VOLUME 34 • NUMBER 22November 1, 2012

Metastatic lesions of the central nervous system are a com-mon disease pathology treated by both neurosurgeons andneuro-oncologists. Less frequently observed, however, aremetastatic lesions of the spinal cord. Intramedullary spinalcord metastasis (ISCM) is rare, with an estimated incidenceof 0.9% to 2.1% among cancer patients. The most commonmetastatic lesion is primary lung carcinoma (29%–54%), withthe remainder attributed to breast (11%–14%), colon (3%–5%),kidney (6%–9%), thyroid (2%), ovarian (1%), melanoma (6%–9%), and lymphoma (4%). Approximately 33% of patientswith ISCM harbor concomitant brain metastases, and 25%suffer from leptomeningeal carcinomatosis.

The advancement of surgical techniques has empoweredspine surgeons, oncologists, and radiation therapists to treat

extradural or bony spinal metastases safely. Unfortunately, theless common ISCM continues to have a significantly worseprognosis and often occurs concomitant with advanced sys-temic disease, with 80% mortality at 3 months. Among thisgroup, breast carcinoma is associated with the longest survival,with a median of 13 months. Of note, the most commonlyaffected spinal cord segment seems to be cervical, althoughISCM can occur at any level. In this review, we survey the pre-sent literature to present a summary of the diagnostic and treat-ment options available for ISCMs and present our experience.

Clinical Presentation and DiagnosisThe clinical presentation of patients with ISCM is highly vari-

able and may include neurologic weakness, pain, loss of sen-sory function, and cauda equina symptoms. A meta-analysisof 138 patients by Kalayci et al. demonstrated that weaknesswas the most common presenting symptom of ISCM (91% ofpatients). The next most common presenting symptoms aresensory loss (79%), sphincter dysfunction (60%), spinal pain(38%), radicular pain (24%), and followed by Brown-Sequardsyndrome (23%). Only 1% of cases are asymptomatic.

Although ISCM is rarely the initial presentation of malig-nancy, it has been observed as such in 23% to 39% of casesdue to the involvement of eloquent structures. The median

Intramedullary Spinal Cord Metastasis, Diagnosis, And ManagementAnand Veeravagu, MD, Yi-Ren Chen, BA, BS, Robert Lieberson, MD, Robert M. Lober, MD, PhD, and Steven D. Chang, MD

Learning Objectives: After participating in this CME activity, the neurosurgeon should be better able to:1. Analyze the incidence, most common primary source, and overall prognosis of patients with intramedullary spinal cord metastasis (ISCM).2. Select the best diagnostic test for ISCM.3. Evaluate the available treatment options for ISCM such as open surgical intervention, radiation therapy, and stereotactic radiosurgery.

A BIWEEKLY PUBLICATION FOR CLINICAL NEUROSURGICALCONTINUING MEDICAL EDUCATION

Category: Tumor, Spine

Key Words: Cancer, Intramedullary, Metastasis, Spinal cordLippincott Continuing Medical Education Institute, Inc. is accredited by the Accreditation Council for Continuing Medical Educationto provide continuing medical education for physicians.

Lippincott Continuing Medical Education Institute, Inc. designates this enduring material for a maximum of 1.5 AMA PRA Category 1Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. To earn CME credit,you must read the CME article and complete the quiz and evaluation on the enclosed form, answering at least 70% of the quiz questionscorrectly. This activity expires on October 31, 2013.

Dr. Veeravagu is a Resident, Department of Neurosurgery, StanfordUniversity Medical Center, Stanford, CA; Mr. Chen is a Medical Student, Stanford University School of Medicine, Stanford, CA; Dr. Lieberson is Assistant Professor, Department of Neurosurgery,Stanford University Medical Center, Stanford, CA; Dr. Lober is Resi-dent, Department of Neurosurgery, Stanford University Medical Cen-ter, Stanford, CA; and Dr. Chang is Robert C. and Jeannette PowellProfessor in the Neurosciences, Department of Neurosurgery, StanfordUniversity Medical Center, 300 Pasteur Dr, R225 MC 5327, Stanford,CA 94305; E-mail: sdchang@stanford.edu.All faculty and staff in a position to control the content of this CMEactivity have disclosed that they and their spouses/life partners (ifany) have no financial relationships with, or financial interests in,any commercial organizations related to this CME activity.

