Tumori

titolo=20 - split_articolo,controlla_titolo=20 - art_titolo

Extra=20 central nervous system metastases from = cerebral=20 glioblastoma multiforme in elderly = patients.=20 Clinico-pathological remarks on our series = of=20 seven cases and critical review of the=20 literature

autori=20 - vau_aut_id

Manolo=20 Piccirilli, Giacoma Maria Floriana = Brunetto,=20 Giovanni Rocchi, Felice Giangaspero, = Maurizio=20 Salvati

affiliazione_autori - ignora

¹Department of Neurological=20 Sciences-Neurosurgery, and ²Department of Experimental = Medicine=20 and Pathology, University of Rome = =E2=80=9CSapienza=E2=80=9D,=20 Rome; ³Neurosurgery, INM-Neuromed, = Pozzilli=20 (IS), Italy

parolechiave - lingua - = vke_key_id

Key=20 words: = elderly patients, = glioblastoma=20 multiforme, metastases

riassunto - art_riassunto

abstract=20

Aims=20 and background.=20 The aim of the = study was=20 to evaluate the treatment of the = extracranial=20 metastases from glioblastoma multiforme in = the=20 elderly, discussing their uncommon = occurrence and=20 their pathogenesis.

Methods.=20 The authors = report seven=20 cases of elderly patients (mean age, 69 = years),=20 with an initial diagnosis of cerebral = glioblastoma=20 multiforme, treated by a grossly total = surgical=20 removal and followed by adjuvant = radiotherapy (64=20 Gy in 6 weeks, using Linac) and adjuvant=20 chemotherapy (temozolomide both = concomitant and=20 sequential to radiotherapy).

Results. All patients presented = a=20 postoperative course characterized by good = functional and clinical conditions = (Karnofsky=20 performance scale =E2=89=A570), which = remained unchanged=20 for a mean period of about 21 months = (range,=20 16-23), with no neuroradiological signs of = lesion=20 regrowth. After this interval, new = clinical signs=20 occurred, and their clinical and = radiological=20 investigation showed metastatic = repetitions in=20 different sites: lung, liver, humerus and = lymph=20 nodes. All the metastases were surgically = treated,=20 but regrowth of the brain tumor and = progression to=20 deep important neural structures caused = the=20 patients=E2=80=99 exitus after a mean = interval of about 10=20 months (range, 8-12) from the diagnosis of = metastasis.

Conclusions. We found=20 128 cases of extra CNS metastases in the = English=20 literature. The main features of the = patients of=20 the previous reports and of those of the = present=20 series were analyzed. The main modalities = of=20 glioblastoma multiforme spread, the few = theories=20 about the rarity of metastasis, and the = probable=20 biological, histological and immunogenetic = mechanisms involved in the pathogenesis = are=20 described. Although several studies have = reported=20 a poor outcome in elderly patients, they = affirm=20 that the treatment of those with a = Karnofsky=20 performance status >60 should be just = as=20 aggressive as in younger patients. This = allows=20 them to obtain a longer survival time and = to also=20 treat metastases, which are uncommon = particularly=20 in the elderly.

testo -=20 art_testo

Introduction=20

Glioblastoma=20 multiforme (GBM) is a highly malignant = glioma with=20 a low potential to metastasize outside the = confines of the central nervous system. = Although=20 the rarity of this condition is well = documented in=20 the literature, patients now have a longer = survival than in the past due to = improvement in=20 treatment modalities (Figures 1-2). Thus, = we can=20 note a significant increase in the = incidence of=20 GBM cases with extracranial repetitions. = The first=20 documented metastatic glial tumor was = described by=20 Davis in 1928¹=20 under the diagnosis of spongioblastoma = multiforme.=20 If we consider that the reported frequency = of=20 extraneural metastases was 0.44% in=20 1966²,=20 we can point out a sensitive increase = until the=20 present value of about 2%³.=20

We present 7=20 cases of GBM in elderly patients with = distant=20 metastases to the lung, liver, arm and = lymph=20 nodes. The potential pathogenetic = mechanisms, the=20 main routes of spread to extracranial = sites, and=20 the problems related to treatment in = elderly=20 patients are discussed.

Materials=20 and methods

Case 1. A=20 66-year-old man presented a right frontal = lobe=20 lesion, which histologically proved to be = a GBM.=20 Gross total removal of the tumor was = performed.=20 The patient underwent adjuvant = radiotherapy (64 Gy=20 in 6 weeks using Linac) and adjuvant = chemotherapy=20 with the administration of temozolomide, = first=20 concomitantly to radiotherapy (75 = mg/m²/die), then sequentially = (200=20 mg/m²/die for 5 days in each = cycle of 28=20 days, for 6 cycles).

