Pediatric adrenocortical neoplasms: can imaging reliably discriminate adenomas from carcinomas?
Kelsey A. Flynt . Jonathan R. Dillman . Matthew S. Davenport . Ethan A. Smith . Tobias Else . Peter J. Strouse . Elaine M. Caoili
Received: 9 October 2014/Revised: 15 December 2014 /Accepted: 5 February 2015 C Springer-Verlag Berlin Heidelberg 2015
Abstract
Background There is a paucity of literature describing and comparing the imaging features of adrenocortical adenomas and carcinomas in children and adolescents.
Objective To document the CT and MRI features of adreno- cortical neoplasms in a pediatric population and to determine whether imaging findings (other than metastatic disease) can distinguish adenomas from carcinomas.
Materials and methods We searched institutional medical re- cords to identify pediatric patients with adrenocortical neo- plasms. Pre-treatment CT and MRI examinations were reviewed by two radiologists in consensus, and pertinent im- aging findings were documented. We also recorded relevant histopathological, demographic, clinical follow-up and survival data. We used the Student’s t-test and Wilcoxon rank sum test to compare parametric and nonparametric continuous data, and the Fisher exact test to compare proportions. We used receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performances of tumor diameter and volume for discriminating carcinoma from adenoma. A P-value ≤0.05 was considered statistically significant.
K. A. Flynt · J. R. Dillman · E. A. Smith · P. J. Strouse Section of Pediatric Radiology, C. S. Mott Children’s Hospital, Department of Radiology, University of Michigan Health System, 1540 East Hospital Drive, Ann Arbor, MI 48109, USA e-mail: jonadill@med.umich.edu
M. S. Davenport · E. M. Caoili Division of Abdominal Imaging, Department of Radiology, University of Michigan Health System, Ann Arbor, MI, USA
T. Else Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
Results Among the adrenocortical lesions, 9 were adenomas, 15 were carcinomas, and 1 was of uncertain malignant poten- tial. There were no differences in mean age, gender or sidedness between adenomas and carcinomas. Carcinomas were signifi- cantly larger than adenomas based on mean estimated volume (581 ml, range 16-2,101 vs. 54 ml, range 3-197 ml; P-value= 0.003; ROC area under the curve=0.92) and mean maximum transverse plane diameter (9.9 cm, range 3.0-14.9 vs. 4.4 cm, range 1.9-8.2 cm; P-value=0.0001; ROC area under the curve=0.92). Carcinomas also were more heterogeneous than adenomas on post-contrast imaging (13/14 vs. 2/9; odds ratio [OR]=45.5; P-value=0.001). Six of 13 carcinomas and 1 of 8 adenomas contained calcification at CT (OR=6.0; P-value= 0.17). Seven of 15 children with carcinomas exhibited metasta- tic disease at diagnosis, and three had inferior vena cava inva- sion. Median survival for carcinomas was 27 months.
Conclusion In our experience, pediatric adrenocortical carci- nomas are larger, more heterogeneous, and more often calci- fied than adenomas, although there is overlap in their imaging appearances.
Keywords Adrenocortical neoplasm · Carcinoma · Adenoma · Children · Computed tomography · Magnetic resonance imaging
Introduction
Adrenocortical neoplasms in the pediatric population are rare, with an incidence of approximately three cases per 1 million; they are clinically and histologically different from those ob- served in the adult population and can be benign (adenomas), malignant (carcinomas), or of uncertain malignant potential [1, 2]. Although sometimes detected incidentally, these tumors most often present as a result of associated increased hormone production [3, 4]. Precocious puberty or virilization caused by
increased androgen production and Cushing syndrome caused by increased cortisol production are frequently reported pre- sentations [1, 2, 5-7]. Pediatric adenomas and carcinomas have very different prognoses, with adenomas typically being cured by surgical resection. Despite aggressive surgical and medical treatment, carcinomas generally have a poor progno- sis [6], with one study reporting a 5-year survival of 0% in children with stage 3 and stage 4 tumors [8]. A large study by Michalkiewicz et al. [6] documented an overall 5-year surviv- al of 54.7% in children with adrenocortical carcinoma, al- though the 5-year event-free survival for stages 1 and 2 ranged from 38.1% in older children (13- to 20-year-olds) to 85.6% in very young children (0- to 3-year-olds).
