(Radiology. 2001;218:91-94.)
© RSNA, 2001
Case 30: Neoplastic Marrow Infiltration due to Neuroblastoma1
Thomas E. Herman, MD and
Marilyn J. Siegel, MD
1 From the Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S Kingshighway Blvd, St Louis, MO 63110. Received March 22, 1999; revision requested May 4; final revision received August 6; accepted August 11. Address correspondence to M.J.S. (e-mail: siegelm@mir.wustl.edu).
Index terms: Bones, CT, 44.1211 • Bones, diseases, 44.325 • Bones, MR, 44.121413, 44.121415 • Bones, US, 44.1298 • Diagnosis Please • Neoplasms, in infants and children, 44.325 • Neuroblastoma, 44.325
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HISTORY
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A 6-year-old boy, who had been in excellent health previously, complained of right leg pain 1 week prior to his initial hospitalization. Physical examination results demonstrated an obvious limp favoring the right leg. There was pain at palpation in both hips, more marked on the right, but full range of passive motion. A complete blood cell count showed a white blood cell count of 8,700 (8.70 x 109/L), with a normal differential count and smear and a hematocrit level of 36.4 (0.364). Immunoglobulin, rheumatoid factors, and antinuclear antibody levels and results from hemoglobin electrophoresis and an enzyme-linked immunosorbent assay for human immunodeficiency virus were all normal. A chest radiograph was also normal. A pelvic radiograph (Fig 1) was obtained followed by bilateral ultrasonographic (US) scans of the hips. The US scan showed an effusion on the right side, and a subsequent aspiration yielded 1,780 (1.78 x 109/L) white blood cells per volume, predominantly monocytes. The Gram stain demonstrated no organisms, and no bacteria were grown in culture. The patient’s leg pain continued to worsen. Magnetic resonance (MR) images of the pelvis and femora (Figs 2, 3) were then obtained.
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Figure 1. Anteroposterior radiograph of the hips and pelvis. Sclerotic lesions (arrowheads) are present in the right ilium medially and in the right femoral neck and proximal diaphysis.
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Figure 2a. (a, b) Transverse T1-weighted MR images (700/17 [repetition time msec/echo time msec]) of the pelvis and (c) coronal T1-weighted MR image (500/12) of the femora demonstrate marrow of diffusely low signal intensity in the pelvic bones, femoral epiphyses (E), proximal and distal metaphyses, and diaphyses. Focal areas of high signal intensity (arrowheads in c) represent islands of residual fatty marrow.
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Figure 2b. (a, b) Transverse T1-weighted MR images (700/17 [repetition time msec/echo time msec]) of the pelvis and (c) coronal T1-weighted MR image (500/12) of the femora demonstrate marrow of diffusely low signal intensity in the pelvic bones, femoral epiphyses (E), proximal and distal metaphyses, and diaphyses. Focal areas of high signal intensity (arrowheads in c) represent islands of residual fatty marrow.
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Figure 2c. (a, b) Transverse T1-weighted MR images (700/17 [repetition time msec/echo time msec]) of the pelvis and (c) coronal T1-weighted MR image (500/12) of the femora demonstrate marrow of diffusely low signal intensity in the pelvic bones, femoral epiphyses (E), proximal and distal metaphyses, and diaphyses. Focal areas of high signal intensity (arrowheads in c) represent islands of residual fatty marrow.
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Figure 3a. (a, b) Transverse fat-suppressed T2-weighted MR images (5,000/119; flip angle, 180°) of the pelvis and (c) coronal fat-suppressed T2-weighted MR image (3,000/119; flip angle, 180°) of the femora demonstrate diffusely heterogeneous signal intensity of the marrow, particularly in the right femoral epiphysis (E) and both diaphyses. The signal intensity of the marrow space is abnormally hyperintense and much higher than that of muscle. Normal fatty marrow in the distal femoral metaphysis and epiphysis is nulled with this fat-suppressed sequence. A small right hip joint effusion (arrow in c) is present. The amount of fluid in the left hip joint is normal.
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Figure 3b. (a, b) Transverse fat-suppressed T2-weighted MR images (5,000/119; flip angle, 180°) of the pelvis and (c) coronal fat-suppressed T2-weighted MR image (3,000/119; flip angle, 180°) of the femora demonstrate diffusely heterogeneous signal intensity of the marrow, particularly in the right femoral epiphysis (E) and both diaphyses. The signal intensity of the marrow space is abnormally hyperintense and much higher than that of muscle. Normal fatty marrow in the distal femoral metaphysis and epiphysis is nulled with this fat-suppressed sequence. A small right hip joint effusion (arrow in c) is present. The amount of fluid in the left hip joint is normal.
