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Long-Term Experience With World Health Organization Grade III (Malignant) Meningiomas at a Single Institution
Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 2, pp. 427–432, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.08.018
CLINICAL INVESTIGATION
Brain
LONG-TERM EXPERIENCE WITH WORLD HEALTH ORGANIZATION GRADE III (MALIGNANT) MENINGIOMAS AT A SINGLE INSTITUTION LEWIS A. ROSENBERG, M.D., PH.D.,*y RICHARD A. PRAYSON, M.D.,z JOUNG LEE, M.D.,x CHANDANA REDDY, M.S.,* SAMUEL T. CHAO, M.D.,* GENE H. BARNETT, M.D.,x MICHAEL A. VOGELBAUM, M.D., PH.D.,x AND JOHN H. SUH, M.D.* Departments of *Radiation Oncology, z Pathology, and x Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH; and y Case Western Reserve University School of Medicine, Cleveland, OH Purpose: To evaluate the outcomes for patients with Grade III meningiomas as defined by the 2007 World Health Organization standards. Methods and Materials: The slides from patients who had been treated at the Cleveland Clinic for malignant meningiomas were reviewed by a single neuropathologist. The data from 13 patients treated between 1984 and 2006 satisfied the World Health Organization 2007 definition of Grade III meningioma. A total of 24 surgeries were performed, including 13 primary, 7 salvage, and 4 second salvage. Also, 14 courses of radiotherapy (RT) were administered, including fractionated RT in 3 patients after primary surgery, fractionated RT in 4 patients after salvage surgery, salvage stereotactic radiosurgery to six separate areas in 3 patients, and salvage intensitymodulated RT in 1 patient. Results: From the primary surgery, the median survival was 3.4 years, the 5-year survival rate was 47.2%, and the 8-year survival rate was 12.2%. The median time to recurrence was 9.6 months. A trend was seen toward longer survival for patients who had received adjuvant RT after initial surgery compared with those treated with surgery alone. Two patients developed radiation necrosis, and three had surgical complications. Conclusion: This is one of the few studies reporting the outcomes for malignant meningioma patients according to recent definitions. Our results are consistent with existing reports of the overall poor outcomes for atypical and malignant meningioma patients. From the available data, surgical resection followed by RT and salvage therapy can lead to extended survival. Ó 2009 Elsevier Inc. Meningioma, Malignant meningioma, Grade III meningioma, Radiotherapy.
INTRODUCTION
shown that the WHO 2000 definition substantially changed which tumors will be defined as Grade III compared with earlier definitions (12). As such, it is important to re-establish the characteristics of malignant meningioma patients using the current definitions. Very few studies, however, have been published using these modern definitions. Our institution previously reported our experience with atypical, or Grade II, meningiomas (13). The present study reports the experience of the Cleveland Clinic Foundation with Grade III meningiomas exclusively determined using the WHO 2007 criteria.
Meningiomas account for 13–26% of intracranial tumors and are typically histologically graded as benign, atypical, or malignant (1). A large majority of meningiomas are benign and are associated with a relatively optimistic outcome, with the 5-year survival rate reported at >80% (2, 3). Atypical and malignant meningiomas, however, are rarer and these patients have a worse prognosis. Malignant meningiomas account for 1.0–2.8% of meningiomas (1) and are particularly aggressive tumors, with reported 5-year patient survival rates of 32–64% (3–9). The published data regarding patient outcomes for malignant meningiomas are complicated by the several different definitions of malignant pathology that have been used. The World Health Organization (WHO) updated the definition of malignant, or Grade III, meningiomas in 2000 (10) and reiterated this definition in 2007 (11). Evidence has
METHODS AND MATERIALS Patients The institutional review board at our institution approved this study. A total of 29 patients were treated at the Cleveland Clinic between 1984 and 2006 for a listed diagnosis of intracranial malignant
Reprint requests to: John H. Suh, M.D., Department of Radiation Oncology, Cleveland Clinic, T28, 9500 Euclid Ave., Cleveland, OH 44195. Tel: (216) 444-5574; Fax: (216) 636-5105; E-mail: suhj@ ccf.org
Conflict of interest: none. Received March 20, 2008, and in revised form Aug 14, 2008. Accepted for publication Aug 14, 2008. 427
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meningioma. Slides were available for 22 patients and were reviewed by a single neuropathologist for conformity to the WHO 2007 definition of Grade III meningioma (11). Four tumors had originally been diagnosed after 2000 and were confirmed to be Grade III. Of the 18 meningiomas originally labeled as malignant before 2000, 9 were redefined as WHO Grade II using the 2007 WHO definition. The remaining 13 patients were included in this study (Table 1). No patients had rhabdoid or papillary histologic features. Of the 13 patients, 8 were men and 5 were women. Their mean age at diagnosis was 65 years (range, 37–87). At the diagnosis, the patients had a median Karnofsky performance status (KPS) of 90 (range, 50–90). Previous meningiomas had been diagnosed and treated in 6 patients. One previous meningioma had been diagnosed 5.2 years before the malignant diagnosis and was identified as WHO Grade II. The other 5 previous meningiomas were of an unknown grade and had been diagnosed 7.8–30.1 years before the diagnosis of the Grade III meningioma. The presenting symptoms included headache in 6, weakness in 5, aphasia/dysphasia in 3, memory loss in 2, seizures in 1, vision loss in 1, numbness in 1, and nausea in 1.