MRI-imaging=20 follow-up at 16 months did not reveal any = signs of=20 local recurrence, the Karnofsky = performance status=20 (KPS) was 80, but the patient started to = present=20 hemoptysis and cough. He was thus studied = with a=20 thoracic CT scan that revealed a left = apical lung=20 lesion. The patient underwent a lung = lobectomy.=20 The histological examination showed the = same=20 features of the primary tumor, and a = diagnosis of=20 GBM metastatic lesion was made. A = whole-body CT=20 scan did not evidence additional lesions. = Six=20 months later the primary brain tumor = presented a=20 regrowth located in the corpus callosum = and=20 central ganglia; his conditions = deteriorated and=20 he died after 3 months (Table 1).=20

Table 1=20 - Our case=20 series

Case No., age, sex=20

GBM localization=20

Metastatic localization, and = time of=20 occurrence (mo) =

CNS GBM progression = from=20 diagnosis of metastasis (mo) =

Death of the patient = after CNS=20 progression (mo) =

Overall survival=20 (mo)

Case 1, = 66,=20 M

R frontal = lobe

Lung, = 16

Case 2, = 74,=20 F

R temporal = lobe

Liver, = 18

Case 3, = 67,=20 F

L frontal = lobe

Humerus, 19

Case 4, = 72,=20 M

R occipital=20 lobe

Lung, = 21

Case 5, = 63,=20 M

R temporal = lobe

Lung, = 19

Case 6, = 70,=20 F

R frontal = lobe

Lymph nodes, 20 =

Case 7, = 69,=20 M

R temporal = lobe

Lung, = 23

R, right; L,=20 = left.

Case=20 2. A = 74-year-old woman=20 was treated for a right temporal lobe GBM. = A=20 craniotomy was performed, followed by a = grossly=20 total resection. She was given adjuvant=20 radiotherapy (64 Gy in 6 weeks using = Linac) and=20 adjuvant chemotherapy with temozolomide, = first=20 concomitantly to radiotherapy (75 = mg/m²/die), then sequentially = (200=20 mg/m²/die for 5 days in each = cycle of 28=20 days, for 6 cycles).

The=20 postoperative course was uneventful, the = KPS was=20 80, but 18 months later she presented = icterus.=20 Serum tests revealed increased = pathological levels=20 of bilirubin and gGT.=20 Abdominal CT scan demonstrated the = presence of an=20 hepatic mass, which was surgically = removed.=20 Histological examination confirmed the = diagnosis=20 of metastatic GBM. A whole-body CT scan = did not=20 reveal the presence of other metastatic = lesions. A=20 brain MRI performed 6 months later showed = regrowth=20 of the lesion, involving the deep = structures. The=20 patient died 2 months later (Table 1).=20

Case=20 3. A = 67-year-old man=20 underwent surgery with grossly total = removal of a=20 left frontal lobe GBM. He underwent = adjuvant=20 radiotherapy (64 Gy in 6 weeks using = Linac) and=20 adjuvant chemotherapy with temozolomide, = first=20 concomitantly to radiotherapy (75 = mg/m²/die), then sequentially = (200=20 mg/m²/die for 5 days in each = cycle of 28=20 days, for 6 cycles). He had a stable = postoperative=20 course and no other clinical events for 19 = months,=20 with a KPS of 80.

After this=20 period, he experienced a pain which = irradiated to=20 the right arm. CT scan demonstrated the = presence=20 of a lesion in the right humerus that was = removed=20 by surgical excision. The histologic = diagnosis was=20 GBM metastasis. Whole-body CT scan did not = report=20 other different metastases. Eight months = later,=20 the original tumor showed regrowth with=20 progression to deep structures, and the = patient=20 died after 3 months (Table 1).=20

Case 4. A=20 72-year-old man was admitted for a right = occipital=20 GBM (Figures 3-6), and a grossly total = excision=20 was performed (Figures 7-8). He underwent = adjuvant=20 radiotherapy (64 Gy in 6 weeks using = Linac) and=20 adjuvant chemotherapy with temozolomide, = first=20 concomitantly to radiotherapy (75 = mg/m²/die), then sequentially = (200=20 mg/m²/die for 5 days in each = cycle of 28=20 days, for 6 cycles). His clinical = situation=20 remained stable as the MRI follow-up = confirmed,=20 with a KPS of 80. However, 21 months later = he=20 developed hemoptysis and cough, which was = studied=20 by a thoracic CT scan. A neoplastic lesion = was=20 found in the left lung (Figures 9 A-B). A=20 lobectomy was performed, and histology = showed the=20 features of a GBM metastasis. Whole-body = CT scan=20 did not reveal other metastases. After 7 = months=20 his clinical conditions worsened because = of brain=20 tumor regrowth involving important deep=20 structures. The patient died 3 months = later (Table=20 1).=20

Case 5. A=20 63-year-old man was treated by grossly = total=20 resection of a right temporal lobe GBM. He = underwent adjuvant radiotherapy (64 Gy in = 6 weeks=20 using Linac) and adjuvant chemotherapy = with=20 temozolomide, first concomitantly to = radiotherapy=20 (75 mg/m²/die), then sequentially = (200=20 mg/m²/die for 5 days in each = cycle of 28=20 days, for 6 cycles). The postoperative = course was=20 uneventful with no other clinical = manifestations=20 for 19 months, with a KPS of 80. After = this=20 period, he began to experience hemoptysis = and=20 cough. A thoracic CT scan demonstrated a=20 neoformation in the apical pulmonary lobe. = The=20 patient underwent a lung lobectomy, and = the=20 histological diagnosis was a GBM = repetition.=20 Whole-body CT scan did not show any = metastatic=20 lesions in other tissues. Eight months = later, the=20 original tumor had regrown and reached = important=20 deep structures. The patient died in only = 2 months=20 (Table 1).

