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Best Practice & Research Clinical Endocrinology & Metabolism
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Clinical Endocrinology & Metabolism
Pediatric adrenocortical tumours
Emilia Modolo Pinto, PhD, Associate Scientist *, Gerard P. Zambetti, PhD, Member, Carlos Rodriguez-Galindo, MD, Global Pediatric Medicine Chair
St. Jude Children’s Research Hospital, Memphis, TN, USA
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Article history: Available online xxx
Keywords: adrenal carcinoma pediatric TP53 11p15
Childhood adrenocortical tumors (ACTs) are rare, representing ~0.2% of all pediatric malignancies and having an incidence of 0.2 -0.3 new cases per million per year in the United States, but in- cidences are remarkably higher in Southern Brazil. At diagnosis, most children show signs and symptoms of virilization, Cushing syndrome, or both. Less than 10% of patients with ACT exhibit no endocrine syndrome at presentation, although some show abnormal concentrations of adrenal cortex hormones. Pediatric ACT is commonly associated with constitutional genetic and/or epigenetic alterations, represented by germline TP53 mutations or chromosome 11p abnormalities. Complete tumor resection is required to achieve cure. The role of chemotherapy is not estab- lished, although definitive responses to several anticancer drugs are documented. For patients undergoing complete tumor resec- tion, favorable prognostic factors include young age, small tumor size, virilization, and adenoma histology. Prospective studies are necessary to further elucidate the pathogenesis of ACT and improve patient outcomes.
@ 2020 Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Pathology, Room DTRC D5005, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS510, USA.
E-mail address: emilia.pinto@stjude.org (E.M. Pinto).
Introduction
Adrenocortical tumor (ACT) is a rare disease in children and adolescents. The National Cancer Institute reports that only 1.3% of all pediatric malignancies are carcinomas, and only 0.2% of those are adrenocortical carcinomas (ACCs) [1]. There is remarkable geographical variation in ACC, with its incidence in South and Southeast Brazil being ~15 times higher than that in the United States (US) [2-4]. Given the rarity of ACT, its demographics, clinical, and biological features are not well estab- lished. However, with the development of registries, knowledge on the etiology, clinical presentation, outcomes, and biology of this rare entity has improved [3,4], although most studies reported are from Brazilian patients.
Pediatric and adult ACTs are distinct in clinical manifestations, histopathology, molecular alter- ations, and prognostic evolution, suggesting that tumorigenesis is different in pediatric and adult patients [5-8]. Incidence of pediatric ACT peaks between 0 and 4 years of age, and at presentation most children show signs and symptoms of virilization, with or without the presence of other adrenocortical hormones. Histological features are used to classify tumors as adrenocortical adenomas (ACA) or adrenocortical carcinomas (ACC); however, the distinction between these two subtypes is often difficult in pediatric patients. Currently, cure for this rare disease is dependent on complete tumor resection, and the role of adjuvant chemotherapy has evolved from adult studies, and mitotane- and cisplatin-based regimens are recommended for patients with advanced disease [2-4].
In this review, we present the demographics, clinical features, and biological characteristics of childhood ACT, and discuss specific features that distinguish it from the adult counterpart.
Historical perspective
In 1912, Harvey Cushing described the classical features of Cushing syndrome in a female patient with clinical findings of obesity, hypertrichosis, and amenorrhea, with overdevelopment of secondary sexual characteristics [9]. Virilization has been recognized since ancient times; Hippocrates described two cases of virilism in married women [10] and it has been also described as one of the most inter- esting symptoms associated with adenoma of the adrenal gland over a wide age range, from 14 months to the fifth and sixth decades of life [11].
In 1756, Willian Cooke gave the first detailed description connecting virilization and adrenal tumors in a 7-year-old female [12]. A subsequent description of a similar case of an 11-year-old girl revealed that the tumor developed in the adrenal cortex [13]. In 1910, Apert performed necropsy studies on 35 cases of individuals of all ages and found differences in clinical manifestations of adrenal disease by age of disease development. He accordingly classified them as embryonal, fetal, prepuberty, and maturity, with most symptoms occurring in women and more marked changes seen with earlier development of this condition [14]. In 1914, the syndrome was named genito-surrenal by Gallais [15]. Given its rarity, clinical and biological features of this rare disease have only been recently characterized in children.
Incidence
A study by the United States Surveillance, Epidemiology, and End Results database showed a lower incidence of adrenocortical carcinoma (ACC) in patients younger than 20 years (0.2-0.3 patients per million) than those older than 20 years [16], and there are an estimated 25 new cases of ACC annually in children and adolescents in the US [16]. These estimates may be lower than the actual incidence, considering that adrenocortical adenomas (ACAs) are not typically included in population-based cancer registries.
