ORIGINAL ARTICLE
ANZJSurg.com
Adrenocortical tumours in children: a review of surgical management at a tertiary care centre
Burak Ardicli ,*t Idil R. User ,*t Arbay O. Ciftci DD,t Canan Akyuz ,# Mustafa T. Kutluk DD,# Bilgehan Yalcin D,# Nazli Gonc D,§ Zeynep A. Ozon OD,§ Ayfer Alikasifoglu DD,§ Berna Oguz , Mithat Haliloglu , Diclehan Orhan , | Feridun C. Tanyel O,t Ibrahim Karnak Ot and Saniye Ekinci *t
*Department of Medical and Surgical Research, Hacettepe University, Institute of Health Sciences, Ankara, Turkey
tDepartment of Paediatric Surgery, Hacettepe University, Faculty of Medicine, Ankara, Turkey
Department of Paediatric, Paediatric Oncology Unit, Hacettepe University, Faculty of Medicine, Ankara, Turkey
§Department of Paediatric, Paediatric Endocrinology Unit, Hacettepe University, Faculty of Medicine, Ankara, Turkey
1Department of Radiology, Paediatric Radiology Unit, Hacettepe University, Faculty of Medicine, Ankara, Turkey and |Department of Paediatrics, Paediatric Pathology Unit, Hacettepe University, Faculty of Medicine, Ankara, Turkey
Key words
adenoma, adrenocortical tumour, carcinoma.
Correspondence
Burak Ardicli, MD, Department of Paediatric Surgery, Hacettepe University Faculty of Medicine, 06100 Sıhhiye, Ankara, Turkey. Email: burakardicli@gmail.com
B. Ardicli MD; I. R. User MD; A. O. Ciftci Prof;
C. Akyuz Prof; M. T. Kutluk Prof; B. Yalcin Prof; N. Gonc Prof; Z. A. Ozon Prof;
A. Alikasifoglu Prof; B. Oguz Prof; M. Haliloglu Prof; D. Orhan Prof;
F. C. Tanyel Prof; I. Karnak Prof; S. Ekinci Prof.
Accepted for publication 7 December 2020.
doi: 10.1111/ans.16542
Abstract
Background: Adrenocortical tumours (ACT) are rare tumours of childhood usually pre- senting with endocrine dysfunction. This retrospective study is designed to review our insti- tutional experience in surgical management.
Methods: Records of children treated for ACT between 1999 and 2019 were reviewed retrospectively.
Results: The median age of 24 children was 78 months. Fourteen patients had adrenocorti- cal carcinoma, nine had adrenocortical adenoma and one had neuroendocrine differentiation of ACT. Endocrine dysfunction was noted in 79% of the patients. Five patients had preoper- ative chemotherapy but none had a decrease in tumour size. Transabdominal approach was used in all but two patients who had thoracoabdominal incision for excision of giant tumours and ipsilateral lung metastases. Two patients had visceral excision to achieve R0 resection. Five patients, four of whom had spillage and one with partial resection died of widespread disease. Two patients with stage 4 adrenocortical carcinoma are still on chemo- therapy. All patients with stage I-III disease who had total excision without spillage (n = 17) are disease-free for 2-170 months.
Conclusions: Our results show the importance of excision in ACT without spillage for sur- vival. However, multicentre prospective studies should enhance the knowledge of children about ACT and develop alternative therapies for stage III and IV cases.
Introduction
Adrenocortical tumours (ACTs) are extremely rare in childhood. They constitute 0.2% of all childhood malignancies. Geographical difference of incidence is remarkable with the highest incidence of 3.4-4.2 per million in southern Brazil in children younger than aged <10 years. The high incidence in Brazil is attributed to TP53 mutation. Most ACTs occur spo- radically but they may be associated with hereditary cancer syndromes such as Li Fraumeni and Beckwith Wiedemann syndrome.1-6
Children with ACT usually present with hypercortisolism, hyper- androgenism, virilization or precocial puberty symptoms. Rarely, asymptomatic ACTs may be detected incidentally during diagnostic procedures for unrelated medical issues.
