ORIGINAL ARTICLE
B. Mukhopadhyay . D. Ganguly . S. Chowdhury
D. Maji . A. K. Sarkar . M. Mukhopadhyay
R. Sarkar · P. K. Mishra
Paediatric adrenocortical neoplasia - a study of 25 cases
Accepted: 26 January 1996
Abstract We reviewed our experience of 25 children with adrenocortical tumours from January 1980 to December 1994. Their ages ranged from 7 months to 15 years; there were 16 girls and 9 boys. Truncal obesity, moon facies, hypertension, and virilisation were the most common clin- ical features. Establishment of the diagnosis of Cushing’s syndrome was accomplished by hormonal and radiological studies. Eighteen patients had adrenocortical carcinomas, but 2 of them refused operation; 7 had adrenocortical adenomas. Twenty-three patients were treated by surgery; 6 with carcinomas are still alive after periods of 6 months to 3 years. The results of treatment of adrenocortical carcino- ma have been poor, but the prognosis is excellent for benign lesions.
Key words Cushing’s syndrome . Adrenocortical carcinoma · Adrenocortical adenoma
B. Mukhopadhyay
Department of Paediatric Surgery, Institute of Postgraduate Medical Education and Research, SSKM Hospital, Calcutta, India
D. Ganguly . S. Chowdhury · D. Maji Department of Endocrinology, Institute of Postgraduate Medical Edu- cation and Research, SSKM Hospital, Calcutta, India
A. K. Sarkar
Department of Paediatric Medicine, Institute of Postgraduate Medical Education and Research, SSKM Hospital, Calcutta, India
M. Mukhopadhyay Department of Pathology, Medical college, Calcutta, India
R. Sarkar Department of Anaesthesiology, Institute of Postgraduate Medical Education and Research, SSKM Hospital, Calcutta, India
P. K. Mishra
Department of Surgery, Institute of Postgraduate Medical Education and Research, SSKM Hospital, Calcutta, India
B. Mukhopadhyay ☒
7E, Dino Bandhu Mukherjee Lane, Sibpur, Howrah-711 102, India
Introduction
The incidence of endogenous or spontaneous Cushing’s syndrome (CS) due to adrenocortical tumours (ACT) in children is extremely rare, accounting for 0.3%-0.4% of all paediatric neoplasias [8]. Descriptions of typical hypercor- tisolism in infancy and childhood appeared in the literature [1, 9] long before the classic report of Harvey Cushing [4]. Because of the low incidence, it has been difficult for any single group to obtain extensive experience with this unusual but interesting clinical problem.
We have had the opportunity to study and treat 25 patients with CS due to adrenocortical carcinoma (ACC) and adrenocortical adenoma (ACA). The purpose of re- viewing our experience with adrenal CS and its diagnostic and therapeutic aspects is to promote familiarity with this disease, earlier recognition, and early surgical intervention whenever indicated, and thereby improve the survival rate.
Materials and methods
From January 1980 to December 1994, we treated 25 patients with spontaneous CS at the Institute of Postgraduate Medical Education and Research, SSKM Hospital, Calcutta. There were 16 girls and 9 boys; ages ranged from 7 months to 15 years, the majority being between 5 and 10 years of age (Table 1). The clinical manifestations are summarised in Table 2. Truncal obesity (Fig. 1), virilisation, and hypertension were the most frequently encountered features. Nine patients had a palpable abdominal mass that proved to be carcinoma at operation.
Establishment of the diagnosis of CS was accomplished by studies of adrenocortical function and the adrenal-pituitary relationship. Ele- vated serum cortisol and urinary 17-hydroxysteroids (17-HS) and loss of diurnal variation were present in all cases. The levels of plasma cortisol and urinary ketosteroids were raised markedly in cases of ACC. A dexamethasone suppression test (low and high doses) was positive in 23 patients and negative in 2. Serum electrolytes were normal in all cases. In 2 patients the blood glucose was high but could be controlled with pre-operative soluble insulin.
