Current Treatment Options in Oncology DOI 10.1007/s11864-014-0290-8
Sarcoma (SH Okuno, Section Editor)
Surgical Treatment of Sarcomas of the Spine Ali K. Ozturk, MD* Ziya L. Gokaslan, MD Jean-Paul Wolinsky, MD Address *Department of Neurosurgery, Johns Hopkins University, The Johns Hopkins Hospital, 600 N. Wolfe Street, Meyer Building, 7th floor, Room 109, Baltimore, MD 21287, USA Email: [email protected]
* Springer Science+Business Media New York 2014
Keywords Sarcoma
I
Spine
I
Ewing’s sarcoma
I
Chordoma
I
Chondrosarcoma
I
Osteosarcoma
I
Surgery
Opinion statement Primary sarcomas of the spine are rare diseases and include osteosarcoma, chondrosarcoma, chordoma, and Ewing’s sarcoma. Surgery for these lesions remains an important part of their treatment. Strong evidence exists for the en bloc resection of chondrosarcoma and chordoma since these lesions respond poorly to both chemotherapy and radiation. Weaker but important evidence suggests that osteosarcoma and Ewing’s sarcoma may also benefit from wide excisions, but after the application of neoadjuvant therapy, which may significantly aid the surgical process as well as independently prolong the survival. The unacceptable morbidity associated with damage to the neural elements makes resection with wide margins difficult in the spine. Nevertheless, this can be achieved in many circumstances and can, on occasion, lead to long term disease-free survival and even cure. There are numerous techniques described for en bloc resections in the mobile spine and pelvis and these vary widely for the region of the spine involved and the preferences of the surgeon. There are constant principles that do apply to all cases. We think of these surgeries as consisting of 2 stages which can be done in 1 or multiple operations. In the first phase, a corridor free of tumor is removed from the bone and the neural elements to be protected are dissected free from surrounding tissues. In the second phase, the tumor and a margin of normal tissue is circumferentially dissected and delivered while sparing the neural structures. Patient selection, in terms of age, overall disease burden, personal preferences, and comorbidities need to be carefully taken into account to optimize the risk benefit ratio. Sarcomas of the spine are a challenging group of lesions to treat but they can also be the most rewarding. Our newly acquired insight into the pathogenesis of these lesions, as well as improved surgical techniques combined with better neoadjuvant and adjuvant therapies are leading to longer survival times as well as long term disease free survivors.
Sarcoma (SH Okuno, Section Editor)
Introduction Sarcomas of the spine are a heterogeneous group of malignant lesions and include osteosarcoma, chondrosarcoma, chordoma, and Ewing’s sarcoma.
Given the differences between the subtypes, these entities will be discussed separately in terms of epidemiology, pathophysiology, and treatment.
Epidemiology and pathogenesis Osteosarcoma Osteosarcomas are aggressive, malignant neoplasms of mesenchymal origin that typically affect the long bones of the appendicular skeleton but arise from spinal elements much more rarely, accounting for 3 %–5 % of all spinal malignancies [1]. Within the spine, the sacral area is most frequently affected, followed by the lumbar and thoracic spine. Osteosarcoma has a bimodal age distribution, with 1 peak occurring in adolescence, likely related to growth spurts at this age, and another in adults older than 65, frequently as a consequence of long standing Paget’s disease [2]. African Americans are more frequently affected in the younger age group, whereas the incidence of the disease is higher in White patients over the age of 60 [3•]. The pathogenesis of osteosarcoma has remained elusive despite being the subject of intense research, but there does appear to be a relationship between the rapid turnover of bone and the development of osteosarcoma. Unlike other types of sarcoma, there does not appear to be characteristic translocations or other molecular genetic abnormalities. Nevertheless, several genetic conditions predispose the patient to osteosarcoma including hereditary retinoblastoma, Li-Fraumeni, and Rothmund-Thomson syndrome [4].
Chondrosarcoma Similar to osteosarcomas, chondrosarcomas are malignant tumors derived from primitive mesenchymal cells that typically involve the proximal ends of long bones, and arise from the spine much less commonly. They include a heterogeneous group of tumors capable of cartilage formation [5]. The incidence of chondrosarcoma is reported to be approximately 1 in 200,000 patients [6]. Most patients present between 30–60 years of age with an equal sex distribution. The majority of chondrosarcomas arise primarily, in the absence of a benign precursor lesion. However, up to 40 % of chondrosarcomas may arise from a pre-existing osteochondroma [7]. Germline mutations in the gene Exostosin (EXT1 and EXT2) predispose patients to multiple osteochondromas, but the development of secondary chondrosarcomas seems to be independent of EXT-related mechanisms [8]. In contrast to osteochondromas, high grade chondrosarcomas tend to have complex karyotypic rearrangements. Most consistent alterations include 12q13-15 and 9p21 which harbors the gene CDKN2A [9].
Ewing’s sarcoma Ewing’s sarcoma arises from bone marrow derived mesenchymal stem cells [10, 11•]. The majority of patients afflicted with this disease tend to be in
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their early adolescence, and the median age of diagnosis is approximately 15 years [12]. The spine can be involved in Ewing’s sarcoma both as the primary site of disease (accounting for only 6 % of cases), or more commonly after metastatic involvement. The overall incidence of this disease is approximately 3 cases per million, but this number is almost 10 times more common in those aged 10–19 than the remainder age groups, and epidemiologic data from the United States indicates that it is 9 times more common in Caucasians than in African Americans [13]. Ewing’s sarcoma is a small, round, blue cell tumor sometimes grouped together with primitive neuroectodermal tumors (PNET) given a common genetic locus responsible for the two, but Ewing’s sarcoma is typically related to bone whereas PNET are usually not associated with osseous structures. A translocation between chromosomes 11 and 22, which fuses the EWS and FLI1 gene is the molecular genetic mechanism contributing to most (980 %) of Ewing’s [14].
