Received: 20 September 1998Revised: 16 November 1998

Abstract To investigate clinical fea-tures, treatment outcome and prog-nostic factors of pediatric supraten-torial primitive neuroectodermal tu-mors(ST-PNETs), 28 ST-PNET caseswere retrospectively analyzed. Theprognostic importance of age, sex,size of tumor, M stage, extent of sur-gical resection, histological features,immunohistochemical labelling indi-ces (Ki-67, p53), and apoptotic indexwere assessed. The mean age at di-agnosis was 6.8 years, and the male-to-female ratio was 18:10. The pre-senting symptoms in 22 cases wereincreased intracranial pressure andfocal neurological deficits. Gross to-tal resection was achieved in 17cases, near-total (>90%) resection in3, and subtotal in 7; biopsy was per-formed in 1 case. The mean duration

of follow-up was 37 months. For 25patients who completed planned ad-juvant therapy, the 3-year survivalrate was 73%. Univariate analysisshowed that the presence of tumornecrosis (P=0.002) and extent of re-section (P=0.04) correlated with sur-vival. Patients with a high Ki-67 la-belling index (>10%) tended to haveshorter survival (P=0.095). In multi-variate analysis, tumor necrosisshowed statistical signifi-cance(P=0.03).

Key words Primitiveneuroectodermal tumor · Child ·Prognosis · Necrosis · Surgical resection

Child’s Nerv Syst (1999) 15:377–383© Springer-Verlag 1999 O R I G I N A L PA P E R

Hee Jin YangDo Hyun NamKyu-Chang WangYeon Mee KimJe G. ChiByung-Kyu Cho

Supratentorial primitive neuroectodermaltumor in children: clinical features,treatment outcome and prognostic factors

Introduction

Primitive neuroectodermal tumor (PNET) arises frompluripotential stem cells and presents predominantly inchildren and young adults. It shows various types of dif-ferentiation, such as neuronal, astrocytic, ependymal ormelanotic. In 1973 Hart and Earle [8] described the enti-ty of cerebral PNET. They described a group of largelyundifferentiated cerebral neoplasms occurring in chil-dren, confining the designation of PNET to lesions locat-ed in the cerebrum. Later, Rorke [16] emphasized thehistological similarity between PNET, medulloblastoma(PNET/MB), pineoblastoma, and other tumors, definingthe term PNET in a broader sense to embrace five sub-types according to differentiation lineages. This defini-tion, however, has not yet been unanimously accepted.

Supratentorial PNETs (ST-PNETs) account for ap-proximately 2.5–6% of childhood brain tumors [4, 11],while PNET/MBs of the posterior fossa constitute ap-proximately 20% of such tumors. Because of the rarityof ST-PNETs, articles on clinical features and responseto treatment are limited to case reports and studies ofsmall series. In contrast to the prognostic factors ofPNET/MB, only a few authors have investigated those ofST-PNET [1, 3, 4, 10].

Twenty-eight cases of pediatric ST-PNET were treat-ed by the most extensive surgical removal possible, fol-lowed by adjuvant irradiation and/or chemotherapy, dur-ing the last 10 years. We assessed clinical features andhistological findings, and their relevance to outcome,and tried to elucidate the prognostic factors and biologi-cal behavior of ST-PNETs.

H.J. Yang · D.H. Nam · K.-C. WangB.-K. Cho (✉)Division of Pediatric Neurosurgery,Seoul National UniversityChildren’s Hospital, 28 Yongon-dong,Chongno-gu, Seoul 110–744, Koreae-mail: ns-office@medicine.snu.ac.krTel.: +82–2-760–2350Fax: +82–2-747–3648

H.J. Yang · D.H. Nam · K.-C. WangB.-K. ChoNeuroscience Research Institute,Medical Research Center,Seoul National University,28 Yongon-dong, Chongno-gu,Seoul 110–744, Korea

Y.M. Kim · J.G. ChiDivision of Pediatric Pathology,Seoul National UniversityChildren’s Hospital, Seoul, Korea

Patients and methods

Patients

Between January 1986 and December 1995, 28 pediatric patientsaged under 17 years with histologically proven ST-PNETs weretreated at Seoul National University Children’s Hospital. Patientswith ependymoblastoma (3) and pineoblastoma (4) were included,in keeping with Rorke’s definition of PNET [16]. Medical recordsand radiological and pathological data were retrospectively re-viewed.

