Adreno-cortical Carcinoma in Infancy and Childhood: A Radiological Report of Ten Cases*
G. S. JONES, K. J. SHAH and J. R. MANN+
Departments of Diagnostic Radiology and tOncology, Birmingham Children’s Hospital, Birmingham
Adreno-cortical carcinoma is a relatively rare neoplasm in infancy and childhood. This review, covering a period of 18 years (1965-83), revealed 10 cases, the study being prompted by three patients in whom the final diagnosis was considerably delayed. There were eight females and two males and their ages ranged from 6 months to 14 years; 50% were below the age of 18 months at the time of the presentation. Seven patients had features of either virilism or precocious puberty and three of these also had stigmas of Cushing’s syndrome. In patients where the endocrine disturbance was evident, the clinical diagnosis was made rapidly. However, delay in diagnosis occurred when endocrinopathy was absent. Radiology, including newer methods of imaging, contributed by revealing the tumour and its spread but did not suggest a conclusive diagnosis. At times, clinical features, bioche- mical findings, radiological investigations and even histological studies mislead, thus delaying the final diagnosis. These cases are illustrated and discussed.
Adreno-cortical carcinoma is a relatively rare neo- plasm in children (Stewart et al., 1974; Schweisguth, 1982). It is commoner in females than in males (Sutow et al., 1973; Zaitoon and Mackie, 1978). Fraumeni and Miller (1967) also reported abnormalities of the con- tralateral adrenal gland including a second tumour, atrophy or absence of the gland. They also reported tumour occurrence in siblings and an increased inci- dence of a second primary tumour of the brain.
The clinical features of this tumour vary consider- ably. It may present with endocrinopathy, the most common manifestation being either virilism or a mixture of virilism and Cushing’s syndrome (Sutow et al., 1973). Alternatively, it may present as an abdo- minal mass with no endocrine activity (Visconti et al., 1978). Functioning tumours tend to be diagnosed earlier than the non-functioning variety (Heinbecker et al., 1957).
This is a retrospective review of 10 cases of adreno- cortical carcinoma which presented to the Birmingham Children’s Hospital in the 18 years from 1965 to 1983. Our study was prompted by three patients whose final diagnoses were delayed. The cases in this series illustrate the considerable diagnostic problem that this tumour can pose when it does not exhibit the typical features of a soft-tissue abdominal mass associated with an endocrine disturbance.
* Based on a paper given by K.J.S. at the 21st Congress of the European Society of Paediatric Radiology, Florence, Italy, 9-14 April 1984.
Correspondence to Dr K. J. Shah, The Children’s Hospital, Ladywood Middleway, Birmingham B16 8ET, UK.
PATIENTS AND METHODS
The hospital disease and radiological classification coding systems revealed 10 patients over the period from 1965 to 1983 seen with a final diagnosis of adreno-cortical carcinoma. There were eight females and two males. Their ages ranged from 6 months to 14 years; five were below the age of 18 months and four of these were in their infancy at the time of initial presentation. The clinical records and radiological examinations of these patients were reviewed and the relevant data extracted for this report.
CLINICAL FINDINGS
Table 1 summarises the relevant clinical details of these 10 patients. Seven patients had features of either virilism or precocious puberty; three of these patients also had stigmas of Cushing’s syndrome. The remain- ing three children had no clinical evidence of endo- crine disturbance at their initial presentation. In pa- tients where the endocrinopathy was evident, the clinical diagnosis was readily made.
RADIOLOGICAL FINDINGS
The radiological investigations carried out in these patients are summarised in Table 2. A plain abdomin- al radiograph was taken in each case and eight patients had intravenous urography. Newer imaging methods were used in the most recent patients: abdominal ultrasound was performed in five and computed tomography (CT) in only one.
