Original Paper Pediatr Neurosurg 1992; ! 8; ! 6-23
Giorgio Perilongoa Leslie N. Suttona Joel W. Goldweinb Debra Gusnarda Luis Schuta Jaclyn A. BiegeP Lucy B. Rorkea Beverly Langea GiulioJ. D'Angiob
Childhood Meningiomas Experience in the Modern Imaging Era
Key Words
Abstract
Brain tumors Oncology, pediatric Cancers, childhood Meningioma Radiation therapy
Twenty children with meningiomas (ages 18 months to 17 years) received ini tial therapy at the Children's Hospital of Philadelphia between January 1975 and June 1991, accounting for 2% of children with primary brain tumors seen during that time interval. All were verified histopathologically, and none had had prior irradiation. Fifteen were male and 5 female. Fifteen tumors were intracranial, all located supratentorially. Two of these also had a component within the optic canal. One tumor was entirely within the orbit. Four menin giomas arose within the spinal canal. Associated conditions were neurofibro matosis (NF) type I (1 patient), NF type II (2 patients), and a facial alveolar rhabdomysarcoma (1 patient). A gross total resection as documented by post operative scan and operative note was accomplished in 12 patients. Four of these relapsed, at a mean of 3.5 years from initial surgery. In 4 patients a near-total resection (>90% ) was performed. Of these, 2 progressed at 9 months and 1.5 years. One of these died of complications associated with reoperation. In 4 patients a partial resection (50-90%) was performed. Two of these progressed at 4 months and 1 year, and the other 2 have been followed for less than 2 years. Five patients received radiation therapy (RT). One patient received RT as adjunctive therapy after primary surgery because of papillary histology. The other 4 had RT following reoperation for recurrence at a mean of 1.5 years from diagnosis (range. 7 months to 2 years). These 4 patients remain alive and with stable disease at a mean of 6 years from diagno sis (range 2-8.8 years) The crude relapse-free and overall survival rates were 60% (12/20) and 95% (19/20), respectively, at a mean of 5.8 years after diag nosis. This single institution series confirms both the relatively favorable out come of these tumors despite a high recurrence rate, and the value of radiation therapy in delaying progression.
Leslie N. Sutton, MD Department of Neurosurgery Children's Hospital of Philadelphia 34th St. and Civic Center Blvd. Philadelphia. PA 19104 (USA)
© 1992 S. Karger AG. Basel 1016-2291/92/0181-0 0 16 $2.75/0
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a Neuro-Oncology Program. The Children’s Hospital of Philadelphia and b The Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pa., USA
Meningiomas have a peak incidence in the 5th and 6th decades of life and are rare in children, only about 2% occurring in patients under the age of 18 years. Single institution review report an approximate incidence of 2% of this tumor type among all pediatric intracranial neo plasms [1-4], Mendiratta et al. [5] collected 15 major series of intracranial tumors in children and found only 38 meningiomas among 2,620 tumors (1.5%). Meningiomas are typically benign, slow-growing tu mors. Nonetheless, they can repeatedly recur, requiring multiple surgical excisions. Radiation therapy (RT) has been advocated as an adjunct following recurrences, but this can be damaging, particularly to the immature brain. Thus, a better understanding of tumor biology is needed to aid in selecting among therapeutic options. We have reviewed the clinical data from our series of childhood meningiomas in order to assess the natural his tory of this condition.
Clinical Material and Methods The 20 patients included in this report were identified through the population-based tumor registry of the Children’s Hospital of Philadelphia (CHOP) and include all those diagnosed and treated at CHOP from January 1975 to June 1991. They represent 2% of the 970 children with primary brain tumors seen during that time inter val. Patients were evaluated by computerized tomography (CT) and. more recently, magnetic resonance imaging (MRI) when it became routinely available. Follow-up consisted of periodic physical, neuro logic and imaging examinations. Medical records and imaging stud ies were reviewed, and the histologic material reevaluated by one of us (L.B.R.). The World Health Organization classification of brain tumors for childhood brain tumors which includes the designation ‘Meningioma-NOS (not otherwise specified)’ was used to classify meningiomas histologically [6], This category encompasses the ma jo r subtypes of meningioma, including meningotheliomatous (syncy tial). fibroblastic, transitional, psammomatous, angiomatous and cystic. Tumors were evaluated for basic pattern, mitotic activity, nuclear atypia and pleomorphism, and evidence of brain invasion, and malignant tumors were classified as ‘anaplastic meningiomas’. Cytogenetic studies were performed on 5 of the tumors using tissue obtained at the time of surgery.
Results
There were 15 males and 5 females under 18 years of age at the time of the initial diagnosis of meningioma. None had a history of prior irradiation. Their clinical characteristics are shown in table 1. The mean age of the
children at diagnosis was 10 years, 6 months, with a range from 18 months to 17 years. The meningiomas in 15 patients were located intracranially: frontal region 4. pari etal lobe/falx 1. temporal region 8, and optic canal/ orbit 2. In 1 patient, the meningioma was confined to the orbit. The remaining 4 patients had tumors originating within the spinal canal. Three of these originated in the cervical area, and in 2 there was extension through the foramen magnum. The 4th child developed a growth in the T6-T7 region. Presenting symptoms were referable to the tumor location and were not specific, consisting mainly of evidence of increased intracranial pressure, sei zures and/or focal motor weaknesses or visual dysfunc tion. Imaging Studies Preoperative CT and MR examinations were available for review in 16 of the 20 patients. All but 2 (those with spinal meningiomas) had noncontrast and contrast-en hanced CTs. One patient with an intraorbital meningio ma, 4 patients with intracranial meningiomas, 2 with intraspinal meningiomas and 2 with optic nerve sheath meningiomas were examined by MR: 5 of these included contrast enhancement with gadolinium-DTPA. On CT, 12 of 14 tumors had a typical appearance: i.e.. isodense to slightly hyperdense extra-axial masses with homogeneous or near homogeneous enhancement. Three demonstrated dense foci of calcification. Two tumors adjacent to the sphenoid wing demonstrated hyperostotic changes in the bone. On MR, as on CT. most of the meningiomas (6 of 9) appeared characteristic with regard to signal intensity, being isointense to gray matter on T1-weighted images and isointense to slightly hyperintense to gray matter on T2-weighted images. One intraspinal meningioma was of low signal intensity on the T2-wcighted images, presum ably due to tumor calcification. Enhancement of the neo plasm was seen in all cases in which gadolinium-DTPA was administered. Two of the 16 tumors had an unusual appearance, however. One was predominantly cystic, and the other appeared on both CT and MR to be entirely intraparenchymal without a dural attachment, which was confirmed at surgery (fig. 1). There were no CT or MR features that distinguished those tumors with histologic findings of necrosis, frequent mitoses or brain invasion. MR angiography was performed in 1 patient with a parasagittal meningioma to determine patency of the superior sagittal sinus (fig. 2). This confirmed that the sinus was occluded, and the meningioma was subse quently resected along with the occluded segment of the sinus.
