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Prognostic factors in medulloblastoma
480
LETTERS to the EDITOR
Prognostic factors
in medulloblastoma
SiRj—Medulloblastoma is a common malignant tumour of the posterior fossa in children. Current surgical and radiotherapy techniques achieve cures in 50-60% of affected children.1 However, prognostic factors, except for metastases,z are not well established and it has proved difficult to identify patients likely to respond to current protocols. We have investigated the prognostic importance of two biological features: expression of the c-erbB2 oncogene product and tumour mitotic index in 55 consecutive patients with medulloblastoma notified to the Northern Region Young Persons’ Malignant Disease Registry during 1968-88. of c-erbB2 was oncogene product Expression with the monoclonal detected immunohistochemically antibody NCL-CB11 in formalin-fixed paraffin-embedded sections. Staining was recorded independently (R. J. G. and R. H. P.) by
counting the proportion of positive
tumour
cells.
Specificity
of
antibody reaction was assessed with breast tumour tissue known to express the c-erbB2 product, primary and secondary antibody substitution, and antigen absorption controls. Mitotic index was calculated for each case in a three-step procedure designed to minimise inaccuracies due to regional heterogeneity of mitotic activity within tumour sections. At least 1000 tumour cells were counted from areas that had the highest concentration of nondisputable mitotic figures within standard haematoxylin and eosin sections prepared from all available tumour blocks. c-erbB2 product was expressed in 46 tumours (84%). In 23 of these cases, less than half the tumour cells were positive. The remaining 23 patients had tumours with more than 50% positive cells. Tumour mitotic index ranged from 0-3% to 5-3%. In patients whose tumours had more than 50% tumour cell, c-erbB2 product positivity was related to significantly reduced survival; only 10% of such cases were alive at 10 years after diagnosis compared with 55% of patients with less than 50% positive cells (figure). Analysis of mitotic index revealed a significant stepwise decrease in patient survival with increasing mitotic index. The 10 year survivals for the categories 0-2%, 2-3%, and over 3% were 42%, 33%, and 0%, respectively (figure). A significant relation between tumour mitotic index and c-erbB2 protein expression was found by correlation statistics (p < 0-001). In combined multivariate analysis of these two variables, mitotic index retained prognostic significance (p < 0-005) whereas c-erbB2 protein expression did not. Tumour mitotic index is a highly significant, independent prognostic factor for childhood medulloblastoma. Expression of the c-erbB2 product in a high proportion of cases (84%)-not previously reported in medulloblastomas-is of interest for two reasons. First, the rodent homologue of the c-erbB2 gene, termed c-neu, was first identified in transplacentally induced, rat primitive neuroectodermal tumours of the central nervous systemSecond, the locus of c-erbB2 gene is found on the long arm of chromosome 17 in the q21 region,’ and hence is potentially involved in the non-random chromosomal commonest abnormality of medulloblastoma-an iso chromosome of the long arm of chromosome 17.
Departments of Child Health and Neuropathology, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK
1. Craft AW, Amineddine
R. J. GILBERTSON E. B. JAROS R. H. PERRY A. D. J. PEARSON
HA, Scott JES, Wagget J. The Northern Region Children s
Malignant Disease Registry
1968-1982: incidence and survival. Br
J Cancer 1987,
56: 853-58.
Jenkin D, Goddard K, Armstrong D, et al. Posterior fossa medulloblastoma in childhood: treatment results and a proposal of a new staging system. Int JRadiat Oncol Biol Phys 1990; 19: 265-74 3. Schecter A, Stem D, Vaidyanathan L, et al. The neu-oncogene; an erb B related encoding a 185,000 MR tumour antigen Nature 1984; 312: 513-16. 4. Fukushige SI, Matsubara KI, Yoshida M, et al. Localisation of a novel v-erb B related 2
Kaplan-Meier survival Top=46 patients
of
patients with medulloblastoma.
with tumours with < 50% or > 50% of cells positive forc-erbB2 Bottom = 55 patients by three levels of mitotic index (log rank
test).