Case 6. A=20 70-year-old woman required radical = surgical=20 removal of a right frontal GBM. The woman=20 underwent adjuvant radiotherapy (64 Gy in = 6 weeks=20 using Linac) and adjuvant chemotherapy = with=20 temozolomide, first concomitantly to = radiotherapy=20 (75 mg/m²/die), then sequentially = (200=20 mg/m²/die for 5 days in each = cycle of 28=20 days, for 6 cycles). Her overall condition = remained unchanged for 20 months, with a = KPS of=20 80. After this period, a tumefaction = appeared in=20 the lateral-cervical lymph nodes. A biopsy = subsequently showed metastatic GBM. = Whole-body CT=20 scan did not show any other tumor lesions. =

A tumor=20 regrowth in the frontal region made a = second=20 craniotomy necessary. The excision was = grossly=20 total, but after 8 months, deeper = structures were=20 involved. The patient died 2 months later = (Table=20 1).

Case 7. A=20 69-year-old man was admitted for the = surgical=20 treatment of a cerebral tumor localized in = the=20 right temporal lobe. A grossly total = excision was=20 performed, and the diagnosis established = the=20 presence of a GBM. The man underwent = adjuvant=20 radiotherapy (64 Gy in 6 weeks using = Linac) and=20 adjuvant chemotherapy with temozolomide, = first=20 concomitantly to radiotherapy (75 = mg/m²/die), then sequentially = (200=20 mg/m²/die for 5 days in each = cycle of 28=20 days, for 6 cycles). Postoperatively, = there were=20 no complications; KPS was 80. After a = period of 23=20 months, the patient manifested hemoptysis = and=20 cough. Thoracic CT scan showed a pulmonary = lesion=20 in the apical area of the left lung. The = whole=20 pulmonary lobe was surgically removed. The = histological diagnosis was GBM metastasis. = A=20 whole-body CT scan did not show any other=20 metastatic lesions.

The right=20 temporal lobe was again involved by tumor=20 regrowth, which was treated by a second = craniotomy=20 and a new surgical removal. Nine months = later the=20 tumor showed progression to deep = structures, and=20 exitus occurred after 3 months (Table 1).=20

Literature=20 review

In the=20 English literature, to the best of our = knowledge,=20 128 cases of extra CNS metastases from GBM = have=20 been reported, including our series (Table = 2^{1,2,4,5-14,25-99}). Of these, we know the age = of 127=20 patients, the sex of 123, and the survival = of 103.=20 There were 82 males and 41 females (M/F = ratio, 2:=20 1). The average age at GBM diagnosis was = 40 years=20 (range, 3-74; Table 3). The mean overall = survival=20 was 17 months (range, 1-60; Figure 1). = Twenty-one=20 cases were reported from 1928 to 1967, and = 107=20 from 1968 to 2006 (Table 3).=20

Table 2 - Division of = the=20 patients according to the period of = diagnosis=20 (1928-1967 and 1968-2006), sex and=20 age=20

Total period =

(1928-2006)

Period 1

(1928-1967)

Period 2

(1968-2006)

No. of = cases

128

107

Sex

Male

67%

57%

69%

Female

33%

43%

31%

Mean

age, = yr

40 (range,=20 3-74)

34 (range,=20 6-61)

42 (range,=20 = 3-74)

Table 3 - = Literature=20 review of studies of extra central nervous = system=20 metastases from glioblastoma =20 = multiforme=20

Case = No.

Investigator(s)

Patient=E2=80=99s

age, = sex

Site

Survival from = primitive GBM=20 (mo)=20

=20

Davis¹

31,=20 F

R Arm, L lung, R = scapula,=20 ribs

Kohlmeier²⁵

38,=20 M

Lung, = pleura

Brandt²⁶

53,=20 M

Lung, = kidney

Nowotny²⁷

33,=20 F

L retroauricular and = cervical=20 lymph nodes =

Cross²⁸ = and Cooper=20 Case 2 (1958)

20,=20 M

Lungs, orbit, = abdominal=20 wall

Zeitlhofer²⁹

40,=20 F

Retroauricular and cervical. Lymph=20 nodes =

Wolf³⁰

14,=20 F

Lungs,=20 pleura, ribs,=20 vertebra, sternum,=20 mediastinum, =

para-aortic lymph=20 nodes

Gropp³¹

48,=20 M

Heart (R=20 ventricle)