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Figure 3c. (a, b) Transverse fat-suppressed T2-weighted MR images (5,000/119; flip angle, 180°) of the pelvis and (c) coronal fat-suppressed T2-weighted MR image (3,000/119; flip angle, 180°) of the femora demonstrate diffusely heterogeneous signal intensity of the marrow, particularly in the right femoral epiphysis (E) and both diaphyses. The signal intensity of the marrow space is abnormally hyperintense and much higher than that of muscle. Normal fatty marrow in the distal femoral metaphysis and epiphysis is nulled with this fat-suppressed sequence. A small right hip joint effusion (arrow in c) is present. The amount of fluid in the left hip joint is normal.
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IMAGING FINDINGS
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The conventional radiograph of the hips demonstrated ill-defined areas of sclerosis in the right ilium, right femoral neck, and proximal right diaphysis. The transverse T1-weighted MR image (Fig 2a) of the pelvis showed marrow of homogeneous low signal intensity in the iliac bones and sacrum. The transverse T1-weighted MR image of the pelvis and proximal femoral epiphyses (Fig 2b) and the coronal T1-weighted MR image of the femoral shafts (Fig 2c) showed marrow of minimally heterogeneous low signal intensity.
For the patient’s age, the epiphyses and diaphyses should contain predominantly fatty marrow. According to Waitches et al (1), fatty marrow of high signal intensity can be seen in the diaphyses of the long bones as early as 3 months of age, and fatty marrow with varying degrees of heterogeneity is always present by 1 year of age. Thus, in this patient, T1-weighted MR images of the marrow should demonstrate a signal intensity equal to that of subcutaneous adipose tissue. The low signal intensity on T1-weighted images can be secondary to neoplastic or hyperplastic cells, edema, or fibrous tissue.
On the transverse fat-suppressed T2-weighted MR images (Fig 3a, 3b) of the pelvis, the signal intensity of the marrow in the iliac bones and proximal right femoral epiphysis increased and was hyperintense to that of subcutaneous fat. On the fat-suppressed T2-weighted coronal MR image, the marrow in the femoral shafts (Fig 3c) was heterogeneous, and the signal intensity remained predominantly hyperintense to both muscle and fat. The fatty marrow in the distal epiphyses and metaphyses was suppressed and had a signal intensity slightly higher than that of muscle, which is normal for the patient’s age. Also noted was a small right hip joint effusion. In this case, the MR image demonstrated more diffuse disease than would be expected from the conventional radiograph, which presumably reflects the increased sensitivity of MR imaging for detection of the same.
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DISCUSSION
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The differential considerations of diffuse bone marrow abnormalities in childhood include replacement or infiltration by neoplastic disease, red cell hyperplasia, myeloid depletion, and myelofibrosis (2–4).
Marrow can be infiltrated or replaced by a number of different neoplastic diseases, but the common causes are metastatic disease and leukemia. In young children, metastatic disease is usually secondary to neuroblastoma. In older children, lymphoma and rhabdomyosarcoma become more common causes (3–5). Neuroblastoma is the most common extracranial solid tumor in children and accounts for 8%–10% of all childhood cancers (6). The median age at diagnosis is 22 months; 79% of patients are younger than 4 years and 97% present by 10 years of age (6). Approximately 70% of children with neuroblastoma have disseminated disease at presentation, and the most common site of metastases is the skeleton (5).
Leukemia is the most common neoplastic disease in childhood and accounts for approximately one-third of all pediatric malignancies (3). Acute lymphocytic leukemia accounts for the majority of cases of childhood leukemia. The peak age of occurrence is approximately 4 years (7). Common signs and symptoms are low-grade fever, bruising, fatigue, bone pain, hepatosplenomegaly, bleeding, and anemia.
Infiltrative neoplastic diseases generally follow the distribution of red marrow. In young children, common sites of involvement by both metastatic disease and leukemia are the proximal and distal metaphyses of the long bones, the flat bones, and the spine. When there is extensive disease, the remainder of the appendicular skeleton can be affected. On conventional radiographs, metastases and leukemia may be seen as osteolytic or osteoblastic lesions or a combination of both. The margins of the metastatic lesions may be well defined or ill defined.
