FALTH & HUMAN SERVICES - USA \\MENT OF HEALTH
HHS Public Access Author manuscript Pediatr Blood Cancer. Author manuscript; available in PMC 2024 June 01.
Published in final edited form as: Pediatr Blood Cancer. 2023 June ; 70(Suppl 4): e29973. doi:10.1002/pbc.29973.
Imaging of Pediatric Adrenal Tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper
Mitchell A. Rees, MD1, Cara E. Morin, MD2, Gerald G. Behr, MD3, J. Christopher Davis, MD4, Hollie Lai, MD5, Ajaykumar C. Morani, MD6, Marguerite T. Parisi, MD, MS7, Gaurav Saigal, MD8, Sudha Singh, MB BS, MD9, Sireesha Yedururi, MD6, Alexander J. Towbin, MD2, Barry L. Shulkin, MD10
1.Department of Radiology, Nationwide Children’s Hospital, Columbus, OH
2.Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
3.Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
4.Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA
5.Department of Radiology, Children’s Health of Orange County, Orange, CA
6.Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX
7.Departments of Radiology and Pediatrics, University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, WA
8.Department of Radiology, University of Miami Miller School of Medicine, Miami, FL
9.Department of Radiology, Vanderbilt University Medical Center, Nashville, TN
10.Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN
Abstract
Adrenal tumors other than neuroblastoma are uncommon in children. The most frequently encountered are adrenocortical carcinoma and pheochromocytoma. This paper offers consensus recommendations for imaging of pediatric patients with a known or suspected primary adrenal malignancy other than neuroblastoma at diagnosis and during follow-up.
Keywords
Oncology; pediatric; adrenal; imaging
Dr. Towbin reports the following conflicts of interest - Grant: Cystic Fibrosis Foundation; Consultant: Applied Radiology; Paid travel: KLAS; Author Royalties: Elsevier.
Drs. Rees, Morin, Behr, Davis, Lai, Morani, Parisi, Saigal, Singh, Yedururi, and Shulkin report no conflict of interest.
Introduction
Adrenal neoplasms are classified by the tissue of origin, either the adrenal cortex or the medulla. Tumors arising from the cortex consist of three main histologic types: benign adrenal adenoma, malignant adrenocortical carcinoma, and lesions of uncertain malignant potential. Together, these are referred to as adrenocortical tumors. The most common adrenal medullary tumors are neuroblastoma and pheochromocytoma. Neuroblastoma is by far the most common adrenal tumor in childhood and is covered in a separate article of this journal edition.
The other adrenal tumors are rare in children. Adrenocortical tumors have an estimated annual incidence of one to three per million1,2. In contrast to adults, where adrenal adenoma predominates, a focal adrenocortical tumor in a child is more likely to be malignant1,3-5. Nevertheless, only 25-30 adrenocortical carcinomas are diagnosed each year in children in the United States5. Pediatric pheochromocytoma has a similar incidence of less than two per million, and most are benign6.
Both adrenocortical tumors and pheochromocytoma have an association with underlying genetic syndromes. Li-Fraumeni, Beckwith-Wiedemann, Carney complex, familial adenomatous polyposis coli, and multiple endocrine neoplasia type 1 increase the risk of a patient developing adrenocortical tumors2,4. Syndromes predisposing to pheochromocytoma include multiple endocrine neoplasia types 2A and 2B, Von Hippel- Lindau, neurofibromatosis type 1, and hereditary pheochromocytoma/paraganglioma6,7. Screening imaging of patients with a cancer predisposition syndrome is detailed in a separate article of this journal edition.
Although some children with an adrenocortical tumor present with nonspecific abdominal pain, a palpable mass, or an incidentally discovered lesion, the majority, over 85%, present with a functional tumor and symptoms of excess hormone production5. This typically manifests as androgen-driven virilization, sometimes combined with Cushing syndrome or hyperaldosteronism resulting in hypertension5. The presence of hormonal symptoms does not distinguish adrenal adenoma from adrenocortical carcinoma, as both tend to be hormonally active in children5. Pheochromocytoma, on the other hand, has a more variable presentation. The hallmark is catecholamine excess, but this is often intermittent and can be difficult to diagnose6. Hypertension is common, as are diaphoresis, headaches, palpitations, and a range of more nonspecific symptoms6. Laboratory assessment includes measurement of plasma free metanephrines and 24-hr urine fractionated metanephrines.
Imaging Modalities
Multiple factors will influence the choice of imaging modality for initial evaluation of an adrenal tumor, including patient characteristics, the expertise of the radiology group, and the resources available at a particular facility. Table 1 lists advantages and disadvantages of different imaging modalities. Recommended MRI, CT, and nuclear medicine protocols are included in Table 2, Table 3, and Table 4.