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interval between onset of symptoms to final diagnosis rangesfrom 1 to 9 weeks, with the greatest range being 17 months.At diagnosis, 20% of patients are independently walking,40% are walking with assistance, and 40% are nonambula-tory. Complete neurologic deficit develops in 75% of patientswith ISCM within 1 month.

Overall, the clinical presentation of ISCM does not distin-guish it from the more common extradural spinal metastasis.However, asymmetric neurologic deficits occur in 1% to 8%of patients with epidural spinal cord compressions, comparedwith 32% to 45% of patients with ISCM.

Diagnosis requires MRI with gadolinium, as it is highly sen-sitive in identifying ISCM lesions. A recent review showed that50 (91%) patients with ISCM demonstrated enhancement ofthe spinal cord lesion with gadolinium. The typical ISCM onMRI appears as an isolated, oval-shaped lesion that is isointenseon T1-weighted images with possible anatomic deformation. Apencil-shaped hyperintensity may be seen on T2-weightedimages, with signal abnormality around the central lesion dueto edema. In a report of 30 patients, there was only 1 false-negative report, with 23 of 25 patients with ISCM havingenhancement of the lesion with gadolinium.

Other studies such as CT, myelography, cerebrospinal fluid(CSF) studies, and positron emission tomography (PET) are ofless importance in the diagnosis of ISCM. Although CT hasbeen observed to be diagnostic in a few patients, MRI has muchhigher sensitivity and specificity. Similarly, myelography maybe normal in up to 40% of patients. One study showed that aprotein level greater than 50 mg/dL in CSF studies is oftenobserved in patients with ISCM; however, only 18% of CSFsamples contained malignant cells in one study of 22 patients.Imaging with PET, though not the first study of choice, mayprovide information on the location of metastatic origin. Onestudy reported the use of PET to diagnose an asymptomaticISCM patient with lung carcinoma.

TreatmentTo our knowledge, no randomized clinical trials, prospec-

tive studies, or matched-pair analyses have been performed

on the treatment of ISCM. We will review here the availabledata from retrospective studies and the articles.

Open Surgical InterventionIn 2009, Dam-Hieu et al. retrospectively reviewed 19 patients

with ISCM at a single institution in France. Thirteen (68%)patients underwent microsurgical excision of an ISCM. Themedian survival was 6.1 months, with surgery increasingmedian survival from 2.6 to 7.4 months (P � 0.03). Elevenof the 13 patients who underwent surgery also underwentpostoperative fractionated external beam radiation therapy(EBRT); of note, both patients who did not receive EBRT hadshorter survival (2 months). Neurologic function improvedin 7 patients, remained stable in 2, and worsened in 4 patientsafter surgery. Overall, the study supports the use of surgeryin conjunction with EBRT in patients with incomplete, rapidlyworsening neurologic deficits.

In 2005, Gasser et al. published a retrospective study of13 patients with ISCM that also supports the use of surgeryin maintaining neurologic function. The study reviewed aseries of 146 patients with intramedullary tumors, 13 of whomwere from metastases, at a single institution in Germany. All13 patients underwent microsurgical excision of the tumor,with a median survival of 6.8 months. After surgery, neuro-logic status remained stable in 11 (85%) patients and worsenedin 2 (15%) patients. Similarly, in 2001, Schick et al. retrospectivelyreviewed 220 patients with spinal metastases, 6 of whom hadISCM, at a single institution in Germany. All 6 patients under-went surgery, and after surgery, neurologic function improvedin 2 patients (33%), remained stable in 3 (50%), and worsenedin 1 (17%). Overall, median survival was 2 months, with arange of 1 to 5 months.