The pathological differentiation of malignant and benign ACTs is still controversial.7 Many clinical and laboratory criteria are stud- ied to define the prognosis of ACTs in adults. ACTs in children are different from their counterparts in adults regarding their origin, clinical manifestation, molecular alteration and prognosis.8-15
Complete surgical excision is the only possible treatment of ACT and R0 resection is the treatment of choice if possible. Radi- cal surgery including resection of adjacent visceral and vascular structures to achieve tumour free margins and avoiding tumour spillage offers the best chance for cure in patients without meta- static disease.16-19 This retrospective study designed to review our institutions experience in the surgical management of childhood ACTs.
Methods
The records of children operated for ACT at our department between 1999 and 2019 were reviewed retrospectively. Age at admission, gender, past medical and family history, presenting signs and symptoms, laboratory tests including hormone analysis (plasma steroids and urinary-free cortisol), imaging tests (ultraso- nography [US], computed tomography, magnetic resonance imag- ing), stage of the disease, preoperative biopsy results, surgical intervention (total excision, partial excision, spillage, visceral exci- sion, lymph node excision), early and late complications of surgery, pathology results, preoperative and postoperative chemotherapy, radiotherapy and outcomes were evaluated.
Patients were staged according to the Modified Children’s Oncol- ogy Group (COG) staging system for paediatric ACC.20 According to this; stage I: completely resected small tumours (<100 g and 200 cm3) with normal postoperative hormone levels, stage 2: completely resected larger tumours (≥100 g or ≥200 cm3) with nor- mal postoperative hormone levels, stage 3: could not be totally resected tumours (tumours that are not amenable for total resection) and stage IV: distant metastatic disease.
Functionality of the tumour was determined by clinical find- ings and serum levels of cortisol, 17-hydroxy progesterone, androstenedione, dehydroepiandrosterone sulphate, testosterone and plasma levels of adrenocorticotropic hormone (ACTH), renin and aldosterone. When a child with adrenal tumour did not have any sign of cortical tumour such as virilization or Cus- hing’s syndrome catecholamines were checked to rule out pheo- chromocytoma. All hormone measurements were carried out regardless of clinical findings. Clinical features of virilization were defined as premature or inappropriate pubic or body hair, acne, deepening of voice, enhanced growth, penile enlargement and clitoromegaly. Findings suggestive of Cushing’s syndrome were rapid increase in weight associated with growth decelera- tion, presence of moon face, buffalo hump, purple or bright red striae and/or hypertension.
Laboratory assessment of hyperandrogenism was defined with elevated serum androgen levels (17-hydroxy progesterone,
| ACC | ACA | |
|---|---|---|
| Age (months) | 108 | 24 |
| Sex | ||
| Male | 5 | 4 |
| Female | 9 | 5 |
| Site | ||
| Left | 11 | 8 |
| Right | 3 | 1 |
| Surgery | ||
| Resection with negative surgical | 9 | 9 |
| margins | ||
| Spillage | 4 | — |
| Partial resection | 1 | — |
| Outcome | ||
| Disease free | 7 | 9 |
| Dead of disease | 5 | — |
| Alive with disease | 2 | — |
ACA, adrenocortical adenoma; ACC, adrenocortical carcinoma.
androstenedione, dehydroepiandrosterone sulphate, testosterone) regardless of clinical signs of virilization. Hypercortisolism on the other hand was defined as increased levels of serum cortisol, 24-h urinary free cortisol and low plasma ACTH level regardless of signs and symptoms of Cushing’s syndrome. Hyperaldosteronism was characterized by high plasma levels of aldosterone, low renin with hypokalaemia.
All patients received steroid coverage perioperatively with a maximum duration of 3 days after the operation. The dose of steroid was 20-30 mg/m2/day prednisolone (100-150 mg/m2/ day hydrocortisone equivalent) on the day of operation which was tapered down and withdrawn on the third postoperative day. All patients were assessed for residual tumour and adrenal suppression by evaluation of their hormone profile within 1 week after cessation of steroid therapy. Adrenal suppression was initially assessed by a fasting, early-morning serum corti- sol level. A basal cortisol level of 15 µg/dL or higher ruled out adrenal suppression, whereas a level less than 3 µg/dL suggested adrenal suppression. A level between 3 and 15 µg/dL required low-dose ACTH test to rule out adrenal suppression. A peak cortisol response of 19.6 µg/dL or more during low- dose ACTH test ruled out adrenal suppression.21 Patients with adrenal suppression were started on hydrocortisone (10-12 µg/m2/day p.o.) were assessed for adrenal glucocorticoid reserve 1 month after the operation and then every 3 months to establish recovery from suppression. All patients were followed for tumour recurrence using adrenal hormones as tumour markers periodically. The first two evaluations were carried out 1 week and 1 month after the operation and the following at 3-month intervals.