Imaging at Diagnosis
Ultrasound (US) is an appropriate initial imaging modality in a child with symptoms, physical exam findings, or laboratory results suspicious for an adrenal mass (GRADE D, SOR 1.33, very strong recommendation). US can confirm or exclude an adrenal lesion and may be diagnostic for a simple adrenal cyst or a benign lesion such as adrenal hemorrhage. US, whether conventional or contrast-enhanced, should not be used to stage adrenal tumors8. US with Doppler can be useful in the evaluation of vascular invasion or other vascular complications in the abdomen. Patients with an underlying cancer predisposition such as Li-Fraumeni may undergo screening ultrasound or whole body screening MRI9. For patients with suspected pheochromocytoma and normal abdominopelvic imaging, additional chest or neck imaging (or the functional imaging described later in this section) may be needed to screen for an extra-adrenal paraganglioma6.
MRI, due to its superior soft tissue contrast resolution and lack of ionizing radiation, is the preferred initial imaging modality for a patient with a known adrenal mass (GRADE C, SOR 1.25, very strong recommendation). This must be balanced with the need for sedation in young children as well as institutional resources and expertise3,4,10 Intravenous contrast material is beneficial for characterization of the tumor and to search for vascular involvement, and it should be used when not contraindicated (GRADE A, SOR 1.17, very strong recommendation). Fat sensitive imaging is recommended. Although microscopic fat, as shown on MRI with in-phase/opposed-phase or Dixon method MR imaging, has not been shown to reliably distinguish benign and malignant adrenocortical tumor in a child, a large amount of macroscopic fat could point to a benign myelolipoma in an adolescent1,10.
CT with intravenous contrast is an appropriate alternative imaging modality when MRI is contraindicated or not feasible (GRADE D, SOR 1.08, very strong recommendation). Oral contrast is not needed. Multiphasic CT (an unenhanced acquisition followed by one or more contrast-enhanced phases) increases radiation dose and should not routinely be performed in a child with an adrenal lesion (GRADE B, SOR 1.25, very strong recommendation)10. While multiphasic CT is used in adults to distinguish benign adrenal adenoma from more concerning adrenal tumors by assessing lipid content and dynamic washout of contrast material, these criteria have not been validated in children. Other imaging features such as tumor size and heterogeneity, and to a lesser extent calcifications and vascular invasion, have been shown in small series to be more useful in children1,10. Nonionic CT contrast material is considered safe for pheochromocytoma imaging, and routine adrenergic blockade, as performed in the past, is not needed3.
Whether the abdomen is imaged with MRI or CT, a chest CT is needed at diagnosis to assess for pulmonary metastasis (GRADE A, SOR 1.25, very strong recommendation). Some centers may elect to perform CT chest, abdomen and pelvis at one time in order to perform all initial imaging under a single anesthesia event. If MRI abdomen and CT chest are performed during one anesthesia event, the chest CT must be performed first, as dependent atelectasis is common in children under anesthesia and may obscure pulmonary metastases.
Functional imaging plays an increasing role in the diagnosis and staging of pheochromocytoma/paraganglioma. 123I-mIBG (Iodine-123 meta-iodobenzylguanidine) has high sensitivity and specificity for pheochromocytoma/paraganglioma and can be used to assess for distant metastases6. Positron emission tomography (PET) with 18FDG (18fluorodeoxyglucose) is very sensitive but less specific than mIBG; it can be very useful in non-mIBG avid disease. Somatostatin receptor imaging with Octreoscan (Indium-111 pentetreotide) has largely been replaced by PET/CT with 68Ga-DOTATATE (Gallium-68 dodecanetetraacetic acid/tyrosine-3-octreotate) or 64Cu-DOTATATE, which are both very sensitive and specific for the somatostatin receptors found on neuroendocrine tumors such as pheochromocytoma/paraganglioma. Other PET agents such as 18F-DOPA (18fluorodihydroxyphenylalanine) do not yet have a routine role in the evaluation of these patients. When available, 68Ga-DOTATATE has become the functional imaging study of choice for these tumors (GRADE B, SOR 1.83, strong recommendation)6,10. Availability and degree of expertise in each modality will vary by site. This should be considered in the development of site-specific diagnosis, staging, and surveillance protocols.
Imaging in Tumor Staging
No imaging-specific staging system has been developed for either adrenocortical tumors or pheochromocytoma, but tumor size, lymph node status and the presence of distant metastases are incorporated into clinical staging systems (GRADE B, SOR 1.58, strong recommendation)2,11. The liver, lymph nodes, bones, and lungs should be scrutinized for evidence of metastatic disease3,5.