Treatment After the diagnosis of Grade III meningioma, 24 surgeries were performed, including 13 primary, 7 salvage, and 4 second salvage. The degree of resection was determined using Simpson’s classification (14). For the purposes of our analyses, gross total resection (GTR) included Simpson Grades 1–3; subtotal resection (STR) was equivalent to Simpson Grade 4. At primary surgery, 8 patients underwent GTR (2 with Simpson Grade I, 2 with Simpson Grade II, 3 with Simpson Grade III, and 1 simply described as GTR), 2 patients underwent STR (Simpson Grade IV), and 3 patients underwent resection of an unknown degree. Various modalities of radiotherapy (RT) were used in this group of patients. In total, 14 courses of RT were administered after a diagnosis of Grade III meningioma. Three patients were treated with fractionated RT (5,900–5,940 cGy) to a partial brain field after primary surgery. Four patients underwent fractionated RT (5,040– 6,000 cGy) to a partial brain field after salvage surgery. Three patients received six treatments of stereotactic radiosurgery (SRS) using a Gamma Knife (including 1 patient who received three and
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another who received two treatments). The SRS doses were 1,410–2,400 cGy, with 4–15 isocenters. A single patient underwent intensity-modulated RT as second salvage therapy (2,500 cGy in five fractions). Only 2 patients underwent chemotherapy. One patient received nine cycles of temozolomide (200 mg/m2 daily for 5 days) as salvage therapy. The other patient received adoptive immunotherapy after primary surgery and fractionated RT.
Statistical analysis We used radiographic reports, pathology reports, and all available inpatient and outpatient records to follow-up patients after primary surgery. Progression was defined as unequivocal radiographic evidence of tumor growth or reappearance. Death was confirmed by searching the Social Security Death Index. The reference points used for this study included the date of primary surgery, date of salvage therapy, date of progression, and date of death. Follow-up times were referenced to the day of primary surgery or the day of salvage therapy. Primary surgery was defined as that which yielded Grade III pathologic findings. Survival curves were generated using the Kaplan-Meier method. The patient and treatment characteristics were analyzed for an association with the time to death and time to progression using Cox proportional hazards regression. The analyzed characteristics included age, KPS, gender, previous diagnosis of meningioma, degree of resection (GTR vs. STR), use of adjuvant RT with primary surgery, and mode of salvage therapy (surgery, surgery plus RT, or SRS).
RESULTS Outcomes after primary therapy In the 13 patients with WHO Grade III meningioma, the median survival was 3.4 years, the 5-year survival rate was 47.2%, and the 8-year survival rate was 12.2% (Fig. 1). Four patients were alive at this analysis. The 3 patients who received adjuvant fractionated RT after their first surgery had a median survival of 5.4 years. In contrast, the 10 who did not receive RT had a median survival of 2.5 years. This difference was not statistically significant (p = 0.13).
Table 1. Patient and treatment characteristics for 13 patients with WHO Grade III (malignant) meningiomas Age at diagnosis* 87 62 69 70 75 73 55 73 66 55 55 59 37
Survival (y) 0.1 1.0 1.6 2.1 2.4 3.3 5.3 7.3 7.7 1.6y 1.8y 3.1y 8.8y
Time to recurrence (mo) 0.4 0.4 0.8 0.4 1.5 1.8 2.8 1.6 0.5 1.5 1.3
Simpson grade IV Unknown II Unknown III Unknown III III Unknown I I IV II
RT with primary surgery No No No No No No Yes No No No No Yes Yes
First salvage therapy None Surgery Surgery + RT Surgery + RT Surgery + RT Surgery None Surgery Surgery + RT SRS SRS SRS None
Tumor location L sphenoid R frontal L temporal R parasagittal R falx L frontal R occipital L occipital R parietal L frontoparietal L falx L frontal R lateral ventricle
Abbreviations: WHO = World Health Organization; L = left; R = right; RT = external beam fractionated radiotherapy; SRS = stereotactic radiosurgery with Gamma Knife. * Age at diagnosis of Grade III meningioma; some patients had had previous lower grade meningiomas. y Patient living at last follow-up.
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val to a second recurrence. The median interval to a second recurrence was 3.8 months for patients who received surgery alone, 12.4 months for those who received surgery plus fractionated RT, and 8.1 months for those treated with SRS. These differences were not statistically significant. No other patient variable significantly affected the interval to a second recurrence, including age, KPS, or gender. Complications One patient had pathologic confirmation of radiation necrosis that developed 14 months after SRS and 30 months after external beam RT. This patient was still alive at last follow-up, 5 months after the diagnosis of the radiation necrosis. Another patient had magnetic resonance imaging findings suspicious for radiation necrosis 10 months after external beam RT in 1984 and died 4 months later; no pathologic confirmation was available for this patient. Surgical complications included 1 patient who died of hemorrhage 3 days after a second salvage surgery, 1 patient whose health declined quickly and died 40 days after primary surgery, and 1 patient who developed a wound infection and recovered to baseline after surgical debridement.
Fig. 1. Overall survival of World Health Organization Grade III (malignant) meningioma patients. Open triangles are censor marks indicating follow-up time for surviving patients.
A lower age at diagnosis was significantly associated with survival (p = 0.04). No other analyzed variable was associated with survival, including degree of resection (GTR vs. STR), previous diagnosis of meningioma, KPS at diagnosis, or gender (Table 2). The median time to recurrence was 9.6 months. The recurrence-free survival rate at 1, 2, and 3 years was 52%, 17%, and 8.7%, respectively (Fig. 2). No variables affected the interval to recurrence, including age, KPS, gender, degree of resection, or adjuvant RT (Table 2). Notably, 1 patient was a long-term survivor whose tumor had not recurred for 8.75 years at the last follow-up. This patient had initially undergone GTR (Simpson Grade II) followed by fractionated RT (5,900 cGy in 32 fractions).
