Tumori

titolo=20 - split_articolo,controlla_titolo=20 - art_titolo

Gliosarcomas in the = elderly:=20 analysis of 7 cases and = clinico-pathological=20 remarks

autori=20 - vau_aut_id

Valerio=20 di Norcia, Manolo Piccirilli, Felice = Giangaspero,=20 Maurizio Salvati

affiliazione_autori - ignora

¹Department of = Neurosurgical=20 Sciences, Neurosurgery, Policlinico = Umberto I,=20 University of Rome
=E2=80=9CLa = Sapienza=E2=80=9D, Rome;=20 ²INM Neuromed, = Neurosurgery, Pozzilli=20 (IS), Italy

parolechiave - lingua - = vke_key_id

Key=20 words: = elderly, gliosarcomas, = multimodality=20 treatment, neurosurgery, survival. =

riassunto - art_riassunto

abstract

Aims=20 and background. Gliosarcomas are rare = malignant=20 primary brain tumors that usually affect = the fifth=20 or sixth decades of life. The purpose of = this=20 study was to describe our experience with = such=20 lesions in elderly patients and to = establish their=20 prognosis factors.

Methods. Between 1993 and 2001, 7 = patients=20 over 60 years of age were treated at our = institute=20 for cerebral gliosarcomas. All patients = underwent=20 surgery for total or at least sub-total = removal of=20 a neoplastic mass.

Results. Owing to poor clinical = conditions=20 (Karnofsky performance score =3D 40), one = patient=20 was not treated postoperatively. Remaining = patients were treated with whole-brain=20 radiotherapy, whereas concomitant = chemotherapy=20 (temozolomide) was administrated only to 4 = patients. Histological examination showed = the=20 prevalence of sarcomatous aspects in 3 = patients;=20 the gliomatous aspect prevailed in 4 = patients.=20

Conclusions. Sarcomatous aspects and=20 multimodality treatment (surgery, = radiotherapy and=20 chemotherapy) were associated with a = better=20 prognosis and showed in these elderly = patients a=20 trend similar to that of young=20 people.

testo -=20 art_testo

Introduction

Gliosarcomas are primary = cerebral=20 tumors characterized by a biphasic tissue = pattern=20 with areas of glial and mesenchymal=20 differentiation¹. Recently, genetic = studies=20 demonstrated a monoclonal origin for = gliosarcoma=20 cells and a mesenchymal phenotype = acquisition from=20 malignant astrocytes^2,3.

The=20 incidence of malignant brain tumors has = increased,=20 especially among the elderly population = (between=20 65 and 85 years of age)⁴. Nevertheless, elderly = patients are=20 often treated suboptimally, because of the = wide-spread opinion that these patients do = not=20 endure surgery and radiotherapy as well as = younger=20 people. Mangiola et=20 al.⁵ showed how age itself = should not be=20 considered a prognostic factor for = under-treatment=20 in the management of cerebral glial = neoplasms,=20 because the overall median survival after = surgery=20 in elderly people is similar to that of = other=20 patients.

We present=20 a series of 7 elderly patients affected by = gliosarcomas and treated in a = multimodality way:=20 surgical, therapeutic and prognostic=20 considerations are made.

Materials=20 and methods

Between=20 1993 and 2001, 7 patients over 60 years of = age=20 were treated at our institute for cerebral = gliosarcomas (Table 1). Their ages ranged = from 61=20 to 81 years (mean, 74), and the Karnofsky=20 Performance Scale (KPS) ranged from 40 to = 90=20 (mean, 74). Histological diagnosis was = made=20 following the criteria of Meis = et al.⁶: the tumor should be = bimorphic,=20 composed of an astrocytic malignant cell=20 population with areas of necrosis and = secondary=20 concomitant sarcomatous spindle cells = elements,=20 and confluent in at least one medium power = field.=20

Table=20 1 - Composition of the study=20 group

Case

Age=20 Sex

KPS

Location

Surgical

Histological

CHT

Concomitant

Recurrence

Reoperation

Survival

no.