On the basis of surgical records and postoperative computer-ized tomography (CT)/magnetic resonance imaging (MRI), the ex-tent of resection was assessed and defined as follows. Gross totalresection (GTR): the surgeon considered the resection completeand CT/MRI showed no residual tumor; near-total resection(NTR): more than 90% of the original volume was resected; sub-total resection (STR): more than 50% was resected; and partial re-section (PR): less than 50% was resected.

The reference point in this study was the date of the surgicalprocedure by which histological diagnosis of PNET was first es-tablished. The end-point was death or the last follow-up. One casewas lost to follow-up after discharge from hospital; the mean dura-tion of follow-up was 37 (range, 2–105) months in the remaining27 cases.

Histological and immunohistochemical techniques

On the basis of light microscopic findings in hematoxylin and eo-sin (H&E)-stained preparations, tumors were classified as follows:(1) PNET without differentiation (not otherwise specified, NOS);(2) PNET with glial differentiation; (3) PNET with ependymal dif-ferentiation; and (4) PNET with neuronal differentiation [16]. His-tological features such as calcification, desmoplasia and tumor ne-crosis were also assessed. Classification of tumors and their histo-logical features were assessed by two neuropathologists (Y.M.K.and J.G.C.).

In order to evaluate proliferation and apoptosis of tumor cells,and to assess the derangement of tumor suppressor gene p53, im-munohistochemical study was done. Immunohistochemical stain-ing for Ki-67 and p53 was performed with the available paraffinblocks of tumor specimens from 23 patients. Terminal deoxynu-cleotidyl transferase (TdT)-mediated dUTP-biotin nick end label-ling (TUNEL) was performed in 18. The specimens had beenfixed in 10% neutral buffered formalin, embedded in paraffin, androutinely processed for pathological examination. Representativesections containing the largest amount of tumor, based on findingsin H&E-stained tissues, were selected from a single tissue blockfor immunohistochemical studies. Serial sections 5 µm thick wereimmunostained with monoclonal antibodies for p53 protein(1:100) and Ki-67 (1:100; both from Zymed, South San Francisco,Calif.). To enhance immunostaining, sections were pretreated bymicrowave in 0.01 M citrate buffer, pH 6. The immunostainingfollowed the streptavidin-conjugated peroxidase technique. Sec-tions were counterstained with hematoxylin. TUNEL was per-formed using ApopTag In Situ Apoptosis Detection Kit (S7100-Kit, Oncor, Gaithersburg, Md.). Labelling indices were expressedas the percentages of positive cells among total neoplastic cells.More than 1,000 cells were counted per patient.

Statistical analysis

Clinical presentation and treatment outcome were analyzed. Theprognostic importance of age, sex, size of tumor, M stage, extentof surgical resection, histological features, immunohistochemicallabelling indices (Ki-67, p53), and apoptotic index were assessed.

In cases with multiple operations, the extent of resection at firstoperation was selected for analysis.

Survival rates were estimated using the Kaplan-Meier method.Comparisons between survival data were made by the log-ranktest. Cox regression analysis was used to evaluate simultaneousmultivariate prognostic importance.

Results

Clinical features

Age at diagnosis ranged from 8 months to 16.9 (mean6.8) years, and the male-to-female ratio was 18:10. Theduration of symptoms before diagnosis ranged from 1 to48 (mean 4.9) months. The most common presentingsymptom/sign were headache (n=12) and focal neurolog-ical deficits (n=7). Six patients presented with seizure, 2with altered mentality, and 1 with decreased visual acui-ty. On CT/MRI, the epicenter of the tumor was found tobe located in the frontal (n=7), temporal (n=6), parietal(n=7), or occipital lobe (n=2). The tumor involved theperiventricular (n=3) and pineal (n=3) areas.

