Primary Malignant Tumors of the Adrenal Glands

REVIEW ARTICLE

Primary malignant tumors of the adrenal glands

Madson Q. Almeida,I,II,* Joao Evangelista Bezerra-Neto,II Berenice B. Mendonc¸a,I Ana Claudia Latronico,I Maria Candida B.V. FragosoI,II I Unidade de Suprarrenal, Laboratorio de Hormonios e Genetica Molecular LIM/42, Servico de Endocrinologia e Metabologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR. II Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR. Almeida MQ, Bezerra-Neto JE, Mendonc¸a BB, Latronico AC, Fragoso MC. Primary malignant tumors of the adrenal glands. Clinics. 2018;73(suppl 1):e756s *Corresponding author. E-mail: [email protected] / [email protected]

Malignancy must be considered in the management of adrenal lesions, including those incidentally identiﬁed on imaging studies. Adrenocortical carcinomas (ACCs) are rare tumors with an estimated annual incidence of 0.7–2 cases per year and a worldwide prevalence of 4–12 cases per million/year. However, a much higher incidence of these tumors (415 times) has been demonstrated in south and southeastern Brazil. Most ACCs cause hypersecretion of steroids including glucocorticoids and androgens. ACC patients have a very poor prognosis with a 5-year overall survival (OS) below 30% in most series. Pheochromocytoma or paraganglioma (PPGL) is a metabolically active tumor originating from the chromafﬁn cells of the adrenal medulla. The incidence of PPGL is 0.2 to 0.9 cases per 100,000 individuals per year. Pheochromocytomas are present in approximately 4-7% of patients with adrenal incidentalomas. Classically, PPGL manifests as paroxysmal attacks of the following 4 symptoms: headaches, diaphoresis, palpitations, and severe hypertensive episodes. The diagnosis of malignant PPGL relies on the presence of local invasion or metastasis. In this review, we present the clinical and biochemical characteristics and pathogenesis of malignant primary lesions that affect the cortex and medulla of human adrenal glands.

KEYWORDS: Adrenocortical Carcinoma; Pheochromocytoma; Paraganglioma; Treatment.

’ INTRODUCTION These malignant tumors can be diagnosed by endocrine signs of steroid excess, compression symptoms due to tumor Human adrenal glands can be affected by several growth or during evaluation of adrenal incidentalomas. The malignant conditions. Indeed, malignancy must be consid- majority of adrenal tumors secrete excess cortisol, although ered in the management of adrenal lesions, including those this cortisol hypersecretion can be subclinical. ACC patients incidentally identified on imaging studies (adrenal inciden- have a very poor prognosis with a 5-year overall survival – talomas). Adrenal incidentalomas are identified in 1 4% of (OS) below 30% in most series. Despite this unfavorable abdominal imaging studies, and the incidence of adrenal outcome, some patients are cured after surgical removal, and incidentaloma increases with age. In medical series, most others have relatively slow metastatic progression. The recent adrenal incidentalomas are adenomas (80%), and only 8% discovery of genetic alterations underlying the pathogenesis of are carcinomas. Therefore, the incidental discovery of an ACC have led to the identification of ACC subgroups with adrenal mass could be considered an opportunity to offer a dismal prognoses (5). curative approach for malignant lesions (1). Pheochromocytoma or paraganglioma (PPGL) is a meta- Adrenocortical carcinomas (ACCs) are rare tumors with an bolically active tumor originating from the chromaffin cells – estimated annual incidence of 0.7 2 cases per year and a of the adrenal medulla. The incidence of PPGL is 0.2 to 0.9 – worldwide prevalence of 4 12 cases per million/year (2). cases per 100,000 individuals per year. Pheochromocytomas 4 However, a much higher incidence of adrenal tumors ( 15 are present in approximately 4-7% of patients with adrenal times) has been demonstrated in the pediatric population incidentalomas. Classically, PPGL manifests as paroxysmal in south and southeastern Brazil, and these tumors are attacks of the following 4 symptoms: headaches, diaphoresis, TP53 associated with a specific germline mutation in (3,4). palpitations, and severe hypertensive episodes. The diagnosis of malignant PPGL relies on the presence of local invasion or metastasis. The most common sites of metastasis Copyright & 2018 CLINICS – This is an Open Access article distributed under the include bones, lymph nodes and the liver. In this review, we terms of the Creative Commons License (http://creativecommons.org/licenses/by/ 4.0/) which permits unrestricted use, distribution, and reproduction in any present the clinical and biochemical characteristics and medium or format, provided the original work is properly cited. pathogenesis of malignant primary lesions that affect the No potential conﬂict of interest was reported. cortex and medulla of human adrenal glands (6). Received for publication on April 24, 2018. Accepted for publication on October 23, 2018 Adrenocortical carcinoma ACC presents a bimodal distribution, with the first peak in Commemorative Edition: 10 years of ICESP children o5 years and the second (7) peak during the 4th and DOI: 10.6061/clinics/2018/e756s 5th decades of life and a slight predominance in women (2,8).

