Spinal Metastases From Myxoid Liposarcoma Warrant Screening With Magnetic Resonance Imaging

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1 1815 Spinal Metastases From Myxoid Liposarcoma Warrant Screening With Magnetic Resonance Imaging Joseph H. Schwab, MD 1 Patrick J. Boland, MD 1 Cristina Antonescu, MD 2 Mark H. Bilsky, MD 3 John H. Healey, MD 1 1 Department of Surgery, Orthopedic Service, Memorial Sloan-Kettering Cancer Center, New York, New York. 2 Department of Pathology, Memorial Sloan- Kettering Cancer Center, New York, New York. 3 Department of Surgery, Orthopedic and Neurosurgery Services, Memorial Sloan-Kettering Cancer Center and Medical College of Cornell University, New York, New York. BACKGROUND. Myxoid liposarcoma (MLS) has an unusual tendency for extrapulmonary metastasis, particularly to the spine and soft tissues. The objective of this study was to determine the prevalence of spinal metastasis, treatment outcomes, and optimal screening method for spinal metastasis in patients with MLS. METHODS. Data from patients with had spinal metastases were obtained from the authors institutional soft tissue sarcoma database. The accuracy with which positron emission tomography (PET) scans and bone scans identified metastatic lesions was compared with the accuracy of magnetic resonance imaging (MRI). Clinical response to treatment was based on pain, neurologic scores, and survivorship analysis. RESULTS. There were 33 patients who developed spinal metastasis after a median 36 months of follow-up (range, from 7.5 months to 33 years). Known spinal metastases were detected by bone scans in 16% of patients and by PET scans in 14% of patients. Patients who underwent surgery had high-grade spinal cord compression more often than patients who did not undergo surgery (72% vs 19%, respectively; P 5.002). Pain and neurologic function were improved or maintained in all patients who received radiation alone (n 5 8 patients) and in all but 1 patient who underwent surgery (n 5 18 patients). The median overall survival was 51.4 months from the time of primary diagnosis and 21.9 months from the time of first metastasis. CONCLUSIONS. Bone scans and PET scan lack sufficient sensitivity to detect spinal metastasis from MLS. Treatment of metastasis is palliative, but local treatment can yield long-term disease control in select patients. Screening with whole-spine MRI may lead to the earlier detection of spinal metastasis. Cancer 2007;110: Ó 2007 American Cancer Society. KEYWORDS: myxoid liposarcoma, spinal metastasis, positron emission tomography scan, bone scan. Address for reprints: John H. Healey, MD, Department of Surgery, Orthopedic Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Suite A342, New York, NY 10021; Fax: (212) ; healeyj@mskcc.org Received February 21, 2007; revision received April 11, 2007; accepted May 22, Myxoid liposarcoma (MLS) has unique clinical features that may warrant a special diagnostic and treatment approach. It has a propensity to metastasize to the spine, which distinguishes MLS from most other soft tissue sarcomas. Isolated case reports and small series have reported this phenomenon, but the true frequency is not known. 1 3 The optimal screening modality for spinal metastasis in this population also is unknown. Bone scintigraphy and magnetic resonance imaging (MRI) have been used, but their sensitivity and specificity have not been analyzed. 4 6 The treatment and outcome of patients with spinal metastasis has not been described well. Currently, systemic therapy is investigational, and the local ª 2007 American Cancer Society DOI /cncr Published online 27 August 2007 in Wiley InterScience (

2 1816 CANCER October 15, 2007 / Volume 110 / Number 8 treatment of spinal metastasis is palliative. Radiation and surgery have been advocated, but the best combination has not been defined. Necessary changes in diagnostic staging and treatment for patients with MLS should be based on an analysis of clinical and outcome data. The objectives of the current study were to describe the prevalence of spinal metastasis from liposarcoma, review the outcome of treatment, and determine the optimal screening modality for spinal metastasis in patients with MLS. MATERIALS AND METHODS With institutional review board approval, we surveyed our database for patients with MLS metastatic to the spine who were treated between 1982 and We excluded well-differentiated, pleomorphic, dedifferentiated liposarcomas. The patient s medical records, including operative reports and follow-up appointments, were