Journal of Pediatric Surgery xxx (xxxx) xxx
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Journal of Pediatric Surgery
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Journal of Pediatric Surgery
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Management of functioning pediatric adrenal tumors
Roberto Iglesias Lopes a,*, Caio Vinicius Suartz ª, Rubens Pedrenho Neto ª, Ricardo Haidar Berjeaut ª, Berenice Mendonca b, Madson Q. Almeida b, Maria Cândida Villares Fragoso b, Francisco Tibor Dénes a
a Pediatric Urology Unit, Division of Urology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, Brazil
b Endocrinology Clinic, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, Brazil
ARTICLE INFO
Article history: Received 17 April 2020 Received in revised form 30 July 2020 Accepted 21 August 2020 Available online xxxx
Key words: Adrenal gland Adenoma Carcinoma Pheochromocytoma Adrenalectomy
ABSTRACT
Aim: The aim of this study is to present our experience in the management of hormonally active adrenal tumors in children.
Material and methods: We did a retrospective chart review of all children with hormonally active adrenal tumors evaluated at the endocrinology clinic and operated at our institution between 1983 and 2019.
Results: There were 75 patients included in the study, 58 with adrenocortical tumors (ACTs) and 17 with pheo- chromocytomas (PCCs). Within the group of patients with ACTs, there were 41 females and 17 males. The mean age was 58.3 (SD: 87.9; range: 9-211) months. The clinical manifestation of the tumor’s hormonal activity was virilization in 37 cases, Cushing syndrome in 5, and mixed in 16. A positive family history was present in 11 pa- tients (18.9%). The mean tumor size was 48.2 (SD: 22.4; range: 7-120) mm. The pathological diagnosis was ad- enoma in 42 cases, carcinoma in 15 cases, and macronodular hyperplasia in 1. Median follow-up was 192 (range: 50-290) months. Tumor recurrence occurred in 6 patients (10.3%), and there were three disease-related deaths (5%). Within the group of patients with PCCs, there were 11 males and 6 females. The mean age was 146.7 (SD: 71.2; range: 60-216) months. A positive family history was present in 7 patients (41.2%). The mean tumor size was 36.6 (SD: 16.7; range: 7-120) mm. The pheochromocytoma was classified as benign in 15 cases and as ma- lignant in 2. During a median follow-up of 180 (range: 127-300) months, recurrence was observed in 6 cases (35.3%) and disease-related death in 1 case (5.9%).
Conclusions: Proper diagnosis and management at our referral center were associated with a high cure rate, even in cases of malignant tumors. Familial surveillance is highly recommended.
Level of evidence: Level IV.
@ 2020 Elsevier Inc. All rights reserved.
Neuroblastic tumors (neuroblastomas, ganglioneuroblastomas and ganglioneuromas) are the most common (60%-75%) pediatric adrenal lesions. These are followed by adrenocortical tumors (ACTs; adenomas, carcinomas and adrenal hyperplasia), which account for 10%-25% of all adrenal lesions. The last group is represented by pheochromocytomas (PCCs), with comprise 2% to 10% of all adrenal lesions [1-3]. Infrequent lesions of the adrenal gland are sarcomas, metastasis, calcifications, cysts and hematomas, which combined represent about 2.5%-6% of all cases [1-3]. Adrenal lesions can be hormonally active (also known as “functional”), or hormonally silent. In this study we reviewed our expe- rience in the management of functional adrenal tumors in children, spe- cifically ACTs and PCCs.
1. Material and methods
After obtaining Institutional Review Board approval (Protocol #1.412.423) we retrospectively reviewed all cases of functional adrenal tumors in children managed between 1983 and 2019. The patients were medically managed at the endocrinology clinic, and were operated by the pediatric Urology service. Collected data included: age, gender, fam- ily history, preoperative diagnosis, location of the lesion, size of the le- sion, operative approach, postoperative hospital stay, complications, pathologic findings, and long-term outcomes (cure; recurrences; disease-related death).
