Cytogenetics of pineoblastoma: four new cases and a literature review

Cancer Genetics and Cytogenetics 170 (2006) 175e179

Short communication

Cytogenetics of pineoblastoma: four new cases and a literature review Angela E. Browna, Kurt Leibundgutb, Felix K. Nigglia, David R. Bettsa,* b

a Department of Oncology, University Children’s Hospital, Zurich, Switzerland Department of Oncology and Haematology, University Children’s Hospital, Bern, Switzerland

Received 11 April 2006; received in revised form 31 May 2006; accepted 6 June 2006

Abstract

Pineoblastoma represents a class of primitive neuroectodermal tumors (PNET) with poorly differentiated neuroepithelial cells that are histologically indistinguishable from medulloblastomas. It is a rare tumor, typically arising in childhood, and to date only a few cytogenetic cases have been published. We report four new cases in which conventional cytogenetics demonstrated the presence of an abnormal clone. The tumors showed a variety of ploidy levels, from hypodiploid to hypertetraploid. Both structural and numerical aberrations were frequent, and in three out of the four cases a large degree of cell-to-cell variation was observed. The most frequently involved chromosome in structural rearrangements was chromosome 1, observed in three of the four cases. The short arm was involved in two of the three cases; in the third case, the anomaly was in the long arm. Two cases showed unbalanced gain of chromosome 17q, one of them showing i(17)(q10). Together, the four cases illustrate the complex karyotypic nature of this tumor type and represent a step toward determining whether a nonrandom cytogenetic picture exists and how this may be related to other associated tumor types. Ó 2006 Elsevier Inc. All rights reserved.

1. Introduction Pediatric brain tumors are the most common solid tumors in children and account for 20% of all childhood malignancies [1], with primitive neuroectodermal tumors (PNET) being the most frequently diagnosed. PNET occur in both infratentorial sites and supratentorial sites. The infratentorial tumors (IPNET), which arise from the cerebellar hemispheres or vermis, are commonly referred to as medulloblastomas. The supratentorial region tumors (SPNET) may include large hemispheric tumors or pineoblastomas (PB) [2]. Although these two tumor groups are histologically identical, the prognosis differs. The outcome for children with SPNET has generally been reported to be poorer than with medulloblastomas [3]. PB are aggressive brain tumors with a propensity for frequent relapse [4]. A report of the Children’s Cancer Group estimated a 3year progression-free survival of 61
13% for children older than 18 months at diagnosis, with an overall survival rate of 73
12% [5]. There has been controversy as to whether PNET arise from a multipotential cell unique to the particular area of the nervous system (e.g., medulloblastomas from external

* Corresponding author. Tel.: þ41-44-266-7849; fax: þ41-44-2667935. E-mail address: [email protected] (D.R. Betts). 0165-4608/06/$ e see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2006.06.009

granule cells in the cerebellum and pineoblastomas from pineoblasts) or from a primitive cell common to all sites [6]. The most common cytogenetic aberration in medulloblastomas are deletions of chromosome 17p, reported in <50% of cases [7]; these are usually the direct result of an isochromosome of 17q. Given the rarity of PB, there have been only a few cytogenetic reports of this tumor in the literature [1,8e14], which has resulted in a lack of clinical and cytogenetic associations. Here we present four new cases of PB, and correlated our findings with both previously reported karyotypes and a comparative genomic hybridization (CGH) report to help to establish whether there are any specific cytogenetic events associated with this tumor type. 2. Patients and methods 2.1. Case reports Four PB tumor biopsies were received for karyotypic analysis at the University Children’s Hospital in Zurich between December 1996 and January 2005. All patients were treated at the University Children’s Hospital, Bern, Switzerland. 2.1.1. Case 1 A 13-year-old girl presented with a 5.3-cm tumor in the pineal region, no dissemination was noted. Due to

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hydrocephalus a Rickham reservoir was implanted. Partial tumor resection was performed and radiotherapy was given. Three years later, a ventriculoperitoneal shunt (VP) shunt was inserted due to ongoing hydrocephalus occlusivus. Shortly after, a relapse occurred with intracerebral and spinal metastases and three cycles of chemotherapy were given, but the patient died due to progressive leptomeningeal metastasis, 40 months after initial diagnosis. 2.1.2. Case 2 A 7-year-old girl presented with two tumors, 2.3 cm and 1.6 cm. Multiple nodular spinal metastases were noted. Subtotal tumor resection was performed and a ventriculoperitoneal shunt was inserted because of hydrocephalus. The patient was given chemotherapy (including three cycles of high-dose treatment with autologous peripheral stem cell rescue) and radiotherapy. At writing, she was alive with no evidence of the disease, 42 months after initial diagnosis. 2.1.3. Case 3 A 4-year-old girl presented with a 3.6-cm tumor and no dissemination was noted. A Rickham reservoir was installed because of hydrocephalus. Complete tumor resection was performed at this time. Subsequently, the patient was given chemotherapy, followed by three cycles of high-dose treatment with autologous peripheral stem cell rescue. Diffuse meningeal relapse occurred, however, and the patient died due to tumor progression, 15 months after initial diagnosis. 2.1.4. Case 4 A 6-year-old girl presented with a 2.6-cm tumor. Tumor cells were detected in the spinal tap. A complete tumor resection was performed, and chemotherapy given. This