reviewed. Imaging studies, including plane x-ray, MRI, computed tomography (CT) scans, bone scans, and positron emission tomography (PET) scans, were reviewed in all patients when available. All patients with spinal metastasis had a spine MRI study obtained with the minimum of T1- and T2-weighted sequences in the axial and sagittal planes. Whole-spine MRI studies were obtained in patients with back pain who had a diagnosis of MLS. In addition, MRI studies were obtained in patients who had a positive bone or PET scan of the spine. Primary tumors were reviewed and confirmed as MLS in all patients. Metastatic lesions were confirmed histologically using the surgical specimen or biopsy in patients who did not undergo surgery. There were 33 patients with spinal metastasis among the total 230 patients who had MLS in our database. The spine was the first site of metastasis in 18 patients. The median time to first metastasis was 22 months (range, months). The median age was 47 years (range, years). Detailed demographic, clinical, pathologic, and treatment data are presented in Table 1. All low-grade tumors were large (>5 cm) and deep; consequently they were categorized as stage IIA according to the sixth edition of the American Joint Commission on Cancer (AJCC) staging manual. 7 Six of the 7 low-grade tumors measured >10 cm. Twenty-three of the 26 high-grade tumors were stage III, and 2 patients presented with AJCC stage IIB disease. Two patients presented with metastasis. The diagnosis of MLS is based on the appearance of uniform, round to oval-shaped cells with a myxoid background associated with a plexiform capillary network. Grading is based largely on the percentage of round cells noted on all individual sections (average, 1 block per 1 cm 3 ). Tumors with >5% round cells are considered high grade, and tumors with <5% round cells are considered low grade. 8,9 Twenty-nine of our patients were diagnosed with spinal metastasis after they presented with signs or symptoms referable to the spine. The most common presenting complaint was back pain, which occurred in 27 patients, and 2 patients presented with a neurologic deficit. The patients symptoms instigated further spinal imaging, including T1- and T2-weighted MRI studies in the axial and sagittal planes in all patients. The diagnosis of spinal metastasis was made incidentally with axial images on 4 occasions. These patients did not present with signs or symptoms that indicated spinal metastasis. A traumatic event prompted the MRI in 1 patient and facilitated the diagnosis. In 2 other patients, an MRI had been ordered to evaluate possible retroperitoneal masses. In 1 patient, a CT scan detected the spinal metastasis. We grouped the spinal metastases into 4 regions, including the cervical, thoracic, lumbar, and sacral spine. Seventeen patients had >1 region involved. The most common site of metastasis was the lumbar spine with 23 events; the thoracic and sacral spine had 19 events and 8 events, respectively; and the cervical spine had 4 events. Pain scores were determined by using a selfassessment visual analog scale from 0 to 10. Patients with mild pain had scores of 0 to 3, moderate pain was scored from 4 to 7, and severe pain was scored as >7. 10 Sixteen patients presented with moderate to severe pain, and 12 patients presented with mild pain (Table 1). Each patient s spinal metastasis was classified further from 0 to 3 according to the degree of epidural extension on MRI Studies (Fig. 1). Any grade >1 is considered high-grade compression, and grade 3 correlates with a complete block of cerebrospinal fluid on myelography. Sixteen patients presented with high-grade epidural involvement. Twenty-two of 33 patients received radiation therapy to the spine. The primary objective of radiation in this group was palliation of symptoms. The median dose was 3000 centigrays (cgy) (range, cgy). Only 1 patient received >4000 cgy. One patient received brachytherapy using I-125. Eleven patients did not receive radiation to the spine. Three patients refused radiation therapy. The 8 other patients who did not receive radiation received chemotherapy. Four of those patients were asymptomatic from their spinal metastasis. They had multi-

