion in this region. However, because of the extensive agricultural activities in southern Brazil, it is possible that environmental pollutants, such as pesticides, may pose a substantial health hazard. Agricultural pesticides are widely used in Parana, usually without safety guidelines. In this regard, British investigators found an association between an increased incidence of ACT and pesticide use in northwestern England (5), whereas in Norway, Kristensen et al. (6) noted an almost 2-fold increase in the relative risk for cancer among children 04 yr of age whose parents were engaged in agriculture. Taken together, these findings suggest that environmental pollutants may play a causative role in the excessive incidence of childhood ACT in southern Brazil.
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Clinical and laboratory features |
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There were 17 boys and 41 girls in this series (Fig. 1). The median age
at diagnosis was 4.3 yr (range, 3 days to 15.7 yr); 42 patients were
younger than 5 yr. Girls predominated over boys (5.3:1) until 4 yr of
age. Thereafter, the distribution was similar (0.8:1) for both sexes,
suggesting different disease etiologies for each age group. Clinical
manifestations of the tumor were present at birth in 4 cases. One girl
presented with an abdominal mass at 3 days of age, and 3 other children
had signs of virilization. Two additional patients with congenital
tumors, not included in our series, were diagnosed in other hospitals
in Curitiba (7).
Virilization was the only presenting feature in 40% of the group.
Isolated signs of Cushings syndrome were rare (3% of the patients),
occurring most often (50%) in combination with clinical signs of an
increased secretion of androgens (Table 1). Three
patients had an abdominal mass and increased blood pressure without any
other signs of virilization or Cushings syndrome, and another patient
had only a palpable abdominal mass.
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An abdominal mass was palpable in 48% of the patients. All tumors were unilateral; the left and right adrenal glands were affected equally.
The heights and weights of these children often exceeded the 50th
percentile (Fig. 2). Patients with height SD
scores above that of the target height included not only those with the
virilizing form of ACT, but also those with the mixed form (9). Bone
age was advanced more than 1 yr in 68% of the patients.
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The absence of certain signs is noteworthy: 1) no patient showed striae; 2) there were no cases of hemihypertrophy or Beckwith-Wiedemann syndrome; and 3) none of the patients had the feminizing form of ACT.
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Diagnosis |
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At present, our routine laboratory evaluation for patients suspected of having ACT includes measurements of urinary 17-KS, 17-OHCS, and free cortisol, as well as plasma cortisol, DHEA sulfate, testosterone, androstenedione, 17-hydroxyprogesterone, aldosterone, PRA, deoxycorticosterone, and other 17-deoxysteroids precursors. This comprehensive panel of tests not only contributes to the diagnosis, but also provides useful markers for the detection of tumor recurrence.
Several different imaging modalities were used to establish the diagnosis of ACT. Until 1982, plain radiographs, excretory urography, and nephrotomograms were the principal modalities. More recently, we have shifted to computed tomography (CT), ultrasonography, and magnetic resonance imaging. In 28 of our patients evaluated with both ultrasonography and CT, the sonograms did not indicate abnormalities in 3 cases (11%), each of which was detected by CT scanning. We recommend that all patients suspected of having an adrenal tumor should be examined by CT or magnetic resonance imaging.
The diagnosis of adrenocortical tumor was made on the basis of the gross and histological appearance of tissue obtained at surgery. Tumor samples from 51 patients were reviewed and classified by a single pathologist (G.A.S.) using previously reported classification schemes (10, 11, 12, 13, 14). Only 1 tumor specimen met the criteria for benign in all 3 systems, whereas the tumors from 2 patients were classified as benign in 2 systems and those from 2 others were classified as benign in only 1 system. Tumor specimens from 2 and 11 patients were considered of indeterminate nature in the classification of van Slooten et al. (12) and Hough et al. (11), respectively. The remaining tumors without benign or indeterminate histology met the criteria for malignancy in at least 2 of the 3 criteria. These data underscore the difficulties in characterizing the ACT histology as being of malignant or benign potential.
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Treatment and outcome |
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Surgery is the single most important procedure in successful treatment of ACT and was considered for each or our patients. Because of tumor friability, rupture of the capsule and tumor spillage were frequent (20% of cases during the initial procedure and 43% after local recurrence). In one case, the presenting clinical manifestations were those of an acute abdomen due to spontaneous tumor rupture; Lack et al. (15) reported a case of adrenocortical tumor with similar presenting features. Infiltration of the vena cava could be expected to make radical surgery difficult in some cases, although successful complete resection of the tumor thrombus has been reported in patients undergoing cardiopulmonary bypass (16). Our experience with tumor thrombi extending into the vena cava is limited to two patients. One had tumor extension into the inferior vena cava and right atrium and was considered too ill to undergo surgery. She died 1 week after admission despite treatment with mitotane. The remaining child, who also had an inoperable tumor extending into the vena cava and right atrium, received two courses of combination chemotherapy (ifosfamide, carboplatinum, and etoposide) without response.