-=20 size (cm)

resection

prevalence

RT/CHT

(wk)

65/M

F =E2=80=93=20 4.5

Yes

Progression

74/M

T =E2=80=93=20 3.2

Yes

Progression

61/F

T =E2=80=93=20 4

Yes

Yes=20 (71)

Yes

80/F

P =E2=80=93=20 3.7

Yes

Yes=20 (59)

77/M

F =E2=80=93=20 5.5

Yes

79/M

T =E2=80=93=20 3

Yes

Yes=20 (52)

Yes

81/M

O =E2=80=93=20 5.5

Progression

KPS,=20 Karnofsky performance scale; RT, = radiotherapy;=20 CHT, chemotherapy; F, frontal; T, = temporal; P,=20 parietal; O, occipital; ST, subtotal; T, = total;=20 G, gliomatous; S,=20 = sarcomatous.

Preoperative study was = managed with=20 magnetic resonance imaging (MRI). In all = patients,=20 early postoperative MRI was performed to = establish=20 the tumor resection degree: total removal = was=20 estimated when residual tumor was = <10%.=20

Postoperative radiotherapy = (60 Gy=20 with LINAC extended 2 cm beyond the edema = margins=20 for 6 weeks) was administrated (alone or=20 concomitant with chemotherapy) on the = average at=20 20 days from surgery in all patients = except one,=20 who had poor clinical conditions (KPS = <40) so=20 that no adjuvant postoperative treatment = was=20 administered.

Chemotherapy was given to = 4=20 patients: temozolomide, 75 = mg/m²/d concomitantly to = radiotherapy,=20 subsequently 200 mg/m²/d for 5 days every 28 = days until=20 disease progression.

Three=20 patients of our group did not receive=20 chemotherapy: one had a very low KPS, and = the=20 other 2 had severe thrombocytopenia = (45,000 and=20 50,000 per mm³). After discussion with = relatives=20 and the patients themselves about the = risks of=20 chemotherapy in such conditions, they = refused the=20 temozolomide administration.

Results=20

The study=20 group was composed by 5 males and 2 = females (M/F=20 ratio: 5/2), ranging in age from 61 to 81 = years=20 (median, 74). The preoperative KPS was 90 = for 2=20 patients, 80 for 4 and 40 for 1. MRI = showed=20 non-homogeneous lesions (average size, 4.2 = cm)=20 with marked enhancement after gadolinium=20 administration and perilesional edema; a=20 broad-dural-based involvement was evident = in 3=20 cases. Cerebral localization was frontal = in 2=20 cases (29%), parietal in 1 (14%), temporal = in 3=20 (43%) and occipital in 1 (14%). =

The=20 surgical procedure showed two types of = lesions:=20 one with well-demarcated margins and dural = involvement similar to an aspect of = meningioma (in=20 3 cases), and the other, necrotic and = infiltrating=20 like glioblastoma (in 4 cases). = Postoperative MRI=20 demonstrated the amount of tumor = resection,=20 showing total removal for 4 and sub-total = for 3=20 patients. Histological examination = confirmed that=20 the 3 lesions with a prevalence of = sarcomatous=20 components were those with radiological = and=20 intra-operative aspects resembling = meningiomas=20 (group S). The other 4 had more gliomatous = aspects=20 resembling glioblastomas at MRI and at = surgery=20 (group G).

Mean=20 survival in group S was 69.7 weeks and in = group G=20 was 52.5 weeks (Table 1). However, = survival=20 differed also with respect to type of = treatment:=20 one patient (group G, case 7), because of = poor=20 clinical conditions, had no additional = therapy=20 after surgery and had the worst prognosis = with=20 only 12 weeks of survival. Two patients = (group S,=20 cases 4 and 6) were treated = postoperatively with=20 radiotherapy alone and had a mean survival = of 63 =C2=B1=20 1 week. Four patients (group G, cases 1, 2 = and 5;=20 group S case 3) underwent concomitant = radiotherapy=20 and chemotherapy and showed the best = results in=20 terms of survival =E2=80=93 mean 70.2 = weeks.

The total=20 median recurrence rate was 60.8 weeks: = 60.7 in=20 group S and 61 in group G. A second = operation was=20 performed in 2 cases of group S who had a = total=20 resection at the first surgery and in = which a new=20 total removal was possible at the second=20 operation. One patient (case 5) was still = alive at=20 the follow-up 65 weeks after surgery, and = in 3=20 patients progression was associated with a = prevalent gliomatous aspect.