3 Spinal Metastasis from Myxoid Lipsarcoma/Schwab et al TABLE 1 Detailed Demographic, Clinical, Pathologic, and Treatment Data of Patients With Myxoid Liposarcoma Pain Patient Sex Age, y Primary site Grade* Spinal segment y ED Surgery XRT, Gy { Preoperative Postoperative LFU, mo Status 1 Man 49 Thigh Yes 3500 Moderate None NED 2 Woman 40 Popliteal Yes 3000 Severe Mild DOD 3 Man 43 Ankle Yes 1600 Severe Moderate 32.3 DOD 4 Woman 62 Buttock Yes 3000 Moderate Mild 44.8 DOD 5 Man 55 Thigh Yes 3000 Moderate Mild 54.8 DOD 6 Man 40 Thigh Yes 0 Moderate Severe 12.5 DOD 7 Woman 56 Thigh 1 2,3 3 Yes 0 Moderate Mild 35.4 DOD 8 Man 37 Pelvis 0 3,4 2 Yes 3250 Severe Mild 34.5 DOD 9 Man 55 Foot Yes 3000 Mild Mild 18 DOD 10 Man 44 Thigh Yes 4000 None None 89.6 AWD 11 Man 51 Thigh 1 3,4 2 Yes 3750 Severe Mild 58.2 DOD 12 Man 29 Thigh 1 1,2 2 Yes 3000 Mild Mild 31.1 DOD 13 Man 41 Thigh Yes 7000 Severe None 40.2 AWD 14 Man 37 Ankle Yes 0 Mild Mild 84.2 NED 15 Woman 50 Thigh 1 1,2,3 3 Yes 3000 Mild Mild 20.6 AWD 16 Woman 53 Calf 1 1,2,3 3 Yes 3000 Severe Mild 34.1 DOD 17 Man 34 Retroperitoneum Yes 2100 Severe Moderate 7.5 DOD 18 Man 48 Thigh Yes 0 Mild Mild DOD 19 Man 38 Thigh 1 3,4 0 No 0 Mild Mild 90 DOD 20 Man 51 Thigh No 3000 Mild Mild 23.4 DOD 21 Man 47 Thigh No 3000 Severe Mild 15.2 DOD 22 Man 45 Thigh 1 2,3,4 0 No 0 Mild Mild 7.7 AWD 23 Man 52 Thigh 1 3,4 1 No 0 Mild Mild 56.5 DOD 24 Woman 64 Thigh 1 2,3,4 0 No 3000 Moderate Mild 11.7 AWD 25 Man 33 Thigh 1 1,2 0 No 4000 None None 18.8 DOD 26 Woman 62 Thigh No 0 Mild Mild 37.3 AWD 27 Man 69 Thigh 0 4,5 2 No 3750 Moderate Mild 20.8 AWD 28 Man 30 Popliteal 0 2,3 2 No 3300 Mild None DOD 29 Man 48 Thigh No 3000 Moderate Mild 51.4 DOD 30 Man 75 Thigh 1 2,3 0 No 0 None None 13 DOD 31 Woman 65 Popliteal 1 2,3 0 No 3750 None None 83.8 AWD 32 Woman 29 Thigh 1 3,4 0 No 0 None None 37 DOD 33 Man 33 Thigh 1 2,3 2 No 0 Mild None 12 AWD ED indicates extent of epidural compression; XRT, external-beam radiotherapy; Gy grays; LFU, last follow-up; NED, no evidence of disease; DOD, dead of disease; AWD, alive with disease. * For grade, 1 indicates high-grade tumor (>5% round cells), and 0 indicates low-grade tumor (<5% round cells). y For spinal segment, 1 indicates cervical spine; 2, thoracic spine; 3, lumbar spine; 4, sacral spine. { Dose in Gy administered to the spine. ple sites of metastases outside the spine; therefore, local treatment was not warranted. Four other patients had only mild pain referable to their spine. They had other, more painful sites of metastasis, and radiation was delivered to these other sites followed by chemotherapy. Surgery was recommended as the primary therapy if there was 1) mechanical instability; 2) symptomatic, high-grade epidural disease or nerve root compression; or 3) a solitary metastasis potentially amenable to curative resection. Eighteen patients underwent surgical decompression (Table 1). One patient was treated with curative intent for a solitary lumbar metastasis, and the other 17 patients were treated with palliative intent. Thirteen of 18 patients who underwent surgery had high-grade spinal cord compression. This differed statistically from the patients who did not undergo surgery (3 of 16 patients; P 5.002). Four patients had mechanical instability without significant epidural involvement. Three of those patients underwent surgical decompression of their spinal roots, which were compressed by a large soft tissue mass in each patient that emanated from the vertebral body. Statistical analyses were performed with SPSS software (version 12; SPSS, Chicago, Ill). The Kaplan- Meier method was used to calculate overall survival. A P value of.05 was designated as the minimum

4 1818 CANCER October 15, 2007 / Volume 110 / Number 8 FIGURE 1. Epidural spinal cord compression (ESCC). Based on axial T2-weighted magnetic resonance images, 0 5 no ESCC with no subarachnoid space obliteration (SSO); 1 5 partial ESCC with no SSO; 2 5 partial ESCC and SSO; 3 5 complete ESCC and SSO. cut-off point for statistical significance. The Fisher exact test was used to make between-group comparisons. We calculated the sensitivity and specificity of bone scans and PET scans to detect spinal metastases. We reviewed the number of spinal metastases that were detected on each scan by considering each vertebral level as a separate entity. We considered a scan positive if it demonstrated tracer uptake in a region that corresponded to abnormal signal on the MRI in patients who had biopsy-proven, metastatic disease. RESULTS Nine patients had bone scans obtained within 2 weeks of being diagnosed with spinal metastasis. The bone scans were ordered to detect other areas of occult bony metastasis. Only 3 of the 9 patients had increased uptake in the spine, although they had known spinal metastasis based on MRI studies. Closer inspection of the bone scans revealed a total of 5 vertebrae that demonstrated increased