FUNCTIONING ADRENAL TUMOURS IN CHILDREN AND ADOLESCENTS: AN INSTITUTIONAL EXPERIENCE
ANJALI MISHRA, GAURAV AGARWAL, ANAND KUMAR MISRA, AMIT AGARWAL AND SAROJ K. MISHRA
Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
Background: The purpose of the present paper was to carry out an audit of clinicopathological profile and treatment outcome in 13 children with functioning adrenal tumours.
Methods: The medical records of 13 children with functioning adrenal tumours who were managed between June 1990 and January 1999 were reviewed. Demographic data, clinical features, biochemical and localization studies, operative details and follow-up records were studied. Children with neuroblastoma were excluded.
Results: The mean age was 7.4 ± 5.3 years. Seven patients had Cushing’s syndrome (CS), two patients had virilizing tumours, three patients had phaeochromocytoma (PCC) and one patient had Conn’s syndrome. All patients (except one child with CS) were treated surgically. Two children with adrenocortical carcinoma (ACCa) died during the perioperative period. Histopathological diag- nosis was adrenal cortical adenoma (ACAd) in four patients, ACCa in five patients and PCC in three patients. Two ACCa patients died of metastases at 12 and 14 months, respectively, while the third is alive and well at 30 months. Children with ACAd are alive and well at 91, 56, 32 and 27 months postoperatively. Children with PCC are free of disease (normal urinary metanephrines) at 63, 18 and 8 months after surgery but require antihypertensive drugs in low doses.
Conclusion: The outcome of surgery is good in cases of ACAd and PCC. Although outcome is poor in ACCa, surgery remains the mainstay of treatment and offers good palliation.
Key words: Conn’s syndrome, Cushing’s syndrome, phaeochromocytoma, virilizing adrenal tumours.
INTRODUCTION
Adrenal tumours are rare childhood tumours.1-3 These constitute less than 1% of all paediatric neoplasms,1 with adrenal cortical car- cinoma comprising only 0.002% of all childhood malignancies.2 Tumours arising from the adrenal cortex and the medulla present with a distinct characteristic and often fascinating spectrum of clinical features. A careful biochemical evaluation is essential to diagnose endocrinopathies associated with these tumours. Com- pared to adults, a higher proportion of adrenal tumours in children is malignant.46 The biological behaviour of these tumours is difficult to predict and it is often difficult to label a tumour as benign or malignant on the basis of histological features.7,8 Surgery remains the mainstay of treatment and offers cure in benign cases, and is the best means of palliation in malignant cases.8,9 We present an audit of 13 cases of adrenal tumours in children treated at Sanjay Gandhi Postgraduate Institute of Medical Sciences over an 81/2-year period.
METHODS
The medical records of 13 children with adrenal tumours managed at Sanjay Gandhi Postgraduate Institute of Medical Sciences between June 1990 and January 1999 were reviewed. Demographic data, clinical details, investigation findings, opera- tive details, histopathological findings and follow-up details were recorded. Diagnostic tests included estimation of basal
serum cortisol, low-dose dexamethasone suppression tests (LDDST) and high-dose dexamethasone suppression tests (HDDST), serum testosterone, serum aldosterone and urinary catecholamines (free catecholamines or metanephrines). Tumours were localized with abdominal ultrasonography (USG) and/or abdominal computed tomography (CT) scanning. X-rays of the chest were done in all cases to check for metastases.
One patient who presented with features of hypercortisolism with virilization refused to undergo surgical treatment. The remaining 12 children were subjected to surgery, with a curative intent. Children with hypercortisolism were given stress doses of steroid beginning on the morning of surgery, in the form of intra- venous infusion. The doses were tapered and patients were switched to oral prednisolone within 3-5 days, which was continued until approximately 6 months postoperatively when recovery of the hypothalamus-pituitary-adrenal (H-P-A) axis was demon- strated by a short adrenocorticotropic hormone (ACTH; synac- thenR, Ciba, UK) test. In children with phaeochromocytoma (PCC), a-blockade was achieved preoperatively with a-blockers.
