Symptomatic malignant spinal cord compression in children: a single-center experience

Background Malignant spinal cord compression (MSCC) is associated withpoor prognosis and may lead to permanent paralysis, sensory loss, and sphincter dysfunction. Very limited data are available on incidence and etiology of MSCC in pediatric population. We aimed to examine etiology, clinical presentation and treatment of pediatric patient with MSCC admitted to the Santobono-Pausilipon Children’s Hospital, Naples, Italy. Methods Forty-four children under 18 yearsadmitedsince 2007 and assessed for MSCC clinical presentations, evaluation, and treatment.were retrospectively collected from our institutional pediatric oncology and neurosurgery database. Results The median age at time of MSCC diagnosis was 52 months, with a peak in young (≤3 years) patients. The leading cause of MSCC was extramedullary tumors (63.6%), in particular neuroblastoma (27.2%) followed by Ewing sarcomas (15.9%). Cord compression was the presenting feature of a new malignancy in 33 (75%) patients, and a consequence of metastatic disease progression or relapse in the remaining 11 (25%) patients. Motor deficit was the initial symptoms of spinal compression in all patients, while pain was present in about 60% of patients, followed by sphincteric deficit (43.2%). The primary tumor site was located in the neck in 3 (6.8%) patients, thorax in 16 (36.4%), cervico-thoracic region in 3 (6.8%), thoraco-lumbar region in 8 (18.2%), abdomen in 5 (11.4%), lumbar-sacral region in 7 (15.9%) and thoracic-lumbar-sacral region in 1 (2.3%). The median length of the interval between symptom onset and tumor diagnosis varied widely from 0 to 360 days in the entire population, however this interval was significantly shorter in patients with known neoplasia in comparisonto patients with new diagnosis (at relapse 7 days [interquartile range 3–10] vs at diagnosis 23 days [7–60]). Pre and post-operative spine magnetic resonance imagingwas performed in all cases, and most(95%) patients underwent neurosurgical treatment as first treatment. Severe motor deficit was associated with younger age and severe motor deficit at diagnosis was associated withworst motor outcomes at discharge from neurosurgery. Patients with progression or relapsed disease showed a worst prognosis, while the majority of patients (70.5%) were alive at 5 years after diagnosis. Conclusions The natural history of MSCC in children is associated to permanent paralysis, sensory loss, and sphincter dysfunction, thus prompt diagnosis and correct management are needed to minimize morbidity. Treatment strategies differed widely among cancer types and study groups in the absence of optimal evidence-based treatment guidelines. When the diagnosis is uncertain, surgery provides an opportunity to biopsy the lesion in addition to treating the mass.


Introduction
Malignant spinal cord compression (MSCC) is one of the most feared complications of pediatric spinal cancers. [1] Cord compression may be the presenting feature of a new malignancy, or a consequence of metastatic disease progression or relapse. [2][3][4][5][6][7][8][9]Spinal cord compression (SCC)can be classified into three groups, based on tumor location:extradural (E-SCC), intradural/extramedullary (I/E-SCC), and  intramedullary (I-SCC), and can be caused by a number of ethiologicmechanisms including direct spread of tumor, extension of tumor through vertebral foramina into epidural space and bony disease within vertebrae with secondary cord compression. In adults, extradural tumors are most common, as they reside in the vertebrae body or structures outside the dura. Intradural-extramedullary tumors are the second most common and come from the leptomeninges or nerve roots inside the dura, but external from the spinal cord. The least common are intramedullary spinal cord tumors which arise from the spinal cord proper, leading to invasion and destruction of the gray and white matter [1]. Despite their impact on patient morbidity and mortality, very limited data are available on incidence and etiology of MSCC in pediatric population [2][3][4][5][6][7][8][9]. Moreover, diagnosis of MSCC in children can be particularly difficult at an early phase, especially in infants, thus increasing short-and longterm morbidity [10]. Yet, further insights in MSCC are key, as its natural history, if untreated, typically entails paralysis, sensory loss, and sphincter dysfunction, and this applies to children as well as to adults.  [11].

Grading of MSCC
The degree of motor deficit was evaluated by prospectively applying the Spinal Injury Association Impairment Scale adapted to patients' age [12]. It was graded as follows: grade 1, mild hypostenia with walking disability for legs, or difficulty in raising hands above head for arms; grade 2, moderate hypostenia with inability to walk and make movements against gravity or raise the hands above the head; grade 3, severe hypostenia with paraplegia, no elicitable tendon reflexes or muscular movements. The other main presenting symptoms (sphincter dysfunctions, pain and respiratory distress) were reported as either being present or absent.