DISCUSSION The WHO and other groups have published several definitions of malignant meningioma based on various histopathologic characteristics. In 1979, the WHO provided early criteria for meningioma classification (15). An anaplastic tumor was considered either Grade II or Grade III and was defined as ‘‘[a]ny meningioma that displays anaplastic features yet has not developed into a frank sarcoma,’’ but no more specific criteria were provided. Ja¨a¨skela¨inen et al. (16) suggested four grades of meningiomas (benign, atypical, anaplastic, and sarcomatous) using a scoring system that considered ‘‘loss of architecture, increased cellularity, nuclear pleomorphism, mitotic figures, focal necrosis, and brain infiltration.’’ In 1993, the WHO also recognized atypical and anaplastic meningiomas as separate entities. Anaplastic meningiomas were designated as Grade III and defined as ‘‘meningioma[s] exhibiting histological features of frank malignancy far in excess of the abnormalities noted in atypical meningioma[s]’’ (17). The 1993 WHO definition further implied that brain invasion was a qualification for a Grade III
Outcomes after salvage therapy Ten patients received salvage therapy as either surgery alone (n = 3), surgery followed by RT (n = 4), or SRS using a Gamma Knife (n = 3). The 3 patients who did not receive salvage therapy included 1 whose tumor did not recur, 1 who died within 2 months of primary surgery, and 1 whose tumor recurred but who had not received salvage therapy at the last follow-up visit. The overall median interval to a second recurrence after salvage therapy was 8.1 months. The mode of salvage therapy did not significantly affect the inter-
Table 2. Univariate analysis of factors affecting survival and recurrence rates after initial surgery Effect on survival
Effect on recurrence
Variable
p
RR (95% CI)
p
RR (95% CI)
Age KPS Gender (female vs. male) Resection (GTR vs. STR) Adjuvant RT (no vs. yes)
0.04 0.44 0.31 0.67 0.1
1.11 (1.00–1.22) 0.97 (0.89–1.05) 2.11 (0.50–8.97) 0.61 (0.06–5.94) 5.10 (0.63–41.6)
0.21 0.18 0.91 0.75 0.13
1.04 (0.98–1.10) 1.09 (0.96–1.25) 0.94 (0.28–3.13) 0.70 (0.08–6.32) 3.35 (0.70–16.0)
Abbreviations: RR = relative risk; CI = confidence interval; KPS = Karnofsky performance status; GTR = gross total resection; STR = subtotal resection; RT = radiotherapy.
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Fig. 2. Recurrence-free survival of World Health Organization Grade III (malignant) meningioma patients. Open triangles are censor marks indicating follow-up time for surviving patients.
designation, regardless of the other tumor characteristics. As a result, studies published using this definition considered brain-invasive meningiomas as malignant, or Grade III (6, 7). In a seminal publication for meningioma classification, Perry et al. (8) analyzed the pathologic features from a large number of meningiomas and demonstrated that histologic anaplasia, $20 mitoses per 10 high-powered fields, and nuclear atypia were independently associated with poor survival. They also found that brain invasion was associated with survival similar to that of patients with atypical, or Grade II, meningiomas, rather than Grade III tumors, as previously thought. The WHO in 2000 adopted these conclusions (18). Brain invasion was recognized to confer outcomes similar to that of Grade II meningiomas. Grade III meningiomas included those with ‘‘obviously malignant cytology (e.g., having an appearance similar to sarcoma, carcinoma or melanoma)’’ or $20 mitoses per 10 high-powered fields. Additionally, the rare meningiomas with papillary or rhabdoid histologic features were also considered Grade III. The
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most recent WHO definition in 2007 for Grade III meningiomas (used for the present study) remained unchanged: anaplastic, rhabdoid, and papillary tumors are considered Grade III, and the parameters for anaplasia are the same as those published in 2000 (11). Regarding brain invasion, the 2007 WHO definition echoes their previous publication stating that brain invasive meningiomas ‘‘should prognostically be considered WHO Grade II.’’ Reassigning brain-invasive meningiomas from Grade III to Grade II might have reduced the number of tumors designated as malignant. Simon et al. (12) found that four of six meningiomas originally defined as Grade III before 2000 were downgraded using the WHO 2000 definition. All four redefined tumors were originally termed ‘‘malignant’’ because of the presence of brain invasion. In the present study, a single pathologist reviewed all slides to confirm the diagnosis of Grade III meningioma. Of 18 patients originally diagnosed before 2000 with Grade III meningiomas, 9 were found to have Grade II tumors on slide review using the WHO 2007 standards. Both of these experiences suggest that the WHO 2000 and 2007 definitions of Grade III meningiomas include a substantially different set of tumors than those of previous definitions. These findings indicate a need to re-establish the patient outcome data for Grade III meningiomas. Exclusively using the WHO 2007 definitions, the present study found a 5-year survival rate of 47.2% for patients with Grade III meningiomas. Table 3 provides a comparison of published studies concerning malignant meningiomas. Table 3 includes only those studies that clearly stated their definition of malignancy. A few studies have used the WHO 2000 definition of Grade III meningioma, which is practically equivalent to the 2007 definition. Harris et al. (4) reported 5-year and 10-year survival rate of 59% and 0%, respectively. Although that study used the WHO 2000 standards, some patients did not have slides available for review, and the study used the original interpretations of the pathology report in such cases.
Table 3. Summary of malignant meningioma studies Investigator
Study period
Patients (n)
Malignancy definition
Present study Harris et al. (4)
1981–2006 1987–2001
13 12
WHO, 2007 WHO, 2000*
Perry et al. (8) Hug et al. (5) Palma et al. (7)
1970–1997 1973–1995 1951–1986
27 16 29
Frank anaplasiay WHO, 1993 WHO, 1993
Ware et al. (9)
1988–2002
17
WHO 1993 or Ja¨a¨skela¨inen et al. (16)
Ojemann et al. (6) Goldsmith et al. (3)
1991–1999 1967–1990
22 23
WHO 1993 or Ja¨a¨skela¨inen et al. (16) Unique grading schemez
Survival 47%, 5 y 59%, 5 y 0%, 10 y 32%, 5 y 51%, 5 y 64%, 5 y 35%, 10 y 59%, 5 y 15%, 10 y 40%, 5 y 58%, 5 y
Abbreviation: WHO = World Health Organization. * This study included some meningiomas without histologic review. y These patients were a subset of those for whom brain invasion was specifically not a factor for malignancy. z All tumors were categorized as benign or malignant; tumors were considered malignant if they included brain invasion or >1 mitosis/400 field and two of the following: increased cellularity, necrosis, large atypical nuclei, and increased cytoplasmic mass.
Long-term experience with malignant meningiomas d L. A. ROSENBERG et al.
