LEARNING OBJECTIVES
After reading this article and taking the test, the reader will:
· Be familiar with the spectrum of clinical, path- ologic, and radiologic findings in children with adrenocortical neoplasms.
· Recognize the differ- ences in clinical presenta- tion and biologic behavior between adrenocortical tumors in children and similar lesions in adults.
· Understand the role of imaging studies in diag- nosis and clinical staging of adrenocortical neo- plasms in children.
From the Archives of the AFIP
Adrenocortical Neoplasms in Children: Radiologic-Pathologic Correlation1
Geoffrey A. Agrons, MD · Gael J. Lonergan, Lt Col, USAF, MC · Glenn E. Dickey, Lt Col, USAF, MC · Juan E. Perez-Monte, MD
Primary neoplasms of the adrenal cortex are rare in children and differ signifi- cantly in epidemiology, clinical characteristics, and biologic features from their counterparts in adults. In children, the inclusive term adrenocortical neo- plasm is applied because adrenal adenoma and adrenal carcinoma may be dif- ficult to distinguish histopathologically. Pediatric adrenocortical neoplasms typically occur before 5 years of age, affect young girls more commonly than boys, and are associated with hemihypertrophy and Beckwith-Wiedemann and Li-Fraumeni syndromes. Most children with an adrenocortical neoplasm pres- ent with signs and symptoms of endocrine abnormality, including virilization and Cushing syndrome. Cross-sectional imaging studies typically demonstrate a large, circumscribed, predominantly solid suprarenal mass with variable het- erogeneity due to hemorrhage and necrosis. Calcification is not uncommon. Local invasion and metastases to the lungs, liver, and regional lymph nodes may be present at diagnosis. When friable tumor thrombus extends into the inferior vena cava, it poses a high risk of pulmonary embolization. The finding of increased retroperitoneal fat due to hypercortisolism on computed tomo- graphic and magnetic resonance images of children with an adrenal mass fa- vors the diagnosis of adrenocortical neoplasm. Surgical resection is the main- stay of therapy, with chemotherapy used for patients with metastases or persis- tent elevated hormone levels following surgery. Patients younger than 5 years with aggressive adrenocortical neoplasms fare better than older children.
Index terms: Adrenal gland, neoplasms, 862.30 · Children, genitourinary system, 862.30 · Infants, genitourinary sys- tem, 862.30 · Neoplasms, in infants and children, 862.30
RadioGraphics 1999; 19:989-1008
1From the Departments of Radiology, Pennsylvania Hospital, 800 Spruce St, Philadelphia, PA, 19107 (G.A.A., J.E.P-M.); Radiologic Pathology (G.J.L.) and Pediatric Pathology (G.E.D.), Armed Forces Institute of Pathology, Washington, DC; Radiology, Children’s Hospital of Philadelphia (G.A.A.), Penn; and Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md (G.J.L.). Received February 4, 1999; revision requested March 3 and re- ceived April 14; accepted April 15. Address reprint requests to G.A.A.
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official nor as reflecting the views of the Departments of the Air Force or Defense.
@RSNA, 1999
INTRODUCTION
Neoplasms of the adrenal cortex are rare in childhood. Unlike similar tumors in adults, adre- nal adenomas in children have no histopatho- logic features that allow them to be reliably dis- tinguished from carcinomas. In addition, the biologic behavior of pediatric adrenocortical neoplasms may be difficult to predict on the basis of morphologic criteria. Thus, the term adrenocortical neoplasm is currently used to designate both benign and malignant tumors of the adrenal cortex in children. Adrenocortical neoplasms of childhood, particularly those oc- curring in infants, merit separate discussion from their counterparts in adults because they have distinctive epidemiologic and clinical fea- tures (1).
Each year, an estimated 25 adrenocortical neoplasms occur in patients younger than 20 years of age, representing an annual incidence rate of three per million (2). Of adrenal tumors in children, adrenocortical neoplasms are far less common than neuroblastomas but more common than pheochromocytomas (3). De- spite their relative rarity, adrenocortical neo- plasms represent the most common tumor of the pediatric adrenal cortex (4,5).
The hormonal activity of childhood adrenal neoplasms has been recognized since 1948, when Wilkins (6) reported an unusual case of an estrogen-secreting adrenal tumor that caused gynecomastia in a 6-month-old-boy. It is now recognized that most children with an adreno- cortical neoplasm show clinical evidence of an endocrine abnormality, in contrast to the be- havior of adrenocortical tumors in adults (1). Thus, diagnostic imaging of adrenocortical neo- plasms in children is typically guided by clinical presentation; similar tumors in asymptomatic adults are discovered incidentally during cross- sectional imaging studies performed for unre- lated indications (7).
This article, illustrated with cases contained in the radiologic pathology archives of the Armed Forces Institute of Pathology, examines the clinical, pathologic, and radiologic features
of adrenocortical neoplasms in children and dis- cusses differential diagnosis, treatment, and prognosis.
