Limits...
Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts.

Ellison DW, Kocak M, Figarella-Branger D, Felice G, Catherine G, Pietsch T, Frappaz D, Massimino M, Grill J, Boyett JM, Grundy RG - J Negat Results Biomed (2011)

Bottom Line: In phase 3, repeat independent review of two cohorts (SFOP/CNS9904) using the novel system was associated with a substantial increase in concordance on grading.Extent of tumor resection was significantly associated with progression-free survival (PFS) in SFOP and AIEOP, but not in CNS9204 and CNS9904.Unfortunately, this appears to have utility in limited clinical settings.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept, of Pathology, St, Jude Children's Research Hospital, Memphis, USA. David.Ellison@stjude.org

ABSTRACT

Background: Histopathological grading of ependymoma has been controversial with respect to its reproducibility and clinical significance. In a 3-phase study, we reviewed the pathology of 229 intracranial ependymomas from European trial cohorts of infants (2 trials - SFOP/CNS9204) and older children (2 trials - AIEOP/CNS9904) to assess both diagnostic concordance among five neuropathologists and the prognostic utility of histopathological variables, particularly tumor grading.

Results: In phase 1, using WHO criteria and without first discussing any issue related to grading ependymomas, pathologists assessed and independently graded ependymomas from 3 of 4 trial cohorts. Diagnosis of grade II ependymoma was less frequent than grade III, a difference that increased when one cohort (CNS9204) was reassessed in phase 2, during which the pathologists discussed ependymoma grading, jointly reviewed all CNS9204 tumors, and defined a novel grading system based on the WHO classification. In phase 3, repeat independent review of two cohorts (SFOP/CNS9904) using the novel system was associated with a substantial increase in concordance on grading. Extent of tumor resection was significantly associated with progression-free survival (PFS) in SFOP and AIEOP, but not in CNS9204 and CNS9904. Strength of consensus on grade was significantly associated with PFS in only one trial cohort (AIEOP). Consensus on the scoring of individual histopathological features (necrosis, angiogenesis, cell density, and mitotic activity) correlated with PFS in AIEOP, but in no other trial.

Conclusions: We conclude that concordance on grading ependymomas can be improved by using a more prescribed scheme based on the WHO classification. Unfortunately, this appears to have utility in limited clinical settings.

Show MeSH

Related in: MedlinePlus

Progression-free (PFS) and overall survival (OS) in four European trials. (a) PFS and (b) OS by trial. Black line = SFOP; red line = CNS9204; blue line = CNS9904; and green line = AIEOP.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3117833&req=5

Figure 1: Progression-free (PFS) and overall survival (OS) in four European trials. (a) PFS and (b) OS by trial. Black line = SFOP; red line = CNS9204; blue line = CNS9904; and green line = AIEOP.

Mentions: Ependymomas (n = 229) from children entered into four European clinical trials were requested for histopathological review, following Newcastle/North Tyneside Research Ethics Committee approval for studies on childhood brain tumors. An AIEOP trial with a postsurgical "stage-determined" protocol for non-infants provided 42 patients with a median age of 6.3 years [16]. Children on this trial were treated with (i) focal hyperfractionated radiotherapy (HFRT), if there was no evidence of post-surgical residual disease, or (ii) 4 courses of VEC followed by HFRT, if there was post-surgical residual disease. The dose of HFRT was 70.4 Gy (1.1 Gy/fraction b.i.d.), and the VEC regimen consisted of VCR 1.5 mg/m2 1/w, VP16 100 mg/m2/day x3, and CTX 3 g/m2/day x1. Where feasible, second-look surgery was recommended. An SFOP trial aiming to treat young (< 5 years) children with chemotherapy alone provided 54 patients with a median age of 1.8 years [4]. Initial treatment was maximal surgical resection, which was classified as complete when post-operative neuroimaging was considered negative. Chemotherapy consisted of cycles of three courses (A: carboplatin/procarbazine, B: etoposide/cisplatin, C: vincristine/cyclophosphamide) delivered each 21 days for 7 cycles. Chemotherapy was discontinued if disease progression or unacceptable toxicity occurred. No radiotherapy was planned after completion of chemotherapy, but salvage therapy (including second-look surgery and radiotherapy) was only indicated for disease progression or a relapse. Two CCLG (UKCCSG) SIOP trials - CNS9204 and CNS9904 - provided 84 and 49 patients respectively. The CNS9204 protocol aimed to evaluate a primary chemotherapy strategy for avoiding or delaying radiotherapy in children aged less than 3 years with intracranial ependymoma [6]. Maximal surgical resection was followed by alternating blocks of myelo- and non-myelosuppressive chemotherapy every 14 days for an intended duration of 1 year. Radiotherapy was withheld unless there was recurrent disease. The overall strategy for CNS 9904 was similar to that of the AEIOP trial. After a complete surgical resection of tumor, radiotherapy (54 Gy) was delivered to the tumor site, but for those with an incomplete resection chemotherapy with VEC preceded radiotherapy (54 Gy). Across all trials, central review of all operative reports was undertaken to establish extent of surgical resection. Despite strenuous efforts, it was not possible to acquire histological preparations from all patients entered into each trial, success rates ranging from 55% (CNS9904) through 67% (AIEOP) and 74% (SFOP) to 95% (CNS9204). The clinical characteristics of children whose tumors were reviewed on this study are provided in Table 1 and are representative of those for the entire trial cohorts. Figure 1 shows progression-free survival (PFS) and overall survival (OS) for the trial cohorts used in this study.


Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts.

Ellison DW, Kocak M, Figarella-Branger D, Felice G, Catherine G, Pietsch T, Frappaz D, Massimino M, Grill J, Boyett JM, Grundy RG - J Negat Results Biomed (2011)

Progression-free (PFS) and overall survival (OS) in four European trials. (a) PFS and (b) OS by trial. Black line = SFOP; red line = CNS9204; blue line = CNS9904; and green line = AIEOP.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117833&req=5

Figure 1: Progression-free (PFS) and overall survival (OS) in four European trials. (a) PFS and (b) OS by trial. Black line = SFOP; red line = CNS9204; blue line = CNS9904; and green line = AIEOP.
Mentions: Ependymomas (n = 229) from children entered into four European clinical trials were requested for histopathological review, following Newcastle/North Tyneside Research Ethics Committee approval for studies on childhood brain tumors. An AIEOP trial with a postsurgical "stage-determined" protocol for non-infants provided 42 patients with a median age of 6.3 years [16]. Children on this trial were treated with (i) focal hyperfractionated radiotherapy (HFRT), if there was no evidence of post-surgical residual disease, or (ii) 4 courses of VEC followed by HFRT, if there was post-surgical residual disease. The dose of HFRT was 70.4 Gy (1.1 Gy/fraction b.i.d.), and the VEC regimen consisted of VCR 1.5 mg/m2 1/w, VP16 100 mg/m2/day x3, and CTX 3 g/m2/day x1. Where feasible, second-look surgery was recommended. An SFOP trial aiming to treat young (< 5 years) children with chemotherapy alone provided 54 patients with a median age of 1.8 years [4]. Initial treatment was maximal surgical resection, which was classified as complete when post-operative neuroimaging was considered negative. Chemotherapy consisted of cycles of three courses (A: carboplatin/procarbazine, B: etoposide/cisplatin, C: vincristine/cyclophosphamide) delivered each 21 days for 7 cycles. Chemotherapy was discontinued if disease progression or unacceptable toxicity occurred. No radiotherapy was planned after completion of chemotherapy, but salvage therapy (including second-look surgery and radiotherapy) was only indicated for disease progression or a relapse. Two CCLG (UKCCSG) SIOP trials - CNS9204 and CNS9904 - provided 84 and 49 patients respectively. The CNS9204 protocol aimed to evaluate a primary chemotherapy strategy for avoiding or delaying radiotherapy in children aged less than 3 years with intracranial ependymoma [6]. Maximal surgical resection was followed by alternating blocks of myelo- and non-myelosuppressive chemotherapy every 14 days for an intended duration of 1 year. Radiotherapy was withheld unless there was recurrent disease. The overall strategy for CNS 9904 was similar to that of the AEIOP trial. After a complete surgical resection of tumor, radiotherapy (54 Gy) was delivered to the tumor site, but for those with an incomplete resection chemotherapy with VEC preceded radiotherapy (54 Gy). Across all trials, central review of all operative reports was undertaken to establish extent of surgical resection. Despite strenuous efforts, it was not possible to acquire histological preparations from all patients entered into each trial, success rates ranging from 55% (CNS9904) through 67% (AIEOP) and 74% (SFOP) to 95% (CNS9204). The clinical characteristics of children whose tumors were reviewed on this study are provided in Table 1 and are representative of those for the entire trial cohorts. Figure 1 shows progression-free survival (PFS) and overall survival (OS) for the trial cohorts used in this study.

Bottom Line: In phase 3, repeat independent review of two cohorts (SFOP/CNS9904) using the novel system was associated with a substantial increase in concordance on grading.Extent of tumor resection was significantly associated with progression-free survival (PFS) in SFOP and AIEOP, but not in CNS9204 and CNS9904.Unfortunately, this appears to have utility in limited clinical settings.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept, of Pathology, St, Jude Children's Research Hospital, Memphis, USA. David.Ellison@stjude.org

ABSTRACT

Background: Histopathological grading of ependymoma has been controversial with respect to its reproducibility and clinical significance. In a 3-phase study, we reviewed the pathology of 229 intracranial ependymomas from European trial cohorts of infants (2 trials - SFOP/CNS9204) and older children (2 trials - AIEOP/CNS9904) to assess both diagnostic concordance among five neuropathologists and the prognostic utility of histopathological variables, particularly tumor grading.

Results: In phase 1, using WHO criteria and without first discussing any issue related to grading ependymomas, pathologists assessed and independently graded ependymomas from 3 of 4 trial cohorts. Diagnosis of grade II ependymoma was less frequent than grade III, a difference that increased when one cohort (CNS9204) was reassessed in phase 2, during which the pathologists discussed ependymoma grading, jointly reviewed all CNS9204 tumors, and defined a novel grading system based on the WHO classification. In phase 3, repeat independent review of two cohorts (SFOP/CNS9904) using the novel system was associated with a substantial increase in concordance on grading. Extent of tumor resection was significantly associated with progression-free survival (PFS) in SFOP and AIEOP, but not in CNS9204 and CNS9904. Strength of consensus on grade was significantly associated with PFS in only one trial cohort (AIEOP). Consensus on the scoring of individual histopathological features (necrosis, angiogenesis, cell density, and mitotic activity) correlated with PFS in AIEOP, but in no other trial.

Conclusions: We conclude that concordance on grading ependymomas can be improved by using a more prescribed scheme based on the WHO classification. Unfortunately, this appears to have utility in limited clinical settings.

Show MeSH
Related in: MedlinePlus