Chordoma Chordomas are a type of sarcoma derived from remnants of the notochord. Contrary to the previous types of sarcoma afflicting the spine, the overwhelming majority of chordomas primarily arise within the spine, although very rarely it may occur in bones elsewhere in the body [15]. They can arise anywhere along the spine although most commonly they involve the clivus or sacrum. Data from the United States and Europe indicate a similar incidence of approximately 1 new case per year per million persons. Chordomas can occur at any age; the median age of diagnosis is somewhat younger for those occurring in the skull base (49 years) compared with those in the sacrum (69 years). There is a 1.5 to 1 male preponderance [16]. Chordomas typically arise sporadically and are not inherited, but almost all patients who harbor chordomas demonstrate a polymorphism in the Brachyury gene. In addition, although extremely rare, families with multiple members afflicted by chordoma commonly have an extra copy of this gene underscoring its importance in the pathogenesis. In addition, Shalaby and colleagues also demonstrated that in as much as 40 % of chordomas there is a high level copy number gain in the EGFR gene [17].
Presentation Most neoplasms of the spine tend to initially present with nonspecific neck or back pain, though several characteristics distinguish neoplastic pain from other benign causes. Neoplastic pain is classically described as unremitting, unalleviated by analgesics, and worse in the recumbent position or at night. Although neurologic deficits in the form of radiculopathy, myelopathy, or cauda equine syndrome are typically later findings, they do occur more frequently with osteosarcoma and Ewing’s sarcoma given the aggressive nature of these neoplasms and some form of neurologic deficit is present in these diseases in the majority of patients at presentation. Chordoma and chondrosarcoma, given their slower growth rates tend to present with localized and non-specific pain which may be insidiously present for a lengthy period of time prior to
Sarcoma (SH Okuno, Section Editor) diagnosis. Neurologic dysfunction tends to occur at lower rates but indeed may be present.
Diagnosis The diagnosis of spinal neoplasms, both primary and malignant, relies heavily on imaging. Although nonspecific, much information can be acquired from plain radiographs including overall spinal alignment and evidence of a destructive osseous process. Normal radiographs, however, should not dissuade the clinician from obtaining higher quality imaging if the clinical suspicion for neoplasm is high, in the form of computed tomography (CT) and magnetic resonance imaging (MRI). The information acquired from CT and MRI is highly complementary with CT showing excellent bony detail whereas MRI is superior in providing information about the neural elements and surrounding soft tissue. The use of technetium bone scans is useful in quantifying the extent of bony involvement when there is suspicion of multifocal disease. The last step in the diagnostic paradigm of spinal sarcoma is biopsy, which can be in the form of core needle biopsy, incisional, or excisional biopsy. Currently, CT-guided core needle biopsy has become the mainstay in the diagnosis of malignant spinal sarcomas as it minimizes spread of tumor cells and technique related complications while providing an accurate tissue diagnosis in over 70 % of attempts [18]. The transvisceral route for biopsy should be avoided at all costs (eg, transrectal biopsy for sacral chordoma) as in our experience this can lead to undesired consequences.
Prognosis Malignant osseous neoplasms of the spine are aggressive tumors but given the rarity with which they are seen, single institution series are typically too small to provide a good understanding of the prognoses of this group of diseases. Much of what is known comes from the Surveillance, Epidemiology, and End Results (SEER) database. A query recently performed on the SEER registry for the 30 year time span of 1973–2003 by Mukherjee et al. identified a total of 827 patients with nonmetastatic osseous spinal neoplasms, of which 158 were osteosarcoma, 282 chondrosarcoma, 172 Ewing’s sarcoma, and 215 chordoma. Overall median survival proved to be histology specific with median survival for chordoma being the highest at 96 months; Ewing’s sarcoma, 90 months; chondrosarcoma, 88 months; and osteosarcoma, 18 months [19••]. As will be discussed in the “Treatment” section, however, these results are very much affected by the various treatment modalities, and also on the extent of surgical resection (Table 1) [20••].
Treatment Surgery Surgical resection of sarcomas of the spine remains a pillar of treatment and when feasible, in isolated, nonmetastatic lesions, the aim of surgery should be gross total resection of the tumor, preferably with a margin of surrounding normal tissue. In their analysis of a 30 year US cancer registry,
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Table 1. Median survival from SEER registry based on treatment and pathology (borrowed from Mukherjee et al. [20]). Survival time is in months. Undetermined refers to median survival not reached during follow up period Median survival All patients No surgery Surgery Surgery + XRT
Ewing’s sarcoma
Osteosarcoma
Chondrosarcoma
Chordoma
90 43 Undetermined 72
18 11 37 43
88 16 192 Undetermined
96 53 87 104
Mukherjee and colleagues, after adjusting for age, radiation therapy, and extent of local tumor invasion, found that patients undergoing surgical resection for primary spinal chordoma, chondrosarcoma, Ewing’s sarcoma, and osteosarcoma demonstrated improved overall survival independent of patient age, extent of local invasion, or location. It should be kept in mind, however, that no distinction was made in the registry between intralesional and en bloc resection (Table 1) [20••]. In a paper describing the 40-year experience with chondrosarcoma at M.D. Anderson Cancer Center, York et al. found that gross total resection when compared with subtotal resection provided the best chance for prolonging disease free survival [21•]. A similar analysis from the same institution on sacral chordomas demonstrated a high rate of recurrence in the absence of wide resection margins [22•]. In the case of Ewing’s sarcoma, in 1 series better local control and longer survival was obtained with gross total resection with negative margins while suggesting that intralesional excision combined with radiation and chemotherapy was less effective than radiation and chemotherapy by themselves [23]. In terms of surgery, several options are available and the most suitable option is highly dependent on the histology of the lesion, the feasibility of surgery and the accessibility of the lesion, and the overall medical health of the patient. Several terms are worth reviewing here:
(1) Intra-lesional excision refers to the piecemeal removal of a tumor, whereby no attempt is made at maintaining the integrity of the tumor or preventing the spread of cancer cells within and around the surgical bed (ie, curettage). (2) Marginal resection refers to the gross total removal of tumor with the capsule intact but no effort made at taking a rim of surrounding normal tissue. (3) Wide resection refers to the gross total removal of tumor along with a cuff of normal surrounding tissue circumferentially. (4) Radical resection refers to en bloc removal of a tumor along with the entire compartment of origin. This is rarely achieved in the spine without an unacceptable level of morbidity (eg, hemicorporectomy for a distal sacral chordoma). Given the difficulty of a true radical resection in most areas of the mobile spine, it is helpful to divide the typical vertebra into compartments. One commonly used system is the Weinstein, Boriani, Biagini (WBB) staging
