Enhancing lesions on spinal MRI is a common finding of patients with malignant tumors and spinal metastasis. Treatment-related vertebral enhancing lesions have seldom been reported, especially in pediatric patients.[10, 11, 13] Our study compared the image findings between treatment-induced IESL and true metastasis to the spine (Figure 5). The main image characteristics of IESL were 1) round/ovoid and well-defined shape; 2) osteoblastic appearance on CT; 3) target-shaped enhancement on contrast enhanced MRI T1WI; 4) hypointensity on MRI T2WI; 5) preserved basivertebral vein; 6) lack of vertebral pathological fracture, paraspinal soft tissue, and expansile vertebral change. An accurate diagnosis of these MR enhancing lesions helps to prevent unnecessary invasive investigation and to promote appropriate management.
SM from extracranial malignant tumors in pediatric patients usually presents as inhomogeneous bone lesions in the CT scan, which can be either lytic, sclerotic, or mixed. [14,15] Typical MRI characteristics of SM include expansile change of the involved vertebrae, pathological fracture, pedicle or posterior element involvement, and paraspinal/epidural mass. [9, 14, 16, 17] These lesions are often hypointense on TIWI, hyperintense on T2WI, and have partial or marked post-contrast enhancement.[14, 15, 18] A hypointense lesion with hyperintense rim on T2WI, i.e., “the halo sign,” is also an indicator of metastasis.[9] Metastatic lesions generally have avid uptake on bone scan.[15] In contrast, pediatric MPBT with distant extraneural SM is rare. MPBT with SM have had image features like those of SM from extracranial malignant tumors. [15, 16, 19–23]
In our 3 IESL cases, neither malignant cells nor active inflammatory process was found on pathology examination. Besides, these lesions developed in the serial follow-up images but were not seen in the initial diagnosis of MPBT. These results suggest that IESL is likely a delayed response to the clinical treatment of MPBT with leptomeningeal seeding.[10, 11, 13] In the acute phase after radiotherapy and chemotherapy (within 1-2 weeks), cellular depletion and marrow edema occurs, with increased signal intensity on T2WI. Subsequently, fatty replacement and fibrosis take place, with disappearance of the red marrow. MRI then has heterogenous hyperintensity on T1WI, consistent with predominantly fat marrow. After 3-6 weeks of treatment, red marrow sometimes regenerates. The red marrow foci are hypointense on T1WI and T2WI, with variable post-contrast enhancement.[11, 13, 24, 25] Radiation-induced hematopoiesis is often patchy or band-like within the radiation portal; by contrast, hematopoiesis induced by chemotherapy, granulocyte-colony stimulating factor treatment, or hematopoietic stem cell transplantation often is diffuse, presenting as multifocal regenerating foci.[11, 13, 24, 26] In the Tc99m bone scan, hematopoietic marrow usually has no abnormal uptake, but increased uptake has been reported owing to high osteoblastic activity by the proliferation of hematopoietic cells. [25, 27] Our IESL patients had predominantly hypointense signals on T1WI and T2WI with post-contrast enhancement on MRI, and 2 of 3 had no uptake in the bone scan; these findings are like those of red marrow regeneration. However, active hyperplastic hematopoiesis was not evident in any of the pathology specimens. Therefore, we suggest that hematopoiesis is a contributing factor but cannot completely explain the mechanism of IESL.
