(Radiographics. 2002;22:911-934.)
© RSNA, 2002
From the Archives of the AFIP
Neuroblastoma, Ganglioneuroblastoma, and Ganglioneuroma: Radiologic-Pathologic Correlation1
Gael J. Lonergan, Lt Col, USAF, MC,
Cornelia M. Schwab, MD,
Eric S. Suarez, CDR, MC, USN and
Christian L. Carlson, 2LT, MC, USA
1 From the Departments of Radiologic Pathology (G.J.L., C.M.S.) and Pediatric Pathology (E.S.S.), Armed Forces Institute of Pathology, 14th and Alaska Sts, NW, Bldg 54, Rm M-121, Washington, DC 20306-6000 and the Department of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md (G.J.L., C.C.). Received February 1, 2002; revision requested March 11 and received March 22; accepted March 22. Address correspondence to G.J.L. (e-mail: lonergan@afip.osd.mil).
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Abstract
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Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma are tumors of the sympathetic nervous system that arise from primitive sympathogonia and are referred to collectively as neuroblastic tumors. They arise wherever sympathetic tissue exists and may be seen in the neck, posterior mediastinum, adrenal gland, retroperitoneum, and pelvis. The three tumors differ in their degree of cellular and extracellular maturation; immature tumors tend to be aggressive and occur in younger patients (median age, just under 2 years), whereas mature tumors occur in older children (median age, approximately 7 years) and tend to behave in a benign fashion. The most benign tumor is the ganglioneuroma, which is composed of gangliocytes and mature stroma. Ganglioneuroblastoma is composed of both mature gangliocytes and immature neuroblasts and has intermediate malignant potential. Neuroblastoma is the most immature, undifferentiated, and malignant tumor of the three. Neuroblastoma, however, may have a relatively benign course, even when metastatic. Thus, these neuroblastic tumors vary widely in their biologic behavior. Features such as DNA content, tumor proto-oncogenes, and catecholamine synthesis influence prognosis, and their presence or absence aids in categorizing patients as high, intermediate, or low risk. Treatment consists of surgery and, usually, chemotherapy. Despite recent advances in treatment, including bone marrow transplantation, neuroblastoma remains a relatively lethal tumor, accounting for 10% of pediatric cancers but 15% of cancer deaths in children.
© RSNA, 2002
Index Terms: Nervous system, neoplasms, 6.3162, 6.3251, 8.3199, 8.325 • Neuroblastoma, 6.3251, 8.325 • Neuroma, 6.3162, 8.3199, 8.325
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LEARNING OBJECTIVES FOR TEST 6
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After reading this article and taking the test, the reader will be able to:
- Describe the histologic spectrum of neuroblastic tumors.
- Describe the imaging features of neuroblastoma, ganglioneuroblastoma, and ganglioneuroma.
- Define the biologic behavior of neuroblastic tumors and the impact of these features on prognosis and treatment.
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Introduction
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Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma are tumors of varying maturity derived from the primordial neural crest cells that form the sympathetic nervous system. These precursor cells may remain undifferentiated (referred to as neuroblasts) or they may mature (to ganglion and Schwann cells) (1,2). A tumor composed primarily of neuroblasts is referred to as neuroblastoma (NB), a tumor composed entirely of mature ganglion cells and other mature tissue is a ganglioneuroma (GN), and a tumor with both immature and mature cell types is a ganglioneuroblastoma (GNB) (1,2). As a group, these tumors define a spectrum of sympathetic neuroectodermal tumors, ranging from the undifferentiated NB to the mature GN. The presence of immature tissue in NB and GNB indicates malignant or potentially malignant behavior; GN is considered benign. This article discusses these neuroblastic tumors, including their clinical presentation, histologic characteristics, biologic behavior, radiologic appearance, staging, and prognosis.
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Neuroblastoma and Ganglioneuroblastoma
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Virchow originally described NB in 1863; early reports described the tumor as a glioma of the adrenal gland. By the beginning of the 20th century, its origin in sympathetic tissue was determined by Zückerkandl and Kohn (3). The surprising discovery that NB could mature to GN was made in 1927 (4).
Approximately 500–525 new cases of NB are diagnosed each year in the United States, making it the third most common pediatric malignancy, after leukemia and central nervous system tumors. The incidence of NB is 8.0 and 8.7 per million per year in the United States for whites and blacks under the age of 15 years, respectively (5,6). NB represents 8%–10% of all childhood cancer, but, because of its aggressive nature, it accounts for close to 15% of childhood cancer fatalities. The median age at diagnosis is 22 months, and more than 95% of cases are diagnosed by 10 years of age (7). Although rare, there are documented cases of familial NB (8–10). NB may occur in newborns and may even be seen at prenatal sonography (11,12). In rare cases, NB, GNB, and GN may occur in patients with other disorders, including von Recklinghausen disease, Beckwith-Wiedemann syndrome, Hirschsprung disease, central failure of ventilation, and DiGeorge syndrome (13–18). Malignant peripheral nerve sheath tumors and pheochromocytoma have been described in neuroblastic tumors, making them composite tumors (19–22).
Because neuroblastic tumors derive from primordial neural crest cells destined for sympathetic differentiation, they may arise anywhere sympathetic tissue naturally occurs (Fig 1). The most common sites of origin of NB and GNB, in order, are the adrenal medulla (35% of cases), extraadrenal retroperitoneum (30%–35%), and posterior mediastinum (20%). Less common sites are the neck (1%–5% of cases) and pelvis (2%–3%) (23). Approximately 1% of patients present with metastatic disease but no discoverable primary tumor. Unusual locations such as the thymus, lung, kidney, anterior mediastinum, stomach, and cauda equina have also been described (24–29).