Discussion=20

Gliosarcoma is a rare = subtype of=20 glioblastoma multiforme that shows a = dimorphic=20 population of glial and mesenchymal = elements.=20 First described by Stroebe in = 1895⁷, it accounts for 1.8-8% = of=20 glioblastomas^8,9, with an incidence of one = new case=20 per million inhabitants¹⁰. It occurs mostly between = 40 and 60=20 years of age, and preferred sites of = localization=20 are temporal lobes, followed by parietal = and=20 frontal lobes^8,11. It is very rare in = younger people,=20 whereas it is increasingly more often = diagnosed in=20 the elderly, as are other malignant = cerebral=20 tumors⁴. More frequently than = gliomas,=20 gliosarcomas may metastasize to = extracranial=20 organs (lung, lymph nodes, pleura, bone = marrow,=20 liver)¹², as shown by Maiuri = et al.⁹, who recorded 15-30% of = metastasis=20 in their study group. Gliosarcomas, still = in=20 analogy with gliomas, may be = radio-induced, as=20 recently demonstrated^13,14.

Histogenesis hypothesises = affirm=20 that gliosarcoma is a malignant = transformation of=20 cells in blood vessels of a pre-existing=20 glioblastoma¹⁵, although recent genetic = studies=20 have shown a monoclonal origin of = sarcomatous and=20 gliomatous elements^16,17. Indeed, sarcomatous = cells appear=20 to derive from glial cells during tumor=20 progression, thereby sharing the same = genetic=20 aberration shown by Biernat et al.² for p53 = mutationand by Reis et al.¹⁸ for p16 deletion and = PTEN=20 mutation.

In our=20 study group, we were able to identify two=20 subgroups: some patient lesions showed = features=20 similar to those of meningiomas at MRI = (marked=20 diffused enhancement after gadolinium=20 administration, well-defined peripheral = margin),=20 designated as group S, whereas others = resembled=20 high-grade gliomas (ring-shaped = enhancement,=20 necrotic areas, barely distinguishable = margins),=20 designated as group G. These radiological = findings=20 were matched with postsurgical = histological=20 findings: group S had a prevalence of = sarcomatous=20 elements in contrast to group G, in which = a=20 predominance of gliomatous cells was = observed.=20

In the=20 literature, the average survival is = estimated to=20 be less than one year^8,17. As already shown in other = studies^9,19, we also found a better = prognosis=20 for lesions with a prevalent sarcomatous = component=20 and with radiological and surgical aspects = of=20 meningioma. All the patients with these = features=20 in our study group survived for more than = a year=20 and benefited from the multimodality = treatment=20 (case 3 obtained the best result and = survived for=20 83 weeks). Indeed, not only a radical=20 cytoreduction seems to be of critical = importance=20 for the prognosis of these patients, but = also the=20 possibility to perform postoperative = radiotherapy=20 and chemotherapy drastically influences = the=20 survival rate. In our series, patients of = group S=20 who were not treated with postoperative=20 radio-chemotherapy had survival rates = similar to=20 those of group G who were received a = multimodality=20 treatment. These data suggest the = importance of=20 the adjuvant postoperative therapeutic = route not=20 only for patients of group G, but also for = those=20 of group S for whom, once a multimodal = treatment=20 is established, the best results in terms = of=20 survival can be reached (case 3). =

We thus=20 consider glioblastoma and gliosarcoma in = the same=20 way as regards the therapeutic choice: = first=20 surgery, supported by functional and = spectroscopic=20 MRI pre-operatively and intraoperative=20 neuronavigation with functional mapping, = for an=20 as-radical-as-possible cytoreduction; = early=20 postoperative (within 24 h) MR = investigation to=20 evaluate residual tumor; 20-40 days later, = radiation treatment with conformational = techniques=20 using LINAC for a total of 60 Gy, = irradiating 2 cm=20 over the borders of the lesion; = chemotherapy with=20 temozolomide concomitantly with = radiotherapy.=20