There is a paucity of literature describing and comparing the routine imaging features of pediatric adrenocortical neo- plasms at CT and MRI. Based on available reports, pediatric adenomas appear different from those typically observed in the adult population (which are generally small, homogeneous adrenal gland nodules or masses) [3, 9]. Also, there is no validated CT or MRI method for assessing adrenal adenomas in children, unlike in the adult population, where a Hounsfield unit cut-off value (CT densitometry) is used to diagnose lipid- rich adenomas [10] and contrast enhancement washout is used to discriminate lipid-poor adenomas from other adrenal le- sions, such as metastases [11, 12]. Pretreatment knowledge of adenoma vs. carcinoma in the pediatric population could help direct surgical management (e.g., laparoscopic resection of adenomas vs. open radical resection of carcinomas) as well as guide the use of neoadjuvant chemotherapy, should this approach become standard of care.
The purpose of our study was to document the routine CT and MRI features of adrenocortical neoplasms in our pediatric patient population. In addition, we sought to de- termine whether any imaging features (e.g., tumor diame- ter/volume, homogeneous vs. heterogeneous appearance, presence of calcification) other than the existence of met- astatic disease can reliably distinguish pediatric adrenocor- tical adenomas from carcinomas.
Materials and methods
This retrospective investigation was approved by our institu- tional review board and complies with the Health Insurance Portability and Accountability Act. The requirement for in- formed consent was waived.
Institutional Departments of Radiology, Pathology and On- cology records were searched to identify all pediatric patients (younger than or equal to 18 years) with adrenocortical neo- plasms (adenomas, carcinomas and lesions of uncertain ma- lignant potential) between January 1995 and June 2014. We excluded children without pertinent pre-treatment (medical or surgical) CT, MRI or US imaging.
Relevant pre-treatment imaging examinations were reviewed by two radiologists in consensus (a third-year radi- ology resident and a fellowship-trained pediatric radiologist with 5 years of clinical experience). Pre-treatment CT and MRI examinations were reviewed (as available), while US imaging was only reviewed if no CT or MRI examination was available. CT and MRI examination parameters varied because imaging examinations were performed over a nearly 20-year period, and many studies were performed at outside institutions. The following pre-treatment imaging findings were documented:
· Side of mass (right vs. left)
· Maximum dimensions of mass in transverse, anteroposterior and craniocaudad planes (cm)
· Estimated tumor volume (ml; using 0.52 x transverse x anteroposterior x craniocaudad maximum dimension measurements)
· Post-contrast enhancement pattern (predominantly homo- geneous vs. predominantly heterogeneous)
· Presence of calcification, if CT imaging available (yes or no)
· Mean attenuation of mass, if non-contrast CT imaging available (Hounsfield unit [HU], using region-of-interest including central two-thirds of lesion)
· Contrast material washout percentage of mass, if non-con- trast, portal venous and delayed phases of imaging available
· Presence of inferior vena cava invasion (yes or no)
· Presence of metastatic disease at time of initial presenta- tion (yes or no)
· Location of metastatic disease at time of initial presenta- tion, if present (e.g., regional lymph nodes, liver, lung).
Available CT, MRI and US examinations acquired af- ter the initiation of medical or surgical treatment as well as pertinent clinical data were reviewed to determine whether children with malignancy that initially presented without metastatic disease eventually developed distant spread.
Relevant histopathological records were reviewed for all children by a single investigator in order to classify pediatric adrenocortical lesions as adenomas, carcinomas or lesions of uncertain malignant potential. Electronic medical records were searched to obtain demographic in- formation (e.g., age and gender) and clinical presentation (e.g., precocious puberty/virilization Cushing syndrome, primary aldosteronism, incidental finding). We document- ed length of follow-up (in months) from diagnosis to most recent clinical encounter in the medical record. For chil- dren with no medical records after Dec. 31, 2013, we searched the United States Social Security Administration death records to allow additional assessment of survival.