The radiological imaging investigations carried out are shown in Table 3. Ultrasonography (US) of the abdomen revealed an adrenal tumour in 19 patients and in 3 was not conclusive. Computed tomography (CT) of the abdomen became available in the latter part
| Age (years) | Males | Females | ACC | ACA |
|---|---|---|---|---|
| 0-5 | 3 | 1 | 4 | 0 |
| 5-10 | 5 | 10 | 13 | 2 |
| 10-15 | 1 | 5 | 1 | 5 |
| Presenting symptoms | Number of patients | Percentage |
|---|---|---|
| Truncal obesity | 19/25 | 76 |
| Hypertension | 22/25 | 88 |
| Hirsutism | 17/25 | 68 |
| Mental aberrations | 4/25 | 16 |
| Ecchymoses | 14/25 | 56 |
| Striae | 7/25 | 28 |
| Muscle weakness | 3/25 | 12 |
| Menstrual changes | 9/16 | 56 |
| Inappropriate deep voice | 7/25 | 28 |
| Inappropriate clitoral enlargement | 9/16 | 56 |
| Inappropriate penile enlargement | 5/9 | 55 |
| Gynaecomastia | 1/9 | 11 |
| Palpable abdominal mass | 9/25 | 56 |
| No. of cases | Findings | |
|---|---|---|
| Skull radiograph | 25/25 | Normal 25/25 |
| Spine radiograph | 16/25 | Osteoporosis 9/25 |
| IV urography with | 7/25 | Adrenal mass 4/7 |
| pneumography | ||
| Ultrasonography of abdomen | 22/25 | Adrenal mass 19/22 |
| CT scan of abdomen | 15/25 | Adrenal mass 15/15 |
| CT scan of brain | 6/25 | Normal 5/6 |
| Metastases 1/6 |
of the study and was the most informative investigation. IV urography with retroperitoneal pneumography was done in 7 patients in the initial part of the study. It was helpful in 4 and was later abandoned because of poor patient acceptance. Spinal radiographs were done in patients who complained of backache, and osteoporosis was noted in 35% of the cases. Skull radiographs were normal in all patients. CT of the brain was done in 6 patients and was reported as normal in 5. One patient showed multiple cerebral metastases 3 months after excision of an ACC. None of the patients had angiography or radionuclide studies. Adrenocorticotropic hormone (ACTH) levels could not be estimated because of a lack of facilities at the Institute.
Two patients diagnosed as having ACC clinically, biochemi- cally, and radiologically refused operation. Perioperatively, patients were prepared and supported with corticosteroids. Of the 16 patients with ACC, 14 underwent unilateral excision of the adrenal tumour and 2 had en-bloc removal of the tumour and the ipsilateral kidney. None of the patients had regional lymph node involvement around the inferior vena cava. Of the 7 patients with ACA, 6 underwent unilat- eral adrenalectomy and 1 a bilateral adrenalectomy (bilateral ade- nomas).
A transverse, transperitoneal upper abdominal approach was used in 22 patients; 1 had a posterior lumbar approach (the 1st patient in the series). The primary site was the right adrenal gland in 16 patients and the left adrenal in 9. The weight, size, and histopathology of the
tumours were analysed. In 14 of the 23 operated patients the tumour weighed more than 150 g (range 150-1,780 g), and all these tumours were malignant. All benign tumours (adenomas) were less than 100 g. In 2 patients with tumour weights of 112 and 135 g the tumours showed marked vascular and capsular invasion and behaved clinically as malignant tumours, and they died within a period of 1 year. All tumours measuring more than 6 cm in diameter were malignant in our series. Tumour necrosis, pleomorphism, and abnormal mitoses were seen in both ACC and ACA, but marked capsular and vascular invasion was seen only in ACC in our series.
Results
One patient with ACA was lost to follow-up 6 months after operation. Six patients with ACA are doing well and are followed regularly with a maximum follow-up of more than 10 years in 2 cases. In contrast, the results of treatment of ACC have been poor. Of the 18 patients, 2 refused ope- ration and died within periods of 3 and 5 months at home. Early in the series, 1 patient aged 11 months died in the immediate post-operative period due to shock that proved refractory to vigorous steroid therapy and other measures. An autopsy could not be done. Eight patients died within 6 months to 4.5 years after operation. Two patients were lost to follow-up 6 and 8 months post- operatively, respectively.
Six patients with ACC are still alive after periods of 6 months to 3 years. Only 3 patients received treatment with Mitotane (o’-p’ DDD; Orthopara isomer of Dichloro Diphenyl Dichloroethane); 2 of them died 3.5 and 4 years after operation and 1 is alive after 2 years and 8 months. The largest tumour removed weighed 1,780 g. Periodic physical examinations, measurement of plasma cortisol and urinary 17-HS, and skull radiographs during follow-up have shown no evidence of hypercortisolism or Nelson’s syn- drome in those with benign lesions.
