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ORIGINAL ARTICLE
Year : 2006  |  Volume : 1  |  Issue : 1  |  Page : 16-20
 

Medulloblastoma in children: Prognostic factors and predictors of outcome


Department of Neurosurgery, Sree Chitra Tirunal Institute for Medical Sciences &Technology, Trivandrum, India

Correspondence Address:
Girish Menon
Department of Neurosurgery, SCTIMST, Trivandrum 695 011
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1817-1745.22942

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  Abstract 

Objective: To determine the relative contributions of clinical, radiological and histopatholgical predictors of survival in children with medulloblastoma (MB) and to compare it with their adult counterparts. Materials and Methods: Retrospective case record analyses of 79 children (<16 y) operated after Jan. 1990, who have completed at least 5 y of follow-up. The following variables were assessed by bivariate analysis: age, CT scan location of the lesion, brainstem invasion, extent of excision, histological subtype. Statistical analysis was performed using Chi-square test, Fischers test and Student's t test. Results: Near-total to total excision could be achieved in 59 (74.6%) cases. Twenty-three patients (29.11%) required CSF diversion procedures. Histopathology revealed features of classical medulloblastoma in 63.2%, thermoplastic variant in 11% and glial differentiation in 25.3% of cases. Postoperative mutism was seen in 14 (17.72%) patients. All patients received adjuvant therapy. On follow-up, 34 patients were found to have posterior fossa recurrence and four patients were re-operated. An additional 17% of patients were found to have either spinal or supratentorial metastasis on follow-up. The overall 5-year recurrence-free survival rate was 19 (24.05%). Mortality was recorded in 23 patients and nearly 29 patients who were severely disabled on follow-up were referred to terminal care centres. Conclusion: In spite of recent advances in management, children with medulloblastoma still carry a poor prognosis. We observed poor outcome in children below 7 y of age. Vermian location had a better outcome in adults but not in children. Desmoplastic variant was observed to be a significant prognostic factor in paediatric, group while brain stem invasion carried poor prognosis for both.



How to cite this article:
Menon G, Nair S, Muthurethinam T, Krishnakumar K, Bhattacharya R N. Medulloblastoma in children: Prognostic factors and predictors of outcome. J Pediatr Neurosci 2006;1:16-20

How to cite this URL:
Menon G, Nair S, Muthurethinam T, Krishnakumar K, Bhattacharya R N. Medulloblastoma in children: Prognostic factors and predictors of outcome. J Pediatr Neurosci [serial online] 2006 [cited 2017 Apr 28];1:16-20. Available from: http://www.pediatricneurosciences.com/text.asp?2006/1/1/16/22942


Medulloblastoma is a common malignancy in the paediatric population, accounting for 25% of all childhood brain tumours.[1],[2] Originally classified a glioma, medulloblastoma is referred to now as a primitive neuro-ectodermal tumour (PNET).[3] It is a highly invasive tumour arising from the cerebellum with tendency to disseminate throughout the CNS early in its course. The median age of diagnosis is 5 y, with 80% of cases being diagnosed in the first 15 y. A retrospective analysis of our operated series of medulloblastoma was carried out to study the various clinicoradiological features and overall surgical outcome. An attempt was made to identify predictors of poor outcome and to assess patterns of relapse.


  Materials and Methods Top


During the period from January 1990 to December 1999, a total of 97 patients underwent surgery for medulloblastoma. There were 79 children and 18 adults in this study (age 16 y and above). The present study was conducted retrospectively by analyzing the clinicoradiological data of these patients as well as radiological outcome in the postoperative period as well as during the follow-up period. All patients were evaluated by oncologist and underwent adjuvant therapy. The various modalities of adjuvant therapy were analysed. All patients were called to the outpatient department and detailed neurological examination was done on review. Letters regarding status of patient were obtained from relatives in case of patients who could not report for review. Statistical analysis was performed using Chi-square test, Fischers test and Student's t test.