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Figure 1. Anatomic distribution of sympathetic ganglia. Diagram illustrates the sympathetic ganglia extending from the neck to the pelvis, including the adrenal medulla (sympathetic tissue shown in blue).
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NB and GNB are grouped together for the purposes of cancer reporting, staging, and survival statistics because both share malignant potential, although clearly this potential is higher for NB than for GNB. They are separated at the time of original diagnosis into favorable and unfavorable types, on the basis of histologic characteristics, genetic information, and other biologic behavior factors. Accurate diagnosis, staging, and prognosis depends on histologic, electron microscopic, immunocytochemical, cytogenetic, and other molecular and biologic information (30).
Clinical Presentation
Patients with NB and GNB most often present with pain, caused by either local effects from the primary tumor or metastatic disease. Abdominal distention is the next most frequent complaint. Other presenting symptoms include malaise, irritability, weight loss, shortness of breath (from a large abdominal tumor), and peripheral neurologic deficit (from neural foraminal invasion and nerve compression by tumor) (31). Less common presentations include Horner syndrome (ptosis, pupillary constriction, and ipsilateral facial anhidrosis and flushing from a mediastinal tumor) and opsoclonus-myoclonus. Opsoclonus-myoclonus is jerking movements of the extremities and eyes, sometimes with cerebellar ataxia; the cause is unknown but it is seen in 2% of patients and is associated with a thoracic primary tumor and a better prognosis (31,32). Up to two-thirds of patients have metastatic bone disease at presentation; when this manifests as limping and irritability, it is known as Hutchinson syndrome (31).
Histologic Characteristics
Each tumor has primary and secondary histologic features. Primary features include neuroblasts and their derivatives (ganglion cells and Schwann cells) and stroma. Neuroblasts are immature, undifferentiated sympathetic cells. They are small, are rounded in contour, show little cytoplasm, and possess darker nuclei and smaller indistinct nucleoli (Fig 2). Ganglion cells are fully mature cells with abundant cytoplasm, rounded contour, and large nuclei with distinct and prominent nucleoli. Stroma is the tissue surrounding the neuroblasts or ganglion cells. It may consist of Schwann cells, fibrovascular septa, or both (Fig 3). Neuropil is the fine pattern of cellular (neuritic) processes extending from neuroblasts; it appears extracellular but is in fact a cellular extension (2,33). One characteristic feature of NB is the formation of Homer Wright rosettes (Fig 4). Rosettes are circular or ovoid columns of tumor cells arranged around a central core of neuropil. Homer Wright rosettes are typical of NB, but they are not always present (34). Secondary histologic features are necrosis, mitosis, hemorrhage, fibrosis, calcification, lymphocytic infiltrate, and karyorrhexis. Karyorrhexis is defined as the fragmentation of a nucleus into scattered pieces within the cytoplasm; it is an event that occurs during cell death. Karyorrhexis may be difficult to distinguish from mitosis in neuroblasts (2,35).
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Figure 2. Immature neuroblastic tissue. High-power photomicrograph (original magnification, x300; hematoxylin-eosin stain) of NB demonstrates neuroblasts, which are the dark purple cells with scant cytoplasm (arrowhead), and neuropil, which is the fine, fibrillary light pink-staining material (arrows).
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Figure 3. Mature ganglion tissue and Schwannian stroma. Medium-power photomicrograph (original magnification, x140; hematoxylin-eosin stain) shows mature ganglion cells with abundant cytoplasm (straight arrow) and thin, wavy Schwann cells (curved arrow) in a GN.
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Figure 4. Homer Wright rosettes in NB. Medium-power photomicrograph (original magnification, x100; hematoxylin-eosin stain) shows a circular arrangement of neuroblasts around neuropil, forming rosettes (arrows).
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Two histologic classification systems are commonly used in the United States to stratify neuroblastic tumors into risk groups: the Shimada classification and the Pediatric Oncology Group (POG) classification. Both systems assess histologic features, such as cellular differentiation, to arrive at a prognostic classification (however, these are not staging systems). The POG system is based solely on the degree of differentiation of the different histologic elements. GN shows completely (100%) differentiated stromal and cellular components, NB contains less than 50% differentiated elements, and GNB is intermediate (greater than 50% differentiated cells). NB may be further subclassified as undifferentiated (the most immature NB), poorly differentiated, or differentiating (the most mature NB). Differentiation of the neuroblastic cells indicates that they demonstrate some characteristics of mature cells (differentiating cells show nuclear enlargement, nucleoli, cytoplasmic eosinophilia and enlargement, distinct cytoplasmic border, and cell processes) (36).