CLINICAL FEATURES
Most adrenocortical neoplasms occur in chil- dren with no underlying disorder. However, in some cases, these tumors are associated with other syndromes. In 1967, an association be- tween adrenocortical neoplasms and congenital hemihypertrophy was established by Fraumeni and Miller (8), who reviewed the charts of 62 pediatric patients with adrenocortical neo- plasms. Of these patients, two (3%) had hemi- hypertrophy. The adrenal tumors did not al- ways lateralize to the enlarged side of the body. Children with Beckwith-Wiedemann syndrome (sometimes referred to as EMG [exomphalos- macroglossia-gigantism] syndrome) have an in- creased risk of benign and malignant tumors of multiple organs (8,9), and the most common neoplasm associated with this syndrome is nephroblastoma (Wilms tumor), followed by adrenocortical carcinoma and hepatoblastoma (1). Beckwith-Wiedemann syndrome is also commonly accompanied by nonneoplastic en- largement of the adrenal glands caused by corti- cal hyperplasia. In addition, fetal adrenocortical cells are characteristically enlarged in patients with Beckwith-Wiedemann syndrome. This con- dition, called bilateral adrenal cytomegaly, has been associated with congenital metastasizing adrenocortical carcinoma in one case report (10). The Li-Fraumeni syndrome, also known as the SBLA (sarcoma; breast and brain tumors; leukemia, laryngeal carcinoma, and lung cancer; and adrenocortical carcinoma) syndrome, repre- sents a familial aggregation of neoplasms that includes adrenocortical carcinoma (11,12). Pa- tients with this syndrome may have alterations in the p53 tumor suppressor gene located on the short arm of chromosome 17, band 13 (13, 14). Finally, in rare cases, adrenocortical neo- plasms have been reported in association with congenital urinary tract abnormalities such as duplication of the collecting system, tumors such as ganglioneuroma and ganglioneuroblas- toma, and congenital adrenal hyperplasia (1,15- 19).
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In a study of 32 pediatric patients with adrenocortical neoplasms, the age at diagnosis ranged from 6 months to 19 years (mean age, 8 years; median age, 5 years), with a predominant number of patients being 5 years of age and younger (20). In another study of 42 patients with adrenocortical neoplasms, two-thirds were younger than 5 years of age (21). In addition, rare examples of congenital adrenocortical neo- plasms have been reported (22-26). In an analy- sis of 40 Brazilian children, in whom adrenocor- tical tumors are more common than in United States children (27), the median age at diagno- sis was 3.9 years and over half were girls (28). A female-to-male ratio of 2.2 to 1 was noted in a recent literature review (29).
The primary tumor may not be apparent at physical examination. In a retrospective review by Teinturier and colleagues (30), a palpable mass was found in only 57% of 45 children with adrenocortical neoplasms. However, unlike adult patients with tumors of the adrenal cor- tex, most children with an adrenocortical neo- plasm present with signs or symptoms of endo-
crine abnormality. In a review of over 200 tu- mors in children by Neblett et al (29), only 17 nonfunctioning adrenocortical neoplasms were identified.
Precocious puberty refers to secondary sex characteristics that appear earlier than 8 years of age in girls and before 9 years in boys. Preco- cious puberty may be gonadotropin-dependent (true precocious puberty) or gonadotropin-in- dependent (pseudoprecocious puberty). Fur- thermore, precocious puberty may be charac- terized as isosexual when secondary sex charac- teristics are appropriate for the patient’s gender or heterosexual when they are inappropriate. Heterosexual precocious puberty manifests as virilization in girls and feminization in boys. Be- cause functioning adrenocortical neoplasms represent a gonadotropin-independent source of endogenous androgens and cortisol, they usually produce pseudoprecocious puberty, Cushing syndrome, or a mixture of the two (Fig 1).
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Young girls with an adrenocortical neoplasm most commonly come to clinical attention be- cause of virilization and less frequently present with a mixed endocrine syndrome composed of cushingoid features and virilization. Viriliza- tion manifests as abnormal size and strength due to increased muscle mass (herculean habi- tus), clitoromegaly (Fig 2), facial hair (Fig 3), advanced pubic and axillary hair development, and advanced bone age. Overproduction of an- drogen by adrenocortical tumor causes isosex-
3a.
ual pseudoprecocious puberty in boys, evi- denced by the early development of acne, pu- bic hair, and penile enlargement (Fig 4). Pure Cushing syndrome, feminization in boys caused by secretion of estrogen, or hypertension due to primary hyperaldosteronism (Conn syn- drome) are unusual (1,31,32). Infants with Cushing syndrome tend to have generalized obesity, rather than the truncal distribution of increased fat found in adults (33).
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Laboratory abnormalities in children with functioning adrenocortical neoplasms include an increase in 24-hour urinary ketosteroid ex- cretion and increased levels of serum cortisol, testosterone, androstenedione, and estradiol (5).
PATHOLOGIC FEATURES
· Microscopic Features
Adrenocortical adenomas comprise a heteroge- neous group of benign neoplasms that histologi- cally resemble the appearance of the normal zona fasciculata, the zona glomerulosa, or most often, a combination of both. Cells are typically arranged in nests separated by a delicate fibro- vascular stroma. Cytologic features vary from large, pale vacuolated cells with vesicular nu- clei characteristic of the zona fasciculata to smaller cells with eosinophilic cytoplasm and condensed chromatin similar to those in the zona glomerulosa and zona reticularis (Fig 5).
In general, adrenocortical adenomas are bland with low nuclear-to-cytoplasmic ratio, very little necrosis or hemorrhage, and absent or exceptionally rare mitoses or bizarre nuclear forms. In children, however, benign adrenocor- tical tumors are more likely to display marked nuclear atypia, pleomorphism, necrosis, and mitotic activity than similar tumors in adult patients. Occasionally, central degenerative changes, including necrosis, hemorrhage, cystic alteration, and vascular proliferation, may be seen in adenomas, particularly as a complica- tion of thrombosis following adrenal venogra- phy (34). Despite some association of cell types with secretory products, it is not possible to re- liably predict endocrine function (eg, hyperal- dosteronism, hypercortisolism, virilization) on the basis of histologic characteristics.