Several population-based studies have been conducted on demographics, clinical presentation, and survival of children with ACTs in several countries [4]. Of note, pediatric ACT remains extremely rare in the US and Europe but is more common in Brazil [17]. In the 1960s, a review of medical files from a charity hospital in São Paulo state, Southeast Brazil, revealed high prevalence of pediatric ACTs [18]. The incidence of pediatric ACTs in South and Southeast Brazil is ~15 times higher than that worldwide. This is likely associated with high prevalence of the founder TP53 p.R337H mutation [19], which has been reported in more than 90% of pediatric ACT patients in South and Southeast Brazil [20,21]. Of note,
Please cite this article as: Pinto EM et al.Pediatric adrenocortical tumours, Best Practice & Research Clinical Endocrinology & Metabolism, https://doi.org/10.1016/j.beem.2020.101448
clinical manifestations and outcomes of children with ACT in Brazil or elsewhere worldwide have shown that despite the diverse geographic, ethnic, environmental, and possibly genetic characteristics, pediatric ACT appears to have a consistent clinical and biological course [6].
Large study series of adrenocortical tumors in children
The largest study on clinical characteristics and treatment outcomes of pediatric ACTs is based on data from 254 patients enrolled in the International Pediatric Adrenocortical Tumor Registry (IPACTR) [3]. Although the population cohort predominantly included Brazilian patients (79.5%), the study included patients from the US and other countries [3]. Another larger study includes 73 children younger than 16 years presenting with ACT admitted at a single institution in Southern Brazil over a period of 30 years (1966-1996) [22].
Although pediatric ACT is strongly associated with germline TP53 mutations [23-26] the clinical features, pathogenesis, and outcomes have been analyzed separately in children with ACTs without germline TP53 mutations [27]. Constitutional abnormalities of chromosome 11p15 occurred in nine of 40 tested patients, with six not showing phenotype or clinical features consistent with the Beckwith-Wiedemann syndrome (BWS). In single-predictor Cox regression analysis, age, disease stage, tumor weight, somatic TP53 mutations, and Ki-67 labeling index were associated with prognosis [27].
In a different series of patients, Lefevre et al. analyzed clinical features and treatment outcomes of 42 children treated in French hospitals over 22 years [28]. Long-term survival was ~50%, and tumor size was the most important prognostic factor [28]. Another study retrospectively evaluated a series of 30 children treated for ACTs in Turkey [29]. In this study, presence of regional disease at presentation was associated with a significantly shorter disease-free interval [29]. A most recent study analyzed a retrospective cohort of 41 children followed at the Mayo Clinic from 1950 to 2017 [30]. Weiss criteria [31] and modified Weiss criteria [3,22,31] were less accurate than the Wieneke index in younger pa- tients (<12 years) (Table 1) [32].
Clinical and demographic features of pediatric adrenocortical tumors
Altogether, these large series studies [3,22,27-30] confirm epidemiological findings showing that ACTs likely follow a bimodal distribution, with peaks during the first and fourth decades [3,22,27-30]. Childhood ACTs typically present during the first 5 years of life (median age, 3-4 years), although there is a second smaller peak during adolescence [3,22,27-30]. An increased incidence of ACTs in females, particularly among children aged ≤3 years and ≥13 years (6.2:1), but not between 4 and 12 years, is consistently observed [3,22,27-30].
Pediatric ACTs are almost always functional whereas less than 50% are overtly functional in adults [33], and a diagnosis is usually made in children months after the first signs and symptoms [3,22,27-30]. Most patients present with virilization (pubic hair, accelerated growth, and skeletal maturation, an enlarged penis or clitoris, hirsutism, and acne) due to excess androgen secretion alone or in combination with hypercortisolism in more than 80% of patients [2-4]. Less frequently, children present with Cushing syndrome (15-40%), with hypertension, obesity, and decreased linear growth due to excess glucocorticoids, feminization (7%) or gynecomastia due to excess estrogens, signs of hyperaldosteronism (1-4%) such as hypertension and hypokalemia, or a mixture of symptoms [34]. Cushing syndrome appears to occur more frequently in ACCs, larger tumors (>10 cm), and older children [35]. Nonfunctional tumors are infrequent in young children and tend to occur more frequently in adolescents [34] and diagnosed incidentally when evaluating abdominal pain, fatigue, or other nonspecific symptoms [33].