Bogdanovich³²

61,=20 F

Lungs

Dewart³³ = or=20 Thiry³⁴

57,=20 F

Liver

>60

Ehrenreich³⁵ or=20 Feigin case = 8=20 (1958)

44,=20 M

R = Lung

Feigin³⁶ = case 12=20 (1958)

6,=20 M

L = Lung

Garret³⁷

55,=20 F

Cervical lymph nodes=20

Giok³⁸

25,=20 F

Lungs

Grampa³⁹

40,=20 M

L = kidney

Brodskaia⁴⁰

24,=20 M

L supraclavicular = and cervical=20 lymph nodes =

Ley⁴¹ case = 2=20 (1961)

22,=20 M

Cervical lymph=20 nodes

Labitzke⁴² = or Smith=20 case 9 (1969)

21,=20 M

Lung, paratracheal, = hilar and cervical = lymph=20 nodes =

Nigogosyan⁴³ case 1=20 (1962)

40,=20 M

Lungs, vertebra, = sternum, lymph=20 nodes =

Schejbal⁴⁴

9,=20 F

R cervical lymph=20 nodes

Wisiol=20 et = al.⁴⁵

31,=20 M

Vertebra,=20 acetabula

Smith⁴⁶ = case 1=20 (1969a)

52,=20 M

Lung, mediastinal lymph=20 nodes

Smith⁴⁶ = case 2=20 (1969a)

38,=20 M

Hilar lymph = nodes

Smith⁴⁶ = case 3=20 (1969a)

24,=20 M

Lung

Smith⁴⁶ = case 4=20 (1969a)

43,=20 M

Liver =

Smith⁴⁶ = case 5=20 (1969a)

45,=20 M

Liver

Smith⁴⁶ = case 6=20 (1969a)

6,=20 M

L = lung

Smith⁴⁶ = case 7=20 (1969a)

58,=20 M

Liver

Smith⁴⁶ = case 8=20 (1969a)

29,=20 M

Lung, periaortic and = cervical=20 lymph nodes =

Smith⁴⁶ = case 10=20 (1969a)

55,=20 M

Ribs

Smith⁴⁶ = case 11=20 (1969a)

54,=20 M

Lung

Smith⁴⁶ = case12=20 (1969a)

45,=20 M

Cervical lymph=20 node

Smith⁴⁶ = case13=20 (1969a)

36,=20 M

Vertebrae, acetabulum

Smith⁴⁶ = case14=20 (1969a)

63,=20 M

Lung, liver, adrenal=20 gland

Smith⁴⁶ = case15=20 (1969a)

44,=20 M

Liver

Smith⁴⁶ = case 16=20 (1969a)

49,=20 M

Liver, pancreas, = cervical lymph=20 nodes, sternum =

Smith⁴⁶ = case 17=20 (1969a)

42,=20 M

Lungs, cervical lymph = nodes

Smith⁴⁶ = case 18=20 (1969a)

63,=20 F

Lungs,=20 vertebrae

(T10-11) =

Smith⁴⁶ = case19=20 (1969a)

42,=20 F

Cervical lymph=20 node

Smith⁴⁶ = case 20=20 (1969a)

38,=20 M

Lung, pleura, hilar lymph=20 nodes =

Smith⁴⁶ = case 21=20 (1969a)

36,=20 F

Ribs, vertebrae, = cervical and=20 mediastinal = lymph=20 nodes =

Smith⁴⁶ = case 22=20 (1969a)

64,=20 M

Liver, = lung

Smith⁴⁶ = case 23=20 (1969a)

36,=20 M

Vertebrae

Anzil⁴⁷

54,=20 F

Liver,=20 vertebra (T11)

Dalla=20 Pria⁴⁸

40,=20 F

R=20 arm, R. = haunch

Dalmer⁴⁹

39,=20 M

Cervical lymph=20 nodes

Wakamatsu^50,51

22,=20 M

R lung, pleurae, = pericardium,=20 diaphragm

Komatsu^52,53

18,=20 F

L cervical lymph=20 nodes

Dolman⁵⁴

35,=20 F

L intraparotid lymph = nodes

Johnson⁵⁵

46,=20 M

Lungs, hilar lymph nodes, = liver =

Nikkanen⁵⁶

12,=20 F

Lungs, skeleton, = cervical lymph=20 nodes =

Yao⁵⁷

18,=20 M

Lung, thyroid gland, = neck,=20 paratracheal =

=20

and mediastinal lymph=20 nodes

Hulbanni⁵⁸

63,=20 M

R lung, bronchial = lymph nodes,vertebra =

Montaut⁵⁹ = case1=20 (1976)

23,=20 M

Lungs, liver, = cervical lymph=20 nodes =

Schuster⁶⁰ = case 6=20 (1976)

