DOI: 10.3171/2014.7.SPINE13802 ©AANS, 2014
Radiation-induced intradural malignant peripheral nerve sheath tumor of the cauda equina with diffuse leptomeningeal metastasis Case report *Darryl Lau, M.D.,1 Dominic H. Moon, B.A., 2 Paul Park, M.D., 4 Shawn Hervey-Jumper, M.D., 4 Paul E. McKeever, M.D., Ph.D., 3 and Daniel A. Orringer, M.D. 4 Department of Neurological Surgery, University of California, San Francisco, California; 2University of Michigan Medical School and Departments of 3Pathology and 4Neurosurgery, University of Michigan, Ann Arbor, Michigan 1
Malignant peripheral nerve sheath tumors (MPNSTs) are rare, affecting only a small portion of the general population. In many cases, MPNSTs occur in association with neurofibromatosis Type 1 and at times arise secondary to previous radiation therapy (RT). These tumors can be found essentially anywhere a peripheral nerve is present, but they rarely originate primarily from the spinal nerve or cauda equina and cause leptomeningeal spread. This report describes the treatment course of a 43-year-old man with a history of testicular seminoma treated with RT a decade before, who was found to have a large sacral MPNST. The patient underwent complete sacrectomy for gross-total resection. Despite this effort, he was eventually found to have metastatic lesions throughout the spine and brain, ultimately resulting in acute hydrocephalus and death. Biopsy results of these metastatic lesions proved to be characteristic of his original MPNST. The literature is also reviewed and the diagnostic modalities, management strategies, and prognosis of MPNST are discussed. (http://thejns.org/doi/abs/10.3171/2014.7.SPINE13802)
T
Key Words • cauda equina • malignant peripheral nerve sheath tumor • radiation therapy • oncology
term “malignant peripheral nerve sheath tumor” (MPNST) was coined by the World Health Organization to describe tumors originating from the connective tissue surrounding peripheral nerves, and it replaced previous nomenclature, including malignant neurilemmoma, malignant schwannoma, and neurofibrosarcoma. These tumors are rare, with an incidence of 0.001% in the general population.15,17 Approximately 20%–50% occur in association with neurofibromatosis Type 1,6,10,17 and up to 11% arise secondary to previous radiation therapy (RT).10,23 The incidence of MPNST has a slight female predominance, and the tumor is seen in patients of all ages, with most presenting in their 3rd decade of life.10 The most common locations for MPNSTs are in the extremities and trunk; they occur less commonly in the head and neck.27 Primary intradural MPNST involving the cauda equina is extremely rare, with only 4 case reports in the literature.1–3,5,9,21,25,28,29 Leptomeningeal spread from such lesions is extremely uncommon.29 We report a unique case of a patient with RT-induced intradural MPNST of the spine com-
plicated by diffuse CNS and leptomeningeal metastases. We also review the literature to discuss the diagnostic modalities, management strategies, and prognosis of MPNST.
Abbreviations used in this paper: MPNST = malignant peripheral nerve sheath tumor; RT = radiation therapy. * Dr. Lau and Mr. Moon contributed equally to this work.
This article contains some figures that are displayed in color online but in black-and-white in the print edition.
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Case Report Presentation and History. A 43-year-old man with a history of testicular seminoma presented with severe back pain and paresthesia radiating to his left buttock and posterolateral thigh for 5 months. He had undergone orchiectomy and adjuvant RT to his right retroperitoneal and inguinal nodal chain 10 years before. There was no personal or family history of neurofibromatosis. On examination, he was neurologically intact. Oral analgesia and physiotherapy were initiated but failed to resolve his symptoms. Sagittal and axial T1-weighted contrast-enhanced MRI of the spine revealed a contrast-enhancing, 5.8 × 5.3–cm sacral mass that encased the S-2 and S-3 vertebral bodies and extended into the sacral spinal canal, involving bilateral sacral nerve roots (Fig. 1).
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Fig. 1. Preoperative MR images of sacral MPNST. Sagittal contrastenhanced T1-weighted MR image (left) showing a large sacral mass involving S-2 and S-3. Axial contrast-enhanced T1-weighted MR image at S2–3 (right) showing the tumor extending into sacral spinal canal and bilateral sacral nerve roots.
Treatment Course and First Surgery. Biopsy guided by CT revealed a high-grade spindle cell sarcoma, consistent with MPNST. The tumor was positive for S100 protein and negative for caldesmon, desmin, and muscle-specific actin. The patient underwent 4 cycles of neoadjuvant chemotherapy, alternating between ifosfamide/doxorubicin and ifosfamide/etoposide, to decrease tumor burden and thus increase the potential for complete resection. Despite this, the tumor continued to grow to 6.2 × 6.3 cm, and the patient developed difficulty with urination. At this time, a decision was made to proceed with complete resection. The patient was then referred to an outside institution for surgical management of the MPNST. The patient underwent complete sacrectomy via a 2-staged approach. By report, an anterior approach was taken to free up the anterior bony portions of the sacrum via bilateral sacroiliac osteotomy, bilateral iliac osteotomy, and osteotomy of the L-5 vertebral body. The second stage consisted of a posterior approach for en bloc removal of the sacral tumor and spinal reconstruction. Osteotomies of the posterior portions of the sacrum, ilium, and L-5 vertebral body were performed, freeing the sacrum and tumor from all bony connections. The sacrum (containing the tumor) was removed en bloc. Therefore, the physical nature and vascularity of the tumor were not directly encountered. The L-5 nerve roots were attached to the specimen by soft-tissue connections during removal but were easily dissected free. Negative margins were confirmed. Spinal reconstruction consisted of L2–5 pedicle screw placement, double iliac screw fixation, and dual rod placement, in conjunction with placement of bilateral fibular strut allograft from the supraacetabular bone to the anterior portion of the inferior endplate of L-5. Grosstotal resection via sacrectomy was achieved (Fig. 2A and C). However, the surgery was complicated by multiple issues, including postoperative wound infection, which required surgical debridement, a yearlong course of antibiotics, and pelvic screw fracture (Fig. 2B). Postoperative Course. The patient had bilateral lumbosacral radiculopathies/plexopathies after surgery, resulting in bilateral paraparesis with partial motor preser-
2
Fig. 2. A and B: Anteroposterior and lateral plain radiographs of the lumbopelvic area showing posterior L-2 to iliac screw fixation and bilateral supraacetabular and L-5 vertebral body placement of fibular allograft performed at another institution. Disconnection of one of the iliac screws and haloing of the pelvic screws suggesting loosening are visible. C: Sagittal T1-weighted MR image demonstrating complete sacrectomy that resulted in gross-total resection of the tumor.
vation of knee extensors, thigh adductors, and hip flexors. Sensation to light touch and pinprick was significantly diminished in L5–S4 distribution. At the time of discharge, the patient had Grade 4+ of 5 bilateral knee extension strength, Grade 4– of 5 hip flexor strength, and absent hip extension and ankle motion. In addition, the patient had a neurogenic bowel with flaccid anal sphincter tone and neurogenic bladder, requiring, respectively, colostomy at the time of sacrectomy and self-catheterization. The patient was evaluated for RT after surgery, but the radiation oncologist felt the patient would not benefit from additional RT at the time, given clear surgical margins and previous RT exposure to the area for seminoma. Instead, the patient underwent an additional 4 cycles of adjuvant chemotherapy with the same preoperative regimen.
Metastasis. The patient subsequently returned to our institution for further management of his MPNST. About 24 months after completing adjuvant chemotherapy and 30 months after sacrectomy, the patient was found to have renal metastasis of his MPNST. He was treated with cryo-
J Neurosurg: Spine / September 12, 2014
Cauda equina MPNST therapy alone, which resulted in remission of his disease, and after his treatment course he continued to do well, attaining Karnofsky Performance Scale score of 70.