The staging system employed may vary slightly among studies, but usually divides tumors into local, regional, or metastatic disease. Most children (~75%) present with local disease, either stage I (<5 cm or ≤200 g with complete resection) or stage II (>5 cm or >200 g with complete resection). A smaller percentage (~10%) present with regional invasion to adjacent areas such as lymph nodes, kidney, and inferior vena cava or have residual tumor after resection (stage III). Another small
| Weiss criteriaª | Modified Weiss criteriaª | Wieneke criteriab |
|---|---|---|
| 1. Nuclear grade: Assessed from grade I to IV following Fuhrman criteria. Nuclear grade III and IV considered malignancy. | ||
| 2. Mitotic rate: Evaluated "by counting 10 random high- power-fields in the area of the greatest numbers of mitotic figures on the five slides with greatest number of mitoses. Higher than 5 mitotic figures per 50 high power fields (40x objective) considered malignancy. | power fields Mitotic rate >5 per 50 high | Increased mitotic activity: >15 mitoses per 20 high power fields |
| 3. Atypical mitosis: Mitosis regarded as atypical "when it definitely showed an abnormal distribution of chromosomes or an excessive number of mitotic spindles." | Abnormal mitoses Cytoplasm (clear cells comprising 25% or less of the tumor) | Presence of atypical mitotic figures |
| 4. Character of cytoplasm: Evaluated for the "percentage of clear or vacuolated cells resembling the normal zona fasciculata." | ||
| 5. Architecture of tumor cells: Assessed as diffuse "if greater than one-third of the tumor formed patternless sheets of cells and non-diffuse if two-thirds of tumor showed organization into patterns as nesting, trabecular, columnar, alveolar or another pattern." | ||
| 6. Necrosis: Annotated "as present when occurring in at least confluent nests of cells." | Necrosis | Presence of tumor necrosis |
| 7. Invasion of venous structures: Defined as an "endothelial- lined vessel with smooth muscle as a component of the wall." | Venous invasion | |
| 8. Invasion of sinusoidal structures: Defined as an "endothelial-lined vessel in the adrenal gland with little supporting tissues." Only sinusoids located within the tumor were considered. | ||
| 9. Invasion of tumor capsule: Accepted as "present when nests or cords of tumor extended into or through the capsule, with a corresponding stroma reaction." | Capsular invasion | Capsular invasion Tumor weight: >400 g Tumor size: >10.5 cm Extension into periadrenal soft tissues and/or adjacent organs Invasion into vena cava |
a Each criterion is scored 0 when absent and 1 when present in the tumor. Malignancy requires 3+ of these criterions.
b Up to two criteria, benign; three criteria, indeterminate for malignancy and four or more criteria, poor clinical outcome.
percentage (~15%) present with distant hematogenous metastasis to the lungs, liver, or both (stage IV) [2-4].
Diagnosis and classification: endocrine work-up
The diagnosis of malignancy is highly suggested by specific clinical, biological, and imaging features and results of laboratory tests. However, definitive diagnosis is made by pathological examination of surgically obtained tissue. Routine laboratory evaluation for suspected ACT includes measuring serum hormone levels of adrenocorticotropic hormone, cortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), testosterone, estradiol, renin, and aldosterone [36,37]. This comprehensive panel of tests not only contributes to the diagnosis but also provides useful markers for detecting tumor recurrence. Plasma DHEA-S concentrations are abnormally high in ~90% of patients, making DHEA-S a very sensitive tumor marker [2-4].
Currently, no single imaging method can characterize a localized adrenal mass as ACC. Imaging modalities to evaluate the extension of disease include computed tomography (CT) and magnetic
Please cite this article as: Pinto EM et al.Pediatric adrenocortical tumours, Best Practice & Research Clinical Endocrinology & Metabolism, https://doi.org/10.1016/j.beem.2020.101448
resonance (MR). Positron emission tomography (PET) can detect disease recurrence that other imaging modalities may not. Lungs, liver, bone, and brain are the most common sites involved in patients with metastatic ACT. The contralateral adrenal gland is rarely affected. By way of traditional imaging, abdominal CT or MR scans are mandatory in suspicion of ACT and also fundamental to define disease staging [36,37]. Despite the various radiological signs in the multimodality practice of radiology, only the presence of regional invasion or distant metastases (liver, lung, or brain) can reliably differentiate benign lesions from malignant tumors. Such invasion can be ascertained at the initial abdominal scans for adequate staging [37]. Although ultrasonography has its limitations, it is important for evaluating tumor extension into the inferior vena cava and right atrium [38]. For evaluating adrenal tumors in children, ultrasound offers advantages of being noninvasive and radiation free. Lesions 3 cm or larger are readily delineated, and smaller tumors may be identified with real-time scanning [38]. However, it cannot reliably identify smaller lesions as accurately as CT does [37]. MR imaging, which has been increasingly used over the past few years, has several advantages over CT, including absence of ionizing radiation, capability of imaging multiple planes, and improved tissue contrast differentiation. Considering the high frequency of constitutional TP53 mutations among children with ACT, MR scans are preferred for the long-term management of these patients.