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Introduction
Table 1. Clinical data
Patient No.
Sex
Age at Site dx, years
Surgery
Recurrence
XRT
Follow-up
1 2 3 4
M M M F
2 8 17 11
temporal temporal c. spine frontal
TR NTR ST TR
_ 4 months 6 years 9 years
— adj.
15.9 years 11.1 years 10.8 years
5 6 7
M M M
16 17 14
temporal temporal temporal
TR TR ST
8 9
M M
4 11
frontal c. spine
TR NTR
10 11 12 13 14 15 16 17 18 19 20
F M M M M F F M F M M
9 6 11 13 8 16 1.5 13 15 16 2
frontal frontal t. spine falx c. spine temporal temporal optic n optic n orbit temporal
TR TR TR NTR TR TR TR ST ST NTR TR
-
-
-
-
-
1 year 2 years 3 years 2 years 9 months
+ + -
7 months 5 years
-
+ + -
-
-
-
-
-
1.5 years -
10.0 years 9.9 years 9.7 years
8.8 years 7.1 years 9 months (dead) 6.1 years 5.9 years 4.5 years 3 years 2.5 years 2.8 years 1.6 years 1.8 years 1 year 4 months 1.4 years
dx = Diagnosis: XRT = radiation therapy: TR = total resection: NTR = near-toral resec tion; ST = subtotal resection; adj. = adjunctive therapy.
Therapy Outcome in relation to tumor location, histology and therapy is outlined in (table 1). A gross total resection as determined by the surgeon’s impression and postopera tive imaging studies was accomplished in 12 patients. Four of these developed local tumor recurrence at 7 months, and 2, 5, and 6 years from diagnosis. Despite
18
surgical reexcision. 1 of these 5 patients experienced a sec ond recurrence at 3 years from the time of first relapse (9 years from diagnosis). All 4 relapsed patients remain alive, none with residual disease after surgery alone in 2, and after reoperation followed by local RT in 2. Follow up from diagnosis ranges from 6 to 10 years. In 4 patients, a near-total resection (>90% ) was per formed. Of these. 2 progressed at 9 and 18 months from diagnosis. One of these patients, who had associated NF I
Fig. 1.a, b Parenchymal meningioma in a 2-year-old. T lweighted images before (a) and after (b) the administration of gado linium demonstrate a round intra-axial tum or mass (arrowheads), isointense to gray matter, which enhanced homogeneously after con trast. At surgery, there was no dural attachment. Fig. 2. a, b Parasagittal meningioma in a 13-year-old male. The gadolinium-enhanced image suggests involvement of the posterior third of the sagittal sinus (a), but the angiographic sequence con firmed occlusion of the sinus (b). which permitted total excision of the tum or along with the occluded sinus segment and falx.
Perilongo/Sutton/Goldwein/Gusnard/ Schut/Biegel/Rorke/Lange/D’Angio
Childhood Meningiomas
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Associated Conditions Four patients had other medical conditions associated with their meningiomas. One had the cutaneous stigmata (multiple café au lait macules and neurofibromata) of type I neurofibromatosis (N F 1. patient 9). Two patients. 1 with a cervical meningioma (patient 14), and 1 with an orbital meningioma (patient 19) were found on imaging studies to also have bilateral acoustic neuromas diagnos tic of type II neurofibromatosis (NF II). An intraparenchymal meningioma was diagnosed in the 3rd patient during staging procedures for a left nasolabial alveolar rhabdomyosarcoma, and the mass was electively excised (patient 20).
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Table 2. Histological features of meningiomas and clinical out
come
100 +*-*----------------------------------- A ------ A4— A ---------A -
80
H «S
So Î
60'
40
••
20
•
♦ ♦ ♦ -A— Survival
—
Relapse-free survival
Features (necrosis, mitotic figures, and/ or brain invasion)
Patient number
Local relapse
Mean follow-up years
Present Necrosis Brain invasion Mitoses Anaplasia Absent Papillary foci
8 3 2 5 1 11 1
4 (50%) 1 0 3 0 3(27%) 1
6.2
5.8
H---------- H
8 12 Time from diagnosis, years
16
Fig. 3. Survival and relapse-free survival for 20 children with meningiomas. Although recurrences are common, survival is gener ally good.
was found to have a schwannoma in the original operative bed at relapse, and died of postoperative complications. Thus. 3 of 4 remain alive with stable disease at follow-up of 4 months. 3 years, and 11 years. 1 having received radiation. A subtotal tumor resection (50-90%) was performed in 4 patients. Surgical excision was limited by involve ment of the vertebral artery in 1, and extensive involve ment of the cranial base and pterygoid muscles in anoth er. Both of these progressed at 4 months and 1 year from initial surgery, but after rercsection and RT remain alive with stable disease at 10 and 8 years from diagnosis. Two patients had optic sheath meningiomas, in whom the intracranial and intracanalicular tumor was resected but in whom the families have deferred resection of the orbi tal mass for the present. These patients have been fol lowed for less than 2 years. Overall, the crude survival rate for our group of child hood meningiomas is 19/20 (95%). at a mean of 5.8 years from diagnosis despite a recurrence rate of 40% (fig. 3). Radiation Therapy Five patients received involved-field RT. One patient received RT as adjunctive therapy after primary surgery because of papillary histology. The other 4 had RT follow ing reoperation for recurrence at a mean of 1.5 years from diagnosis (range. 7 months to 2 years). These patients all remain alive with stable disease at a mean of 6 years from diagnosis (range. 2-8 years).
