Pediatric adrenocortical carcinoma: clinical features and application of neoadjuvant chemotherapy

Adrenal cortical carcinoma (ACC) is an aggressive malignant tumor with one of the incidence peaks in children and adolescents, with 0.5–2.0 new cases per 1 million children per year, accounting for 0.2% of childhood malignant tumors [1, 2]. Due to the rarity of ACC, research on the disease is still mainly based on small numbers of case reports [3]. Surgery is a critical component of ACC treatment, but a high risk of recurrence remains [4]. After comprehensive treatment, the 5-year overall survival (OS) of stage IV patients who were previously not considered for surgery is 16% [5, 6]. Therefore, exploring new treatment modalities may be of great significance for improving the prognosis of ACC. In our study, we aimed to summarize the clinical data of ACC patients with a clear pathological diagnosis and to explore the best indication for and efficacy of neoadjuvant chemotherapy.

ACC is a rare primary adrenal endocrine malignancy associated with germline TP53 pathogenic variant [11, 12], and optimal treatment strategies have yet to be determined. In our study, we summarized the clinical data of 40 pediatric ACC patients and preliminarily explored the indications for and efficacy of neoadjuvant chemotherapy.

Adrenocortical tumors can autonomously secrete excessive amounts of adrenocortical hormones, each of which is associated with specific clinical syndromes [13, 14]. In our study, 14 (35%) patients were newly diagnosed with sexual precocity, 12 (30%) with Cushing’s syndrome, and 5 (12.5%) with virilization. Some studies have reported that there is a correlation between endocrine phenotype and tumor stage. In a retrospective study of 77 ACC patients, Cushing’s syndrome and hypertension were more likely to be found in stage IV disease [5]. In our study, among the 17 children without hormone-related clinical manifestations, 11 patients had abnormal hormone levels at the initial diagnosis, suggesting a time window between the onset of functional tumors and the appearance of related clinical manifestations. We also found that a small number of children had elevated adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) hormones, which are rare in ACC. However, most were only slightly elevated and were considered to be disorders of the hypothalamic–pituitary–gonadal axis due to disturbances in sex hormone levels; they can be analogous to the polycystic ovary syndrome in women [15‐17]. There were 3 cases of elevated LH, FSH, and PRL in our study, and they were all female, aged 7 months, 3 months, and 13 years old, respectively. Causes of the abnormalities may include the 2 younger children being in mini-puberty, and physiological elevation of hormone levels during puberty in the 13-year-old. Regardless of whether clinical manifestations are present, endocrine levels should be tested comprehensively to facilitate clinical diagnosis and treatment evaluation.

Surgery is still the most effective treatment for ACC. Complete tumor resection can directly affect prognosis, especially for patients without distant metastasis [18‐20]. According to the Children’s Oncology Group (COG) ARAR0332 study, radical surgery is the first choice for children with COG stage I/II disease [5]. Previous studies have also confirmed the benefit of repeated surgical resection for recurrent lesions [4, 21]. In our study, 30 children with ENSAT stage I/II disease underwent complete resection; 24 survived without disease, 5 were lost to follow-up, and 1 died (parental refusal due to children poor condition). Postoperative chemotherapy is another important treatment strategy. A regimen of mitotane alone or in combination with EDP is currently the recommended first-line chemotherapy [5, 22, 23]. In our study, 6 of the 16 patients with ENSAT stage II disease were treated with postoperative chemotherapy, and all survived without tumor progression or recurrence. Notably, the survival rate of patients with stage II was 100% in our cohort, which a satisfactory result. In addition to stage III and IV patients, application of postoperative chemotherapy may also be recommended for stage II patients to improve prognosis. Prospective clinical trials are required for further validation.