Statistical analysis
Continuous data were summarized using means and ranges, while categorical data were summarized using counts and per- centages. Continuous data were graphically explored using box-and-whisker plots, as appropriate. We used the Student’s t-test and Wilcoxon rank sum test to compare parametric and nonparametric continuous data, and the Fisher exact test to compare proportions. We performed receiver operating char- acteristic (ROC) curve analyses to evaluate the diagnostic per- formances of maximum transverse plane diameter and esti- mated tumor volume for discriminating adrenocortical carci- noma from adenoma. The Kaplan-Meier method was used to compare the median survival of children with adenomas com- pared to carcinomas. A P-value ≤0.05 was considered statis- tically significant for all inference testing. Statistical analyses were performed using GraphPad Prism 6 (GraphPad Software Inc., La Jolla, CA).
Results
Histopathological diagnosis
All 25 pediatric patients with adrenocortical lesions and avail- able CT, MRI or US imaging had correlative histopathological data. Of the adrenocortical lesions, 9 were adenomas, 15 were carcinomas, and 1 was of uncertain malignant potential.
Demographic data and clinical presentations
Demographic data and clinical presentations are presented in Table 1. There was no significant difference in the proportion of girls vs. boys when comparing adrenocortical adenomas to carcinomas in our patient population (P-value=0.66). Similar- ly, there was no significant difference in the mean ages of children with adenomas vs. carcinomas (11.4 vs. 11.5 years; P-value=0.92).
Imaging features of pediatric adrenocortical neoplasms
Adenoma
Eight (89%) children with adenomas were imaged with CT, while a single (11%) child was imaged with MRI. Six adeno- mas were located on the right (66%); three were located on the left (33%). Mean maximum transverse plane dimension of adenomas was 4.4 cm (range 1.9-8.2 cm), while mean esti- mated tumor volume of adenomas was 54 ml (range 3-197 ml) (Fig. 1). Two (22%) adenomas appeared predominantly het- erogeneous on post-contrast imaging, while only one (13%) adenoma contained calcification based on CT imaging (Fig. 2). Five (63%) of eight children with CT imaging had a
| Adenoma (n=9) | Carcinoma (n=15) | Uncertain malignant potential (n=1) | |
|---|---|---|---|
| Gender | |||
| Girls (n, %) | 7 (78%) | 9 (60%) | - |
| Boys (n, %) | 2 (22%) | 6 (40%) | 1 |
| Mean age (years) | |||
| Overall (range) | 11.4 (2-17) | 11.5 (0.17-18) | 3 (no range) |
| Girls (range) | 12.0 (2-17) | 14.1 (3-18) | - |
| Boys (mean, range) | 9.5 (9-10) | 7.5 (0.17-17) | 3 (no range) |
| Clinical presentations | |||
| Precocious puberty/ | 5 | 5 | 1 |
| virilization (n) | |||
| Cushing syndrome (n) | 1 | 4 | - |
| Primary aldosteronism (n) | 1 | - | - |
| Abdominal pain | - | 2 | |
| Incidental/other (n) | 2 | 4 | - |
n number of subjects; - no subjects
non-contrast phase; only one of these adenomas demon- strated a mean HU measurement value of less than 10, suggesting a lipid-rich adenoma. The other four adenomas with non-contrast CT imaging appeared lipid-poor based on CT densitometry, with HU measurements ranging from 30 to 46. Only two children had sufficient imaging avail- able to calculate the washout percentage of contrast ma- terial from the mass, calculated to be 59% and 68%, re- spectively. As anticipated, no histologically confirmed ad- enoma showed evidence of inferior vena cava invasion or metastatic disease.
Carcinoma
Twelve (80%) children with carcinomas were imaged with CT only, one (6.7%) child was imaged with MRI only, and one (6.7%) child was imaged with both CT and MRI. An addition- al single child (6.7%) was imaged with US but had no avail- able CT or MR imaging; only demographic, tumor side and size, and follow-up/survival data were collected for this child.