Adrenocortical carcinomas show a wide range of differentiation on histologic examina- tion, not only between different tumors but within the same tumor. Morphology ranges from normal-appearing adrenal cells to com- pletely undifferentiated cells. Broad fibrous bands often separate the tumor into multiple nodules. Most cells are lipid-poor and eosino- philic, and they may be arranged in nests, trabe- culae, or sheets. Hyperchromatic nuclei, pleo-
morphism with bizarre giant cells and multi- nucleated forms, necrosis (especially confluent areas), mitotic activity (including atypical mito- ses), and vascular or capsular invasion may be seen (Fig 5). However, none of these histologic features is necessarily diagnostic of malignancy in children (see adenoma vs carcinoma) (2,35).
· Gross Features
In a clinicopathologic study of 30 patients with adrenocortical neoplasms by Lack et al (2), 60% of lesions arose in the right adrenal gland, and no patients had bilateral involvement. Ectopic adrenocortical tumors are exceedingly rare (36).
Adenomas are typically spherical, unilateral and solitary, and well-demarcated but often un- encapsulated, and they weigh less than 50 g. Adenomas range in color from yellow to red- dish-brown and may appear black if the tumor contains a large amount of the piment lipofus- cin (34,37-39).
Carcinomas are usually over 100 g (although smaller weights have been reported) with coarse trabeculations, multinodular contour, and yellow to brown color. Areas of hemor- rhage and necrosis are frequently seen (Fig 5) (38,40). In adrenocortical neoplasms of child- hood, malignant behavior is usually associated with lesions that weigh more than 500 g, where- as most tumors that weigh less than 500 g are benign (35). Cystic change may be seen in both adenomas and carcinomas, but it is more com- mon in carcinomas and larger adenomas.
· Adenoma versus Carcinoma
An attempt to clarify the pathologic distinction between adrenocortical adenomas and carcino- mas has been made in at least several studies re- viewing adrenocortical tumors in the general population. These classification attempts in- clude criteria for malignancy based on tumor weight, clinical findings, and histologic features proposed by Hough and coworkers (41) and two systems based solely on histologic criteria proposed by Weiss and colleagues and van Slooten and colleagues (42-44). Division of car- cinomas into low grade and high grade based on mitotic rate has also been proposed (45,46). Adrenocortical tumors in children, however, cannot be reliably distinguished based on these systems (39,46,47).
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Lack et al (2) considered mitotic activity, vas- cular invasion, and extent of tumor necrosis to be the most prognostically useful histologic pa- rameters in pediatric adrenocortical neoplasms. In children, histologic characteristics and tumor size may be suggestive of malignant potential, but no single parameter (except for detection of metastases) allows benign tumors to be dis- criminated from malignant ones.
Special studies are often of limited value in the pathologic diagnosis of adrenocortical tu-
mors. Immunohistochemistry is not helpful in distinguishing between benign and malignant adrenocortical tumors, but it may be helpful in diagnosing other primary neoplasms that metas- tasize to the adrenal gland (48). Adrenocortical carcinomas are usually vimentin positive and often negative for cytokeratin, epithelial mem- brane antigen, and carcinoembryonic antigen.
The electron microscopic appearance of ad- enomas resembles that of cells of the normal ad- renal cortex, with steroid-producing cells show- ing tubulovesicular or tubulolamellar mitochon- dria, abundant smooth endoplasmic reticulum, and parallel stacks of rough endoplasmic reticu- lum. In addition, carcinomas may show abnor- mal numbers and morphology of mitochondria and dissolution of the basement membrane sur- rounding alveolar groups of cells (2,34). At DNA analysis, the presence of aneuploidy tends to fa- vor malignancy, although this characteristic is also found in benign tumors, especially larger ones (44,49). Cytogenetic studies of carcinomas have shown loss of heterozygosity of several gene loci in some cases (44,50).
The histologic differential diagnosis of adre- nocortical neoplasms includes nonneoplastic adrenal nodules, multinodular hyperplasia (which is usually bilateral and associated with hyperplasia of intervening cortical areas), pheo- chromocytoma, and metastatic carcinoma (par- ticularly renal cell carcinoma, which is rare in children).
· Metastases
The lung is the most common site of metastases from adrenocortical carcinoma, followed in fre- quency by the liver. Other metastatic sites in- clude the peritoneum (29% of cases), pleura or diaphragm (24%), abdominal lymph nodes (24%), and kidney (18%) (2). Direct extension of tumor thrombus from the adrenal veins into the inferior vena cava represents an important mechanism of nonhematogenous malignant spread and may be clinically silent.
Tumor invasion of the inferior vena cava has been reported in six of 17 (35%) patients with clinically malignant adrenocortical neoplasms, sometimes producing lower extremity and trun- cal edema (2). There has been a case report of spontaneous regression of metastatic skin nod- ules and brain metastases 4 months after surgi- cal resection of a right-sided adrenocortical car- cinoma that manifested at birth (22).
RADIOLOGIC FEATURES
The clinical presentation of an infant or child with a functioning adrenocortical tumor may be indistinguishable from that of patients with ad- renal hyperplasia or extraadrenal causes of iso- sexual or heterosexual precocious puberty (5). Moreover, the adrenal mass may be radiologi- cally occult. In a review of 17 children with adrenocortical neoplasms, conventional radiog- raphy of the abdomen demonstrated a soft-tis- sue mass in eight, of whom only three had tu- mor calcification (5). Thus, before the wide- spread availability of ultrasound (US) and CT, the final diagnosis of adrenocortical tumor was often delayed (3,4). Cross-sectional imaging studies, including US, CT, and magnetic reso- nance (MR) imaging, have largely supplanted use of invasive procedures such as arteriogra-
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phy (Fig 6), venography, and venous sampling in the evaluation of adrenal abnormalities in children (51).