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Histology Table 2 shows a summary of clinical outcome relative to brain invasion and histopathological features, particu larly, necrosis, mitotic figures, and papillary patterns. Eight patients had histologic features of malignancy (mi toses. necrosis, brain invasion). Four of these experienced local relapse, compared with 3/11 patient without histo logic features of malignancy. These numbers are too small to draw any firm conclusions regarding the predictive value of histology in childhood meningioma, however adverse histological features do not preclude prolonged survival. Of interest was one meningioma that presented a pat tern of a cord-like growth of large eosinophilic cells dis playing a striking resemblance to liver (patient 13). This tumor contained mitotic figures and foci of necrosis, and recurred locally 20 months following initial resection when the ‘hepatic pattern' was no longer prominent. Another tumor manifested features of anaplasia, contain ing large, hyperchromatic. bizarre nuclei (patient 5). No mitotic figures were observed, nor was there necrosis or brain invasion and the patient is alive and free of disease 9 years after surgery. No pure papillary meningiomas were observed in our series. One meningioma had foci of papillary growth (pa tient 3). The tumor recurred soon after partial resection and RT. No further recurrence has been observed after a second radical surgical excision at 114 months from diag nosis. Cytogenetics Cytogenetic studies were performed on surgical speci mens from 5 of the 18 patients (see table 1, cases 13-16, and 20). Abnormal karyotypes were obtained in 3 tumors.
Perilongo/Sutton/Goldwein/Gusnard/ Schut/Biegcl/Rurke/Langc/D'Angio
Childhood Meningiomas
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dren being clustered together. Twelve of the 5i Mayo Clinic meningioma patients under 21 years of age [2] had evidence of NF, whereas there was only 1 among the 19 from the University of Rome [3], According to Deen et al. [2], patients with NF and meningiomas are similar to other children with meningiomas with respect to age at surgery, sex ratio and histologic subtype, except for tumor location. Their NF group had an increased incidence of Discussion spinal (5/12) and orbital nerve sheath (3/12) tumors. In Childhood meningiomas were more common in males our series, upper cervical meningiomas were seen in in our series. This differs from adult series, in whom patients with both types of neurofibromatosis, suggesting females predominate, but is in agreement with other that this site is not specific. While bilateral acoustic neuromas are the hallmark of pediatric series [3, 7], Congenital and infantile meningio mas were rare, and meningiomas became relatively more NF II. meningiomas and neurofibromas arc the next most common in adolescence. This suggests an increased inci frequent tumors encountered. Interestingly, specific loss of alleles from chromosome 22 have been detected in all dence with age. as has been noted by others [8, 9]. All 15 intracranial tumors we observed were located three types of tumors in patients with NF II, suggesting a supratentorially, confirming the rarity of posterior fossa common genetic mechanism [17]. In addition, loss of meningiomas in children [ 1-3 .7 , 10], No multiple menin chromosome 22 and, less frequently, deletion of the long arm of chromosome 22, have been consistently reported giomas were observed in our series. There have been no studies that specifically address in human meningioma cells [18.19], These studies hint at the radiographic findings of childhood meningiomas the presence of a meningioma tumor suppressor locus on since the advent of MR. Though the CT and MR features distal 22q, which may function in a fashion similar to the were variable in our series, they were similar to those retinoblastoma and Wilm's tumor genes. Most of these described in adults [11-14], Meningiomas on CT typi data have been accumulated from adult meningioma cally appear as well-defined, homogeneous, dense masses patients and to date, no correlation between the cytoge that abut the dura. They frequently are partially calcified netic findings and survival has been found. In the limited and are marginated by mild vasogenic edema in the number of childhood meningiomas studied in our institu underlying brain. Adjacent bony abnormalities consisting tion, involvement of chromosome 22, specifically loss of of hyperostosis, bony destruction or pressure erosion are all or part of 22. was seen in 3 patients. Clearly, a larger seen in 15-20% of cases. On MR. meningiomas typically number of tumors need lobe analyzed before any clinical appear isointense or nearly isointense to gray matter on implications of an abnormal karyotype can be drawn. The extent of surgical resection seems to be the most all pulse sequences, though a granular or whorled texture important prognostic factor for tumor control. The risk of may be seen on T1-weighted images. MR is more accurate than CT in confirming the extra-axial location of these recurrence after total gross removal has been reported to tumors, since it more sensitively demonstrates 'buckling' range from 4 to 9% in large series of pediatric and adult of the underlying white matter as well as displaced corti meningiomas [1.2. 20-22]. but in our series of pediatric cal veins or cerebrospinal fluid at the brain-tumor inter patients it was 33%. suggesting that pediatric meningio face. In our 16 patients with intracranial meningiomas, mas are potentially more aggressive than those seen in atypical radiographic manifestations were seen in 2: a pre adults. Subtotally resected tumors progress with even dominantly cystic tumor with small solid component, and greater frequency [3, 21], All 3 of our meningiomas of the skull base (2 cribriform plate. 1 sphenoid wing) relapsed, a totally intraparenchymal mass. Meningiomas are reported to be more common in as did one of the 2 that extended through the foramen patients with neurofibromatosis type II than in those with magnum to C1-C2. It is likely that the high relapse rate neurofibromatosis type I, and in this setting they tend to for meningiomas involving the skull base is at least in part occur in the posterior fossa or upper spinal region [15, related to the technical difficulties in obtaining complete 16]. In our series. 1 patient had the clinical findings of tumor removal. Recurrences following apparent total resection, and NF I. and 2 patients satisfied criteria for NF II. Even in recent reports of childhood meningiomas, no distinction the difficulty in achieving total excision of meningiomas is made between patients with NF I and II. the NF chil in some locations has prompted interest in the use of local
21
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Patient 14. who also had clinical manifestations of NF II. had tumor-specific loss of a chromosome 22 as the only abnormality. Tumors from patients 13 and 16 demon strated an abnormal chromosome 22 as well as additional numerical and structural changes.