Katz et al. (19) also used the WHO 2000 definition of malignant meningiomas and reported 5-year local control in 4 (44%) of 9 patients; they did not report survival separately for those with Grade III tumors. Perry et al. (8) analyzed a subset of 27 patients with ‘‘clearly anaplastic’’ histologic features who had 5-year estimated survival rate of 32%. The criteria for inclusion into this category were consistent with the WHO 2007 definition of malignancy. In the present study, a trend was found toward increased survival and a reduced risk of recurrence in patients receiving upfront RT. The benefits of RT have not been explicitly demonstrated in the context of Grade III meningiomas; however, studies have suggested that patients with various aggressive meningiomas benefit from RT. Dziuk et al. (20) analyzed the effects of concurrent RT and surgery compared with surgery alone in 38 patients with aggressive meningiomas. They found significantly improved disease-free survival at 2 years with RT and surgery (94%) compared with surgery alone (61%). Furthermore, several studies have found that greater radiation doses corresponded with better outcomes. Hug et al. (5) demonstrated that patients treated with $60 Gy had a 5-year local control rate of 100% compared with those treated with <60 Gy, who had a 5-year local control rate of 0%. The greater doses were typically received by patients treated with both proton and photon therapy. Milosevic et al. (21) presented data concerning 59 patients treated with RT for atypical and malignant meningiomas either at diagnosis or after recurrence. They demonstrated that patients treated with $50 Gy had a 5-year cause-specific survival rate of 42% vs. 0% in those patients treated with <50 Gy (p = 0.0005). Goldsmith et al. (3) presented data concerning 23 patients with aggressive meningiomas according to a variety of pathologic factors, including brain invasion. They found that the radiation dose was positively associated with increased survival when analyzed as a continuous variable. Retrospective studies have also demonstrated that postoperative RT significantly extends survival in patients with subtotally resected benign meningiomas (22, 23). Studies concerning RT for aggressive meningiomas have often been statistically limited owing to the rarity of the tumors. However, from the available data, many publications have recommended RT, in addition to surgical resection, for patients with malignant meningiomas (1, 5, 7, 19, 20).
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Although RT is becoming a common element in the treatment of malignant meningiomas, surgical resection remains the primary therapy in most contexts. It has been well documented that a greater degree of resection improves the outcome for patients with aggressive meningioma (7, 8, 13, 20), although this association has not been specifically demonstrated for WHO 2000 or 2007 Grade III meningiomas. The present study did not identify the degree of resection as a significant contributor to patient outcome. Only 2 of 13 patients, however, had undergone subtotal resection, which markedly limited our statistical power for this determination. Despite the advances in the understanding and treatment of malignant meningiomas, patient outcomes remain poor. Several groups have used a variety of aggressive regimens in an attempt to improve the treatment of aggressive meningiomas. Katz et al. (19), for example, reported the results of twice-daily RT. Patients with atypical and malignant meningiomas were administered either 60 Gy using 1.5-Gy fractions twice daily or 55–60 Gy using 1.8-Gy fractions daily (19). The twice-daily regimen did not improve the outcomes but did lead to increased complications. The investigators did not recommend the twice-daily regimen. Ware et al. (9) analyzed the outcomes of 17 patients with recurrent malignant meningiomas (using the WHO 1993 criteria or Ja¨a¨skela¨inen et al. [16]) treated with 125I brachytherapy postoperatively. They reported a 5-year survival rate of 24% from implantation. Complications from the brachytherapy included radiation necrosis in 27% of patients and wound breakdown in 27%. Hug et al. (5) reported a 5- and 8-year survival rate of 100% for a small number of malignant meningioma patients treated with combined proton and photon therapy. This achievement was attributed to the fact that all of these patients had received $60 cobalt-gray equivalents, a significantly greater dose than their photon-only patients, who had a 5-year survival rate of 44%. CONCLUSION The survival for malignant meningioma patients remains poor. On the basis of our experience and the experience of others as described in this report, aggressive treatment, including surgical resection followed by RT and salvage therapy, can lead to prolonged survival.
REFERENCES 1. Modha A, Gutin PH. Diagnosis and treatment of atypical and anaplastic meningiomas: A review. Neurosurgery 2005;57:538–550. 2. Glaholm J, Bloom HJ, Crow JH. The role of radiotherapy in the management of intracranial meningiomas: The Royal Marsden Hospital experience with 186 patients. Int J Radiat Oncol Biol Phys 1990;18:755–761. 3. Goldsmith BJ, Wara WM, Wilson CB, et al. Postoperative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 1994;80:195–201.
4. Harris AE, Lee JY, Omalu B, et al. The effect of radiosurgery during management of aggressive meningiomas. Surg Neurol 2003;60:298–305. 5. Hug EB, Devries A, Thornton AF, et al. Management of atypical and malignant meningiomas: Role of high-dose, 3D-conformal radiation therapy. J Neurooncol 2000;48:151– 160. 6. Ojemann SG, Sneed PK, Larson DA, et al. Radiosurgery for malignant meningioma: Results in 22 patients. J Neurosurg 2000;93(Suppl. 3):62–67.
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7. Palma L, Celli P, Franco C, et al. Long-term prognosis for atypical and malignant meningiomas: A study of 71 surgical cases. J Neurosurg 1997;86:793–800. 8. Perry A, Scheithauer BW, Stafford SL, et al. ‘‘Malignancy’’ in meningiomas: A clinicopathologic study of 116 patients, with grading implications. Cancer 1999;85:2046–2056. 9. Ware ML, Larson DA, Sneed PK, et al. Surgical resection and permanent brachytherapy for recurrent atypical and malignant meningioma. Neurosurgery 2004;54:55–63, 54. 10. Louis DN, Scheithauer BW, et al. Meningiomas. In: Kleihues P, Cavenee WB, editors. World Health Organization classification of tumors: Pathology and genetics of tumors of the nervous system. Lyon, France: IARC Press; 2000. 11. Perry A, Louis D, Scheithauer B, et al. Meningiomas. In: Louis DN, Ohgaki H, Wiestler OD, editors. World Health Organization classification of tumors. 4th ed. Lyon: International Agency for Research on Cancer; 2007. p. 164–172. 12. Simon M, Bostrom J, Koch P, et al. Interinstitutional variance of postoperative radiotherapy and follow up for meningiomas in Germany: Impact of changes of the WHO classification. J Neurol Neurosurg Psychiatry 2006;77:767–773. 13. Goyal LK, Suh JH, Mohan DS, et al. Local control and overall survival in atypical meningioma: A retrospective study. Int J Radiat Oncol Biol Phys 2000;46:57–61. 14. Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry 1957;20: 22–39.