  Results and Analysis Top


There were 79 children (Age range 4 mo to 12 y) with 44 males and 35 females. Headache was the predominant symptom in 70 (88%) patients. Vomiting was present in 73 (92%) cases, 34 (43%) had visual blurring and 16(20.2%) presented with diplopia. Cerebellar symptoms in the form of gait unsteadiness were present in 55 (69%). History of seizures or loss of consciousness was present in 17 (23.45%) patients. Eleven patients (13.9%) presented in altered sensorium and papilledema was present in 65 (82.1%) on admission to hospital. Cranial nerve palsies were seen in 23 patients and 32 patients (40.5%) had nystagmus. While 4 patients (5.06%) presented with hemiparesis, cerebellar signs were observed in 52 (65.8%) patients. All patients underwent CT scan of head for evaluation and 15 patients underwent preoperative MRI scan of head. The postoperative analysis however was only on the basis of CT scan. MRI was done in few patients postoperatively, but all the films could not be retrieved and hence was not included in the study. The tumour was located in vermis in 71 patients (89.8%), while 3 lesions (3.7%) were in right cerebellar hemisphere and 4 lesions (5.06%) were located in left cerebellar hemisphere. Calcification was observed in 18 cases (22.7%). CT head showed hydrocephalus in 70 cases (88.6%) and IV ventricle could be visualized only in 16 cases (22.5%). MRI evidence of brainstem infiltration was present in 8 cases (10.1%). All patients underwent surgical excision of lesion. Total excision was performed in 28 cases (35.4%), near-total excision in 31 cases (39.2%) and subtotal excision in 18 (22.7%) cases. In 2 cases, only partial excision could be performed. In spite of establishing clear CSF pathway perioperatively in 57 (72.1%) cases, 64 patients (81.8%) required external ventricular drain in the perioperative period and 23 patients (29.1%) in whom raised intracranial pressure was persistent in the postoperative period underwent VP shunt. Histopathological examination showed classical medulloblastoma in 50 cases (63.2%), while desmoplastic variant was observed in 9 (11%) cases. Twenty patients (25.3%) had medulloblastoma with glial differentiation. Operative complications included fresh cranial nerve deficits in 7 (9.86%) cases, hemiparesis and gait unsteadiness in 15 cases (18.3%), mutism in 14 cases and meningitis in 6 cases.

All patients underwent adjuvant radiotherapy in the form of craniospinal irradiation with posterior fossa booster radiation. On follow-up, 34 patients (43.06%) were observed to have recurrence in posterior fossa in follow-up CT head scans. Seventeen (12%) patients were detected in follow-up MRI to have spinal metastasis. Supratentorial metastasis occurred in follow-up in 15 (10.65%) patients. After detection of supratentorial/spinal metastasis, patients subsequently were subjected to chemotherapy. Four (5%) patients had to undergo re-surgery due to residual/recurrent lesion causing raised intracranial symptoms. Twenty-one patients (26.5%) could be followed up for more than 5 y. Follow-up data in May 2005 showed that 19 patients (24.05%) were alive and 23 patients (29.11%) died in the follow-up period. Thiry-seven patients (46.8%) were lost in follow-up. Of them, 29 were referred to local hospital for terminal and palliative care from oncology centre due to poor general physical condition. A comparison between the adult and paediatric population is given in [Table - 1][Table - 2][Table - 3][Table - 4][Table - 5][Table - 6].

The following variables were assessed by bivariate analysis for adult and paediatric study groups: age, CT location of lesion, brainstem invasion, total excision of tumour, histological subtype. Statistical tests for relevance performed include Pearson Chi-square test, Fisher's exact test and T - test. CSF seeding, MRI evidence of metastasis could not be analysed due to insufficient data. As all the patients were subjected to the same pattern of adjuvant radiotherapy, the role of radiotherapy in prognostication was not attempted.

Poor outcome was observed in the paediatric population with age below 7 y. Bivariate analysis showed influence of CT location of tumour with outcome only in adult medulloblastoma - vermian location carrying better prognosis than other locations. Significant association was observed between radiological evidence of brainstem involvement and outcome. Desmoplastic variant of medulloblastoma was observed to be a significant prognostic factor in paediatric group. The known predictors of outcome like sex and extent of resection did not have any statistically significant effect on outcome in our series. Five-year survival data showed that adults fared better than children with 55.5% 5-yr survival, whereas only 24.05% children survived for five years [Table - 6]. The effects of radiotherapy in outcome were difficult to assess as all the patients received the same dose. However, the patients who received chemotherapy immediately following radiotherapy were found to have a better outcome than those who received chemotherapy following the detection of recurrence.