22
that had at least one of these features. Our numbers were too small to determine the prognostic significance of the individual histologic features. Thus, no firm conclusions on the relevance of those features can be drawn, but when they are documented, closer follow-up would seem pru dent. All but one of the recurring tumors in our series mim icked the histologic pattern originally noted at diagnosis.
Conclusions
Complete surgical excision of the tumor without mi croscopic residual is the most reliable method of achiev ing long-lasting control of childhood meningiomas. Rou tine postoperative RT should be deferred until tumor recurrence becomes apparent. It could then be used as an adjunct to surgery if reexcision seems incomplete. Delay in the use of radiation is particularly important in the young patient whose immature brain is especially vulner able to the deleterious secondary effects of RT. Our expe rience does not mandate the use of RT after partial tumor removal but it does demonstrate the effectiveness of this modality in slowing progression after early recurrence. The presence of necrosis, mitotic figures or histologic evidence of brain invasion does not warrant more radical treatment. Close follow-up under these circumstances, regardless of the completeness of the surgical resection, would nonetheless seem prudent. In contrast, papillary meningiomas and hemangiopericytomas of the meninges carry a dismal prognosis, and an aggressive surgical-radiotherapeutic attack is appropriate for these tumor types.
Perilongo/Sutton/Goldwein/Gusnard/ Schut/Biegel/Rorke/Langc/D'Angio
Childhood Meningiomas
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radiation therapy in this disease, but there have been no prospective randomized studies of the use of postopera tive RT in either adults or children. Viewed retrospective ly, the actuarial local control rates at 10 years are reported to be 77% for total excision alone, 82% for subtotal exci sion plus RT, and only 18% for subtotal excision alone [21], The benefit of RT at the time of recurrence nonethe less remains a controversial issue. Some authors have failed to demonstrate any benefit of RT at relapse [22], while others have reported a 43% 10-year actuarial sur vival for patients with recurrent meningiomas not irra diated and an 87% rate for the ones who had RT [21]. More recently, Glaholm et al. [10] claimed that patients treated with RT for recurrent meningioma fared as well as new patients when survival was measured from the time of first diagnosis [23]. Four of our patients received RT following reresection at their initial recurrence, and have remained without disease progression for a considerably longer time than their time to initial recurrence, suggest ing the effectiveness of RT in controlling recurrent dis ease. In the present series, the crude overall survival rate was 19/20 (95%) at a median follow-up of 5.8 years. The relapse rate, however, was 40%, which is similar to that reported in other pediatric series [1. 2], The outlook for children with these tumors is thus generally favorable, despite the frequency of local recurrence. Seven of the 8 patients in our series who relapsed have been salvaged by surgery and/or RT. The single patient who died suc cumbed to postoperative complications, not progressive disease. The relationship between histologic patterns of meningioma and biological behavior remains unclear. It has been reported that papillary meningiomas have an aggressive clinical course, and are capable of extracranial dissemination [24], In the Mayo Clinic experience, 4 of the 5 childhood meningiomas with the papillary pattern recurred, with a mean time to recurrence of 2 years, com pared with 9 years for all other histological types [2], Papillary meningioma occurs with particular frequency in the young. One of our patients had a focus of papillary growth within the meningioma without any other histo logical evidence of malignancy. There was rapid local recurrence despite initial partial resection and postopera tive RT. The patient remains free of disease for more than 9 years after a second operation. The fact that papillary histology is not incompatible with prolonged survival has also been pointed out by others [25]. The prognostic importance of necrosis within the tu mor, mitotic figures and brain tissue invasion is uncer tain. In the present series. 4 tumors recurred among the 8
R eferences 11 Bydder G, et al: MR imaging of meningiomas including studies with and without gadolinium-DTPA. JCAT 1985:9:690-697. 12 Sutton D. Claveria L: Meningiomas diagnosed by scanning: A review of 100 intracranial cases; in du Bouloy G, Mosley I (eds): The First Euro pean Seminaron Computerized Axial Tomog raphy in Clinical Practice. Heidelberg, Springer, 1977, pp 102-110. 13 Wiggli U. ct al: The CT pattern of mcningiomaIs it specific?: in Lanksch W. Kazner E (eds): Cranial Computerized Tomography. Heidel berg, Springer. 1976. pp 162-166. 14 Zimmermann R. el al: Magnetic resonance imaging of meningiomas. AJNR 1985:6:149— 157. 15 Conference NIoHCD: Neurofibromatosis Conference Statement. National Institutes of Health, 1988. 16 Riccardi V. Eichner .1. Non-Von Reckling hausen NF; in Riccardi V, Eichncr J (eds): Neurofibromatosis. Phenotype, Natural His tory and Pathogenesis, Baltimore. Johns Hop kins University Press. 1986. pp 169-184. 17 Seizinger B. et al: Common pathogenetic mech anism for three tumor types in bilateral acous tic neurofibromatosis. Science 1987:236:317— 319.
18 Dumanski J. et al: Deletion mapping of a locus on human chromosome 22 involved in the oncogenesis of meningioma. Proc Natl Acad Sci 1987:84:9275-9279. 19 Mitleman F: Catalog of Chromosome Aberra tions in Cancer, ed 3. New York. Liss. 1988. pp 1146-1988. 20 Berger M, Ojemann G. I.ettich E: Neurophysi ological monitoring during astrocytoma sur gery. Neurosurg Clin North Am 1990:1:65-80. 21 Taylor B. et al: The meningioma controversy: Post-operative radiation therapy. Int .1 Radial Oncol Biol Phys 1988:15:299-304. 22 Yasmashita J, et al: Recurrence of intracranial meningiomas with special reference to radio therapy. Surg Neurol 1980:14:33-40. 23 Glar.holm J. Bloom H. Crow J: The role of radiotherapy in the management of intracra nial meningioma: The Royal Marsden Hospital experience with 186 patients. Int.I Radiat On col Biol Phys 1990:18:755-761. 24 Ludwin S. Rubcnstein L. Russel D: Papillary meningioma: A malignant variant of meningio ma. Cancer 1975:36:1363-1375. 25 Drake J. et al: Intracranial meningiomas in children Pediatr Neurosci 1985/1986:12:134139.