The other possible explanation for IESL of pediatric MPBT is bone marrow ischemia/necrosis. Marrow fibrosis is induced by radiotherapy and chemotherapy, which may lead to marrow ischemia and necrosis.[28–30] Radiation-induced marrow necrosis usually is localized within the radiation portal, i.e., osteoradionecrosis, which could have occurred in our patients, as they were treated with whole spine irradiation for leptomeningeal seeding.[11] Typical image characteristics of spinal necrosis are discrete, well-defined, nonexpansile lesions, which lack soft tissue mass.[31] Osteonecrosis/infarction usually has a sclerotic appearance on CT scan, indicating calcification of the necrotic tissue or osteoblastic reparation of the focal ischemic insult.[18, 30] In MRI, these lesions often appear hypointense on T1WI and hyperintense on T2WI, which may become hypointense in late disease.[18, 31, 32] The “double line sign” is an image feature of early avascular necrosis, consists of a high-signal inner line representing hyperemic granulation and a low-signal outer parallel rim representing sclerotic bone on T2WI. [13,32] The layer of granulation tissue between necrotic and viable bone appears as rim enhancement in contrast-enhanced images.[32] One of our IESL patients had hyperintense spinal lesions with “double line sign” on T2WI and ring enhancement on post-contrast T1WI (Figure 1E, G), which is compatible with the common finding of bone infarction/necrosis.[13, 32] The Tc99m bone scan demonstrates variable uptake in bone infarcts and no uptake in the necrotic regions.[18, 33] In 2 of our 3 IESL patients, no uptake was evident on the bone scan, which is compatible with ischemia/necrosis or hematopoiesis.[18, 25, 33] However, some hot spots were seen in 1 IESL patient’s scan; this finding may be related to the uncommon presentation of bone infarct or focal hematopoiesis.[27, 33] In contrast, all SM patients had significantly increased uptake in the bone scan.
In our study, the imaging presentation of all IESL was mostly compatible with bone infarction/necrosis. Irradiation-induced cellular depletion and marrow fibrosis had been reported to progressively worsen over time, especially after 6 months of radiotherapy, which might explain the progressive change in our IESL.[28] Therefore, we favor dynamic marrow response with fibrosis and delayed ischemic/necrotic bone insult as the major mechanism of IESL in pediatric MPBT patients who were treated with craniospinal irradiation and chemotherapy. This view is compatible with the histologic findings of hypocellular marrow with fat replacement and fibrosis in 2 of our 3 IESL patients. The pathology finding in the other IESL patient was nearly normal hematopoiesis, which can be explained by the combination of early infarction followed by late marrow conversion.
By close examination, a target enhancement pattern of larger lesions on contrast enhanced T1WI was seen consistently in the IESL. The peripheral rim enhancement has been reported by Tang et al.[32] in osteonecrosis, while the target enhancing pattern has not been described. We suggest that the reparative process of the outer vascular bone marrow to the inner ischemic insult contributes to this layered enhancement. We also hypothesize that the peripheral enhancement is related to red marrow regeneration, and the central enhancing foci are composed of a fatty focus. [25, 34]
Our study has limitations. First, it is a retrospective study with a modest number of cases. Second, all IESL were found in pediatric patients with MPBT; we could not find MPBT with SM on MRI in our institute for comparison. As mentioned previously, SM from MPBT is extremely rare, and their image characteristics are much the same as those from extracranial malignant tumors. [15, 16, 19–23] Their similar image feature supports our nine SM patients being representative of all “true-metastasis” when comparing to IESL from MPBT. Further study comparing IESL and SM from MPBT may be considered. Third, although not reaching significance statistically, the IESL group had longer time intervals between the diagnosis of primary tumor and presence of spinal lesions. This is possibly related to the small number of cases, knowing that one IESL patient had his spinal lesions developed 17 years after the initial diagnosis of brain tumor, which is much longer than the other two IESL patients. Fourth, all IESL patients had received whole-spine irradiation, while none of the SM patients had prior spinal radiotherapy. It is noteworthy that whole-spine irradiation is commonly performed in MPBT due to the high incidence of neuroaxial metastasis; by contrary, spinal irradiation is not routinely performed in extracranial malignancy until the occurrence of spinal metastasis. Fifth, we did not analyze the difference between IESL and SM with advanced MRI techniques, such as dynamic contrast-enhanced T1WI, chemical-shift (in-out phase), diffusion-weighted imaging, and perfusion study.[35, 36] At last, we did not perform biopsies for all lesions with abnormal MRI signal, which may reflect hesitancy of practitioners to avoid repeated invasive procedure in pediatric patients.
In conclusion, indolent enhancing spinal lesions of malignant primary brain tumor in pediatric patients is related to treatment-induced delayed bone marrow change. We suggest that ischemic insult, such as bone infarction or necrosis, is the main mechanism responsible. IESL in pediatric patients with malignant primary brain tumors can be differentiated from spinal metastasis by their image characteristics. We recommend close follow-up rather than aggressive investigation and treatment for these IESL.