Treatment

The extent of surgical resection was as follows: GTR in17 cases, NTR in 3, STR in 7, and biopsy only in 1. Thecause of incomplete resection was tumor location veryclose to eloquent areas. In a patient with a small mass anddiffuse subarachnoid seeding, stereotactic biopsy only wasperformed. In 24 cases, the M stage was evaluated accord-ing to Chang’s classification for PNET/MBs; dissemina-tion of a tumor nodule in the spinal canal (M3) was de-tected in 3 cases, and skull invasion by a tumor (M4) in 2.

All patients except 2, who declined further treatment,underwent postoperative radiation and/or chemotherapy.Thirteen patients underwent pre-radiation chemotherapy,radiation therapy and postradiation chemotherapy (pre-and postradiation ‘8 drugs in 1 day’: methylpredniso-lone, vincristine, CCNU, procarbazine, hydroxyurea, cis-platin, cytosine arabinoside, cyclophosphamide). Amongthem, 1 patient received cranial irradiation only, at an-other hospital, while the remainder underwent craniospi-nal radiation therapy (CSRT). CSRT with post-radiationchemotherapy was performed in 7 cases, while 3 patientsunderwent radiation therapy only. Three patients whowere younger than 3 years received chemotherapy only.

Histological findings

The main differentiation lineages of the tumors ascer-tained in H&E-stained specimens were as follows (Fig.1): glial (n=13), neuronal (n=8), ependymal (n=5), andmesenchymal (n=1) differentiation. Differentiation into

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more than one lineage was detected in 12 cases. Syn-aptophysin staining was positive in cases that showedneuronal differentiation, and glial fibrillary acidic pro-tein (GFAP) was detected in cases that showed glial dif-ferentiation. Because there was no definite differentia-tion lineage, 7 cases were designated PNET-NOS (nototherwise specified).

Desmoplasia was detected in 16, calcification in 9,and tumor necrosis in 11 cases. In cases that showed des-moplasia on H&E staining, abundant collagen fiberswere detected by Masson’s trichrome staining (Fig. 2).

The Ki-67 labelling index(LI) ranged from 0.4% to20.0% (mean standard error: 6.4 1.2), p53 LI from zero

to 19.0% (5.6 1.2), and TUNEL LI from zero to 2.6%(0.6 0.2).

Treatment outcome and prognostic factors

The status of patients at the last follow-up was as fol-lows: survival without evidence of tumor recurrence in14 cases, stable disease with residual or recurrent tumorin 3 cases (duration of follow-up was 4, 24, 50 months),a moribund state in 1, death in 9. We performed five re-operations on 4 patients: two for residual tumors and theother three for recurrences. Excluding the 1 patient whowas lost to follow-up after discharge, the mean survivaltime after surgery in 27 cases was 68 months, and the 2-,3-, and 5-year survival rates were 70%, 70% and 51%,respectively. The mean disease-free survival time was 57months, and 2-, 3-, and 5-year disease-free survival rateswere 60%, 60% and 38%, respectively. The mean surviv-al time of the 5 patients who completed planned adjuvanttherapy was 71 months, and the 2-, 3-, and 5-year surviv-al rates were 73%, 73%, and 53%, respectively.

Table 1 summarizes the 3-year overall survival for thefollowing variables: age at diagnosis (<3 years vs >3

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a

dc

b

Fig. 1a–d Differentiation of tumor cells. a A PNET without differ-entiation (PNET-NOS; H&E, original magnification ×400) showssmall to medium-sized, poorly differentiated, round-to-oval cellswith basophilic nuclei, large nucleoli and scanty cytoplasm. b APNET with glial differentiation (H&E, original magnification×400) demonstrates abundant fibrillary material in background,and cells have abundant eosinophilic cytoplasm. c In a PNET withneuronal differentiation (H&E, original magnification ×200), tumorcells are arranged in a nodular pattern. They have clear cytoplasmand vesicular nuclei, similar to ganglion cells (arrow). d A PNETwith ependymal differentiation (H&E, original magnification×200) reveals ependymal rosettes, canals and/or pseudorosettes