Second Surgery and Histopathology Analysis. Twenty-four months after remission from his renal metastasis, the patient presented with acute pain and weakness in his right upper extremity. However, he also endorsed worsening bilateral lower-extremity weakness that started 5 months before. He also had decreased sensation in bilateral lower extremities. In his right upper extremity he had Grade 2 of 5 deltoid strength, Grade 3 of 5 bicep strength, and Grade 4+ of 5 hand grip strength. Otherwise, he had Grade 5 of 5 strength in the right triceps and left upper extremity. There was no movement in bilateral lower extremities and no sensation below approximately the T-12 dermatome. Sagittal T1-weighted contrast-enhanced MRI of brain and spine demonstrated leptomeningeal enhancement and contrast-enhancing masses throughout brainstem and upper cervical cord surfaces (Fig. 3 left). The largest mass was in the midcervical region, with marked cord compression (Fig. 3 right). The patient underwent urgent cervical decompression via C3–6 laminectomy and biopsy of the large cervical mass. The mass adhered widely over the pial surface of the spinal cord. Biopsy staining with H & E revealed features characteristic of MPNST, including high cellular density, fascicles of tissue weaving in different directions (Fig. 4A), and pleomorphic long, wavy nuclei with tapered ends (Fig. 4B), confirming metastatic MPNST. There were at least 5 mitoses per high-power field (Fig. 4C). Type IV collagen was present around individual and small clusters of cells (Fig. 4D). The biopsy was negative for S100 protein and glial fibrillary acidic protein, and the tumor did not overexpress p53. Histological features of specimens from first and second surgeries were similar. Outcome. The patient remained at his preoperative neurological baseline after biopsy. However, 6 days later, he developed new-onset headaches and seizures. Noncontrast head CT revealed hydrocephalus, likely secondary to metastatic disease (Fig. 5). After consultation with the patient and family, they elected comfort care, and the patient died of cardiac arrest shortly thereafter. The patient’s total length of survival from the time of MPNST diagnosis, sacrectomy, and renal metastasis was 60 months, 56 months, and 20 months, respectively.
Discussion
Most MPNSTs arise de novo from normal peripheral nerves, perineuriomas, and neurofibromas.9,15 Thus, MPNSTs may arise from any site, but they are most commonly located in the extremities, followed by the trunk, and less commonly the head and neck region.27 Primary intradural MPNST involving the spine is extremely rare, with only 20 adult cases reported in the literature: 7 cervical,2,9,25,29 6 thoracic,3,9,25,29 3 lumbar,9,25 and 4 cauda equina1,5,21,28 (Table 1). Here we present the fifth case of an intradural MPNST of the cauda equina; what makes this case unique compared with the other case reports of J Neurosurg: Spine / September 12, 2014
Fig. 3. Diffuse leptomeningeal metastasis. Sagittal contrast-enhanced T1-weighted MR image (left) revealing an enhancing metastatic lesion on the anterior surface of the medulla. Sagittal contrastenhanced T1-weighted MR image of cervical spine (right) showing a contrast-enhancing mass causing severe posterior compression of cervical cord at C-4.
intradural MPNST is that our patient developed diffuse leptomeningeal and CNS metastases causing mass effect on the brainstem and spinal cord. In addition, long-term follow-up is provided. It is well recognized that a history of RT increases the risk of MPNST.2,7,8,30 Our patient underwent adjuvant RT for testicular seminoma 10 years before presenting with a sacral mass. Interestingly, there are 4 reported cases of patients developing RT-induced MPNST after treatment for testicular seminomas. The oncological histories of these patients are very similar to that of our patient, each with an MPNST diagnosis made 7–10 years after adjuvant RT.5,18,33 Three of the 4 patients underwent RT to the ipsilateral paraaortic and/or inguinal regions and subsequently developed MPNST involving the sacrum: L3–S1, 5 S-2 nerve root and plexus,18 and S-2 nerve root.33 Studies have shown that RT for testicular cancer confers increased risk of developing secondary malignancies, with one study showing a 2.6-fold increase.30 As a result, National Comprehensive Cancer Network guidelines updated in 2009 recommend surveillance as the preferred option for management of Stage I seminoma patients,22 and European Association of Urology guidelines revised in 2011 recommend against RT for localized testicular seminoma.4 The alternative to RT is single-agent carboplatin for Stage I seminoma,20 which may not be associated with secondary cancers.31 Although RT-induced MPNSTs are extremely rare, suspicion is warranted, as there is a real risk of developing secondary cancers a decade after RT. The diagnosis of spinal intradural MPNST depends on high clinical suspicion on both imaging and histopathology analyses,6,11 especially since patients present with nonspecific signs and symptoms of pain, paresthesia, weakness, and/or incontinence, depending on the anatomical site. Imaging alone may lead to an incorrect diagnosis.19 In general, spinal MPNSTs are described as large tumors with irregularly lobulated borders that are indistinguishable from the surrounding soft tissue and bone, suggestive of malignant properties.19 On MR images, MPNSTs are inhomogeneously contrast enhancing and have scattered areas of T2-weighted hyperintensities, 3
D. Lau et al.
Fig. 4. Histology analysis and characteristics of the MPNST discussed in this case report. A: Densely cellular tumor, organized in fascicles (arrows) weaving in different directions. H & E, original magnification ×100. B: Long, wavy nuclei. H & E, original magnification ×600. C: Mitoses (circled). H & E, original magnification ×400. D: Focal abundance of Type IV collagen (brown). Immunohistochemical stain, original magnification ×250.
Fig. 5. Axial noncontrast head CT image showing acutely enlarged ventricles with hydrocephalus secondary to leptomeningeal spread.