Patients were discharged once the stitches were removed and postoperative drug (steroid and/or antihypertensives) require- ments were stabilized. The children were followed up 3- monthly twice, 6-monthly during the subsequent 1 year, and annually thereafter. On the follow-up visits biochemical (serum basal cortisol and/or testosterone, short ACTH test in adrenal cortical tumours; and urinary metanephrines in PCC) and imaging studies (if required) were carried out.
RESULTS
Of the 13 children managed during the study period, 10 children had adrenal cortical tumours while three had PCC. The mean
Correspondence: Dr S. K. Mishra, Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, India. Email: skmishra@sgpgi.ac.in
age of these children was 7.4 ± 5.3 years. The mean age did not differ significantly in cortical tumours and PCC (7.3 ± 5.8 years vs 7.6 ± 4.0 years). Because the number of cases is small the sex predilection cannot be commented upon. The median follow up was 28.5 months (range: 8-91 months).
Adrenocortical tumours
The mean duration of illness was 14.2 ± 10.9 months (range: 4-36 months). Seven patients predominantly had symptoms and signs of hypercortisolism (CS), two had purely virilizing tumours, and one had Conn’s syndrome. The clinical features of these patients are summarized in Table 1. Biochemical findings and tumour characteristics are summarized in Table 2.
One child, while on follow up for congenital adrenal hyperpla- sia (CAH) developed features of virilization and growth acceler- ation. Ultrasonography revealed a left adrenal tumour along with bilateral hyperplastic adrenals. The tumour was found to be increasing in size on repeat ultrasonographic examination 6 months later, and it was resected.
Imaging studies carried out included abdominal USG alone in four cases, CT scanning alone in one case and both in five cases.
As well as localizing the adrenal tumours, CT scanning was able to detect lymph node enlargement in one case, inferior vena cava (IVC) thrombosis in one case, and it documented the presence of bilateral adrenal hyperplasia with a left-sided adrenal tumour in a child with CAH. The patient with IVC thrombosis (Conn’s syn- drome) also underwent magnetic resonance angiography (MRA), and thrombus was found extending into the bilateral iliac veins and right femoral vein. Head CT scans were reported as normal in both the cases with convulsions.
The parents of one child with CS (case 2; Table 1) refused surgery. An abdominal CT scan in this case showed a large left adrenal tumour with calcification and necrosis, leading to a high suspicion of malignancy. All other cases were explored through an anterior transperitoneal route. Nine adrenalectomies were performed (five left-sided and four right-sided). Lymph node dis- section was performed in two cases of adrenocortical carcinoma (ACCa). En bloc removal of the left adrenal tumour, left kidney and lymph nodes, along with a thrombectomy from the IVC and both iliac veins, was performed in the child with Conn’s syndrome.
Two children died during the perioperative period. The child with Conn’s syndrome needed mechanical ventilation in the postoperative period and could not be weaned off the ventilator.
| Age (years) | Sex | Duration of illness (months) | Cushingoid features Virilization | Hypertension | Abdominal lump Proximal myopathy |
|---|---|---|---|---|---|
| 6 | F | 6 | + + | + | + – |
| 16 | M | 36 | + + | + | + – |
| 6 | F | 6 | + + | – | – – |
| 1 | F | 4 | + + | + | + – |
| 6 | M | 36 | + – | – | – – |
| 3 | M | 6 | + + | + | – – |
| 4 | F | 6 | + – | – | + – |
| 16 | F | 12 | – – | + | + – |
| 14 | M | 12 | + + | – | + – |
| 1.6 | F | 12 | + + | + | – – |
| Serum cortisol (nmol/L) (normal range: 138-698) | LDDST* | HDDST+ | Serum testosterone (nmol/L)* | Serum aldosterone (pg/mL) (normal range: 10-160) | Tumour characteristics Weight Size (g) (cm) | Histopathology | |
|---|---|---|---|---|---|---|---|
| 1027.86 | Non-suppressed | Non-suppressed | 17.36 | — | 32 | 6.0 | Carcinoma |
| 987.6 | Non-suppressed | Non-suppressed | — | — | — | — | — |
| 1104 | Non-suppressed | Non-suppressed | 19.08 | — | 35 | 5.0 | Carcinoma |
| 916.4 | Non-suppressed | Non-suppressed | 32.8 | — | 12 | 3.8 | Adenoma |
| — | — | — | 24.73 | — | 25 | 3.0 | Adenoma |
| 491 | Non-suppressed | Non-suppressed | — | — | 81 | 8.0 | Adenoma |
| 17 | Suppressed | — | 440 | — | 600 | 13 | Carcinoma |
| — | Suppressed | — | 2.2 | 210 | 500 | 20 | Carcinoma |
| 2207.2 | Non-suppressed | Non-suppressed | — | — | 370 | 14 | Carcinoma |
| 1379.5 | Non-suppressed | Non-suppressed | — | — | 56 | 4.0 | Adenoma |
LDDST, low-dose dexamethasone suppression test; HDDST, high-dose dexamethasone suppression test.