1 Adrenal tumors CLINICS 2018;73(suppl 1):e756s Almeida MQ et al.

In the pediatric population, only 25 new cases are diagnosed and inactivating the CDKN1C and H19 genes, which are a each year in the USA. In south and southeastern Brazil, negative cell cycle regulator and a transcriptional repressor of approximately 78% of children and 13% of adults with IGF2, respectively. BWS is an example of epigenetic alterations adrenal tumors harbor a specific germline mutation in the 11p15 region (18). Macrosomia, macroglossia, viscer- (p.R337H) of the p53 tumor suppressor (9,10). A founder omegaly, neonatal hypoglycemia, and ear and abdominal wall effect has been demonstrated in the great majority of pedia- abnormalities characterize BWS. Children with BWS also have tric Brazilian patients with adrenocortical tumors caused by a high risk of developing Wilms’ tumors, hepatoblastomas, this p53 mutation (11). rhabdomyosarcomas, and ACCs (19). Virilization syndrome is the most frequent presentation of The gene expression profiles of 94 ACCs in adults demon- adrenal tumors during childhood. Hypercortisolism can be strated that the DGL7 and PINK1 genes were differentially associated with androgen overproduction, mainly of dehy- expressed between recurrent and nonrecurrent tumors (20). droepiandrosterone sulfate (DHEAS) and testosterone, lead- Furthermore, the difference between BUB1B and PINK1 gene ing to gonadotropin-independent precocious puberty (3,12). expression was a significant predictor of OS in adults. The In adults, cortisol hypersecretion is the most common prognostic importance of the combined expression of these hormone disorder. Adult ACC can also be associated with genes was subsequently validated in adult ACC patients virilization alone or a mixed syndrome (virilization and from our institution but not in pediatric patients (21). Cushing’s syndrome). Estrogen and aldosterone overproduction are highly uncommon (2). Although uncommon, patients Diagnostic evaluation with advanced disease can present with cachexia and body Autonomous cortisol secretion may be identified in almost weight loss (13). 70% of patients with ACC, although this finding is clinically Most ACCs are sporadic, but some inherited disorders unapparent in many patients (22). The European Network are associated with a high incidence of ACC, such as for the Study of Adrenal Tumors (e-mail: ENS@T) has sug- Li-Fraumeni syndrome (LFS), Beckwith-Wiedemann syn- gested a comprehensive hormone investigation for cortisol drome (BWS), Lynch syndrome (LS) and multiple endocrine oversecretion (1 mg dexamethasone supression test at 23 h), neoplasia syndrome type 1 (MEN1) (14) (Table 1). LFS is a basal cortisol and ACTH levels, and free 24-h urinary cortisol cancer predisposition syndrome usually caused by an concentrations), excess of sexual steroid and steroid pre- inherited TP53 gene mutation and is characterized by a high cursors [DHEA-S, 17-OH-progesterone, androstenedione, occurrence of sarcomas, early onset breast cancer, brain cancer testosterone and 17-b-estradiol levels (only in men and and leukemia (15). ACC accounts for approximately 3% to postmenopausal women)], primary aldosteronism (aldoster- 10% of LFS-associated cancers (5). one and renin levels in patients with hypertension and/or Somatic TP53 mutations have been identified in 25–35% of hypokalemia) and pheochromocytoma (total 24-h urinary sporadic ACCs. Nevertheless, these mutations represent a metanephrine or plasma free metanephrine concentrations) late event during carcinogenesis and have been associated (23). In our center, 11-deoxycortisol levels are also evaluated with larger tumors and more advanced disease (14). Somatic in patients with masses suspicious for malignancy due to the mutations in the TP53 gene are a predictor of poor overall prognostic value of this parameter. survival in adults with ACC (16). Most ACCs are large, heterogeneous lesions with irregular The overexpression of IGF2 is one of the most important contrast uptake (Table 2). On CT, ACC is characterized by a mechanisms of adrenocortical tumorigenesis. IGF2 is a potent precontrast density greater than 10 Hounsfield units (HU), in vitro growth promoter of adrenal cortex carcinoma cell lines indicating low lipid content, and absolute contrast wash- (17). The IGF2 gene is located on chromosome 11p15 and out o40% to 50% (1). In fact, malignant primary adrenal encodes a growth factor that is expressed only through the lesions usually have a precontrast density 430 HU. Magnetic inherited paternal allele, while the maternal allele is silenced. resonance imaging (MRI) with gadolinium has the same Genetic or epigenetic alterations in the 11p15 region may alter accuracy as CT but may be superior for evaluating vascular the expression of the CDKN1C, IGF2 and H19 genes, which are invasions. Positron emission tomography (PET) using 18F- structurally organized in a cluster, increasing IGF2 expression fluorodeoxyglucose (FDG) coupled to a CT scan is helpful for

