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Pediatric Hematology and Oncology 0
Pediatric Hematology and Oncology
ISSN: 0888-0018 (Print) 1521-0669 (Online) Journal homepage: http://www.tandfonline.com/loi/ipho20
Adrenal Cortical Tumors in Childhood
C. P. Driver, J. Birch & J. Bruce
To cite this article: C. P. Driver, J. Birch & J. Bruce (1998) Adrenal Cortical Tumors in Childhood, Pediatric Hematology and Oncology, 15:6, 527-532, DOI: 10.3109/08880019809018314
To link to this article: http://dx.doi.org/10.3109/08880019809018314
Published online: 09 Jul 2009.
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ADRENAL CORTICAL TUMORS IN CHILDHOOD
C. P. Driver, FRCS (Ed) ☐ Department of Paediatric Surgery, Royal Manchester Children’s Hospital, Manchester, UK
J. Birch ☐ Manchester Children’s Tumor Registry, Royal Manchester Children’s Hospital, Manchester, UK
D. C. S. Gough and J. Bruce, FRCS (Ed) ☐ Department of Paediatric Surgery, Royal Manchester Children’s Hospital, Manchester, UK
D In a 41-year period, 18 children with a diagnosis of an adrenal cortical tumor were identified ☐ (14 carcinoma : 4 adenoma). The majority of patients had clinical signs of endocrine dysfunction at presentation, with virilization (11 patients) and a cushingoid appearance (8 patients) the commonest findings. Abnormal biochemical activity was identified in 16 tumors (94 % ). The primary treatment in 17 patients was surgical. In addition, 12 children, all with carcinomas, had radiotherapy. Of those children with a carcinoma, 12 are dead, with a median survival of 52 months (range 1-317 months). The three second primary tumors all developed at sites within the field of previous radiotherapy, and proved fatal at 127, 176, and 317 months (median 207 months). This series confirms the poor prognosis in adrenocortical carcinoma in childhood, but a complete resection is compatible with cure of the primary disease. The frequency of second, fatal, primary tumors is of particular concern and long-term follow-up is mandatory in survivors, especially if radiotherapy was part of the treatment protocol.
Keywords. adrenal cortical carcinoma, pediatric, surgery
Adrenocortical tumors are rare in the general population, and are es- pecially unusual in children [1, 2]. They account for 0.3% of all referrals to specialist pediatric oncology units, and the majority of cases occur in children less than 5 years old [2].
In 1974, a report from the Royal Manchester Children’s Hospital sug- gested an improved prognosis in patients with adrenocortical carcinoma- the first in the pediatric literature to do so [3]. Our recent experience, how- ever, identifies a much poorer prognosis, with several long-term survivors developing second primary tumors. The experience of adrenocortical tu- mors in the northwest of England is reviewed and discussed.
PATIENTS AND METHODS
In the 41-year period between 1954 and 1995, 18 children with a diagnosis of an adrenal cortical tumor were identified from the Manchester Children’s Tumour Registry. This registry is population-based and collects detailed infor- mation and histopathological material on all malignant and certain benign tumors occurring in children aged less than 15 years who were resident in a defined area of northwest England at the time of diagnosis. The registry has almost complete ascertainment of cases and is described in detail elsewhere [4]. There were 15 girls and 3 boys. The tumor registry records and hospital case notes were reviewed. All histological diagnoses had been confirmed by the tumor registry panel of pathologists.
RESULTS
Clinical
Of the 18 patients presenting with an adrenal cortical tumor, 14 had carcinomas and 4 had an adenoma. The age at presentation and duration of symptoms are shown in Table 1. The majority of patients had clinical signs of endocrine dysfunction at presentation, with virilization (11 patients) and a cushingoid appearance (8 patients) the commonest findings. Four patients were both cushingoid and virulized and 4 showed signs of precocious puberty. In 11 children an abdominal mass was palpable at presentation, and all subsequently had a carcinoma diagnosed.
Biochemical Function
Abnormal biochemical activity was identified in 16 of 17 tumors (94%), with no data available on one other tumor. All four adenomas were andro- gen secreting, as were 7 of the carcinomas. There were 3 steroid-secreting carcinomas and 2 tumors were both androgen and steroid producing. Only one tumor was definitely nonfunctional.
Pathology
Histological examination showed 14 with carcinoma and 4 with adenoma, with 8 lesions originating in the left adrenal and 10 in the right. The size of
| Overall | Carcinoma | Adenoma | |
|---|---|---|---|
| Age at presentation | 67 (8-180) | 72 (8-180) | 53 (17-94) |
| Duration of symptoms | 7 (0-24) | 6 (0-24) | 12 (8-18) |
Note. Values are means (ranges) in months.
the adenomas ranged from 3 to 6 cm in diameter and the carcinomas 8 to 25 cm.
Metastases at presentation were identified in 8 of the children with a carcinoma (64%). The most common site of metastasis was lung (6 patients), followed by liver (3 patients), regional lymph nodes (2 patients), and local spread (2 patients).