technetium uptake in areas that corresponded to disease on MRI studies. There were 27 false-negative vertebrae among 229 vertebrae that were negative on bone scans and MRI studies. Bone scans did not falsely identify any spinal metastasis (no false-positive results). The sensitivity of bone scans for detecting spinal metastasis among our patients with known spinal metastasis was 16%, and the specificity was 100%. The frequency of spinal metastasis in patients with MLS is 14% (33 of 230 patients). The predictive power of a positive bone scan in this patient population is 100%, whereas the predictive power of a negative bone scan is 88%. Three of 5 bones scans that were false-negative in the spine revealed bony lesions in long bones and ribs. Six patients had PET scans obtained to evaluate the extent of their disease, and only 2 were positive,

5 Spinal Metastasis from Myxoid Lipsarcoma/Schwab et al although they all had positive MRI studies (Figure 2). In contrast, in all patients who had them, PET scans were positive at the primary site. Upon closer inspection of the PET scans, there were 4 vertebrae with increased signal corresponding to areas of known metastasis on MRI studies. There were 25 vertebrae with no demonstrable F 18 -deoxyglucose (FDG) despite positive MRI findings, for a sensitivity of 14%. One hundred forty-five vertebrae were negative on PET scans and MRI studies. Again, there were no false-positive PET scans of the spine. Based on the prevalence of spinal metastasis in patients with MLS, the predictive value of a positive PET scan is 100%, and the predictive value of a negative PET scan is 85%. Two of the 4 PET scans that were false-negative in the spine detected metastatic lesions in soft tissues, including the brain, lungs, and the opposite thigh. The purpose of radiation was to palliate symptoms of pain (n 5 4 patients) or neurologic dysfunction (n 5 2 patients) and to help prevent further bony destruction, which may lead to fracture and/or instability. Four of 8 patients who received only radiation improved from moderate or severe pain to mild or no pain. The other 4 patients either had no pain or had mild pain, and they did not worsen after radiation. Two patients who were without pain had lower extremity motor weakness that improved with radiation therapy. These patients symptoms emanated from compression of their nerve roots by tumor outside the spinal canal. Eleven of 18 patients who underwent surgery had improved pain scores postoperatively. Nine of 18 patients with moderate to severe pain preoperatively improved to mild or no pain postoperatively. Six patients had mild to no pain preoperatively, and their pain scores did not change postoperatively. One patient had moderate to severe pain preoperatively and reported severe pain postoperatively. Fourteen of 18 patients who underwent surgery also received radiation therapy: All 14 patients received adjuvant radiation. Ten of those 14 patients underwent surgical decompression on an urgent basis because of progressive weakness and high-grade epidural disease. In all 10 patients, palliative radiation was administered postoperatively. Eight of those 10 patients died of disease, and the remaining 2 patients remained alive with disease. Four patients underwent surgery on an elective basis followed by radiation: Three of those 4 patients had no epidural involvement, and only 1 patient had mild neurologic symptoms from the compression of an exiting nerve root in the intervertebral vertebral foramina. Two of those patients presented with a solitary spinal metastasis. One of those patients remained alive with no FIGURE 2. Top: Sagittal T1-weighted image of the lumbar spine (left) demonstrating the abnormal signal in the first lumbar vertebra (L-1) and sagittal inversion recovery (IR) image of the lumbar spine (right) again showing the abnormal signal in L-1. Bottom: Positron emission tomography scans demonstrate normal signal in the lumbar spine. An arrow marks the first lumbar vertebrae (1). evidence of disease, and another patient remained alive with disease. The 2 remaining patients presented with multiple spinal metastases, and both died of disease. Twenty-one patients received systemic therapy. Eighteen patients were treated with doxorubicinbased therapy, and 11 of those patients also received ifosfamide. Additional agents that were used in 3 patients included navelbin, gemcitibin, ET-743, taxol, vincristine, and dacarbazine. All patients who underwent surgery patients maintained their preoperative neurologic status, and 4 patients had improved neurologic function postoperatively (Table 1). One patient had complete paralysis preoperatively and did not have any improvement in her neurologic status postoperatively. Seven patients with spinal metastases did not receive radiation or undergo surgery (Table 1). Four of 7 patients in this group had progressive systemic disease and died. The other 3 patients remained alive with multiple sites of disease. All 7 patients had ei-