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1 Davidson G. Hope J: Meningeal tumors of childhood. Cancer 1988:63:1205-1210. 2 Deen G. Scheithauer B. Ebcrsold M: Clinical and pathological study of meningiomas of the first two decades of life. J Neurosurg 1982:56: 317-322. 3 Ferrante L. et al: Cerebral meningioma in chil dren. Childs Nerv Syst 1989:5:83-86. 4 Schut L. Canady A. Sutton L: Meningeal tu mors in children. Concepts Pcdiatr Neurosurg 1983;4:335-347. 5 Mendiratta S. Rosenblum J. Strobos R: Con genital meningioma. Neurology 1967; 17:914— 918. 6 Rorke L, ct al: Revision of the World Health Organization classification of brain tumors for childhood brain tumors. Cancer 1985:56: 1869-1886. 7 Kepes J: Meningiomas, Biology. Pathology and Differential Diagnosis. New York. Masson Publishing USA. 1982. 8 Herz D. Shapiro K. Shulman K: Intracranial meningiomas of infancy, childhood and ado lescence. Review of the literature and addition of 9 case reports. Childs Brain 1980:7:43-56. 9 Pasztor A, et al: A rare case of infantile menin gioma. Childs Nerv Syst 1986;1:352-356. 10 Burger P. et al: Surgical Pathology of the Ner vous System and Its Coverings, ed. 2. New York, Wiley, 1982. pp 83-170.
Giorgio Perilongoa Leslie N. Suttona Joel W. Goldweinb Debra Gusnarda Luis Schuta Jaclyn A. BiegeP Lucy B. Rorkea Beverly Langea GiulioJ. D'Angiob
Childhood Meningiomas Experience in the Modern Imaging Era
Key Words
Abstract
Brain tumors Oncology, pediatric Cancers, childhood Meningioma Radiation therapy
Twenty children with meningiomas (ages 18 months to 17 years) received ini tial therapy at the Children's Hospital of Philadelphia between January 1975 and June 1991, accounting for 2% of children with primary brain tumors seen during that time interval. All were verified histopathologically, and none had had prior irradiation. Fifteen were male and 5 female. Fifteen tumors were intracranial, all located supratentorially. Two of these also had a component within the optic canal. One tumor was entirely within the orbit. Four menin giomas arose within the spinal canal. Associated conditions were neurofibro matosis (NF) type I (1 patient), NF type II (2 patients), and a facial alveolar rhabdomysarcoma (1 patient). A gross total resection as documented by post operative scan and operative note was accomplished in 12 patients. Four of these relapsed, at a mean of 3.5 years from initial surgery. In 4 patients a near-total resection (>90% ) was performed. Of these, 2 progressed at 9 months and 1.5 years. One of these died of complications associated with reoperation. In 4 patients a partial resection (50-90%) was performed. Two of these progressed at 4 months and 1 year, and the other 2 have been followed for less than 2 years. Five patients received radiation therapy (RT). One patient received RT as adjunctive therapy after primary surgery because of papillary histology. The other 4 had RT following reoperation for recurrence at a mean of 1.5 years from diagnosis (range. 7 months to 2 years). These 4 patients remain alive and with stable disease at a mean of 6 years from diagno sis (range 2-8.8 years) The crude relapse-free and overall survival rates were 60% (12/20) and 95% (19/20), respectively, at a mean of 5.8 years after diag nosis. This single institution series confirms both the relatively favorable out come of these tumors despite a high recurrence rate, and the value of radiation therapy in delaying progression.
Leslie N. Sutton, MD Department of Neurosurgery Children's Hospital of Philadelphia 34th St. and Civic Center Blvd. Philadelphia. PA 19104 (USA)
© 1992 S. Karger AG. Basel 1016-2291/92/0181-0 0 16 $2.75/0
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a Neuro-Oncology Program. The Children’s Hospital of Philadelphia and b The Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pa., USA
Meningiomas have a peak incidence in the 5th and 6th decades of life and are rare in children, only about 2% occurring in patients under the age of 18 years. Single institution review report an approximate incidence of 2% of this tumor type among all pediatric intracranial neo plasms [1-4], Mendiratta et al. [5] collected 15 major series of intracranial tumors in children and found only 38 meningiomas among 2,620 tumors (1.5%). Meningiomas are typically benign, slow-growing tu mors. Nonetheless, they can repeatedly recur, requiring multiple surgical excisions. Radiation therapy (RT) has been advocated as an adjunct following recurrences, but this can be damaging, particularly to the immature brain. Thus, a better understanding of tumor biology is needed to aid in selecting among therapeutic options. We have reviewed the clinical data from our series of childhood meningiomas in order to assess the natural his tory of this condition.
Clinical Material and Methods The 20 patients included in this report were identified through the population-based tumor registry of the Children’s Hospital of Philadelphia (CHOP) and include all those diagnosed and treated at CHOP from January 1975 to June 1991. They represent 2% of the 970 children with primary brain tumors seen during that time inter val. Patients were evaluated by computerized tomography (CT) and. more recently, magnetic resonance imaging (MRI) when it became routinely available. Follow-up consisted of periodic physical, neuro logic and imaging examinations. Medical records and imaging stud ies were reviewed, and the histologic material reevaluated by one of us (L.B.R.). The World Health Organization classification of brain tumors for childhood brain tumors which includes the designation ‘Meningioma-NOS (not otherwise specified)’ was used to classify meningiomas histologically [6], This category encompasses the ma jo r subtypes of meningioma, including meningotheliomatous (syncy tial). fibroblastic, transitional, psammomatous, angiomatous and cystic. Tumors were evaluated for basic pattern, mitotic activity, nuclear atypia and pleomorphism, and evidence of brain invasion, and malignant tumors were classified as ‘anaplastic meningiomas’. Cytogenetic studies were performed on 5 of the tumors using tissue obtained at the time of surgery.