Radiology confirmed the presence of a mass in nine of the patients. In Case 6 an unsuspected tumour was found incidentally during a post-mortem examination after unsuccessful surgery for congenital heart disease. Analysis of the plain radiographs demonstrated a soft-tissue abdominal mass in nine patients, with associated calcification in five (Fig. 1). The ipsilateral kidney was seen to be depressed in six of the eight intravenous urograms (IVUs) and the kidney was separate from the mass in five cases (Fig. 2). Abdo- minal ultrasound, carried out in five patients, con- firmed the presence of a mass and localised it to the adrenal gland in four (Fig. 3). The tumour was of mixed echogenicity in all cases and had an irregular outline in four. Tumour calcification was seen on ultrasound in four out of five cases and its presence confirmed either by plain radiography or histology.
Arteriography was performed in only one patient. A
| Case | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | |
| Sex | F | M | M | F | F | F | F | F | F | F |
| Age | 16 months | 1 year | 1year | 3.5 years | 10 years | 3 years | 6 months | 8 years | 14 years | 10 months |
| Virilisation/sexual precocity | + | + ☒ | + ☒ | + ☒ | + ☒ | + ☒ | + | |||
| Cushing's syndrome | ☐ | + ☒ | ☐ | + ☒ | ☐ | ☐ | ☐ | + ☒ | ☐ | ☐ |
| Abdominal mass | + ☒ | ☐ | ☐ | + ☒ | + ☒ | |||||
| Hepatomegaly | ☐ | ☐ | ☐ | + ☒ | + ☒ | + ☒ | ||||
| Hypertension | ☐ | + ☒ | + ☒ | ☐ | ☐ | + ☒ | + ☒ | ☐ | ☐ ☐ | |
| Height 50+ percentile | + ☒ | + ☒ | ☐ | + ☒ | ☐ | + ☒ | + ☒ | |||
| Weight change | Gain | Gain | ☐ | Gain | Gain | Gain | Loss | Gain | Loss | Gain |
| Case | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | |
| Plain film | ||||||||||
| Soft-tissue mass | + ☒ | + ☒ | + ☒ | + ☒ | + ☒ | ☐ | + | + | + ☒ | + |
| Calcification | + ☒ | + ☒ | + | + | + | |||||
| Increased bone age | + ☒ | + ☒ | ||||||||
| Pulmonary metastases | + ☒ | + ☒ | + | + | ||||||
| Bone metastases | + | |||||||||
| IVU | ||||||||||
| Depressed kidney | + ☒ | + ☒ | + | + | + | + | ||||
| Mass separate from upper renal pole | + ☒ | + ☒ | + | + ☒ | ☐ | + | ||||
| Correct localisation | + ☒ | + ☒ | ☐ | + | + ☒ | ☐ | ☐ | + | ||
| Ultrasound | ||||||||||
| Mass of mixed echogenicity | + ☒ | + | + | + | + ☒ | |||||
| Separate from upper renal pole | + ☒ | + | + | | | + ☒ | |||||
| Calcification | + ☒ | - + | + | |||||||
| Correct localisation | + | + | + | + | ||||||
R
H
F
H
F
(a)
(b)
(a)
(b)
hypertrophied splenic artery was demonstrated which was bowed superiorly by a lobulated mass arising from the suprarenal region. Its blood supply was from numerous anomalous vessels, some of which appeared to come from the splenic artery (Fig. 4).
An inferior venocavogram was carried out in Case 8. It confirmed the deviation of the inferior vena cava previously shown on ultrasound. The inferior vena cava was partially obstructed above the level of the renal veins and there was a well established collateral venous circulation draining via the hemi-azygos system to the proximal portion of the cava.
A brief account of the case histories of three patients illustrates the features of this disorder and the difficulty sometimes encountered in making the diagnosis.
ILLUSTRATIVE CASE REPORTS
Case 5. A 10-year-old girl presented in 1975 with features of sexual precocity. Biochemical tests at that time revealed elevated urinary 17-oxo-steroid and pregnanetriol levels following ACTH stimulation which were supressed by dexamethasone. A clinical and biochemical diagnosis of 21-hydroxylase congenital adrenal hyper- plasia was made. She was treated with cortisone for 2 years and during this period there was no significant clinical or biochemical change. During the subsequent year, despite increasing cortisone dosage, rising urinary 17-oxo-steroid levels were noted. This led to a clinical and radiological reassessment and the investigations re- vealed a left-sided adrenal mass which was subsequently confirmed to be an adreno-cortical carcinoma by surgery and histology.