Sonography is an effective screening study for a child with a suspected abdominal mass. When carefully performed, US helps character- ize the mass as solid, cystic, or complex and of- ten reveals preserved tissue planes between the tumor and adjacent organs, allowing distinction of a suprarenal mass from one arising in the ad- jacent kidney or liver. Large adrenal masses may rotate the ipsilateral kidney or displace it inferi-
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orly (52). In addition to its usefulness in the ini- tial detection of the primary tumor, US with color flow imaging facilitates the detection of venous tumor thrombus from adrenocortical carcinoma, which may extend into the right atrium and pose a risk of embolism (53).
Hamper et al (54) described the sonographic features of adrenocortical tumors in 26 patients, including seven children with pathologically proved adrenocortical carcinoma. The size of the adrenal lesions ranged from 3 to 22 cm. All were rounded or ovoid circumscribed masses that commonly displayed a lobulated border and, in seven (27%), a thin echogenic capsule- like rim. Five adrenocortical carcinomas that measured 6 cm or less were homogeneous solid masses nearly isoechoic to renal cortex (Fig 7).
The larger lesions were heterogeneous and con- tained central or diffuse hypoechoic regions that corresponded to necrotic foci in the surgi- cal pathology specimens (Fig 8). In two pa- tients, central tumor necrosis produced a multiseptated cystic appearance at sonography. Tumor calcification was demonstrated in five cases (19%) (Fig 9).
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Fourteen children with adrenocortical carci- noma were evaluated with US in a study by Prando et al (55). The lesions, which ranged from 2.5 to 19 cm in maximum diameter, were all well-circumscribed. Smaller lesions were ho- mogeneous and either uniformly hypoechoic or hyperechoic. A complex, predominantly hyper- echoic pattern was demonstrated in the 10 pa-
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tients with larger tumors, of which eight showed radiating linear echoes. The authors called this nonspecific stellate pattern the “scar sign,” and considered it suggestive of cortical carcinoma. To our knowledge, the predictive value of this sign has not been determined. Vas- cular invasion or retroperitoneal adenopathy was noted in three patients.
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CT is considered the most valuable tech- nique for examining the adrenal glands (56). The CT findings of adrenocortical neoplasms in adults and children have been described (5,57- 59). On CT scans, adrenocortical tumors are typically circumscribed, appear variably hetero- geneous due to hemorrhage and necrosis, and may display a thin capsule-like rim (Fig 9). Larger lesions tend to enhance heterogeneously following intravenous administration of contrast material. In a study of 38 patients with adreno- cortical carcinoma by Fishman et al (59), nine (24%) had detectable calcification at CT (Fig 10).
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The distinction between adrenocortical car- cinoma and adenoma in children is difficult to make radiologically unless there is evidence of hematogenous metastases or venous spread. In adult patients, unenhanced CT densitometry al- lows adrenal adenomas to be accurately differ- entiated from nonadenomas because of the rela- tively high lipid content in adenomas (60,61). To our knowledge, this method has not been
studied in adrenocortical tumors in children. It has been proposed that tumor size greater than 6 cm in diameter and heterogeneity of the pri- mary mass at imaging studies are useful indica- tors of malignancy (55,62). However, Fishman and colleagues (59) concluded that adrenocorti- cal carcinoma may manifest as a well-margin- ated, homogeneous mass 6 cm or less in diam- eter on CT scans.
There are few descriptions of the MR imag- ing appearance of hyperfunctioning adrenocor- tical tumors occurring in childhood (51,53,58, 63). In one study of five pediatric patients with pathologically proved adrenocortical tumors (four adenomas, one of indeterminate histologic characteristics) ranging in size from 1.0 to 7.5 cm, all lesions were of intermediate signal in- tensity on T1-weighted MR images and of high signal intensity relative to liver on T2-weighted images (Figs 10, 11). There was no significant difference in signal intensity characteristics be- tween the larger indeterminate lesion and the four adenomas. Similar MR imaging features in two adenomas and one carcinoma were illus- trated in a pictorial review by Westra et al (51).
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The multiplanar capability of MR imaging fa- cilitates detection of inferior vena cava tumor thrombus (Fig 12) (53). The accuracy of op- posed-phase chemical shift MR imaging of adre- nal masses, which allows adrenal adenomas to be differentiated from nonadenomas based on their relative fat content, has been established in adult patients (64-69). However, the utility of this technique has not been studied in the pediatric population.
Excess serum cortisol may produce interest- ing secondary findings on cross-sectional imag- ing studies that carry a high specificity for the diagnosis of adrenocortical neoplasm. Of the many causes of medullary nephrocalcinosis, hy- percalcemia due to Cushing syndrome is un- usual (70). Hyperechoic renal medullary pyra- mids at sonography or high-attenuation medul- lary areas on unenhanced CT images of patients
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with a suprarenal mass support the diagnosis of adrenocortical neoplasm (Fig 13). Similarly, an increase in the amount of retroperitoneal fat in infants or young children, who normally have little, is a useful anatomic clue to the nature of an adrenal mass (Fig 13).
DIFFERENTIAL DIAGNOSIS
The combination of clinical features of hor- mone overproduction in a child, supportive laboratory findings, and a circumscribed adrenal mass at cross-sectional imaging studies is virtu- ally diagnostic of a functioning adrenocortical neoplasm. Other pediatric adrenal masses in- clude neuroblastoma, pheochromocytoma, ad- renal hemorrhage, and, rarely, metastases.