Fig. 3 Kaplan-Meier curve for survival by extent of removal(GTR gross total removal, NTR near-total removal, STR subtotalremoval, PR partial removal, Bx biopsy)

Fig. 5 Kaplan-Meier curve for survival by Ki-67 labelling index(LI)

years); sex; tumor size (<5 cm vs >5 cm in its longest di-ameter); M stage (M0 vs M1–4); extent of surgical re-section (‘biopsy and STR’ vs ‘NTR and GTR’); presenceof tumor necrosis, desmoplasia, and calcification; differ-

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a

b

c

Fig. 2a–c Histological features of PNET. a PNET with desmopla-sia. (Masson’s trichrome, original magnification ×200). b PNETwith calcification. (H&E, original magnification ×200). c PNETwith necrosis (H&E, original magnification ×200)

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entiation lineage (glial, neuronal, ependymal); labellingindices of Ki-67, p53, and TUNEL; apoptotic index-to-mitotic index ratio (AI/MI: TUNEL LI divided by Ki-67LI). The extent of surgery (‘biopsy and STR’ vs ‘:NTR

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Table 1 Survival rates accord-ing to the possible prognosticfactors (univariate analysis;GTR gross total resection, NTRnear-total resection, STR subto-tal resection, NOS not other-wise specified, AI/MI apoptoticindex to mitotic index, LI label-ling index)

Variable Patient group 3-year P-valueb

survival rate(%)a

Age <3 years vs 3 years 67 vs 78 0.62Sex Male vs female 74 vs 76 0.95Size of tumor ≤5 cm vs >5 cm 76 vs 70 0.87M stage M0 vs M1–M5 67 vs 74 0.83Extent of surgery Bx, STR vs NTR, GTR 0 vs 79 0.04Necrosis of tumor Necrosis (+) vs no necrosis (–) 38 vs 100 0.0002Desmoplasia Desmoplasia (+) vs no desmoplasia (–) 72 vs 86 0.43Calcification Calcification (+) vs no calcification (–) 86 vs 71 0.54Differentiation Glial (+) vs not glial(–) 80 vs 63 0.38

Neuronal (+) vs (–) 75 vs 58 0.36ependymal (+) vs (–) NAc vs 64 0.15Differentiation (+) vs NOS 76 vs 61 0.28

Immunohistochemistry p53 LI ≤5% vs >5% 90 vs 54 0.26Ki67 LI ≤5% vs >5% 81 vs 56 0.23Ki67 LI ≤10% vs >10% 79 vs 50 0.095TUNEL LI ≤0.5% vs >0.5% 73 vs 66 0.67AI/MId ratio ≤0.1 vs >0.1 50 vs 66 0.24

a Kaplan-Meier methodb Log rank testc Survival estimates cannot becomputed since all observa-tions are censoredd TUNEL LI divided by Ki-67LI

Table 2 Prognostic factors(Cox model; PR partial resec-tion, Bx biopsy)

Covariates Increased survival Decreased survival Relative risk P-value

Extent of resection GTR, NTR STR, PR, Bx 5.25 0.27Necrosis Necrosis (–) Necrosis (+) 9.24 0.03Differentiation NOS differentiation (+) 2.02 0.61Ki-67 LI ≤10 >10 4.07 0.27

and GTR’) and the presence of tumor necrosis were sta-tistically significant in univariate analysis (Figs. 3, 4).The Ki-67 LI showed borderline significance (Fig. 5).Cox multivariate regression analysis revealed that tumornecrosis was associated with a significantly greater riskof death (Table 2).

Discussion

Incidence and clinical features

According to Swedish data, the annual incidence of braintumors in the pediatric age group (less than 15 years)was 34.9 per million, with PNET accounting for 27.3%.Most, however, were PNET/MB, with ST-PNET com-prising only 6%. The annual incidence of ST-PNET isthus 2 per million [11]. Our data showed that 26.6% ofpediatric patients (aged less than 16 years) were PNETs.Among these, 6.6% were ST-PNETs.