Patients with stage I and R0 resection were not given chemother- apeutics and mitotane. Mitotane was used in the maintenance ther- apy, as indicated. Neoadjuvant chemotherapy was used in giant tumour, as cisplatin, etoposide and mitotane. Adjuvant chemother- apy regimen consists of cisplatin, adriamycin, etoposide and mitotane. Patients with progressive disease were given ifosfamide, adriamycin, vincristine and mitotane or gemcitabine, capecitabine and mitotane.
Data were analysed with SPSS 23.0 software (Macintosh, IBM Corp., Armonk, NY ). Descriptive data are expressed as frequency and percentage and continuous variables as medians, interquartile ranges (IQR) and minimum and maximum values. For the survival outcomes, Kaplan-Meier method was used. This study was approved by the Institutional Ethical Committee (GO:20/401).
Results
There were 24 children who underwent surgery for ACT during the study period. The clinical characteristics of the patients are shown in Table 1. The female to male ratio was 1.66/1 (15 girls and 9 boys). The median age at diagnosis was 78 months (IQR 15-138 months). Fourteen patients had ACC, nine patients had ACA, and an 11-year-old-girl with giant tumour weighing 1300 g and 20 cm in diameter had neuroendocrine differentiation of ACT. Total excision of the tumour was followed by good recovery and 1 year of follow-up.
Familial cancer-related syndromes were detected in two children with ACC: Li Fraumeni Syndrome and Peutz Jeghers Syndrome. Two patients had genetic evaluation. One patient with Peutz Jeghers Syndrome had a missense STK11 mutation (amino acid E199D) in our previous report.22 Total excision was performed due to ACC at 16-month-old. She was operated intussusception caused by hamartomatous polyp at fifth years of her life. A year later, thyroidectomy was performed for papillary thyroid can- cer. At 8 years, hamartomatous polyp was excised from stom- ach. At 14 years, intussusception due to hamartomatous polyps occurred. Same year she had anaplastic astrocytoma. She is still followed-up at our centre. Other patients with Li-Fraumeni syn- drome did not have TP53 mutations. Total excision of ACC and lateral left hepatectomy was performed for hepatocellular carcinoma at 3.5 years. She was recently diagnosed with acute myeloid leukaemia and on treatment.
Twenty-two of 24 (91.7%) patients had functional ACT. All adrenocortical adenomas were functional. Clinical presentation was mainly the signs of virilization (15/24 patients; 62.5%) and the fol- lowing Cushing syndrome (10/24 patients; 41.6%). Five out of nine (55.5%) adrenocortical adenomas and 10 out of 14 (71.4%) adreno- cortical carcinomas (ACC) had signs of virilization at presentation. When all adrenocortical hormones were measured regardless of signs of clinical presentation, 13 patients were shown to secrete multiple hormones representing 54.2% had mixed type hormonal profile. Nine (37.5%) patients had isolated hormone over secretion; six (25%) cases isolated hyperandrogenism, two (8.3%) cases iso- lated hypercortisolism and one (4.2%) patient isolated hyper- aldosteronism. Five patients who had no signs of Cushing syndrome, had hypercortisolism. Six patients (46%) out of 13 whose clinical presentation was of only one hormone excess, had more than one oversecreted hormone. A total of 55.5% (5/9) of adreno- cortical adenomas and 57.1% (8/14) of ACC were of mixed type hormone secretion. Two of three patients with a presentation of abdominal pain also had functional tumour (Table 2). Tumour was left sided in six patients and right sided in 18 patients. No bilateral tumour was identified.
Adrenocortical carcinoma (ACC)
Fourteen patients were diagnosed with ACC. The female to male ratio was 9:5. The median age at diagnosis was 108 months (IQR 36-144). All patients had a palpable abdominal mass.