*LDDST: suppressed if plasma cortisol < 0.15 nmol/L.
¡HDDST: suppressed if plasma cortisol suppressed to < 50% of basal cortisol.
¿normal range: prepubertal, 0.3 nmol/L; post-pubertal male, 10-34 nmol/L; post-pubertal female, 0.7-26 nmol/L.
She developed pneumonitis leading to septicaemia, dissemi- nated intravascular coagulation and multiorgan system failure and died on the 9th postoperative day. A male child with Cushing’s syndrome (case 9; Tables 1,2) carcinoma succumbed to respiratory failure. His family did not opt for artificial ventilation due to financial reasons. In addition, one patient each suffered minor wound collection and superficial wound gaping.
On histological examination four tumours were reported as adrenal cortical adenoma (ACAd) and five as ACCa. One case of adenoma had evidence of focal vascular invasion but no capsular invasion. The diagnosis of ACCa was based on the presence of metastatic lymph nodes in two cases, liver metastases in one case and the presence of major vascular and capsular invasion in two cases. The mean tumour weight of cortical tumours was 190 ± 233 g (range: 12-600 g) and was higher for malignant as compared to benign tumours (490 ± 115.3 vs 40 ± 24.6 g). Mean tumour size was 8.5 ± 5.8 cm (range: 3-20 cm) and was con- siderably more for malignant as compared to benign tumours (11.6 ± 6.2 vs 4.7±2.2 cm).
Surgical treatment resulted in a good clinical and biochemical response in all patients. Two patients with ACCa died 12 and 14 months after operation, respectively. The first death was due to liver and lung metastases while the second death was due to liver metastases. One patient with virilizing ACCa was alive 30 months after operation without any clinical, biochemical or radi- ological evidence of metastatic or recurrent disease. All four cases of ACAd are alive without any evidence of disease at 91, 56, 32 and 27 months of follow up.
Phaeochromocytoma
During the study period five children with PCC were managed at Sanjay Gandhi Postgraduate Institute of Medical Sciences. The two children with extra-adrenal PCC were excluded from the present study of adrenal tumours. The median duration of illness was 14 months (range: 3-36 months). The classical clini- cal triad of headache, palpitations and sweating was present in only one case (case 3). The nature of hypertension was sustained with paroxysmal rise in all three children. There was no family history of PCC or other familial syndromes associated with PCC in these cases. The clinical findings in these cases are summarized in Table 3. Abdominal CT scanning was done in all three cases for localization. In addition, USG was done in two cases. Head CT scanning was done in two cases with neuro- logical complications. The child who presented with hemiplegia had evidence of right basal ganglion and external capsule haemorrhage, while the child with convulsions had postictal oedema alone. Investigation findings and tumour characteristics are summarized in Table 4.
The children were prepared with a-blockers (phenoxybenzamine
in the first child, prazosin in the other two), which were given for 10-22 days prior to surgery. The dosages of prazosin required to achieve blockade were 15 and 13 mg, respectively. Beta-blocker (propanolol, 40 mg) was required in case 3 only. All three cases required calcium channel blockers and angiotensin converting enzyme inhibitor (ACE inhibitor) in addition to a-blockers because blood pressure control was not adequate despite high doses of a-blockers. All cases were explored through an ante- rior transperitoneal route. Two left-sided and one right-sided adrenalectomy were performed. The postoperative period was uneventful. The contralateral adrenal gland and ectopic sites were found to be free of tumours on exploration in all.