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15. Zulch K. Histological typing of central nervous system tumours. Geneva: World Health Organization; 1979. p.53–55. 16. Ja¨a¨skela¨inen J, Haltia M, Servo A. Atypical and anaplastic meningiomas: Radiology, surgery, radiotherapy, and outcome. Surg Neurol 1986;25:233–242. 17. Kleihues P, Burger P, Scheithauer B. Histological typing of tumours of the central nervous system. 2nd ed. New York: Springer-Verlag; 1993. 18. Louis D, Scheithauer B, Budka H, et al. Meningiomas. In: Kleihues P, Cavenee W, editors. World Health Organization classification of tumors: Pathology and genetics of tumors of the nervous system. 3rd ed. Lyon, France: IARC Press; 2000. p. 176–184. 19. Katz TS, Amdur RJ, Yachnis AT, et al. Pushing the limits of radiotherapy for atypical and malignant meningioma. Am J Clin Oncol 2005;28:70–74. 20. Dziuk TW, Woo S, Butler EB, et al. Malignant meningioma: An indication for initial aggressive surgery and adjuvant radiotherapy. J Neurooncol 1998;37:177–188. 21. Milosevic MF, Frost PJ, Laperriere NJ, et al. Radiotherapy for atypical or malignant intracranial meningioma. Int J Radiat Oncol Biol Phys 1996;34:817–822. 22. Condra KS, Buatti JM, Mendenhall WM, et al. Benign meningiomas: Primary treatment selection affects survival. Int J Radiat Oncol Biol Phys 1997;39:427–436. 23. Soyuer S, Chang EL, Selek U, et al. Radiotherapy after surgery for benign cerebral meningioma. Radiother Oncol 2004;71: 85–90.
doi:10.1016/j.ijrobp.2008.08.018
CLINICAL INVESTIGATION
Brain
LONG-TERM EXPERIENCE WITH WORLD HEALTH ORGANIZATION GRADE III (MALIGNANT) MENINGIOMAS AT A SINGLE INSTITUTION LEWIS A. ROSENBERG, M.D., PH.D.,*y RICHARD A. PRAYSON, M.D.,z JOUNG LEE, M.D.,x CHANDANA REDDY, M.S.,* SAMUEL T. CHAO, M.D.,* GENE H. BARNETT, M.D.,x MICHAEL A. VOGELBAUM, M.D., PH.D.,x AND JOHN H. SUH, M.D.* Departments of *Radiation Oncology, z Pathology, and x Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH; and y Case Western Reserve University School of Medicine, Cleveland, OH Purpose: To evaluate the outcomes for patients with Grade III meningiomas as defined by the 2007 World Health Organization standards. Methods and Materials: The slides from patients who had been treated at the Cleveland Clinic for malignant meningiomas were reviewed by a single neuropathologist. The data from 13 patients treated between 1984 and 2006 satisfied the World Health Organization 2007 definition of Grade III meningioma. A total of 24 surgeries were performed, including 13 primary, 7 salvage, and 4 second salvage. Also, 14 courses of radiotherapy (RT) were administered, including fractionated RT in 3 patients after primary surgery, fractionated RT in 4 patients after salvage surgery, salvage stereotactic radiosurgery to six separate areas in 3 patients, and salvage intensitymodulated RT in 1 patient. Results: From the primary surgery, the median survival was 3.4 years, the 5-year survival rate was 47.2%, and the 8-year survival rate was 12.2%. The median time to recurrence was 9.6 months. A trend was seen toward longer survival for patients who had received adjuvant RT after initial surgery compared with those treated with surgery alone. Two patients developed radiation necrosis, and three had surgical complications. Conclusion: This is one of the few studies reporting the outcomes for malignant meningioma patients according to recent definitions. Our results are consistent with existing reports of the overall poor outcomes for atypical and malignant meningioma patients. From the available data, surgical resection followed by RT and salvage therapy can lead to extended survival. Ó 2009 Elsevier Inc. Meningioma, Malignant meningioma, Grade III meningioma, Radiotherapy.
INTRODUCTION
shown that the WHO 2000 definition substantially changed which tumors will be defined as Grade III compared with earlier definitions (12). As such, it is important to re-establish the characteristics of malignant meningioma patients using the current definitions. Very few studies, however, have been published using these modern definitions. Our institution previously reported our experience with atypical, or Grade II, meningiomas (13). The present study reports the experience of the Cleveland Clinic Foundation with Grade III meningiomas exclusively determined using the WHO 2007 criteria.