Because ACT is metabolically active, fluorodeoxyglucose-PET imaging is increasingly used in pa- tients with ACT, but its routine use requires validation. Most recently, metomidate ([11C]MTO), a marker of sustained 11-ß-hydroxylase activity, has been investigated as an alternative PET tracer for adreno- cortical imaging [39]. Presently, the IPACTR [3,4] recommends that in addition to ultrasonography, all patients with a suspected adrenal tumor be examined by CT or MR imaging. To determine the extent of newly diagnosed disease, CT or MR imaging of the chest and abdomen is recommended for all patients.
Histology
Pathological assessment is key for the final diagnosis of ACC, but it remains challenging as histo- logical differentiation of pediatric adenomas and carcinomas is difficult. Even experienced pathologists can find it difficult to differentiate adenoma from carcinoma, and multiple parameters (macroscopic and microscopic) are evaluated to discriminate benign from malignant tumor.
Clinicopathologic studies by Weiss [31] have established criteria to distinguish adenomas from carcinomas in adults; however, many ACTs display benign and malignant morphologic characteristics, often precluding an unequivocal classification. Some patients whose tumors exhibit histologically benign features have late metastases or local recurrence, whereas others whose tumors have a microscopic appearance typical of malignancy have survived for years [31]. The inconsistency in tumor behavior with histologic findings is even more pronounced in children [37,40].
Macroscopically, adenomas tend to be well defined and spherical, and they never invade sur- rounding structures. They are typically small (usually <200 cm3), and some studies include size as a criterion for adenoma [3,16,30]. By contrast, carcinomas are usually large, heterogeneous, and show marked lobulation with extensive areas of hemorrhage and necrosis. Importantly, the presence of a tumoral invasion at different levels, as the tumor capsule, the extra-adrenal soft tissue, or direct in- vasion of lymphatic channels or blood vessels are key features of ACC [3,16,30]. Microscopically, car- cinomas have larger cells with eosinophilic cytoplasm, arranged in alveolar clusters. Architectural disarray, frequent mitoses including bizarre mitotic features, broad fibrous bands, marked cellular pleomorphism, nuclear atypia, and hyperchromasia are common features [37]. In contrast, the microscopic appearance of adenomas includes a well-preserved architecture; less variation in cell size and less nuclear pleomorphism; minimal mitotic activity; rare presence of necrosis, hemorrhage, or calcification; and no evidence of invasion of the tumor capsule or blood vessels [37]. Diagnostically useful immunohistochemical markers include inhibin, melan A (MART-1), synaptophysin, and chro- mogranin A. Most tumors are positive for the first three but negative for chromogranin A. In some tumors, few cells might be positive for chromogranin A, suggesting neuroendocrine differentiation in an otherwise typical ACT [41]. In adult ACTs, the Weiss score [31], a microscopic diagnostic score, and other immunohistochemical properties are used to determine malignant potential and prognosis [42,43]. The Weiss score looks at nuclear grade, mitotic rate and atypia, vascular and capsular invasion, and necroses to predict malignancy [31]. Proliferation index, as Ki-67 immunomarker or mitotic count,
can help define the diagnosis and prognosis of ACC. It is well established that ACC generally show a Ki- 67 ≥ 5% [36]. Recent studies demonstrate that Ki-67 is a powerful prognostic marker in both localized and metastatic ACC and can help guide the treatment decision [44,45]. Moreover, a mitotic count >20 mitoses/50 high-power fields (HPF) defines “high-grade ACC,” which has the worst prognosis [46].
To date, the modified Weiss score [22] and Wieneke index [32] have been proposed to assess malignancy in children (Table 1). Determining proliferation antigen Ki-67 [27] and altered gene expression by cDNA microarrays [47] and changes in MHC-class II expression [48] are promising techniques in differentiating carcinomas from adenomas in children.
Treatment
Treatment of pediatric ACTs has evolved from findings of adult studies, and the same guidelines are used. Surgery is the mainstay of treatment in stages I-III and is the only therapy that unquestionably cures or prolongs survival significantly [3]. There is no documented instance of chemotherapy alone leading to complete local response of a primary unresected tumor. Because of tumor friability, rupture of the capsule with resultant tumor spillage is frequent (~20% of initial resections and 43% of resections after recurrence) [3,22]. Laparoscopic resection is associated with a high risk of rupture and is discouraged due to excess locoregional recurrences; thus, open adrenalectomy remains the standard of care [36]. The aim of surgery should be to achieve a negative margin, that is, R0 resection of the tumor [49]. An aggressive approach toward primary tumors and metastatic sites is recommended. En bloc resection, which may include the kidney, portions of pancreas and/or liver, or other adjacent structures, may be necessary in rare cases of large, locally invasive tumor [37]. The role of regional lymph node dissection in pediatric ACT is under investigation by the Children’s Oncology Group [50]. Infiltration of the vena cava may make radical surgery difficult in some cases, although successful complete resection of the tumor thrombus with cardiopulmonary bypass has been reported [37]. All patients with a functioning tumor are assumed to have suppression of the contralateral adrenal gland; therefore, steroid replacement therapy is given. Special attention to electrolyte balance, hypertension, surgical wound care, and infectious complications is critical.
