6
URRENT PINION
Pediatric adrenocortical tumor - review and management update
Vania B. Brondania and Maria Candida B.V. Fragosoa,b
Purpose of review
Adrenocortical tumor (ACT) is a rare disease with an annual worldwide incidence of 0.3-0.38/million children below 15 years old, and Brazilian population presents the highest incidence because of germline mutation in the TP53. Pediatric ACT is associated with virilizing features and hypercortisolism in most cases. Malignancy is defined when local invasion or metastasis is found, and it is associated with a poor prognosis. However, the correct and early diagnosis and treatment may impact on overall and disease-free survival.
Recent findings
A complete understanding of the disease and its singularities facilitates the assistance to the pediatric patient with ACT. The new insights about adrenal tumorigenesis have provided a better understanding of this disease. In this scenario, the era of molecular studies is leading to the refinement of the taxonomy, and it is offering the opportunity to discover new biomarkers and pathways of tumorigenesis, beyond the knowing ß-catenin, Insulin-like growth factor-II/IGF-IR, and the p53/Rb signaling.
Summary
The rarity of this disease makes it a real challenge. Here, we present a review focusing on clinical practice. A methodic approach aiming to clarify the diagnosis and a follow-up are suggested to guide physicians in the assistance of pediatrics patients, improving the prognosis.
Keywords
adrenocortical tumors, disease management, pediatric tumor
INTRODUCTION
Adrenocortical tumors (ACTs) can occur rarely in children and adolescents. This pediatric adrenal disorder was first described in 1865 [1]. The Ameri- can National Cancer Institute [2] considers the pedi- atric adrenocortical tumors (PACTs) a very rare neoplasia affecting approximately 0.2% of all child- hood malignancies, and the majority is identified in the context of Li-Fraumeni syndrome (LFS) [2-7]. PACT has an annual worldwide incidence of 0.3- 0.38/million children below the age of 15 years old. However, in southern Brazil, the frequency of PACTs ranges from 10 to 15 times more (per million chil- dren) than the worldwide occurrence [8,9]. This high frequency is because of a specific germline mutation at codon 337 (c.1010G>A, p.Arg337His) in the TP53 gene [10-12]. Pinto et al. [11] and Garritano et al. [13] demonstrated the founder effect for p.Arg337His in the population of southern Brazil [11,13]. Interesting, there is high percentual of pedi- atric patients in the Brazilian cohort with ACT from the Hospital das Clinicas/Universidade de São Paulo
(HC/USP) which age ranging from 0 to 10 years old compared with European cohort to German registry [14] that presents only few patients with ACT in this decade of life.
There is a great variability in the literature regarding which age is considered pediatric or non- pediatric, ranging from 14 to 22 years in different countries [4,8,15-30]. However, the majority of patients are seen under five years old [8,17,18], with
aUnidade de Suprarrenal, Laboratório de Hormônios e Genética Molec- ular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo and bServiço de Endocrinologia da Clínica de Bases do Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil
Correspondence to Maria Candida B.V. Fragoso, PhD, MD, Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Facul- dade de Medicina da Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 155, São Paulo, Brazil. Tel: +55 11 2661 3358; e-mail: maria.fragoso@uol.com.br
Curr Opin Endocrinol Diabetes Obes 2020, 27:177-186 DOI:10.1097/MED.0000000000000540
KEY POINTS
· ACT is a rare disease, although Brazil presents the highest worldwide incidence because of germline mutation on TP53.
· Virilizing syndrome or hypercortisolism in children under five years of age must indicate a methodic evaluation to exclude an ACT.
. Currently, the best option to treat ACT is surgical resection, although all the advances in medicine.
· The new era of molecular studies is bringing new insights into adrenal tumorigenesis, and it may facilitate the development of targeted therapies according to molecular data, improving the assistance for the patients.
a high frequency up to the third year of life [18,25,31]. Although it rarely occurs in the fetus or newborn [32], PACTs probably derive from the fetal zone of the adrenal gland, which justifies the early age of onset and hormonal secretion, causing virilization because of tumor androgen production [9,24,33,34].