Eight carcinomas were located on the right (53%), while seven were located on the left (47%). Mean maximum trans- verse plane dimension of carcinomas was 9.9 cm (range 3.0- 14.9 cm), while mean carcinoma estimated tumor volume was 581.0 ml (range 16-2,101 ml) (Fig. 1); carcinoma volume could not be calculated for one lesion because the inferior- most portion of the mass was excluded from available CT imaging. Thirteen (93%) of 14 carcinomas with CT or MR imaging appeared predominantly heterogeneous on post-
a
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contrast imaging (Figs. 3, 4 and 5). Six (46%) of 13 carcino- mas with CT imaging contained calcification (Figs. 3 and 4).
Three (23%) of 13 children with carcinomas and available CT imaging had a non-contrast phase; all three of these carci- nomas demonstrated a mean Hounsfield unit measurement of greater than 10 (range 36-64 HU). No child with carcinoma had sufficient imaging available to calculate the washout per- centage of contrast material from the mass.
Seven (47%) of 15 children with carcinomas showed evi- dence of metastatic disease at the time of initial diagnosis. Metastatic disease was noted to involve the following sites: lung (n=5), liver (n=4), regional lymph nodes (n=2) and peritoneum (n=1) (Fig. 4). Three children exhibited delayed presentation of metastatic disease, all experiencing local ret- roperitoneal recurrences as well as pulmonary metastases or
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Estimated Tumor Volume (ml)
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metastatic disease to regional lymph nodes. Three children had evidence of inferior vena cava invasion at the time of initial diagnosis (Fig. 5); all three of these children had local retroperitoneal recurrences as well as evidence of pulmonary metastases (two at the time of diagnosis and one during ther- apy). There was no significant difference in the size of carci- nomas presenting with vs. without metastatic disease (448.1 ml vs. 758.2 ml; P-value=0.3).
Adenomas vs. carcinomas
There were no significant differences in mean age of presen- tation, gender or sidedness (right vs. left) between adrenocor- tical adenomas and carcinomas. Although of variable size, carcinomas were significantly larger than adenomas based on mean estimated tumor volume (581 ml vs. 54 ml; P-value=0.003) and mean maximum transverse plane diame- ter (9.9 cm vs. 4.4 cm; P-value=0.0001) (Figs. 1, 6, 7, 8 and 9). Carcinomas also were significantly more heterogeneous than adenomas (13/14 vs. 2/9; P-value=0.001; OR=45.5; 95% confidence interval [CI], 3.5-595.1). Six of 13 carcino- mas and 1 of 8 adenomas contained calcification on CT (P-value=0.17; OR=6.0; 95% CI, 0.57-63.7).
ROC curves were created to assess the diagnostic perfor- mances of estimated tumor volume and maximum transverse plane diameter for discriminating adrenocortical carcinoma from adenoma. Areas under the curves were both 0.92, respec- tively (Fig. 10). An estimated tumor volume cut-off of 212.5 ml provided 79% sensitivity and 100% specificity for discriminating carcinoma from adenoma, while a maximum transverse plane diameter cut-off of 8.5 cm provided 80% sensitivity and 100% specificity.
Adrenocortical lesion of uncertain malignant potential
Our only adrenocortical lesion of uncertain malignant poten- tial based on histopathological analysis arose in a 3-year-old boy with Li-Fraumeni syndrome (p53 tumor suppressor gene mutation) who presented with precocious puberty. His pre- dominantly homogeneous tumor had a maximum transverse plane diameter of 2.7 cm and an estimated tumor volume of 6.3 ml. No metastatic disease was identified at initial presen- tation or upon 43 months of follow-up.
a
b
Subject follow-up
Adenoma
All nine adrenocortical adenomas were surgically resected because of hormonal activity or concern about potential ma- lignancy. Median follow-up for adenomas was 29 months (range 1-192 months). No child with an adenoma experienced local or distant recurrence, based on available medical records.