The mean diameter of tumour was 11.02 ± 4.42 cm (range 6-20) in cross-sectional imaging. The median weight of the tumour was 340 g (IQR 160-773). Four patients had distant metastases in liver (n = 2), lung (n = 3) at the time of diagnosis. These patients and a patient with giant tumour (Figs 1a,b,2) had preoperative chemother- apy. All of these cases had stable disease according to Response Evaluation Criteria in Solid Tumours23 after three to four cycles of chemotherapy. None of them had any decrease in tumour size or progression of disease.
Transabdominal (n = 12) and thoracoabdominal (n = 2) approach were used. An unresectable tumour was noted in one patient because of extensive intraabdominal disease, and partial excision could be managed only. Tumour spillage due to rupture occurred in four patients. Total excision was performed in 10 patients without rupture. Two patients who were operated with thoracoabdominal approach had metastasectomy for ipsilateral lung masses simulta- neously. One patient had nephrectomy and another had multiviscera resection (distal pancreatectomy and splenectomy) to achieve R0 resection. Routine retroperitoneal lymph node dissection was not performed. Four patients had resection of regional lymph nodes and final pathology result was metastases in none of them. Operative mortality was not seen in our series. There was no adverse event secondary to adrenal insufficiency in perioperative or postoperative period. All patients but one who had chylous leak for 6 days recov- ered uneventfully. He was treated with total parenteral nutrition and nil per oral. In the long-term follow up, five patients who had par- tial excision (n = 1) and tumour spillage (n = 4) died from wide- spread disease (n =4) and lung metastases (n = 1) in 1-4 years. Recurrence was seen in three patients who have spillage during the operation after 7, 13 and 23 months (Fig. 1a). Five patients died of disease. The median time to death was 9 months. The 5-year OS and RFS were 58% and 71%, respectively (Figs 3,4). The median follow-up time was 35 months (IQR 9-169). One patient had
| Clinical presentation | Number of patients, n (%) | Pathological classification | Laboratory assessment Isolated Mixed type hormone hormone excess, n (%) excess (%) Nonfunctional | ||
|---|---|---|---|---|---|
| Virilization | 9 (37.5) | ACA (3) | 1 (33.3) | 2 (66.7) | — |
| ACC (6) | 4 (66.7) | 2 (33.3) | — | ||
| Cushing's syndrome | 4 (16.6) | ACA (2) | 1 (50) | 1 (50) | — |
| ACC (2) | 1 (50) | 1 (50) | — | ||
| Virilization + Cushing's | 6 (25) | ACA (2) | — | 2 (100) | — |
| syndrome | ACC (4) | — | 4 (100) | — | |
| Abdominal pain | 3 (12.5) | ACA (1) | 1 (100) | — | — |
| ACC (2) | — | 1 (50) | 1 (50) | ||
| Muscle weakness + lethargy | 1 (4.2) | ACA (1) | 1 (100) | — | — |
| Abdominal swelling | 1 (4.2 | NEDACT | — | — | 1 (100) |
| Total | 24 | 9 (37.5) | 13 (54.2) | 2 (8.3) | |
ACA, adrenocortical adenoma; ACC, adrenocortical carcinoma.
MRG abdominal
(a)
H
(b)
metastasectomy for pulmonary nodules twice and still receiving chemotherapy. The other patient with liver and lung metastases is also under chemotherapy treatment.
Adrenocortical adenoma (ACA)
Nine patients were diagnosed with ACA. The female to male ratio was 5:4. The median age at diagnosis was 24 months (IQR 12-72). The mean diameter of tumour was 4.16 ± 1.8 cm (2-5.5 cm) in cross-sectional imaging. The median weight of the tumour was 23 g (IQR 16-40). Preoperative steroid coverage was done in all patients. Total excision with transabdominal approach was
10
performed in all cases. Operative mortality was not seen and post- operative period was uneventful. The median follow-up time was 48 months (IQR 20-84). There was no recurrence.