Meningiomas account for 13–26% of intracranial tumors and are typically histologically graded as benign, atypical, or malignant (1). A large majority of meningiomas are benign and are associated with a relatively optimistic outcome, with the 5-year survival rate reported at >80% (2, 3). Atypical and malignant meningiomas, however, are rarer and these patients have a worse prognosis. Malignant meningiomas account for 1.0–2.8% of meningiomas (1) and are particularly aggressive tumors, with reported 5-year patient survival rates of 32–64% (3–9). The published data regarding patient outcomes for malignant meningiomas are complicated by the several different definitions of malignant pathology that have been used. The World Health Organization (WHO) updated the definition of malignant, or Grade III, meningiomas in 2000 (10) and reiterated this definition in 2007 (11). Evidence has
METHODS AND MATERIALS Patients The institutional review board at our institution approved this study. A total of 29 patients were treated at the Cleveland Clinic between 1984 and 2006 for a listed diagnosis of intracranial malignant
Reprint requests to: John H. Suh, M.D., Department of Radiation Oncology, Cleveland Clinic, T28, 9500 Euclid Ave., Cleveland, OH 44195. Tel: (216) 444-5574; Fax: (216) 636-5105; E-mail: suhj@ ccf.org
Conflict of interest: none. Received March 20, 2008, and in revised form Aug 14, 2008. Accepted for publication Aug 14, 2008. 427
I. J. Radiation Oncology d Biology d Physics
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meningioma. Slides were available for 22 patients and were reviewed by a single neuropathologist for conformity to the WHO 2007 definition of Grade III meningioma (11). Four tumors had originally been diagnosed after 2000 and were confirmed to be Grade III. Of the 18 meningiomas originally labeled as malignant before 2000, 9 were redefined as WHO Grade II using the 2007 WHO definition. The remaining 13 patients were included in this study (Table 1). No patients had rhabdoid or papillary histologic features. Of the 13 patients, 8 were men and 5 were women. Their mean age at diagnosis was 65 years (range, 37–87). At the diagnosis, the patients had a median Karnofsky performance status (KPS) of 90 (range, 50–90). Previous meningiomas had been diagnosed and treated in 6 patients. One previous meningioma had been diagnosed 5.2 years before the malignant diagnosis and was identified as WHO Grade II. The other 5 previous meningiomas were of an unknown grade and had been diagnosed 7.8–30.1 years before the diagnosis of the Grade III meningioma. The presenting symptoms included headache in 6, weakness in 5, aphasia/dysphasia in 3, memory loss in 2, seizures in 1, vision loss in 1, numbness in 1, and nausea in 1.
Treatment After the diagnosis of Grade III meningioma, 24 surgeries were performed, including 13 primary, 7 salvage, and 4 second salvage. The degree of resection was determined using Simpson’s classification (14). For the purposes of our analyses, gross total resection (GTR) included Simpson Grades 1–3; subtotal resection (STR) was equivalent to Simpson Grade 4. At primary surgery, 8 patients underwent GTR (2 with Simpson Grade I, 2 with Simpson Grade II, 3 with Simpson Grade III, and 1 simply described as GTR), 2 patients underwent STR (Simpson Grade IV), and 3 patients underwent resection of an unknown degree. Various modalities of radiotherapy (RT) were used in this group of patients. In total, 14 courses of RT were administered after a diagnosis of Grade III meningioma. Three patients were treated with fractionated RT (5,900–5,940 cGy) to a partial brain field after primary surgery. Four patients underwent fractionated RT (5,040– 6,000 cGy) to a partial brain field after salvage surgery. Three patients received six treatments of stereotactic radiosurgery (SRS) using a Gamma Knife (including 1 patient who received three and
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another who received two treatments). The SRS doses were 1,410–2,400 cGy, with 4–15 isocenters. A single patient underwent intensity-modulated RT as second salvage therapy (2,500 cGy in five fractions). Only 2 patients underwent chemotherapy. One patient received nine cycles of temozolomide (200 mg/m2 daily for 5 days) as salvage therapy. The other patient received adoptive immunotherapy after primary surgery and fractionated RT.
Statistical analysis We used radiographic reports, pathology reports, and all available inpatient and outpatient records to follow-up patients after primary surgery. Progression was defined as unequivocal radiographic evidence of tumor growth or reappearance. Death was confirmed by searching the Social Security Death Index. The reference points used for this study included the date of primary surgery, date of salvage therapy, date of progression, and date of death. Follow-up times were referenced to the day of primary surgery or the day of salvage therapy. Primary surgery was defined as that which yielded Grade III pathologic findings. Survival curves were generated using the Kaplan-Meier method. The patient and treatment characteristics were analyzed for an association with the time to death and time to progression using Cox proportional hazards regression. The analyzed characteristics included age, KPS, gender, previous diagnosis of meningioma, degree of resection (GTR vs. STR), use of adjuvant RT with primary surgery, and mode of salvage therapy (surgery, surgery plus RT, or SRS).
RESULTS Outcomes after primary therapy In the 13 patients with WHO Grade III meningioma, the median survival was 3.4 years, the 5-year survival rate was 47.2%, and the 8-year survival rate was 12.2% (Fig. 1). Four patients were alive at this analysis. The 3 patients who received adjuvant fractionated RT after their first surgery had a median survival of 5.4 years. In contrast, the 10 who did not receive RT had a median survival of 2.5 years. This difference was not statistically significant (p = 0.13).
Table 1. Patient and treatment characteristics for 13 patients with WHO Grade III (malignant) meningiomas Age at diagnosis* 87 62 69 70 75 73 55 73 66 55 55 59 37
Survival (y) 0.1 1.0 1.6 2.1 2.4 3.3 5.3 7.3 7.7 1.6y 1.8y 3.1y 8.8y
Time to recurrence (mo) 0.4 0.4 0.8 0.4 1.5 1.8 2.8 1.6 0.5 1.5 1.3
Simpson grade IV Unknown II Unknown III Unknown III III Unknown I I IV II
RT with primary surgery No No No No No No Yes No No No No Yes Yes
First salvage therapy None Surgery Surgery + RT Surgery + RT Surgery + RT Surgery None Surgery Surgery + RT SRS SRS SRS None
Tumor location L sphenoid R frontal L temporal R parasagittal R falx L frontal R occipital L occipital R parietal L frontoparietal L falx L frontal R lateral ventricle
Abbreviations: WHO = World Health Organization; L = left; R = right; RT = external beam fractionated radiotherapy; SRS = stereotactic radiosurgery with Gamma Knife. * Age at diagnosis of Grade III meningioma; some patients had had previous lower grade meningiomas. y Patient living at last follow-up.
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val to a second recurrence. The median interval to a second recurrence was 3.8 months for patients who received surgery alone, 12.4 months for those who received surgery plus fractionated RT, and 8.1 months for those treated with SRS. These differences were not statistically significant. No other patient variable significantly affected the interval to a second recurrence, including age, KPS, or gender. Complications One patient had pathologic confirmation of radiation necrosis that developed 14 months after SRS and 30 months after external beam RT. This patient was still alive at last follow-up, 5 months after the diagnosis of the radiation necrosis. Another patient had magnetic resonance imaging findings suspicious for radiation necrosis 10 months after external beam RT in 1984 and died 4 months later; no pathologic confirmation was available for this patient. Surgical complications included 1 patient who died of hemorrhage 3 days after a second salvage surgery, 1 patient whose health declined quickly and died 40 days after primary surgery, and 1 patient who developed a wound infection and recovered to baseline after surgical debridement.