Carcinoma
Median follow-up of adrenocortical carcinomas was 19 months (range 6-229 months). Twelve of 15 children had complete follow-up using the methods described above, while
three children were lost to follow-up after 12, 25 and 39 months, respectively. Median survival in our patient pop- ulation was 27 months.
Discussion
Based on our study population, there was no significant de- mographic difference between children and adolescents with adrenocortical adenomas and carcinomas. The mean age of children with adenomas was 11.4 years compared to 11.5 years for those with carcinomas. This result differs from other pub- lished studies where pediatric adrenocortical lesions were found to occur more often in younger children [1, 2]. Interest- ingly, one of our adrenocortical carcinomas was likely con- genital, coming to attention as a palpable mass at 2 months of age. Congenital adrenocortical carcinomas and adenomas are very rare but have been described [13]. Both adenomas and carcinomas were more common in girls, an observation that has been described by others [1, 5-8].
The majority of adrenocortical tumors in our study were hormonally active, often causing precocious puberty or virilization or Cushing syndrome (three children, including two who presented prior to 2000, did not have available lab- oratory data). A small but substantial number of adenomas and carcinomas presented with abdominal pain or were inci- dentally detected, with six of eight of these tumors shown to be hormone-producing based upon laboratory evaluation. Based on our experience, aldosterone-producing tumors and associated Conn syndrome (hypertension and hypokalemia) is probably rare in the pediatric population; feminization in boys from estrogen production was not observed but has been re- ported [1].
At CT and MRI, several differences between adenomas and carcinomas were observed. First, on average, carcinomas were
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much larger than adenomas based on maximum transverse plane diameter (P-value=0.0001) and estimated volume (P= 0.003) of tumor. Both of these imaging features allowed sim- ilar discrimination between adenoma and carcinoma based on ROC analysis, with respectable areas under the curve of 0.92. Two adenomas were quite large (approximately 8 cm in max- imum diameter), suggesting that a lower cut-off value for maximum transverse plane diameter might falsely classify a small number of adenomas as carcinomas. A cut-off maxi- mum transverse plane diameter of 8.5 cm and cut-off estimat- ed tumor volume of 212.5 ml were both 100% specific for carcinoma based on our data. Not surprisingly, in three chil- dren adrenocortical carcinomas were diagnosed with diame- ters and volumes that clearly overlapped with the majority of adenomas and which did not have imaging evidence of metastatic disease. It is such malignant lesions that pediatric radiologists cannot reliably distinguish from benign adenomas based on standard CT and MRI techniques.
Other imaging features were also seen more commonly in carcinomas compared to adenomas, including a predominant- ly heterogeneous pattern of enhancement on post-contrast imaging (P-value=0.001) and presence of calcification (P-value=0.17). All but one carcinoma heterogeneously en- hanced (commonly with a central stellate appearance), while only two adenomas shared this imaging feature. The magni- tude of association between adrenocortical lesion heterogene- ity and the histological diagnosis of carcinoma was striking, with an odds ratio of 45.5. That is, the odds of an adrenocor- tical lesion being carcinoma (vs. adenoma) are 45.5 times greater when post-contrast enhancement is heterogeneous. Al- though the 95% confidence interval accompanying this odds ratio is very wide because of our relatively small sample
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population, the effect size suggests a very strong relationship. We want to acknowledge, however, that adrenocortical lesion heterogeneity might be impacted by the timing of imaging as well as the rapidity of injection of the intravenous contrast material. Six of 13 carcinomas also contained calcification, while only a single adenoma shared this imaging feature. Al- though this difference in the proportion of calcified carcino- mas vs. adenomas was not statistically significant, the lack of significance again may be a result of our relatively small sam- ple population and insufficient power, because a large magni- tude of effect was observed (OR=6.0; 95% CI, 0.57-63.7). It is noteworthy that intralesional calcifications were detected in numerous children despite the presence of intravenous con- trast material, highlighting the fact that non-contrast imaging is often unnecessary to detect calcification. Our results suggest that adrenocortical neoplasms that both heterogeneously en- hance and contain calcification are at substantially increased odds of being carcinoma as opposed to adenoma, and such lesions greater than 8.5 cm are almost certainly malignant.