Sarcoma (SH Okuno, Section Editor) system. In this system, the vertebra in the transverse plane is divided into 12 radiating zones (numbered 1 through 12 in a clockwise fashion), and 5 circumferential layers (A through E) with A representing paravertebral and E dural involvement. This and other systems aid the surgeon in preoperative planning. Regardless of the system used, the most important criterion is the presence of a tumor-free region in the vertebra (most conveniently located in the posterior elements) whereby the spinal cord can be delivered, and the vertebra (along with the tumor and a margin of healthy tissue) can be removed. Although the pathologies that affect the spine are virtually identical to those affecting the musculoskeletal system elsewhere in the body, the presence of neural tissue and the anatomy of the spine poses unique surgical challenges. Each section of the spine brings with it a different set of anatomic considerations. Even though the full extent of the subtleties of each vertebral segment is beyond the scope of this review, they will be briefly reviewed here. The cervical spine is unique for several reasons. The presence of the vertebral artery (typically between C6-atlas) needs to be carefully planned for as damage to this structure, aside from catastrophic bleeding, can also cause devastating strokes in the brainstem. Although the C2 and 3 nerve roots can typically be sacrificed with impunity, damage to the C3, 4, and 5 nerve roots leads to ipsilateral diaphragmatic paralysis. C5 and C6 nerve roots are essential for deltoid and biceps strength, respectively, and weakness in these muscles are poorly tolerated whereas damage to C7 and resultant triceps weakness interferes with daily activities somewhat less. C8 and T1 nerve roots are critical for intrinsic hand muscles and damage significantly impairs fine hand motor function. Thoracic spinal nerve roots (T2-12) can all be sacrificed with some residual chest wall numbness which typically resolves and is not debilitating. In addition, the rib cage provides additional stability to this segment and once the ribs are resected laterally, the surgical corridor from a posterior approach becomes quite comprehensive and most operations can be done in a single stage in the prone position. The absence of the spinal cord and presence of the cauda equina (which can be retracted safely) in the lumbar spine provides a surgical advantage but sacrifice of the lumbar nerve roots (including S1) results in significant lower extremity weakness and is typically avoided. There are many different descriptions and variations that exist for performing en bloc excisions in the mobile spine, but many of the principles remain constant. We think of these operations as having 2 stages which can be done as 1 or more operations. In the first stage, the neural elements to be protected are dissected free from the surrounding tissues, and a window is created where the spinal cord and/or spinal nerves can be delivered. In the second stage, the tumor and accessible margin of healthy tissue is dissected circumferentially and the specimen is removed. The appropriate implants are inserted and reconstruction is achieved accordingly. Thus, a typical operation in the thoracic spine may all be done from a posterior approach since the ribs and nerve roots can be sacrificed, and a wide corridor obtained whereby the specimen can be dissected and removed posteriorly. In the cervical and lumbar spine, on the other hand, the inability to sacrifice nerve roots usually necessitates an anterior approach to dissect the specimen and deliver it, since no such corridor can be obtained between the nerve roots that are to be preserved. Reconstruction needs to address both
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the anterior load sharing column and the restoration of the posterior tension band, typically achieved with an anterior cage and multi-level dorsal instrumentation. Once again, this can all be achieved from a posterior approach in the thoracic spine whereas the anterior column reconstruction in the lumbar and cervical segments is more easily done from a ventral approach. This is demonstrated in 2 illustrative cases in Fig. 1. Figure 1a–f demonstrates a case of tumor involvement of the L2 vertebral body (Fig. 1a and b). This is approached in a 2-stage fashion. In the first stage, from a posterior approach, the posterior elements are removed (Fig. 1c), posterior segmental instrumentation is inserted (Fig. 1d) and circumferential tumor dissection is initiated. In the second stage, from a retroperitoneal approach, the tumor dissection is completed, the specimen is removed en bloc (Fig. 1f), and reconstruction of the anterior column is achieved (Fig. 1e). Figure 1g–l demonstrates a second case in the thoracic spine with a significant epidural component (Fig. 1g and h). This tumor is resected in 1 operation from a posterior approach. The ribs and nerve roots above and below the lesion are resected and sacrificed creating a large enough corridor for tumor removal in one piece. Posterior (Fig. 1i), as well as anterior column (Fig. 1j) reconstruction can all be achieved from the posterior approach.
Chemotherapy In a practical sense, we divide malignant sarcomas of the spine into 2 broad groups; those which benefit most from neoadjuvant therapy followed by surgery (osteosarcoma and Ewing’s sarcoma) and those in which surgical resection is the main pillar of treatment, which can occasionally be followed by adjuvant therapy (chondrosarcoma and chordoma). Neoadjuvant chemotherapy for osteosarcoma followed by surgery, if technically feasible, and postoperative radiotherapy is considered the standard of care. The Cooperative Osteosarcoma Study Groups (COSS) protocol for neoadjuvant chemotherapy includes high dose methotrexate, doxorubicin, cisplatin, ifosfamide, and/or BCD (bleomycin, cyclophosphamide, and dactinomycin) [24]. In effect, the preoperative use of these agents help to shrink the tumor size significantly, can aid the surgeon in its resection at a subsequent time, potentially reduce operative blood loss, and theoretically may eradicate micrometastases. Numerous studies have also confirmed that presurgical chemotherapy is the standard of care for patients with Ewing’s sarcoma. Furthermore, the response to presurgical chemotherapy is also predictive of event-free survival (EFS), with patients having minimal or no viable residual tumor having significantly longer EFS than those with larger amounts of remaining tumor after neoadjuvant therapy. The Cooperative Ewing’s Sarcoma Study (CESS) group recommends the use of 12 courses of vincristine, ifosfamide, and doxorubicin alternating with actinomycin D in the treatment of Ewing’s sarcoma [25–27]. In general, both chordoma and chondrosarcoma (especially for the most frequently observed conventional and clear cell subtype) is considered to be fairly refractory to chemotherapy. Given their slow growing nature, most trials investigating the use of chemotherapeutic agents, which target rapidly dividing cells, have been disappointing. Though mild, there are some reports of
Sarcoma (SH Okuno, Section Editor)
Fig. 1. Illustrative case #1 (a–f): Sagittal T1 (a) and axial T2 (b) weighted images demonstrating tumor involvement of the L2 vertebral body in zones 7-9/C in the WBB staging system. This tumor had to be approached using a 2-stage operation from posterior and anterior. The red lines show the osteotomies that were performed and the green line outlines the extent of the tumor. The posterior elements are removed in the first stage (c) and posterior instrumentation is inserted (d). A retroperitoneal approach is used to the deliver the tumor along with the vertebral body in 1 piece (f) with insertion of an expandable cage and lateral plate (e). Illustrative case #2 (g–l): Sagittal (g) and axial (h) T2 weighted images demonstrating extent of tumor involvement with a significant epidural component in the thoracic spine (WBB zones 2-10/D). This tumor was approached posteriorly given the ability for extensive rib resection and sacrifice of the thoracic nerve roots, thus, creating a wide corridor through which the tumor can be delivered. Once again, red lines demonstrate the osteotomies and the green outline shows the extent of tumor involvement. Posterior segmental instrumentation (i) with an expandable cage (j) is inserted and the tumor specimen (k and l) can be removed in an en bloc fashion.