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Neuroblastoma, a neoplasm of the adrenal medulla and extraadrenal sympathetic tissue, typically affects young children, and its age of manifestation may overlap with that of child- hood adrenocortical neoplasm. However, neu- roblastoma often produces an increase in the serum and urinary levels of catecholamines. In addition, neuroblastoma is more commonly metastatic at presentation than adrenocortical carcinoma, and patients with this neoplasm of- ten appear ill. Neuroblastoma may be associ- ated with the paraneoplastic syndrome of myo- clonic encephalopathy of infancy, and tumor elaboration of vasoactive intestinal peptide may
produce watery diarrhea and hypokalemia. Al- though the protean manifestations of neuroblas- toma are well-recognized (71), cross-sectional imaging studies of patients with neuroblastoma typically demonstrate a large, irregular, retro- peritoneal mass that frequently encases vascular structures, often contains characteristic punc- tate calcifications, and may extend into the ex- tradural spinal canal through neural foramina. Nevertheless, neuroblastoma may also mani- fest as a circumscribed suprarenal mass that is
indistinguishable from an adrenocortical tumor, and adrenocortical tumors may also be associ- ated with calcifications (Fig 14), retroperitoneal adenopathy, and vascular encasement (Figs 3, 8). Unlike adrenocortical neoplasms, neuroblas- toma accumulates iodine-labeled metaiodoben- zoguanidine (MIBG) at scintigraphy.
Although rare in children, pheochromocy- toma, like neuroblastoma, is a neoplasm derived from neural crest tissue, and also secretes cat- echolamines and concentrates I-123 MIBG at scintigraphy. However, pheochromocytoma usually occurs in older children (6-14 years) than does neuroblastoma or adrenocortical tu- mors. Children with pheochromocytoma typi- cally present with constant or paroxysmal head- aches caused by hypertension (71,72). Pheo- chromocytoma may occur in patients with neurofibromatosis, von Hippel-Lindau disease,
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Sturge Weber syndrome, and multiple endo- crine neoplasia types IIA and IIB. Less than 10% of pheochromocytomas in children are malig- nant (73). Pheochromocytoma characteristi- cally appears as a rounded, circumscribed mass at imaging studies. On T1-weighted MR images, the lesion has lower signal intensity than that of the liver but shows higher signal intensity than does adrenocortical tumor on T2-weighted im- ages (72).
Adrenal hemorrhage typically occurs in neo- nates, which is an unusual age of presentation for adrenocortical tumors. Hemorrhage can usu- ally be distinguished from a neoplastic adrenal mass by temporal evolution over serial sono- grams, which typically depict liquefaction, clot retraction, and shrinkage of the hematoma.
Large adrenocortical neoplasms may appear to invade or arise from the upper pole of the kidney at cross-sectional imaging studies and thus may mimic a primary renal tumor (Fig 10). Solid renal neoplasms of childhood include Wilms tumor (nephroblastoma), mesoblastic nephroma, renal cell carcinoma, clear cell sar- coma, and rhabdoid tumor of the kidney. Meso- blastic nephroma may be congenital and is typi- cally discovered in the neonatal period or early infancy. Nevertheless, the age of presentation of adrenocortical tumor in childhood may over- lap that of mesoblastic nephroma and other pe- diatric renal tumors. None of the renal tumors produces the clinical findings of hormonally ac- tive adrenocortical neoplasms. However, rhab- doid tumor and mesoblastic nephroma may be associated with hypercalcemia.
TREATMENT AND PROGNOSIS
Following characterization of the primary tu- mor mass and possible metastases by means of cross-sectional imaging studies, surgery is the mainstay of treatment for adrenocortical neo- plasms. Evaluation of the renal veins and infe- rior vena cava with US, CT, or MR imaging is critical, because tumor thrombus in the intrahe- patic segment of the inferior vena cava or right atrium requires a thoracoabdominal surgical ap- proach. The optimal role of adjuvant chemo- therapy in children who develop recurrent dis- ease, who have metastases at diagnosis, or who
have persistent elevation of hormone levels fol- lowing surgery continues to be investigated (74). There have been limited reports of the palliative use of radiation therapy (75).
In the older literature, a relatively poor prog- nosis had been assigned to children with adre- nocortical neoplasms (2). In a compendium of adrenocortical tumors in children reported up to 1962, only 23 of 222 patients survived 2 or more years after treatment (76). However, the rarity of adrenocortical neoplasms in the pedi- atric age group limits the experience of many pathologists, and a tendency to overdiagnose the lesions as carcinoma has been recognized (2,20,35). Unless metastases are present (Figs 14, 15), this difficulty in distinguishing ad- enoma from carcinoma is compounded by the absence of universally accepted histologic prog- nostic factors. The study by Cagle et al (35) concluded that pediatric adrenocortical neo- plasms were more likely to be benign than had previously been thought. Improved survival rates may reflect the benefits of earlier detec- tion because of the advent of cross-sectional im- aging, the availability of cortisone replacement therapy, and refinements in surgical techniques and postoperative clinical care (1).
The prognosis for children with a pathologic diagnosis of adrenocortical carcinoma is strati- fied by age of presentation. In an analysis by
Lack and colleagues (2), the survival rate for pa- tients older than 5 years was only 13%, com- pared with 70% for children 5 years or younger. A review by Humphrey et al (77) showed an overall survival rate of 53% for infants with adrenocortical carcinoma compared with 17% for adolescents. Most deaths caused by adreno- cortical carcinoma occur within 1-2 years after diagnosis (2,77).