6 1820 CANCER October 15, 2007 / Volume 110 / Number 8 ther mild or no pain attributed to their spine. Four patients had no epidural involvement, and 2 patients had grade 1 involvement. One patient had highgrade epidural compression with very little pain: He received doxorubicin and ifosfamide, and he remained alive with disease. Four of 18 patients who underwent surgery developed clinically significant local recurrences in the region of their spinal decompression. In all patients, the primary tumor was >10 cm, deep, and had 10% round cells (ie, high grade). Three of 4 patients who had recurrences presented with pain and weakness caused by high-grade epidural spinal cord compression, and all 3 patients underwent surgical decompression on an urgent basis. All 3 patients died of their disease. The fourth patient had a recurrence identified in the paravertebral soft tissues adjacent to the first lumbar vertebrae. He underwent local excision of his recurrence, and he remained alive with disease. Two of 33 patients were alive with no evidence of disease at last follow-up. Both of those patients had low-grade MLS in their extremities and had undergone wide excision. The first patient developed spinal metastasis to his lumbar spine 6 years later: His spinal metastasis was treated with 5 cycles of doxorubicin (25 mg/m 2 ) and ifosfamide (2230 mg/m 2 ) followed by wide excision, and he remained tumor free. The other patient had 3 previous sites of metastasis before his diagnosis of spinal metastasis. All sites of metastasis were treated surgically, and radiation was used twice as an adjuvant. All of his metastatic lesions were low grade, and he remained disease free as of Twenty-two of 33 patients died of their disease. Nine patients remained alive with disease, and 2 patients had no evidence of disease at their last follow-up. The median survival from primary cancer diagnosis was 51.4 months (95% confidence interval, months). The median survival from the time of cancer diagnosis for patients who had low-grade MLS was 105 months compared with 26 months for patients who had high-grade MLS (P 5.07). The average time to first metastasis from the date of diagnosis was 52 months in patients who had low-grade MLS compared with 25 months in patients who had high-grade MLS (P 5.06). The 5-year survival rate from the time of primary cancer diagnosis was 33%. (Fig. 3) DISCUSSION Several authors have reported that bone scans are unreliable for diagnosing spinal metastases from FIGURE 3. Kaplan-Meier survival curve for patients with metastatic myxoid liposarcoma to the spine from the time of their primary cancer diagnosis. MLS. 4 6 We previously reported a patient who had MLS detected by MRI after a negative FDG-PET study, which prompted the current investigation. 11 It is disappointing that the sensitivity of bone scanning (16%) and PET scanning (14%) was insufficient for the reliable detection of spinal metastases. It is unclear why these modalities are less reliable with MLS than with other cancers that metastasize to the spine. The myxoid stroma may prevent the labeled glucose from reaching cells in sufficient quantity to be detected by the scanner. In our previous study, pulmonary metastasis preceded bony metastasis in only 3 of 40 patients who had MLS metastatic to bone. 12 If clinicians rely on chest CT alone as a staging and follow-up tool, then a significant number of metastases will be missed. Thirty-five events occurred in 25 patients outside the thoracic spine in our series, and they would have been missed by chest CT alone. We use whole-spine MRI when staging patients with MLS. The entire spine is visualized with a minimum of T1- and T2-weighted sequences in the axial and sagittal planes. We use the same sequence for metastatic surveillance. In addition, these patients are screened with CT scans of the chest, abdomen, and pelvis. Our understanding of the etiology and treatment for metastatic liposarcoma continues to evolve. Primary MLS commonly is associated with the exon 5 to exon 2 TLS-CHOP fusion transcript. 9,13 A recent study of metastatic MLS to bone demonstrated that the type II TLS-CHOP (exon 5 of TLS fused to exon 2 of CHOP) fusion protein was present in >80% of patients who were tested. The overall rate of metas-

