Adrenocortical tumors in children
R.C. Ribeiro1,2,3, E.L. Michalkiewicz1,4, B.C. Figueiredo5,
L. DeLacerda5, F. Sandrini5, M.D. Pianovsky6,
G. Sampaio7 and R. Sandrini5
1Department of Hematology-Oncology, 2International Outreach Program, St. Jude Children’s Research Hospital, and 3Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN, USA
4Departamento de Cirurgia Pediátrica, Hospital Erasto Gaertner, Curitiba, PR, Brasil
5Departamento de Pediatria, 6Divisão de Endocrinologia, Hematologia/Oncologia and 7Departamento de Patologia, Hospital das Clínicas, Curitiba, PR, Brasil
Correspondence
R.C. Ribeiro Department of Hematology-Oncology St. Jude Children’s Research Hospital 332 North Lauderdale Memphis, TN 38105 USA
Fax: + 1-901-495-3122 E-mail: raul.ribeiro@stjude.org
Presented at the First International Meeting on Adrenal Disease: Basic and Clinical Aspects, Ribeirão Preto, SP, Brazil, August 31-September 2, 1999.
Research supported in part by the National Cancer Institute (Nos. P30 CA-21765 and PO1 CA-20180) and by the American Lebanese Syrian Associated Charities (ALSAC).
Received December 20, 1999 Accepted June 14, 2000
Abstract
Childhood adrenocortical tumors (ACT) are rare. In the USA, only about 25 new cases occur each year. In Southern Brazil, however, approximately 10 times that many cases are diagnosed each year. Most cases occur in the contiguous states of São Paulo and Paraná. The cause of this higher rate has not been identified. Familial genetic predisposition to cancer (p53 mutations) and selected genetic syn- dromes (Beckwith-Wiedemann syndrome) have been associated with childhood ACT in general but not with the Brazilian counterpart. Most of the affected children are young girls with classic endocrine syn- dromes (virilizing and/or Cushing). Levels of urinary 17-ketosteroids and plasma dehydroepiandrosterone sulfate (DHEA-S), which are abnormal in approximately 90% of the cases, provide the pivotal clue to a diagnosis of ACT. Typical imaging findings of pediatric ACT consist of a large, well-defined suprarenal tumor containing calcifica- tions with a thin capsule and central necrosis or hemorrhage. The pathologic classification of pediatric ACT is troublesome. Even an experienced pathologist can find it difficult to differentiate carcinoma from adenoma. Surgery is the single most important procedure in the successful treatment of ACT. The role of chemotherapy in the man- agement of childhood ACT has not been established although occa- sional tumors are responsive to mitotane or cisplatin-containing regi- mens. Because of the heterogeneity and rarity of the disease, prognos- tic factors have been difficult to establish in pediatric ACT. Patients with incomplete tumor resection or with metastatic disease at diagno- sis have a dismal prognosis. In patients with localized and completely resected tumors, the size of the tumor has predictive value. Patients with large tumors have a much higher relapse rate than those with small tumors.
Key words
· Adrenocortical adenoma
· Adrenocortical carcinoma
· Adrenal gland disorders
· Pediatric cancers
· Childhood adrenocortical tumors
Introduction
Adrenocortical tumors (ACT) are rare in children. The first case of childhood ACT was reported in 1865 (1). Up until 1937, most children undergoing adrenalectomy for a functioning ACT would die postopera-
tively due to acute adrenocortical insuffi- ciency. When cortisone became widely avail- able, the outcome for these patients improved dramatically (2).
Childhood ACT has peculiar clinical and biological features that contrast with those observed in other pediatric carcinomas. The
incidence of most childhood carcinomas in- creases with age, whereas 65% of ACT oc- cur in children younger than 5 years of age (3). In fact, this age distribution resembles that of tumors of embryonic origin. More- over, most children with ACT appear healthy and usually have normal development. Fi- nally, smaller-sized ACT can cause exuber- ant endocrine syndromes that often mask or delay the diagnosis (4).
In this report, we will summarize the clinical and biological characteristics and treatment outcome of children with ACT. To this end, we have reviewed information on 520 published and unpublished cases from institutions worldwide.