On T1-weighted MR images, metastatic tumor and leukemia can produce focal or diffuse areas of low signal intensity (2–4). On conventional T2-weighted images, the signal intensity increases, and the tumor or leukemia becomes isointense or minimally hyperintense to normal marrow. On T2-weighted images, the signal intensities of leukemic and normal marrow may overlap, and differentiation may be difficult. The difference in signal intensity becomes apparent with fat-suppressed sequences, such as short inversion time inversion recovery, or STIR, and radio-frequency presaturation of the lipid peak (fat suppression). On images obtained with fat-suppressed and short inversion time inversion recovery sequences, infiltrated marrow is abnormally hyperintense relative to normal marrow. In this patient, the abnormally high signal intensity of the marrow on fat-suppressed T2-weighted images, in combination with the low intensity on T1-weighted images, supports a diagnosis of neoplastic marrow infiltration—either neuroblastoma or leukemia.
Diffuse red cell hyperplasia may result from severe anemia (including sickle cell disease, thalassemia, and hereditary spherocytosis), chronic and severe blood loss, marrow replacement by neoplastic cells, and treatment with granulocyte-macrophage colony stimulating factor (8). When the hematopoietic capacity of existing red marrow stores is exceeded and there is a need for more red marrow, yellow marrow undergoes reconversion to hematopoietic marrow. This process is termed "reconversion" (2–4). Reconversion of yellow to red marrow occurs first in the spine, flat bones, and skull, followed by in the long bones. Within long bones, reconversion begins in the proximal metaphyses, then in the distal metaphyses, followed by the diaphyses. Marrow reconversion is unusual in the epiphyses and apophyses of long bones, except in severe anemia (2–4).
Hyperplastic red marrow usually has a signal intensity similar to or slightly higher than that of muscle on T1-weighted MR images and similar to or slightly higher than that of adjacent muscle on images obtained with fat-suppressed T2-weighted and short inversion time inversion recovery sequences. In this patient, the abnormally high signal intensity of the marrow on the fat-suppressed T2-weighted MR images is not typical of normal hematopoietic marrow and does not support the diagnosis of red cell hyperplasia.
Children with chronic anemias, such as sickle cell disease, often undergo repeated blood transfusions. A sequela of repeated transfusion is hemosiderosis, characterized by deposition of excess iron in the reticuloendothelial cells of the liver, spleen, and bone marrow (9). The magnetic susceptibility effects of hemosiderin produce hypointense marrow on T2-weighted and gradient-echo MR images and, when particularly severe, on T1-weighted images. The high signal intensity of the marrow on the T2-weighted images in this patient would not be expected in hemosiderosis and makes the diagnosis unlikely.
Myelofibrosis is characterized by replacement of normal marrow cells by fibrotic tissue. In childhood, it usually is secondary to radiation therapy or chemotherapy for leukemia, lymphoma, or metastatic disease (2–4). Primary myelofibrosis is rare in children. Replacement of marrow by fibrosis results in relatively low signal intensity on T1-weighted and fat-suppressed MR images. The absence of prior medical treatment and the high signal intensity of the marrow on fat-suppressed T2-weighted images argue against the diagnosis of myelofibrosis in this patient.
Myeloid depletion, also known as aplastic anemia, may be a sequela of viral infections, medications, toxins, chemotherapy, and radiation therapy, but in many instances, the cause is unknown (3). Pathologically, normal marrow is replaced with fat cells, which results in high signal intensity on T1-weighted images and low signal intensity on images obtained with fat-suppressed T2-weighted and short inversion time inversion recovery sequences. The excess fatty marrow is best appreciated in areas that have a relatively high percentage of hematopoietic marrow, such as the proximal femoral metaphyses and the spine. In this patient, the absence of high signal intensity of the marrow on T1-weighted images makes myeloid depletion an unlikely diagnosis.
In this patient, an abdominal computed tomographic (CT) scan (Fig 4) was obtained 1 day after the MR examination because of the suspicion of neuroblastoma. The CT scan demonstrated a 5 x 5-cm left suprarenal mass, which subsequently was removed surgically; it was a neuroblastoma histologically. Bone marrow aspiration was performed and demonstrated normal myeloid elements and numerous clumped small round blue cells. The patient received chemotherapy with cyclophosphamide, doxorubicin, and vincristine in a protocol for stage IV neuroblastoma.
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Figure 4. Transverse CT scan of the abdomen at the level of the upper poles of the kidneys demonstrates a heterogeneous noncalcified left suprarenal neuroblastoma (arrowheads) displacing the kidney posteriorly and inferiorly.