Case 7. A 6-month-old girl presented in 1975 with a 4-month history of multiple subcutaneous nodules on her head, neck and abdomen. She was a thin infant with a distended abdomen. Hepatomegaly and a large mass were palpable in the right upper abdominal quadrant (Mann et al., 1983).
(a)
A large, mainly right-sided mass extending to the left and containing patchy calcification was seen on the plain abdominal radiograph. There was also a separate paravertebral mass extending into the posterior mediastinum (Fig. 5a, b). Metastatic deposits were present within the lungs (Fig. 5c), proximal humeri, femora, radius and skull. An ultrasound examination suggested that the mass originated from the right retroperitoneal region. It was of mixed echogenicity and extended under the liver, towards both domes of the diaphragm, downwards to the umbilicus and laterally to the abdominal wall on the right side.
A radiological diagnosis of a neuroblastoma was made, although pulmonary metastases are unusual in this condition. Histology of an inguinal lymph node biopsy was at first thought to be consistent with either a hepatoblastoma or a teratoma. None of these three diagnoses was supported by biochemical evidence, so the exact nature of the tumour remained in doubt until signs of virilisation developed 6 months later. The radiological and pathological findings were then reviewed and were found to be consistent with adreno- cortical carcinoma. In view of the widespread nature of the malignancy, she had not received any specific therapy during the period of observation.
Case 9. A 14-year-old female presented with a 1-year history of malaise, weight loss and amenorrhoea. Abdominal examination revealed a hard, tender liver, palpable to 4 cm below the costal margin, and a large, irregular mass in the right loin. She was also found to be hypertensive.
Abdominal radiographs confirmed the presence of a mass which contained faint calcification. An ultrasound examination carried out by the referring hospital was reported as showing an enlarged right kidney and a mass of mixed echogenicity distorting the renal pelvis. It was considered that the tumour was of renal origin. Computed tomography was also interpreted as showing a renal mass (Fig. 6).
1
(b)
(c)
The para-aortic nodes were enlarged and there were also metastatic deposits in the lungs. Histology of a right renal biopsy was suggestive of a hypernephroma or another clear-cell tumour.
This was treated as a case of metastatic hypernephroma with medroxyprogesterone acetate 100 mg t.d.s. Four months after the initial presentation she developed Cushing’s syndrome. The diagno- sis was then revised to adreno-cortical carcinoma, which was confirmed at the necropsy examination.
DISCUSSION
Adreno-cortical carcinoma in childhood may pre- sent a considerable diagnostic problem by virtue of its rarity, its variable clinical presentation and biochemis- try, its non-specific radiological findings and, at times, its confusing histology.
During the 18-year period of the study, 10 cases were seen at Birmingham Children’s Hospital, which is a regional referral centre in the West Midlands for paediatric oncology and endocrinology, covering a childhood population of about one million. This compares with a study based in Toronto where 13
L
L
(a)
(b)
patients were seen in 38 years (Daneman et al., 1983), while in a Manchester series covering a period of 20 years only five cases of functioning adreno-cortical carcinoma were reviewed (Stewart et al., 1974).
It seems logical that only major centres or mul- ticentre groups can hope to gain significant experience in the diagnosis and treatment of this disorder (Shah et al., 1984). The poor survival of these patients may, in part, be attributed to a lack of familiarity with the disease (Hayles et al., 1966; Stewart et al., 1974).
In our study, when there was clinical and biochemic- al evidence of an adrenal hypersecretory state and the presence of a palpable mass, the diagnosis was made rapidly. However, when the presentation varied from this form, the diagnosis was often delayed. Seven of the 10 cases presented with either virilisation or a mixed endocrinopathy. The presence of these mixed forms of endocrine disturbance in children favours the diagnosis of an adreno-cortical tumour rather than hyperplasia (Stewart et al., 1974). Of the remaining three cases where there was delay in diagnosis, two developed endocrine dysfunction after their initial presentation and the third had an endocrinopathy which was considered to have a benign rather than a malignant aetiology.