4
likely representing areas of necrosis.1,3,19 There is also evidence of abundant blood supply and edema.19 Histologically, MPNST can resemble other tumors (fibrosarcoma, leiomyosarcoma, and cellular schwannomas).11,25 Typically, MPNST cells weave in different directions, and long, wavy nuclei have tapered ends. Fascicle formation, mitoses, necrosis, and extreme nuclear anaplasia are also common.3,11 In addition, a wide variety of “divergent” histological patterns may be present: epithelial structures, rhabdomyoblastic differentiation, cartilage, and even bone. On immunohistochemistry, MPNSTs are negative for glial fibrillary acidic protein and variably immunoreactive for S100 protein (40% lack S100 protein) and Type IV collagen.11,25 Cellular schwannomas, in contrast, are diffusely positive for S100 protein and Type IV collagen and have fewer mitoses than do MPNSTs. Leiomyosarcomas have desmin. Fibrosarcomas lack S-100 protein. Alterations in the p53- and Rbdependent pathways are common in MPNSTs.11 Necrosis and positive S100 protein immunohistochemistry can be focal features and could be missed on some specimens. Patients with MPNSTs are best treated by complete resection with wide margins, an independent factor associated with improved survival.6 However, resectability and extent of resection depend greatly on tumor location. The ability to obtain complete tumor resection ranges from 20% for spinal tumors to 95% for extremity tumors.10,16,18 Spinal tumors are often less amenable to wide resection, given their intimate proximity to the spinal cord, major vessels, and vital nerves. In this patient, gross-total resection via complete sacrectomy offered him the best survival benefit but resulted in loss of ambulatory ability and J Neurosurg: Spine / September 12, 2014
J Neurosurg: Spine / September 12, 2014
30, F
37, M
Celli et al., 1995
not mentioned
22, F
not mentioned
not mentioned
36, F
30, M
not mentioned
43, M
10 yrs previously for testicular seminoma; paraaortic strip (total 30 Gy/15 fractions over 3 wks) not mentioned
not mentioned
NF1
Location
back pain, leg weak- cauda ness, bowel & bladequina der dysfunction lt C-6 radiculopathy cervical
Presentation
cauda equina
pain for 2 yrs, weakness & incontinence pain for 6 yrs, weakness
pain for 5 mos
thoracic
cervical
thoracic
pain for 8 mos, weak- thoracic ness pain for 9 mos, weak- lumbar ness pain for 3 mos lumbar
back pain, leg weakness, bowel & bladder dysfunction
6 yrs previously for nodular sclerosing Hodgkin lymphoma rt Horner syndrome, cervical 5 yrs previously for nodular sclerosing rt C-6 radiculopaHodgkin lymphoma, thy, & weakness of rt triceps & wrist & again for recurrent lymphoma extensor not mentioned paraparesis & urinary upper thoincontinence racic
not mentioned
Previous RT
68, F
52, F
Amin et al., 38, M 2004
Albayrak et 25, M al., 2006
Adamson et al., 2004
NF1
Age (yrs), NF Sex History
Acharya et 32, M al., 2001
Authors & Year
TABLE 1: Cases of primary intradural MPNST reported in the literature*
no
partial
complete
complete
complete
complete
complete
complete
biopsy
yes
yes
yes
no
no
no
no
no
yes
partial
complete
yes
RT
partial
Surgery (biopsy or partial or complete resection)
no
no
no
no
no
no
yes, palliative
no
no
no
no
Chemotherapy Treatment
yes
yes
yes
no
no
no
not mentioned
yes, in 7 wks
not mentioned
not mentioned
no
Recurrence
lung
lung
no
no
no
no
thoracic spine, lung not mentioned
no
no
no
Metastasis
(continued)
dead at 14 mos
alive & disease free at 6 yrs alive & disease free at 2 yrs alive & disease free at 6 yrs alive & disease free at 4 yrs dead at 6 mos
not mentioned
alive at 7 wks
dead after 1 yr
dead after 1 yr & a few mos
alive at 18 mos
Survival
Cauda equina MPNST
5
6
not mentioned
47, M
43, M
neck pain radiating to rt shoulder for 9 mos, rt arm weakness for 1 mo not mentioned lt shoulder & arm pain for 4 mos not mentioned neck pain radiating to rt shoulder for 6 mos 10 yrs previously, severe back pain & adjuvant therapy for paresthesia radiattesticular seminoma ing to lt buttock & thigh for 5 mos
* NF = neurofibromatosis (NF1 = Type 1; NF2 = Type 2).
present study
70, F
18, M
NF1
cauda equina
cervical
cervical
cervical
complete
complete
complete
complete
partial
no
no
no
no
no
yes, after 3 mos
yes, after 8 yrs
yes, after 2 yrs yes, after 3 yrs, in T9–11
yes
yes
not mentioned
Recurrence
yes, neoadjuvant & yes, about adjuvant therapy 60 mos alternating btwn ifosfamide/doxo rubicin & ifos famide/etoposide
no
no
yes, at time of recurrence; Adriamycin 120 mg every 3 wks (total 1080 mg) yes, total 24 Gy after no 1st op, total 32 Gy after 2nd op at time of recurrence yes, total 10 Gy no yes, adjuvant, T11– S4 2.5 Gy 4×/wk for 6 wks (total 60 Gy)
no
not mentioned
complete
not mentioned yes
not mentioned
Chemotherapy Treatment
no yes, adjuvant, total 36 Gy entire spine & brain, additional 14.4 Gy to lumbosacral lesion/28 fractions not mentioned not mentioned
RT
complete
Valdueza et 43, F al., 1991
back pain for 9 yrs worsening for 4 mos, impotence for 4 wks, leg weakness for 3 wks low-back pain for 1 lower thomo, leg weakness racic for 2 wks
upper thoracic lower cervical cauda equina
not mentioned
not mentioned
not mentioned
Thomeer et 42, M al., 1981
NF2
partial
not mentioned
NF2
47, F
37, F
Mitsuhara et al., 2013
complete
Location
not mentioned
Presentation
complete
Previous RT
Seppälä et 35, M al., 1993 23, F
Age (yrs), NF Sex History
Surgery (biopsy or partial or complete resection)
back pain, parapacauda 15 yrs previously for equina resis of rt leg, Stage Ib uterine cervical cancer urinary/bowel incontinence, acute (total 22 Gy adjuvant consciousness intraop paraaortic RT) disturbance not mentioned not mentioned lumbar
Authors & Year
TABLE 1: Cases of primary intradural MPNST reported in the literature* (continued)
alive & disease free at 8 mos alive & disease free at 7 mos
dead at 18 mos
alive at 10 yrs w/ recurrence
alive at 3 yrs w/ recurrence
dead at 6 yrs
dead at 8 mos
dead at 18 mos
not mentioned
Survival
renal, cervi- died at 5 yrs cal cord, from CNS & brainmetastasis stem
no
no
lumbar spine, brain
no
no
systemic
systemic
systemic
no
Metastasis
D. Lau et al.
J Neurosurg: Spine / September 12, 2014
Cauda equina MPNST bladder/bowel control. While aggressive resection is warranted, consideration of functionality and quality of life needs to be carefully balanced. Postoperative adjuvant RT, chemotherapy, or both have yet to be systematically studied for the treatment of spinal MPNST, but there are indications that adjuvant RT may be beneficial.29 A large case series by Baehring et al.6 of 54 patients with MPNSTs in various locations showed a mortality hazard ratio of 0.22 for adjuvant RT on multivariate analysis. Adjuvant RT is particularly beneficial for local tumor control when radical resection is not possible, or for recurrent tumors. 5 Chemotherapy has not proven to be effective in the treatment of MPNST6 but can be used in cases without alternatives for disseminated metastatic disease.13 The expanding scientific literature suggests that MPNST can be treated more effectively with the addition of agents that target and inhibit specific pathways and/or cellular processes: PI3K/mTOR pathway with XL765,12 autophagy with chloroquine,12 and plateletderived growth factor receptor with sunitinib.35 The reported 5-year survival rate for patients diagnosed with MPNST is poor, ranging from 16% to 52%.10,18,34 Among reported cases of spinal intradural MPNST, the calculated 1-year, 3-year, and 5-year survival rates are 81%, 50%, and 25%, respectively. In a study of 21 patients with spinal MPNSTs, the local recurrence rate was extremely high: 71%.9 This is approximately twice the rate associated with extraspinal MPNSTs (20%– 40%)14,24,32 and is likely secondary to lower resectability. Of the 20 reported cases of patients with intradural MPNSTs of the spine, eventual metastasis was seen in 8 (40%), but these rates depend on the length of follow-up in each case report/series. Intradural MPNSTs represent a unique clinical entity, as these tumors can be associated with greater morbidity and worse prognosis secondary to direct access for metastatic spread and seeding of the CNS. Our patient succumbed to diffuse leptomeningeal spread and seeding of the brainstem and cervical cord. This is an extremely rare event in patients with an intradural MPNST. Only 1 other patient in the literature demonstrated CNS spread of an intradural MPNST,29 which occurred a little more than 1 year after complete removal of the original tumor, with death shortly thereafter. There is only 1 other reported case of leptomeningeal spread of an MPNST,26 which is rapidly fatal. Additional surveillance for these potential sequelae should be carefully considered in patients with intradural MPNST. Primary intradural MPNST of the spine is a rare tumor that may arise secondary to prior RT. It is difficult to diagnose and has a poor prognosis. Given that adjuvant RT is relatively common, RT-induced intradural MPNST of the spine may be more widespread than reported. Better awareness of this entity and its potential for metastasis to the CNS may enable physicians to provide early intervention in patients who have signs and symptoms associated with this condition. Disclosure Dr. Park reports being a consultant for Globus Medical and Medtronic and receiving royalties from Globus Medical.
