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From the Archives of the AFIP

Neuroblastoma, Ganglioneuroblastoma, and Ganglioneuroma: Radiologic-Pathologic Correlation¹

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).

	Abstract

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Neuroblastoma and... Ganglioneuroma Conclusions References

 
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

	LEARNING OBJECTIVES FOR TEST 6

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Neuroblastoma and... Ganglioneuroma Conclusions References

 
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.
  

	Introduction

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Neuroblastoma and... Ganglioneuroma Conclusions References

 
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.

	Neuroblastoma and Ganglioneuroblastoma

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Neuroblastoma and... Ganglioneuroma Conclusions References

 
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).

View larger version (52K): [in this window] [in a new window] [Download PPT slide]   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).

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).

View larger version (171K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (191K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (186K): [in this window] [in a new window] [Download PPT slide]   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).

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).

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).

View larger version (133K): [in this window] [in a new window] [Download PPT slide]   Figure 5.  Adrenal NB. Photograph of a bisected kidney reveals a heterogeneous, hemorrhagic adrenal NB arising above the kidney.

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).

View larger version (119K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (141K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (160K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (105K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (141K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   Figure 8.  Bone metastases from NB. Frontal radiograph of a 2-year-old boy who presented with weight loss shows an ill-defined lucent area in the submetaphyseal region (arrows).

View larger version (153K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (156K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (127K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (140K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (108K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (136K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (134K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (133K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (144K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (154K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (117K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (146K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (96K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (138K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (172K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (123K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (153K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (114K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (141K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (152K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (160K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (90K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (102K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (149K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (127K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (122K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (135K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (85K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (96K): [in this window] [in a new window] [Download PPT slide]   Figure 22b.  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.

View larger version (125K): [in this window] [in a new window] [Download PPT slide]   Figure 23a.  GNB in a 5-year-old girl with right upper abdominal fullness. (a) Axial contrast-enhanced CT scan through the upper abdomen reveals a densely calcified right flank mass. (b) Anterior Tc-99m MDP scan of the chest and abdomen shows uptake in the mass.

View larger version (142K): [in this window] [in a new window] [Download PPT slide]   Figure 23b.  GNB in a 5-year-old girl with right upper abdominal fullness. (a) Axial contrast-enhanced CT scan through the upper abdomen reveals a densely calcified right flank mass. (b) Anterior Tc-99m MDP scan of the chest and abdomen shows uptake in the mass.

Children with low- or intermediate-risk tumors have a relatively good prognosis (Table 3). Low-risk tumors are treated with surgery only; in the unlikely event of recurrence, chemotherapy and additional surgery may be performed. Intermediate-risk tumors are surgically removed and then treated with chemotherapy. High-risk tumors are substantially more aggressive, and these patients fare considerably worse. Treatment for high-risk tumors consists of surgery and chemotherapy, with bone marrow transplantation in some cases. Even with aggressive treatment, however, the 3-year event-free survival rate for these patients is less than 15% (14). Improved 2-year survivalafter bone marrow transplantation has been documented in some studies; prolonged survival is currently being assessed (89).

Complete macroscopic tumor removal at surgery (at the time of initial surgery or at subsequent exploration) influences the prognosis of some, but not all, stages. It improves survival for patients with stage 3 disease (90) (the exception to this is the child less than 1 year old who has a stage 3 tumor with favorable biologic behavior; that is, normal Myc-N expression, favorable histologic characteristics, and DNA index > 1) (91). Survival is not influenced by the timing of the surgery. Stage 3 tumors are large and may be difficult to resect completely. Because chemotherapy may cause changes in the tumor that may facilitate resection, and because timing does not affect survival, it may be advisable to perform curative surgery after chemotherapy for tumors that appear difficult to completely resect (13).

Surgery for stage 4 tumors is controversial; some studies show that gross complete resection conveys minimal increased survival (92). Chemotherapy appears to be a more potent weapon against stage 4 tumors, particularly against metastatic disease (13). Survival of patients with stage 4S tumors is unchanged by surgery; in these patients, surgery is primarily used for diagnosis and to relieve symptoms from tumor burden (13,93).

Radiation therapy is used in patients with NB and positive intracavitary lymph nodes. Event-free survival is significantly improved by using both chemotherapy and radiation therapy in these patients. In 76% of patients with stage C disease (Pediatric Oncology Group classification: complete resection of primary tumor but with residual intracavitary lymph nodes) treated with chemotherapy and radiation therapy, a complete response was achieved, compared with 46% for patients treated with chemotherapy alone. Event-free survival and overall survival were also significantly higher in this group than in the chemotherapy only group (94).

Metastases
Bone is the most common site of metastasis, and bone metastases are present in up to two-thirds of patients at the time of diagnosis. Metastases are demonstrated at Tc-99m MDP imaging, which is a standard part of the imaging evaluation at presentation and follow-up.