SUMMARY
Adrenocortical neoplasms are rare in children but differ substantially in clinical characteris- tics and biologic behavior from similar tumors found in adults. Although the older literature as- signed a relatively poor prognosis to pediatric patients with adrenocortical neoplasms, recent work suggests that these tumors are more likely to be benign than previously thought. Never- theless, it is often difficult to distinguish benign from malignant lesions in the absence of meta- static disease. The survival rate for patients with aggressive adrenocortical tumors is age stratified, with children younger than 5 years faring significantly better. Use of cross-sectional imaging studies, particularly CT and MR imag- ing, has streamlined the evaluation of a child with pseudoprecocious puberty or Cushing syndrome, and the combination of finding an adrenal mass and clinical features of adrenocor- tical hyperfunction is diagnostic of adrenocorti- cal neoplasm.
REFERENCES
1. Lack EE. Adrenal cortical neoplasms in child- hood. In: Lack EE, ed. Atlas of tumor pathol- ogy: tumors of the adrenal gland and extra-ad- renal paraganglia, fasc 19, ser 3. Washington, DC: Armed Forces Institute of Pathology, 1997; 153-168.
2. Lack EE, Mulvihill JJ, Travis WD, Kozakewich HP. Adrenal cortical neoplasms in the pediatric and adolescent age group: clinicopathologic study of 30 cases with emphasis on epidemio- logical and prognostic factors. Pathol Ann 1992; 27(pt 1):1-53.
3. Stewart DR, Jones PH, Jolleys A. Carcinoma of the adrenal gland in children. J Pediatr Surg 1974; 9:59-67.
4. Zaitoon MM, Mackie GG. Adrenal cortical tu- mors in children. Urology 1978; 12:645-649.
5. Daneman A, Chan HS, Martin J. Adrenal carci- noma and adenoma in children: a review of 17 patients. Pediatr Radiol 1983; 13:11-18.
6. Wilkins L. A feminizing adrenal tumor causing gynecomastia in a boy of five years contrasted with a virilizing tumor in a five-year-old girl: classification of seventy cases of adrenal tumor in children according to their hormonal mani- festations and a review of eleven cases of femi- nizing adrenal tumor in adults. J Clin Endo- crinol Metab 1948; 8:111-132.
7. Korobkin M, Francis IR, Kloos RT, Dunnick NR. The incidental adrenal mass. Radiol Clin North Am 1996; 34:1037-1054.
8. Fraumeni JF Jr, Miller RW. Adrenocortical neo- plasms with hemihypertrophy, brain tumors, and other disorders. J Pediatr 1967; 70:129- 138.
9. Wiedemann HR. Tumours and hemihypertro- phy associated with Wiedemann-Beckwith syn- drome. Eur J Pediatr 1983; 141:129.
10. Sherman FE, Bass LW, Fetterman GH. Congeni- tal metastasizing adrenal cortical carcinoma as- sociated with cytomegaly of the fetal adrenal cortex. Am J Clin Pathol 1958; 30:439-446.
11. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms: a familial syndrome? Ann Intern Med 1969; 71:747-752.
12. Lynch HT, Mulcahy GM, Harris RE, Guirgis HA, Lynch JF. Genetic and pathologic findings in kindred with hereditary sarcoma, breast can- cer, brain tumors, leukemia, lung, laryngeal, and adrenal cortical carcinoma. Cancer 1978; 41:2055-2064.
13. Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast can- cer, sarcomas, and other neoplasms. Science 1990; 250:1233-1238.
14. Grayson GH, Moore S, Schneider BG, Saldivar V, Hensel CH. Novel germline mutation of the p53 tumor suppressor gene in a child with inci- dentally discovered adrenal cortical carcinoma. Am J Pediatr Hematol Oncol 1994; 16:341-347.
15. Gershanik JJ, Elmore M, Levkoff AH. Congenital concurrence of adrenal cortical tumor, ganglio- neuroma, and toxoplasmosis. Pediatrics 1973; 51:705-709.
16. Dahms WT, Gray G, Vrana M, New MI. Adreno- cortical adenoma and ganglioneuroblastoma in a child: a case presenting as Cushing syndrome with virilization. Am J Dis Child 1973; 125: 608-611.
17. Daeschner GL. Adrenal cortical adenoma aris- ing in a girl with congenital adrenogenital syn- drome. Pediatrics 1965; 36:140-142.
18. Bauman A, Bauman CG. Virilizing adrenocorti- cal carcinoma: development in a patient with salt-losing congenital adrenal hyperplasia. JAMA 1982; 248:3140-3141.
19. Pang S, Becker D, Cotelingam J, Foley TP Jr, Drash AL. Adrenocortical tumor in a patient with congenital adrenal hyperplasia due to 21- hydroxylase deficiency. Pediatrics 1981; 68: 242-246.
20. Zerbini CA, Kozakewich HP, Weinberg DS, Mundt DJ, Edwards JAI, Lack EE. Adrenocorti- cal neoplasms in childhood and adolescence: analysis of prognostic factors including DNA content. Endocr Pathol 1992; 3:116-128.
21. Lefevre M, Gerard-Marchant R, Gubler JP, Chaussain JL, Lemerle J. Adrenal cortical carci- noma in children: 42 patients treated from 1958 to 1980 at Villejuif. In: Humphrey GB, Grindey GB, Dehner LP, eds. Adrenal and endo- crine tumors in children. Boston, Mass: Nijhoff, 1983; 265-276.