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Author contributions to the study and manuscript preparation include the following. Conception and design: Orringer, Hervey-Jumper. Acquisition of data: Lau, Moon, Hervey-Jumper, McKeever. Analysis and interpretation of data: Lau, Moon, Park, Hervey-Jumper, McKeever. Drafting the article: Lau, Moon. Critically revising the article: Orringer, Park, Hervey-Jumper, McKeever. Reviewed submitted version of manuscript: all authors. Study supervision: Orringer. References 1. Acharya R, Bhalla S, Sehgal AD: Malignant peripheral nerve sheath tumor of the cauda equina. Neurol Sci 22:267–270, 2001 2. Adamson DC, Cummings TJ, Friedman AH: Malignant peripheral nerve sheath tumor of the spine after radiation therapy for Hodgkin’s lymphoma. Clin Neuropathol 23:245–255, 2004 3. Albayrak BS, Gorgulu A, Kose T: A case of intra-dural malignant peripheral nerve sheath tumor in thoracic spine associated with neurofibromatosis type 1. J Neurooncol 78:187–190, 2006 4. Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark G, Fizazi K, et al: EAU guidelines on testicular cancer: 2011 update. Eur Urol 60:304–319, 2011 5. Amin A, Saifuddin A, Flanagan A, Patterson D, Lehovsky J: Radiotherapy-induced malignant peripheral nerve sheath tumor of the cauda equina. Spine (Phila Pa 1976) 29:E506– E509, 2004 6. Baehring JM, Betensky RA, Batchelor TT: Malignant peripheral nerve sheath tumor: the clinical spectrum and outcome of treatment. Neurology 61:696–698, 2003 7. Bergstrom R: Changes in peripheral nerve tissue after irradiation with high energy protons. Acta Radiol 58:301–312, 1962 8. Braunstein S, Nakamura JL: Radiotherapy-induced malignancies: review of clinical features, pathobiology, and evolving approaches for mitigating risk. Front Oncol 3:73, 2013 9. Celli P, Cervoni L, Tarantino R, Fortuna A: Primary spinal malignant schwannomas: clinical and prognostic remarks. Acta Neurochir (Wien) 135:52–55, 1995 10. Ducatman BS, Scheithauer BW, Piepgras DG, Reiman HM, Ilstrup DM: Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 57:2006–2021, 1986 11. Frosch MP, Anthony DC, DeGirolami U: The central nervous system, in Kumar V, Abbas AK, Fausto N, et al (eds): Robbins and Cotran Pathologic Basis of Disease, ed 8. Philadelphia: Saunders Elsevier, 2010, pp 1279–1344 12. Ghadimi MP, Lopez G, Torres KE, Belousov R, Young ED, Liu J, et al: Targeting the PI3K/mTOR axis, alone and in combination with autophagy blockade, for the treatment of malignant peripheral nerve sheath tumors. Mol Cancer Ther 11:1758–1769, 2012 13. Goldman RL, Jones SE, Heusinkveld RS: Combination chemotherapy of metastatic malignant schwannoma with vincristine, adriamycin, cyclophosphamide, and imidazole carboxamide: a case report. Cancer 39:1955–1958, 1977 14. Grobmyer SR, Reith JD, Shahlaee A, Bush CH, Hochwald SN: Malignant peripheral nerve sheath tumor: molecular pathogenesis and current management considerations. J Surg Oncol 97:340–349, 2008 15. Gupta G, Maniker A: Malignant peripheral nerve sheath tumors. Neurosurg Focus 22(6):E12, 2007 16. Hruban RH, Shiu MH, Senie RT, Woodruff JM: Malignant peripheral nerve sheath tumors of the buttock and lower extremity. A study of 43 cases. Cancer 66:1253–1265, 1990 17. Kim DH, Murovic JA, Tiel RL, Moes G, Kline DG: A series of 397 peripheral neural sheath tumors: 30-year experience at Louisiana State University Health Sciences Center. J Neurosurg 102:246–255, 2005
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HD: Primary spinal malignant schwannoma: clinical, histological and cytogenetic findings. Neurosurg Rev 14:283–291, 1991 30. van den Belt-Dusebout AW, de Wit R, Gietema JA, Horenblas S, Louwman MW, Ribot JG, et al: Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 25:4370–4378, 2007 31. van Leeuwen FE, Stiggelbout AM, van den Belt-Dusebout AW, Noyon R, Eliel MR, van Kerkhoff EH, et al: Second cancer risk following testicular cancer: a follow-up study of 1,909 patients. J Clin Oncol 11:415–424, 1993 32. Vauthey JN, Woodruff JM, Brennan MF: Extremity malignant peripheral nerve sheath tumors (neurogenic sarcomas): a 10-year experience. Ann Surg Oncol 2:126–131, 1995 33. West DA, Parra RO, Manepalli A, Bernardi RJ, Cummings JM: Development of a malignant peripheral nerve sheath tumor following treatment for testicular seminoma. Urology 50:292–294, 1997 34. Wong WW, Hirose T, Scheithauer BW, Schild SE, Gunderson LL: Malignant peripheral nerve sheath tumor: analysis of treatment outcome. Int J Radiat Oncol Biol Phys 42:351– 360, 1998 35. Zietsch J, Ziegenhagen N, Heppner FL, Reuss D, von Deimling A, Holtkamp N: The 4q12 amplicon in malignant peripheral nerve sheath tumors: consequences on gene expression and implications for sunitinib treatment. PLoS ONE 5:e11858, 2010 Manuscript submitted August 27, 2013 Accepted July 11, 2014 Please include this information when citing this paper: published online September 12, 2014; DOI: 10.3171/2014.7.SPINE13802. Address correspondence to: Daniel A. Orringer, M.D., Department of Neurosurgery, University of Michigan, 1500 E. Medical Center Dr., Rm. 3552 TC, Ann Arbor, MI 48109-5338. email: [email protected].