Epidemiology
Approximately 10,000 new cases of can- cer are diagnosed each year in the United States in patients younger than 20 years. Carcinomas are rare, accounting for only 2- 12% of all cancers in this age group (5-8). Adrenocortical tumors are even rarer, repre- senting 3 to 6% of all carcinomas. In a recent report of the Surveillance, Epidemiology, and End Results (SEER) program, Lack et al. (9) found 28 cases of adrenocortical car- cinomas registered between 1973 and 1987 in patients younger than 20 years. From these data, they estimated that there are 19 new cases of adrenocortical carcinomas per year in the United States in this age group. How- ever, the true incidence of adrenocortical carcinoma may be higher. The estimated figures do not account for those cases of adrenocortical carcinomas that are misdiag- nosed as adenomas, and therefore are not reported. If it is assumed that one third of all ACT are adenomas, an estimated number of 25 to 30 cases of ACT occur annually in patients under the age of 20 years in the United States.
The international incidence of ACT ap- pears to vary substantially. Most estimates of the worldwide incidence of this pediatric
neoplasm are provided by the International Agency for Research on Cancer (IARC) (10). Data from the IARC corroborate the concept that there are geographic differences in the incidence of ACT (6-8,11,12). Particularly remarkable is the incidence of ACT in South- ern Brazil. For example, from 1966 to 1996, 73 children under 16 years of age were ad- mitted to the Division of Pediatric Endocri- nology at the University Hospital, Federal University of Paraná, with the diagnosis of ACT (13). The University Hospital is a ter- tiary referral center for approximately 10 million inhabitants, 3.5 million of whom are children less than 15 years of age. With 12 to 14 new cases of childhood ACT diagnosed in the State of Paraná each year, the annual incidence of ACT within this region can be estimated to range from 3.4 to 4.2 per million children below the age of 15 years. By com- parison, the annual worldwide incidence of childhood ACT ranges from only 0.3 to 0.38 per million children below the age of 15 years (14,15).
Definitive explanations for this apparent excess of ACT cases in Southern Brazil are presently lacking. The Paraná region is lo- cated below the Tropic of Capricorn and has no known endemic transmissible diseases. The population is mainly of European ex- traction - Italy, Poland and Germany - lo- cales in which the incidence of ACT in children has not been unduly increased. Moreover, as compared with other regions of Brazil, the southern states have had the least native Indian influence during coloni- zation. A genetic predisposition towards can- cer, which appears to play a role in many childhood tumors, is not a common feature among Southern Brazilian families of chil- dren with ACT (16). However, multiple cases of childhood ACT have been noted in some families, suggesting a possible genetic basis for this disease. Industrial pollutants, a ma- jor contributor to increased rates of solid tumor development (17), cannot be accorded more than a minor role in the Paraná cases
due to the slow pace of industrial expansion in this region.
Pathogenesis
Predisposing constitutional genetic fac- tors have been found in approximately 50% of children with ACT. Two genetic syn- dromes are clearly associated with ACT. These are Li-Fraumeni syndrome, which is associated with alterations of the tumor sup- pressor gene p53 on chromosome 17p (18,19) and Beckwith-Wiedemann syndrome (20), associated with alteration of the 11p15 re- gion. In families with the Li-Fraumeni syn- drome the frequency of adrenocortical tu- mor is 100 times that of the general popula- tion.
The Li-Fraumeni syndrome is a rare au- tosomal dominant condition with incomplete penetrance in which affected members de- velop many different types of tumors (21- 23). In addition to childhood sarcoma and pre-menopausal breast cancer, members of these families have an increased risk for the development of other malignancies, includ- ing leukemia, brain tumors, osteosarcomas and adrenocortical carcinomas (23). Other possible tumors associated with this syn- drome include melanoma, carcinomas of lung, pancreas and prostate, and gonadal germ cell tumors (19,24).
The relationship between environmental factors and ACT is difficult to prove. Prena- tal exposure to carcinogens has been postu- lated as a possible etiologic factor because of early age of onset of ACT. Mann et al. (25) reported a case of a child with ACT, whose mother ingested hydroxyprogester- one hexanoate during pregnancy to prevent miscarriage. Hornstein et al. (26) described a case of adrenocortical carcinoma in a child with fetal alcohol syndrome; however, the child also had hemihypertrophy and a famil- ial history of cancer. Consequently, factors other than alcohol could have played a role in tumor development.