Surgery and postoperative chemotherapy can significantly improve the prognosis of ACC, but some patients are unfit for surgery at the time of diagnosis due to various conditions. In such cases, neoadjuvant chemotherapy may be an alternative. A 2021 consensus has recently emerged in the pediatric field [13], stating that neoadjuvant chemotherapy can be recommended in children with inoperable and metastatic tumors. However, the definition of “inoperable” has neither been clearly defined nor is evidence-based. Neoadjuvant chemotherapy is rarely used in children with ACC at present. A previous study proposed that “borderline resectability”, the risk of incomplete resection or recurrence, in adult ACC is unacceptable, and immediate surgery is not recommended for these patients [24]. The study divided 53 adults with ACC into 2 groups according to whether complete resection was possible and found that the 5-year OS in the neoadjuvant chemotherapy group was higher than that in the direct surgery group. It was concluded that neoadjuvant chemotherapy was beneficial for these patients [24]. Another study looked at 72 advanced ACC adult patients at first diagnosis who had not been amenable to radical surgery, and were treated with palliative chemotherapy; among them, 5 patients achieved complete remission (CR) and 30 achieved partial response (PR), with an overall response rate of 48.6%. Furthermore, 10 patients underwent radical surgical resection of residual disease after chemotherapy and achieved a disease-free status (13.9%) [25]. To some extent, palliative chemotherapy for advanced ACC confirms the effectiveness of neoadjuvant chemotherapy. Taking into consideration the conclusions of our study and previous studies, we believe that neoadjuvant chemotherapy should be attempted in the following situations for ACC patients: first, a large tumor (largest diameter > 10 cm) that invades the surrounding important blood vessels and tissues; second, preoperative evaluation shows the presence of distant metastases or intravenous tumor thrombus; and third, the patient’s general condition is poor (e.g., cachexia or pulmonary embolism) and precludes surgery. Patients who meet one of these criteria may be eligible to try neoadjuvant chemotherapy. Final treatment decisions should only be made after a multidisciplinary tumor board meeting (MDT) that includes medical oncology, surgical oncology, pediatrics, intensive care unit, and anesthesiology. Benefits of neoadjuvant chemotherapy in children with ACC mainly include the following points. First, reducing the tumor volume can reduce the tumor burden and maximize the possibility of R0 resection. Second, neoadjuvant chemotherapy may help to reduce hormone secretion and ameliorate symptoms of hormonal abnormalities (hormone levels dropped to normal after 3 cycles of neoadjuvant chemotherapy in one of our cases). Third, for children with conditions precluding surgery such as pulmonary embolism or poor nutritional status, neoadjuvant chemotherapy can create an opportunity to resolve correctable complications and thus allow surgery. Fourth, response evaluation during neoadjuvant chemotherapy can help to guide the formulation and adjustment of postoperative chemotherapy regimens. Fifth, chemotherapy may reduce micro-metastasis in particular in case of extend tumor and reduce the risk of distant tumor spread. Based on the above benefits, and used carefully under the guidance of MDT, we expect neoadjuvant chemotherapy to become another important aspect of the treatment strategy for certain children with ACC, especially in stage III and IV disease.

Regarding the better prognosis that was achieved in our study, in addition to the role of neoadjuvant chemotherapy, other conducive factors include high percentage of children with stage I/II (n = 30/40) and postoperative chemotherapy that some with stage II underwent. Furthermore, using the Weiss system grading instead of the Wieneke score may have also attributed to better prognosis [26, 27]. Although the Weiss score has a higher sensitivity, its lower specificity might have allowed the more biologically benign ACCs to be treated as malignant. However, confirmation is required via the joint efforts of pathologists and clinicians through prospective trials.

There are some limitations in our study. This was a retrospective study spanning 15 years, some children were lost to follow-up, and the pathologic diagnosis of the children in our study relied on the Weiss score rather than the Wieneke score [19, 28]. Due to the rarity of ACC, the sample size of this study is small, and only 7 patients were treated with neoadjuvant chemotherapy. The specific role of neoadjuvant chemotherapy remains unclear and needs to be demonstrated in prospective randomized controlled trials. A definitive recommendation on the indications for neoadjuvant chemotherapy still cannot be made. Furthermore, mitotane was not used in patients in this cohort because it has not been approved for marketing in China and is difficult to obtain. Pediatric patients should be included in prospective trials in order to define the exact role of medical therapy in such very rare tumor.

In conclusion, for children with ACC, a comprehensive endocrine evaluation is necessary during the treatment process. Early surgical resection should be performed to ensure complete tumor removal, and neoadjuvant chemotherapy can be attempted for certain children to create an opportunity for radical surgery and improve their prognosis.