J Neurosurg: Spine / September 12, 2014
Radiation-induced intradural malignant peripheral nerve sheath tumor of the cauda equina with diffuse leptomeningeal metastasis Case report *Darryl Lau, M.D.,1 Dominic H. Moon, B.A., 2 Paul Park, M.D., 4 Shawn Hervey-Jumper, M.D., 4 Paul E. McKeever, M.D., Ph.D., 3 and Daniel A. Orringer, M.D. 4 Department of Neurological Surgery, University of California, San Francisco, California; 2University of Michigan Medical School and Departments of 3Pathology and 4Neurosurgery, University of Michigan, Ann Arbor, Michigan 1
Malignant peripheral nerve sheath tumors (MPNSTs) are rare, affecting only a small portion of the general population. In many cases, MPNSTs occur in association with neurofibromatosis Type 1 and at times arise secondary to previous radiation therapy (RT). These tumors can be found essentially anywhere a peripheral nerve is present, but they rarely originate primarily from the spinal nerve or cauda equina and cause leptomeningeal spread. This report describes the treatment course of a 43-year-old man with a history of testicular seminoma treated with RT a decade before, who was found to have a large sacral MPNST. The patient underwent complete sacrectomy for gross-total resection. Despite this effort, he was eventually found to have metastatic lesions throughout the spine and brain, ultimately resulting in acute hydrocephalus and death. Biopsy results of these metastatic lesions proved to be characteristic of his original MPNST. The literature is also reviewed and the diagnostic modalities, management strategies, and prognosis of MPNST are discussed. (http://thejns.org/doi/abs/10.3171/2014.7.SPINE13802)
T
Key Words • cauda equina • malignant peripheral nerve sheath tumor • radiation therapy • oncology
term “malignant peripheral nerve sheath tumor” (MPNST) was coined by the World Health Organization to describe tumors originating from the connective tissue surrounding peripheral nerves, and it replaced previous nomenclature, including malignant neurilemmoma, malignant schwannoma, and neurofibrosarcoma. These tumors are rare, with an incidence of 0.001% in the general population.15,17 Approximately 20%–50% occur in association with neurofibromatosis Type 1,6,10,17 and up to 11% arise secondary to previous radiation therapy (RT).10,23 The incidence of MPNST has a slight female predominance, and the tumor is seen in patients of all ages, with most presenting in their 3rd decade of life.10 The most common locations for MPNSTs are in the extremities and trunk; they occur less commonly in the head and neck.27 Primary intradural MPNST involving the cauda equina is extremely rare, with only 4 case reports in the literature.1–3,5,9,21,25,28,29 Leptomeningeal spread from such lesions is extremely uncommon.29 We report a unique case of a patient with RT-induced intradural MPNST of the spine com-
plicated by diffuse CNS and leptomeningeal metastases. We also review the literature to discuss the diagnostic modalities, management strategies, and prognosis of MPNST.
Abbreviations used in this paper: MPNST = malignant peripheral nerve sheath tumor; RT = radiation therapy. * Dr. Lau and Mr. Moon contributed equally to this work.
This article contains some figures that are displayed in color online but in black-and-white in the print edition.
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J Neurosurg: Spine / September 12, 2014
Case Report Presentation and History. A 43-year-old man with a history of testicular seminoma presented with severe back pain and paresthesia radiating to his left buttock and posterolateral thigh for 5 months. He had undergone orchiectomy and adjuvant RT to his right retroperitoneal and inguinal nodal chain 10 years before. There was no personal or family history of neurofibromatosis. On examination, he was neurologically intact. Oral analgesia and physiotherapy were initiated but failed to resolve his symptoms. Sagittal and axial T1-weighted contrast-enhanced MRI of the spine revealed a contrast-enhancing, 5.8 × 5.3–cm sacral mass that encased the S-2 and S-3 vertebral bodies and extended into the sacral spinal canal, involving bilateral sacral nerve roots (Fig. 1).
1
D. Lau et al.
Fig. 1. Preoperative MR images of sacral MPNST. Sagittal contrastenhanced T1-weighted MR image (left) showing a large sacral mass involving S-2 and S-3. Axial contrast-enhanced T1-weighted MR image at S2–3 (right) showing the tumor extending into sacral spinal canal and bilateral sacral nerve roots.
Treatment Course and First Surgery. Biopsy guided by CT revealed a high-grade spindle cell sarcoma, consistent with MPNST. The tumor was positive for S100 protein and negative for caldesmon, desmin, and muscle-specific actin. The patient underwent 4 cycles of neoadjuvant chemotherapy, alternating between ifosfamide/doxorubicin and ifosfamide/etoposide, to decrease tumor burden and thus increase the potential for complete resection. Despite this, the tumor continued to grow to 6.2 × 6.3 cm, and the patient developed difficulty with urination. At this time, a decision was made to proceed with complete resection. The patient was then referred to an outside institution for surgical management of the MPNST. The patient underwent complete sacrectomy via a 2-staged approach. By report, an anterior approach was taken to free up the anterior bony portions of the sacrum via bilateral sacroiliac osteotomy, bilateral iliac osteotomy, and osteotomy of the L-5 vertebral body. The second stage consisted of a posterior approach for en bloc removal of the sacral tumor and spinal reconstruction. Osteotomies of the posterior portions of the sacrum, ilium, and L-5 vertebral body were performed, freeing the sacrum and tumor from all bony connections. The sacrum (containing the tumor) was removed en bloc. Therefore, the physical nature and vascularity of the tumor were not directly encountered. The L-5 nerve roots were attached to the specimen by soft-tissue connections during removal but were easily dissected free. Negative margins were confirmed. Spinal reconstruction consisted of L2–5 pedicle screw placement, double iliac screw fixation, and dual rod placement, in conjunction with placement of bilateral fibular strut allograft from the supraacetabular bone to the anterior portion of the inferior endplate of L-5. Grosstotal resection via sacrectomy was achieved (Fig. 2A and C). However, the surgery was complicated by multiple issues, including postoperative wound infection, which required surgical debridement, a yearlong course of antibiotics, and pelvic screw fracture (Fig. 2B). Postoperative Course. The patient had bilateral lumbosacral radiculopathies/plexopathies after surgery, resulting in bilateral paraparesis with partial motor preser-
2
Fig. 2. A and B: Anteroposterior and lateral plain radiographs of the lumbopelvic area showing posterior L-2 to iliac screw fixation and bilateral supraacetabular and L-5 vertebral body placement of fibular allograft performed at another institution. Disconnection of one of the iliac screws and haloing of the pelvic screws suggesting loosening are visible. C: Sagittal T1-weighted MR image demonstrating complete sacrectomy that resulted in gross-total resection of the tumor.
vation of knee extensors, thigh adductors, and hip flexors. Sensation to light touch and pinprick was significantly diminished in L5–S4 distribution. At the time of discharge, the patient had Grade 4+ of 5 bilateral knee extension strength, Grade 4– of 5 hip flexor strength, and absent hip extension and ankle motion. In addition, the patient had a neurogenic bowel with flaccid anal sphincter tone and neurogenic bladder, requiring, respectively, colostomy at the time of sacrectomy and self-catheterization. The patient was evaluated for RT after surgery, but the radiation oncologist felt the patient would not benefit from additional RT at the time, given clear surgical margins and previous RT exposure to the area for seminoma. Instead, the patient underwent an additional 4 cycles of adjuvant chemotherapy with the same preoperative regimen.
Metastasis. The patient subsequently returned to our institution for further management of his MPNST. About 24 months after completing adjuvant chemotherapy and 30 months after sacrectomy, the patient was found to have renal metastasis of his MPNST. He was treated with cryo-
J Neurosurg: Spine / September 12, 2014
Cauda equina MPNST therapy alone, which resulted in remission of his disease, and after his treatment course he continued to do well, attaining Karnofsky Performance Scale score of 70.
Second Surgery and Histopathology Analysis. Twenty-four months after remission from his renal metastasis, the patient presented with acute pain and weakness in his right upper extremity. However, he also endorsed worsening bilateral lower-extremity weakness that started 5 months before. He also had decreased sensation in bilateral lower extremities. In his right upper extremity he had Grade 2 of 5 deltoid strength, Grade 3 of 5 bicep strength, and Grade 4+ of 5 hand grip strength. Otherwise, he had Grade 5 of 5 strength in the right triceps and left upper extremity. There was no movement in bilateral lower extremities and no sensation below approximately the T-12 dermatome. Sagittal T1-weighted contrast-enhanced MRI of brain and spine demonstrated leptomeningeal enhancement and contrast-enhancing masses throughout brainstem and upper cervical cord surfaces (Fig. 3 left). The largest mass was in the midcervical region, with marked cord compression (Fig. 3 right). The patient underwent urgent cervical decompression via C3–6 laminectomy and biopsy of the large cervical mass. The mass adhered widely over the pial surface of the spinal cord. Biopsy staining with H & E revealed features characteristic of MPNST, including high cellular density, fascicles of tissue weaving in different directions (Fig. 4A), and pleomorphic long, wavy nuclei with tapered ends (Fig. 4B), confirming metastatic MPNST. There were at least 5 mitoses per high-power field (Fig. 4C). Type IV collagen was present around individual and small clusters of cells (Fig. 4D). The biopsy was negative for S100 protein and glial fibrillary acidic protein, and the tumor did not overexpress p53. Histological features of specimens from first and second surgeries were similar. Outcome. The patient remained at his preoperative neurological baseline after biopsy. However, 6 days later, he developed new-onset headaches and seizures. Noncontrast head CT revealed hydrocephalus, likely secondary to metastatic disease (Fig. 5). After consultation with the patient and family, they elected comfort care, and the patient died of cardiac arrest shortly thereafter. The patient’s total length of survival from the time of MPNST diagnosis, sacrectomy, and renal metastasis was 60 months, 56 months, and 20 months, respectively.