Imaging at Follow-up
Advanced imaging is needed in follow-up of malignant adrenal tumors. Specific pediatric guidelines for imaging frequency during the treatment phase are not yet available. Guidelines from the National Comprehensive Cancer Network (NCCN), which are not age-specific, leave some discretion to the clinician, recommending imaging of patients with adrenocortical carcinoma every 12 weeks to 12 months for up to 5 years after initial treatment12. Regular measurement of laboratory biomarkers is recommended for functional tumors, and PET/CT is suggested for metastatic disease13. For patients with pheochromocytoma, the NCCN recommends follow-up that is primarily clinical and extends over a longer period of time, including blood pressure assessment and collection of relevant laboratory biomarkers every 12 weeks to 12 months for up to 10 years, with consideration of imaging (MRI/CT abdomen and pelvis with intravenous contrast and CT chest)13. For patients with locally unresectable or metastatic disease, PET (18F-FDG, 68Ga-DOTATATE) or neuroendocrine imaging (123I-mIBG) are suggested13.
As with initial diagnosis, MRI is preferred in most situations for morphologic assessment, and imaging parameters are unchanged from initial imaging. In the absence of known residual disease, some centers may opt for MRI without intravenous contrast, relying on unenhanced images and diffusion-weighted imaging for the detection of recurrent disease (GRADE D, SOR 2.5, moderate recommendation).
CT abdomen and pelvis is an acceptable alternative to MRI. It has the benefit of often not requiring sedation, but MRI is preferred due to the cumulative radiation dose of repeated CT imaging.
CT chest is needed until resolution of any pulmonary metastases identified on initial imaging.
Functional imaging also is useful for follow-up imaging. This primarily applies to pheochromocytoma/paraganglioma, but 18FDG PET could be used in follow-up of adrenocortical carcinoma.
Tumor Response
No specific imaging criteria have been established for follow-up (GRADE D, SOR 1.83, strong recommendation). A radiologist may wish to apply the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 when evaluating treatment response of adrenal tumors8.
Surveillance Imaging Off-Therapy
As with follow-up imaging during the treatment phase, specific pediatric guidelines are not yet available for imaging during the surveillance phase. For adrenocortical tumors, recommendations are not defined beyond 5 years. For pheochromocytoma, follow-up after 10 years is based on clinical indications, with some authors recommending lifelong follow- up13,14. Individuals with hereditary paraganglioma/pheochromocytoma may require more frequent and longer follow-up13.
The recommended imaging modalities are the same in the surveillance phase as for follow- up during the treatment phase. The goals of imaging are to assess for residual or recurrent tumor at the primary site and to assess for regional or distant metastasis. Whole body MRI can be a useful tool for follow-up of children with pheochromocytoma/paraganglioma15.
Future Direction
Multiple positron emitting tracers analogous to the single photon emitting tracer 123I-mIBG have been developed to characterize pheochromocytomas and neuroblastomas. Use of 68Ga-DOTATATE is likely to become more widespread. 18F-DOPA may become FDA approved and available. Another agent that may become available for clinical use is 18F- metaflouro benzylguanidine (mFBG). This compound has the potential to replace mIBG for clinical purposes as the injection to imaging interval is only about an hour, PET imaging quality is superior to single photon emission computed tomography (SPECT), PET imaging is inherently quantitative and tomographic, and iodine blockade of the thyroid is not necessary16. Radiomic information from both PET and SPECT may also provide further options to assess response17. Use of theranostic agents such as 131I-mIBG and 177 Lutetium is likely to increase.
Acknowledgments
This work was funded in part by the National Clinical Trials Network Operations Center Grant U10CA180886.
Abbreviations
| US | Ultrasound |
| mIBG | Meta-iodobenzylguanidine |
| PET | Positron emission tomography |
| FDG | Fluorodeoxyglucose |
| DOTATATE | Dodecanetetraacetic acid/tyrosine-3-octreotate |
| DOPA | Dihydroxyphenylalanine |
| NCCN | National Comprehensive Cancer Network |
| RECIST | Response Evaluation Criteria in Solid Tumors |
| mFBG | Metaflouro benzylguanidine |
| SPECT | single photon emission computed tomography |
References
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| Procedure Name | Timepoint(s) | Advantage(s) | Disadvantage(s) | |
|---|---|---|---|---|
| Ultrasound | Diagnosis | · | Evaluate intralesional vascularity | · Not specific for tumor types · Deep lesions (> 10cm) not well assessed |
| · Assess relationship with adjacent vessels and vessel patency, especially the inferior | ||||
| vena cava | · Cannot be used to stage or assess response | |||
| Magnetic Resonance Imaging | Diagnosis Staging Follow-up | Excellent lesion detection and • characterization | · Longer exam time · Motion sensitive · Frequent need for sedation | |
| Computed Tomography | Diagnosis Staging Follow-up | · Rapid acquisition · Sedation usually not needed · Better evaluation of small vessels than MRI · Simultaneous imaging of chest and abdomen | · May be less sensitive for small tumor deposits and bone marrow involvement | |
| FDG PET | Staging Follow-up | · Detect distant metastatic disease and follow-up response to therapy · DOTATATE offers very high sensitivity and specificity for somatostatin receptors in pheochromocytoma | · Availability · Cost | |
| mIBG | Staging Follow-up | · Sensitive and specific for pheochromocytoma · Wide availability | Decreased spatial resolution • versus PET · 2 day protocol | |
FDG = fluorodeoxyglucose. PET = positron emission tomography. mIBG = meta-iodobenzylguanidine.