The ability to discriminate adrenocortical adenomas from carcinomas prior to treatment could have benefits. First, al- though hormone-producing suspected adrenocortical masses in children are almost always removed, the surgical approach could be personalized to improve patient outcomes and de- crease morbidity and mortality. Current preference is to laparoscopically resect adenomas, while carcinomas require radical open resection to remove the tumor en bloc [14]. If a lesion could be shown to be benign, a laparoscopic approach would be much preferred because of its lower surgical mor- bidity, lesser cosmetic impact, more rapid postoperative re- covery with shorter hospitalization, and lower cost. Outcomes in children with carcinomas are strongly impacted by the
ability to achieve complete surgical resection of the tumor; thus open surgery is preferred in this setting [5, 14-16]. A recent study by Miller et al. [15] concluded that “open adre- nalectomy is superior to laparoscopic adrenalectomy for adre- nocortical carcinoma based on completeness of resection, site and timing of initial tumor recurrence, and survival in stage II patients.” Second, distinguishing adenomas from carcinomas could help direct chemotherapy if neoadjuvant treatment is considered prior to definitive surgery. A recent German non- randomized, single-arm study indicated that neoadjuvant che- motherapy may play a role in certain children with adrenocor- tical carcinomas, such as those that are unresectable at the time of diagnosis; however, in general, surgical resection of the tumor should be performed as soon as possible after diagnosis [17].
Almost half of our subjects with carcinomas presented with metastatic disease, most often to the liver and lung. These are the two most common sites of metastases described in the existing literature as well [1, 4]. Surprisingly, no relationship between size of the primary tumor and the presence of distant metastatic disease was identified. Although only three of 15 children with carcinoma demonstrated inferior vena cava in- vasion, all of these children experienced pulmonary metastatic disease as well as local retroperitoneal recurrences. In some instances, tumor thrombus extends into the heart [18].
Based on available follow-up data, the median survival of children with carcinoma was 27 months. At the time of pub- lication 8 of 15 children had died, while 4 were alive and 3 were lost to follow-up after varying lengths of follow-up. In the end, and based in part on prior studies, overall survival in children with adrenocortical neoplasms likely relates to a va- riety of factors, including patient age, histological features of the lesion, tumor biology/genetics, and tumor size (weight) [6, 19]. Remarkably, all adrenocortical lesions confirmed to be adenomas by histopathology behaved in a benign manner suggesting a correct diagnosis, despite the fact that distinguishing benign from malignant adrenocortical neo- plasms in the pediatric population has been historically diffi- cult [1, 2]. This suggests that the ability of pathologists to correctly discriminate adrenocortical adenomas from carcino- mas may have substantially improved in recent years based on better diagnostic criteria. All children with adenomas were alive at the time of this report based on available records.
Our study has limitations. First, we have a relatively small number of pediatric adrenocortical lesions (n=25), a fact that restricts the conclusions we can make from our data. Howev- er, our study is still one of the largest investigations documenting and comparing the imaging features of adeno- mas and carcinomas in children and adolescents given the rarity of these neoplasms. Second, many more children had undergone CT evaluation than MRI evaluation. Thus, we have insufficient data from which to draw conclusions regarding specific MRI findings that might discriminate adenomas from
carcinomas, such as apparent diffusion coefficient value or loss of signal on T1-weighted gradient recalled echo out-of- phase imaging. Third, we are unable to adequately assess tu- mor washout of contrast material based on multi-phase CT, a technique that is fundamental to characterizing adrenocortical masses (in particular, adenomas) in adults. Necessary imaging data for washout percentage calculation was available for only two children because pediatric CT examinations performed at our institution are most often a single portal venous phase in order to adhere to “Image Gently” and “as low as reasonably achievable” (ALARA) principles. Finally, in a small number of children (three) with carcinoma we have incomplete fol- low-up, although Social Security Administration data suggest that these children are still alive.