According to the International Registry for PACTs, the female-male ratio varies widely with age. Females predominated in the age groups 0 to 3 years (ratio 1.7:1) and at least 13 years (ratio 6.2:1) [4,17,20,22,24,35]. In contrast to adults, PACTs with apparent poor prognosis based on histopathological features often have a good clinical outcome. In this review, we summarize the clinical and molecular data of PACTs.
MOLECULAR PATHWAYS OF TUMORIGENESIS AND PREDISPOSITION SYNDROMES
The most involved pathways in the adrenal tumori- genesis are ß-catenin, Insulin-like growth factor (IGF)-II/IGF-IR, and p53/Rb signaling and the chro- matin remodeling process [20,36-38]. Germline mutations associated with cancer predisposition syndrome contribute to childhood ACT, corre- sponding to approximately 50% of cases, whereas in the adult group, this rate is approximately 10% [21,33,39,40]. LFS [41] and Beckwith Wiedemann syndrome [42] are more related to PACT.
TP53 mutation may contribute to the cause of the majority of cases of ACT in children [43-46]. This high incidence suggests that normal p53 func- tion is essential for the physiological process of postnatal fetal adrenal regression [20]. The diagnosis of ACT in a child is an indication to use genetic testing to search for TP53 mutations, and posteriorly
in the parents [20,45]. Genetic counseling should be offered to the affected families with TP53 mutations. An inherited TP53 p.Arg337His mutation appar- ently confers a low penetrance for the development of adrenocortical tumors, and its presence was not related to unfavorable prognosis in children [12].
The IGF pathway contributes to normal cell growth and development. IGF-I functions almost exclusively postnatally, whereas IGF-II has a more prominent role during fetal development and a minimal role after birth [9]. The system IGF-II/ IGF-IR participates in adrenal tumorigenesis. Almeida et al. [47] showed overexpression of the IGF-IR gene in pediatric ACT, and its expression was significantly correlated with malignant behav- ior in children.
De Sousa et al. [27] showed that DAX1 genetic expression, a stem-cell fate regulator, was more frequent in pediatric ACTs than in adults and revealed a significant and positive correlation between DAX1 and SF1 expression, which suggests a role in adrenocortical tumorigenesis. Nevertheless, a prognostic value could not be associated in either children or adults [27].
The overexpression of the FGFR4 gene was observed in pediatric and adult ACTs [48,49]. Brito et al. [29] reported an overexpression of FGFR4, with a positive correlation to IGFII, in PACTs and adre- nocortical carcinoma (ACC). In the adult group, the overexpression was a predictor of poor outcome [29].
DeReynies et al. [50] identified three genes, DLGAP5, BUB1B, and PINK1, that, when their expres- sion was combined, resulted in a strong association with outcomes in adult patients with ACTs [50]. DLGAP5 and BUB1B are overexpressed in ACCs [28], whereas the PINK1 gene, which is regulated by the PTEN gene, was found to be downregulated in ACTs [51]. Fragoso et al. [28] validated the prog- nostic value of the combined expression of DLGAP5, BUB1B, and PINK1 in a Brazilian adult cohort of ACTs, and for pediatric patients, these molecular markers still lack sufficient discriminatory efficiency [28].
The new era of molecular studies has led to the refinement of the cancer taxonomy, and it has offered the opportunity for the discovery of new biomarkers and new pathways of tumorigenesis. In this scenario, three extensive studies [36-38] have provided a comprehensive view of the molecular changes in adrenal tumors using a pan-genomic approach. As a result of these studies, ATRX and ZNRF3 genes were associated with adrenal tumori- genesis for the first time. The ATRX gene is respon- sible for chromatin remodeling and the telomeric structure maintenance [52-54], and Pinto et al. [38] reported that PACTs with germline TP53 and
somatic ATRX mutations were associated with high tumor weight, advanced disease and poor event-free survival [38]. The ZNRF3 gene acts as a suppressor gene of the ß-catenin pathway [55-57], and no prognostic value was determined in PACTs or ACC cohorts.