| MRI abdomen and pelvis without and with intravenous contrast | ||||
|---|---|---|---|---|
| Coronal | T2 SSFSE | Non-contrast | Coverage from diaphragm to pubic symphysis for all sequences unless otherwise specified | FS optional • |
| Axial | T2 SSFSE without FS | Non-contrast | · Recommend scanning without FS to identify macroscopic fat on subsequent FS images | |
| Sag | T2 SSFSE with FS | Non-contrast | · With FS to aid evaluation of the spine and bone marrow | |
| Axial | T2 turbo/flash spin-echo with FS | Non-contrast | · Either with breath hold or respiratory gating/motion correction | |
| Axial | Diffusion weighted imaging | Non-contrast (can be post-contrast) | · Aids identification of small tumor deposits and lymph nodes · Assessment of primary tumor | |
| Axial | T1 Dixon or in phase/ opposed phase imaging | Non-contrast | Identification of fat content • | |
| Axial | T1 FS 3D GRE | Post-contrast; arterial phase | Cover abdomen only, diaphragm to iliac crest | |
| Axial | T1 FS 3D GRE | Post-contrast; portal venous phase | ||
| Cor | T1 FS 3D GRE | Post-contrast | ||
SSFSE = single shot fast spin echo. FS = fat saturation. 3D = three dimensional. GRE = gradient recall echo.
| CT Abdomen and Pelvis | Diaphragm to pubic symphysis | 1.5-3 mm | Portal venous phase | Coronal and sagittal multi- planar reformats Consider 3D reconstructions of vascular structures and tumor | · Dual phase (arterial and portal venous) may be requested for surgical planning · Dual energy technique helps with tissue characterization where available · Pelvis coverage may be omitted for tumor isolated to abdomen |
|---|---|---|---|---|---|
| CT Chest | Thoracic inlet to upper abdomen | 1.5-3 mm | Venous | Axial MIP reformat useful for locating pulmonary nodules | · Intravenous contrast optional for pulmonary nodules but useful for mediastinal evaluation |
3D = three dimensional. MIP = maximum intensity projection.
TABLE 4
Recommended nuclear medicine protocols
| Patient Prep | Radiophar maceutical | Dose Range | Time from dose to imaging | Image acquisition | Comment |
|---|---|---|---|---|---|
| DOTATATE PET | |||||
| No preparation | 68Ga- DOTATATE | 0.054 mCi/ kg(max 5.4 mCi) | 60 minute uptake phase | Whole body(vertex to toes) | Neuroendocrine tumors: *short acting somatostatin analogs can be used up to 24 hours prior to injection *if on long-acting selective somatostatin antagonist, scan should be performed just prior to next dose |
| 64Cu- DOTATATE | 4mCi for adults | 45-90 min | 64Cu-DOTATATE not currently FDA-approved for pediatric indications | ||
| FDG PET | |||||
| Nothing by mouth 4-6 hours before imaging (non-caloric liquids generally allowed if not being sedated) No glucose in intravenous fluid 4-6 hours prior to injection. Blood glucose < 150 -200 mg/dL Brown fat warming protocol +/- medication per local practice | 18F-FDG | 1.1 mCi/kg (min 1 mCi, max 10 mCi) | 60 minute uptake phase | Whole body (vertex to toes) | |
| mIBG | |||||
| Pretreatment with saturated solution of potassium iodide or potassium iodate tablets for thyroid blockade (dosing varies by local practice) Cessation of interfering medications, particularly pseudoephedrine, phenyleprine, labetolol and others. Do not resume interfering medications before scans are acquired. | 123 I-mIBG | 0.14 mCi/kg (Minimum dose 1.5 mCi Maximum dose 10mCi) | 18-24 hours; can perform 48-hour imaging if needed | Whole body anterior and posterior whole- body views; selected spot views; SPECT CT highly recommended. | |
DOTATATE = dodecanetetraacetic acid/tyrosine-3-octreotate. PET = positron emission tomography. FDA = Food and Drug Administration. FDG = fluorodeoxyglucose. mIBG = meta-iodobenzylguanidine. SPECT = single photon emitting computed tomography.