A comprehensive preoperative workup was conducted in all cases owing to the symptoms associated to the tumors’ hormonal production, including a complete biochemical and hormonal profile, and a variety of imaging studies. Ultrasound (US) and computed to- mography (CT) were performed to characterize the lesions and to determine the presence of metastases. Patients with large lesions also underwent a magnetic resonance imaging (MRI) to evaluate vascular invasion. In addition, patients with functional adrenal
* Corresponding author at: Pediatric Urology Unit, Division of Urology, Department of Surgery, Hospital das Clínicas, University of São Paulo Medical School, Av. Dr. Enéas Carvalho de Aguiar, 255-Cerqueira César, São Paulo-SP, 05402-000, Brazil. Tel .: +55 11 26618080.
E-mail address: roberto.iglesias@hc.fm.usp.br (R.I. Lopes).
medullary lesions underwent 123I-metaiodobenzylguanidine (MIBG) scintigraphy, when necessary.
In cases of PCC, medical management was initiated at least 14 days be- fore surgery. It included a high-sodium and fluid intake, and selective œ1- receptor blockers [4]. Selective &1-receptor blockers (extended-release prazosin or doxazosin) was started at 1 mg bid and titrated up to 10-14 mg/d. Preoperative ß-receptor blockers were indicated to control tachycardia after administration of @1-receptor blockers. Use of ß- adrenergic receptor blockers should not be started before &- adrenoceptor blockers. The treatment goal was a blood pressure of less than 130/80 mmHg while seated and greater than 90 mmHg systolic while standing. The surgical resections were done only after this blood pressure goal was achieved, and all patients were managed intraopera- tively by experienced anesthesiologists. The &1-receptor blockers were interrupted 12 h before surgery to avoid the refractory hypotension that can occur after the removal of the tumor. The anesthesia management in- cluded invasive cardiovascular monitoring and the use of nitroprusside and beta-blockers as needed.
Open surgery (lumbolaparotomy or thoracophrenolaparotomy) was the standard approach in the beginning of our experience. Laparoscopic adrenalectomy was introduced in the late 1990’s and was rapidly adopted at many centers. Once this technique became available in our institution it became our standard approach, and since then we have done open sur- gery only in patients with large tumors, visceral infiltration or venous tumor thrombus, which are indicators of malignancy. The tumor size was always correlated with the body habitus of the patient in order to de- termine the proper surgical approach. In general, tumors more than 7 cm in diameter, or those with any indications of potential malignancy underwent open surgery. An en-bloc complete resection was done when surrounding organs were infiltrated by the tumor, as long as the re- section was deemed not to result in significant organ dysfunction.
ACTs were classified histologically as benign or malignant using the Wienecke’s score [5]. PCCs were classified histologically as benign or malignant using the PASS (Pheochromocytoma of the Adrenal gland Scaled Score) [6].
For the statistical analysis, the Shapiro-Wilk test was used to test nor- mal distribution of variables. Mean and standard deviations were re- ported for normally distributed variables, whereas median and interquartile ranges were used for nonnormally distributed variables. Sur- vival curves for both ACTs and PCCs were performed, and the log-rank test was used to compare groups (Fig. 1). An event-free curve was done comparing the open and the laparoscopic cases on the recurrence rates (Fig. 2). A P value of less than 0.05 was considered statistically significant.
2. Results
Seventy-five patients between the ages of 9 months and 18 years were managed during the study period. There were 58 ACTs (77.3%) and 17 PCCs (22.7%).