20,=20 M

L cervical lymph=20 nodes

Schuster⁶⁰ = case 7=20 (1976)

55,=20 M

R cervical lymph=20 nodes

Russell⁶¹

25,=20 M

Lungs, pleurae, = pericardium, L.=20 pulmonary hilar lymph=20 nodes =

>60

Russell⁶¹

70,=20 F

Pleurae,=20 pericardium

Russell⁶¹

3,=20 F

Lungs, pleurae, = pulmonary hilar lymph=20 nodes =

Russell⁶¹

7,=20 F

Liver, adrenal = medulla, hilar lymph nodes, = pleurae,=20 vertebra =

Russell⁶¹

16,=20 F

R Pleurae, = peritoneum,=20 diaphragm, lumbar region

O=E2=80=99Connor⁶²

53,=20 F

L supraclavicular = lymph nodes,=20 pleura =

Terheggen⁴

12,=20 M

Bone marrow, pubic = and ischiac bones, L=20 ileum =

Pasquier⁶³

21,=20 F

Liver, L submandibular = lymph=20 nodes =

Slowik⁶⁴ = case 1=20 (1980)

Bones, soft tissues, = sinus=20 vertebrae

Slowik^{64 =}case 2=20 (1980)

Bones, soft tissues, = sinus=20 vertebrae =

Slowik⁶⁴ = case 3=20 (1980)

Bones, soft tissues, = sinus=20 vertebrae =

Slowik⁶⁴ = case 4=20 (1980)

Bones, soft tissues, = sinus=20 vertebrae =

Mousavi⁶⁵

55,=20 F

Bone marrow,=20 liver

Dietz⁶⁶

24,=20 M

Thoracic vertebrae,=20 sternum

Yung⁶⁷ = case 1=20 (1983)

57,=20 M

Bone marrow, L femur, = R=20 sacroiliac joint, ribs, R humerus, = pleura =

Yung⁶⁷ = case 2=20 (1983)

24,=20 F

Bone marrow =

Sadik⁶

48,=20 M

Lumbar = vertebra

Steinbok⁶⁸

27,=20 F

Cervical lymph nodes=20

Wakabayashi⁶⁹

43,=20 M

Peritoneal=20 cavity

Yokoyama¹⁴

22,=20 F

Hilar lymph nodes, lung, = pleura,=20 sternal bone = marrow,=20 liver =

Ogata A⁷=20 ⁰

68,=20 M

Lungs, bronchial = lymph nodes,=20 liver, kidney, heart, spleen =

Trattnig = S⁷¹

29,=20 M

Cervical lymph nodes, = bones

Gamis²

11,=20 F

Thoracic bones, humerus, calvarium, facial = bones,=20 mandible,

=20

femurs, tibias, = pelvis,=20 shoulders, manubrium,=20 L iliac crest,

=20

ankles, L = foot

Newton⁷² = case=20 1(1992)

13,=20 M

Peritoneal cavity, = omental

Newton⁷² = case 2=20 (1992)

9,=20 F

Peritoneal cavity, = omental

Zappia⁷³

39,=20 M

Submandibular, jugulodigastric, = deep=20 cervical,

parotid chains lymph = nodes=20

Malca⁷⁴

46,=20 M

Thoracic, lumbar and = sacral=20 vertebrae, ileum, femur, ribs,=20 pleurae =

Chesnut⁷⁵

42,=20 M

Cervical=20 vertebrae

Gonzales=20 Campora⁷⁶

47,=20 M

Cervical and supraclavicular = lymph=20 nodes =

Minami⁷⁷

9,=20 M

Meninges,=20 spinal metastases

Mihara⁷⁸

35,=20 F

Vertebra=20 (T1)

Shuto⁷⁹

42,=20 F

Liver, = skull

Granjon⁸⁰

50,=20 M

Parotid gland, lung, = pleura,=20 endobronchial=20 masses =

Jonas⁸¹

48,=20 F

Liver

Vural, Hagmar⁸ = case 1=20 (1996)

40,=20 M

R side of = neck

Wallace⁹ = case 1=20 (1996)

41,=20 M

Neck, cervical and = supraclavicular = lymph nodes,=20

=20

extraocular muscle, R = eye

Wallace⁹ = (1996) case=20 2

39,=20 M

R orbit, preauricular lymph = nodes =

Al-Rikabi⁸²

4,=20 M

L cervical lymph=20 nodes

Fecteau⁸³

18,=20 F

Omentum, stomach, abdominal = wall,=20 pelvis =

Greif⁸⁴

51,=20 M

Pleurae, lungs,=20 liver

Datta⁸⁵

35,=20 F

R cervical lymph=20 nodes

Waite⁸⁶

40,=20 M

L=20 parotid = region

>24

Frappaz⁸⁷

52,=20 M

L=20 ribs, lumbar vertebra, R = lung

100

Widjaja⁸⁸

58,=20 M

Liver, = spleen

101

Beauchesne⁷

54,=20 M

Dorsolumbar vertebrae, iliac = bone, lung,=20 heart

102

Park¹² = case 1 (2000)=20

31,=20 M

Vertebrae, humerus

103

Park CC, Hartmann C=20

31,=20 M

Neck, = pelvis

et = al.¹² case 2 = (2000)