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Our congratulations to the 40 individuals who submitted the most likely diagnosis (neoplastic marrow infiltration due to neuroblastoma) for Diagnosis Please, Case 30. Credit was given only if neoplastic marrow disease, neuroblastoma, or leukemia was mentioned. The names and locations of the individuals, as submitted, are as follows:
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- Julio Almeida Llanos, MD, Rosario, Argentina
- Lionel Arrivé, Paris, France
- Richard Barth, MD, Stanford, Calif
- Mark A. Bisesi, MD, Bloomington, Ind
- Michael P. Buetow, MD, Okemos, Mich
- Martin I. Cohen, Westlake Village, Calif
- Dr. H. E. Daldrup-Link, Munich, Germany
- Laura Z. Fenton, MD, Denver, Colo
- Kai Frentzel, MD, Hopsten, Germany
- Dietrich Gerhardt, Waterloo, Iowa
- Ronald B. J. Glass, MD, New York, NY
- W. Zev Goldstein, MD, Poughkeepsie, NY
- Jesus Gomez Pacheco
- Helen T. Ho, MD, Chicago, Ill
- Steven A. Klein, Shrewsbury, Mass
- Stefanos Lachanis, MD, Athens, Greece
- Dr. Eduardo Lassalle, Quilmes, Argentina
- Antonio Jose Madureira, MD, Porto, Portugal
- Yoji Maetani, Kyoto, Japan
- Dr. I. Mainard-Simard, Nancy, France
- N. B. S. Mani, MD, Chandigarh, India
- Edward Menges, MD, Aptos, Calif
- Dr. Eduardo Mondello, Buenos Aires, Argentina
- Sanford M. Ornstein, MD, Phoenix, Ariz
- David M. Panicek, MD, New York, NY
- Harish Panicker, Pontiac, Mich
- Michel A. Panuel, Marseille, France
- John Plotke, Naperville, Ill
- Shawn P. Quillin, MD, Charlotte, NC
- R. Rajesh, Ahmedabad, India
- Bjorn Relefors, Hudiksvall, Sweden
- Matt Rheinboldt, Lafayette, La
- Mourad Said, MD, Monastir, Tunisia
- Anthony J. Scuderi, Johnstown, Pa
- Matt Shapiro, MD, Lowell, Mass
- Taro Shimono, MD, Kyoto, Japan
- Paolo Siotto, MD, Cagliari, Italy
- Christopher Vittore, MD, Rockford, Ill
- Dr. Vinay Vyas, Ahmedabad, India
- Keith H. Wittenberg, MD, Rochester, Minn
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FOOTNOTES
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Part 1 of this case appears 4 months previously and may contain larger images.
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REFERENCES
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Waitches G, Zawin JK, Poznanski AK. Sequence and rate of bone marrow conversion in the femora of children as seen on MR imaging: are accepted standards accurate?. AJR Am J Roentgenol 1994; 162:1399-1406.[Abstract/Free Full Text]
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Moore SG, Bisset GS, III, Siegel MJ, Donaldson JS. Pediatric musculoskeletal MR imaging. Radiology 1991; 179:345-360.[Abstract/Free Full Text]
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Moore SG, Sebag GH. Primary disorders of bone marrow. In: Cohen MD, Edwards MK, eds. Magnetic resonance imaging of children. Philadelphia, Pa: B.C. Decker, 1990; 765-824.
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Siegel MJ, Luker GD. Bone marrow imaging in children. Magn Reson Imaging Clin N Am 1996; 4:771-796.[Medline]
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Bousvaros A, Kirks DR, Grossman H. Imaging of neuroblastoma: an overview. Pediatr Radiol 1986; 16:89-106.[Medline]
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Brodeur GM, Castleberry RP. Neuroblastoma. In: Pizzo PA, Poplack DG, eds. Principles and practices of pediatric oncology. 3rd ed. Philadelphia, Pa: Lippincott-Raven, 1997; 761-797.
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Margolin JF, Poplack DG. Acute lymphoblastic leukemia. In: Pizzo PA, Poplack DG, eds. Principles and practices of pediatric oncology. 3rd ed. Philadelphia, Pa: Lippincott-Raven, 1997; 409-462.
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Fletcher BD, Wall JE, Hanna SL. Effect of hematopoietic growth factors on MR images of bone marrow in children undergoing chemotherapy. Radiology 1993; 189:745-751.[Abstract/Free Full Text]
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Levin TL, Sheth SS, Hurlet A, et al. MR marrow signs of iron overload in transfusion-dependent patients with sickle cell disease. Pediatr Radiol 1995; 25:614-619.[Medline]
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HISTORY
IMAGING FINDINGS