  Discussion Top


Medulloblastoma is the most common malignant brain tumour of childhood, accounting for 20-25% of paediatric CNS neoplasms. Medulloblastomas are undifferentiated embryonal neuroepithelial tumours of the cerebellum [1],[2],[3] arising predominantly from the cerebellar vermis and primarily affecting children in the first decade of life. The cell of origin and the exact histological classification of this highly malignant tumour are still controversial.[3],[4] Although the majority occur as sporadic cases, hereditary conditions have been associated with medulloblastoma, including (1) Gorlin syndrome (nevoid basal cell carcinoma syndrome), (2) blue rubber-bleb nevus syndrome, (3) Turcot syndrome (e.g, glioma polyposis syndrome) and (4) Rubenstein-Taybi syndrome. The most frequent cytogenetic abnormality in sporadic medulloblastoma is an isochromosome 17q [i (17q)].[1] Of tumours analysed, 40-50% have a deletion of the short arm of chromosome 17, implicating the presence of a tumour suppressor gene that maps to 17p, which is distinct from the p53 gene. The nuclear protein p53 is thought to represent a tumour suppressor gene and has been mapped to the short arm of chromosome 17. Recently, Raffle et al have shown that medulloblastomas have p53 mutations as identified by cDNA sequencing, suggesting inactivation or faulty transcription of the active protein encoded for by p53. These p53 mutations may be important in the pathogenesis of human medulloblastoma.[4],[16] Recently the role of biologic markers in risk stratification and prognostication is assuming greater relevance. [16],[17],[18] The predictive value of these markers is still controversial and a matter of research. [Table - 7] shows a list of risk factors with their predictive value.[18]

Gender is a debatable prognostic factor in paediatric series. Weil[22] et al and Prados[8] et al found female gender to be a significant favourable prognostic factor in medulloblastoma. Sex did not reveal any bearing on outcome in our series. Complete resection should be performed if possible as several studies have correlated outcome with extent of resection and amount of residual tumour.[15],[19],[23],[24],[25] In our paediatric population, near total to near total excision of lesion could be performed in 74.6%. Our results however are similar to U Tabori[5] et al who found similar rates of local relapse between patients with gross total resection and patients with less extensive surgery. We noted a higher incidence of brain stem infiltration in our series unlike Park[26] et al who found 36% of patients with radiological evidence of brainstem infiltration. Brain stem infiltration could be one of the major reasons of a relatively high incidence of subtotal excision in our series. Infiltration of the floor of the 4th ventricle was confirmed as a strong independent negative predictor in our series too, like in most series.[4],[6],[15],[19] Histopathological examination of tumour in the present study showed clear predominance of classical medulloblastoma in children. Available literature suggests desmoplastic histological variant to be of favourable prognostic significance.[20],[21],[27],[28] Our series too could establish a statistically significant correlation with better outcome in children having desmoplastic medulloblastoma.

Standard therapy consists of total surgical removal of tumour followed by radiation to the entire craniospinal axis with boost to both the primary tumour size and focal CNS metastatic sites.[4],[5],[21],[27], [29],[30],[31] In contrast to a previous report,[4] we did not find an influence of the interval between surgery and start of radiotherapy on survival. Certain studies have shown a correlation between improved posterior fossa control and shorter periods for the completion of radiotherapy.[7],[32] In Chan[7] et al' s series, the 5-year posterior fossa control rate was 81% for patients who completed radiotherapy in less than 48 d, compared with 51% for patients who completed radiotherapy in 48 d or more. As we followed a uniform protocol of radiotherapy, we failed to observe any difference in outcome related either to the interval between surgery and radiotherapy or to the total duration of radiotherapy. Recently, adjuvant chemotherapy also has been shown to be beneficial in children with medulloblastoma. The efficacy of chemotherapy in the treatment of medulloblastoma has been assessed previously in two large randomized trials conducted by the Societe Internationale d' Oncologie Pediatrique (SIOP).[1],[15],[21],[33] The addition of chemotherapy for high-risk patients seems to improve their survival and has contributed better outcome even in average-risk patients. In our series, the patients who received chemotherapy immediately following radiotherapy were found to have a better outcome than those who received chemotherapy following the detection of recurrence. Among children, even after a good response to surgery and radiation, recurrence is common; most recurrence occur within 2 y after treatment .[16],[20],[25] We too observed a very high rate of recurrence both locally and as metastatic lesions. Probably due to the high rate of recurrence and failure to provide chemotherapy based on risk stratification, we had a poor overall survival outcome of only 24.05%, quite unlike what is reported in literature.


  Conclusions Top


In spite of recent advances in management, children with medulloblastoma still carry a poor prognosis. In our series of medulloblastomas, among the classical predictors of outcome, only location, only age, histological subtype and brain stem invasion were found to have any significant correlation on outcome. We observed a poor outcome in children up to 7 y of age. Radiological and intraoperative evidence of brain stem invasion was associated with poor outcome, while desmoplastic variant was associated with a better outcome in children with medulloblastomas. Classical outcome determinants like extent of excision and residual tumour did not show any correlation with outcome in our series.