Clinical features
Based on our review, children and ado- lescents (those younger than 20 years of age) diagnosed with ACT have a median age of approximately 3 years. Fewer than 10% of patients are 15 years or older at diagnosis. The incidence is higher among girls with the overall female/male ratio being 2.3:1; how- ever, the ratio ranges from 5:1 in the 0- to 4- year-old group to 1:1 in adolescents. Al- though the reason(s) for this prevalence in females is not understood, there is evidence of gender-specific physiologic changes in the adrenal glands (27).
The presenting manifestations of ACT depend largely on the specific tumor’s secre- tion of adrenocortical hormones (Table 1). Hormone-secreting tumors and the associ- ated classic endocrine syndromes (viriliz- ing, feminizing, Cushing’s and Conn’s syn- dromes) represent the most common presen- tation in this age group. Although the clini- cal manifestations of one endocrine syn- drome may predominate, ACT usually se- crete several hormones and thus present signs and symptoms of multiple syndromes (mixed forms). Nonfunctional tumors, the most com-
| Feature | N | % |
|---|---|---|
| Pubic hair | 53 | 91 |
| Hypertrophy | ||
| Clitoris | 36 | 62 |
| Penis | 13 | 22 |
| Acne | 42 | 72 |
| Deep voice | 32 | 55 |
| Hypertension | 32 | 55 |
| Facial hair | 29 | 50 |
| Facial hyperemia | 28 | 48 |
| Palpable tumor | 28 | 48 |
| Weight gain | 22 | 38 |
| Hirsutism | 21 | 36 |
| Moon face | 19 | 33 |
| Accelerated growth velocity | 17 | 29 |
| Centripetal fat distribution | 14 | 24 |
| Buffalo hump of the neck | 11 | 19 |
| Seizures | 7 | 12 |
mon type in adults, comprise approximately 10% of the pediatric/adolescent cases.
The virilizing syndrome was the most com- mon presentation in this age group, corre- sponding to 80% of all patients in this review. The signs and symptoms could be explained by increased secretion of androgens alone, in more than half the patients. The remaining patients exhibit signs of other adrenal hor- mones as well. The common virilization mani- festations include deepening of the voice, acne, hirsutism, increase of muscle mass and secre- tion and proliferation of the sebaceous glands with characteristic adult odor. In addition, gen- der-specific changes were noted. In females, clitoral enlargement, facial and pubic hair with male escutcheon, amenorrhea and rarely tem- poral balding were the most common. Corre- sponding signs in males include penile en- largement and precocious isosexual pseudo- puberty.
Cushing’s syndrome occurred in approxi- mately one third of the patients, but only 8% of them had isolated hyperadrenocorticalism. Most of them had signs and symptoms mixed with those from virilizing syndrome. Signs and symptoms include moon facies, weight gain, centripetal distribution of fat (abdo- men and upper dorsal region), plethora, hy- pertension, and striae.
Conn’s syndrome or primary aldosteron- ism is commonly seen in bilateral cortical hyperplasia. Aldosterone-producing ad- enoma is very rare in children (28). Five patients were identified in this review com- prising 1.6% of all ACT cases (29,30). Only one patient was identified to have pure al- dosteronism (30). Headache, weakness of proximal muscle groups, polyuria, tachycar- dia with or without palpitation, hypocalce- mia and hypertension were the most com- mon presenting clinical features. Like Cushing’s syndrome, the signs and symp- toms of Conn’s syndrome can be obscured by other manifestations. Feminization was also a rare form of presentation accounting for 2.2% of the cases (31-39). The most
frequent sign was gynecomastia.
The median tumor weight was 126 g (range, 2 to 6,000 g). There was no tumor laterality predominance, with half of the cases occur- ring in the left and the other half in the right adrenal gland. Bilateral tumors were observed in 1.3% (34,40-42) and were rarely ectopic. Ectopic ACT was described in the spinal canal (43) and intrathoracic cavity (44). One patient had a left renal hilus tumor with no contiguity with the left adrenal gland. These findings are not surprising as ectopic adrenal cortical tissue is commonly detected retroperitoneally in the coeliac plexus, kidney, genitalia, broad liga- ments, epididymis, and spermatic cord (45), which therefore act as potential sites for the development of ACT.