On histological examination all three tumours were reported as benign adrenal medullary tumours, consistent with the diagnosis of PCC. There was no evidence of malignancy. Case 3 had exudative ascitis, although no malignant cells were found on cytological analysis of the peritoneal fluid. Thus this case needs careful fol- low up to exclude the possibility of malignancy.
The child with hemiplegia improved with conservative treat- ment and had grade 4-5 muscle powers in various muscle groups at the time of discharge. All three children had normal urinary metanephrines at their last follow-up visit (63, 18 and 8 months, respectively), but required antihypertensive treatment for control of persistent blood pressure problems, although in reduced doses.
DISCUSSION
Adrenal cortical tumours
Adrenal tumours are rare in childhood. Most of the adrenal corti- cal tumours in children present with signs of virilization with or without hypercortisolism.10,11 In our experience all children with cortical tumours, except one with hyperaldosteronism, had virilizing features. Seven children had features of hypercortisolism along with virilization while two had pure virilizing tumours. Pluri-hor- monal manifestations predominate in other series as well.12 The mean age in our series was higher as compared to other previously published series and probably reflects a delay in diagnosis and man- agement in our socio-economically poor population.12,13 A female preponderance as observed in the present series has been reported by others as well.5,13,14
Due to wider application of increasingly sensitive radiological investigation techniques adrenal tumours are being detected more frequently in children with untreated congenital adrenal hyperplasia. There have been numerous such reports, including one from our own centre.15-17 In one study the incidence of adrenal masses was found to be as high as 82% in homozygous and 45% in heterozygous patients with CAH.15 In contrast, virilizing adrenal tumour in female children can be confused with CAH.16 Because CAH is a more frequently occurring disorder, it is
| Age (years) | Sex | Duration (months) | Headache | Sweating | Palpitation | Hypertension | Abdominal pain | Others |
|---|---|---|---|---|---|---|---|---|
| 3 | M | 14 | + | + | – | Sustained | + | Constipation |
| 10 | F | 3 | + | + | – | Sustained+ Paroxysm | + | Convulsion |
| 10 | M | 36 | + | + | + | Sustained+ | + | Convulsion |
| Paroxysm | Hemiplegia |
| Fundus | Renal scan | Catecholamines* (ug/dL) (normal range: 31-61) | Metanephrines* (mg/24 h) (normal range: 0.05-1.2) | Tumour characteristics | Histopathology | |
|---|---|---|---|---|---|---|
| Weight (g) | Size (cm) | |||||
| Papilloedema | — | 72.75 | — | PCC | ||
| Grade 4 retinopathy | Left renal artery stenosis | — | 4.6 | 34 | PCC | |
| Normal | — | — | 12.1 | 80 | PCC | |
*Urinary levels.
PCC, phaeochromocytoma.
recommended that CAH should be ruled out in cases of incidentally detected adrenal masses.14 The presence of a hyperplastic con- tralateral adrenal gland is a useful diagnostic sign in a CAH patient with complicating adrenal tumour. Although virilization and CS are common, aldosterone-secreting tumours are extremely rare in children.18
Once diagnosis of CS, virilization or hyperaldosteronism has been substantiated by biochemical tests, abdominal imaging by USG and CT plays an important role in the localization and anatomic delineation of these tumours, and helps in strategy planning for surgical intervention.10,18,19 Abdominal CT is superior in this regard.20 Tumours as small as 0.5 cm have been detected by CT. It can readily detect local invasion, intravenous extension of tumour, lymph node involvement and liver metastases. In a study of seven children, large tumour size (>6 cm diameter) and a complex echo pattern were considered to provide a useful indication of malignancy.19 Although MRI holds considerable promise, its role is still under scrutiny. The most useful application of MRI is in the detection and delineation of venous exten- sion.21
Most of the childhood adrenal tumours are thought to be malignant.4-6 Definitive diagnosis, however, is not possible because there are no absolute histological criteria to distinguish benign from malignant tumours. Some patients whose tumours exhibited benign features have had late metastasis or local recur- rence,22 while others having a microscopic appearance of malig- nancy have survived for years.23,24 Paediatric benign tumours have been found to have frequent mitosis, necrosis, moderate-to- severe pleomorphism and broad fibrous bands when compared with adult tumours and these features are seen in both benign and malignant tumours.7,8,23 Considering all these facts, some investi- gators have concluded that paediatric tumours are more likely to be benign than previously thought.7 In the literature the main criteria for distinguishing benign from malignant tumours are higher tumour weight and mitotic activity.23,24 In the present series we also found that the mean tumour weight of malignant tumours was considerably higher as compared to benign tumours.