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ACT
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PCC
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Survival (%)
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P-value: 0.72
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Follow-up (months)
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90
Recurrence rate (%)
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Laparoscopic
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Open
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P-value: 0.7
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0
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Follow-up (months)
Within the group of patients with ACTs, 41 were females and 17 were males. The mean age was 58.3 (SD: 87.9; range: 9 to 211) months. The clinical manifestation of the tumor’s hormonal activity was virilization in 37 cases, Cushing syndrome in 5 cases, and mixed in 16 cases. A positive family history was present in 11 pa- tients (18.9%). The tumors were located on the right side in 30 pa- tients, on the left side in 26 patients, and bilaterally in two patients. The mean tumor size was 48.2 (SD: 22.4; range: 7 to 120) mm. The surgical approach was open in 28 patients and laparoscopic in 29 patients, and there was one case of a cryoablation in a patient with a local recurrence of a carcinoma who had undergone several previous interventions at another center (Fig. 3). The final pathologic diagnosis was adenoma in 42 cases, carcinoma in 15 cases, and macronodular hyperplasia in 1 case. One adrenal carcinoma required a concomitant nephrectomy and liver segmentectomy for an en-bloc complete resection. The median follow-up was 192 (range: 50-290) months. Recurrences were observed in 6 patients (10.3%), and there were three disease-related deaths (5%, all carcinomas) at the time of this review. One patient died from metastatic disease. One patient died on the second postoperative day owing to pulmonary tumor embolism. This patient had a large right adrenal tumor which ex- tended into the supradiaphragmatic vena cava, and despite careful dissection, tumor detachment and pulmonary embolism occurred during surgery. One patient died owing to complications of Cushing’s syndrome.
A very interesting case is depicted in Fig. 3. A 2.5-year-old patient with a right virilizing ACT underwent several operations plus and adju- vant chemotherapy and radiation elsewhere before being referred to our institution. She presented to us with a local 3.5 cm recurrence. The recurrent lesion was managed with cryoablation. At one year of follow-up she is asymptomatic, the hormonal studies are normal, and the control MRI shows a 1.1 cm hemorrhagic nodule, which has no ac- tivity in the PET-CT.
Within the group of patients with PCCs there were 11 males and 6 females. The mean age was 146.7 (SD: 71.2; range: 60 to 216) months. A positive family history was present in 7 patients (41.2%). The PCCs were located on the right side in 11 cases, on the left side in three cases, and bilaterally in three cases. In two patients with bilateral PCCs, a paraganglioma was also present. The mean tumor size was 36.6 (SD: 16.7; range: 7 to 120) mm. Open adrenalectomy was per- formed in 7 cases, and laparoscopic adrenalectomy in 10. In two patients with metachronous bilateral PCCs, a unilateral total adrenalec- tomy was performed at the time of the initial presentation, and a contra- lateral partial adrenalectomy was performed subsequently to preserve adrenocortical function. In one of these patients, the residual adrenal tissue underwent secondary atrophy, and the patient required cortico- steroid replacement therapy. In the other, despite preserving a part of the gland, which had normal corticosteroid production for almost 5 years, a recurrent PCC developed in the residual adrenal tissue. We
A
B
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did a completion laparoscopic adrenalectomy and the patient now re- quires, as expected, corticosteroid replacement therapy. PCC was con- sidered benign in 15 cases and malignant in 2. At a median follow-up of 180 (range: 127 to 300) months, recurrence was observed in 6 cases (35.3%), and death occurred in case (5.9%, malignant PCC).
3. Discussion
ACTs have an incidence of 0.3 case per million per year in children younger than 15 years of age [6]. They represent less than 0.5% of all pe- diatric solid tumors, generally affecting only one of the glands, but occa- sionally being bilateral (2% to 10%) [7]. They are more frequent in females than in males. It has been shown that in the southern and south- eastern regions of Brazil, the incidence of ACTs is 15 times higher than the incidence reported in the literature, likely owing to a p53 germline mutation with high prevalence in those areas [8]. A family history is fairly common in cases of ACT, as seen in our cohort (19% of cases). Functional ACTs are typically suspected when a patient presents signs and
symptoms of excessive hormonal activity, such as cushingoid features or virilization. However, early clinical manifestations are subtle and may be overlooked, leading to a late diagnosis. As previously reported, adolescents and young adults usually have Cushing’s syndrome, al- though nonfunctional tumors can also be diagnosed [8]. On the contrary, more than 90% of young children have virilizing features at presentation. Mutations of the p53 gene, which are always searched for in our institu- tion, are frequently reported in young children with ACTs. As one of the main referral centers in the country, the endocrinology clinic at our insti- tution receives a high number of patients of all ages each year, many of which require surgery and are operated on by the urologists [9,10].