The Shimada classification combines histologic features and patient age at diagnosis. The histologic features consist of stroma, grade and architecture of cellular differentiation, and nuclear morphology. Tumors are classified as stroma-rich or stroma-poor. The stroma-rich (more mature) category is characterized by extensive growth of Schwannian stroma; the stromapoor shows thin fibrovascular septa. The stroma-rich group is further subdivided into well differentiated (most mature) if composed of mature tissue, intermixed (least mature) if interrupted by randomly distributed clusters of neuroblastic cells, and nodular if showing one or a few sharply defined stroma-poor areas trapped in a mature stroma (2). Cellular characteristics are then assessed. Undifferentiated neoplasms are composed almost entirely of undifferentiated neuroblasts and less than 5% being differentiated cells (ie, neuroblasts showing differentiation into ganglion cells). Differentiating tumors show at least 5% differentiated cells. Mitosis and karyorrhexis of the tumor cells are then evaluated. Since it may be difficult to differentiate mitoses from karyorrhexis, cells with these features are counted in a sample of 5,000 cells and reported as an index (which is the total number of mitotic and karyorrhectic cells in the 5,000-cell sample). On the basis of the mitosis-karyorrhexis index (MKI), NB and GNB are subdivided into low (less than 100), intermediate (100–200), or high (over 200) MKI. High MKI correlates with unfavorable histologic characteristics and a worse prognosis (1,30). Finally, patient age is factored into the classification. The age groups of the Shimada classification system are less than 1.5 years, 1.5–5 years, and more than 5 years of age (2). On the basis of the combination of patient age, MKI, and cellular and stromal maturity and differentiation, patients are classified as having unfavorable histologic characteristics or favorable histologic characteristics (Table 1). Children with favorable histologic characteristics are either less than 1.5 years of age with a low or intermediate MKI and differentiating or partially differentiating tumor or 1.5–5 years old with a low MKI differentiating tumor. All other combinations are considered unfavorable histologic characteristics (1).
As an aside, it is interesting to note that microscopic neuroblastic nodules may frequently be found in infants less than 3 months of age dying of other unrelated causes. Since they are up to 40 times more common than NBs detected clinically, these nodules were initially regarded as NBs in situ that underwent spontaneous regression. Subsequent studies demonstrated that these nodules are a normal occurrence during fetal development, peaking during 17–20 weeks gestation, then regressing as part of normal fetal adrenal development. These studies suggest that such neuroblastic nodules are remnants of normal developing fetal adrenal tissue, not NB in situ (37–39).
Gross Pathologic Features
Neuroblastic tumors may be circumscribed or infiltrative, and most are less than 10 cm in greatest diameter. Those arising within the adrenal gland or posterior mediastinum are more likely to be circumscribed and give the appearance of having a capsule, although NB, GNB, and GN do not typically have capsules. The consistency of NB typically is soft, compared with that of the firmer GNB and GN. The cut surface of specimens may vary from tan to hemorrhagic; necrosis, hemorrhage, and calcification may be detected. The tan areas are usually composed of stroma. Hemorrhagic foci or nodules are often neuroblastic tissue (Fig 5) (33). The consistency and appearance of neuroblastic tumors vary considerably, and areas of tan stroma interposed between areas of hemorrhagic neuroblastic tissue are common. This latter feature may give the tumor a lobular appearance (40,41).
Staging
In 1986, an international consensus group devised the International Neuroblastoma Staging System (INSS), based on clinical, radiologic, and surgical features (Table 2). A few specific points regarding staging follow. Tumors that are grossly completely resected and have no nonadherent positive lymph nodes or metastases are stage 1, irrespective of whether they cross the midline. Tumors that invade one side of the neural canal are stage 2 (not stage 3). Tumors that extend across the midline to the contralateral aspect of the vertebral body are stage 3. Marrow involvement in stage 4S is defined as tumor cells representing less than 10% of all marrow cells in the biopsy specimen; when the marrow involvement is such that greater than 10% of all marrow cells are tumor cells, the NB is stage 4, irrespective of patient age. In the unusual case of bilateral tumors, the higher stage tumor takes precedence for patient staging (43).
Biologic Behavior
Neuroblastic tumors are remarkable for their varied tumoral biologic behavior. This variability is manifest in their genetic makeup and in the products they may elaborate (eg, catecholamines). Some of these features may be assessed as evidence of maturity; some are used to assist in staging and prognosis. One of the hallmarks of NB and GNB is their propensity to secrete catecholamines. Most often, the catecholamines secreted are vanillylmandelic acid (VMA) and homovanillic acid (HVA). The vast majority (90%–95%) of NB and GNB secrete catecholamines, although the tumors rarely cause symptoms of catecholamine excess. Generally, the better differentiated the tumor, the more mature the catecholamine. HVA is secreted as a metabolite of dopamine, and its level may be elevated in more mature NBs and GNBs. In comparison, VMA is a less mature metabolite of epinephrine and norepinephrine. Some centers assess a VMA-to-HVA ratio as an indicator of maturity. Ratios of less than 1 are considered favorable; ratios greater than 1 suggest an immature tumor and therefore a worse prognosis (44,45). Vasoactive intestinal peptide (VIP) may also be secreted by the tumor and may result in watery diarrhea, hypokalemia, and acidosis. It is believed that VIP is elaborated by ganglion cells within the tumor; not surprisingly, VIP-producing tumors tend to be more mature and have a better prognosis (46).
Some genetic features of NB and GNB correlate with biologic behavior. The best known is Myc-N, a proto-oncogene located on the distal end of chromosome arm 2p. When present in multiple copies (especially 10 or more), known as Myc-N amplification, it portends rapid tumor progression and a poor outcome for all patients except those less than 1 year of age and those with unfavorable histologic features according to the Shimada classification (47–49). Thirty percent of all NBs display Myc-N amplification; less than 10% of stages 1 and 2 NBs show Myc-N amplification (50). Recent studies suggest that amplification alone is not the significant feature of the Myc-N oncogene. Rather, expression of the Myc-N protein has been found to correlate with prognosis and aggressive tumor behavior in children older than 1 year. Infants with increased Myc-N expression do not have a worse prognosis, however (51).
