Nine cases of childhood adrenal tumour presenting with hypertension and a review of the literature
Xiumin Wang (wangxiumin1019@126.com), Li Liang, Youjun Jiang
Department of Endocrinology, The Children’s Hospital of Zhejiang, University School of Medicine, Hangzhou 310003, China
Keywords
Adrenal tumour, Children, Computed tomography, Hypertension
Correspondence
Li Liang, M.D., Department of Endocrinology, The Children’s Hospital of Zhejiang, University School of Medicine, 57 Zhugan Xiang, Hangzhou 310003, China. Tel: +86 571 88050412 or +86-139 57107509 | Fax: +86 571 87033296 | Email: wangxiumin 1019@126.com, zdliangli@163.com
Received
8 December 2006; revised 3 March 2007; accepted 7 March 2007. DOI:10.1111/j.1651-2227.2007.00307.x
Abstract
Aim: To describe the clinical features, treatment and outcome of children adrenal tumors presenting with hypertension.
Methods: The records of nine children under 16 years of age with adrenal tumours presenting with hypertension were analysed. Details were recorded for family history, clinical presentation, biochemistry, imaging, histology, treatment and outcome.
Results: Abdominal mass was palpable only in one patient at diagnosis. Besides hypertension- associated symptoms, Cushing’s syndrome was the common presentation form (n = 4). Abdominal computed topography showed adrenal mass in all patients. Tumours were completely resected for each patient. The median tumour weight was 73 g (11-530 g) and the size ranged from 1.5 x 1.5 to 12 × 14 cm2. Pheochromocytoma (n = 2), adrenocortical adenoma (n = 3), adrenocortical carcinoma (n = 1), neuroblastoma (n = 2) and ganglioneuromas (n = 1) were found. In one case, adrenal pheochromocytoma first occurred and non-functioning islet cell tumour successively occurred at pancreas. A better status is common at a median follow-up time of 3.5 years.
Conclusions: Childhood adrenal tumours presented with hypertension showed an atypical course, variable presentation. We report a unique case of adrenal pheochromocytoma followed by the occurrence of non-functioning islet cell tumour. Reversal of hypertension by surgery is crucial. Imaging techniques are important to detect adrenal tumours.
NINE CASES OF CHILDHOOD ADRENAL TUMOUR PRESENTING WITH HYPERTENSION AND A REVIEW OF THE LITERATURE
The prevalence of childhood hypertension is about 0.6-11% worldwide, and most of it is secondary. Adrenal tumours are one of the potentially fatal causes of childhood hyper- tension (1,2). Because the clinical presentation of adrenal tumours is variable and aspecific, it is often discovered in- cidentally. Hypertensive encephalopathy may occur among these patients (3). Considering the rarity of the disease, clini- cal unpredictability and availability of diagnostic techniques it is understandable that diagnosis and treatment are often delayed in some patients. In order to enhance the general public’s awareness of adrenal tumour and build up a numer- ical index for the prognosis, here we retrospectively analysed the clinical profiles, laboratory findings, treatment and out- come of nine cases of childhood adrenal tumour presenting with hypertension in the past 11 years.
PATIENTS AND METHODS
From January 1995 to February 2006, nine children under 16 years of age with adrenal tumours presenting with hyperten- sion were admitted to the Children’s Hospital, Zhejiang Uni- versity School of Medicine, Hangzhou, China. The records of these patients were analysed for age, gender, family his- tory, presentation, biochemistry, imaging, histology, diagno- sis, treatment and outcome. The pathological features were
reanalysed by our pathologist. The endocrine profiles of the tumours were also retrieved from the records.
RESULTS
Signs and symptoms
The median (range) age at referral of the nine children was 7.3 (0.4-15.7) years; four were girls and five boys. The mean time from initial symptoms to diagnosis was 1.5 years (range, 7 days-5.2 years). An elevated blood pressure was noted in all of the patients. Fever and an abdominal mass at diagnosis were present in case 7. The abdominal mass was impalpa- ble in other patients. Four patients presented with clinical features of Cushing’s syndrome. Two boys had features of polydipsia and polyuria. Due to hypertension, five children presented with convulsion, three presented with headache and vomiting and two were comatose (Table 1).