Surgery required careful and precise perioperative planning. All patients with a functioning tumor were assumed to have suppression of the contralateral adrenal gland, so that steroid replacement therapy was given to those patients. Special attention to electrolyte balances, hypertension, surgical wound care, and infectious complications was imperative. There were no perioperative deaths in this series.
Surgical resection was complete in 98% of the 48 operable cases and partial in the remaining 2%. Of the 10 patients whose tumors were considered inoperable, 1 patient with localized disease had a substantial oncolytic response to mitotane, permitting complete resection of the mass. This child is alive and free of disease 5 yr after definitive surgery.
Surgery was also attempted in six patients with local recurrences, five of whom eventually died from metastatic disease. One patient, who in addition to a third surgical procedure received adjuvant chemotherapy that included cisplatin and etoposide, has been alive for 8 yr.
Chemotherapy.
The role of chemotherapy in the management of childhood ACT has not been established. Mitotane \[1,1-dichloro-2-(O-chlorophenyl)-2-(p-chlorophenyl)-ethane, or o,p'-DDD\], an insecticide derivative that produces adrenocortical necrosis, has been used extensively in adults with ACT, but its efficacy in children is not known. Since 1990, we have been conducting a multinstitutional study to determine the efficacy and toxicity of mitotane as an adjuvant therapy for newly diagnosed children at high risk of relapse (see below). However, it is still too early to reach conclusions as to the efficacy of this compound. Mitotane toxicity has been dose dependent and considerable. The most important toxicity was gastrointestinal and neurological, with nausea, vomiting, diarrhea, and abdominal pain also present in a high proportion of patients. Less frequent reactions included somnolence, lethargy, ataxic gait, depression, and vertigo. Of interest, all prepubertal patients developed gynecomastia or thelarche. Another shortcoming of mitotane treatment is that it significantly alters steroid hormone metabolism, so that steroid measurements in blood and urine cannot be used as a marker of tumor relapse. Thus, mitotane should be considered an experimental agent in the treatment of children with ACT. Other antineoplastic drugs, including the combination of cisplatin with etoposide, 5-fluorouracil with leucovorin, and ifosfamide and carboplatinum with etoposide were used in too few patients to permit meaningful conclusions. Adjuvant radiation therapy was not attempted in this group of patients.
Outcome.
Of the 54 patients with known outcomes, 24 (44%) died, and 30 (56%) have been disease free for periods of 1214 months from diagnosis (median, 63 months). The survival rate in our series is similar to that reported by others (17).
All but 2 of the 24 deaths were attributable to the primary ACT (Table 2). One child died from a second neoplasm (choroid
plexus carcinoma), and another as the consequence of encephalopathy
that developed during a hypertensive crisis. Sites of metastasis were
confined mainly to the liver, lungs, and regional lymph nodes. The time
to tumor recurrence ranged from 148 months postsurgery (median, 6
months). Only 2 of 15 patients relapsed more than 1 yr from the initial
surgery, (1.8 and 4.0 yr, respectively). Recurrences were rapidly fatal
in nearly all cases (median time from relapse to death, 5 months;
range, 211 months). It should be noted that local relapse in these
patients always preceded distant metastasis.
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Prognostic factors |
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In an effort to identify at last marginal predictors of outcome, we retrospectively analyzed 40 cases from our institution in which treatment was essentially uniform (10). The presence of metastases at diagnosis or failure to completely resect the tumor was associated with an extremely poor outcome. Among patients without metastatic disease, a univariate statistical analysis indicated several clinical and laboratory variables with an adverse impact on outcome: age more than 3.5 yr, interval of more than 6 months between the first signs and diagnosis, urinary excretion of 17-OHCS of 4 mg/m2 · day or more, tumor volume of 200 cm3 or greater, and tumor weight of 80 g or more. Tumor size was highly correlated with a delay in diagnosis and, to a lesser degree, with older age, indicating that patients diagnosed more than 6 months after the first symptoms and/or older than 3.5 yr tended to have larger tumors. Multivariate analysis indicated that only tumor size was independently associated with disease-free survival.
On the basis of these results, we proposed a set of staging
classifications of childhood ACT (19) (Table 3). The
staging criteria are highly predictive of outcome among patients with
either stage I or stage IV disease, that is 90% or more of patients
with stage I disease are long term survivors (median follow-up time of
6.2 yr; range, 1.413.7 yr) compared with virtually none of those with
stage IV disease. Predicting outcome for patients with intermediate
stages of disease is much more difficult. In this regard, only 52% (12
of 23) of the patients with stage II disease remain alive and free of
disease (median, 6.3 yr; range, 0.117.8 yr). Among 4 patients with
stage III disease, only 1 remains alive and has been free of disease
for 6 yr. This patients tumor regressed with mitotane and could be
completely excised.
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Future plans |
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Acknowledgments |
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Footnotes |
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Received August 16, 1996.
Revised March 10, 1997.
Accepted March 20, 1997.
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References |
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