For the=20 latter step, there is some controversy in = the=20 literature. It is unknown whether = gliosarcomas=20 respond to sarcoma-based = chemotherapy^6,8,17, whereas the role of = temozolomide=20 is uncertain²⁰. It is used because of = the glial=20 origin of these lesions, and only Morantz=20 et = al.²¹ noted a modest increase = in terms of=20 survival using this therapeutic protocol = compared=20 with a control group treated only by = radiation (36=20 vs 33 weeks of = survival). In our=20 series, we found positive results using=20 chemotherapy not only for group G but also = for=20 group S, which suggests a therapeutic = effect also=20 in lesions with a prevalence of = sarcomatous=20 components. However, more data are = necessary to=20 establish the correlation between survival = rates=20 and temozolomide administration in these = patients.=20

We found=20 no difference in survival rate in our = elderly=20 group compared to younger study groups = when a=20 complete therapeutic strategy could be = performed.=20

According=20 to that observed by Mangiola et al.⁵ for glioblastomas, we = found that age=20 itself was not a prognostic factor, = whereas more=20 important for outcome were clinical and=20 neurological pre-operative conditions (KPS = score).=20 Indeed, as for younger patients affected = by=20 gliosarcomas, higher KPS allow = multimodality=20 treatment, and the possibility of = postoperative=20 radiotherapy and chemotherapy = administration is=20 the most valuable prognostic factor. When = the KPS=20 did not allow adjuvant treatment other = than=20 surgery, we observed the worst results = (case 7),=20 whereas when the KPS permitted = multimodality=20 treatment, especially for group S, we = obtained the=20 best results (case 3). Of course, in our = series=20 too radical a surgery (cytoreduction = >90%)=20 dramatically increased the median survival = rate,=20 which demonstrated it to be another = primary=20 prognostic factor.

Conclusions

As for=20 other younger patients, in the elderly it = is also=20 possible to identify two subtypes of = gliosarcomas=20 that correspond to two different = prognostic groups=20 of patients: lesions with a predominance = of=20 sarcomatous components are associated to a = better=20 prognosis, whereas the prognosis worsens = when a=20 predominance of gliomatous elements is = identified.=20 Moreover, the most important predictive = factors=20 are the entity of surgical removal of the=20 neoplastic mass and the possibility to = administer=20 postoperative adjuvant therapy = (radio- and=20 concomitant chemotherapy). Age itself is = not a=20 prognostic factor when the KPS allows = total=20 surgical removal and multimodality = treatment.=20

biblio_titolo=20 - ignora

References

bibliografia - art_bibliografia

=E2=80=821.=20 Salvati M, Caroli E, Raco A, Giangaspero = F,=20 Delfini R, Ferrante L: Gliosarcomas: = analysis of=20 11 cases. Do two subtypes exist? J = Neuro-Oncol,=20 74: 59-63, 2005.

=E2=80=822.=20 Biernat W, Aguzzi A, Sure U, Grant JW, = Kleihues P,=20 Hegi ME: Identical mutation of p53 tumor=20 suppressor gene in the gliomatous and = sarcomatous=20 components of gliosarcomas suggest a = common origin=20 from glial cells. J Neuropathol Exp = Neurol, 54:=20 651-656, 1995.

=E2=80=823.=20 Boerman RH, Anderl K, Herath J, Borrel T, = Johnson=20 N, Schaeffer-Klein J, Kirchhof A, Raap AK, = Scheitauer BW, Jenkins RB: The glial and=20 mesenchymal elements of gliosarcomas share = similar=20 genetic alterations. J Neuropathol Exp = Neurol, 55:=20 973-981, 1996.

=E2=80=824.=20 Chinot OL, Barrie M, Frauger E, Doufour H, = Figarella-Brager D, Palmari J, Brauger D,=20 Hoang-Xuan K, Moktari K, Peragut JC, = Martin PM,=20 Grisoli F: Phase II study of temozolomide = without=20 radiotherapy in newly diagnosed = glioblastoma=20 multiforme in an elderly population. = Cancer, 100:=20 2208-2214, 2004.

=E2=80=825.=20 Mangiola A., G. Maira, P. De Bonis, M. = Porso, B.=20 Pettorini, G. Sabatino, Anile C: = Glioblastoma=20 multiforme in the elderly: a therapeutic=20 challenge. J Neuro-Oncol, 76: 159-163, = 2006.=20

=E2=80=826.=20 Meis JM, Martz KL, Nelson JS: Mixed = glioblastoma=20 multiforme and sarcoma. A = clinicopathologic study=20 of 26 radiation therapy oncology group = cases.=20 Cancer, 7: 2342-2349, 1991.