Children and adolescents with a func- tioning ACT are subject to growth distur- bances (40). Pure androgen and estrogen excess most often results in increased growth rate and premature epiphyseal closure. It is not clear if this abnormal exposure to adre- nal hormones will compromise the final adult height. Some investigators suggest that it will result in shorter than expected final adult height (46,47). In contrast, Salt et al. (48) found a tendency to high rather than short stature in nine children treated by sur- gical excision of ACT. In the Curitiba series, the heights and weights of children with ACT often exceeded the 50th percentile at diagnosis (13). Patients with greater than expected heights for age included not only those with the virilizing form of ACT, but also those with the mixed form. Bone age was advanced more than 1 year in 68% of the patients. Markers of growth and develop- ment have consistently remained within the normal range in long-term survivors. In most cases, the initial predicted adult height was smaller than the target height; however, due to a “catch-down” effect that was more pro- nounced for bone age than for growth ve- locity, the final predicted adult height did not differ from the target height. True preco- cious puberty was noted in only one patient,
who lacked a period of bone age catch- down.
In many instances, the increased somatic growth of these children, their generally healthy appearance, and the lack of a pal- pable abdominal mass diverted pediatricians from the possibility of a malignancy. The resulting delay in diagnosis can be appreci- ated from the long median interval (10 months; range, 3 days to 61 months) be- tween the first clinical manifestations of ACT and its diagnosis in the Curitiba series (13). To avoid delaying diagnosis of ACT, any child less than 4 years with pubarche should be considered to have an ACT until proven otherwise. In addition, presence of acne in an infant can also be considered pathogno- monic of an adrenocortical lesion (49). Fi- nally, because Cushing’s syndrome is very rare in children, it should be considered highly indicative of ACT in children younger than 10 years of age (50).
Diagnosis
Adrenocortical tumors arise from one of three adrenal cortex layers: glomerulosa, fas- ciculata and reticularis. It has classically been considered an epithelial tumor and there- fore is classified as carcinoma or adenoma. The diagnosis of an adrenocortical tumor is made on the basis of the gross and histologic appearance of tissue obtained at surgery.
The pathologic classification of pediatric ACT is troublesome. Even an experienced pathologist can find it difficult to differenti- ate carcinoma from adenoma. Weiss et al. (51,52) and Hough et al. (53) formulated classification systems based on macroscopic, microscopic and clinical features present at diagnosis. Bugg et al. (54) applied a modi- fied criterion of Weiss and colleagues (51,52) to analyze a large series of pediatric ACT. In this study, the adrenal tumors were divided into three groups: adrenocortical adenomas, and high-grade or low-grade carcinomas. This classification was based on the mitotic
index, confluent necrosis, atypical mitoses and nuclear grade (Table 2). High-grade car- cinoma and tumor weight were the most reliable predictors of outcome.
Measurements of urinary 17-ketosteroids (17-KS) frequently provide the pivotal clue to a diagnosis of ACT. 17-KS levels are elevated in the majority of the patients tested. In one review (13), 48 of the 49 patients tested positive for elevated 17-KS levels, whether their tumors caused Cushing’s syn- drome or virilization. Plasma dehydroepi- androsterone sulfate (DHEA-S) levels are abnormal in approximately 90% of the cases, suggesting that increase in plasma DHEA-S levels is the second most sensitive tumor marker. Abnormal urinary DHEA concen- trations are less sensitive, occurring in only 2/3 of the patients. Urinary 17-hydroxycorti- costeroid (17-OH) levels are elevated in cases with clinical signs of excessive glucocorti- coids. In our experience, a dexamethasone suppression test was rarely necessary. The presence of elevated levels of glucocorticoid and androgen is a strong indication of an adrenal tumor.
Routine laboratory evaluation for patients suspected of having ACT includes measure- ment of urinary 17-KS, 17-OH, and free cortisol, as well as plasma cortisol, DHEA- S, testosterone, androstenedione, 17-hy- droxyprogesterone, aldosterone, renin activ- ity, DOC and other 17-deoxysteroid precur- sors. This comprehensive panel of tests not only contributes to the diagnosis, but also provides useful markers for the detection of
| Diagnosis | Mitotic index+ | Confluent necrosis | Atypical mitoses | Nuclear grade* |
|---|---|---|---|---|
| ACA | 0-5 | Absent | Absent | 1-2 |
| ACC low grade | 6-20 | Present | Present | 3 |
| ACC high grade | >20 | - | - | - |
tumor recurrence.