beneficial treatment with doxorubicin-cisplatin based chemotherapies on mesenchymal chondrosarcomas, which are beyond the scope of this review [28].
Radiation therapy Osteosarcoma, chondrosarcoma, and chordoma in general are relatively refractory to radiation therapy. There may be a role for radiation, however, in 2 specific scenarios: first, as a palliative measure in patients who are not candidates for surgery, and second, postoperatively in situations of subtotal tumor removal. The doses of radiation required to kill these cells are quite high (60 Gy), and this often precludes the administration of effective doses where these lesions are often encountered in the skull base or axial spine given the proximity of vital neural elements. There is some evidence, how-
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ever, that the small cell variant of osteosarcoma may respond better to radiation than other subtypes [29]. In contrast, radiation therapy is effective in the treatment of Ewing’s sarcoma. In the absence of randomized trials, both surgery and radiation are considered viable treatment options for this disease. Most clinical protocols still emphasize the role for surgery when negative margins can be obtained, but there is some evidence to suggest that where positive margins are anticipated despite induction chemotherapy, high dose radiation therapy alone may be advantageous compared with debulking surgery followed by radiation [23].
Diet and lifestyle There is no evidence to suggest that diet or lifestyle contribute to the formation or treatment of primary sarcomas affecting the spine.
Conclusions Sarcomas of the spine are rare disorders that are challenging to treat. Surgical resection, ideally with negative margins, remains an important part of the treatment paradigm yet this is not always possible and is highly dependent on patient and tumor specific variables. When achieved, combined with advancements in neoadjuvant and adjuvant therapy, long term survival and even cure is possible. The care of these patients therefore needs to be multidisciplinary and performed in highly specialized centers.
Compliance with Ethics Guidelines Conflict of Interest Ali K. Ozturk and Jean-Paul Wolinsky declare that they have no conflict of interest. Ziya L. Gokaslan is a stock shareholder with US Spine and Spinal Kinetics; received honoraria from AO Foundation and had travel/accommodations and or meeting expenses covered or reimbursed by AO Spine. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
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Shives TC, Dahlin DC, Sim FH, Pritchard DJ, Earle JD. Osteosarcoma of the spine. J Bone Joint Surg Am. 1986;68:660–8. Ottaviani G. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13. Mirabello L, Troisi RJ, Savage S. Osteosarcoma incidence and survival rates from 1973 to 2004: data
from the Surveillance, Epidemiology, and End Results Program. Cancer. 2009;115:1531–43. This article is one of the few articles surveying a large database about the incidence and survival rates for osteosarcoma. 4. Hauben EI, Arends J, Vandenbroucke JP, van Asperen CJ, Van Marck E, Hogendoorn PC. Multiple primary malignancies in osteosarcoma patients. Incidence
Sarcoma (SH Okuno, Section Editor) and predictive value of osteosarcoma subtype for cancer syndromes related with osteosarcoma. Eur J Hum Genet. 2003;11:611–8. 5. Boriani S, De Iure F, Bandiera S, Campanacci L, Biagini R, Di Fiore M, et al. Chondrosarcoma of the mobile spine: report on 22 cases. Spine. 2000;25:804–12. 6. Giuffrida AY, Burgueno JE, Koniaris LG, Gutierrez JC, Duncan R, Scully SP. Chondrosarcoma in the United States (1973 to 2003): an analysis of 2890 cases from the SEER database. J Bone Joint Surg Am. 2009;91:1063–72. 7. Brien EW, Mirra JM, Kerr R. Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical basis with an emphasis on radiology, pathology and clinical biology. I. The intramedullary cartilage tumors. Skelet Radiol. 1997;26:325–53. 8. de Andrea CE, Reijnders CM, Kroon HM, de Jong D, Hogendoorn PC, Szuhai K, et al. Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT. Oncogene. 2012;31:1095–104. 9. Bovee JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den Broek LJ, Taminiau AH, Cornelisse CJ, et al. Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Gene Chromosome Cancer. 1999;26:237–46. 10. Suva ML, Riggi N, Stehle JC, Baumer K, Tercier S, Joseph JM, et al. Identification of cancer stem cells in Ewing’s sarcoma. Cancer Res. 2009;69:1776–81. 11.• Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P, Delattre O. Mesenchymal stem cell features of Ewing tumors. Cancer Cell. 2007;11:421–9. This article provides vital information regarding the molecular features of Ewing’s Sarcoma. 12. van den Berg H, Dirksen U, Ranft A, Jurgens H. Ewing tumors in infants. Pediatr Blood Cancer. 2008;50:761–4. 13. Jawad MU, Cheung MC, Min ES, Schneiderbauer MM, Koniaris LG, Scully SP. Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973–2005. Cancer. 2009;115:3526–36. 14. de Alava E, Kawai A, Healey JH, Fligman I, Meyers PA, Huvos AG, et al. EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol. 1998;16:1248–55. 15. Tirabosco R, Mangham DC, Rosenberg AE, Vujovic S, Bousdras K, Pizzolitto S, et al. Brachyury expression in extra-axial skeletal and soft tissue chordomas: a