Discussion
Most MPNSTs arise de novo from normal peripheral nerves, perineuriomas, and neurofibromas.9,15 Thus, MPNSTs may arise from any site, but they are most commonly located in the extremities, followed by the trunk, and less commonly the head and neck region.27 Primary intradural MPNST involving the spine is extremely rare, with only 20 adult cases reported in the literature: 7 cervical,2,9,25,29 6 thoracic,3,9,25,29 3 lumbar,9,25 and 4 cauda equina1,5,21,28 (Table 1). Here we present the fifth case of an intradural MPNST of the cauda equina; what makes this case unique compared with the other case reports of J Neurosurg: Spine / September 12, 2014
Fig. 3. Diffuse leptomeningeal metastasis. Sagittal contrast-enhanced T1-weighted MR image (left) revealing an enhancing metastatic lesion on the anterior surface of the medulla. Sagittal contrastenhanced T1-weighted MR image of cervical spine (right) showing a contrast-enhancing mass causing severe posterior compression of cervical cord at C-4.
intradural MPNST is that our patient developed diffuse leptomeningeal and CNS metastases causing mass effect on the brainstem and spinal cord. In addition, long-term follow-up is provided. It is well recognized that a history of RT increases the risk of MPNST.2,7,8,30 Our patient underwent adjuvant RT for testicular seminoma 10 years before presenting with a sacral mass. Interestingly, there are 4 reported cases of patients developing RT-induced MPNST after treatment for testicular seminomas. The oncological histories of these patients are very similar to that of our patient, each with an MPNST diagnosis made 7–10 years after adjuvant RT.5,18,33 Three of the 4 patients underwent RT to the ipsilateral paraaortic and/or inguinal regions and subsequently developed MPNST involving the sacrum: L3–S1, 5 S-2 nerve root and plexus,18 and S-2 nerve root.33 Studies have shown that RT for testicular cancer confers increased risk of developing secondary malignancies, with one study showing a 2.6-fold increase.30 As a result, National Comprehensive Cancer Network guidelines updated in 2009 recommend surveillance as the preferred option for management of Stage I seminoma patients,22 and European Association of Urology guidelines revised in 2011 recommend against RT for localized testicular seminoma.4 The alternative to RT is single-agent carboplatin for Stage I seminoma,20 which may not be associated with secondary cancers.31 Although RT-induced MPNSTs are extremely rare, suspicion is warranted, as there is a real risk of developing secondary cancers a decade after RT. The diagnosis of spinal intradural MPNST depends on high clinical suspicion on both imaging and histopathology analyses,6,11 especially since patients present with nonspecific signs and symptoms of pain, paresthesia, weakness, and/or incontinence, depending on the anatomical site. Imaging alone may lead to an incorrect diagnosis.19 In general, spinal MPNSTs are described as large tumors with irregularly lobulated borders that are indistinguishable from the surrounding soft tissue and bone, suggestive of malignant properties.19 On MR images, MPNSTs are inhomogeneously contrast enhancing and have scattered areas of T2-weighted hyperintensities, 3
D. Lau et al.
Fig. 4. Histology analysis and characteristics of the MPNST discussed in this case report. A: Densely cellular tumor, organized in fascicles (arrows) weaving in different directions. H & E, original magnification ×100. B: Long, wavy nuclei. H & E, original magnification ×600. C: Mitoses (circled). H & E, original magnification ×400. D: Focal abundance of Type IV collagen (brown). Immunohistochemical stain, original magnification ×250.
Fig. 5. Axial noncontrast head CT image showing acutely enlarged ventricles with hydrocephalus secondary to leptomeningeal spread.
4
likely representing areas of necrosis.1,3,19 There is also evidence of abundant blood supply and edema.19 Histologically, MPNST can resemble other tumors (fibrosarcoma, leiomyosarcoma, and cellular schwannomas).11,25 Typically, MPNST cells weave in different directions, and long, wavy nuclei have tapered ends. Fascicle formation, mitoses, necrosis, and extreme nuclear anaplasia are also common.3,11 In addition, a wide variety of “divergent” histological patterns may be present: epithelial structures, rhabdomyoblastic differentiation, cartilage, and even bone. On immunohistochemistry, MPNSTs are negative for glial fibrillary acidic protein and variably immunoreactive for S100 protein (40% lack S100 protein) and Type IV collagen.11,25 Cellular schwannomas, in contrast, are diffusely positive for S100 protein and Type IV collagen and have fewer mitoses than do MPNSTs. Leiomyosarcomas have desmin. Fibrosarcomas lack S-100 protein. Alterations in the p53- and Rbdependent pathways are common in MPNSTs.11 Necrosis and positive S100 protein immunohistochemistry can be focal features and could be missed on some specimens. Patients with MPNSTs are best treated by complete resection with wide margins, an independent factor associated with improved survival.6 However, resectability and extent of resection depend greatly on tumor location. The ability to obtain complete tumor resection ranges from 20% for spinal tumors to 95% for extremity tumors.10,16,18 Spinal tumors are often less amenable to wide resection, given their intimate proximity to the spinal cord, major vessels, and vital nerves. In this patient, gross-total resection via complete sacrectomy offered him the best survival benefit but resulted in loss of ambulatory ability and J Neurosurg: Spine / September 12, 2014
J Neurosurg: Spine / September 12, 2014
30, F
37, M
Celli et al., 1995
not mentioned
22, F
not mentioned
not mentioned
36, F
30, M
not mentioned
43, M
10 yrs previously for testicular seminoma; paraaortic strip (total 30 Gy/15 fractions over 3 wks) not mentioned
not mentioned
NF1
Location
back pain, leg weak- cauda ness, bowel & bladequina der dysfunction lt C-6 radiculopathy cervical
Presentation
cauda equina
pain for 2 yrs, weakness & incontinence pain for 6 yrs, weakness
pain for 5 mos
thoracic
cervical
thoracic
pain for 8 mos, weak- thoracic ness pain for 9 mos, weak- lumbar ness pain for 3 mos lumbar
back pain, leg weakness, bowel & bladder dysfunction
6 yrs previously for nodular sclerosing Hodgkin lymphoma rt Horner syndrome, cervical 5 yrs previously for nodular sclerosing rt C-6 radiculopaHodgkin lymphoma, thy, & weakness of rt triceps & wrist & again for recurrent lymphoma extensor not mentioned paraparesis & urinary upper thoincontinence racic
not mentioned
Previous RT
68, F
52, F
Amin et al., 38, M 2004
Albayrak et 25, M al., 2006
Adamson et al., 2004
NF1
Age (yrs), NF Sex History
Acharya et 32, M al., 2001
Authors & Year
TABLE 1: Cases of primary intradural MPNST reported in the literature*
no
partial
complete
complete
complete
complete
complete
complete
biopsy
yes
yes
yes
no
no
no
no
no
yes
partial
complete
yes
RT
partial
Surgery (biopsy or partial or complete resection)
no
no
no
no
no
no
yes, palliative
no
no
no
no
Chemotherapy Treatment
yes
yes
yes
no
no
no
not mentioned
yes, in 7 wks
not mentioned
not mentioned
no
Recurrence
lung
lung
no
no
no
no
thoracic spine, lung not mentioned
no
no
no
Metastasis
(continued)
dead at 14 mos
alive & disease free at 6 yrs alive & disease free at 2 yrs alive & disease free at 6 yrs alive & disease free at 4 yrs dead at 6 mos
not mentioned
alive at 7 wks
dead after 1 yr
dead after 1 yr & a few mos
alive at 18 mos
Survival
Cauda equina MPNST
5
6
not mentioned
47, M
43, M
neck pain radiating to rt shoulder for 9 mos, rt arm weakness for 1 mo not mentioned lt shoulder & arm pain for 4 mos not mentioned neck pain radiating to rt shoulder for 6 mos 10 yrs previously, severe back pain & adjuvant therapy for paresthesia radiattesticular seminoma ing to lt buttock & thigh for 5 mos
* NF = neurofibromatosis (NF1 = Type 1; NF2 = Type 2).