104

Park¹² = case 3=20 (2000)

27,=20 M

R = lung

105

Park¹² = case 4 (2000)=20

25,=20 F

Parotid gland,=20 neck

106

Park¹² = case 5 (2000)=20

60,=20 M

Hip, cervical=20 vertebrae

107

Laraqui⁸⁹

40,=20 M

Lung, endobronchial=20 masses

108

Hata = N⁹⁰

Lung, lymph=20 nodes

109

Kuhn⁹¹ = case 2=20 (2003)

58,=20 M

R parotid = gland

110

Yasuhara¹⁰

47,=20 F

Spleen, = lung

111

Ueda¹³

42,=20 M

Cervical lymph nodes, = thoracic=20 vertebrae, L clavicle, epicardium, =

R kidney, pancreas, = liver, L=20 cervical and auricle soft = tissue =

=20

112

Erdem⁹²

37,=20 F

Infratemporal fossa, R orbit, = lateral and=20 medial pterygoid =

muscles, R carotid=20 artery

113

Fabi⁹³

43,=20 M

Lumbar=20 vertebrae = (L1,L3)

114

Montagne⁹⁴

74,=20 M

Vertebrae, lungs, = mediastinal lymph=20 nodes =

115

Utsuki⁵

42,=20 M

Axis

>36

116

Chivukula⁹⁵

62,=20 M

R = lung

117

Mirzayan¹¹

30,=20 M

Bones (lumbar and = thoracic=20 vertebrae), =

L 7^th = costovertebral = junction,=20 nodal, paravertebral =

=20

and mediastinal=20 metastases

118

Tuominem⁹⁶

25,=20 M

Mediastinum

119

Taha⁹⁷

33,=20 M

Parotid gland, = cervical lymph=20 nodes =

120

Rajagopalan⁹⁸

60,=20 M

Lumbar and sacral = vertebrae,=20 epidural soft tissue =

121

Didelot⁹⁹

74,=20 M

Bone marrow, lung, = mediastinal lymph=20 nodes =

122

Piccirilli=20 case 1=20 (2006)

66,=20 M

Lung

123

Piccirilli=20 case 2 (2006)

74,=20 F

Liver

124

Piccirilli=20 case 3 (2006)

67,=20 F

Humerus

125

Piccirilli=20 case 4 (2006)

72,=20 M

L=20 lung

126

Piccirilli=20 case 5 (2006)

63,=20 M

Lung

127

Piccirilli=20 case 6 (2006)

70,=20 F

Cervical=20 lymph nodes

128

Piccirilli=20 case 7 (2006)

69,=20 M

Lung

R, right; L, left; = NA, not=20 available.=20 =

The=20 mean age in the first period (i.e., = 1928-1967) was=20 34 years (range, 6-61) and in the second = period,=20 42 years (range, 3-74; Table 3). The sex=20 distribution was 12 males and 9 females in = the=20 first and 70 males and 32 females in the = second=20 period (Table 3). The mean survival in the = first=20 was 19 months and in the second period, 16 = months=20 (even though these values were not = statistically=20 relevant, logrank, 0.417) (Figure 2).=20

Discussion=20

GBM is a=20 highly malignant primary brain tumor. = According to=20 the characteristic behavior of these = neoplasms,=20 the occurrence of extracranial metastases = is a=20 very uncommon event, with a reported = frequency in=20 the literature of less than 2%³.=20 Several attempts have been made to explain = the=20 rarity of extraneural metastases. Neidhart = et = al.⁴=20 described the following six reasons: the = absence=20 of lymphatic vessels in the CNS, = intracranial=20 perivascular spaces do not communicate = with=20 extracranial fluid space, the connections = between=20 the subarachnoid space and extracranial = lymphatic=20 vessels are very sparse, intracerebral = veins are=20 thin walled and would probably collapse = from=20 compression before a tumor=E2=80=99s=20 penetration^4-6, meningeal tumors grow on = the dura=20 mater but remain only on the surface, = dural veins=20 are protected by a dense connective=20 tissue^4,6.