Results
There were 15 males and 5 females under 18 years of age at the time of the initial diagnosis of meningioma. None had a history of prior irradiation. Their clinical characteristics are shown in table 1. The mean age of the
children at diagnosis was 10 years, 6 months, with a range from 18 months to 17 years. The meningiomas in 15 patients were located intracranially: frontal region 4. pari etal lobe/falx 1. temporal region 8, and optic canal/ orbit 2. In 1 patient, the meningioma was confined to the orbit. The remaining 4 patients had tumors originating within the spinal canal. Three of these originated in the cervical area, and in 2 there was extension through the foramen magnum. The 4th child developed a growth in the T6-T7 region. Presenting symptoms were referable to the tumor location and were not specific, consisting mainly of evidence of increased intracranial pressure, sei zures and/or focal motor weaknesses or visual dysfunc tion. Imaging Studies Preoperative CT and MR examinations were available for review in 16 of the 20 patients. All but 2 (those with spinal meningiomas) had noncontrast and contrast-en hanced CTs. One patient with an intraorbital meningio ma, 4 patients with intracranial meningiomas, 2 with intraspinal meningiomas and 2 with optic nerve sheath meningiomas were examined by MR: 5 of these included contrast enhancement with gadolinium-DTPA. On CT, 12 of 14 tumors had a typical appearance: i.e.. isodense to slightly hyperdense extra-axial masses with homogeneous or near homogeneous enhancement. Three demonstrated dense foci of calcification. Two tumors adjacent to the sphenoid wing demonstrated hyperostotic changes in the bone. On MR, as on CT. most of the meningiomas (6 of 9) appeared characteristic with regard to signal intensity, being isointense to gray matter on T1-weighted images and isointense to slightly hyperintense to gray matter on T2-weighted images. One intraspinal meningioma was of low signal intensity on the T2-wcighted images, presum ably due to tumor calcification. Enhancement of the neo plasm was seen in all cases in which gadolinium-DTPA was administered. Two of the 16 tumors had an unusual appearance, however. One was predominantly cystic, and the other appeared on both CT and MR to be entirely intraparenchymal without a dural attachment, which was confirmed at surgery (fig. 1). There were no CT or MR features that distinguished those tumors with histologic findings of necrosis, frequent mitoses or brain invasion. MR angiography was performed in 1 patient with a parasagittal meningioma to determine patency of the superior sagittal sinus (fig. 2). This confirmed that the sinus was occluded, and the meningioma was subse quently resected along with the occluded segment of the sinus.
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Introduction
Table 1. Clinical data
Patient No.
Sex
Age at Site dx, years
Surgery
Recurrence
XRT
Follow-up
1 2 3 4
M M M F
2 8 17 11
temporal temporal c. spine frontal
TR NTR ST TR
_ 4 months 6 years 9 years
— adj.
15.9 years 11.1 years 10.8 years
5 6 7
M M M
16 17 14
temporal temporal temporal
TR TR ST
8 9
M M
4 11
frontal c. spine
TR NTR
10 11 12 13 14 15 16 17 18 19 20
F M M M M F F M F M M
9 6 11 13 8 16 1.5 13 15 16 2
frontal frontal t. spine falx c. spine temporal temporal optic n optic n orbit temporal
TR TR TR NTR TR TR TR ST ST NTR TR
-
-
-
-
-
1 year 2 years 3 years 2 years 9 months
+ + -
7 months 5 years
-
+ + -
-
-
-
-
-
1.5 years -
10.0 years 9.9 years 9.7 years
8.8 years 7.1 years 9 months (dead) 6.1 years 5.9 years 4.5 years 3 years 2.5 years 2.8 years 1.6 years 1.8 years 1 year 4 months 1.4 years
dx = Diagnosis: XRT = radiation therapy: TR = total resection: NTR = near-toral resec tion; ST = subtotal resection; adj. = adjunctive therapy.
Therapy Outcome in relation to tumor location, histology and therapy is outlined in (table 1). A gross total resection as determined by the surgeon’s impression and postopera tive imaging studies was accomplished in 12 patients. Four of these developed local tumor recurrence at 7 months, and 2, 5, and 6 years from diagnosis. Despite
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surgical reexcision. 1 of these 5 patients experienced a sec ond recurrence at 3 years from the time of first relapse (9 years from diagnosis). All 4 relapsed patients remain alive, none with residual disease after surgery alone in 2, and after reoperation followed by local RT in 2. Follow up from diagnosis ranges from 6 to 10 years. In 4 patients, a near-total resection (>90% ) was per formed. Of these. 2 progressed at 9 and 18 months from diagnosis. One of these patients, who had associated NF I
Fig. 1.a, b Parenchymal meningioma in a 2-year-old. T lweighted images before (a) and after (b) the administration of gado linium demonstrate a round intra-axial tum or mass (arrowheads), isointense to gray matter, which enhanced homogeneously after con trast. At surgery, there was no dural attachment. Fig. 2. a, b Parasagittal meningioma in a 13-year-old male. The gadolinium-enhanced image suggests involvement of the posterior third of the sagittal sinus (a), but the angiographic sequence con firmed occlusion of the sinus (b). which permitted total excision of the tum or along with the occluded sinus segment and falx.