Fig. 1. Overall survival of World Health Organization Grade III (malignant) meningioma patients. Open triangles are censor marks indicating follow-up time for surviving patients.
A lower age at diagnosis was significantly associated with survival (p = 0.04). No other analyzed variable was associated with survival, including degree of resection (GTR vs. STR), previous diagnosis of meningioma, KPS at diagnosis, or gender (Table 2). The median time to recurrence was 9.6 months. The recurrence-free survival rate at 1, 2, and 3 years was 52%, 17%, and 8.7%, respectively (Fig. 2). No variables affected the interval to recurrence, including age, KPS, gender, degree of resection, or adjuvant RT (Table 2). Notably, 1 patient was a long-term survivor whose tumor had not recurred for 8.75 years at the last follow-up. This patient had initially undergone GTR (Simpson Grade II) followed by fractionated RT (5,900 cGy in 32 fractions).
DISCUSSION The WHO and other groups have published several definitions of malignant meningioma based on various histopathologic characteristics. In 1979, the WHO provided early criteria for meningioma classification (15). An anaplastic tumor was considered either Grade II or Grade III and was defined as ‘‘[a]ny meningioma that displays anaplastic features yet has not developed into a frank sarcoma,’’ but no more specific criteria were provided. Ja¨a¨skela¨inen et al. (16) suggested four grades of meningiomas (benign, atypical, anaplastic, and sarcomatous) using a scoring system that considered ‘‘loss of architecture, increased cellularity, nuclear pleomorphism, mitotic figures, focal necrosis, and brain infiltration.’’ In 1993, the WHO also recognized atypical and anaplastic meningiomas as separate entities. Anaplastic meningiomas were designated as Grade III and defined as ‘‘meningioma[s] exhibiting histological features of frank malignancy far in excess of the abnormalities noted in atypical meningioma[s]’’ (17). The 1993 WHO definition further implied that brain invasion was a qualification for a Grade III
Outcomes after salvage therapy Ten patients received salvage therapy as either surgery alone (n = 3), surgery followed by RT (n = 4), or SRS using a Gamma Knife (n = 3). The 3 patients who did not receive salvage therapy included 1 whose tumor did not recur, 1 who died within 2 months of primary surgery, and 1 whose tumor recurred but who had not received salvage therapy at the last follow-up visit. The overall median interval to a second recurrence after salvage therapy was 8.1 months. The mode of salvage therapy did not significantly affect the inter-
Table 2. Univariate analysis of factors affecting survival and recurrence rates after initial surgery Effect on survival
Effect on recurrence
Variable
p
RR (95% CI)
p
RR (95% CI)
Age KPS Gender (female vs. male) Resection (GTR vs. STR) Adjuvant RT (no vs. yes)
0.04 0.44 0.31 0.67 0.1
1.11 (1.00–1.22) 0.97 (0.89–1.05) 2.11 (0.50–8.97) 0.61 (0.06–5.94) 5.10 (0.63–41.6)
0.21 0.18 0.91 0.75 0.13
1.04 (0.98–1.10) 1.09 (0.96–1.25) 0.94 (0.28–3.13) 0.70 (0.08–6.32) 3.35 (0.70–16.0)
Abbreviations: RR = relative risk; CI = confidence interval; KPS = Karnofsky performance status; GTR = gross total resection; STR = subtotal resection; RT = radiotherapy.
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Fig. 2. Recurrence-free survival of World Health Organization Grade III (malignant) meningioma patients. Open triangles are censor marks indicating follow-up time for surviving patients.
designation, regardless of the other tumor characteristics. As a result, studies published using this definition considered brain-invasive meningiomas as malignant, or Grade III (6, 7). In a seminal publication for meningioma classification, Perry et al. (8) analyzed the pathologic features from a large number of meningiomas and demonstrated that histologic anaplasia, $20 mitoses per 10 high-powered fields, and nuclear atypia were independently associated with poor survival. They also found that brain invasion was associated with survival similar to that of patients with atypical, or Grade II, meningiomas, rather than Grade III tumors, as previously thought. The WHO in 2000 adopted these conclusions (18). Brain invasion was recognized to confer outcomes similar to that of Grade II meningiomas. Grade III meningiomas included those with ‘‘obviously malignant cytology (e.g., having an appearance similar to sarcoma, carcinoma or melanoma)’’ or $20 mitoses per 10 high-powered fields. Additionally, the rare meningiomas with papillary or rhabdoid histologic features were also considered Grade III. The
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most recent WHO definition in 2007 for Grade III meningiomas (used for the present study) remained unchanged: anaplastic, rhabdoid, and papillary tumors are considered Grade III, and the parameters for anaplasia are the same as those published in 2000 (11). Regarding brain invasion, the 2007 WHO definition echoes their previous publication stating that brain invasive meningiomas ‘‘should prognostically be considered WHO Grade II.’’ Reassigning brain-invasive meningiomas from Grade III to Grade II might have reduced the number of tumors designated as malignant. Simon et al. (12) found that four of six meningiomas originally defined as Grade III before 2000 were downgraded using the WHO 2000 definition. All four redefined tumors were originally termed ‘‘malignant’’ because of the presence of brain invasion. In the present study, a single pathologist reviewed all slides to confirm the diagnosis of Grade III meningioma. Of 18 patients originally diagnosed before 2000 with Grade III meningiomas, 9 were found to have Grade II tumors on slide review using the WHO 2007 standards. Both of these experiences suggest that the WHO 2000 and 2007 definitions of Grade III meningiomas include a substantially different set of tumors than those of previous definitions. These findings indicate a need to re-establish the patient outcome data for Grade III meningiomas. Exclusively using the WHO 2007 definitions, the present study found a 5-year survival rate of 47.2% for patients with Grade III meningiomas. Table 3 provides a comparison of published studies concerning malignant meningiomas. Table 3 includes only those studies that clearly stated their definition of malignancy. A few studies have used the WHO 2000 definition of Grade III meningioma, which is practically equivalent to the 2007 definition. Harris et al. (4) reported 5-year and 10-year survival rate of 59% and 0%, respectively. Although that study used the WHO 2000 standards, some patients did not have slides available for review, and the study used the original interpretations of the pathology report in such cases.