marker that distinguishes chordoma from mixed tumor/myoepithelioma/parachordoma in soft tissue. Am J Surg Pathol. 2008;32:572–80. 16. McMaster ML, Goldstein AM, Bromley CM, Ishibe N, Parry DM. Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes Control. 2001;12:1–11. 17. Shalaby A, Presneau N, Ye H, Halai D, Berisha F, Idowu B, et al. The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target. J Pathol. 2011;223:336–46. 18. Phadke DM, Lucas DR, Madan S. Fine-needle aspiration biopsy of vertebral and intervertebral disc lesions: specimen adequacy, diagnostic utility, and pitfalls. Arch Pathol Lab Med. 2001;125:1463–8. 19.•• Mukherjee D, Chaichana KL, Gokaslan ZL, Aaronson O, Cheng JS, McGirt MJ. Survival of patients with malignant primary osseous spinal neoplasms: results from the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2003. J Neurosurg Spine. 2011;14:143–50. This article once again surveys the SEER database for the survival of patients with primary osseous neoplasms. Given the rarity of these lesions, much of what is known regarding the epidemiology and prognosis of these lesions comes from this database. 20.•• Mukherjee D, Chaichana KL, Parker SL, Gokaslan ZL, McGirt MJ. Association of surgical resection and survival in patients with malignant primary osseous spinal neoplasms from the Surveillance, Epidemiology, and End Results (SEER) database. Eur Spine J. 2013;22:1375–82. This article once again surveys the SEER database for the survival of patients with primary osseous neoplasms. Given the rarity of these lesions, much of what is known regarding the epidemiology and prognosis of these lesions comes from this database. 21.• York JE, Berk RH, Fuller GN, Rao JS, Abi-Said D, Wildrick DM, et al. Chondrosarcoma of the spine: 1954 to 1997. J Neurosurg. 1999;90:73–8. These articles provide significant evidence for the en bloc resection of chrodoma and chondrosarcoma. 22.• York JE, Kaczaraj A, Abi-Said D, Fuller GN, Skibber JM, Janjan NA, et al. Sacral chordoma: 40-year experience at a major cancer center. Neurosurgery. 1999;44:74–9. discussion 79–80. These articles provide significant evidence for the en bloc resection of chrodoma and chondrosarcoma. 23. Bacci G, Longhi A, Briccoli A, Bertoni F, Versari M, Picci P. The role of surgical margins in treatment of Ewing’s sarcoma family tumors: experience of a sin-
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gle institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys. 2006;65:766–72. Bielack S, Carrle D, Casali PG, Group EGW. Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20 Suppl 4:137–9. Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing’s Sarcoma Study CESS 86. J Clin Oncol. 2001;19:1818–29. Oberlin O, Deley MC, Bui BN, Gentet JC, Philip T, Terrier P, et al. Prognostic factors in localized Ewing’s tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer. 2001;85:1646–54.
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Wunder JS, Paulian G, Huvos AG, Heller G, Meyers PA, Healey JH. The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am. 1998;80:1020–33. Nooij MA, Whelan J, Bramwell VH, Taminiau AT, Cannon S, Hogendoorn PC, et al. Doxorubicin and cisplatin chemotherapy in high-grade spindle cell sarcomas of the bone, other than osteosarcoma or malignant fibrous histiocytoma: a European Osteosarcoma Intergroup Study. Eur J Cancer. 2005;41:225–30. Stea B, Cavazzana A, Kinsella TJ. Small-cell osteosarcoma: correlation of in vitro and clinical radiation response. Int J Radiat Oncol Biol Phys. 1988;15:1233–8.
Sarcoma (SH Okuno, Section Editor)
Surgical Treatment of Sarcomas of the Spine Ali K. Ozturk, MD* Ziya L. Gokaslan, MD Jean-Paul Wolinsky, MD Address *Department of Neurosurgery, Johns Hopkins University, The Johns Hopkins Hospital, 600 N. Wolfe Street, Meyer Building, 7th floor, Room 109, Baltimore, MD 21287, USA Email: [email protected]
* Springer Science+Business Media New York 2014
Keywords Sarcoma
I
Spine
I
Ewing’s sarcoma
I
Chordoma
I
Chondrosarcoma
I
Osteosarcoma
I
Surgery
Opinion statement Primary sarcomas of the spine are rare diseases and include osteosarcoma, chondrosarcoma, chordoma, and Ewing’s sarcoma. Surgery for these lesions remains an important part of their treatment. Strong evidence exists for the en bloc resection of chondrosarcoma and chordoma since these lesions respond poorly to both chemotherapy and radiation. Weaker but important evidence suggests that osteosarcoma and Ewing’s sarcoma may also benefit from wide excisions, but after the application of neoadjuvant therapy, which may significantly aid the surgical process as well as independently prolong the survival. The unacceptable morbidity associated with damage to the neural elements makes resection with wide margins difficult in the spine. Nevertheless, this can be achieved in many circumstances and can, on occasion, lead to long term disease-free survival and even cure. There are numerous techniques described for en bloc resections in the mobile spine and pelvis and these vary widely for the region of the spine involved and the preferences of the surgeon. There are constant principles that do apply to all cases. We think of these surgeries as consisting of 2 stages which can be done in 1 or multiple operations. In the first phase, a corridor free of tumor is removed from the bone and the neural elements to be protected are dissected free from surrounding tissues. In the second phase, the tumor and a margin of normal tissue is circumferentially dissected and delivered while sparing the neural structures. Patient selection, in terms of age, overall disease burden, personal preferences, and comorbidities need to be carefully taken into account to optimize the risk benefit ratio. Sarcomas of the spine are a challenging group of lesions to treat but they can also be the most rewarding. Our newly acquired insight into the pathogenesis of these lesions, as well as improved surgical techniques combined with better neoadjuvant and adjuvant therapies are leading to longer survival times as well as long term disease free survivors.
Sarcoma (SH Okuno, Section Editor)
Introduction Sarcomas of the spine are a heterogeneous group of malignant lesions and include osteosarcoma, chondrosarcoma, chordoma, and Ewing’s sarcoma.
Given the differences between the subtypes, these entities will be discussed separately in terms of epidemiology, pathophysiology, and treatment.