In additional to preserving neurologic status, open surgerymay also increase survival for patients with ISCM. In 1996,a study from Schiff and O’Neil reviewed 40 patients withISCM at the Mayo Clinic (Rochester, MN). Thirty-five (87.5%)patients underwent fractionated EBRT at 1630 to 4520 cGy,5 (12.5%) underwent surgery (4 of whom had previouslyundergone EBRT), and 3 (7.5%) received neither EBRT nor

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EDITOR: Ali F. Krisht, MD Director, Arkansas Neuroscience InstituteLittle Rock, Arkansas

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surgery. Median survival among the surgery patients was 8months, compared with 4 months for EBRT and 2 monthsfor patients who received no treatment.

Further support for surgery is provided by the fact thatISCMs tend to be well circumscribed and amenable to opera-tive intervention. Advances in microsurgical techniques mayalso make surgery a more attractive option in selected patients.

Radiation TherapyIn 2007, Conill et al. retrospectively reviewed 6 patients

with ISCM from lung cancer at a single institution in Spain.All 6 patients underwent EBRT at 2300 to 4000 cGy. Five (83%)patients had improvement in neurologic status after EBRT,with a mean duration of 17.2 days (range, 6–40 days). Mediansurvival was 5 months, with the cause of death being systemicdisease progression in most patients. This study supports theuse of radiation therapy to preserve spinal cord function, albeitonly for a short duration.

Similarly, in the 1996 study by Schiff and O’Neil mentionedearlier, 35 (87.5%) of the 40 patients received EBRT as a stand-alone therapy. Neurologic status of the overall cohort wasreported; 35 (87.5%) patients had the same ambulatory statusas admission, 3 (7.5%) had neurologic improvement, and 2 (5%)had worsening neurologic function. Outcomes by treatmentgroup were not reported. Overall, the study also supports theuse of EBRT or surgery to preserve neurologic function inpatients who are ambulatory at diagnosis.

In contrast, Lee et al. in 2007 showed that EBRT alone haslittle benefit in patients with significant neurologic deficits.

The study retrospectively reviewed 12 patients diagnosed withISCM in a single center in Korea. Eleven patients underwentfractionated EBRT at 2000 to 3000 cGy, and none recovered ofmotor function.

Radiosurgery/The Stanford ExperienceRadiation therapy does carry the risk of radiation myelitis

and its associated comorbidities. Stereotactic radiosurgery (SRS)may offer an alternative to traditional radiotherapy in the treat-ment of ISCMs. Previous studies have demonstrated the effi-cacy of SRS on primary vascular tumors of the spinal cord, suchas hemangioblastomas. A review of the available literaturerevealed 8 patients with ISCM who were treated with SRS,7 of whom had detailed treatment information (Table 1). Six(86%) patients received a single SRS treatment of 10 to 16 cGyand 1 patient received 5 SRS treatments (14%). Overall, theaverage survival was 11 months. Six (86%) patients had im -proved neurologic function and 1 (14%) had stable functionafter treatment. No patient had any reported complications,and the median survival was 5.2 months (range, 5.2–26 months).

At Stanford University Hospital and Clinics, we have treated9 patients with ISCM from 2000 to 2010 with SRS. Sevenpatients were female, and the mean age at presentation was64 (range, 33–77) years. Three patients were asymptomatic atdiagnosis, whereas the other 6 had symptoms of pain (2), weak-ness (4), and numbness (3). Primary tumor sources includebreast (5), non-small-cell lung cancer (2), cystic adenocarci-noma (1), and epithelioid hemangioepithelioma (1). Sevenlesions (64%) were in the cervical spinal cord, compared with

Table 1. Previously Published ISCMs Treated With SRS

Age Primary Dose (Gy)/

(years), Location, Volume Type/No. of Clinical Survival

Authors Date Location Sex Presentation Pathology (cm3) Sessions Notes Condition (months) Complications

Shin et al. 2009 C6 51, M Arm and leg Skin, 0.4 16/IMRT/1 Improved 5.2 Nonumbness Melanoma