Parise et al. [58""] studied the prognostic role of CD8+ T lymphocytes in PACTs and reported an association between infiltrated CD8+ cells and a better prognosis [58""]. This study contributes to our scant knowledge of the immune response in ACTs, although functional analyses are necessary to clarify some mechanisms aiming to provide future targeted therapies.
CLINICAL PRESENTATION
Patients with PACTs usually present isolated androgen secretion by the tumor, in 40% of cases, and present with virilizing features characterized by linear growth acceleration, advanced bone age, pubic hair, hirsut- ism, acne, deepening voice, muscle hypertrophy, clitoromegaly or increase in penis size [8,9,15,17,21,23,24,45,59]. This peripheral precocious puberty could also lead to central precocious puberty (CPP), depending on hypothalamic time androgens exposition. In addition, gonadotropin-dependent pubertal disorders, such as CPP and early fast puberty have been reported in pediatric patients with ACTs [30]. The mixed secretion of androgen and glucocorti- coids in PACTs ranges between 25 and 50% of cases, and rarely, they present isolated hypercortisolism and much more infrequent, isolated hyperaldosteronism or estrogen secretion [8,9,15,17,24,45,59]. Approxi- mately, one-third of patients present with arterial hypertension, which is usually caused by glucocorti- coid excess production [45] (Fig. 1).
This hormonal secretion pattern contrasts with the adolescents and adult group, which shows a higher frequency of isolated hypercortisolism, fol- lowed by combined secretion of glucocorticoid and androgens, and the minority of cases releasing iso- lated androgen [8,9,15,17,60""].
In addition, cases with feminization or no clini- cal evidence of hormonal production at presenta- tion correspond to less than 10% of patients [17,24]. Data from the International Pediatric ACT Registry show that most patients [75.5% (192 of out 254 patients)] present with localized disease, and meta- static disease was found at diagnosis in less than 5% of cases [45].
DIAGNOSIS
All patients below five years of age presenting viri- lization must be evaluated for ACT, because of its
known peak of incidence. Based on the evaluation proposed by European network for the study of Adrenal Tumours [60""] for adult patients who are suspected of having ACC, we encourage an adapted systematic approach to the pediatric population suspected of presenting ACT (Table 1).
The hormonal secretion of the adrenal cortex should be tested, and when positive, it is useful as a surveillance parameter during the follow-up. The plasma hormones return to normal on the day after surgery, as a microscopically complete resection (R0) has been performed. A new increase in hormone tests is indicative of recurrence. ACTs usually present defective steroidogenesis with an increase in releas- ing hormonal precursors, with abnormal function, because of a dedifferentiated and thus incomplete pattern of steroidogenic enzyme expression [66,67]. Arlt et al. [67] reported the urinary steroid profiling (USP) as a diagnostic tool to distinct adrenocortical adenomas from ACC, and 11-deoxycortisol metabo- lite tetrahydro-11-deoxycortisol (THS) was the most discriminative steroid in the differentiation [67]. Chortis et al. [68”] also demonstrated the importance of USP and THS as diagnostic tool for recurrence detection in patients with microscopically complete (RO) resection of ACC [68”]. For this reason, hormone precursors should also be evaluated. In addition to adrenal hormones, the gonadal axis should be tested because of the possibility of the development of precocious central puberty triggered by adrenal hor- mones. Bone age should also be documented with an X-ray. Sandrini et al. [8] showed an advanced bone age of more than one year in 68% of their cohort.
All patients should undergo an abdominal imag- ing study focusing on the adrenal gland [computed tomography (CT) or MRI]. CT and MRI are equally efficient in establishing diagnoses of adrenal tumors [69,70], although MRI has been considered advan- tageous because of the absence of ionizing radiation [71] (Fig. 2). Frequently, imaging studies cannot define the benignity of the lesion, and only the presence of metastases determines the malignancy [72]. However, the image is particularly useful to the surgeon before surgery [45].