Laboratory investigation
The white blood cell and platelet concentrations of the pa- tients ranged from 5.6 x 109 to 12.9 x 109/L and 277 x 109 to 398 × 109/L, respectively. Biochemistry profile showed nor- mal levels of fasting blood glucose and serum sodium, the pH values varied from 7.498 to 7.317. Eight children had serum potassium levels below 3.5 mmol/L (3.4-2.22 mmol/L). Ala- nine aminotransferase (ALT) abnormalities were not com- mon in the patients; only one child had ALT value of 79 IU/L. The other blood test results, including serum
| Case | Gender | Age (years) | Diagnosis | Family history | Blood pressure (mmHg)# | Headache vomiting | Convulsion | Coma | Obesity | Polydipsia polyuria | Cushing syndrome | Pathology | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Male | 11.9 | Bilateral adrenal pheochromocytoma Hypertensive encephalopathy | His father had | 220/140 | + | + | − | − | Figure 1 | ||||
| Pheochromocytoma | ||||||||||||||
| 2 | Male | 10 | Right adrenal pheochromocytoma | His mother had | 190/99 | + | + | − | − | Figure not | ||||
| Hypertensive encephalopathy | Pheochromocytoma | listed | ||||||||||||
| 3 | Male | 4 | Right adrenocortical carcinoma | − | 155/95 | − | + | − | + | + | + | Figure 2 | ||
| 4 | Male | 0.5 | Right adrenal neuroblastoma hypertensive encephalopathy | − | 135/95 | − | + | − | − | Figure3 | ||||
| 5 | Female | 0.8 | Left adrenal cortical adenoma hypertensive encephalopathy | − | 160/90 | - | − | + | Figure 4 | |||||
| 6 | Female | 7 | Left adrenal ganglioneuroma, Hypertensive encephalopathy | − | 164/120 | + | + | + | − | Figure 5 | ||||
| 7 | Male | 0.5 | Left adrenal neuroblastoma | − | 152/90 | − | − | − | − | Figure not listed | ||||
| 8 | Female | 0.8 | Left adrenal cortical adenoma | − | 184/114 | − | + | − | + | Figure not listed | ||||
| 9 | Male | 15.7 | Left adrenal cortical adenoma | − | 198/145 | − | + | − | + | Figure not listed | ||||
*Blood pressure in this table indicates the value before treatment. Symbols ”+” means positive and ”-” means negative.
creatinine (Cr) and blood urea nitrogen (BUN), were within the normal range.
The endocrine profile was available in all cases. Testos- terone levels were raised in three subjects, and aldosterone in two. The symptoms of Cushing’s syndrome were seen in patients 3, 5, 8 and 9. The ACTH values at 8 a.m. were less than 10 pg/mL. They had cortisol levels of 563.0, 455.4, 325.7 and 632.0 nmol/L at 8 a.m., 706.6, 544.7, 383.6 and 736.9 nmol/L at 4 p.m., respectively, which indicated sup- pressed basal ACTH levels and loss of diurnal rhythm of cortisol. Further investigations showed failure to suppress on low dose dexamethasone suppression test. Cases 1, 2, 4, 6 and 7 had normal ACTH and cortisol values and rhythms. Cases 4, 6 and 7 had elevated catecholamines or cate- cholamines metabolites both in the blood and urine.
Computed tomography (CT) or magnetic resonance imaging (MRI)
All patients were examined by abdominal CT. Abdominal CT showed bilateral adrenal mass in one patient, left adrenal mass in three patients, right adrenal mass in four patients and left adrenal hyperplasia in one patient. The results of pelvic ultrasound or abdominal magnetic resonance imaging in some patients were in accordance with abdominal CT.