Epidemiology and pathogenesis Osteosarcoma Osteosarcomas are aggressive, malignant neoplasms of mesenchymal origin that typically affect the long bones of the appendicular skeleton but arise from spinal elements much more rarely, accounting for 3 %–5 % of all spinal malignancies [1]. Within the spine, the sacral area is most frequently affected, followed by the lumbar and thoracic spine. Osteosarcoma has a bimodal age distribution, with 1 peak occurring in adolescence, likely related to growth spurts at this age, and another in adults older than 65, frequently as a consequence of long standing Paget’s disease [2]. African Americans are more frequently affected in the younger age group, whereas the incidence of the disease is higher in White patients over the age of 60 [3•]. The pathogenesis of osteosarcoma has remained elusive despite being the subject of intense research, but there does appear to be a relationship between the rapid turnover of bone and the development of osteosarcoma. Unlike other types of sarcoma, there does not appear to be characteristic translocations or other molecular genetic abnormalities. Nevertheless, several genetic conditions predispose the patient to osteosarcoma including hereditary retinoblastoma, Li-Fraumeni, and Rothmund-Thomson syndrome [4].
Chondrosarcoma Similar to osteosarcomas, chondrosarcomas are malignant tumors derived from primitive mesenchymal cells that typically involve the proximal ends of long bones, and arise from the spine much less commonly. They include a heterogeneous group of tumors capable of cartilage formation [5]. The incidence of chondrosarcoma is reported to be approximately 1 in 200,000 patients [6]. Most patients present between 30–60 years of age with an equal sex distribution. The majority of chondrosarcomas arise primarily, in the absence of a benign precursor lesion. However, up to 40 % of chondrosarcomas may arise from a pre-existing osteochondroma [7]. Germline mutations in the gene Exostosin (EXT1 and EXT2) predispose patients to multiple osteochondromas, but the development of secondary chondrosarcomas seems to be independent of EXT-related mechanisms [8]. In contrast to osteochondromas, high grade chondrosarcomas tend to have complex karyotypic rearrangements. Most consistent alterations include 12q13-15 and 9p21 which harbors the gene CDKN2A [9].
Ewing’s sarcoma Ewing’s sarcoma arises from bone marrow derived mesenchymal stem cells [10, 11•]. The majority of patients afflicted with this disease tend to be in
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their early adolescence, and the median age of diagnosis is approximately 15 years [12]. The spine can be involved in Ewing’s sarcoma both as the primary site of disease (accounting for only 6 % of cases), or more commonly after metastatic involvement. The overall incidence of this disease is approximately 3 cases per million, but this number is almost 10 times more common in those aged 10–19 than the remainder age groups, and epidemiologic data from the United States indicates that it is 9 times more common in Caucasians than in African Americans [13]. Ewing’s sarcoma is a small, round, blue cell tumor sometimes grouped together with primitive neuroectodermal tumors (PNET) given a common genetic locus responsible for the two, but Ewing’s sarcoma is typically related to bone whereas PNET are usually not associated with osseous structures. A translocation between chromosomes 11 and 22, which fuses the EWS and FLI1 gene is the molecular genetic mechanism contributing to most (980 %) of Ewing’s [14].
Chordoma Chordomas are a type of sarcoma derived from remnants of the notochord. Contrary to the previous types of sarcoma afflicting the spine, the overwhelming majority of chordomas primarily arise within the spine, although very rarely it may occur in bones elsewhere in the body [15]. They can arise anywhere along the spine although most commonly they involve the clivus or sacrum. Data from the United States and Europe indicate a similar incidence of approximately 1 new case per year per million persons. Chordomas can occur at any age; the median age of diagnosis is somewhat younger for those occurring in the skull base (49 years) compared with those in the sacrum (69 years). There is a 1.5 to 1 male preponderance [16]. Chordomas typically arise sporadically and are not inherited, but almost all patients who harbor chordomas demonstrate a polymorphism in the Brachyury gene. In addition, although extremely rare, families with multiple members afflicted by chordoma commonly have an extra copy of this gene underscoring its importance in the pathogenesis. In addition, Shalaby and colleagues also demonstrated that in as much as 40 % of chordomas there is a high level copy number gain in the EGFR gene [17].
Presentation Most neoplasms of the spine tend to initially present with nonspecific neck or back pain, though several characteristics distinguish neoplastic pain from other benign causes. Neoplastic pain is classically described as unremitting, unalleviated by analgesics, and worse in the recumbent position or at night. Although neurologic deficits in the form of radiculopathy, myelopathy, or cauda equine syndrome are typically later findings, they do occur more frequently with osteosarcoma and Ewing’s sarcoma given the aggressive nature of these neoplasms and some form of neurologic deficit is present in these diseases in the majority of patients at presentation. Chordoma and chondrosarcoma, given their slower growth rates tend to present with localized and non-specific pain which may be insidiously present for a lengthy period of time prior to
Sarcoma (SH Okuno, Section Editor) diagnosis. Neurologic dysfunction tends to occur at lower rates but indeed may be present.
Diagnosis The diagnosis of spinal neoplasms, both primary and malignant, relies heavily on imaging. Although nonspecific, much information can be acquired from plain radiographs including overall spinal alignment and evidence of a destructive osseous process. Normal radiographs, however, should not dissuade the clinician from obtaining higher quality imaging if the clinical suspicion for neoplasm is high, in the form of computed tomography (CT) and magnetic resonance imaging (MRI). The information acquired from CT and MRI is highly complementary with CT showing excellent bony detail whereas MRI is superior in providing information about the neural elements and surrounding soft tissue. The use of technetium bone scans is useful in quantifying the extent of bony involvement when there is suspicion of multifocal disease. The last step in the diagnostic paradigm of spinal sarcoma is biopsy, which can be in the form of core needle biopsy, incisional, or excisional biopsy. Currently, CT-guided core needle biopsy has become the mainstay in the diagnosis of malignant spinal sarcomas as it minimizes spread of tumor cells and technique related complications while providing an accurate tissue diagnosis in over 70 % of attempts [18]. The transvisceral route for biopsy should be avoided at all costs (eg, transrectal biopsy for sacral chordoma) as in our experience this can lead to undesired consequences.