GBM has a=20 poor prognosis and presents an average = survival=20 time of approximately 1 year^3,7. Extracerebral metastases = usually=20 occur in regional lymph nodes (51%), = particularly=20 in the cervical group, in lungs and pleura = (60%),=20 and in the skeleton (31%), where vertebral = bodies=20 are the most involved. Bone metastases = from GBM=20 can be differentiated in lytic or = sclerotic=20 lesions on neuroimaging, and they are = usually seen=20 as a multiple extracranial spread. Only = particular=20 cases present an isolated vertebral = localization=20 (i.e., axis)⁵.=20 Other target tissues for metastases are = the liver=20 (22%), the operative flap, dural veins, = meninges,=20 the scalp, the kidney, the = orbit⁴,=20 the spleen⁵,=20 and the heart⁷.=20

The tumor is=20 able to use several routes to metastasize, = anad we=20 can describe five main ways⁴:=20 hematogenous spread via the vessels of the = primary=20 tumor, hematogenous spread after tumor = invasion of=20 the dural veins, hematogenous and/or = lymphogenous=20 spread after infiltration of the skull and = extracranial soft tissues, spread via the=20 cerebrospinal fluid, spread via = ventriculoatrial=20 or ventriculo-pleural shunts. =

Hematogenous=20 and/or lymphogenous spread after = infiltration of=20 the skull and extracranial soft tissues = represents=20 the most common route, above all in = patients who=20 have undergone a surgical intervention. In = fact,=20 the operation alters the brain anatomy and = gives=20 the tumor the possibility to reach the=20 extracranial soft tissue and to gain = access to=20 blood or lymphatic vessels. This is the = main=20 reason why so many different metastases to = lymph=20 nodes have been demonstrated^4,8,9. The hematogenous system is = the=20 preferential way involved in lung, osseous = and=20 spleen metastases. When the vertebrae are=20 involved, the glioma cells probably enter = the=20 Batson plexus (which is situated in the = anterior=20 lumbar cord) and disseminate in the = cerebrospinal=20 fluid. The capacity of the Batson plexus = to give=20 blood to the inferior vena cava and also = to lumbar=20 and sacral vertebrae allows the formation = of=20 metastases in the lung and liver and in = the lumbar=20 and sacral vertebrae⁵.=20

Hematogenous=20 spread can follow particular vein = connections:=20 this is the case of the axis metastasis. = According=20 to Utsuki et=20 al.⁵,=20 there could be some connections between = part of=20 the meningeal venous system and = craniocervical=20 venous system, which is connected to the = internal=20 vertebral venous plexus. The internal = vertebral=20 venous plexus flows back to the anterior = and=20 posterior surface of the cervical = vertebrae, and=20 there is also blood flow to the body of = the=20 axis⁵.=20

The=20 so-called =E2=80=9Cdrop = metastases=E2=80=9D, due to metastatic=20 dissemination with drainage of the CSF, as = well as=20 for the placement of ventricular systemic=20 shunts¹⁰, are a well-documented=20 event^4,11, but tumor expansion = through the=20 cerebrospinal circulation remains an = unusual way.=20

Various=20 hypotheses have been made to find a = pathogenesis=20 for the metastasis phenomenon. Interesting = considerations surely derive from Park=20 et = al.¹². They suggested that the = metastatic=20 potential of GBM might be correlated with=20 particular molecular features, P53 gene = mutations=20 and differential clonal = selection^3,12,13. In fact, some metastases = arise from=20 genetically altered subclones of the = primary=20 tumor. Several biological and molecular=20 studies¹³ have closely examined = the=20 different patterns of genetic expression = between=20 the primary tumor and some metastatic = samples,=20 using the cDNA microarray technique. They = showed=20 the following common results in both: the=20 overexpression of insulin growth factor = and a=20 decrease of DNA-PK genetic expression, = which is a=20 DNA-dependent protein kinase involved in = DNA=20 repair mechanisms. The first probably = plays a role=20 in tumor progression; the second = contributes to=20 the malignant transformation of the = glioma.=20

In other=20 words, the present study underlines the = similar=20 patterns of genetic expression in = intracranial=20 tumors as well as in metastases, = suggesting that=20 distant dissemination is the consequence = of direct=20 infiltration of tumor cells into = extracranial=20 blood vessels¹³.

An=20 alternative explanation for the major = tendency to=20 metastasize is related to the appearance = of a=20 sarcomatous component in the original=20 glioblastoma^10,14. In fact, we know that the = gliosarcoma can metastasize more easily = than other=20 malignant gliomas. Moreover, patients with = extracranial metastases from GBM with a=20 sarcomatous component have a worse = prognosis than=20 patients with other gliomas. Most of the=20 previously reported cases did not present = a=20 sarcomatous component in the early state, = so it is=20 thought that adjuvant radiotherapy and=20 chemotherapy may have caused changes in = the=20 histological features¹⁰. All our patients = presented a=20 primary GBM and none of them showed a = sarcomatous=20 component after the histological = examination. All=20 of them received adjuvant radiotherapy and = chemotherapy, but most of them did not = undergo a=20 second surgical removal of the brain = lesion, which=20 allowed us to verify histologically if a=20 sarcomatous transformation took place. The = only=20 two patients who underwent a second = surgical=20 approach at the brain did not present any=20 sarcomatous cells. Moreover, histological=20 examination of metastatic GBM did not = report any=20 sarcomatous elements.