Bone marrow metastases are found in 40%–60% of patients at presentation. The presence of marrow disease is best assessed with marrow aspirate or biopsy. Two patterns of marrow disease have been observed: diffuse and nodular. The nodular form corresponds to nodular marrow disease as seen in biopsy specimens and has a better prognosis, with a lower frequency of coexistent cortical metastases and excellent response to chemotherapy. The diffuse form is almost always seen with cortical metastases, is less responsive to chemotherapy, and conveys a worse prognosis (95).

Hepatic metastases are also common. Like marrow disease, liver disease may occur in nodular or diffuse form. Massive liver metastases in infants have been called Pepper syndrome (Fig 13); occasionally, the intraabdominal pressure is so severe that a mesh abdominal wall insert is needed to allow expansion and relieve pressure. Skin metastases are relatively common, especially in children younger than 1 year, and may appear as dark purple or blue masses, resembling blueberries (this appearance has been given the eponym blueberry muffin syndrome) (Fig 24). Other less common areas of metastases include the dura mater, lung, and brain, although virtually every location and organ has been documented as a site of NB metastases (68–71,96,97). Over the past several decades, there has been an increase in the frequency of aggressive and unusual metastatic disease; it is believed that this is a result of increased survival and more aggressive treatment regimens (70).

View larger version (97K): [in this window] [in a new window] [Download PPT slide]   Figure 24.  Blueberry muffin syndrome in an 8-month-old girl with NB. Autopsy photograph shows multiple bluish skin masses of metastatic NB.

Fetal NB may be discovered at obstetric US and has been discovered as early as 19 weeks, although the mean age at discovery is 36 weeks (Fig 25). Fetal NB is almost always (90% of cases) adrenal in origin and is usually stage 1, 2, or 4S. Fetal NB is associated with hepatic and, less commonly, marrow metastases (cortical metastases rarely, if ever, occur). Placental metastases are typically confined to the placental vessels, although they may rarely be discovered in the placental parenchyma. Fetal hydrops may result from placental vascular metastases, and they are theorized to cause maternal preeclampsia from catecholamine secretion (42,98,99). Fetal NB has an almost universally good outcome, and a conservative approach to tumor management in these patients is being advocated by some (11,100).

View larger version (128K): [in this window] [in a new window] [Download PPT slide]   Figure 25a.  Congenital NB. (a) Prenatal US scan (longitudinal view of the right flank; baby’s head is to the right of the image) obtained at 24 weeks gestation reveals an echogenic mass in the right flank (arrows). (b) Longitudinal US scan of the right flank obtained a few days after birth helps confirm the echogenic right suprarenal mass (arrows). (c) Photograph of the bivalved adrenal gland and adjacent right kidney shows the lobulated, solid mass arising from the adrenal gland.

View larger version (133K): [in this window] [in a new window] [Download PPT slide]   Figure 25b.  Congenital NB. (a) Prenatal US scan (longitudinal view of the right flank; baby’s head is to the right of the image) obtained at 24 weeks gestation reveals an echogenic mass in the right flank (arrows). (b) Longitudinal US scan of the right flank obtained a few days after birth helps confirm the echogenic right suprarenal mass (arrows). (c) Photograph of the bivalved adrenal gland and adjacent right kidney shows the lobulated, solid mass arising from the adrenal gland.

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   Figure 25c.  Congenital NB. (a) Prenatal US scan (longitudinal view of the right flank; baby’s head is to the right of the image) obtained at 24 weeks gestation reveals an echogenic mass in the right flank (arrows). (b) Longitudinal US scan of the right flank obtained a few days after birth helps confirm the echogenic right suprarenal mass (arrows). (c) Photograph of the bivalved adrenal gland and adjacent right kidney shows the lobulated, solid mass arising from the adrenal gland.

Screening for Neuroblastic Tumors
Because approximately 90% of NBs and GNBs secrete VMA and HVA, interest in childhood screening via urine assay grew in hopes that earlier detection would lead to improved cure rates. Screening began in Japan in 1973 in 6-month-old infants. Unfortunately, epidemiologic analysis showed that the incidence of tumor in older children did not change, that the incidence of stage 1 tumors dramatically increased, and that the tumors discovered at screening were of low stage and favorable histologic characteristics. These results suggest that the tumors discovered at urinary screening are those likely to remain occult, to regress, or to mature (7). Similar studies and results have come from Quebec (103). Screening for NB in infancy does not appear to decrease the incidence of advanced stage disease in older children nor does it improve survival in younger children with aggressive disease (7). The impact of screening on prognosis in children 1 year of age and older is unknown (104).

	Ganglioneuroma

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Neuroblastoma and... Ganglioneuroma Conclusions References

 
GN is a rare tumor composed entirely of ganglion cells and Schwannian stroma; by definition, GN does not contain neuroblasts, intermediate cells, or mitotic figures (105). Because NB and GNB may mature to GN, certainly some GNs arise from NB and GNB. GNs are also documented to have arisen in NBs that were treated with chemotherapy, and they may arise de novo (56). The relative frequency of spontaneously occurring GN, GN arising from maturing NB and GNB, and GN arising from treated NB and GNB is unknown. There are rare reports of metastatic GN. It is believed that these tumors represent metastases of NB or GNB that have subsequently matured to GN; these patients have an excellent prognosis (105,106).