Another important genetic feature of NB and GNB is loss of heterozygosity or deletion of the short arm (p) of chromosome 1. It is theorized that there is a tumor suppressor gene on chromosome arm 1p that is deleted in NB (52). Loss of heterozygosity correlates with aggressive tumor behavior (53,54). Gain of chromosome arm 17q is also linked with advanced stage tumors, increased age at diagnosis, Myc-N amplification, and deletions of chromosome arm 1p (55).
Deoxyribonucleic acid (DNA) content of the NB cells is another important prognostic indicator. Cells with normal or near-normal DNA content (a DNA index of 1) are diploid or near-diploid cell lines. These cell lines are associated with aggressive tumor behavior and a worse prognosis. Tumor cells with increased DNA content (DNA index greater than 1, referred to as hyperdiploid) have a better prognosis and display less aggressive tumor behavior (56,57). Some research findings suggest that hyperdiploid NB tumor with normal chromosome arm 1p stimulates Schwannian proliferation within the tumor; this Schwannian proliferation is believed to promote tumoral maturation (58). Hyperdiploid NB with normal chromosome arm 1p are thought likely to mature spontaneously (58).
Other tumor features that influence prognosis include CD44, a glycoprotein on the surface of NB cells. Increased levels of CD44 correlate with better prognosis. Elevated serum levels of neuron-specific enolase (>100 ng/mL) and ferritin (>142 ng/mL) indicate a worse prognosis. Expression of TRK-A, a nerve growth factor, correlates with a favorable outcome (59).
By combining the Shimada classification, INSS stage, and some of the risk factors listed above, it is possible to stratify NB and GNB into low-, intermediate-, and high-risk groups. Treatment is based on risk group. Table 3 defines the risk groups and their features (42,60).
Radiologic Appearances
Because NB and GNB arise in a variety of locations, they have varied appearances and growth patterns. The radiologic appearance of these tumors is discussed by imaging modality, beginning with plain radiography. Radiographs may show a posterior retroperitoneal, mediastinal, or neck mass (Fig 6). Calcification is evident in at least 30% of NB at plain radiography (Fig 7) (61). Posterior mediastinal tumors may cause spreading or erosion of adjacent ribs, and both retroperitoneal and posterior mediastinal tumors maycause pedicle erosion from intraspinal extension (62). Metastatic disease may be radiographically manifested as hepatomegaly, lucent submetaphyseal zones (Fig 8), periostitis, and cranial sutural widening (from dural metastases). Skeletal metastases may also appear as focal lucent (occasionally sclerotic) areas (Fig 9) (61,63).
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Figure 6a. NB arising in the neck. (a) Lateral plain radiograph of the neck in a 12-month-old girl with stridor reveals a prevertebral soft-tissue mass (*), resulting in anterior displacement of the hypopharynx, larynx, and upper trachea. (b) Axial computed tomographic (CT) scan obtained after intravenous (IV) contrast material enhancement at the level of the tongue base reveals a mass in the right side of the neck, resulting in lateral displacement of the right carotid artery and jugular vein (arrow).
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Figure 6b. NB arising in the neck. (a) Lateral plain radiograph of the neck in a 12-month-old girl with stridor reveals a prevertebral soft-tissue mass (*), resulting in anterior displacement of the hypopharynx, larynx, and upper trachea. (b) Axial computed tomographic (CT) scan obtained after intravenous (IV) contrast material enhancement at the level of the tongue base reveals a mass in the right side of the neck, resulting in lateral displacement of the right carotid artery and jugular vein (arrow).
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Figure 7a. NB in a 2-year-old boy with a left upper quadrant mass. (a) Frontal radiograph of the abdomen reveals calcification in the left upper and mid abdomen (arrows). (b) Axial, oral and IV contrast-enhanced CT scan through the midabdomen shows a large, well-circumscribed mass in the left flank, with calcification, cystic change, and hemorrhage. One of the cystic areas contains a fluid-fluid level, indicating hemorrhage (arrow). (c) Photograph of the bisected gross specimen shows the calcification and hemorrhage.
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Figure 7b. NB in a 2-year-old boy with a left upper quadrant mass. (a) Frontal radiograph of the abdomen reveals calcification in the left upper and mid abdomen (arrows). (b) Axial, oral and IV contrast-enhanced CT scan through the midabdomen shows a large, well-circumscribed mass in the left flank, with calcification, cystic change, and hemorrhage. One of the cystic areas contains a fluid-fluid level, indicating hemorrhage (arrow). (c) Photograph of the bisected gross specimen shows the calcification and hemorrhage.
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Figure 7c. NB in a 2-year-old boy with a left upper quadrant mass. (a) Frontal radiograph of the abdomen reveals calcification in the left upper and mid abdomen (arrows). (b) Axial, oral and IV contrast-enhanced CT scan through the midabdomen shows a large, well-circumscribed mass in the left flank, with calcification, cystic change, and hemorrhage. One of the cystic areas contains a fluid-fluid level, indicating hemorrhage (arrow). (c) Photograph of the bisected gross specimen shows the calcification and hemorrhage.
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Figures 9. Bone metastases from NB. Frontal radiograph of a 2 -year-old boy who presented with right hip pain shows a lytic area in the femoral neck (arrowhead) and a patchy area of decreased mineralization in the intertrochanteric and subtrochanteric regions (arrows).
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At ultrasonography (US), NB and GNB are heterogeneously echogenic. There may be anechoic areas within the tumor corresponding to hemorrhage or necrosis (Fig 10). Calcification is common and appears as focal echogenic areas or diffuse increased echogenicity (from very fine calcifications); distal acoustic shadowing may or may not be present (61,64). US may help delineate the tumor from adjacent organs such as the kidney, although the tumor may occasionally invade the kidney, making determination of organ of origin difficult. US may also aid in evaluation of other organs such as the liver for evidence of metastases, although this is better accomplished with CT or magnetic resonance (MR) imaging. Doppler US may be used to evaluate flow in encased vessels (63).