The liver and lungs are the most frequent sites of metastasis, whereas the skeleton and central ner- vous system have been involved in a few cases [45]. The abdominal image shows the tumor structure and evaluates the local extension and invasion, and it can assess the possibility of metastatic disease in the liver. CT scans of the thorax are indicated for all patients aiming to diagnose lung metastasis earlier and are recommended for all newly diagnosed patients [45]. Other imaging studies, such as MRI of brain and bone scintigraphy, are required only under suspected metastasis. The patient must
A
B
C
D
E
F
undergo brain MRI if TP53 mutation is confirmed, because of the possibility of LFS related brain tumor. Follow-up with cautious surveillance must be performed by a responsible assistant (Table 2), focus- ing on tumoral markers and imaging studies (CT or MRI). Patients with TP53 mutation should be fol- lowed with the modified Toronto protocol [73,74], which is associated with early tumor detection and with improved long-term survival in LFS patients.
The diagnosis is often delayed for approximately five months [17]. Nevertheless, it is crucial to ensure the earlier and methodic diagnosis workup and planning of the surgical procedure, as complete tumor resection remains the cornerstone of treat- ment and offers the best chance of cure [75].
STAGING
When histopathological analyses confirm ACTs, it is necessary to stage the patient and determine the prognosis and plan surveillance. The classic Weiss criteria, proposed in 1984, are the most commonly used histologic criteria for the diagnosis of ACC in adult patients. The Weiss score is based on nine histologic parameters (nuclear grade, mitotic rate, atypical mitosis, clear cells, diffuse pattern, necrosis, venous, sinusoidal and capsular invasion), and ACC is diagnosed when three items are present [76]. The mitotic rate and atypical mitosis are related to worse tumor behavior [77]. Interestingly, based only on histologic parameters, the correlation of PACT and prognosis is not reached. In contrast to the adult
| Hormonal and laboratory evaluation | Clinical presentation Observations |
|---|---|
| Virilizing syndrome | |
| DHEA-S | |
| Androstenedione | |
| Testosterone | |
| 17-B-Estradiol | |
| 17-OH-progesterone | |
| 11-deoxycortisol | |
| Cushing's syndrome | |
| Basal plasmatic ACTH | |
| Dexamethasone suppression test overnight | 20 µg/kg weight below 40kg; 1 mg dexamethasone if >40 kg |
| Urinary free cortisol in 24 h (if feasible) | 3 consecutive collections (correct for body surface area) |
| Late-night salivary cortisol Serum cortisol levels (if feasible) | |
| Hyperaldosteronism | |
| Aldosterone, renin, and potassium | If severe arterial hypertension and/or hypokalemia is present |
| To exclude pheochromocytoma | |
| Free plasma-metanephrines | In cases with heterogeneous adrenal lesion and without evidence of virilizing and Cushing's syndrome |
| Central precocious puberty | |
| LH | Complement to gonadal axis evaluation |
| Imaging studies | |
| Abdominal MRI | |
| Thorax CT | |
| Brain MRI (if TP53 mutation present) | |
CT, computed tomography. Ref. [60"",61-65].
(a)
(b)
42,55 mm
| After surgical resection | Frequency | Description |
|---|---|---|
| First year | Every three months | Hormonal laboratory tests Imaging studies (thorax CT and abdomen MRI) |
| Second year | Every four months | |
| Third year | Every six months | |
| Fourth and fifth years | Once a year | |
| Sixth year and after | Once a year | Hormonal laboratory tests |
| Bone age should be seen once a year before puberty, during puberty every semester until epiphyseal closure. | ||
| If metastasis is suspected a cautious evaluation must be done. | ||
group, the pediatric patients with unfavorable his- tologic presentation show a favorable evolution, without disease recurrence in 69% of cases [78,79]. Faria et al. [33] showed that a Weiss score at least 3 was not a good predictor of survival in children, whereas it was much more discriminative in adults. The definitive malignancy criteria for the pediatric group are the invasion of tissues or adjacent organs or the presence of metastasis, whereas the Weiss criteria are not recommended to define pediatric adrenocortical adenomas and carcinomas [33].
The staging system widely used is that proposed by MacFarlane [80] and modified by Sullivan et al. [81] (Table 3). This classification presents four stages and is based on tumor size, local invasion, the involvement of adjacent organs or regional lymph nodes, and the presence of metastasis. Stages 1 and 2 present with a tumor confined to the adrenal gland, without local invasion or metastasis. Both stages are related to the best cure rates when surgical resection is performed [81].