Statistics
Descriptive statistics were used in terms of absolute frequencies and percentages for categorical variables and the Pearson's chi-square test or Fisher's exact test, if appropriate, was applied to compare proportions. Quantitative data were described in terms of median values with their interquartile range (IQR) and differences between groups were assessed by the Mann-Whitney Test. More advanced statistical analysis was not carried out, because the numbers in each diagnostic and etiological group were so low. All tests were two-tailed and a P-value < 0.05 was considered statistically significant. All data were performed by using MedCalc for Windows, version 9.6.4.0 (MedCalc Software, Mariakerke, Belgium).

Etiology
Since 2007, a total of 57 patients aged 0-18 years have sustained a tumor SCC.    . The majority of patients received partial removal (E-I/ E-SCC26/33 vs I-SCC 7/9, p ns). There were no perioperative deaths in the two groups. Post-operative MRI scanning established adequate decompression in all patients, while reoperation was required in 1 patient for spinal stenosis within 36 h. Twenty-one (64%) patients affected with E-I/E-SCCunderwent laminotomy, 10 (30%) laminectomy and 2 (6%) corpectomy (Fig. 2).

Five-year survival
Thirteen patients (29.5%) died, of which 5 (38.4%) as a direct result of the tumour, 8 (61.6%) for metastatic progression or relapse. Details on individual patients are reported in Table 5 Discussion Spinal cord compression secondary to cancer is a rare diagnosis but represents an oncology emergency as itmay lead quickly to permanent paralysis, if not treated effectively and promptly. Acute compression of the spinal cord occurs in 3 to 5% of children with cancer, often at diagnosis [13,14].  [6,15]. The median length of the interval symptomtumor diagnosis varied widely from 0 to 360 days in the entire population, however this interval was significantly shorter in patients with known neoplasia respect to patients with new diagnosis (at relapse 7 days, IQR 2.8-10.3 vs at diagnosis 22.5 days, IQR 7-60 days). It is widely accepted that MSCC is considered as a medical emergency and any diagnostic delay should be avoided. For children presenting in District General Hospitals with a strong suspicion of SCC, transfer to a principal treatment centreis recommended because management is highly complex and requires the input of a Neurosurgery and Clinical Oncology. In our case series, pre and post-operative spine MRI was performed in all the cases It is widely recognized that pre and post contrast MRI spine is the gold standard for diagnosis, and should be performed before 24 h have elapsed [16]. In our study, severe motor deficit was associated with younger age and severe motor deficit at diagnosis was associated to worst motor outcomes at discharge from neurosurgery. Our patients with progression or relapsed disease showed a worst prognosis, while the majority of patients (70.5%) were alive at 5 years after diagnosis.
Recently, a systematic review showed that patients with SCC due to NBL differ from patients without intraspinal extension with younger age at diagnosis. Moreover the severity of the neurological motor deficit at diagnosis had the most predictive power for the neurological outcome [17]. Classification in E, I/E and I-SCC is helpful in developing a differential diagnosis and guiding appropriate clinical management. Surgical resection is the treatment of choice for I-spinal tumors leading to SCC. Instead, the discussion whether to perform immediate surgical decompression in cases of E-I/E spinal cord compromise due to cancer is still open. In our case series, the   [18]. Results of various retrospective studies showed that chemotherapy can be an effective initial treatment option in NBL and Ewing Sarcoma, however population size of these studies is too small to make definite conclusions. [15,17,19]. Actually, a SIO-PEN prospective study registry of Peripheral Neuroblas-ticTumours (PNTs) presenting with spinal canal involvement aims to describe the natural history of PNTs presenting with SCC and describe the diagnostic and therapeutic approaches adopted in participating centers. As results from this and other clinical studies will become available, physicians will be able to make better-informed decisions on treatment for future pediatric patients.
Limitations of this work are several, and of course include the retrospective, observational, single-center design. In addition, we did not focus on the inclusion of asymptomatic MSCC, and thus additional studies are required to confirm our findings in general, and in particular to detail the outlook of MSCC without symptoms or clinical signs.

Conclusions
The natural history of MSCC typically entails a poor prognosis as well as permanent paralysis, sensory loss, and sphincter dysfunction. This case series emphasize the need to consider cancer in the differential diagnosis of more common diseases in pediatric patients, especially because early diagnosis and proactive treatment are vital to improve prognosis and survival. For children with a high suspicion of MSCC, transfer to a principal centreis recommended because management is complex and requires multidisciplinary discussion about best treatment. Moreover, a child with history of cancer who develops back/extremity pain should be considered to have spinal cord compromise until proved otherwise. Spine MRI is the gold standard for diagnosis, and should be performed before 24 h have elapsed. Treatment strategies differ widely among cancer types and study groups in the absence of optimal evidence-based treatment guidelines. When the diagnosis is uncertain, surgery provides an opportunity to biopsy the lesion in addition to treating the mass.