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Figure 10a. NB in a 2-year-old girl with an abdominal mass and hypertension. (a) Longitudinal US scan of the left flank reveals a large, heterogeneous mass with multiple anechoic areas, representing hemorrhage or cystic change (arrows). (b) Axial oral and IV contrast-enhanced CT scan through the midabdomen reveals a large left flank mass, with some rounded areas of low attenuation. (c) Photograph of the bisected gross specimen shows a hemorrhagic mass with fluid-filled cavities, which at further inspection proved to be a combination of hemorrhage and cystic change.
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Figure 10b. NB in a 2-year-old girl with an abdominal mass and hypertension. (a) Longitudinal US scan of the left flank reveals a large, heterogeneous mass with multiple anechoic areas, representing hemorrhage or cystic change (arrows). (b) Axial oral and IV contrast-enhanced CT scan through the midabdomen reveals a large left flank mass, with some rounded areas of low attenuation. (c) Photograph of the bisected gross specimen shows a hemorrhagic mass with fluid-filled cavities, which at further inspection proved to be a combination of hemorrhage and cystic change.
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Figure 10c. NB in a 2-year-old girl with an abdominal mass and hypertension. (a) Longitudinal US scan of the left flank reveals a large, heterogeneous mass with multiple anechoic areas, representing hemorrhage or cystic change (arrows). (b) Axial oral and IV contrast-enhanced CT scan through the midabdomen reveals a large left flank mass, with some rounded areas of low attenuation. (c) Photograph of the bisected gross specimen shows a hemorrhagic mass with fluid-filled cavities, which at further inspection proved to be a combination of hemorrhage and cystic change.
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CT is the most commonly used imaging modality for assessment of neuroblastic tumors, because it reveals extent of tumor, organ of origin, regional invasion, vascular encasement, adenopathy, and calcification. CT of the chest, abdomen, and pelvis is standard for all newly diagnosed cases. Abdominal and pelvic tumors are usually large and heterogeneous (Fig 11), although small tumors may be homogeneous. Approximately 80%–90% of NBs demonstrate calcification on CT scans (61,63). Low-attenuation areas of necrosis or hemorrhage are frequently noted at CT and may measure up to 4 cm in diameter (61,63, 65). Vascular encasement and compression of the renal vessels, splenic vein, inferior vena cava, aorta, celiac artery, and superior mesenteric artery may occur (Fig 12), although vascular invasion is rare. Renal vessels may be sufficiently compressed to result in hypertension (66). Regional invasion of psoas and paraspinal musculature may occur, and invasion of the neural foramen into the epidural space is also frequent; these are better evaluated at MR imaging, as is regional organ invasion. Adenopathy of the renal hilum, porta hepatis, and retroperitoneum may be seen. Metastatic disease of the liver and lung are readily evaluated with CT. Liver metastases may take two forms: diffuse infiltration (seen in infants with stage 4S disease and sometimes missed at CT because it may uniformly increase the parenchymal attenuation) and focal hypoenhancing masses (Fig 13) (63). Lung metastases may appear as discreet nodules or confluent areas of parenchymal consolidation (67). Pleural disease is infrequent. Brain metastases are distinctly unusual but do occur; they may have a variety of appearances including hemorrhagic, solid, and rim-enhancing cystic lesions (Fig 14), all of which are demonstrated by both CT and MR imaging (68–70). A more common intracranial metastatic pattern is dural disease, which may appear as enhancing meninges and meningeal cakes and masses (Fig 15); these may cause regional mass effect on underlying brain tissue and may extend into sutures, resulting in sutural widening (Fig 16) (71). An unusual appearance exists for metastatic disease to the sphenoid bone with intraorbital extension; in these cases, a red-bluish discoloration in the orbits is seen and may be mistaken for child abuse (63).
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Figure 11a. GNB in an 8-year-old boy with a 2-year history of increasing constipation. (a) On an abdominal radiograph obtained after oral and IV contrast enhancement, the bladder is elevated because of a pelvic mass. (b) Axial unenhanced CT scan shows the heterogeneous pelvic mass (*) and the anteriorly displaced bladder (arrow).
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Figure 11b. GNB in an 8-year-old boy with a 2-year history of increasing constipation. (a) On an abdominal radiograph obtained after oral and IV contrast enhancement, the bladder is elevated because of a pelvic mass. (b) Axial unenhanced CT scan shows the heterogeneous pelvic mass (*) and the anteriorly displaced bladder (arrow).
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Figure 12. NB in a 2-year-old girl with an abdominal mass. Axial IV contrast-enhanced CT scan shows a mass arising in the retroperitoneum and encasing the aorta (straight black arrow) and left renal artery (arrowheads). The inferior vena cava is displaced anteriorly (curved arrow), and the left kidney (white arrow) is pushed laterally and rotated.
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Figure 13a. Massive liver metastases (Pepper syndrome) in a 2-month-old infant with NB. (a) Axial IV contrast-enhanced CT scan shows multiple areas of low attenuation throughout the liver. There is also a heterogeneous mass in the right flank and crossing to the left flank, which was the adrenal primary tumor (arrows). (b) Photograph of the bisected liver at autopsy shows diffuse parenchymal replacement with multiple metastatic nodules.