Diagnosis
The clinical diagnosis was made according to the clinical presentation, biochemical and imaging results. Urinary 24 h vanillylmandelic acid (VMA) values were detected and the clonidine test was performed in some selected patients. Be- sides CT or MRI, [131 I]-Metaiodobenzylguanidine (MIBG) scintigraphy was used in the diagnosis of some suspected pheochromocytoma patients.
Treatment
Cases 1, 2, 3, 4 and 6 had hypertensive encephalopathy dur- ing hospital stay. An intravenous infusion of sodium nitro- prusside (1-8 µg/kg/min) or - phentolamini mesylate proinj (1-4µg/kg/min) were administrated to them. Captopril (0.5-1 µg/kg/day) was given orally at the same time. When headache and vomit stopped and blood pressure dropped, captopril, dibenzyline or nifedipine was given orally. Cap- topril, nifedipine, spironolactone and hydrochlorothiazide were administrated to cases 5, 7, 8 and 9. All of the patients responded well to captopril, either alone or in combination with other medications.
Surgery was performed for each patient when the blood pressure decreased to normal levels. Tumours were com- pletely resected. The median tumour weight was 73 g (11- 530 g) and their sizes ranged from 1.5 x 1.5 to 12 x 14 cm2. Tumour tissues from nine patients collected at surgery underwent standard histopathologic diagnosis by a single pathologist (Wz.G). Histological findings showed dif- ferent kinds of tumours (Figs. S1-S5).
Cases 3, 5, 8 and 9 were given hydrocortisone succinate (intravenous infusion) for 5 days after operation, followed by oral hydrocortisone acetate (20-25 mg/m2). The dose was modified according to their ACTH and cortisone lev- els. Cases 4 and 7 received chemotherapy after surgery.
Outcome
Before operation, the 24-h urine vanillylmandelic acid (VMA) values in patients 1, 3, 6 and 8 were 38.2, 9.8, 5.1 and 7.8 mg/day, respectively. They dropped to 6.2, 3.2, 5.0 and 5.3 mg/day, respectively 1 week after operation. The blood pressure of patients 1 and 2 quickly returned to normal on the first day after pheochromocytoma was re- sected. Patient 1 had pancreatic tumour 15 months after the
operation and was reoperated. Histopathology showed non- functioning islet cell tumour (Figs. S6 and S7). He is in good condition now. Patient 2 remained disease-free for 7 years without adjuvant therapy since tumour resection. Patient 3 had been lost to follow-up. The hypertension of patients 4, 6 and 7 resolved within 1-10 days following excision of the adrenal tumour. Patient 4 and 6 are now on chemotherapy. The blood pressure of patient 5 decreased a little after op- eration; however, it was still higher than normal. The blood pressure was 120/60 mmHg when out of hospital, he did not have any drug for decreasing blood pressure and re- mained disease-free for 4 years. Patients 8 and 9 had higher blood pressure, their blood pressure was 130/85 and 135/ 92 mmHg, respectively. They had captopril or nifedip- ine continually and responded well. Tumour recurrence or metastases were not present in eight cases at a median follow-up time of 3.5 years.
DISCUSSION
Adrenal tumours are rare in children, which comprised 0.05-0.5% of all childhood tumours (4,5). The Children’s Hospital of Zhejiang University School of Medicine is the largest referral centre for approximately 46 million inhab- itants, 8 million of whom are children below the age of 16 years. With less than one new case diagnosed in this chil- dren’s hospital each year, the annual incidence of adrenal tu- mours presenting with hypertension within this region may be estimated as 0.10/million children below age of 16 years old.