Shin et al. 2009 C7 50, F Paraplegia Breast, 0.7 14/IMRT/1 Unchanged 2.2 Noadenocarcinoma

Shin et al. 2009 C3 71, F Paraparesis Kidney, 1.0 14/IMRT/1 Improved 5.2 Noand arm Renal Cellnumbness

Shin et al. 2009 C5 47, F Radicular pain Breast, Invasive 1.8 12/IMRT/1 Previously Improved 19.4 NoDuctal treated

with EBRT

Shin et al. 2009 C6 67, F Hemiparesis Lung, 3.7 16/IMRT/1 Improved 5.2 Noand voiding Non-Small-Celldifficulty

Shin et al. 2009 T11–T12 14, M Radicular Brain, 12.0 10/dynamic Previously Improved 14.0 Nopain Glioma conformal/1 treated

with EBRT

Parikh 2009 C5 50, M Arm pain, Kidney, Clear Cell NA 15/Cyber Previously Improved Alive at 26 Noand numbness, (9/7 mm Knife/5 treated monthsHeron and in greater with

weakness extent) EBRT

Chamberlain 2010 T1–T3 67, M Paraparesis Lung, Mesothelioma NA NA/Cyber NA NA NA NAet al. Knife/NA

EBRT, external beam radiation therapy; ISCM, intramedullary spinal cord metastasis; IMRT, intensity-modulated radiation therapy; NA, not available; SRS,stereotactic radiosurgery.

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3 (27%) in the thoracic cord and 1 in the conus medullaris (9%).All patients had progressive systemic metastases, and 3 hadsimultaneous metastatic lesions in the brain at the time of pre-sentation. Patient characteristics are summarized in Table 2.

Patients received 14 to 27 Gy (median, 21 Gy) in 1 to 5(median, 3) sessions of CyberKnife Radiosurgical System withMultiPlan software. The median tumor volume was 0.48 mL(range, 0.12–6.4 mL). No patient suffered deterioration in gaitor other neurologic worsening related to SRS. One patientremained alive at 14 months after therapy. Of the 8 deceasedpatients, median survival was 4.1 months (range, 1.1–9.1months) (Figure 1). No radiation toxicity was detected clini-cally during the follow-up period, and no abnormality within

the spinal cord on T2-weighted or contrast-enhanced imageswas present to suggest radiation injury.

ConclusionThe goal of treatment in patients with ISCM should be to

maximize survival, maintain quality of life, and improve orsustain neurologic function. Review of the literature availablesuggests that radiation therapy is a crucial treatment of ISCM,both as an independent or adjuvant therapy to surgery. Sur-gical resection can also be considered in patients with incom-plete, rapidly progressive neurologic deficits. Furthermore,SRS seems to improve both survival and neurologic functionin patients with ISCM, and should be considered as a viablealternative to open surgery or conventional radiotherapy.Prospective studies are needed to compare the efficacy of var-ious treatment modalities on morbidity and mortality, and toaid in the development of a standardized treatment protocolin patients with ISCM.

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J Radiol. 1999;72:89-91.Bizzozero L, Ferrara M, Villa F, et al. Intramedullary spinal cord metastasis.

Case report. J Neurosurg Sci. 1994;28:193-195.Castro S, Duca S, Davini O, et al. MRI diagnosis of intramedullary metastases

from extra-CNS tumors. Eur Radiol. 1997;7:732-736.Chamberlain MC, Eaton KD, Fink JR, et al. Intradural intramedullary spinal

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intramedullary spinal cord metastases from lung cancer. Clin Transl Oncol.2007;9:172-176.

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Figure 1. Stanford radiosurgery for ISCM: Kaplan-Meier survivalcurve.