Perilongo/Sutton/Goldwein/Gusnard/ Schut/Biegel/Rorke/Lange/D’Angio
Childhood Meningiomas
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Associated Conditions Four patients had other medical conditions associated with their meningiomas. One had the cutaneous stigmata (multiple café au lait macules and neurofibromata) of type I neurofibromatosis (N F 1. patient 9). Two patients. 1 with a cervical meningioma (patient 14), and 1 with an orbital meningioma (patient 19) were found on imaging studies to also have bilateral acoustic neuromas diagnos tic of type II neurofibromatosis (NF II). An intraparenchymal meningioma was diagnosed in the 3rd patient during staging procedures for a left nasolabial alveolar rhabdomyosarcoma, and the mass was electively excised (patient 20).
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Table 2. Histological features of meningiomas and clinical out
come
100 +*-*----------------------------------- A ------ A4— A ---------A -
80
H «S
So Î
60'
40
••
20
•
♦ ♦ ♦ -A— Survival
—
Relapse-free survival
Features (necrosis, mitotic figures, and/ or brain invasion)
Patient number
Local relapse
Mean follow-up years
Present Necrosis Brain invasion Mitoses Anaplasia Absent Papillary foci
8 3 2 5 1 11 1
4 (50%) 1 0 3 0 3(27%) 1
6.2
5.8
H---------- H
8 12 Time from diagnosis, years
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Fig. 3. Survival and relapse-free survival for 20 children with meningiomas. Although recurrences are common, survival is gener ally good.
was found to have a schwannoma in the original operative bed at relapse, and died of postoperative complications. Thus. 3 of 4 remain alive with stable disease at follow-up of 4 months. 3 years, and 11 years. 1 having received radiation. A subtotal tumor resection (50-90%) was performed in 4 patients. Surgical excision was limited by involve ment of the vertebral artery in 1, and extensive involve ment of the cranial base and pterygoid muscles in anoth er. Both of these progressed at 4 months and 1 year from initial surgery, but after rercsection and RT remain alive with stable disease at 10 and 8 years from diagnosis. Two patients had optic sheath meningiomas, in whom the intracranial and intracanalicular tumor was resected but in whom the families have deferred resection of the orbi tal mass for the present. These patients have been fol lowed for less than 2 years. Overall, the crude survival rate for our group of child hood meningiomas is 19/20 (95%). at a mean of 5.8 years from diagnosis despite a recurrence rate of 40% (fig. 3). Radiation Therapy Five patients received involved-field RT. One patient received RT as adjunctive therapy after primary surgery because of papillary histology. The other 4 had RT follow ing reoperation for recurrence at a mean of 1.5 years from diagnosis (range. 7 months to 2 years). These patients all remain alive with stable disease at a mean of 6 years from diagnosis (range. 2-8 years).
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Histology Table 2 shows a summary of clinical outcome relative to brain invasion and histopathological features, particu larly, necrosis, mitotic figures, and papillary patterns. Eight patients had histologic features of malignancy (mi toses. necrosis, brain invasion). Four of these experienced local relapse, compared with 3/11 patient without histo logic features of malignancy. These numbers are too small to draw any firm conclusions regarding the predictive value of histology in childhood meningioma, however adverse histological features do not preclude prolonged survival. Of interest was one meningioma that presented a pat tern of a cord-like growth of large eosinophilic cells dis playing a striking resemblance to liver (patient 13). This tumor contained mitotic figures and foci of necrosis, and recurred locally 20 months following initial resection when the ‘hepatic pattern' was no longer prominent. Another tumor manifested features of anaplasia, contain ing large, hyperchromatic. bizarre nuclei (patient 5). No mitotic figures were observed, nor was there necrosis or brain invasion and the patient is alive and free of disease 9 years after surgery. No pure papillary meningiomas were observed in our series. One meningioma had foci of papillary growth (pa tient 3). The tumor recurred soon after partial resection and RT. No further recurrence has been observed after a second radical surgical excision at 114 months from diag nosis. Cytogenetics Cytogenetic studies were performed on surgical speci mens from 5 of the 18 patients (see table 1, cases 13-16, and 20). Abnormal karyotypes were obtained in 3 tumors.
Perilongo/Sutton/Goldwein/Gusnard/ Schut/Biegcl/Rurke/Langc/D'Angio
Childhood Meningiomas
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4
dren being clustered together. Twelve of the 5i Mayo Clinic meningioma patients under 21 years of age [2] had evidence of NF, whereas there was only 1 among the 19 from the University of Rome [3], According to Deen et al. [2], patients with NF and meningiomas are similar to other children with meningiomas with respect to age at surgery, sex ratio and histologic subtype, except for tumor location. Their NF group had an increased incidence of Discussion spinal (5/12) and orbital nerve sheath (3/12) tumors. In Childhood meningiomas were more common in males our series, upper cervical meningiomas were seen in in our series. This differs from adult series, in whom patients with both types of neurofibromatosis, suggesting females predominate, but is in agreement with other that this site is not specific. While bilateral acoustic neuromas are the hallmark of pediatric series [3, 7], Congenital and infantile meningio mas were rare, and meningiomas became relatively more NF II. meningiomas and neurofibromas arc the next most common in adolescence. This suggests an increased inci frequent tumors encountered. Interestingly, specific loss of alleles from chromosome 22 have been detected in all dence with age. as has been noted by others [8, 9]. All 15 intracranial tumors we observed were located three types of tumors in patients with NF II, suggesting a supratentorially, confirming the rarity of posterior fossa common genetic mechanism [17]. In addition, loss of meningiomas in children [ 1-3 .7 , 10], No multiple menin chromosome 22 and, less frequently, deletion of the long arm of chromosome 22, have been consistently reported giomas were observed in our series. There have been no studies that specifically address in human meningioma cells [18.19], These studies hint at the radiographic findings of childhood meningiomas the presence of a meningioma tumor suppressor locus on since the advent of MR. Though the CT and MR features distal 22q, which may function in a fashion similar to the were variable in our series, they were similar to those retinoblastoma and Wilm's tumor genes. Most of these described in adults [11-14], Meningiomas on CT typi data have been accumulated from adult meningioma cally appear as well-defined, homogeneous, dense masses patients and to date, no correlation between the cytoge that abut the dura. They frequently are partially calcified netic findings and survival has been found. In the limited and are marginated by mild vasogenic edema in the number of childhood meningiomas studied in our institu underlying brain. Adjacent bony abnormalities consisting tion, involvement of chromosome 22, specifically loss of of hyperostosis, bony destruction or pressure erosion are all or part of 22. was seen in 3 patients. Clearly, a larger seen in 15-20% of cases. On MR. meningiomas typically number of tumors need lobe analyzed before any clinical appear isointense or nearly isointense to gray matter on implications of an abnormal karyotype can be drawn. The extent of surgical resection seems to be the most all pulse sequences, though a granular or whorled texture important prognostic factor for tumor control. The risk of may be seen on T1-weighted images. MR is more accurate than CT in confirming the extra-axial location of these recurrence after total gross removal has been reported to tumors, since it more sensitively demonstrates 'buckling' range from 4 to 9% in large series of pediatric and adult of the underlying white matter as well as displaced corti meningiomas [1.2. 