22. Saracco S, Abramowsky C, Taylor S, Silverman RA, Berman BW. Spontaneously regressing adrenocortical carcinoma in a newborn: a case report with DNA ploidy analysis. Cancer 1988; 62:507-511.
23. Burrington JD, Stephens CA. Virilizing tumors of the adrenal gland in childhood: report of eight cases. J Pediatr Surg 1969; 4:291-302.
24. Artigas JL, Niclewicz ED, Padua GSA, Ribas DB, Athayde SL. Congenital adrenal cortical carci- noma. J Pediatr Surg 1976; 11:247-252.
25. Mann JR, Cameron AH, Gornall P, Rayner PH, Shah KJ. Transplacental carcinogenesis (adre- nocortical carcinoma) associated with hydroxy- progesterone hexanoate. Lancet 1983; 2:580.
26. Butler H, Bick R, Morrison S. Unsuspected adre- nal masses in the neonate: adrenal cortical car- cinoma and neuroblastoma: a report of two cases. Pediatr Radiol 1988; 18:237-239.
27. Sabbaga CC, Avilla SG, Schulz C, Garbers JC, Blucher D. Adrenocortical carcinoma in chil- dren: clinical aspects and prognosis. J Pediatr Surg 1993; 28:841-843.
28. Ribeiro RC, Sandrini Neto RS, Schell MJ, Lacerda L, Sambaio GA, Cat I. Adrenocortical carcinoma in children: a study of 40 cases. J Clin Oncol 1990; 8:67-74.
29. Neblett WW, Frexes-Steed M, Scott HWJ. Ex- perience with adrenocortical neoplasm in child- hood. Am Surg 1987; 53:117-125.
30. Teinturier C, Brugieres L, Lemerle J, Chaussain JL, Bougneres PF. Adrenocortical carcinoma in children: retrospective study of 54 cases. Arch Pediatr 1996; 3:235-240.
31. Howard CP, Takahashi H, Hayles AB. Feminiz- ing adrenal adenoma in a boy: case report and literature review. Mayo Clin Proc 1977; 52: 354-357.
32. Ganguly A, Bergstein J, Grim CE, Yum MN, Weinberger MH. Childhood primary aldoste- ronism due to an adrenal adenoma: preopera- tive localization by adrenal vein catheteriza- tion. Pediatrics 1980; 65:605-609.
33. Gilbert MG, Cleveland WW. Cushing’s syn- drome in infancy. Pediatrics 1970; 46:217-229.
34. Page DL, DeLellis RA, Hough AJ. Adrenal corti- cal tumors and tumor-like conditions. In: Page DL, DeLellis RA, Hough AJ, eds. Atlas of tumor pathology: tumors of the adrenal, fasc 23, ser 2. Washington, DC: Armed Forces Institute of Pathology, 1986; 56-149.
35. Cagle PT, Hough AJ, Pysher TJ, et al. Compari- son of adrenal cortical tumors in children and adults. Cancer 1986; 57:2235-2237.
36. Kepes JJ, O’Boynick P, Jones S, Baum D, McMillan J, Adams ME. Adrenal cortical ad- enoma in the spinal canal of an 8-year-old girl. Am J Surg Pathol 1990; 14:481-484.
37. Kay S. Hyperplasia and neoplasia of the adrenal gland. Pathol Ann 1976; 11:103-139.
38. Tang CK, Gray GF. Adrenocortical neoplasms: prognosis and morphology. Urology 1975; 5: 691-695.
39. Wenig BM, Heffess CS, Adair CF. Neoplasms of the adrenal gland. In: Atlas of endocrine pa- thology. Philadelphia, Pa: Saunders, 1997; 288- 329.
40. Gandour MJ, Grizzle WE. A small adrenocorti- cal carcinoma with aggressive behavior: an evaluation of criteria for malignancy. Arch Pathol Lab Med 1986; 110:1076-1079.
41. Hough AJ, Hollifield JW, Page DL, Hartmann WH. Prognostic factors in adrenal cortical tu- mors: a mathematical analysis of clinical and morphologic data. Am J Clin Pathol 1979; 72:390-399.
42. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocor- tical tumors. Am J Surg Pathol 1984; 8:163- 169.
43. van Slooten H, Schaberg A, Smeenk D, Moole- naar AJ. Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 1985; 55:766-773.
44. Medeiros LJ, Weiss LM. New developments in the pathologic diagnosis of adrenal cortical neoplasms: a review. Am J Clin Pathol 1992; 97:73-83.
45. Weiss LM, Medeiros LJ, Vickery AL Jr. Patho- logic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989; 13:202-206.
46. Bugg MF, Ribeiro RC, Roberson PK, et al. Cor- relation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia: a study of a Brazilian population. Am J Clin Pathol 1994; 101:625-629.
47. Dehner LP. Neoplasms of the adrenal cortex: preoccupation bordering on obsession (edito- rial). Am J Clin Pathol 1994; 101:557-558.
48. Cote RJ, Cordon-Cardo C, Reuter VE, Rosen PP. Immunopathology of adrenal and renal cor- tical tumors: coordinated change in antigen ex- pression is associated with neoplastic conver- sion in the adrenal cortex. Am J Pathol 1990; 136:1077-1084.
49. Cibas ES, Medeiros LJ, Weinberg DS, Gelb AB, Weiss LM. Cellular DNA profiles of benign and malignant adrenocortical tumors. Am J Surg Pathol 1990; 14:948-955.