Because of the rarity of ACT, the role of chemotherapy remains undetermined. In adults, mitotane [1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane or o,p/-DDD], an insecticide derivative causing adrenocortical necrosis, is commonly used as a single agent in the adjuvant setting after complete resection [51]. Little information is available on using mitotane in children, although response rates appear to be like those in adults [2-4]. Objective responses to mitotane have been noted in adult patients [52]. The wide variation in response rates may be in part due to the pharmacokinetics of mitotane. There has been evidence of therapeutic response with plasma concentrations of mitotane >14 mg/L [53]. However, the major difficulty in managing mitotane treatment is related to adverse effects and the risk of toxicity, which is related to plasmatic levels >20 mg/L, the considered upper limit of the therapeutic window [53]. In the nonrandomized single-arm study GPOH-MET 97, pediatric patients given mitotane treatment longer than 6 months and achieving mitotane levels greater than 14 mg/L had significantly better survival [54]. The most important common toxicities of mitotane are nausea, vomiting, diarrhea, and abdominal pain. Less frequent reactions include somnolence, lethargy, ataxic gait, depression, and vertigo. A review of 11 children with advanced ACTs with mitotane and a cisplatin-based chemotherapeutic regimen revealed measurable responses in seven patients [55]. The mitotane daily dose required for therapeutic levels was ~4 g/m2, and therapeutic levels were achieved after 4-6 months of therapy [55]. Patients with severe symptoms or unresectable or recurrent tumors require chemotherapy to control tumor growth and the symptoms of hormonal excess. Patients might require steroid replacement during therapy with mitotane. Palliative cisplatin-based chemotherapy can be an alternative to surgical debulking.
Because many children with ACTs carry germline TP53 mutations [6,23-26], radiation therapy in pediatric patients with ACTs has not been consistently investigated. Other chemotherapeutic agents, including 5-fluorouracil, etoposide, cisplatin, carboplatin, cyclophosphamide, doxorubicin, and strep- tozocin, have been used alone or in combination to treat ACT, with varied results [2-4]. The combi- nation used most often in children comprises cisplatin and etoposide with or without doxorubicin
given with mitotane. Despite this multimodality approach, prognosis of pediatric ACC with metastatic disease remains poor, with an estimated 5-year survival below 20% [3,16,22,32,54].
Novel therapeutic strategies aimed at tumor-specific aberrant pathways have not been studied in pediatric ACT. In addition, lack of cell lines and animal models of pediatric ACC has hampered the development of new therapies. To date, only one animal model of pediatric ACT derived from a pe- diatric patient harboring a germline TP53 mutation (p.G245C) has been developed [56]. Screening the xenograft for drug responsiveness showed that cisplatin had a potent antitumor effect. However, etoposide, doxorubicin, and a panel of other common cancer drugs had little or no antitumor activity, apart from topotecan, which significantly inhibited tumor growth [56,57].
Prognostic factors
Given the heterogeneity and rarity of ACTs, prognostic factors have been difficult to establish. The presence of metastases at diagnosis or failure to completely resect the tumor is associated with extremely poor outcomes [2-4]. Although complete resection of ACC provides the best chance for cure, long-term survival is limited [3,58]. In children, 5-year survival ranges from 30% to 70%, with sub- stantial variation by disease presentation [3,22,34].
Staging in adults typically follows the TNM system proposed by the American Joint Committee on Cancer, which includes size and extent of tumor (T), number of nearby lymph nodes (N), and metas- tases (M) or a modified staging system proposed by the European Network for The Study of Adrenal Tumors [59]. In children, the staging system proposed by Sandrini and collaborators [22] has been modified by the Children’s Oncology Group [50], based on clinical data from the IPACTR [2-4]. The current staging system for childhood ACTs (Table 2) attempts to stratify patients by prognosis, to identify patients who should receive more intensive therapy. However, the staging system proposed does not account for age, which has been associated with survival [3,16,60].
In addition to the tumor’s inherently aggressive nature, poor survival has been attributed to a delay in diagnosis, even though these tumors generally have a phenotypical manifestation. Children with tumors producing excess glucocorticoids appear to have a poorer prognosis than those having pure virilizing manifestations [3]. Another adverse prognostic factor is age: patients older than 4 or 5 years have a worse prognosis [3]. For patients with completely resected disease (disease stages I and II), analysis of prognostic factors shows that stage I disease, age less than 3 years, and virilization alone are independently associated with a greater probability of Event Free Survival (EFS) [3]. For ACC, local disease with a smaller tumor burden (<10 cm) is likely associated with improved prognosis [32,61]. Conversely, for children with metastatic or residual disease, the prognosis is dismal [32,61]. The overall probability of 5-year survival for children with ACTs is greater than 80% if they are younger than 4 years, have completely resected tumors weighing less than 200 g, and no metastasis [3,16,22,32,62].