gene c-erb B2 on human chromosome 17 and its amplification in gastnc cancer cell line. Mol Cell Biol 1986; 6: 955-58
LETTERS to the EDITOR
Prognostic factors
in medulloblastoma
SiRj—Medulloblastoma is a common malignant tumour of the posterior fossa in children. Current surgical and radiotherapy techniques achieve cures in 50-60% of affected children.1 However, prognostic factors, except for metastases,z are not well established and it has proved difficult to identify patients likely to respond to current protocols. We have investigated the prognostic importance of two biological features: expression of the c-erbB2 oncogene product and tumour mitotic index in 55 consecutive patients with medulloblastoma notified to the Northern Region Young Persons’ Malignant Disease Registry during 1968-88. of c-erbB2 was oncogene product Expression with the monoclonal detected immunohistochemically antibody NCL-CB11 in formalin-fixed paraffin-embedded sections. Staining was recorded independently (R. J. G. and R. H. P.) by
counting the proportion of positive
tumour
cells.
Specificity
of
antibody reaction was assessed with breast tumour tissue known to express the c-erbB2 product, primary and secondary antibody substitution, and antigen absorption controls. Mitotic index was calculated for each case in a three-step procedure designed to minimise inaccuracies due to regional heterogeneity of mitotic activity within tumour sections. At least 1000 tumour cells were counted from areas that had the highest concentration of nondisputable mitotic figures within standard haematoxylin and eosin sections prepared from all available tumour blocks. c-erbB2 product was expressed in 46 tumours (84%). In 23 of these cases, less than half the tumour cells were positive. The remaining 23 patients had tumours with more than 50% positive cells. Tumour mitotic index ranged from 0-3% to 5-3%. In patients whose tumours had more than 50% tumour cell, c-erbB2 product positivity was related to significantly reduced survival; only 10% of such cases were alive at 10 years after diagnosis compared with 55% of patients with less than 50% positive cells (figure). Analysis of mitotic index revealed a significant stepwise decrease in patient survival with increasing mitotic index. The 10 year survivals for the categories 0-2%, 2-3%, and over 3% were 42%, 33%, and 0%, respectively (figure). A significant relation between tumour mitotic index and c-erbB2 protein expression was found by correlation statistics (p < 0-001). In combined multivariate analysis of these two variables, mitotic index retained prognostic significance (p < 0-005) whereas c-erbB2 protein expression did not. Tumour mitotic index is a highly significant, independent prognostic factor for childhood medulloblastoma. Expression of the c-erbB2 product in a high proportion of cases (84%)-not previously reported in medulloblastomas-is of interest for two reasons. First, the rodent homologue of the c-erbB2 gene, termed c-neu, was first identified in transplacentally induced, rat primitive neuroectodermal tumours of the central nervous systemSecond, the locus of c-erbB2 gene is found on the long arm of chromosome 17 in the q21 region,’ and hence is potentially involved in the non-random chromosomal commonest abnormality of medulloblastoma-an iso chromosome of the long arm of chromosome 17.
Departments of Child Health and Neuropathology, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK
1. Craft AW, Amineddine
R. J. GILBERTSON E. B. JAROS R. H. PERRY A. D. J. PEARSON
HA, Scott JES, Wagget J. The Northern Region Children s
Malignant Disease Registry
1968-1982: incidence and survival. Br
J Cancer 1987,
56: 853-58.
Jenkin D, Goddard K, Armstrong D, et al. Posterior fossa medulloblastoma in childhood: treatment results and a proposal of a new staging system. Int JRadiat Oncol Biol Phys 1990; 19: 265-74 3. Schecter A, Stem D, Vaidyanathan L, et al. The neu-oncogene; an erb B related encoding a 185,000 MR tumour antigen Nature 1984; 312: 513-16. 4. Fukushige SI, Matsubara KI, Yoshida M, et al. Localisation of a novel v-erb B related 2
Kaplan-Meier survival Top=46 patients
of
patients with medulloblastoma.
with tumours with < 50% or > 50% of cells positive forc-erbB2 Bottom = 55 patients by three levels of mitotic index (log rank
test).
gene c-erb B2 on human chromosome 17 and its amplification in gastnc cancer cell line. Mol Cell Biol 1986; 6: 955-58