50. Fogt F, Vargas MP, Zhuang Z, Merino MJ. Utili- zation of molecular genetics in the differentia- tion between adrenal cortical adenomas and carcinomas. Hum Pathol 1998; 29:518-521.
51. Westra SJ, Zaninovic AC, Hall TR, Kangarloo H, Boechat MI. Imaging of the adrenal gland in children. RadioGraphics 1994; 14:1323-1340.
52. Yeh HC, Mitty HA, Rose J, Wolf BS, Gabrilove JL. Ultrasonography of adrenal masses: unusual manifestations. Radiology 1978; 127:475-483.
53. Godine LB, Berdon WE, Brasch RC, Leonidas JC. Adrenocortical carcinoma with extension into inferior vena cava and right atrium: report of 3 cases in children. Pediatr Radiol 1990; 20: 166-168.
54. Hamper UM, Fishman EK, Hartman DS, Roberts JL, Sanders RC. Primary adrenocortical carci- noma: sonographic evaluation with clinical and pathologic correlation in 26 patients. AJR 1987; 148:915-919.
55. Prando A, Wallace S, Marins JL, Pereira RM, de Oliveira ER. Sonographic findings of adrenal cortical carcinomas in children. Pediatr Radiol 1990; 20:163-165.
56. Dunnick NR. Adrenal imaging: current status. AJR 1990; 154:927-936.
57. Filiatrault D, Perreault G, Laberge JM, Duchar- me JC. CT localization of an aldosteronoma in a 10-year-old boy. Pediatr Radiol 1986; 16:85-86.
58. Hanson JA, Weber A, Reznek RH, et al. Mag- netic resonance imaging of adrenocortical ad- enomas in childhood: correlation with com- puted tomography and ultrasound. Pediatr Radiol 1996; 26:794-799.
59. Fishman EK, Deutch BM, Hartman DS, Gold- man SM, Zerhouni EA, Siegelman SS. Primary adrenocortical carcinoma: CT evaluation with clinical correlation. AJR 1987; 148:531-535.
60. Korobkin M, Brodeur FJ, Yutzy GG, et al. Dif- ferentiation of adrenal adenomas from nonade- nomas using CT attenuation values. AJR 1996; 166:531-536.
61. Lee MJ, Hahn PF, Papanicolaou N, et al. Benign and malignant adrenal masses: CT distinction with attenuation coefficients, size, and ob- server analysis. Radiology 1991; 179:415-418.
62. Boothroyd AE, Dicks-Mireaux C, Malone M. Ad- renal cortical tumours in children. Eur J Radiol 1994; 18:199-204.
63. Li JT, Shu SG, Chi CS. Aldosterone-secreting ad- renal cortical adenoma in an 11-year-old child and collective review of the literature. Eur J Pediatr 1994; 153:480-482.
64. Bilbey JH, McLoughlin RF, Kurkjian PS, et al. MR imaging of adrenal masses: value of chemi- cal-shift imaging for distinguishing adenomas from other tumors. AJR 1995; 164:637-642.
65. Mitchell DG, Crovello M, Matteucci T, Petersen RO, Miettinen MM. Benign adrenocortical masses: diagnosis with chemical shift MR imag- ing. Radiology 1992; 185:345-351.
66. Korobkin M, Lombardi TJ, Aisen AM, et al. Characterization of adrenal masses with chemi- cal shift and gadolinium-enhanced MR imaging. Radiology 1995; 197:411-418.
67. Reinig JW, Stutley JE, Leonhardt CM, Spicer KM, Margolis M, Caldwell CB. Differentiation of adrenal masses with MR imaging: compari- son of techniques. Radiology 1994; 192:41-46.
68. Schwartz LH, Panicek DM, Koutcher JA, et al. Adrenal masses in patients with malignancy: prospective comparison of echo — planar, fast spin-echo, and chemical shift MR imaging. Ra- diology 1995; 197:421-425.
69. Tsushima Y, Ishizaka H, Matsumoto M. Adrenal masses: differentiation with chemical shift, fast low-angle shot MR imaging. Radiology 1993; 186:705-709.
70. Shultz PK, Strife JL, Strife CF, McDaniel JD. Hyperechoic renal medullary pyramids in in- fants and children. Radiology 1991; 181:163- 167.
71. Abramson SJ. Adrenal neoplasms in children. Radiol Clin North Am 1997; 35:1415-1453.
72. Velchik M, Alavi A, Kresse LH. Localization of pheochromocytoma: MIBG, CT, and MR corre- lation. J Nucl Med 1989; 30:328-336.
73. Cohen M. Endocrine tumors. In: Cohen M, ed. Imaging of children with cancer. St Louis, Mo: Mosby-Year Book, 1992; 134-176.
74. Arico M, Bossi G, Livieri C, Raiteri E, Severi F. Partial response after intensive chemotherapy for adrenal cortical carcinoma in a child. Med Pediatr Oncol 1992; 20:246-248.
75. Markoe AM, Serber W, Micaily B, Brady LW. Ra- diation therapy for adjunctive treatment of ad- renal cortical carcinoma. Am J Clin Oncol 1991; 14:170-174.
76. Hayles AB, Hahn HB Jr, Sprague RG, Bahn RC, Priestly JT. Hormone-secreting tumors of the adrenal cortex in children. Pediatrics 1966; 37: 19-25.
77. Humphrey GB, Pysher T, Holcombe JEA. Over- view on the management of adrenocortical car- cinoma. In: Humphrey GB, Grindey GB, Deh- ner LP, Acton RT, Pysher TJ, eds. Adrenal and endocrine tumors in children. Boston, Mass: Marinus Nijhoff, 1983; 349-358.