Table 1 - Inherited disorders associated with ACC [Adapted from Patsy et al. (14).

Syndrome* Gene mutation General population Prevalence in Other characteristics prevalence ACC patients

LFS TP53 1:20.000 3–7% (adults) 50–80% (children) Sarcomas, choroid plexus tumors, cerebral tumors, breast cancer, leukemia, lymphoma. MEN1 MEN1 1:30 000 1-2% (adults) Neuroendocrine tumors, pituitary tumors, parathyroid hyperplasia, adrenal adenomas, angioﬁbromas. Lynch MSH2, MSH6, 1:440 3% (adults) Colorectal cancer, endometrial cancer, ovarian cancer, MLH1, PMS2 pancreatic cancer, brain tumors. BWS IGF2, CDKN1C 1:13.000 Very rare (children) Wilms’ tumors, hepatoblastomas, adrenal adenomas, macrosomia, macroglossia, omphaloceles. FAP APC 1:30.000 o1% Colonic polyposis, colorectal cancer, desmoid tumors, thyroid cancer, adrenal adenomas, congenital retinal hyperplasia, epidermoid cysts. NF1 NF1 1:3.000 o1% Pheochromocytomas, cafe´ -au-lait spots, neuroﬁbromas, optic gliomas, Lisch nodules, skeletal abnormalities.

* LFS: Li-Fraumeni syndrome, MEN1: Multiple endocrine neoplasia type 1, BWS: Beckwith-Wiedemann syndrome, FAP: Familial adenomatous polyposis, NF1: Neuroﬁbromatosis type 1.

2 CLINICS 2018;73(suppl 1):e756s Adrenal tumors Almeida MQ et al.

Table 2 - Imaging characteristics of the most prevalent tumoral lesions in the adrenal gland (23). Adrenal Adenoma Frequently o4 cm, homogeneous and well-deﬁned in shape CT: density o10 HU