The lack of strong prognostic indicators has limited the progress in managing childhood ACT. Tumor weight, volume, and surgical resectability form the basis of the current COG disease-stage classification [50]. However, this system needs improvement, as many patients experience relapse despite having small, completely excised tumors [62,63]. Prognostic factor analysis can be further refined by adding other predictive factors. Increased expression of MHC class II genes, in particular HLA-DPA1, is
| Stage | Sandrini system | IPACTR |
|---|---|---|
| I | Tumor totally excised, tumor vol <200 cm, absence of metastasis, normal hormonal levels after surgery. | Tumor completely excised with negative margins, tumor weight ≤200 g, absence of metastatic disease. |
| II | Microscopic residual tumor, tumor >200 cm, tumor spillage during surgery, or persistence of abnormal hormone levels after surgery. | Tumor completely excised with negative margins, tumor weight >200 g, absence of metastatic disease. |
| III | Gross residual or inoperable tumor. | Residual (defined by presence of microscopic or gross tumor after surgical resection) or inoperable tumor. |
| IV | Distant metastasis. | Hematogenous metastasis at presentation. |
Please cite this article as: Pinto EM et al.Pediatric adrenocortical tumours, Best Practice & Research Clinical Endocrinology & Metabolism, https://doi.org/10.1016/j.beem.2020.101448
associated with better prognosis for pediatric ACTs, independent of histopathological diagnosis [48]. In addition, expression patterns of p53, beta-catenin, and ATRX are important predictors of malignancy in pediatric ACTs [6]. Moreover, Ki-67 index is a strong prognostic indicator and should be investigated to improve the histologic classification of pediatric ACTs [27].
Adrenal gland development
The adrenal gland is an endocrine organ that continuously evolves from early embryogenesis to later stages. Furthermore, recent studies suggest that the adrenal cortex shares a common embryonic origin with the early gonad [5]. The adrenal gland has a dual embryologic origin: the cortex arising from the coelomic mesoderm of the urogenital ridge, and the medulla from neural crest tissue. Appearance of the adrenal gland in form of the adrenogonadal primordium at 28-30 after conception in humans is marked by the expression of steroidogenic factor 1 (SF1, NR5A1), a nuclear receptor essential for adrenal development and steroidogenesis [64]. During the fifth week of fetal develop- ment, mesothelial cells from the posterior abdominal wall, between the root of the bowel mesentery and developing mesonephros/gonad (urogenital ridge), proliferate and delineate two histologically distinct components: an outer zone from which the “adult cortex” originates and a more central zone called the “fetal cortex” [5]. The latter comprises the largest portion of the adrenal cortex at birth. Starting at approximately the ninth week of gestation, the embryonal adrenal is surrounded by the adrenal capsule formed by mesenchymal cells. Fetal adrenal cells, which are large and rich in lipids, express the steroidogenic enzyme CYP17, which enables them to produce high levels of DHEA and its sulfoconjugate DHEAS, which play key roles in maintaining pregnancy, being metabolized into es- trogens by the placenta [65]. By the end of the second trimester of gestation, a distinct zone (transi- tional zone) differentiates between the definitive and fetal zones, which express HSD3B2, thereby initiating cortisol synthesis in the fetus. Close to birth, HSD3B2 is expressed in the definitive zone, which becomes capable of synthesizing the mineralocorticoid hormone aldosterone. After birth, the fetal zone shrinks due to increased apoptotic activity. In contrast, the definitive adult cortex arises from cellular hyperplasia associated with decreased apoptosis. The adrenal cortex differentiates fully into the three zones by age 3 years. The zona glomerulosa and zona fasciculata are present at birth, but the zona reticularis develops later [66]. After being suppressed following regression of the fetal zone, adrenal production of DHEA/DHEAS progressively increases again by approximately age 8 years. This phenomenon is termed adrenarche and is concomitant with full differentiation of the reticularis zone, which expresses CYP17 but not HSD3B2. DHEA/DHEAS levels continue to increase until adulthood and then progressively decline (adrenopause), reaching pre-adrenarche levels by the ninth decade, correlating with progressive atrophy of the zona reticularis [67].
Genetic predisposition to adrenocortical tumors
Recent developments in molecular biology and genetics have enabled the identification of germline alterations underlying constitutive syndromes predisposing to ACTs. Studies on familial forms of ACTs identified TP53-inactivating mutations and IGF2 overexpression as key drivers in adult and pediatric tumors. Increased risk for ACTs is well established in Li-Fraumeni syndrome (LFS) and BWS. In both predisposing syndromes, ACT occurs at a relatively young age. However, even in LFS and BWS, pene- trance of the ACC phenotype is very low, suggesting significant contribution of other additional genetic (somatic and germline) events.