Prognosis Malignant osseous neoplasms of the spine are aggressive tumors but given the rarity with which they are seen, single institution series are typically too small to provide a good understanding of the prognoses of this group of diseases. Much of what is known comes from the Surveillance, Epidemiology, and End Results (SEER) database. A query recently performed on the SEER registry for the 30 year time span of 1973–2003 by Mukherjee et al. identified a total of 827 patients with nonmetastatic osseous spinal neoplasms, of which 158 were osteosarcoma, 282 chondrosarcoma, 172 Ewing’s sarcoma, and 215 chordoma. Overall median survival proved to be histology specific with median survival for chordoma being the highest at 96 months; Ewing’s sarcoma, 90 months; chondrosarcoma, 88 months; and osteosarcoma, 18 months [19••]. As will be discussed in the “Treatment” section, however, these results are very much affected by the various treatment modalities, and also on the extent of surgical resection (Table 1) [20••].
Treatment Surgery Surgical resection of sarcomas of the spine remains a pillar of treatment and when feasible, in isolated, nonmetastatic lesions, the aim of surgery should be gross total resection of the tumor, preferably with a margin of surrounding normal tissue. In their analysis of a 30 year US cancer registry,
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Table 1. Median survival from SEER registry based on treatment and pathology (borrowed from Mukherjee et al. [20]). Survival time is in months. Undetermined refers to median survival not reached during follow up period Median survival All patients No surgery Surgery Surgery + XRT
Ewing’s sarcoma
Osteosarcoma
Chondrosarcoma
Chordoma
90 43 Undetermined 72
18 11 37 43
88 16 192 Undetermined
96 53 87 104
Mukherjee and colleagues, after adjusting for age, radiation therapy, and extent of local tumor invasion, found that patients undergoing surgical resection for primary spinal chordoma, chondrosarcoma, Ewing’s sarcoma, and osteosarcoma demonstrated improved overall survival independent of patient age, extent of local invasion, or location. It should be kept in mind, however, that no distinction was made in the registry between intralesional and en bloc resection (Table 1) [20••]. In a paper describing the 40-year experience with chondrosarcoma at M.D. Anderson Cancer Center, York et al. found that gross total resection when compared with subtotal resection provided the best chance for prolonging disease free survival [21•]. A similar analysis from the same institution on sacral chordomas demonstrated a high rate of recurrence in the absence of wide resection margins [22•]. In the case of Ewing’s sarcoma, in 1 series better local control and longer survival was obtained with gross total resection with negative margins while suggesting that intralesional excision combined with radiation and chemotherapy was less effective than radiation and chemotherapy by themselves [23]. In terms of surgery, several options are available and the most suitable option is highly dependent on the histology of the lesion, the feasibility of surgery and the accessibility of the lesion, and the overall medical health of the patient. Several terms are worth reviewing here:
(1) Intra-lesional excision refers to the piecemeal removal of a tumor, whereby no attempt is made at maintaining the integrity of the tumor or preventing the spread of cancer cells within and around the surgical bed (ie, curettage). (2) Marginal resection refers to the gross total removal of tumor with the capsule intact but no effort made at taking a rim of surrounding normal tissue. (3) Wide resection refers to the gross total removal of tumor along with a cuff of normal surrounding tissue circumferentially. (4) Radical resection refers to en bloc removal of a tumor along with the entire compartment of origin. This is rarely achieved in the spine without an unacceptable level of morbidity (eg, hemicorporectomy for a distal sacral chordoma). Given the difficulty of a true radical resection in most areas of the mobile spine, it is helpful to divide the typical vertebra into compartments. One commonly used system is the Weinstein, Boriani, Biagini (WBB) staging
Sarcoma (SH Okuno, Section Editor) system. In this system, the vertebra in the transverse plane is divided into 12 radiating zones (numbered 1 through 12 in a clockwise fashion), and 5 circumferential layers (A through E) with A representing paravertebral and E dural involvement. This and other systems aid the surgeon in preoperative planning. Regardless of the system used, the most important criterion is the presence of a tumor-free region in the vertebra (most conveniently located in the posterior elements) whereby the spinal cord can be delivered, and the vertebra (along with the tumor and a margin of healthy tissue) can be removed. Although the pathologies that affect the spine are virtually identical to those affecting the musculoskeletal system elsewhere in the body, the presence of neural tissue and the anatomy of the spine poses unique surgical challenges. Each section of the spine brings with it a different set of anatomic considerations. Even though the full extent of the subtleties of each vertebral segment is beyond the scope of this review, they will be briefly reviewed here. The cervical spine is unique for several reasons. The presence of the vertebral artery (typically between C6-atlas) needs to be carefully planned for as damage to this structure, aside from catastrophic bleeding, can also cause devastating strokes in the brainstem. Although the C2 and 3 nerve roots can typically be sacrificed with impunity, damage to the C3, 4, and 5 nerve roots leads to ipsilateral diaphragmatic paralysis. C5 and C6 nerve roots are essential for deltoid and biceps strength, respectively, and weakness in these muscles are poorly tolerated whereas damage to C7 and resultant triceps weakness interferes with daily activities somewhat less. C8 and T1 nerve roots are critical for intrinsic hand muscles and damage significantly impairs fine hand motor function. Thoracic spinal nerve roots (T2-12) can all be sacrificed with some residual chest wall numbness which typically resolves and is not debilitating. In addition, the rib cage provides additional stability to this segment and once the ribs are resected laterally, the surgical corridor from a posterior approach becomes quite comprehensive and most operations can be done in a single stage in the prone position. The absence of the spinal cord and presence of the cauda equina (which can be retracted safely) in the lumbar spine provides a surgical advantage but sacrifice of the lumbar nerve roots (including S1) results in significant lower extremity weakness and is typically avoided. There are many different descriptions and variations that exist for performing en bloc excisions in the mobile spine, but many of the principles remain constant. We think of these operations as having 2 stages which can be done as 1 or more operations. In the first stage, the neural elements to be protected are dissected free from the surrounding tissues, and a window is created where the spinal cord and/or spinal nerves can be delivered. In the second stage, the tumor and accessible margin of healthy tissue is dissected circumferentially and the specimen is removed. The appropriate implants are inserted and reconstruction is achieved accordingly. Thus, a typical operation in the thoracic spine may all be done from a posterior approach since the ribs and nerve roots can be sacrificed, and a wide corridor obtained whereby the specimen can be dissected and removed posteriorly. In the cervical and lumbar spine, on the other hand, the inability to sacrifice nerve roots usually necessitates an anterior approach to dissect the specimen and deliver it, since no such corridor can be obtained between the nerve roots that are to be preserved. Reconstruction needs to address both
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the anterior load sharing column and the restoration of the posterior tension band, typically achieved with an anterior cage and multi-level dorsal instrumentation. Once again, this can all be achieved from a posterior approach in the thoracic spine whereas the anterior column reconstruction in the lumbar and cervical segments is more easily done from a ventral approach. This is demonstrated in 2 illustrative cases in Fig. 1. Figure 1a–f demonstrates a case of tumor involvement of the L2 vertebral body (Fig. 1a and b). This is approached in a 2-stage fashion. In the first stage, from a posterior approach, the posterior elements are removed (Fig. 1c), posterior segmental instrumentation is inserted (Fig. 1d) and circumferential tumor dissection is initiated. In the second stage, from a retroperitoneal approach, the tumor dissection is completed, the specimen is removed en bloc (Fig. 1f), and reconstruction of the anterior column is achieved (Fig. 1e). Figure 1g–l demonstrates a second case in the thoracic spine with a significant epidural component (Fig. 1g and h). This tumor is resected in 1 operation from a posterior approach. The ribs and nerve roots above and below the lesion are resected and sacrificed creating a large enough corridor for tumor removal in one piece. Posterior (Fig. 1i), as well as anterior column (Fig. 1j) reconstruction can all be achieved from the posterior approach.