Most imaging modalities (US, CT and MRI) can detect the adrenal le- sions (Fig. 4A and B). Carcinomas are suggested by the presence of me- tastases and/or vascular invasion on the pathology analysis. Large tumor size, internal necrosis, and/or hemorrhage are also features that suggest of malignancy. In the postoperative follow-up, positron emission to- mography with computer tomography (PET-CT) (Fig. 4C) can be help- ful in the detection of secondary lesions. In children, the most accurate
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pathological classification of adrenocortical tumors is the Wienecke score, in which a score of 4 or more indicates a carcinoma [5].
Adrenalectomy is the standard treatment for functioning adrenal tu- mors. Alternative treatments such as cryoablation should be considered in rare selected cases of tumors that are not amenable to a surgical re- section. Generally, normal pubertal development is observed in the ma- jority of cases after adrenocortical tumor is removed, with most patients reaching their target height [11]. The clinical features related to virilization, like hirsutism, acne, and clitoral or penile growth, tend to re- gress with time, and become imperceptible in the long-term. One fea- ture that does not tend to improve is the presence of cutaneous stretch marks associated with hypercortisolism. Not infrequently, cen- tral puberty may develop owing to prolonged hormonal hypothalamic exposure with need of therapeutic blockade with gonadotropin- releasing hormone analogs (even after the resection of the primary tumor) [11].
PCC originates in the catecholamine-producing cells of the adrenal medulla, but can also develop in the chromaffin cells of the neural crest tissue (up to 25% of cases), either alone or associated with adrenal lesions [12-14]. The estimated incidence of PCCs is 1/100,000 people in the adult population, and much lower in children [15]. One fourth of the PCCs in children are related to predisposing genetic conditions such as MEN 2, von Recklinghausen, von Hippel Lindau and Sturge-Weber syn- dromes [16].
The clinical manifestations of PCC are well-known and include ele- vated blood pressure, tachycardia, palpitations and excessive sweating. All of these are secondary to the overproduction of catecholamines, metanephrines and renin. Despite the seemingly clear clinical signs, late diagnosis is not unusual. PCCs can easily be detected by CT or MRI. MIBG scintigraphy is a helpful study to detect secondary lesions [16]. The sensitivity of this exam is approximately 80% for pheochromocyto- mas and 50% for paragangliomas [17,18]. MIBG scintigraphy is therefore recommended for patients with increased risk of metastatic disease, namely those with large tumors, with a positive genetic background, or those with extraadrenal, multifocal or recurrent disease [17,18]. In these particular cases, a 123I-MIBG associated with single photon emission com- puted tomography (SPECT) is critical for the pre- and postoperative stag- ing. These tumors are considered malignant when they present metastases or when they have a PASS score of 4 or more points [6].
A total adrenalectomy is the standard treatment for sporadic PCCs cases, while a partial adrenalectomy should be considered for syndromic cases and bilateral lesions [9,19]. A higher prevalence of he- reditary PCCs, extraadrenal disease (paragangliomas), and multifocal tumors was observed in children when compared to the adult popula- tion [15]. This is associated to a higher incidence of metastatic cases and recurrent disease in children than in adults, observed in our cohort (35.2% recurrence rate).
The overall survival of our cohort was high for ACTs and PCCs as shown in Fig. 1. Similar recurrence rates were observed between pa- tients operated by open surgery versus those operated laparoscopically (Fig. 2). This could have been influenced by two factors: first, a selection bias (open surgery was done in all patients with suspected malignant tumors), and second, a higher proportion of laparoscopic procedures in cases of PCC and paragangliomas (since they were usually benign).
4. Conclusions
A prompt and proper diagnosis of adrenal functional tumors, adequate preoperative preparation, meticulous surgical technique, and careful postoperative management, as provided at referral center like ours, result in low recurrence rates and high survival. Familial surveillance for pa- tients with functional adrenal lesions is highly recommended.
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