LFS is a rare autosomal dominant syndrome characterized by a spectrum of tumor types, a young age at tumor onset, and the potential for multiple primary malignancies during the lifetime of the affected individuals [68]. The tumor spectrum is wide and includes brain tumors (choroid plexus carcinoma, Sonic Hedgehog subtype medulloblastoma, glioma), ACC, a range of soft tissue sarcomas and bone tumors, hematologic malignancies, early onset breast cancer, and other cancer types (lung, skin, gastrointestinal tract, kidney, thyroid, and neuroblastoma) [68]. LFS was first described in 1969 by Frederick Li and Joseph Fraumeni, Jr., based on the observation of a unique spectrum of cancers in four families in whom index cases presented with rhabdomyosarcoma [69]. In 1990, germline TP53 mu- tations were discovered as the cause of LFS [70]. Of note, in pediatric ACTs, more than 50% of affected
children carry a germline TP53 mutation [6,23-26]. Also, the type of TP53 mutations in children with ACT appears to differ from those found in carriers with other tumors, as many children with ACTs carry low-penetrant TP53 mutations encoding a partially functional p53 protein (Fig. 1) [6,23-26]. TP53 is located on chromosome 17p13, and its main functions are halting the cell cycle and/or inducing apoptosis in response to DNA damage [71,72]. The prevalence of germline TP53 mutations in apparently sporadic ACT patients varies by age group and is low in adults (3-6%) [73-75], but significantly higher in children. Data from the US and Europe indicate that the prevalence of germline TP53 mutations in children is ~50-80% [6,23-26]. Interestingly, the most significant and well-characterized genetic risk factor for pediatric ACTs in Southern Brazil is the p.R337H founder mutation [19-21], which occurs in ~0.3% of the general population [76]. Initially, the p.R337H mutation was thought to predispose only to childhood ACC, but it has now been demonstrated that carriers are at increased risk of developing other malignancies associated with LFS, such as choroid plexus tumors, osteosarcoma, and breast cancer
.. R158H-OR158CA159F
R248Q
R283H
T125T
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·R273H R282W
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V157F
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.1332F
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6
7
8
9
10
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80
120
160
200
240
280
320
360
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c.51_53 del CAAT ins GACCTG ·
g. 11555insAAAAdeITTTCC ·
c. 108_110 dupl GTTTCCGO
c.375+1 G>A 00
c.134_135 insTo
c. 151_156 del12bp·
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c.754_762 del9bpo
g.13991_13999deICTCACCATC
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☒ p53 transactivation domain
· Missense
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· Nonsense
☒ p53 tetramerization domain
· Splice
[77-80]. In addition, the p.R337H mutation also predisposes to adult ACC in this population [21]. Given the importance of identifying a germline TP53 mutation to both the patient and family members, genetic testing is recommended for all patients with ACC, even in absence of a family history of cancer.
Other constitutional disorders associated with increased incidence of ACT include BWS, a somatic overgrowth syndrome characterized by prenatal and postnatal overgrowth, visceromegaly, macro- glossia, neonatal hypoglycemia, ear abnormalities, and abdominal wall defects [81]. The molecular basis of this syndrome is complex, including genetic and epigenetic alterations at chromosomal locus 11p15, which has a large cluster of imprinted genes, including IGF2, CDKN1C, KCNQ1, and H19. IGF2 is a paternally expressed fetal growth factor, whereas the cell cycle inhibitor CDKN1C (p57), potassium channel protein KCNQ1, and noncoding H19 transcripts are expressed from the maternal allele [82].
Development of the fetal adrenal gland is a complex and highly regulated process, and IGF2 is a major modulator in fetal adrenal growth and steroidogenesis [67,83]. In ACTs, IGF2 overexpression and CDKN1C and H19 downregulation is observed in ~90% of cases [6,84,85]. The IGF2 overexpression is caused by somatic structural alterations of the 11p15 locus, such as paternal isodisomy (loss of maternal allele and duplication of paternal allele), and loss of imprinting because of demethylation of the maternal allele [6,84,85]. However, constitutional abnormalities of chromosome 11p15 without clinical features of BWS has been observed in pediatric adrenocortical tumors [27].