In relation=20 to a study of 1977¹⁵, some authors examined the = different=20 immunologic responsiveness of GBM to = several=20 antigens in long- and short-term = survivors. The=20 experiments demonstrated at the beginning = an=20 anergic reaction, but after a relative = short=20 period, a progressive increase in immune=20 responsiveness in all tests performed = in vivo and=20 in = vitro. This last event probably = represents=20 a host immune attempt to arrest tumor=20 proliferation. This is only a transitory = phase for=20 the short-term survivors but represents = the=20 expression of a different immunogenetic = pattern=20 for the long-term survivors. In fact, = particular=20 antigens were present only in the cells of = the=20 long-term survival glioblastoma and were = not seen=20 in short-term survival GBM material. In = the same=20 way, a meningioma-related dicentric = chromosome=20 marker appeared only in the cells of=20 long-surviving glioblastoma patients. = Another=20 important consideration derives from the=20 comparison of PAGE (polyacrylamide gel=20 electrophoretic) separation of serum: in = fact,=20 between their long- and short-surviving = patients=20 there was a significant quantitative = difference in=20 the measurement of two prealbumin = components, and=20 the a1-acid = glycoprotein/prealbumin ratio=20 gave a sensitive index of the degree of=20 malignancy¹⁵.

The elderly=20 age of our patients is another important = point of=20 discussion. In fact, several authors have=20 confirmed a growing incidence of tumors in = elderly=20 patients^16-19. In particular, a study = conducted in=20 France between 1983 and 1990^16,18 showed an increase of 5% = per year in=20 the incidence of malignant astocytomas in = the=20 population over 65 years of age. We also = have to=20 consider the great increase in life = expectancy of=20 the population of industrialized = countries. This=20 fact probably created a large potential = target=20 sample for this neoplasm¹⁸. The increasing incidence = of primary=20 and malignant brain tumors seems to be = specific in=20 elderly patients^18,19, and this observation can = only=20 partially be attributed to the extensive = use of=20 new diagnostic neuroimaging like MRI and = CT.=20

Elderly=20 patients with a diagnosed GBM may often = present a=20 concomitance of important diseases such as = diabetes, chronic broncho-pulmonary = disease,=20 ischemic heart disease, and hypertension. = These=20 factors can determinate a shorter = survival. The=20 other situations characterized by a poor = survival=20 in elderly patients without such diseases = can be=20 explained by a less aggressive = multimodality=20 treatment that the neurosurgeon chooses = for the=20 lower KPS generally observed in elderly=20 patients^18,20,21. Some studies, only in = particular=20 cases, have evidenced that multimodality = treatment=20 could be less effective in elderly = patients for=20 the presence of specific mutations able to = render=20 tumor cells more resistant to adjuvant=20 chemotherapy (p-53 mutations)^18,22 and radiotherapy (deletions = in=20 chromosome 10)^18,23.

These=20 considerations persuaded us to perform=20 macroscopically complete surgical = debulking,=20 according to the concept that if the = extent of the=20 surgical removal is greater, the outcome = is better=20 for the patient^18,24. In fact, radical removal = of GBM=20 through an aggressive approach can delay = tumor=20 recurrence and reinforce the effect of = adjuvant=20 therapy. For these reasons, according to = our=20 experience, elderly patients, in a good = functional=20 state of health, should be treated in the = same way=20 as younger patients with the same=20 diagnosis¹⁸.

In the past,=20 the mean survival time of a patient with = GBM did=20 not exceed 6 months, but today this time = can reach=20 and also surpass 2 years. Our patients had = an=20 average survival time of 29 months (range, = 25-35),=20 although they were all elderly patients. = Such a=20 long survival time shows that the chosen = treatment=20 was appropriate for these patients. =

Metastasis=20 always preceded regrowth of the primary = GBM (mean=20 value, 7 months; range, 6-9). = Nevertheless, in=20 each case death was the result of cerebral = GBM=20 regrowth involving important deeper = structures.=20 Although the literature confirms the = scarce=20 tendency to metastasize, we have to report = an=20 important documented increase. In the 40 = years=20 between 1928 and 1967 in the literature, = 21 cases=20 of GBM extra-CNS metastases were reported, = whereas=20 in the 39 years between 1968 and 2006 = there were=20 107 cases, about five times more. Advances = in the=20 multimodality treatment of gliomas, the = earlier=20 diagnosis due to a wide diffusion and = improvement=20 in neuroimaging techniques, and the = subsequent=20 longer patient survival may partially = justify the=20 growing incidence of extracranial = metastases, from=20 the value of 0.44%, reported by Smith = et al. in=20 1969²,=20 to the present value of 2%³.=20

This=20 phenomenon may also depend on the = potential=20 modification of the histological and = genetic=20 features of primary GBM. This new aspect = adds=20 another conditioning element to the GBM = prognosis:=20 metastasis treatment.

biblio_titolo=20 - ignora

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