Discussion
ACTs are rare in childhood with an estimated incidence of 0.3 cases per year and constitute less than 0.2% of all paediatric neo- plasms. There is a remarkable geographical difference in incidence
Survival Function
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1.0
0.8-
Recurrence rate
0.6-
0.4
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Months
ranging from 0.1/106 in Hong Kong and Bombay to 3.4-4.2/10° in Southern Brazil, which is attributed to genetic differences (1-4). According to Turkish Paediatric Oncology Group Registry 0.18% of childhood cancer cases in our country are ACTs.24
ACTs have a bimodal age distribution with a peak under age of 5 and another after 10 years of age. More than half of the patients are under 5 years of age. Mean age at diagnosis was 90 months (1-192 months) in our series and 63.6% of patients were above 5 years of age. In the previously presented series of our centre, mean age was 80 months.25 These two series are the only two case series from Turkey presented in English literature. Considering these data age distribution of ACTs in Turkish children may be esti- mated to be different than their counterparts in other countries. This estimation of different age distribution in Turkish children needs to be confirmed and reason of this variation should be investigated.
Female sex is predominant in most series of childhood adenocar- cinoma. Sex distribution in our series is with a female to male ratio of 1.7/1 is compatible with literature.
ACTs are mostly sporadic but may be associated with genetic alterations and syndromes. Familial adenomatous polyposis, multi- ple endocrine neoplasia type 1, Lynch syndrome and neurofibroma- tosis type 1 can be associated with ACT in adults. In children, ACT may be associated with Beckwith Wiedemann syndrome, Li Fraumeni syndrome and endemic germline TP53 mutations. ACC may be associated with familial cancer susceptibility syndromes. Congenital malformations, bilateral or metachronous tumours, fam- ily members with rare cancers, consecutive occurrence of new can- cer/cancers in the patient with ACC should raise the suspicion of hereditary cancer susceptibility syndromes.5 In our series two
children were diagnosed with such syndromes; Li Fraumeni and Peutz Jeghers syndrome. ACC was the first detected malignancy in these patients. Our patient with Li Fraumeni syndrome had syn- chronous hepatocellular carcinoma and the one with Peutz Jeghers syndrome had papillary thyroid carcinoma, glioblastoma and phyl- lodes tumour of breast during follow up period. Diagnosis of the familial cancer susceptibility syndrome is important for both the surveillance of the patient and identification of family members at risk for development of any tumour. Any child with ACT should be evaluated for the presence of a cancer susceptibility syndrome. A detailed family history and thorough evaluation of patient to detect any evidence of these syndromes is mandatory.26
ACTs are mostly functional in paediatric cases due to adrenocor- tical hormones secreted from the tumour. Virilization is the most common presentation of excess hormone secretion followed by Cushing’s syndrome and hyperaldosteronism. In our series nine patients had virilization, four had Cushing’s syndrome and six had both. Hypercortisolism may be subtle without any clinical sign of Cushing’s syndrome and hyperandrogenism may occur without clinically evident virilization. Excess cortisol secretion by the tumour may suppress contralateral normal adrenal gland and exci- sion of tumour may lead to adrenal insufficiency during the surgery or in the postoperative period. Patients with normal basal cortisol levels may also experience adrenal insufficiency because of the dis- turbed circadian rhythm of cortisol secretion. Early morning and late evening samples of blood for cortisol secretion as well as 24-h urinary free cortisol levels may help the detection of hypercortisolism.27-30 The surgeon should be aware that the deter- mination of excess hormones and steroid coverage is essential for a safe surgery and postoperative period.
Regardless of clinical presentation, 15 patients (62.5%) had hypercortisolism in our series, and five out of 15 patients had no clinical presentation. Therefore, steroid coverage was beneficial to prevent adrenal insufficiency in all patients.
Complete analysis of adrenal hormones disregarding clinical signs of excess hormones is also essential to detect the activity of tumour definitively to use hormone levels as tumour markers during follow-up period.