Adrenocortical carcinoma has a poor prognosis. Complete surgi- cal resection is the only effective and potentially curative treat- ment.8,9,24-26 Even for recurrent and metastatic disease, surgery provides the only hope for effective palliation or cure.25 A chemotherapeutic regimen using mitotane, and combination chemotherapy with dacarbazine and other drugs has been used by many, but its role is not yet established.8,24-26 Considering the high cost and toxicity of chemotherapy and the minimal benefit in improving quality of life, we did not use chemotherapy to treat ACCa.
Phaeochromocytoma
Phaeochromocytoma is a rare cause of hypertension in child- hood, accounting for less than 1% of all hypertensive chil- dren.3,27,28 Phaeochromocytomas are more likely to be familial, bilateral, multifocal and extra-adrenal in children. In our short series of five children with PCC, two children (40%) had PCC at extra-adrenal sites. No bilaterality or multifocality, however, was present in the three cases of adrenal PCC. All the three children with adrenal PCC in the present series had sustained hypertension, a finding that is consistent with other series. 131Iodine- metaiodobenzyl guanidine (131I-MIBG) scanning is very helpful in localization of adrenal, extra-adrenal, metastatic and ectopic sites of these tumours and in total removal of this potentially curable cause of hypertension.29 This radiopharmaceutical was not routinely available at Sanjay Gandhi Postgraduate Institute of Medical Sciences until recently, and so 131I-MIBG scanning could not be performed in the present study.
Complete surgical excision of adrenal and/or extra-adrenal PCC results in cure of hypertension in most children.3,27 Persistent postoperative hypertension may result due to incomplete removal of the tumour in the primary site, unidentified multifocal disease at adrenal or extra-adrenal sites, and local residual malignant or metastatic PCC. In all these conditions the urinary cat- echolamines and metanephrines would remain high, unlike that of our three PCC patients, who remained hypertensive postoperatively. Causes for persistent postoperative hypertension without cate- cholamine hypersecretion include reno-vascular hypertension, as was the case in one of our patients, irreversible vascular changes caused by prolonged hypertension due to delay in seeking medical attention, as could be in the remaining two cases, and high set baro-receptors. If the urinary metanephrine level is normal than antihypertensives are used for control of blood pressure. In inoperable and metastatic cases, besides pharmaco- logical treatment, 131I-MIBG therapy can offer some palliation.29
As for most endocrine tumours, conventional histological fea- tures are inaccurate in predicting the biological behaviour of the PCC. The presence of metastatic disease at non-chromaffin sites, such as the lymph nodes, liver etc. or a major vascular and capsular invasion and tumour thrombi can be considered as being diagnostic only of a malignant nature. These cases require a careful lifelong follow up to identify and manage a recurrent malignant or metachronous multifocal disease, which can manifest long after the primary management. If a patient is found to have raised catecholamines or metanephrines during follow up, appropriate imaging by CT and 131I-MIBG is useful in identifying recurrent or metastatic disease.3
ACKNOWLEDGEMENTS
The authors wish to acknowledge the contribution of Dr Vijay- alakhsmi Bhatia (Additional Professor, Department of Medical Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow) who was the treating paediatric endocrinologist for all the subjects in the present study.
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