present study
70, F
18, M
NF1
cauda equina
cervical
cervical
cervical
complete
complete
complete
complete
partial
no
no
no
no
no
yes, after 3 mos
yes, after 8 yrs
yes, after 2 yrs yes, after 3 yrs, in T9–11
yes
yes
not mentioned
Recurrence
yes, neoadjuvant & yes, about adjuvant therapy 60 mos alternating btwn ifosfamide/doxo rubicin & ifos famide/etoposide
no
no
yes, at time of recurrence; Adriamycin 120 mg every 3 wks (total 1080 mg) yes, total 24 Gy after no 1st op, total 32 Gy after 2nd op at time of recurrence yes, total 10 Gy no yes, adjuvant, T11– S4 2.5 Gy 4×/wk for 6 wks (total 60 Gy)
no
not mentioned
complete
not mentioned yes
not mentioned
Chemotherapy Treatment
no yes, adjuvant, total 36 Gy entire spine & brain, additional 14.4 Gy to lumbosacral lesion/28 fractions not mentioned not mentioned
RT
complete
Valdueza et 43, F al., 1991
back pain for 9 yrs worsening for 4 mos, impotence for 4 wks, leg weakness for 3 wks low-back pain for 1 lower thomo, leg weakness racic for 2 wks
upper thoracic lower cervical cauda equina
not mentioned
not mentioned
not mentioned
Thomeer et 42, M al., 1981
NF2
partial
not mentioned
NF2
47, F
37, F
Mitsuhara et al., 2013
complete
Location
not mentioned
Presentation
complete
Previous RT
Seppälä et 35, M al., 1993 23, F
Age (yrs), NF Sex History
Surgery (biopsy or partial or complete resection)
back pain, parapacauda 15 yrs previously for equina resis of rt leg, Stage Ib uterine cervical cancer urinary/bowel incontinence, acute (total 22 Gy adjuvant consciousness intraop paraaortic RT) disturbance not mentioned not mentioned lumbar
Authors & Year
TABLE 1: Cases of primary intradural MPNST reported in the literature* (continued)
alive & disease free at 8 mos alive & disease free at 7 mos
dead at 18 mos
alive at 10 yrs w/ recurrence
alive at 3 yrs w/ recurrence
dead at 6 yrs
dead at 8 mos
dead at 18 mos
not mentioned
Survival
renal, cervi- died at 5 yrs cal cord, from CNS & brainmetastasis stem
no
no
lumbar spine, brain
no
no
systemic
systemic
systemic
no
Metastasis
D. Lau et al.
J Neurosurg: Spine / September 12, 2014
Cauda equina MPNST bladder/bowel control. While aggressive resection is warranted, consideration of functionality and quality of life needs to be carefully balanced. Postoperative adjuvant RT, chemotherapy, or both have yet to be systematically studied for the treatment of spinal MPNST, but there are indications that adjuvant RT may be beneficial.29 A large case series by Baehring et al.6 of 54 patients with MPNSTs in various locations showed a mortality hazard ratio of 0.22 for adjuvant RT on multivariate analysis. Adjuvant RT is particularly beneficial for local tumor control when radical resection is not possible, or for recurrent tumors. 5 Chemotherapy has not proven to be effective in the treatment of MPNST6 but can be used in cases without alternatives for disseminated metastatic disease.13 The expanding scientific literature suggests that MPNST can be treated more effectively with the addition of agents that target and inhibit specific pathways and/or cellular processes: PI3K/mTOR pathway with XL765,12 autophagy with chloroquine,12 and plateletderived growth factor receptor with sunitinib.35 The reported 5-year survival rate for patients diagnosed with MPNST is poor, ranging from 16% to 52%.10,18,34 Among reported cases of spinal intradural MPNST, the calculated 1-year, 3-year, and 5-year survival rates are 81%, 50%, and 25%, respectively. In a study of 21 patients with spinal MPNSTs, the local recurrence rate was extremely high: 71%.9 This is approximately twice the rate associated with extraspinal MPNSTs (20%– 40%)14,24,32 and is likely secondary to lower resectability. Of the 20 reported cases of patients with intradural MPNSTs of the spine, eventual metastasis was seen in 8 (40%), but these rates depend on the length of follow-up in each case report/series. Intradural MPNSTs represent a unique clinical entity, as these tumors can be associated with greater morbidity and worse prognosis secondary to direct access for metastatic spread and seeding of the CNS. Our patient succumbed to diffuse leptomeningeal spread and seeding of the brainstem and cervical cord. This is an extremely rare event in patients with an intradural MPNST. Only 1 other patient in the literature demonstrated CNS spread of an intradural MPNST,29 which occurred a little more than 1 year after complete removal of the original tumor, with death shortly thereafter. There is only 1 other reported case of leptomeningeal spread of an MPNST,26 which is rapidly fatal. Additional surveillance for these potential sequelae should be carefully considered in patients with intradural MPNST. Primary intradural MPNST of the spine is a rare tumor that may arise secondary to prior RT. It is difficult to diagnose and has a poor prognosis. Given that adjuvant RT is relatively common, RT-induced intradural MPNST of the spine may be more widespread than reported. Better awareness of this entity and its potential for metastasis to the CNS may enable physicians to provide early intervention in patients who have signs and symptoms associated with this condition. Disclosure Dr. Park reports being a consultant for Globus Medical and Medtronic and receiving royalties from Globus Medical.