Several different imaging modalities are used to establish the diagnosis of ACT (55). Until 1982, plain radiographs, excretory urog- raphy and nephrotomograms were the prin- cipal modalities. More recently, computed tomography (CT) scan, sonogram and mag- netic resonance imaging (MRI) have replaced these modalities. In the Curitiba series, 28 patients had both ultrasound and CT scan evaluations; ultrasound did not demonstrate abnormalities in 3 cases (11%); the three tumors were detected by CT scanning. Al- though ultrasound examination has its limi- tations, it is an important modality for evalu- ating tumor extension into the inferior vena cava and right atrium. In our institution, the use of MRI has steadily increased over the last few years. This modality has several advantages over CT, including lack of ioniz- ing radiation, capability of imaging multiple planes and improved tissue contrast differ- entiation. Moreover, recent studies have in- dicated that MRI may discriminate between benign and malignant lesions. Whether MRI will replace CT scanning as the first and most useful imaging procedure or provide the clinician with prognostic information re- mains to be determined. Presently, our rec- ommendation is that, in addition to ultra- sonogram, all patients suspected to have an adrenal tumor should be examined by CT scanning or MRI (55).
Treatment
Surgery
Surgery is the single most important pro- cedure in the successful treatment of ACT. Because of tumor friability, rupture of the capsule and tumor spillage are frequent (oc- curring in approximately 20% of cases dur- ing the initial procedure and in 43% after local recurrence) (13). In one of the Curitiba’s cases, the presenting clinical manifestations were those of an acute abdomen due to spon-
taneous tumor rupture. Lack et al. (9) have reported a case of adrenocortical tumor with similar presenting features. Infiltration of the vena cava can be expected to make radi- cal surgery difficult in some cases, although successful complete resection of the tumor thrombus has been reported in patients un- dergoing cardiopulmonary bypass (56). 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 consid- ered too ill to undergo surgery. She died one 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 re- sponse.
Surgery requires careful and precise perioperative planning. All patients with a functioning tumor are assumed to have sup- pression of the contralateral adrenal gland, so that steroid replacement therapy is man- datory. Special attention to electrolyte bal- ance, hypertension, surgical wound care and infectious complications is imperative.
Chemotherapy
The role of chemotherapy in the manage- ment of childhood ACT has not been estab- lished. Mitotane [1,1-dichloro-2-(0-chloro- phenyl)-2-(p-chlorophenyl)-ethane, or o,p’- DDD], an insecticide derivative that pro- duces adrenocortical necrosis, has been used extensively in adults with ACT, but its effi- cacy in children is not known. Since 1990, we have been conducting a multi-institu- tional study to determine the efficacy and toxicity of mitotane as an adjuvant therapy for newly diagnosed children at high risk of relapse (see below). Preliminarily, mitotane has not modified the rate of relapse in this group of patients. The most important toxici- ties have been gastrointestinal and neuro-
logical including nausea, vomiting, diarrhea, and abdominal pain in a high proportion of patients. Less frequent reactions included somnolence, lethargy, ataxic gait, depres- sion and vertigo. Of interest, all prepubertal patients developed gynecomastia or the- larche. Another shortcoming of mitotane treatment is that it significantly alters ste- roid 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 chil- dren with ACT. Other antineoplastic drugs, including the combination of cisplatin with etoposide, 5-fluorouracil with leucovorin and ifosfamide, and carboplatinum with etoposide have been used in too few pa- tients to permit meaningful conclusions. Adjuvant radiation therapy has not yet been evaluated in childhood ACT.
Outcome
In the Curitiba series, of the 54 patients with known outcomes, 24 (44%) died and 30 (56%) are disease-free for periods of 1 to 214 months from diagnosis (median, 63 months) (13). The survival rate in our series is similar to that reported by others (57).
All but two of the 24 deaths were attribut- able to the primary ACT. 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 re- gional lymph nodes. The time to tumor re- currence ranged from 1 to 48 months postsurgery (median, 6 months). Only 2 of 15 patients relapsed more than one year from the initial surgery (1.8 and 4.0 years, respec- tively). Recurrences were rapidly fatal in nearly all cases (median time from relapse to death, 5 months; range, 2 to 11 months). It should be noted that local relapse in these patients always preceded distant metastasis.