20-22]. but in our series of pediatric cal veins or cerebrospinal fluid at the brain-tumor inter patients it was 33%. suggesting that pediatric meningio face. In our 16 patients with intracranial meningiomas, mas are potentially more aggressive than those seen in atypical radiographic manifestations were seen in 2: a pre adults. Subtotally resected tumors progress with even dominantly cystic tumor with small solid component, and greater frequency [3, 21], All 3 of our meningiomas of the skull base (2 cribriform plate. 1 sphenoid wing) relapsed, a totally intraparenchymal mass. Meningiomas are reported to be more common in as did one of the 2 that extended through the foramen patients with neurofibromatosis type II than in those with magnum to C1-C2. It is likely that the high relapse rate neurofibromatosis type I, and in this setting they tend to for meningiomas involving the skull base is at least in part occur in the posterior fossa or upper spinal region [15, related to the technical difficulties in obtaining complete 16]. In our series. 1 patient had the clinical findings of tumor removal. Recurrences following apparent total resection, and NF I. and 2 patients satisfied criteria for NF II. Even in recent reports of childhood meningiomas, no distinction the difficulty in achieving total excision of meningiomas is made between patients with NF I and II. the NF chil in some locations has prompted interest in the use of local
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Patient 14. who also had clinical manifestations of NF II. had tumor-specific loss of a chromosome 22 as the only abnormality. Tumors from patients 13 and 16 demon strated an abnormal chromosome 22 as well as additional numerical and structural changes.
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that had at least one of these features. Our numbers were too small to determine the prognostic significance of the individual histologic features. Thus, no firm conclusions on the relevance of those features can be drawn, but when they are documented, closer follow-up would seem pru dent. All but one of the recurring tumors in our series mim icked the histologic pattern originally noted at diagnosis.
Conclusions
Complete surgical excision of the tumor without mi croscopic residual is the most reliable method of achiev ing long-lasting control of childhood meningiomas. Rou tine postoperative RT should be deferred until tumor recurrence becomes apparent. It could then be used as an adjunct to surgery if reexcision seems incomplete. Delay in the use of radiation is particularly important in the young patient whose immature brain is especially vulner able to the deleterious secondary effects of RT. Our expe rience does not mandate the use of RT after partial tumor removal but it does demonstrate the effectiveness of this modality in slowing progression after early recurrence. The presence of necrosis, mitotic figures or histologic evidence of brain invasion does not warrant more radical treatment. Close follow-up under these circumstances, regardless of the completeness of the surgical resection, would nonetheless seem prudent. In contrast, papillary meningiomas and hemangiopericytomas of the meninges carry a dismal prognosis, and an aggressive surgical-radiotherapeutic attack is appropriate for these tumor types.
Perilongo/Sutton/Goldwein/Gusnard/ Schut/Biegel/Rorke/Langc/D'Angio
Childhood Meningiomas
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radiation therapy in this disease, but there have been no prospective randomized studies of the use of postopera tive RT in either adults or children. Viewed retrospective ly, the actuarial local control rates at 10 years are reported to be 77% for total excision alone, 82% for subtotal exci sion plus RT, and only 18% for subtotal excision alone [21], The benefit of RT at the time of recurrence nonethe less remains a controversial issue. Some authors have failed to demonstrate any benefit of RT at relapse [22], while others have reported a 43% 10-year actuarial sur vival for patients with recurrent meningiomas not irra diated and an 87% rate for the ones who had RT [21]. More recently, Glaholm et al. [10] claimed that patients treated with RT for recurrent meningioma fared as well as new patients when survival was measured from the time of first diagnosis [23]. Four of our patients received RT following reresection at their initial recurrence, and have remained without disease progression for a considerably longer time than their time to initial recurrence, suggest ing the effectiveness of RT in controlling recurrent dis ease. In the present series, the crude overall survival rate was 19/20 (95%) at a median follow-up of 5.8 years. The relapse rate, however, was 40%, which is similar to that reported in other pediatric series [1. 2], The outlook for children with these tumors is thus generally favorable, despite the frequency of local recurrence. Seven of the 8 patients in our series who relapsed have been salvaged by surgery and/or RT. The single patient who died suc cumbed to postoperative complications, not progressive disease. The relationship between histologic patterns of meningioma and biological behavior remains unclear. It has been reported that papillary meningiomas have an aggressive clinical course, and are capable of extracranial dissemination [24], In the Mayo Clinic experience, 4 of the 5 childhood meningiomas with the papillary pattern recurred, with a mean time to recurrence of 2 years, com pared with 9 years for all other histological types [2], Papillary meningioma occurs with particular frequency in the young. One of our patients had a focus of papillary growth within the meningioma without any other histo logical evidence of malignancy. There was rapid local recurrence despite initial partial resection and postopera tive RT. The patient remains free of disease for more than 9 years after a second operation. The fact that papillary histology is not incompatible with prolonged survival has also been pointed out by others [25]. The prognostic importance of necrosis within the tu mor, mitotic figures and brain tissue invasion is uncer tain. In the present series. 4 tumors recurred among the 8
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