 
  References Top

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10.Taylor MD, Mainpriz TG, Rutka JT. Molecular Insight into Medulloblastoma and Central Nervous System Primitive Neuroectodermal Tumour Biology from Hereditary Syndromes: A Review. Neurosurgery 2000;47:888-901.  Back to cited text no. 10    
11.Paul Graham Fisher, Biologic Risk Stratification of Medulloblastoma: The Real Time Is Now. J Clin Oncol 2004;22:971-4.  Back to cited text no. 11    
12.Segal R, Goumnerova LC, Kwon YK, Stiles CD, Pomeroy SL. Expression of the neurotrophin receptor TrkC is linked to a favourable outcome in medulloblastoma. Proc Natl Acad Sci USA 1994;91:12867-71.  Back to cited text no. 12    
13.Herrlinger U, Steinbrecher A, Rieger J. Adult medulloblastoma Prognostic factors and response to therapy at diagnosis and at relapse. J Neurol 2005;252:291-9.  Back to cited text no. 13    
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15.Abacioglu U, Uzel O, Sengoz M, Turkan S, Ober A. Medulloblastoma in adults: Treatment results and prognostic factors. Int J Radiat Oncol Biol Phys 2002;54:855-60.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Chan AW, McL Black P. Adult medulloblastoma; prognostic factors and patterns of relapse. Neurosurgery 2000;47:623-32.  Back to cited text no. 16    
17.Prados MD, Warnick RE, Wara WM, Larson DA, Lamborn K, Wilson CB. Medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1995;32:1145-52.  Back to cited text no. 17    
18.Weil MD, Lamborn K, Edwards MS, Wara WM. Influence of a child's sex on medulloblastoma outcome. JAMA 1998;279:1474-6.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Balter-Seri J, Mor C, Shuper A. Cure of recurrent medulloblastoma: the contribution of surgical resection at relapse. Cancer 1997;79:1241-7.  Back to cited text no. 19    
20.Albright AL, Wisoff JH, Zeltzer PM. Effects of medulloblastoma resections on outcome in children: a report from the Children's Cancer Group. Neurosurgery 1996;38:265-71.  Back to cited text no. 20    
21.Gajjar A, Sanford RA, Bhargava R, Heidman R, Walter A, Li Y, et al. Medulloblastoma with brain stem involvement: the impact of gross total resection on outcome. Pediatr Neuro Surg 1996;25:182-7.  Back to cited text no. 21    
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24.Brown HG, Kepner JL, Perlman EJ, Freidman HS, Strother DR, Diffner PK, et al. Large cell/anaplastic medulloblastoma; a Paediatric Oncology Group Study. J Neuropathol Exp Neurol 2000;59:857-65.  Back to cited text no. 24    
25.Packer RJ, Sutton LN, Rorker LB. Prognostic importance of cellular differentiation in medulloblastoma of childhood. J Neurosurg 1984;61:296-301.  Back to cited text no. 25    
26.Berry MP, Jenkin RD, Keen CW, Nair BD, Simpson WJ. Radiation treatment for medulloblastoma: A 21-year review. J Neurosurg 1981;55:43-51.  Back to cited text no. 26    
27.Skolyszewski J, Glinski B. Results of postoperative irradiation of medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1989;16:479-82.  Back to cited text no. 27    
28.Skolyszewski J, Glinski B. Results of postoperative irradiation of medulloblastoma in adults. J Radiat Oncol Biol Phys 1988;16:479-82.  Back to cited text no. 28    
29.del Charco JO, Bolek TW, McCollough WM, Maria BL, Kedar A, Braylan RC, et al. Medulloblastoma: Time-dose relationship based on a 30-year review. Int J Radiat Oncol Biol Phys 1998;42:147-54.  Back to cited text no. 29    
30.Taylor RE, Bailey CC, Robinson K, Weston CL, Ellison D, Ironside J, et al. Results of a Randomized Study of Preradiation Chemotherapy Versus Radiotherapy Alone for Nonmetastatic Medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study. J Clin Oncol 2003;21:1581-91.  Back to cited text no. 30    
31.Yock TI, Friedman H, Kun L, Kepner J, Barnes P, Tarbell NJ. Response to pre-radiation chemotherapy is predictive of improved survival in high risk medulloblastoma: results from the Paediatric Oncology Group (POG 9031). Int J Radiatio Oncol Biol Phys 2001;51:120-1.  Back to cited text no. 31    
32.Prados MD, Wara W, Edwards MS, Ater J, Rabbit J, Lamborn K et al. Treatment of high risk medulloblastoma and other primitive neuroectodermal tumours with reduced dose craniospinal radiation therapy and multiagent nitrosourea based chemotherapy. Paediatr Neurosurg 1996;25:174-81.  Back to cited text no. 32    
33.Pollack IF, Polinko P, Albright AL. Mutism and pseudobulbar symptoms after resection of posterior fossa tumours in children: incidence and pathophysiology Neurosurgery 1995;37:885-93.  Back to cited text no. 33    


    Tables

[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6], [Table - 7]


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