In this paper, we attempted to portray a comprehensive clinical and laboratory picture in children and adolescent patients with functioning adrenal tumors and also to present for the first time the hormonal constituents of the effluent adrenal vein in cases with this rare disease.
Adrenocortical tumors comprise 0.3-0.5% of the neoplasms detected in patients under the age of 15 (3
). Data of most patients are published as single case reports, and there are few case series addressing the problem (1
). In two previous large reports on 209 and on 254 pediatric and adolescent cases, the most common presentation was virilization followed by a mixed picture of virilization and Cushing’s syndrome (15
). The disease is more prevalent in girls, as seen in our report as well. Tumors are functionally active in 95% of cases with overproduction of androgens, corticosteroids, aldosterone and estradiol in decreasing order of frequency. Sometimes, the tumors are polyhormone secretors or their secretion pattern changes; hence, the clinical presentation may be mixed and may also change with the passage of time.
As shown in , virilization in 6 out of seven patients resulted from high serum testosterone and DHEA-S concentrations which in some cases reached levels exceeding normal values tenfold. In cases who presented with virilization, the most prominent symptoms were rapid growth, acne, deepening of voice, advancement of bone age and cliteromegaly or penile enlargement.
Cases no 1, 4 and 5 had concomitant hypersecretion of cortisol but showed no symptoms of Cushing’s syndrome. It seems that high testosterone levels obscure the usual manifestations of hypercortisolism (17
). This finding emphasizes the importance of careful evaluation of patients for hypercortisolism in order to prevent post-surgical adrenal insufficiency which could be fatal. The high morbidity and mortality previously reported after surgical removal of these tumors might have been partly due to lack of adequate steroid supplementation during surgery (19
Cases no 1, 2, and 5 were incorrectly diagnosed as CAH and were treated with corticosteroids for 2 to 9 months. This mismanagement was partly due to the higher incidence of CAH and partly because of the misconception that 17-OH progesterone is a specific marker for CAH, while the metabolite may be highly elevated in adrenocortical tumors and also in hormone-secreting testicular tumors as well (21
). In the case reported by Hishiki et al (23
), high serum 17(OH) progesterone that was used for evaluation of CAH led to diagnosis of adrenocortical tumor in a newborn. We therefore propose that adrenocortical tumors be considered in the differential diagnosis of hyperandrogenism in children. Careful consideration of testosterone, DHEA-S and androstenedione besides 17(OH) progesterone are imperative. Higher levels of testosterone and DHEA-S, lack of suppression after corticosteroid treatment, and demonstration of a lesion in adrenal gland imaging should raise the possibility of adrenocortical tumors.
Hyperestrogenism was prominent in case no 3 which had led to massive gynecomastia in the setting of Cushing’s syndrome. This patient responded well to the surgery with completion of male habitus after 1 year ( and ). In addition to the case 3 who had massive gynecomastia, serum estradiol was elevated in cases 1, 3 and 4 without any symptoms and signs of feminization, a finding indicating that secretion of estradiol by adrenocortical tumors is not as unusual as is currently thought. This finding is also in accordance with the fact that functioning adrenocortical tumors have polyhormone secreting behavior, but the clinical picture is governed by the dominant hormone, namely, testosterone in virilizing syndromes and cortisol in Cushing’s syndrome. This can also be the case in patient no 6 who had Cushing’s syndrome without any virilizing symptoms despite abnormally high serum testosterone. Hence, we propose that a thorough hormonal evaluation is needed for a more accurate classification of functioning adrenocortical tumors even if there are no clinical signs or symptoms of hormone excess. As shown in , concentration of hormones in adrenal venous effluent is extremely high. As an example, the concentration of testosterone in case no 7 who was a 5.5-year-old girl was 2000 ng/dL, a figure which is nearly 2000 times in excess of the normal range.
The high ratio of the hormone levels in the adrenal vein as compared to levels in the peripheral vein points not only to the adrenal origin of the hormone (24
), but also to the fact that peripheral synthesis contributed little, if any, to the hormone levels. Rapid and marked reduction of the hormones during the early postoperative week was strongly in favor of tumoral origin of the hormones and also elimination of the tumors.
In our series, all of the tumors were located in the left adrenal. It seems that adrenocortical tumors are more prevalent in the left side (13,14,25,26); although this has not always been the case (2
). Histopathologic diagnosis was benign adrenocortical adenoma in all cases, but vascular and capsular invasion noted in cases no 1 and 4, and the weight of the tumor in case no 3 raised a possibility of malignant nature of these tumors; however, the long-term post-surgical follow-up of 2 to 12 years showed the benign nature of these neoplasms.
Our findings are in accordance with data reported by other investigators who showed that in childhood functioning adrenocortical tumors, the size and weight of the tumors are more important factors in determining the benign or malignant nature of the tumor. Indeed, tumors weighing less than 100 grams have a benign nature and a favorable prognosis (29
In some studies, functioning adrenocortical tumors are reported to have a good prognosis (13
). This finding may be just due to earlier diagnosis because of earlier clinical manifestations secondary to hormone over secretion (19
). There has been no significant difference in prognosis between functional and nonfunctional tumors in other series (19
). Some but not all studies have shown that prognosis is better in children in comparison to adults (2
). Age may not be a major prognostic determinant when other more important factors such as size and weight of the tumor are taken into account.
In conclusion, this study supports the notion that childhood and adolescence adrenocortical tumors usually present with clinical manifestations that should be immediately diagnosed and surgically treated to avoid untoward complications. Thorough evaluation of hormonal profile, irrespective of hormone-related clinical manifestations, will reveal the usually multi-hormonal secreting nature of the tumors. Assessment of adrenal venous effluent hormones has shown that hormones are directly secreted from the tumor and peripheral conversion has little contribution to peripheral hormone levels.
The authors wish to thank the patients and their parents for making the study possible.