Surgery is the mainstay of treatment in ACTs in children as cur- rently available chemotherapy and radiotherapy regimens are unsat- isfactory. Some tumours may present with radiologic evidence of locally advanced disease in which safe surgical resection is questioned. Neoadjuvant chemotherapy with mitotane and etoposide or cisplatin-based regimens have been suggested for patients with questionable metastatic disease, poor performance due to hormonal status and presumed unresectable tumour. Redlich et al. reported 11 children with inoperable ACC who had two to four cycles of neoadjuvant chemotherapy with mitotane. Eight of these patients underwent surgery and five had total tumour resec- tion. In that particular study, criteria to define inoperable tumour is not clear and whether the tumour size decreased with chemotherapy or not is not mentioned.31 Bednarski et al.32 characterized tumour resection of which may have unacceptable risk of morbidity/mortal- ity, incomplete resection and recurrence as ‘borderline resectable tumour’. Tumours of patients who had imaging suggesting a need for multiorgan/vascular resection or potentially resectable
oligometastases and having marginal performance status/precluding immediate surgery were defined as borderline resectable tumours. In this series, 15 patients with a mean age of 40 years (range 20-70.3) had preoperative chemotherapy. Of the 13 patients having surgery after chemotherapy, five had partial response, seven had stable disease and one had progressive disease according to Response Evaluation Criteria in Solid Tumours.23 These patients had better disease-free survival rates than patients who had initial surgery and five-year overall survival rates were similar for both groups.32 These studies suggest promising effect of neoadjuvant chemotherapy. In our series, five patients received neoadjuvant che- motherapy because of stage IV disease (n = 4) and presumptive unresectable tumour (n = 1) but none had a decrease in primary tumour size or metastases. All of these patients had stable disease according to Response Evaluation Criteria in Solid Tumours and eventually underwent surgery for primary tumour excision.23
Complete surgical removal without any spillage offers the best chance for long-term survival. When adrenal capsule is violated by biopsy or rupture during the surgery or adrenal capsule is invaded by malignant cells, these cells reach peritoneal cavity and cause peritoneal carcinomatosis with worse prognosis.16-19 Thus, every attempt should be made to maintain tumour integrity during the sur- gery. Preoperative identification of malignancy is important for sur- gical decision making. Tumour size, location, local or vascular invasion pattern and any lymph node involvement should be evalu- ated precisely with computed tomography or magnetic resonance imaging. However, any cut off value for tumour size in children should be considered controversial since none of the previously described cut off values are age dependent. Extent of resection and preferred incision should be tailored for every patient individually with respect to the imaging results and particular anatomic charac- teristics of the patient.
Importance of good surgical exposure to achieve tumour re- section without violation of tumour integrity cannot be over- emphasized. An enhanced exposure by a particularly chosen incision provides delineation of the anatomy precisely, facilitates resection and improves local control. All but two patients in this series had tumour resection through transabdominal route by sub- costal incision. Thoracoabdominal incision was preferred in two patients with huge tumours and a narrow costal angle. Ipsilateral lung metastases were excised simultaneously in these patients. Thoracoabdominal incision provides an excellent exposure in upper retroperitoneum avoiding the telescopic effect of abdominal inci- sion and eases control of large retroperitoneal veins draining the tumour. Simultaneous excision of lung metastases is another advan- tage provided by thoracoabdominal incision.33
The ultimate goal of surgery in locoregional disease is to achieve microscopically margin-free total resection avoiding capsule violation. Incomplete resection, tumour rupture or spillage leads high-recurrence rates and poor overall survival. Complete surgical resection maintaining capsule integrity and preventing tumour spill- age may require adjacent visceral resection. If there is any presump- tive evidence of ACC en bloc resection of tumour including the neighbouring viscera when necessary offers best oncological outcome. The capsule of ACC is a delicate structure which may disintegrate under the smallest pressure. With the retraction of a
large tumour to dissect from adjacent viscera, this fragile capsule may not be strong enough to maintain the integrity of the tumour with necrotic and friable components. Considering the previous experience of tumour spillage in three patients, two patients with huge tumours had en bloc resection of tumour with neighbouring viscera.34-36 One patient with stage III ACC who had partial re- section died of locally recurrent and metastatic disease. Two patients with stage III tumour who had spillage of tumour during the surgery are died of locally recurrent disease. One patient with stage IV tumour who had spillage of tumour during the surgery died from metastatic disease.