Prognostic factors
Because of the heterogeneity and rarity of ACT, prognostic factors have been diffi- cult to establish. The prognostic importance of histology has been controversial (51,52, 54). However, none of the patients with tumor specimens classified as adenoma or benign histology (in any of the three classifi- cation schemes mentioned above) died of the disease. These findings have been cor- roborated in another study of 54 patients from our and two other Brazilian institutions (54). In that study, none of 11 patients with tumors of adenoma histology or diploid DNA content died from disease. However, cure was often possible for patients whose tumor specimens were classified as carcinoma or had an aneuploid DNA content (54).
In an effort to identify marginal predic- tors of outcome, we retrospectively analyzed 40 cases from our institution in which treat- ment was essentially uniform (3). The pres- ence of metastases at diagnosis or failure to completely resect the tumor was associated with an extremely poor outcome. Among patients without metastatic disease, a uni- variate statistical analysis indicated that sev- eral clinical and laboratory variables had an adverse impact on outcome. These included age more than 3.5 years, interval of more than 6 months between the first symptoms and diagnosis, urinary excretion of 17-OH ≥4 mg m-2 day-1, tumor volume ≥200 cm3, and tumor weight ≥80 g. Tumor size was highly correlated with a delay in diagnosis and to a lesser degree with older age, indicat- ing that patients diagnosed more than 6 months after the first symptoms and/or older than 3.5 years tended to have larger tumors. Multivariate analysis indicated that only tu- mor size was independently associated with disease-free survival.
On the basis of these results, we pro- posed a set of staging criteria for the classifi- cation of childhood ACT (Table 3) (58). The staging criteria are highly predictive of out-
Table 3 - Staging criteria for childhood adrenocortical tumor.
Note: Tumor spillage, defined as the rupture of the tumor capsule or breakage of a venous thrombus during surgery, does not upgrade disease stage I to stage II, provided that it was completely removed.
| Stage | Description |
|---|---|
| I | Tumor totally excised with negative margins. The tumor weight is ≤200 g, there is no evidence of metastasis and the abnormal hormone levels return to normal after surgery. |
| II | Tumor totally excised with negative margins. The tumor weight is >200 g or there is persistence of abnormal hormone levels after surgery. Gross tumor excision with microscopic residual tumor. |
| III | Gross residual or inoperable tumor. |
| IV | Distant metastasis. |
come among patients with either stage I or IV disease, that is 90% or more of patients with stage I disease are long-term survivors compared with 10% of those with stage IV disease (median follow-up time of 6.2 years; range of 1.4 to 13.7 years). Predicting out- come for patients with intermediate stages of disease is much more difficult. In this re- gard, only 52% (12 of 23) of the patients with stage II disease remain alive and free of disease (median 6.3 years; range 0.1 to 17.8 years). Among 4 patients with stage III dis- ease, only one remains alive and free of disease for 6 years. This patient’s tumor regressed with mitotane and subsequently could be completely excised.
In summary, two distinct prognostic groups of patients with ACT can be recog- nized: one with a very poor prognosis - patients with metastatic disease or gross re- sidual tumor - and another with a very good prognosis - patients with completely resected tumor of small size or adenoma histology. Together, the latter patients represent 40% newly diagnosed children with ACT.
Future directions
We are now planning a new treatment protocol for patients at high risk of relapse.
Because local recurrence is commonly the first site of relapse, we will perform careful surgical and pathological assessment of re- gional lymph nodes obtained at surgery. Be- cause mitotane, as adjuvant chemotherapy, has been of little benefit, it will not be in- cluded in the initial treatment of patients whose tumors have been completely excised. For patients with local recurrence, surgery will be attempted and local radiotherapy will be considered for selected patients.
We are excited about the observations that Southern Brazilian children with ACT carry a specific germline p53 mutation (59). We plan to investigate the consequences of this molecular lesion vis-à-vis the epidemio- logical aspects of ACT in Southern Brazil and hope to shed light on the biology of this tumor.
Moreover, to learn more about the natu- ral history of pediatric ACT, we have devel- oped an international registry for this rare tumor. After informed consent is obtained, investigators register demographic, clinical, and laboratory information; follow-up data are obtained yearly. An Internet Web site (60) has been established to disseminate in- formation about the tumor to medical pro- fessionals.
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