Adrenal tumours can be divided into functional and non-functional tumours. Most adrenal Tumours are non- functional in adults; however, in children functional tu- mours are more common (6,7). Functional adrenal tumours produce symptoms of Cushing’s syndrome, primary al- dosteronism and adrenogenital syndrome as a result of overproduction of cortisol, aldosterone, testosterone and es- trogen. Excessive cortisol can lead to hypertension, so hyper- tension is common in patients with glucocorticoid-secreting tumours. We delineated the diverging clinical course based on nine cases of adrenal tumour presented with hyperten- sion referred to us. Among these patients, three patients had hypertensive crises associated with seizures. Four patients presented with clinical features of Cushing’s syndrome. Cushing’s syndrome was the second most common pre- sentation after hypertension in our patients. This was in accordance with the outcome reported by Narasimha et al. (8). The longest time from initial symptoms to diagnose in our patients was over 5 years. His blood pressure was still high after surgery, which may result from blood vessel fi- brointimal hyperplasia induced by long-term hypertension, so early diagnosis and treatment are important. Abdominal mass was palpable in only one case. In the other patients, no palpable abdominal mass was found even in the presence of hypertension. Thus imaging is particularly important in de- tection of an adrenal mass.
Adrenal tumours in our cases comprised of pheochro- mocytoma, adrenocortical adenoma, adrenocortical carci-
noma, neuroblastoma and ganglioneuromas with a male and left adrenal gland preference. Pheochromocytoma is a rare, catecholamine-producing tumour with preferential lo- calization in the adrenal gland presenting with severe, of- ten therapy-resistant hypertension (9). Ninty per cent of pheochromocytoma occurs at adrenal gland, the other 10% locates out of adrenal gland. Its incidence is about 2 peo- ple/million/year, rarely in children. Pheochromocytomas are usually curable if diagnosed early and treated appro- priately. However, if the disease remains undiagnosed, the excessive catecholamine secretion might have serious, even fatal consequences. Some pheochromocytomas have family history; some are sporadic (10). Both of our pheochromo- cytoma patients had family history. Patient 1 had bilateral, multicentral adrenal pheochromocytoma. His father died of pheochromocytoma 11 years ago. The mother of case 2 had pheochromocytoma and recovered well after surgery. Pa- tient 1 received bilateral adrenal tumour resection. Non- functioning islet cell tumour was found in his pancreas in a routine follow-up 15 months after operation. The levels of thyroid hormones, VMA, calcitonin, serum Ca2+ and fasting blood sugar were within normal range. The immunohisto- chemistry of the second excised tumour showed strong pos- itive staining of chromogranin A (CgA). Now it is 17 months after the second operation, his blood pressure is normal. No cortisol is given for compensation and no new tumour is found. It is the first reported case that pheochromocytoma first occurred at adrenal gland and non-functioning islet cell tumour successively occurred at pancreas. Considering that CgA was expressed both in adrenal pheochromocytoma and non-functioning islet cell tumour in case 1, we suppose that the tumour at adrenal gland and pancreas may share the same origin.
The annual incidence of childhood adrenocortical tumour (ACT) ranges from only 0.3-0.38/million children below the age of 15 years. Adrenocortical carcinoma with an unpre- dictable prognosis is often diagnosed late due to paucity of information in children. Up to date, there are no markers that can reliably distinguish between benign and malignant adrenocortical tumours (10,11). Generally, tumour on the right side, systemic hypertension, age greater than or equal to 3.5 years at diagnosis, interval of greater than or equal to 6 months between first symptoms and diagnosis, tumour weight greater than 100 g, tumour size greater than 200 cm3 and high levels of urinary 17-ketosteroids (17-KS) and 17-hydroxycorticosteroids (17-OH) are associated with an poor prognosis (11,12). In our study, results of endocrino- logical tests were consistent with histological findings. The adrenocortical carcinoma was in the right, with an 11-cm di- ameter. Three adrenal cortical adenomata were in the left, all with a diameter less than 5 cm. So among the variables pre- dicting the unfavourable outcome of adrenocortical tumour, tumour size and tumour side on adrenal gland are important predictors.