Sandrini et al. [8] proposed a disease staging system that was modified by Michalkiewicz et al. [17]. This staging system considers surgical resec- tion, tumor volume, laboratory tests after the surgi- cal procedure, and the presence of metastasis. This scheme distinguishes two groups - those with completely excised tumors less than 200 cm3 (stage I) and those with distant metastasis (stage IV) - with different outcomes. However, the intermediate groups, stages II and III, are heterogeneous and are likely to include different prognostic categories.
Michalkiewicz et al. [17] showed that patients with complete resection of tumors weighing 200 g or less presented an excellent prognosis; in addition, patients with either microscopic or gross residual disease presented a poor prognosis [17,82]. In 2012, this staging system was improved by Ribeiro et al. [35], and the postoperative status of hormone levels was included in the classification (Table 4).
Wieneke et al. [79] proposed a new score for the diagnosis of malignancy in PACT through evalua- tion a set of nine items (tumor weight and size, invasion to periadrenal tissues or adjacent organs, vena cava, venous invasion, capsular invasion, necrosis, mitotic index, and the presence of atypical mitoses) (Table 5). According to the score acquired, it is possible to classify ACT as having benign, inter- mediate, and malignant behavior.
Beyond these classifications, different published cohorts reported that the presence of metastasis at diagnosis [24,25,83] mitotic index, necrosis, atypi- cal mitoses, nuclear grade [17,84], tumor size [25,85], Ki67-labeling index at least 15% [23] and glucocorticoid-producing tumors [17,22,45,79] were associated with poor prognosis. In contrast, age younger than four years [17,25,86], pure viriliz- ing clinical presentation [17,22,45,79], localized dis- ease, absence of spillage during surgery, and tumor weight less than 200 g [17,45] were associated with a better probability of disease-free survival.
Children with ACT are living longer, probably because of better resection techniques that do not rupture the capsule. This scenario is different from the beginning when fatal outcomes were because of
| Stage | Size | Nodes and invasion | Metastases |
|---|---|---|---|
| I | Small tumors (≤5 cm) | No nodes or local invasion | No distant metastases |
| II | Large tumors (>5 cm) | No nodes or local invasion | No distant metastases |
| III | Any size | Nodes or local invasion | No distant metastases |
| IV | Any size | Nodes and local invasion | Distant metastases |
| Stage | Description |
|---|---|
| I | Tumor completely resected Small tumors* Normal postoperative hormone levels |
| II | Tumor completely resected Large tumors* Normal postoperative hormone levels |
| III | Presence of microscopic or gross tumor after surgical resection Inoperable tumor Tumor spillage Patients with Stage I and II tumors and abnormal postoperative hormone levels Patients with retroperitoneal lymph node involvement |
| IV | Presence of distant metastases |
“Small tumors: less than 100g and less than 200 cm3; large tumors: at least 100g or at least 200 cm3.
carcinomatosis or local recurrence [87]. Most patients have a localized or regional disease at the time of diagnosis [45]. The overall survival rate at five years varies 46-54.7% from different cohorts [15,17,20,24]. Metastasis may be observed in 5-81% [15,17,24-26,45] and usually affects the lungs, liver, regional lymph nodes, kidneys, and bone [9,17,22,24,26,45,83,87].
TREATMENT
Surgical treatment is still considered the best option for PACT patients, impacting on overall and disease-free survival. Complete resection is mandatory even if it requires the removal of adja- cent structures [88]. This approach aims to avoid local recurrence and improve the outcome. If PACT is localized, with no sign of invasion, the laparo- scopic approach is reasonable by an experienced
Table 5. Wieneke criteria for malignancy of PACT [79]
Criteria for malignancy of PACT
Tumor weight of >400g
Tumor size >10.5 cm
Extension into periadrenal soft tissues and/or adjacent organs
Invasion into vena cava
Venous invasion
Capsular invasion
Presence of tumor necrosis
>15 mitoses per 20 high-power field (400x)
Presence of atypical mitotic figures
surgeon. The paraaortic and paracaval regions should be examined, and if lymph nodes are favor- able for metastatic disease, they should also be excised [88]. The vena cava should also be palpated before resection. If extensive tumor thrombus is present, a combined thoracic and abdominal approach may be required [9]. In the case of large and locally invasive tumors, an en bloc resection may be necessary, which includes the removal of adjacent structures [45,60""].