The delay in diagnosis caused by non- or late- functioning tumours has been reported by other work- ers (Heinbecker et al., 1957; Marsden et al., 1978). Adreno-cortical carcinoma is reported to be common- er in females (Sutow et al., 1973; Zaitoon and Mackie, 1978) and this was supported by our series, where there were eight females and two males. Fifty per cent of our patients were below 18 months of age at the time of presentation. When an endocrinopathy pre- sents acutely before the age of 1 year, carcinoma is more likely than adenoma or hyperplasia (Jones and Campbell, 1976).
Radiology plays an important role in the diagnosis and management of these patients. It localises the tumour to the suprarenal region, detects tumour spread and can give useful guidance for needle biopsy (Kuhns, 1981). Without evidence of local or metastatic
spread it cannot distinguish beween an adenoma and a carcinoma.
In our series abdominal radiographs demonstrated a soft-tissue mass in nine cases and calcification in five. In the Toronto study (Daneman et al., 1983) a mass was detected in 10 of the 13 patients and calcification in only three. These two findings are said to be more common in carcinomas than in adenomas (Daneman et al., 1983). Plain radiographs also help to detect bone and pulmonary metastases. The lungs were the most common site for metastatic spread, occurring in four of our patients. This form of spread helps to distin- guish the disorder from neuroblastoma, as pulmonary metastases are uncommon in the latter (Russell and Rubenstein, 1971).
Localisation of the tumour by intravenous urogra- phy relies on demonstration of the mass separate from the upper pole of the kidney (Sutton, 1975). Evidence of extracapsular spread, such as an indistinct renal outline or loss of renal opacification, suggests the malignant nature of the lesion (Daneman et al., 1983). In our series eight patients had IVUs and in five the adrenal tumour was accurately localised. Of the re- maining three patients, in one the IVU demonstrated an indistinct upper renal pole whereas a subsequent ultrasound examination showed the mass to be sepa- rate from the kidney. Intravenous urography and ultrasonography are complementary rather than mutually exclusive. The IVU in Case 4 failed to demonstrate the smallest tumour in the series. Renal invasion in Case 3 was interpreted as indicating a primary renal tumour.
Ultrasound examinations were carried out using a static B-mode scanner with grey-scale facilities. In Case 10, where ultrasound demonstrated a well de- fined smooth margin, the lack of extracapsular spread was confirmed at surgery. None of our patients had isotope studies and only in one case was a CT scan performed. This was mainly because these facilities were not present within our own hospital. Computed tomography was used in Case 9 which proved to be a difficult diagnostic problem and, despite extensive
investigations, including ultrasound, CT and needle biopsy, the final diagnosis was not made until the patient subsequently developed clinical features of endocrinopathy. Tumours as small as 0.5 cm in diameter have been detected by CT, although larger ones may be missed in thin patients, in children and where movement artefacts occur (Eghari et al., 1980). It has been suggested that CT is the single most important method for assessing primary and metastatic disease at diagnosis and follow-up (Daneman et al., 1983). It has the advantage over other methods of showing the extent of the tumour in the abdomen, thorax and brain at the same examination.
The two cases where there was some difficulty in interpreting tumour histology illustrated the import- ance of close communication between the clinician, the radiologist and the pathologist. In both instances, review of the results after the development of an endocrinopathy led to the correct diagnosis being made.
This study highlights the variability of the clinical, radiological and histological findings of this tumour. It also emphasises that a multidisciplinary approach at a regional centre is essential in the diagnosis and man- agement of this rare tumour.
Acknowledgements. These children were under the care of consultant paediatricians and surgeons at the Birmingham Chil- dren’s Hospital and in the West Midlands region. Our thanks to them, to Dr A. H. Cameron for the histopathological studies, to Dr P. H. W. Rayner for advice on the endocrine features and investigations and Mrs S. Sheahan for secretarial assistance.
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