7 Spinal Metastasis from Myxoid Lipsarcoma/Schwab et al tasis was 31% (72 of 230 patients). The rate of osseous metastasis (17%) was as least as high as the rate of pulmonary metastasis (14%). 12 By comparison, there were 528 well-differentiated liposarcomas, 217 dedifferentiated liposarcomas, and 100 pleomorphic liposarcomas treated during the same period. Osseous metastasis developed in 7 patients (3%) with dedifferentiated liposarcoma, including 3 patients (1%) with spinal metastasis; and pleomorphic liposarcoma spread to bone in 6 patients (6%), including 2 patients (2%) with spinal metastasis. Currently, metastatic MLS is considered incurable. However, there have been advances in the systemic treatment of patients with primary liposarcoma. In a study by Eilber et al., ifosfamide-based chemotherapy demonstrated improved survival when it was given to high-risk patients who had high-grade MLS. 14 Although that finding has not been proven in the metastatic setting, it does hold promise for this patient population. Local therapy for metastatic disease, by and large, is palliative. However, if a solitary metastasis is detected early, then wide resection is a reasonable consideration. 15 We had 2 long-term survivors who remained disease free at the time of this report. Both of these patients had a solitary spinal metastasis without epidural disease, and both of underwent complete excision of their metastases; these results support the value of surgery for patients who have solitary metastases to regions that are amenable to surgical excision. There are several limitations to our study. Although, our database is maintained on a prospective basis, the data sought for our study were obtained through a retrospective review of each patient s chart. We have no control over and we have not established a gold standard for the detection of metastatic lesions. In addition, the treatment of these patients has evolved. This is particularly true for systemic therapy. Few of our patients who were treated with systemic therapy received the same regimen. In addition, once disease progression occurred, the subsequent agents that we used often were reflective of which clinical trial was occurring during that period. It is important to note that our study was not designed to investigate the ability of PET or bone scans to identify metastatic lesions in sites other than the spine. Indeed, several of our false-negative spine scans were positive in other tissues, including bone. MRI appears to be the most reliable method for diagnosing spinal metastasis in patients with MLS. Because multifocal spine involvement is common, whole-spine MRI imaging is recommended. On average, metastases were detected 31 months after the primary tumor was diagnosed. Twenty-seven patients (82%) who had spinal metastasis presented with back pain, which prompted further spinal imaging. If spinal imaging were part of staging and follow-up, then metastases conceivably could be diagnosed and treated earlier, before the onset of pain or neurologic compromise. It is unclear whether earlier detection would lead to longer survival in patients with MLS. However, our only long-term survivors underwent complete surgical excision of each metastasis. Furthermore, urgent decompression was required in 12 of our 18 patients who underwent surgery. All of those patients had high-grade spinal cord compression and neurologic deficits. It is possible that early detection would prevent the need for urgent palliative decompression and that definitive surgical excision of metastatic lesions would be fostered by earlier detection. In conclusion, spinal metastasis is common and often is the first metastasis in patients with MLS. Treatment of metastasis generally is palliative, but local treatment can yield long-term disease control. Early diagnosis with whole-spine MRI has the potential to improve outcomes. Early treatment with local radiation and/or surgery preserves neurologic function and controls pain. REFERENCES 1. Reszel PA, Soule EH, Coventry MB. Liposarcoma of the extremities and limb girdles: a study of two hundred twenty-two cases. J Bone Joint Surg Am. 1966;48: Cheng EY, Springfield DS, Mankin HJ. Frequent incidence of extrapulmonary sites of initial metastasis in patients with liposarcoma. Cancer. 1995;75: Pearlstone DB, Pisters PW, Bold RJ, et al. 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