Table 3. Summary of malignant meningioma studies Investigator
Study period
Patients (n)
Malignancy definition
Present study Harris et al. (4)
1981–2006 1987–2001
13 12
WHO, 2007 WHO, 2000*
Perry et al. (8) Hug et al. (5) Palma et al. (7)
1970–1997 1973–1995 1951–1986
27 16 29
Frank anaplasiay WHO, 1993 WHO, 1993
Ware et al. (9)
1988–2002
17
WHO 1993 or Ja¨a¨skela¨inen et al. (16)
Ojemann et al. (6) Goldsmith et al. (3)
1991–1999 1967–1990
22 23
WHO 1993 or Ja¨a¨skela¨inen et al. (16) Unique grading schemez
Survival 47%, 5 y 59%, 5 y 0%, 10 y 32%, 5 y 51%, 5 y 64%, 5 y 35%, 10 y 59%, 5 y 15%, 10 y 40%, 5 y 58%, 5 y
Abbreviation: WHO = World Health Organization. * This study included some meningiomas without histologic review. y These patients were a subset of those for whom brain invasion was specifically not a factor for malignancy. z All tumors were categorized as benign or malignant; tumors were considered malignant if they included brain invasion or >1 mitosis/400 field and two of the following: increased cellularity, necrosis, large atypical nuclei, and increased cytoplasmic mass.
Long-term experience with malignant meningiomas d L. A. ROSENBERG et al.
Katz et al. (19) also used the WHO 2000 definition of malignant meningiomas and reported 5-year local control in 4 (44%) of 9 patients; they did not report survival separately for those with Grade III tumors. Perry et al. (8) analyzed a subset of 27 patients with ‘‘clearly anaplastic’’ histologic features who had 5-year estimated survival rate of 32%. The criteria for inclusion into this category were consistent with the WHO 2007 definition of malignancy. In the present study, a trend was found toward increased survival and a reduced risk of recurrence in patients receiving upfront RT. The benefits of RT have not been explicitly demonstrated in the context of Grade III meningiomas; however, studies have suggested that patients with various aggressive meningiomas benefit from RT. Dziuk et al. (20) analyzed the effects of concurrent RT and surgery compared with surgery alone in 38 patients with aggressive meningiomas. They found significantly improved disease-free survival at 2 years with RT and surgery (94%) compared with surgery alone (61%). Furthermore, several studies have found that greater radiation doses corresponded with better outcomes. Hug et al. (5) demonstrated that patients treated with $60 Gy had a 5-year local control rate of 100% compared with those treated with <60 Gy, who had a 5-year local control rate of 0%. The greater doses were typically received by patients treated with both proton and photon therapy. Milosevic et al. (21) presented data concerning 59 patients treated with RT for atypical and malignant meningiomas either at diagnosis or after recurrence. They demonstrated that patients treated with $50 Gy had a 5-year cause-specific survival rate of 42% vs. 0% in those patients treated with <50 Gy (p = 0.0005). Goldsmith et al. (3) presented data concerning 23 patients with aggressive meningiomas according to a variety of pathologic factors, including brain invasion. They found that the radiation dose was positively associated with increased survival when analyzed as a continuous variable. Retrospective studies have also demonstrated that postoperative RT significantly extends survival in patients with subtotally resected benign meningiomas (22, 23). Studies concerning RT for aggressive meningiomas have often been statistically limited owing to the rarity of the tumors. However, from the available data, many publications have recommended RT, in addition to surgical resection, for patients with malignant meningiomas (1, 5, 7, 19, 20).
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Although RT is becoming a common element in the treatment of malignant meningiomas, surgical resection remains the primary therapy in most contexts. It has been well documented that a greater degree of resection improves the outcome for patients with aggressive meningioma (7, 8, 13, 20), although this association has not been specifically demonstrated for WHO 2000 or 2007 Grade III meningiomas. The present study did not identify the degree of resection as a significant contributor to patient outcome. Only 2 of 13 patients, however, had undergone subtotal resection, which markedly limited our statistical power for this determination. Despite the advances in the understanding and treatment of malignant meningiomas, patient outcomes remain poor. Several groups have used a variety of aggressive regimens in an attempt to improve the treatment of aggressive meningiomas. Katz et al. (19), for example, reported the results of twice-daily RT. Patients with atypical and malignant meningiomas were administered either 60 Gy using 1.5-Gy fractions twice daily or 55–60 Gy using 1.8-Gy fractions daily (19). The twice-daily regimen did not improve the outcomes but did lead to increased complications. The investigators did not recommend the twice-daily regimen. Ware et al. (9) analyzed the outcomes of 17 patients with recurrent malignant meningiomas (using the WHO 1993 criteria or Ja¨a¨skela¨inen et al. [16]) treated with 125I brachytherapy postoperatively. They reported a 5-year survival rate of 24% from implantation. Complications from the brachytherapy included radiation necrosis in 27% of patients and wound breakdown in 27%. Hug et al. (5) reported a 5- and 8-year survival rate of 100% for a small number of malignant meningioma patients treated with combined proton and photon therapy. This achievement was attributed to the fact that all of these patients had received $60 cobalt-gray equivalents, a significantly greater dose than their photon-only patients, who had a 5-year survival rate of 44%. CONCLUSION The survival for malignant meningioma patients remains poor. On the basis of our experience and the experience of others as described in this report, aggressive treatment, including surgical resection followed by RT and salvage therapy, can lead to prolonged survival.
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