Discussion
Ideal objectives in the treatment of CS have been outlined by Orth and Liddle [16]. They include: (1) removal of any functioning tumour that threatens health; (2) reduction of excessive cortisol secretion to normal; (3) retention of normal pituitary and adrenal function; and (4) avoidance of permanent dependance on hormonal substitution therapy. A female preponderance was observed in our series, as has also been reported by Gold [11] and Lobo et al. [13]. The English literature indicates that children under the age of 8 years with CS are more likely to have an ACT [14].
The presence of a palpable abdominal mass in a patient with CS is almost always indicative of a malignancy [18, 19], and this was confirmed in our experience. US and CT are the most effective imaging modalities to establish the diagnosis of primary adrenal disease, with an estimated accuracy of 90% [5, 6]. CT is the most informative investigation, but remains an expensive technique. We have not done radioiodinated cholesterol scans and magnetic resonance imaging because of non- availability of these investigations. Selective adrenal venous sampling and renal arteriography are now rarely used [10].
Most paediatric ACTS are hormonally functional, and virilisation is seen with most of the malignant tumours [18]. Establishment of hypercortisolism can be made using a variety of rather simple screening tests, none of which is infallible [15]. These include determination of basal plasma cortisol, basal urinary excretion of free cortisol and 17-HS, and studies of their diurnal variation, and suppressibility by dexamethasone. Recently developed cytochemical or iso- lated adrenal cell assays are still tedious and not available to clinicians. Radioimmunoassay is the method of choice for measuring plasma ACTH, but is not available at our Institute. The finding of extremely elevated urinary excre- tion of 17-HS is suggestive of ACC. Determination of serum or urinary androgens, oestrogens, or aldosterone is useful when virilisation, feminisation (a rare presentation seen in 1 of our patients), or salt retention are dominant clinical features [2].
A long, transverse, transabdominal incision gives the best exposure of large and malignant tumours [7]. Compli- cations after operations included a wound infection in 1 patient and persistent hypokalaemia in another. It is difficult to differentiate histologically most of the time between benign and malignant ACTs in the absence of metastasis and capsular invasion [20]. We agree with the opinion that tumours more than 6 cm in diameter [21] behave in a malignant manner. All benign tumours in our series were less than 6 cm in diameter. Tumour weight is one of the most important suggestive criteria to differentiate between ACC and ACA [3, 20]. Except in 2 cases (the tumours weighed 112 and 135 g and showed malignant behaviour during follow-up), we found that tumours weighing more than 150 g were malignant.
Guidelines for diagnosing ACC according to our criteria are: (1) clinical behaviour, e.g., marked virilisation and a palpable abdominal mass; (2) weight (more than 150 g) and size (more than 6 cm in diameter); (3) marked vascular and capsular invasion; (4) radiological findings suggestive of a metastatic lesion (e. g. multiple cerebral metastases on CT); and most important, (5) the post-operative course and follow-up.
The results of treatment of ACC with conventional surgery, radiotherapy, and chemotherapy (Mitotane) have been poor [12, 17]. Our experience with Mitotane is limited because the drug has to be imported and is very expensive. The surgical results of benign tumours were excellent in our study. The contralateral, suppressed adrenal gland usually recovers in 3 to 6 months, and steroid replacement may then be tapered gradually. Some patients have relative adrenocortical insufficiency for varying periods and must be warned that steroid replacement will be necessary in times of stress.
In conclusion, ACTs in children are rare and are most frequently functional. Unlike adenomas, carcinomas are biochemically pleuripotent and produce excessive quanti- ties of androgens, glucocorticoids, and oestrogens (where these have been measured). In malignant ACTs, virilisation is most often marked and the mass is palpable. The tumour is usually advanced at the time of diagnosis, and complete surgical excision offers the best prospect of cure.
Acknowledgements We are grateful to the Director, Institute of Postgraduate Medical Education and Research, and the Surgeon-Su- perintendent, SSKM Hospital, Calcutta, for allowing us to publish this article and to Drs. Pradip Deb and Prabir Sengupta from the Depart- ment of Radiodiagnosis for their help.
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