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Figure 13b. Massive liver metastases (Pepper syndrome) in a 2-month-old infant with NB. (a) Axial IV contrast-enhanced CT scan shows multiple areas of low attenuation throughout the liver. There is also a heterogeneous mass in the right flank and crossing to the left flank, which was the adrenal primary tumor (arrows). (b) Photograph of the bisected liver at autopsy shows diffuse parenchymal replacement with multiple metastatic nodules.
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Figure 14. Brain metastases from NB in a 19-month-old child with emesis. Axial IV contrast-enhanced CT scan of the brain reveals a rim-enhancing area of low attenuation in the right frontoparietal region, resulting in subfalcial herniation. High-attenuation dural metastases are present in both frontal regions (arrow).
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Figure 15. Meningeal and skull metastases in a 9-month-old girl with proptosis and an abdominal mass. Axial CT scan through the anterior skull shows a bilateral soft-tissue mass along the inner table of the skull (black arrows), with extension into the coronal sutures bilaterally (white arrows).
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Figure 16a. Skull metastases in a 14-month-old boy with a small primary NB. (a) Axial oral and IV contrast-enhanced CT scan of the upper abdomen shows a poorly defined, heterogeneous, low-attenuation mass anterior to the left kidney (*). (b) Axial CT scan of the skull shows destruction and expansion of the right parietal region (arrows).
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Figure 16b. Skull metastases in a 14-month-old boy with a small primary NB. (a) Axial oral and IV contrast-enhanced CT scan of the upper abdomen shows a poorly defined, heterogeneous, low-attenuation mass anterior to the left kidney (*). (b) Axial CT scan of the skull shows destruction and expansion of the right parietal region (arrows).
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At MR imaging, NB and GNB are typically heterogeneous, variably enhancing, and of relatively low signal intensity on T1-weighted images and high signal intensity on T2-weighted images (Figs 17, 18). Calcification may be difficult to detect at MR imaging; signal voids may be apparent. Hemorrhagic areas may manifest as areas of high signal intensity on T1-weighted images, and cystic change may appear bright on T2-weighted images (72). Because of excellent tissue discrimination and multiplanar imaging, MR imaging is superior to CT for determination of the organ of origin and regional invasion (63). MR imaging is the preferred modality for investigating intraspinal extension of primary tumor (the so-called dumbbell NB, seen in 10% of abdominal NBs, 28% of thoracic NBs, and occasionally in cervical NBs) (Fig 19) (73). MR imaging should be performed on any patient with a paraspinal tumor (62). Epidural tumor is well demonstrated on coronal, sagittal, and axial MR images; it may be shown to displace the spinal cord or nerve roots and spread extensively up and down the epidural space (Fig 20) (74). Another advantage of MR imaging is its ability to depict marrow disease, which appears as areas of low signal intensity on T1-weighted images and high areas on T2-weighted images. This MR imaging appearance has been shown to correlate well with results of bone marrow biopsy (72,75,76). Finally, MR imaging is superior to CT in the detection of diffuse hepatic metastases in infants with stage 4S disease; these metastases manifest as areas of high signal intensity on T2-weighted images (63).
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Figure 17a. NB arising from the organ of Zückerkandl in a 5-month-old girl with a right lower quadrant mass. (a) Sagittal T1-weighted MR image of the abdomen shows a low-signal-intensity mass arising anterior to the lower lumbar spine (*). (b) Axial T1-weighted MR image shows a low-signal-intensity mass growing between the right psoas muscle (*) and the spine and beginning to invade the right first sacral foramen (arrow). (c) On an axial T2-weighted MR image obtained at the same level as b, the mass is high signal intensity.
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Figure 17b. NB arising from the organ of Zückerkandl in a 5-month-old girl with a right lower quadrant mass. (a) Sagittal T1-weighted MR image of the abdomen shows a low-signal-intensity mass arising anterior to the lower lumbar spine (*). (b) Axial T1-weighted MR image shows a low-signal-intensity mass growing between the right psoas muscle (*) and the spine and beginning to invade the right first sacral foramen (arrow). (c) On an axial T2-weighted MR image obtained at the same level as b, the mass is high signal intensity.
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Figure 17c. NB arising from the organ of Zückerkandl in a 5-month-old girl with a right lower quadrant mass. (a) Sagittal T1-weighted MR image of the abdomen shows a low-signal-intensity mass arising anterior to the lower lumbar spine (*). (b) Axial T1-weighted MR image shows a low-signal-intensity mass growing between the right psoas muscle (*) and the spine and beginning to invade the right first sacral foramen (arrow). (c) On an axial T2-weighted MR image obtained at the same level as b, the mass is high signal intensity.
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Figure 18a. GNB in a 15-year-old girl who presented with a cough. (a) Frontal chest radiograph demonstrates an oblong, left-sided posterior mediastinal mass (arrow). (b) Lateral chest radiograph helps confirm the posterior mediastinal mass (arrows). (c) Axial IV contrast-enhanced CT scan through the lower thorax depicts the left-sided posterior mediastinal mass (straight arrow), with a small focus of calcification. The mass encircles the aorta (curved arrow). (d) Coronal T1-weighted MR image of the posterior thorax better depicts the longitudinal extent of the paraspinal mass, which is well circumscribed.