Conclusion
Pediatric adrenocortical carcinomas are larger and more het- erogeneous than adenomas and commonly contain calcifica- tion. Using the tumor diameter and estimated volume cut-off values mentioned above, CT and MRI discriminate carcino- mas from adenomas with a good degree of accuracy (areas under the curve=0.92 and 0.92, respectively); however very small carcinomas and very large adenomas occur, making complete discrimination of these two histological entities im- possible based on conventional imaging findings. Further re- search is needed to determine whether more advanced imag- ing techniques, such as dynamic contrast-enhanced, chemical- shift and diffusion-weighted MRI, can allow definitive dis- crimination of adenomas from carcinomas in children and adolescents.
Conflicts of interest None
References
1. Agrons GA, Lonergan GJ, Dickey GE et al (1999) Adrenocortical neoplasms in children: radiologic-pathologic correlation. Radiographics 19:989-1008
2. Wieneke JA, Thompson LD, Heffess CS (2003) Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 27: 867-881
3. Daneman A, Chan HS, Martin J (1983) Adrenal carcinoma and ad- enoma in children: a review of 17 patients. Pediatr Radiol 13:11-18
4. Ribeiro J, Ribeiro RC, Fletcher BD (2000) Imaging findings in pedi- atric adrenocortical carcinoma. Pediatr Radiol 30:45-51
5. Hubertus J, Boxberger N, Redlich A et al (2012) Surgical aspects in the treatment of adrenocortical carcinomas in children: data of the GPOH-MET 97 trial. Klin Padiatr 224:143-147
6. Michalkiewicz E, Sandrini R, Figueiredo B et al (2004) Clinical and outcome characteristics of children with adrenocortical tumors: a
report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 22:838-845
7. Neblett WW, Frexes-Steed M, Scott HW Jr (1987) Experience with adrenocortical neoplasms in childhood. Am Surg 53:117-125
8. Hanna AM, Pham TH, Askegard-Giesmann JR et al (2008) Outcome of adrenocortical tumors in children. J Pediatr Surg 43:843-849
9. Hanson JA, Weber A, Reznek RH et al (1996) Magnetic resonance imaging of adrenocortical adenomas in childhood: correlation with computed tomography and ultrasound. Pediatr Radiol 26:794-799
10. Israel GM, Korobkin M, Wang C et al (2004) Comparison of unenhanced CT and chemical shift MRI in evaluating lipid-rich ad- renal adenomas. AJR Am J Roentgenol 83:215-219
11. Caoili EM, Korobkin M, Francis IR et al (2002) Adrenal masses: characterization with combined unenhanced and delayed enhanced CT. Radiology 222:629-633
12. Korobkin M, Brodeur FJ, Francis IR et al (1998) CT time-attenuation washout curves of adrenal adenomas and nonadenomas. AJR Am J Roentgenol 170:747-752
13. Sarwar ZU, Ward VL, Mooney DP et al (2004) Congenital adreno- cortical adenoma: case report and review of literature. Pediatr Radiol 34:991-994
14. Miller BS, Doherty GM (2014) Surgical management of adrenocor- tical tumours. Nat Rev Endocrinol 10:282-292
15. Miller BS, Gauger PG, Hammer GD et al (2012) Resection of adre- nocortical carcinoma is less complete and local recurrence occurs sooner and more often after laparoscopic adrenalectomy than after open adrenalectomy. Surgery 152:1150-1157
16. Else T, Williams AR, Sabolch A et al (2014) Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab 99:455-461
17. Redlich A, Boxberger N, Strugala D et al (2012) Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial. Klin Padiatr 224:366-371
18. Godine LB, Berdon WE, Brasch RC et al (1990) Adrenocortical carcinoma with extension into inferior vena cava and right atrium: report of 3 cases in children. Pediatr Radiol 20:166-168, discussion 169
19. Bugg MF, Ribeiro RC, Roberson PK et al (1994) Correlation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia. A study of a Brazilian population. Brazilian Group for Treatment of Childhood Adrenocortical Tumors. Am J Clin Pathol 101:625-629