Ganglioneuromas (GNs) are neural crest cell-derived tumours and rarely occur in the adrenal gland. Immuno- histochemical staining of the GN is positive for vasoac- tive intestinal peptide, a hormone commonly expressed in
ganglion cells (13,14). Histopathological examination re- vealed a mature adrenal GN in case 6. The results of bio- chemical test, scintigraphy, immunohistochemical staining were consistent with the benign tumour morphology in this patient. Ten days after surgery his blood pressure returned to normal. The patient has been in good condition for 2 years since operation. Neuroblastoma is the immature form of GN. Histology and hormone results confirmed neu- roblastoma in our two patients. The moderate to severe preoperative hypertension disappeared or improved after surgery. One of the patients was also given chemotherapy.
Although childhood adrenal tumours presented with hy- pertension may an ominous course, extremely variable size and weight, a better outcome was achieved in our cases. Reversal of hypertension by surgery depends on an early di- agnosis. In patients with adrenal masses causing excessive adrenal hormone secretion, careful hormonal investigation should be performed. Decreased levels of hormones secreted by adrenal tumours not only ameliorate hypertension, but also improve the accompanying dysfunctions, which under- lines the importance of early diagnosis and treatment of functioning adrenal tumours. However, no sign accurately predicts the course of adrenal tumours coexisting with ma- lignant arterial hypertension and the most sensitive test for diagnosis remains to be defined (15). It is necessary to find diagnostic molecular markers that can reliably distinguish benign and malignant adrenal neuroendocrine tumours to improve the prognosis.
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Supplementary material
The following supplementary material is available for this article:
Figure S1 Histopathological findings of the resected adrenal tumour from case 1, which was diagnosed as pheochromo- cytoma. Microscopic appearance of the tumour showing the tumour cells were arranged in nestlike pattern, separated by fibrous tissue. The tumour cells were polygonal with abun- dant cytosol, cell nucleus was round and nucleus division was rare (H-E stain ×200) (Microsoft Word format).
Figure S2 Histopathological findings of the resected adrenal tumour from case 3, which was diagnosed as adrenocortical carcinoma. Microscopic appearance of the carcinoma was characterized by lobulated, acidophilus cells rich in cytosol with irregular nucleus. Nucleus division and giant carcinoma cell could be found.Necrotic cells were obvious (H-E stain ×200) (Microsoft Word format).
Figure S3 Histopathological findings of the resected neu- roblastoma from case 4, Small round tumour cell in various cell differentiation stages could be seen under miscroscopy. Cell arrangement was lobulated. Some cells looked pseu- dorosette, areas between carcinoma cells was fibrous tissue without cell. Some carcinoma cells differentiate into gan- gliocyte (H-E stain ×200) (Microsoft Word format).
Figure S4 Histopathological findings of the resected adrenal cortical adenoma from case 5. Microscopic appearance of the tumour showing cell arrangement was patchy or lobu- lated, which was composed of clear cell with hyaline cytosol and dark cell with acidophilus cytosol. Lipofuscin accumu- lation was found in some cells, nucleus division was rare (H-E stain ×200) (Microsoft Word format).
Figure S5 Histopathological findings of the resected adrenal ganglioneuroma from case 6. The tumour consisted of ma- ture gangliocyte, nerve fiber and nerve sheath cells. Nerve fibers expressed as bunchiness, gangliocytes located longely or clusterly among nerve fiber, cell was polygonal, nucleus was big and nucleolus was obvious (H-E stain ×100) (Mi- crosoft Word format).
Figure S6 Histopathological findings of the second biopsy specimens from case 1, which was diagnosed as non- functioning islet cell tumour. The tumour cell arrangement
was nestle and solid, cytosol was abundant and hyaline, nu- cleolus was in the central, nucleus division was rare (H-E stain ×100) (Microsoft Word format).
Figure S7 Immunohistochemical staining of for chromo- granin A (CgA) the second biopsy specimens from case 1(non-functioning islet cell tumour). The immunohisto- chemical evaluation was strongly positive for CgA (SP ×100) (Microsoft Word format).
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