The reported mean age of ST-PNET patients in the lit-erature ranges from 3.1 to 17 years [4, 7, 10, 14, 19], andthis is comparable to that in our series (6.8 years). A fewstudies have revealed no predilection for either sex [3,10] or a female predominance [14], but most series haveshown a male predominance [4, 8, 18], as did ours.

M stage was graded by Chang’s classification in 24 of28 cases, and nodular seeding in the spinal subarachnoidspace was detected in 3. In 2 cases, the tumor had invad-ed adjacent skull. The reported rate of spinal seeding inST-PNET ranged from 7% to 12%, comparable to that inour series but lower than that in PNET/MB [3, 5].

The presenting symptoms and signs consisted in in-creased intracranial pressure and focal neurological defi-cits, and the mean duration of symptoms before diagno-sis ranged from 3 weeks to 4 months [8, 10, 18].

Treatment outcome

Because of the rarity of these neoplasms, the principlesof treatment remain controversial. Much of what is in-ferred about ST-PNET is derived from experience withPNET/MB. The best treatment for ST-PNET patients ap-pears to be radical resection, postoperative CSRT andaggressive chemotherapy, though no series has demon-strated the statistical significance of radical resection [1,3, 7, 18].

The incidence of remote dissemination of ST-PNETat initial diagnosis is not high, but this is very frequentlyfound at recurrence or in the end-stage. This evidencemay justify irradiation of the entire neuraxis and fre-

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quent examination of CSF cytology or spinal MRI dur-ing the follow-up period [18, 19]. CSRT has deleteriouseffects in itself, however, and to prevent relapses and re-duce delayed morbidity, the selection criteria for CSRTand the dose of radiation need to be established. Trials ofreduced-dose radiation to the spinal axis, such as hyper-fractionated CSRT with 24 Gy or CSRT with 18 Gy pluschemotherapy, for the prevention of spinal seeding werenot successful [6, 15].

The impact of adjuvant chemotherapy has been stud-ied in various PNET/MB series. The majority of re-searchers agree that chemotherapy has a definite role inthe management of children with PNET/MB [13]. It isstill not clear, however, whether adjuvant chemotherapyprolongs survival in ST-PNET. Comparisons of long-term survival rates between patients with and without ad-juvant chemotherapy showed no statistically significantdifference [18]. Long-term survival rates with adjuvantchemotherapy have, however, been higher in recent arti-cles than the rates previously reported [3, 7].

The overwhelming impression from the literature isthat ST-PNET is a more aggressive neoplasm thanPNET/MB and does not respond to treatment as favorably[4, 18]. The poorer outcomes of ST-PNET than ofPNET/MB, even with aggressive treatment, suggest thatthe biological behaviors of these tumors are different andprovide evidence that the two tumors are not identical innature [4, 18]. In our institute, however, the outcome oftreatment for ST-PNET was comparable to that inPNET/MB patients treated during the same period (3-yearsurvival rate 67.8%; 5-year survival rate 64.1%) [20].

Because of high morbidity after radiation therapy,children below the age of 2 or 3 years are usually treatedby chemotherapy only. Geyer et al. [5] used intensivechemotherapy to treat children with PNET or malignantependymoma who were aged less than 18 months. The

3-year progression-free survival rate for ST-PNET wasbetter (55%) than that for PNET/MB (22%). In our seriesof patients under the age of 3 years, the 2-year survivalrate for ST-PNET was 67%, while that for PNET-MBwas 38% (P>0.05; unpublished data). Although the dif-ference was not statistically significant, the data suggestthat if ST-PNET were treated by chemotherapy the sur-vival rate might be better than that for PNET/MB.

In our series, the survival rate was better than previ-ously reported (Table 3). This was probably due to ourprinciple of treatment: resection of as much of a tumoras possible, craniospinal radiation therapy, and adjuvantchemotherapy. Aggressive treatment is justified for long-term survival.