GN occurs in older patients; the median age at diagnosis is approximately 7 years, with different studies reporting a median age of 5.5 years, 7 years, and over 10 years (105,107–109). There is a slight female predominance, ranging from 1.13:1 to 1.5:1 (105,107). It has been estimated that the ratio of NB to GN is approximately 6:1 to 10:1 (110,111). GN occurs in the same anatomic locations as NB and GNB, although at different frequencies. The most common locations are the posterior mediastinum (41.5% of cases), retroperitoneum (37.5%), adrenal gland (21%), and neck (8%). Unusual sites include the spermatic cord, heart, bone, and intestine (108,112–114).

GN most often manifests as an asymptomatic mass discovered on a routine radiographic study, such as a chest radiograph. Sometimes GN causes local mass effect and patients present with cough, abdominal pain, or dyspnea (105). In rare cases, GN secretes sufficient quantities of VMA or HVA to manifest with flushing and other symptoms of catecholamine excess (107). Catecholamine production by GN was previously believed to be unusual, because it was theorized that more mature tumors have more mature biologic behavior. However, in the largest series of GNs to date (49 cases), 37% of the patients had elevated VMA or HVA levels (105). Other reports confirm these findings (81,110,115). Thus, although elevated catecholamine production by NB and GNB occurs in 90%–95% of patients, elevated levels may also be seen in GN and therefore do not aid in discriminating among NB, GNB, and GN (105). GN is staged with the INSS.

Pathologic Features
The histologic characteristics and gross pathologic features of neuroblastic tumors were previously described in detail. Briefly, GN is composed of ganglion cells (some of which may be immature) and mature Schwann cells (mature stroma) (Fig 3). Cellular atypia, mitotic activity, and necrosis are not features of GN. The presence of neuroblasts indicates that the tumor is a GNB or NB and excludes GN. GN averages 8 cm in diameter and may appear encapsulated, although a true capsule is infrequent. The tumors are firm, are white to yellow in color, and may appear trabeculated or whorled (Fig 26) (1,35).

View larger version (157K): [in this window] [in a new window] [Download PPT slide]   Figure 26.  GN. Photograph of a bisected tumor shows a relatively homogeneous, tan appearance typical of GN.

At MR imaging, GN has low signal intensity on T1-weighted images and heterogeneous high signal intensity on T2-weighted images. Several reports indicate that relatively high, heterogeneous signal intensity on T2-weighted images correlates with GN; the appearance is presumed to be caused by a combination of myxoid material and relatively low amounts of ganglion cells (119–121). MR imaging enhancement varies from mild to marked; early enhancement at dynamic MR imaging is not typically seen in GN. GN does appear to accumulate contrast material over time, however, so delayed images may show increasing enhancement (116,119,121). MR imaging is the preferred modality for detection of intraspinal extension (Fig 20) (116).

GN, like GNB and NB, may accumulate MIBG; this has been reported in up to 57% of GNs in one study (105). In this study, most of the tumors that were MIBG-avid also produced increased amounts of catecholamines. Other reports of MIBG-positive GNs confirm that MIBG uptake does not allow differentiation among NB, GNB, and GN (81,105,106,110,122).

Treatment and Prognosis
Treatment consists of complete surgical resection when possible. Complete resection ensures thorough sampling of the tumor, such that a confident diagnosis of GN can be made. Local recurrence has been reported, so periodic radiologic surveillance is performed after resection (105,123).

	Conclusions

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Neuroblastoma and... Ganglioneuroma Conclusions References

 
The neuroblastic tumors NB, GNB, and GN are a spectrum of sympathetic tissue tumors ranging from the very immature and malignant NB to the mature and benign GN. The great variance in biologic behavior of NB, GNB, and GN indicates that many factors influence the prognosis for a patient with a neuroblastic tumor. It is the interplay of histologic maturity, genetic composition, and patient features that make NB, GNB, and GN an enigmatic group of tumors. Although GN tends to be a more homogeneous tumor than NB or GNB, it is not possible at imaging evaluation to discriminate among these three tumors.

	Footnotes

 
Abbreviations: GNB = ganglioneuroblastoma, GN = ganglioneuroma, HVA = homovanillic acid, INSS = International Neuroblastoma Staging System, IV = intravenous, MDP = methylene diphosphonate, MIBG = metaiodobenzylguanidine, MKI = mitosis-karyorrhexis index, NB = neuroblastoma, VMA = vanillylmandelic acid

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official nor as reflecting the views of the Departments of the Air Force, Navy, Army, or Defense.

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Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Neuroblastoma and... Ganglioneuroma Conclusions References

 

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