ACT is a friable tumor, and manipulation during the procedure could result in tumor rupture and spillage, which impact the outcome [8,17,45,79]. Teinturier et al. showed a survival rate of 70% when surgical resection was microscopically complete and 7% when it was not [15]. Therefore, an experi- enced surgeon is required, and at surgery, all ACTs should be considered malignant tumors [89]. If local recurrence or metastatic disease occurs, a new surgery should be offered, if possible, and then pharmacological treatment should be prescribed, aiming for a better prognosis. This approach differs from the adult group. The recurrence rate in adults varies from 60 to 70%, even with complete tumor resection, and pharmacological treatment is pre- scribed earlier, aiming to reduce tumor recurrence and increase recurrence-free and overall survival [90,91”].
As a rare disease, there is a lack of data, and there are few studies [17,23,25,26,35,86,92] in pediatric cohorts focusing on pharmacological treatment and metastatic disease. It is clear that compared with adult patients, pediatric patients show a better prognosis, but systemic chemother- apy and mitotane may have a role in patients with malign behavior PACT [92]. Redlich et al. [26] suggest that neoadjuvant therapy should be con- sidered for patients with primarily incomplete resectable or inoperable tumors, and when tumor spillage occurs during the surgical procedure, it is an indication for adjuvant chemotherapy and mitotane [26].
Mitotane (o,p’DDD) is the only drug approved for the treatment of ACC [90]. It inhibits steroido- genesis and presents antiproliferative and direct adrenolytic functions, leading to apoptosis of the fasciculata and reticular zones of the adrenal cortex [92-94]. The adjuvant use of mitotane was associ- ated with an important decrease in tumor recur- rence and with better overall and disease-free survival in adults [14,90]. Institutional reports and results of adult studies [60"",90,94,95] justify the use of mitotane in treating pediatric patients with malign behavior PACT [26] however, mitotane is not fully recommended to pediatric patients with ACT with R0 tumor resection. Redlich et al. [26]
reported an association between pediatric outcomes and mitotane plasma level (>14 mg/l) as well as the duration of mitotane treatment (>6 months), result- ing in a better overall survival. Patients receiving mitotane should be considered to have adrenal insufficiency, and hormonal replacement with hydrocortisone and fludrocortisone must be pre- scribed [9,92]. It is necessary to maintain surveil- lance related to hydrocortisone dosage because mitotane alters its bioavailability, and greater doses may be required [96]. Dexamethasone is not recom- mended as the first option because of its negative impact on growth and metabolism. Thyroid func- tion should also be evaluated because of the possi- bility of hypothyroidism associated with mitotane, as seen in the adult group and in some reported cases in pediatric patients [97].
Combined chemotherapy and surgical resec- tions of recurrent disease are associated with pro- longed survival [45]. All pediatric patients who need chemotherapy should be treated in pediatric tertiary centers according to a consistent protocol in a highly interdisciplinary setting [26].
Radiotherapy is not an option because many children with ACT carry germline TP53 pathogenic allelic variants, which predispose them to cancer, and radiation may increase the incidence of second- ary tumors [9].
CONCLUSION
The rarity of PACT turns it a real challenge. Over recent years, the large-scale pangenomic analyses have increased our understanding of the genetic and epigenetic changes underlying PACT pathogenesis. New signaling pathways and biomarkers have been discovered and have changed neoplasm taxonomy. An international effort to combine molecular and data resources may facilitate the studies with larger PACT cohorts. It is expected that with these results, hopefully, new targeted therapies could be pre- scribed according to molecular data, improving the assistance for the patient and providing personalized treatment.
Acknowledgements
None.
Financial support and sponsorship
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (2017/26345-5).
Conflicts of interest
There are no conflicts of interest.
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