=E2=80=827.=20 Stroebe H: Uber entstehung und bau der = hirngliome.=20 Beitr Pathol Anat, 18: 405-486, 1895.=20

=E2=80=828.=20 Galanis E, Buckner JC, Dinapoli RP, = Scheithauer=20 BW, Jenkis RB, Wang CH, O=E2=80=99Fallon = JR, Farr G Jr:=20 Clinical outcome of gliosarcoma compared = with=20 gliosarcoma multiforme: North Central = Cancer=20 Treatment Group results. J Neurosurg, 89: = 425-430,=20 1998.

=E2=80=829.=20 Maiuri F, Stella L, Benvenuti D, Giamundo = A,=20 Pettinato G: Cerebral gliosarcomas: = correlation of=20 computed tomographic findings, surgical = aspect,=20 pathological features and prognosis. = Neurosurgery,=20 26: 261-267, 1990.

10.=20 Lantos PL, Vandenberg SR, Kleihues P: = Tumours of=20 the Nervous System. In: = Greenfield=E2=80=99s=20 Neuropathology, Graham DI, Lantos PL = (Eds), pp=20 583-879, Edward Arnold, London, 1996.=20

11.=20 Ohgaki H, Biernat W, Reis R, Hegi M, = Kleihues P:=20 Gliosarcoma. In: Pathology and genetics of = tumours=20 of the the nervous system, Kleihues P., = Cavenee WK=20 (Eds.), pp. 42-44, IARC Press, Lyon, 2000. =

12.=20 Witwer BP, Salamat MS, Resnick DK: = Gliosarcoma=20 metastatic to the cervical spinal cord: = case=20 report and review of the literature. Surg = Neurol,=20 54: 373-379, 2000.

13.=20 Salvati M, Frati A, Russo N, Caroli E, = Polli FM,=20 MinnitiG, Delfini R: Radiation-induced = gliomas:=20 report of 10 cases and review of the = literature.=20 Surg Neurol, 60: 60-67, 2003. =

14.=20 Sarkar C, Sharma MC, Sudha K, Gaikwad S, = Varma A:=20 A clinico-pathological study of 29 cases = of=20 gliosarcoma with special reference to two = unique=20 variants. Indian J Med Res, 106: 229-235, = 1997.=20

15.=20 Feign I, Allen LB, Lipkin L, Groos SW: The = endothelial hyperplasia of the cerebral = blood=20 vessels within brain tumors and its = sarcomatous=20 transformation. Cancer, 11: 264-277, 1958. =

16.=20 Jones H, Steart PV, Weller RO: Spinal cell = glioblastoma or gliosarcoma? Neuropathol = Appl=20 Neurobiol, 17: 177-187, 1991. =

17.=20 Meis JM, Ho KL, Nelson JS: Gliosarcoma: a=20 histologic and immunohistochemical = reaffirmation.=20 Mod Pathol, 3: 19-24 1990.

18.=20 Reis RM, K=C3=B6n=C3=BC-Lebleblicioglu D, = Lopes JM, Kleihues=20 P, Ohgaki H: Genetic Profile of = Gliosarcomas. Am J=20 Pathol, 156: 2000: 425-432.

19.=20 Parekh HC, Keogh AJ: Primary cerebral = gliosarcoma:=20 report of 17 cases. Br J Neurosurg, 9: = 171-178,=20 1995.

20.=20 Woll PJ, Judson I, Lee SM, Rodenhuis S, = Nielsen=20 OS, Buesa JM, Lorigan PC, Leyvraz S, = Hermans C,=20 van Glabbeke M, Verweij J: Temozolomide in = adult=20 patients with advanced soft tissue = sarcoma: a=20 phase II study of the EORTC soft tissue = and bone=20 sarcoma group. Eur J Cancer, 35: 410-412, = 1999.=20

21.=20 Morantz RA, Feigin I, Ransohoff J: = Clinical and=20 pathological study of 24 cases of = gliosarcoma. J=20 Neurosurg, 45: 398-408, 1976. =