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Figure 18b. GNB in a 15-year-old girl who presented with a cough. (a) Frontal chest radiograph demonstrates an oblong, left-sided posterior mediastinal mass (arrow). (b) Lateral chest radiograph helps confirm the posterior mediastinal mass (arrows). (c) Axial IV contrast-enhanced CT scan through the lower thorax depicts the left-sided posterior mediastinal mass (straight arrow), with a small focus of calcification. The mass encircles the aorta (curved arrow). (d) Coronal T1-weighted MR image of the posterior thorax better depicts the longitudinal extent of the paraspinal mass, which is well circumscribed.
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Figure 18c. GNB in a 15-year-old girl who presented with a cough. (a) Frontal chest radiograph demonstrates an oblong, left-sided posterior mediastinal mass (arrow). (b) Lateral chest radiograph helps confirm the posterior mediastinal mass (arrows). (c) Axial IV contrast-enhanced CT scan through the lower thorax depicts the left-sided posterior mediastinal mass (straight arrow), with a small focus of calcification. The mass encircles the aorta (curved arrow). (d) Coronal T1-weighted MR image of the posterior thorax better depicts the longitudinal extent of the paraspinal mass, which is well circumscribed.
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Figure 18d. GNB in a 15-year-old girl who presented with a cough. (a) Frontal chest radiograph demonstrates an oblong, left-sided posterior mediastinal mass (arrow). (b) Lateral chest radiograph helps confirm the posterior mediastinal mass (arrows). (c) Axial IV contrast-enhanced CT scan through the lower thorax depicts the left-sided posterior mediastinal mass (straight arrow), with a small focus of calcification. The mass encircles the aorta (curved arrow). (d) Coronal T1-weighted MR image of the posterior thorax better depicts the longitudinal extent of the paraspinal mass, which is well circumscribed.
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Figure 19a. NB in a 9-month-old girl who continually leaned to one side. (a) Axial unenhanced CT scan through the upper abdomen shows a posterior left-sided mass with calcification that extends into the costovertebral junction (arrow) and crosses to the right side of the patient. (b) Coronal T1-weighted MR image through the posterior thorax helps confirm the large posterior mediastinal and retroperitoneal mass extending from left to right. (c) Coronal T1-weighted IV contrast-enhanced MR image shows heterogeneous enhancement of the mass. (d) Axial T1-weighted IV contrast-enhanced MR image shows neural foraminal invasion (straight arrow), with marked thecal sac (curved arrow) displacement toward the right of the patient. The paraspinal musculature is also invaded (arrowhead).
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Figure 19b. NB in a 9-month-old girl who continually leaned to one side. (a) Axial unenhanced CT scan through the upper abdomen shows a posterior left-sided mass with calcification that extends into the costovertebral junction (arrow) and crosses to the right side of the patient. (b) Coronal T1-weighted MR image through the posterior thorax helps confirm the large posterior mediastinal and retroperitoneal mass extending from left to right. (c) Coronal T1-weighted IV contrast-enhanced MR image shows heterogeneous enhancement of the mass. (d) Axial T1-weighted IV contrast-enhanced MR image shows neural foraminal invasion (straight arrow), with marked thecal sac (curved arrow) displacement toward the right of the patient. The paraspinal musculature is also invaded (arrowhead).
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Figure 19c. NB in a 9-month-old girl who continually leaned to one side. (a) Axial unenhanced CT scan through the upper abdomen shows a posterior left-sided mass with calcification that extends into the costovertebral junction (arrow) and crosses to the right side of the patient. (b) Coronal T1-weighted MR image through the posterior thorax helps confirm the large posterior mediastinal and retroperitoneal mass extending from left to right. (c) Coronal T1-weighted IV contrast-enhanced MR image shows heterogeneous enhancement of the mass. (d) Axial T1-weighted IV contrast-enhanced MR image shows neural foraminal invasion (straight arrow), with marked thecal sac (curved arrow) displacement toward the right of the patient. The paraspinal musculature is also invaded (arrowhead).
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Figure 19d. NB in a 9-month-old girl who continually leaned to one side. (a) Axial unenhanced CT scan through the upper abdomen shows a posterior left-sided mass with calcification that extends into the costovertebral junction (arrow) and crosses to the right side of the patient. (b) Coronal T1-weighted MR image through the posterior thorax helps confirm the large posterior mediastinal and retroperitoneal mass extending from left to right. (c) Coronal T1-weighted IV contrast-enhanced MR image shows heterogeneous enhancement of the mass. (d) Axial T1-weighted IV contrast-enhanced MR image shows neural foraminal invasion (straight arrow), with marked thecal sac (curved arrow) displacement toward the right of the patient. The paraspinal musculature is also invaded (arrowhead).
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Figure 20a. GN in an 8-year-old boy with long-standing right leg and hip pain. (a) Lateral radiograph of the lumbar spine shows posterior scalloping of the first through fourth lumbar vertebral bodies (arrows). (b) Sagittal T2-weighted MR image of the lumbar spine reveals an enhancing intraspinal mass invading the first through third lumbar vertebral bodies (arrows). (c) Axial T1-weighted IV contrast-enhanced MR image through the second lumbar vertebra shows the mass filling the spinal canal (straight arrows), invading the vertebral body (*), and extending laterally to the right paravertebral area (curved arrow). (d) Axial CT scan of the second lumbar vertebra shows replacement of bone with tumor. The area of replacement has sclerotic margins, suggesting it is a remodeling from invasion of a slow-growing tumor.