Chemotherapy In a practical sense, we divide malignant sarcomas of the spine into 2 broad groups; those which benefit most from neoadjuvant therapy followed by surgery (osteosarcoma and Ewing’s sarcoma) and those in which surgical resection is the main pillar of treatment, which can occasionally be followed by adjuvant therapy (chondrosarcoma and chordoma). Neoadjuvant chemotherapy for osteosarcoma followed by surgery, if technically feasible, and postoperative radiotherapy is considered the standard of care. The Cooperative Osteosarcoma Study Groups (COSS) protocol for neoadjuvant chemotherapy includes high dose methotrexate, doxorubicin, cisplatin, ifosfamide, and/or BCD (bleomycin, cyclophosphamide, and dactinomycin) [24]. In effect, the preoperative use of these agents help to shrink the tumor size significantly, can aid the surgeon in its resection at a subsequent time, potentially reduce operative blood loss, and theoretically may eradicate micrometastases. Numerous studies have also confirmed that presurgical chemotherapy is the standard of care for patients with Ewing’s sarcoma. Furthermore, the response to presurgical chemotherapy is also predictive of event-free survival (EFS), with patients having minimal or no viable residual tumor having significantly longer EFS than those with larger amounts of remaining tumor after neoadjuvant therapy. The Cooperative Ewing’s Sarcoma Study (CESS) group recommends the use of 12 courses of vincristine, ifosfamide, and doxorubicin alternating with actinomycin D in the treatment of Ewing’s sarcoma [25–27]. In general, both chordoma and chondrosarcoma (especially for the most frequently observed conventional and clear cell subtype) is considered to be fairly refractory to chemotherapy. Given their slow growing nature, most trials investigating the use of chemotherapeutic agents, which target rapidly dividing cells, have been disappointing. Though mild, there are some reports of
Sarcoma (SH Okuno, Section Editor)
Fig. 1. Illustrative case #1 (a–f): Sagittal T1 (a) and axial T2 (b) weighted images demonstrating tumor involvement of the L2 vertebral body in zones 7-9/C in the WBB staging system. This tumor had to be approached using a 2-stage operation from posterior and anterior. The red lines show the osteotomies that were performed and the green line outlines the extent of the tumor. The posterior elements are removed in the first stage (c) and posterior instrumentation is inserted (d). A retroperitoneal approach is used to the deliver the tumor along with the vertebral body in 1 piece (f) with insertion of an expandable cage and lateral plate (e). Illustrative case #2 (g–l): Sagittal (g) and axial (h) T2 weighted images demonstrating extent of tumor involvement with a significant epidural component in the thoracic spine (WBB zones 2-10/D). This tumor was approached posteriorly given the ability for extensive rib resection and sacrifice of the thoracic nerve roots, thus, creating a wide corridor through which the tumor can be delivered. Once again, red lines demonstrate the osteotomies and the green outline shows the extent of tumor involvement. Posterior segmental instrumentation (i) with an expandable cage (j) is inserted and the tumor specimen (k and l) can be removed in an en bloc fashion.
beneficial treatment with doxorubicin-cisplatin based chemotherapies on mesenchymal chondrosarcomas, which are beyond the scope of this review [28].
Radiation therapy Osteosarcoma, chondrosarcoma, and chordoma in general are relatively refractory to radiation therapy. There may be a role for radiation, however, in 2 specific scenarios: first, as a palliative measure in patients who are not candidates for surgery, and second, postoperatively in situations of subtotal tumor removal. The doses of radiation required to kill these cells are quite high (60 Gy), and this often precludes the administration of effective doses where these lesions are often encountered in the skull base or axial spine given the proximity of vital neural elements. There is some evidence, how-
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ever, that the small cell variant of osteosarcoma may respond better to radiation than other subtypes [29]. In contrast, radiation therapy is effective in the treatment of Ewing’s sarcoma. In the absence of randomized trials, both surgery and radiation are considered viable treatment options for this disease. Most clinical protocols still emphasize the role for surgery when negative margins can be obtained, but there is some evidence to suggest that where positive margins are anticipated despite induction chemotherapy, high dose radiation therapy alone may be advantageous compared with debulking surgery followed by radiation [23].
Diet and lifestyle There is no evidence to suggest that diet or lifestyle contribute to the formation or treatment of primary sarcomas affecting the spine.
Conclusions Sarcomas of the spine are rare disorders that are challenging to treat. Surgical resection, ideally with negative margins, remains an important part of the treatment paradigm yet this is not always possible and is highly dependent on patient and tumor specific variables. When achieved, combined with advancements in neoadjuvant and adjuvant therapy, long term survival and even cure is possible. The care of these patients therefore needs to be multidisciplinary and performed in highly specialized centers.
Compliance with Ethics Guidelines Conflict of Interest Ali K. Ozturk and Jean-Paul Wolinsky declare that they have no conflict of interest. Ziya L. Gokaslan is a stock shareholder with US Spine and Spinal Kinetics; received honoraria from AO Foundation and had travel/accommodations and or meeting expenses covered or reimbursed by AO Spine. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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