Treatment
The primary treatment in 17 patients was surgical; the remaining child had only a biopsy due to extensive metastatic disease at presentation. Of the carcinoma patients, a “curative” resection, as assessed at operation, was achieved in 3 children, with 11 patients having a “paliative” procedure. In addition, 12 children, all with carcinomas, had radiotherapy. Adjuvant chemotherapy was given to 6 patients, 3 of whom had mitotane (op-DDD). No benefit to survival was seen following op-DDD administration.
Survival
All the patients with an adenoma are still alive. Of those with a carcinoma, 12 are dead, with a median survival of 52 months (range 1-317 months). Eight children succumbed to the primary tumor, 1 to marrow aplasia subsequent to cyclophosphamide chemotherapy, and 3 from second primary tumors. The 2 children still alive are currently each 114 months following presenta- tion. Both had a “curative” resection of the primary tumor and had definite carcinomas on histological review. The three second primary tumors all de- veloped at sites within the field of previous radiotherapy and proved fatal at 127, 176, and 317 months (median 207 months). If they are excluded, the median survival of those children dying from their primary pathology was only 6 months (range 1-28 months).
DISCUSSION
The first childhood case of an adrenal tumor was reported in 1865 [5] and is still considered to have a poor prognosis, with local recurrence and eventual death from metastatic disease the rule [6]. Most carcinomas, as in our series, present at a stage where “curative” surgical resection is not possible, thus adversly affecting prognosis.
A delay between the onset of symptoms and the time of final diagnosis [3, 7] is, however, not uncommon. The deep retroperitoneal location of the adrenal gland makes early identification of a tumor difficult and a time lapse of 1 to 4 years has been reported [8]. Although 79% of our patients with carcinoma had an abdominal mass on initial examination, this was the presenting feature in only one child.
Almost all of our children presented with clinical signs of endocrine dysfunction. In contrast with adult experience, nonfunctioning tumors are extremely rare in children [3, 9, 10]. Androgenic effects, producing viriliza- tion and precocious puberty, are more common than cushingoid effects, as was seen in our series. A mixed picture, with features of both virilization and Cushing’s syndrome, is more suggestive of neoplasia than hyperplasia, which usually produces a pure endocrine syndrome [3, 11].
Surgical excision is the mainstay of therapy in the management of adreno- cortical tumors, with complete excision of the primary tumor and metastases the aim. Although local recurrence or metastases occur in up to 80% of cases after radical surgery [12], repeated aggressive surgical resection of recurrent tumor has led to prolonged survival in some cases [13, 14]. Unfortunately, a “curative” resection was possible in only 3(21%) of the children in our series with carcinomas. All three survived their primary tumor, although one child succumbed at 176 months from a second primary tumor. The outcome of those undergoing a palliative resection was bleak, with 73% dying from carci- nomatosis at a median of 14 months. Two long-term survivors, however, both died of a second primary tumor at 127 and 317 months. A complete resec- tion is therefore compatible with cure of the primary disease. The identifica- tion of metastatic disease at presentation was also a poor prognostic feature in our series, with no patient surviving beyond 28 months, and all succumbing to their primary tumor.
The combination of adjuvant therapy with surgery is controversial. Ra- diotherapy has been both advocated and condemned [3, 15-18], but may be useful in palliation of local disease [6]. Chemotherapy, using cisplatin and etoposide, has also been tried, but with little success [19, 20]. Mitotane (opDDD), an analog of the insecticide DDT, has been used widely, but with variable results. However, a randomized or controlled trial has yet to show a significant increase in duration of survival even in patients who show a clinical response to the drug [21-23]. It may have a role in the management of patients with inoperable, recurrent, and metastatic disease [24].
The frequency of second, fatal, primary tumors in our series is of partic- ular concern. Of the five patients who survived their primary adrenal tumor, 3 (60%) sucumbed to a second primary tumor at a median of 207 months af- ter diagnosis of the adrenocortical carcinoma. All three second tumors were sarcomas, and it is probable that they were radiotherapy-induced, since all were within the field of therapy. However, adrenocortical carcinoma may be associated with an increased risk of other cancers [25] and with other conge- nital abnormalities, including hemihypertrophy, the Beckwith-Wiedemann syndrome, and urinary tract anomalies [26, 27]. A strong family history of malignancy has been described and adrenocortical tumors are known to be part of the Li-Frameni cancer family syndrome (LFS), which includes sarco- mas, brain tumors, breast cancer, and leukemias. A detailed family history is
thus an important part of the assessment of a new patient [28, 29]. Families with LFS frequently carry germline mutations in the P53 tumor suppressor gene. Two patients in the present series of children with adrenal cortical tu- mors have family histories consistent with LFS and have been found to carry P53 mutations [30].
In conclusion, in contrast to a previous report from this institution, this series confirms the poor prognosis in adrenocortical carcinoma in child- hood. Early diagnosis allowing complete surgical resection appears to be the only opportunity to improve outcome, although this is rarely possible. With the significant incidence of second primary tumors and the association of adrenocortical tumors with family cancer syndromes, long-term follow-up is mandatory in survivors, especially if radiotherapy was part of the treatment protocol.
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