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Figure 20b. GN in an 8-year-old boy with long-standing right leg and hip pain. (a) Lateral radiograph of the lumbar spine shows posterior scalloping of the first through fourth lumbar vertebral bodies (arrows). (b) Sagittal T2-weighted MR image of the lumbar spine reveals an enhancing intraspinal mass invading the first through third lumbar vertebral bodies (arrows). (c) Axial T1-weighted IV contrast-enhanced MR image through the second lumbar vertebra shows the mass filling the spinal canal (straight arrows), invading the vertebral body (*), and extending laterally to the right paravertebral area (curved arrow). (d) Axial CT scan of the second lumbar vertebra shows replacement of bone with tumor. The area of replacement has sclerotic margins, suggesting it is a remodeling from invasion of a slow-growing tumor.
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Figure 20c. GN in an 8-year-old boy with long-standing right leg and hip pain. (a) Lateral radiograph of the lumbar spine shows posterior scalloping of the first through fourth lumbar vertebral bodies (arrows). (b) Sagittal T2-weighted MR image of the lumbar spine reveals an enhancing intraspinal mass invading the first through third lumbar vertebral bodies (arrows). (c) Axial T1-weighted IV contrast-enhanced MR image through the second lumbar vertebra shows the mass filling the spinal canal (straight arrows), invading the vertebral body (*), and extending laterally to the right paravertebral area (curved arrow). (d) Axial CT scan of the second lumbar vertebra shows replacement of bone with tumor. The area of replacement has sclerotic margins, suggesting it is a remodeling from invasion of a slow-growing tumor.
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Figure 20d. GN in an 8-year-old boy with long-standing right leg and hip pain. (a) Lateral radiograph of the lumbar spine shows posterior scalloping of the first through fourth lumbar vertebral bodies (arrows). (b) Sagittal T2-weighted MR image of the lumbar spine reveals an enhancing intraspinal mass invading the first through third lumbar vertebral bodies (arrows). (c) Axial T1-weighted IV contrast-enhanced MR image through the second lumbar vertebra shows the mass filling the spinal canal (straight arrows), invading the vertebral body (*), and extending laterally to the right paravertebral area (curved arrow). (d) Axial CT scan of the second lumbar vertebra shows replacement of bone with tumor. The area of replacement has sclerotic margins, suggesting it is a remodeling from invasion of a slow-growing tumor.
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Scintigraphic evaluation of NB and GNB falls into two categories: identification of the primary tumor and metastatic surveillance. Identification of the primary tumor is performed with either a catecholamine analog (metaiodobenzylguanidine labeled to iodine-123, referred to as MIBG) or a somatostatin analog (pentetreotide labeled to indium-111). Scintigraphy performed with both of these radiopharmaceuticals shows uptake in primary tumor and metastases (Figs 21, 22). MIBG is taken up by catecholamine-producing tumors, so NB, GNB, GN, pheochromocytoma, carcinoid tumor, and medullary thyroid cancer may all take up this radiotracer. Although 90%–95% of NB and GNB secrete catecholamines, only about 70% of NB and GNB are MIBG positive; one of the drawbacks of MIBG imaging is that a considerable minority of tumors (30%) are not MIBG avid. MIBG scintigraphy is highly sensitive (88%) and specific (99%) for sympathetic tissue such as those found in NB, GNB, GN, carcinoid, and pheochromocytoma (but it does not enable discrimination among these tumors) (77). When MIBG-avid disease is evaluated and results are positive, MIBG scintigraphy gives an excellent map of disease (both primary and metastatic), although it does not allow marrow to be distinguished from cortical disease, which may be important for staging (78,79). Because approximately 30% of NBs and GNBs are MIBG negative, normal results do not exclude the diagnosis (80). The use of MIBG scintigraphy in routine patient assessment is controversial; a recent study showed that MIBG results did not alter staging or treatment for any of the patients studied. In the same study, recurrent NB failed to show uptake in 50% of patients with recurrence, results that suggest that MIBG scintigraphy is an unreliable indicator of recurrent disease (81). In-111 pentetreotide scintigraphy may also demonstrate neuroblastic tumors, although it does not appear to be superior to MIBG scintigraphy. Some tumors are not pentetreotide-avid, and pentetreotide uptake is not specific for neuroblastic tumors (82).
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Figure 21a. NB in a 13-year-old girl with right upper quadrant pain. (a) Longitudinal US scan of the right flank reveals a predominantly cystic mass with thick septations. (b) Axial unenhanced CT scan demonstrates a low-attenuation mass in the right suprarenal area. (c) Anterior MIBG scintigram of the abdomen reveals uptake in the right upper abdomen at the site of the primary tumor.
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Figure 21b. NB in a 13-year-old girl with right upper quadrant pain. (a) Longitudinal US scan of the right flank reveals a predominantly cystic mass with thick septations. (b) Axial unenhanced CT scan demonstrates a low-attenuation mass in the right suprarenal area. (c) Anterior MIBG scintigram of the abdomen reveals uptake in the right upper abdomen at the site of the primary tumor.
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Figure 21c. NB in a 13-year-old girl with right upper quadrant pain. (a) Longitudinal US scan of the right flank reveals a predominantly cystic mass with thick septations. (b) Axial unenhanced CT scan demonstrates a low-attenuation mass in the right suprarenal area. (c) Anterior MIBG scintigram of the abdomen reveals uptake in the right upper abdomen at the site of the primary tumor.
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Figure 22a. Metastatic NB in a 3-year-old girl with a limp. (a) Anterior Tc-99m MDP scintigram of the lower legs shows increased uptake diffusely at the diametaphyseal regions of the distal femora and proximal tibiae (arrowheads). (b) Anterior MIBG scintigram of the lower legs demonstrates multiple focal areas of increased uptake in the femora and tibiae.
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Abstract
LEARNING OBJECTIVES FOR TEST...