Table 2. Stanford Radiosurgery for ISCM: Patient Characteristics, Treatment Parameters, Clinical Response to Treatment

Age, Volume Dose Isodose Survival

Pt No. Year Location Sex Diagnosis (cm3) (Gy) Fractions Dmax % BED CI (months) Complications

1 2006 T6 77, F Breast, 0.20 18 2 24.3 74 38 2.88 6.0 Noadenocarcinoma

2 2010 C5–C6 65, F Breast, 1.4 21 3 27.3 90 39 2.49 9.1 Noadenocarcinoma

3 2007 T2 67, M Lung, 0.80 25 5 31.2 80 40 1.89 2.7 Nonon-small cell

4 2003 C2–C3 39, F Breast, 1.9 22 2 26.2 84 50 1.31 5.4 Noadenocarcinoma

5 2010 C3 40, F Breast, 0.12 20 2 25.0 80 44 1.21 5.0 Noinfiltrating ductal

6 2006 C5 43, M Epithelioid 0.29 27 3 35.5 76 55 1.79 3.3 Nohemangioepithelioma

6 2006 T2 43, M Epithelioid 0.30 27 3 37.0 73 55 1.64 3.3 Nohemangioepithelioma

6 2006 L2 43, M Epithelioid 0.48 18 1 24.6 73 55 1.74 3.3 Nohemangioepithelioma

7 2010 C1–C2 51, F Teratoma 0.64 20 2 26.7 75 44 1.43 Alive No

8 2000 C1 75, F Breast, 6.4 14 4 16.8 83 22 1.41 1.1 Noinflammatory

9 2005 C6–C7 67, F Lung, 0.38 21 3 27.2 77 39 1.24 2.2 Nonon-small cell

BED, biologically effective dose; CI, confidence interval; Dmax, maximum dose; ISCM, intramedullary spinal cord metastasis.[AQ4]

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Cormio G, Di Vagno G, Di Fazio F, et al. Intramedullary spinal cord metastasisfrom ovarian carcinoma. Gynecol Oncol. 2001;81:506-508.

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Dam-Hieu P, Seizeura R, Mineoa JF, et al. Retrospective study of 19 patientswith intramedullary spinal cord metastasis. Clin Neurol Neurosurg. 2009;111(1):10-17.

Decker RE, Sundrani S, Citron ML, et al. Intramedullary spinal cord metastasesby complete resection of tumor before radiotherapy and chemotherapy:case report and review. Spine. 1987;12:393-395.

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Gasser T, Sandalcioglu EE, Hamalawai B, et al. Surgical treatment ofintramedullary spinal cord metastases of systemic cancer: functional outcome and prognosis. J Neurooncol. 2005;73(2):163-168.

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Ikeda D, Harrop MD, James S. Intramedullary spinal cord metastases andradiation therapy: a case report. JHN Journal. 2009;4(2):2.

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1. Breast cancer is the most common primary source for ISCM.True or False?

2. ISCM has a better prognosis than extradural or bony spinalmetastasis.

True or False?

3. Weakness is the most common presenting symptom of ISCM.True or False?

4. MRI with gadolinium is the diagnostic imaging technique ofchoice for ISCM.

True or False?

5. Radiation therapy is not necessary if a patient with ISCMreceived open surgery.

True or False?

6. SRS is not an acceptable alternative to open surgery or conven-tional radiation therapy for ISCM.

True or False?

7. Breast carcinoma is associated with the longest survival period.True or False?

8. The most commonly affected spinal cord segment seems tobe the thoracic region.

True or False?

9. Imaging with PET is the first study of choice in a patient with ISCM,as it provides information on the location of the metastatic origin.

True or False?

10. ISCMs tend to be well circumscribed and amendable to opera-tive intervention.

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AUTHOR QUERIES

TITLE: CNEv34n22

[AQ1]: Copyright transfer/disclosure forms need to be submitted for Drs. Veeravagu and Lieberson before the articlecan be printed. Please return these with corrected proofs.

[AQ2]: Present radiation doses in the text in Gy instead of cGy, like the Tables?[AQ3]: In Table 1, footnotes, please verify the expansion for NA.[AQ4]: In Table 2, please confirm abbreviations are defined correctly in headlings and footnote.

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