Genome-wide studies
The most comprehensive genetic and molecular analysis of pediatric ACTs included whole-genome sequencing and transcriptome analysis studies in 37 patients [6]. Copy-neutral loss of heterozygosity (LOH) of chromosome 11p, with selection against the maternal chromosome and consequent IGF2 overexpression, was determined as an early event and a hallmark of pediatric adrenocortical tumor- igenesis [6]. Additional findings included frequent TP53 mutations, widespread 9q copy number gain, and 4q34 loss. TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 allele occurred in 76% of patients. Chromosomes 11p and 17 undergo copy-neutral LOH early during tumorigenesis, suggesting tumor-driver events [6]. Additional genetic alterations include recurrent somatic mutations in ATRX and CTNNB1 and integration of human herpesvirus-6 in chromosome 11p. A dismal outcome is predicted by concomitant TP53 and ATRX mutations and associated genomic ab- normalities, including massive structural variations and frequent background mutations [6]. Collec- tively, these findings demonstrate the nature, timing, and potential prognostic significance of key genetic alterations in pediatric ACT and outline a hypothetical model of pediatric adrenocortical tumorigenesis [6].
Genomic characterization of adult ACTs highlights similarities and differences in genetic changes in the pediatric counterpart [6,7]. Remarkably, 11p15 LOH involving the IGF2 locus was observed in both groups, underscoring the critical role of deregulated IGF2 expression in adrenal cortex tumorigenesis. Aneuploidy with widespread chromosomal copy number changes was also observed in both groups. However, amplification of chromosome 9q, which includes NOTCH1 and NR5A1 (steroidogenic factor- 1), occurred in 90% of pediatric ACTs but not in adult ACC [6,7]. Activating mutations in CTNNB1 were common to both, but additional mutations in the Wnt/b-catenin signaling pathway, in particular ZNRF3, occurred only in adult tumors [6,7]. Germline TP53 mutations were predominantly associated with pediatric ACT, whereas acquired TP53 mutations were relatively infrequent in both groups. Alternative lengthening of telomere phenotype was associated with DAXX or ATRX mutations in adult tumors, but exclusively with ATRX mutations in children. TERT was amplified in both groups, but there were no TERT mutations in children, consistent with the absence of TERT expression [6,7]. Methylome studies were performed in adult and pediatric ACC [8,86,87]. Based on DNA methylation levels, ma- lignant tumors in adults were divided into two groups: one displaying low and the other high levels of methylation in CpG islands (CpG island methylator phenotype, CIMP). This hypermethylated tumors group was further subdivided into CIMP-high and CIMP-low subgroups. This had prognostic relevance, as the CIMP-high phenotype was clearly associated with worse prognosis [86,87]. In the pediatric group, methylation analysis identified two groups, one enriched in CTNNB1 variants and having un- favorable outcomes, and the other enriched in TP53 germline variants, and having younger age at onset and more favorable outcome [88].
Funding
This work was supported by the American Lebanese Syrian Associated Charities (ALSAC).
Practice Points
· Adrenocortical tumors (ACTs) are a component of several hereditary tumor syndromes, including Li-Fraumeni and Beckwith-Wiedemann syndromes. Genetic events in cancer predisposition syndromes have also been identified in sporadic tumors.
· Patients with ACT typically present with endocrine manifestations resulting from increased production of androgens (virilization) and/or cortisol (hypercortisolism or Cushing syn- drome). Clinical manifestations of ACT are similar in familial and sporadic forms.
. TP53 mutations are inherited genetic abnormalities most commonly associated with increased ACT frequency in familial cancer syndromes. A cluster of pediatric ACTs occurs in Southeast Brazil due to the founder TP53 mutation (p.R337H).
· Surgical intervention with en bloc resection is the main treatment for ACT. ACT is chemo- sensitive, but the role of chemotherapy (including mitotane) in managing this disease is not established.
· Disease stage, which incorporates tumor size, is the most important predictor of outcome. Completely resected small tumors are associated with excellent outcome. Prognosis is dismal for patients with residual disease after incomplete tumor resection or those who have metastatic disease.
· Childhood ACTs are classified as adenomas or carcinomas based on several pathologic criteria. Expression patterns of p53, beta-catenin, and ATRX are important predictors of malignancy in pediatric adrenocortical tumors. Ki-67 labeling index is a strong prognostic indicator and needs further investigation for improving the histological classification of pe- diatric ACTs.
Research agenda
· Developing preclinical models to study the biology of adrenocortical tumors and evaluate conventional and new therapeutic strategies for managing this disease.
· Determining molecular and genetic events that disrupt normal adrenocortical embryology development and contribute to pediatric adrenocortical tumorigenesis.
· Validating molecular predictors of recurrence and survival.
· Implementing and maintaining an international pediatric ACT registry and biological sam- ples bank for long-term follow up of children with ACT and for genotype-phenotype asso- ciation analyses.
Declaration of Competing Interest
None.
Acknowledgements
We thank patients and their families and Vani Shanker for expert scientific review of the manuscript.
Please cite this article as: Pinto EM et al.Pediatric adrenocortical tumours, Best Practice & Research Clinical Endocrinology & Metabolism, https://doi.org/10.1016/j.beem.2020.101448
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