Prognostic factors

Identification of the prognostic factors that distinguishpatients at relatively low risk of tumor recurrence fromthose at high risk have important implications for treat-ment planning. Most reports on prognostic factors forPNET involve PNET/MB; there is a paucity of articlesdealing with ST-PNET. The impact of clinical factorssuch as sex, age at diagnosis, and tumor stage on theprognosis of PNET/MB is controversial. Although it isnot clear whether the extent of resection has any impacton survival, radical resection of a tumor is recommendedfor improved local control and possibly a reduced risk ofrecurrence [1, 3, 5, 13]. Most studies concerning M stagehave demonstrated a statistically significant influence onoutcome [1, 3, 5, 13].

Tumor factors may provide additional information ofcomparable or greater prognostic value than clinical fac-tors. For PNETs, however, efforts to identify biologicalfactors of prognostic significance, including DNA ploidy,

Table 3 Outcomes (of ST-PNET) reported in series (MTX metho-trexate, VCR vincristine, Pd prednisolone, CCNU 1-(2-chloroeth-yl)-3-cyclohexyl-1-nitrosourea, CTX cyclophosphamide; “8 in 1”

solumedrol plus vincristine, CCNU, procarbazine, hydroxyurea,CDDP, Ara-C, and Cytoxan, CSRT craniospinal radiation therapy,SR survival rate)

Reference No. of cases Radiation therapy Chemotherapy Outcome

[8] 23 ? ? Mean survival 18 monthsa

[14] 7 Regional (2 case) Not done 2-year SR 33%b

[10] 18 Regional? Intrathecal MTX; VCR, Pd, CCNU 2-year SR 0%[4] 15 Brain or CSRT CCNU, VCR in 6 cases 3-year SR 29%

5-year SR 25%[18] 17 Brain or CSRT Variable 5-year SR 27%

[7] 5 CSRT CTX, VCR, cis-platin 80% alive (4.3–8 years)[5] 11 CSRT “8 in 1” 3-year SR 55%[3] 55 CSRT “8 in 1” 3-year SR 57%[1] 27 CSRT “8 in 1” 5-year SR 34%

Present study 28 CSRT “8 in 1” 3-year SR 71%5-year SR 50%

a Calculated from onset of symptomsb There were 4 postoperative deaths; 5-year SR would be 14% including these

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mitotic index, or immunohistochemical characterizationof differentiation have been unsuccessful or inconsistent.

In this study, the extent of surgery (‘biopsy and STR’vs ‘NTR and GTR’) and presence of tumor necrosis wasstatistically significant in univariate analysis, while onlythe latter was statistically significant in multivariateanalysis (Table 2). The relevance of tumor necrosis tothe survival of PNET/MB patients has been described ina few series [2, 12], though its impact on ST-PNET caseshas not yet been reported. The reported mean Ki-67 LIof PNET/MBs ranges from 17.2 to 30.9 [17], higher thanin our study. Ki-67 LI showed borderline prognostic sig-nificance in univariate analysis, but lost this significancein multivariate analysis. The reported mean apoptotic in-dex(AI) of PNET/MBs, as measured by TUNEL, rangesfrom 0.36 to 1.3, and is thus comparable to ours [17].Neither the AI nor the AI/MI ratio had a statistically sig-

nificant influence on survival. Mutations in the p53 genemay cause an accumulation of p53 protein. Jaros et al.[9] stated that intense overexpression of p53 proteinidentifies a group of PNET patients with increased riskof death. In our series, p53 LI had no impact on survival.

Whether trends of differentiation have any impact onsurvival is controversial [2, 4]. In this study, the presenceof differentiation or its direction according to the findingsin H&E-stained specimens had no statistically significantimpact. It is known that during development of the cen-tral nervous system different intermediate filament pro-teins and other cell type-specific polypeptides are ex-pressed sequentially. Assessment of differentiation by de-tection of these substances may show different results.

Acknowledgement This study was supported in part by a grantfrom Seoul National University Hospital.

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