Minimally invasive surgical methods provide good cosmetic result, short hospital stays and less pain. Some studies reveal that adrenalectomy seems to have similar oncologic outcomes when compared to open surgery when margin-free resection and avoid- ance of tumour spillage is achieved in adult patients.37,38 Other studies indicate higher rates of spillage and earlier recurrence for ACC when laparoscopic excision is preferred.39 However, small sample sizes regarding these rare tumours prevent to design pro- spective randomized studies to compare open and minimally inva- sive techniques in children. We think that whether minimally invasive or open technique used, gentle dissection of tumour to achieve R0 resection has the utmost importance. We did not prefer laparoscopic surgery to avoid rupture but we think that laparoscopic excision of ACTs could be performed in experienced hands when surrounding structures are not infiltrated.
Indications and extent of retroperitoneal lymphadenectomy is controversial in the treatment of ACC. Surgical management regarding lymphadenectomy is heterogeneously applied. In the reported series, the extent of lymphadenectomy with regard to nodal count and station is not clear. Heterogeneity in extent and type of pathological and surgical approach and arbitrary definition of lymphadenectomy in literature hardens to evaluate the rate of real lymph node positivity at the time of resection. Regional lymphadenectomy is offered for improved control and better staging. 40-43 On the other hand, results of the Children’s Oncology Group ARAR0332 protocol revealed that RPLND did not improve outcome.44 None of our patients had RPLND. Only regional lymph nodes suspected to be metastatic were removed and none had tumour. A SEER-based study showed that there was no association between large tumour sizes or higher neoplasm grades and lymph node involvement.45 Similarly, another SEER-based study reported no association between tumour size and lymph node metastasis. However, a relationship was found between higher rates of lymph node metastasis and higher tumour grades.42 On the other hand, positive lymph node ratio was found to be significantly higher in right-sided ACC than left. This finding has been explained by the anatomical differences between right and left adrenal venous drain- age. The rate of lymph node metastasis has been stated low in pre- vious studies. It may be related to the fact that lymphadenectomy is performed less frequently in ACC and/or because of the hematoge- nous spread of ACC.42,45
In our series five patients who had partial excision (n = 1) and tumour spillage died from widespread disease (n = 4), lung metasta- ses (n = 1) in 1-4 years. All patients who had total excision without tumour spillage (n = 19) were alive during the follow-up period (1-
13 years). All of these patients but two with stage IV ACC on diag- nosis are disease free. Two patients with stage IV ACC on diagno- sis who had primary tumour resection with negative microscopic margins are alive and on chemotherapy.
A major limitation in our study is lower number of cases with genetic testing for familial cancer susceptibility syndrome in chil- dren with ACT both for patient surveillance and for identifying family members at risk for the development of any tumour.
Conclusion
Although limited number of cases prevents an absolute decision, our results indicate the importance of the excision of ACTs without spillage. Team work on surgical decision making and clinical prac- tice by experienced teams are important for better prognosis. Multi- centre prospective studies with larger patient series are necessary to expand the knowledge about ACTs of children and develop alterna- tive therapies for stage III and stage IV ACC. Molecular targeting and development of the more efficient therapeutics should also be a focus for the future investigations.
Conflicts of interest
None declared.
Author contributions
Burak Ardıçlı: Data curation; formal analysis; investigation; meth- odology; project administration; software; validation; visualization; writing-original draft; writing-review and editing. idil user: Data curation; methodology; writing-original draft; writing-review and editing. Arbay Ciftci: Methodology; writing-review and editing. Canan Akyüz: Writing-review and editing. Mustafa Kutluk: Methodology; project administration; supervision. Bilgehan Yalçın: Data curation; formal analysis; methodology; writing- review and editing. Nazlı Gönç: Data curation; investigation; meth- odology; writing-review and editing. Zeynep Özon: Methodology; writing-review and editing. Ayfer Alikasifoglu: Conceptualization; methodology; writing-review and editing. Berna Oğuz: Data curation; investigation; methodology; writing-original draft; writing-review and editing. Mithat Haliloğlu: Methodology; soft- ware; supervision; writing-review and editing. Diclehan Orhan: Formal analysis; writing-original draft; writing-review and editing. Cahit Tanyel: Methodology; writing-review and editing. Ibrahim Karnak: Methodology; writing-review and editing. Saniye Ekinci: Conceptualization; formal analysis; investigation; methodology; project administration; supervision; writing-original draft; writing- review and editing.
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