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Author contributions to the study and manuscript preparation include the following. Conception and design: Orringer, Hervey-Jumper. Acquisition of data: Lau, Moon, Hervey-Jumper, McKeever. Analysis and interpretation of data: Lau, Moon, Park, Hervey-Jumper, McKeever. Drafting the article: Lau, Moon. Critically revising the article: Orringer, Park, Hervey-Jumper, McKeever. Reviewed submitted version of manuscript: all authors. Study supervision: Orringer. References 1. Acharya R, Bhalla S, Sehgal AD: Malignant peripheral nerve sheath tumor of the cauda equina. Neurol Sci 22:267–270, 2001 2. Adamson DC, Cummings TJ, Friedman AH: Malignant peripheral nerve sheath tumor of the spine after radiation therapy for Hodgkin’s lymphoma. Clin Neuropathol 23:245–255, 2004 3. Albayrak BS, Gorgulu A, Kose T: A case of intra-dural malignant peripheral nerve sheath tumor in thoracic spine associated with neurofibromatosis type 1. J Neurooncol 78:187–190, 2006 4. Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark G, Fizazi K, et al: EAU guidelines on testicular cancer: 2011 update. Eur Urol 60:304–319, 2011 5. Amin A, Saifuddin A, Flanagan A, Patterson D, Lehovsky J: Radiotherapy-induced malignant peripheral nerve sheath tumor of the cauda equina. Spine (Phila Pa 1976) 29:E506– E509, 2004 6. Baehring JM, Betensky RA, Batchelor TT: Malignant peripheral nerve sheath tumor: the clinical spectrum and outcome of treatment. Neurology 61:696–698, 2003 7. Bergstrom R: Changes in peripheral nerve tissue after irradiation with high energy protons. Acta Radiol 58:301–312, 1962 8. Braunstein S, Nakamura JL: Radiotherapy-induced malignancies: review of clinical features, pathobiology, and evolving approaches for mitigating risk. Front Oncol 3:73, 2013 9. Celli P, Cervoni L, Tarantino R, Fortuna A: Primary spinal malignant schwannomas: clinical and prognostic remarks. Acta Neurochir (Wien) 135:52–55, 1995 10. Ducatman BS, Scheithauer BW, Piepgras DG, Reiman HM, Ilstrup DM: Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 57:2006–2021, 1986 11. Frosch MP, Anthony DC, DeGirolami U: The central nervous system, in Kumar V, Abbas AK, Fausto N, et al (eds): Robbins and Cotran Pathologic Basis of Disease, ed 8. Philadelphia: Saunders Elsevier, 2010, pp 1279–1344 12. Ghadimi MP, Lopez G, Torres KE, Belousov R, Young ED, Liu J, et al: Targeting the PI3K/mTOR axis, alone and in combination with autophagy blockade, for the treatment of malignant peripheral nerve sheath tumors. Mol Cancer Ther 11:1758–1769, 2012 13. Goldman RL, Jones SE, Heusinkveld RS: Combination chemotherapy of metastatic malignant schwannoma with vincristine, adriamycin, cyclophosphamide, and imidazole carboxamide: a case report. Cancer 39:1955–1958, 1977 14. Grobmyer SR, Reith JD, Shahlaee A, Bush CH, Hochwald SN: Malignant peripheral nerve sheath tumor: molecular pathogenesis and current management considerations. J Surg Oncol 97:340–349, 2008 15. Gupta G, Maniker A: Malignant peripheral nerve sheath tumors. Neurosurg Focus 22(6):E12, 2007 16. Hruban RH, Shiu MH, Senie RT, Woodruff JM: Malignant peripheral nerve sheath tumors of the buttock and lower extremity. A study of 43 cases. Cancer 66:1253–1265, 1990 17. Kim DH, Murovic JA, Tiel RL, Moes G, Kline DG: A series of 397 peripheral neural sheath tumors: 30-year experience at Louisiana State University Health Sciences Center. J Neurosurg 102:246–255, 2005
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D. Lau et al. 18. Kourea HP, Bilsky MH, Leung DH, Lewis JJ, Woodruff JM: Subdiaphragmatic and intrathoracic paraspinal malignant peripheral nerve sheath tumors: a clinicopathologic study of 25 patients and 26 tumors. Cancer 82:2191–2203, 1998 19. Lang N, Liu XG, Yuan HS: Malignant peripheral nerve sheath tumor in spine: imaging manifestations. Clin Imaging 36:209–215, 2012 20. Mead GM, Fossa SD, Oliver RT, Joffe JK, Huddart RA, Roberts JT, et al: Randomized trials in 2466 patients with stage I seminoma: patterns of relapse and follow-up. J Natl Cancer Inst 103:241–249, 2011 21. Mitsuhara T, Yamaguchi S, Takeda M, Eguchi K, Morishige M, Sugiyama K, et al: A case of a primary radiation-induced malignant peripheral nerve sheath tumor in the cauda equina in a patient with neurofibromatosis type 2. J Spine 2:129, 2013 22. Motzer RJ, Agarwal N, Beard C, Bolger GB, Boston B, Carducci MA, et al: NCCN clinical practice guidelines in oncology: testicular cancer. J Natl Compr Canc Netw 7:672–693, 2009 23. Perrin RG, Guha A: Malignant peripheral nerve sheath tumors. Neurosurg Clin N Am 15:203–216, 2004 24. Ramanathan RC, Thomas JM: Malignant peripheral nerve sheath tumours associated with von Recklinghausen’s neurofibromatosis. Eur J Surg Oncol 25:190–193, 1999 25. Seppälä MT, Haltia MJ: Spinal malignant nerve-sheath tumor or cellular schwannoma? A striking difference in prognosis. J Neurosurg 79:528–532, 1993 26. Stark AM, Mehdorn HM: Leptomeningeal metastasis of an intradural malignant peripheral nerve sheath tumor. J Clin Neurosci 20:1181–1183, 2013 27. Stucky CC, Johnson KN, Gray RJ, Pockaj BA, Ocal IT, Rose PS, et al: Malignant peripheral nerve sheath tumors (MPNST): the Mayo Clinic experience. Ann Surg Oncol 19:878–885, 2012 28. Thomeer RT, Bots GT, van Dulken H, Luyendijk W, Helle P: Neurofibrosarcoma of the cauda equina. Case report. J Neurosurg 54:409–411, 1981 29. Valdueza JM, Hagel C, Westphal M, Hänsel M, Herrmann
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HD: Primary spinal malignant schwannoma: clinical, histological and cytogenetic findings. Neurosurg Rev 14:283–291, 1991 30. van den Belt-Dusebout AW, de Wit R, Gietema JA, Horenblas S, Louwman MW, Ribot JG, et al: Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 25:4370–4378, 2007 31. van Leeuwen FE, Stiggelbout AM, van den Belt-Dusebout AW, Noyon R, Eliel MR, van Kerkhoff EH, et al: Second cancer risk following testicular cancer: a follow-up study of 1,909 patients. J Clin Oncol 11:415–424, 1993 32. Vauthey JN, Woodruff JM, Brennan MF: Extremity malignant peripheral nerve sheath tumors (neurogenic sarcomas): a 10-year experience. Ann Surg Oncol 2:126–131, 1995 33. West DA, Parra RO, Manepalli A, Bernardi RJ, Cummings JM: Development of a malignant peripheral nerve sheath tumor following treatment for testicular seminoma. Urology 50:292–294, 1997 34. Wong WW, Hirose T, Scheithauer BW, Schild SE, Gunderson LL: Malignant peripheral nerve sheath tumor: analysis of treatment outcome. Int J Radiat Oncol Biol Phys 42:351– 360, 1998 35. Zietsch J, Ziegenhagen N, Heppner FL, Reuss D, von Deimling A, Holtkamp N: The 4q12 amplicon in malignant peripheral nerve sheath tumors: consequences on gene expression and implications for sunitinib treatment. PLoS ONE 5:e11858, 2010 Manuscript submitted August 27, 2013 Accepted July 11, 2014 Please include this information when citing this paper: published online September 12, 2014; DOI: 10.3171/2014.7.SPINE13802. Address correspondence to: Daniel A. Orringer, M.D., Department of Neurosurgery, University of Michigan, 1500 E. Medical Center Dr., Rm. 3552 TC, Ann Arbor, MI 48109-5338. email: [email protected].
J Neurosurg: Spine / September 12, 2014