treatment had no effect. An altered chemotherapy was then given, to which the patient did not respond. The patient died due to progressive leptomeningeal metastasis, 6 months after initial diagnosis. 2.2. Conventional cytogenetics and fluorescence in situ hybridization (FISH) The cytogenetic procedure for processing of the tumors was as previously described [15]. Subsequently, the slides were prepared and GTG-banded using standard techniques. The karyotypic analysis and determination of ploidy status was made according to ISCN 1995 recommendations [16], with a clonal change being defined by the presence of a structural rearrangement or additional chromosome in two or more cells and the loss of a chromosome in three or more cells. FISH analysis was performed on two cases (cases 2 and 4) for which fixed suspension remained following the conventional cytogenetic analysis using the commercially available telomere probe 17p (D17S2199) and 17q (D17S928) (Vysis, Downers Grove, IL). The manufacturer’s recommendations were followed for the hybridization and post washing procedures.

3. Results Conventional cytogenetic analysis demonstrated the presence of an abnormal clone in all four cases. The results are shown in Table 1, together with those from previously reported cases. The karyotypes demonstrated a broad spectrum of ploidy types, from hypodiploid to hypertetraploid. Cases 1, 2, and 4 exhibited the cell-to-cell variation that resulted in a composite karyotype; case 3 did not.

Table 1 Karyotypic features of reported pineoblastoma patients Case

Age/Sex

Karyotype

Survival, mo

References

8 9 1 482 44 45

3 yr/F 10 yr/M 6 wk/M 18 mo/F NA/F NA/F

NA NA NAa NA NA NA

Griffin et al., 1988 [8] Griffin et al., 1988 [8] Sreekantaiah et al., 1989 [9] Bigner et al., 1997 [10] Roberts et al., 2001 [11] Roberts et al., 2001 [11]

1 1

6 mo/F 13 yr/F

NA 40

Sawyer et al., 2003 [12] Present study

2

7 yr/F

O41

Present study

3

4 yr/F

15

Present study

4

6 yr/F

42~46,XX,add(1)(p36),del(1)(p13p21),inc 45~47,XY,add(1)(q44),inc 46,XY,del(11)(q13.1q13) 46,XX,þ14,22[2]/46,idem,20þmar[3] 45,XX,22 63~82,XXX,þX,þ2,3,þ4,þ5,þ7,þ9,þ11,þ12,14, þ15,þ16,þ17,þ18,þ20,þ21,þ22[cp6] 46,XY,t(16;22)(p13.3;q11.2~12)c 93~99,XXXX,þ9,13,þ14,i(17)(q10),þ19,þ19,þ20, þ0~5mar[cp7]/93~99,idem,der(1)t(1;11)(p36;q14),6,þ12[cp7] 80~83!4nO,XXXX,1,2,3,4,6,9,add(12)(p13), 13,16,20,21,þmar[cp6] 42,XX,þ1,dup(1)(q11q25)2,8,der(11)t(11;17)(p11.2;q11), der(13)t(13;?;17)(p11;?;q11),16,17,18,19,20,21,þ2mar[7]/42, idem,add(2)(p21)[3] 54~56,XX,t(1;16)(p13;q13),þadd(1)(p21)2,15,þ19,þ19,del(19)(q13), þ21,þ21,þ2~5mar[cp8]/46,XX[1]

6

Present study

Abbreviation: NA, not available. a Short follow-up time, patient was reported to be still alive with progressive disease at time of writing.

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Table 2 Karyotypes of three pineoblastoma-derived cell lines Cell line

Age/Sex

Case 1 PER-453(1) PER-452(2)

8 mo/F

Case 2 PER-480

11 mo/M

Karyotype description

Reference Kees et al., 1994 [13]

Near-diploid karyotype with random loss. The only structural rearrangement was i(17q). The hypotetraploid karyotype (72-86 chromosome range) contained an i(17q), 13qþ, and 2 copies of Xpþ; numerical changes included loss of 3, 9, 10, 12, 13 and 17; 2 out of 31 cells had dmin. Kees et al., 1998 [1] 46,XY,der(10)t(10;17)(q21;q22~23),der(16)t(1;16)(q12;q11.2)

previously reported cases was one with a constitutional rearrangement without evidence for acquired changes [12]. The cases from the present study tend to be more complex than those previously described, although two previously reported cases did have incomplete karyotypes. In addition, three of our cases had a ploidy of high-hyperdiploid or greater, compared to the mostly near-diploid karyotypes of previously reported cases. Both numerical and structural aberrations are frequent events in PB (Figs. 1 and 2). In contrast to many other childhood neoplasms, chromosome loss and gain shows no nonrandom pattern. The only possible exception is loss of chromosome 20, which occurred in three cases. Chromosome 1p represents the most frequently rearranged chromosome arm in PB, and aberrations have been described in four cases (three by cytogenetics and the fourth by CGH) [17]. Chromosome 1q was also frequently rearranged, and has been reported in three cases, including one case in

Given the frequent association of chromosome 17 aberrations in PB-related tumors, we investigated for the presence of cryptic chromosome 17 aberrations in the two cases where no aberration was defined by conventional banding analysis. FISH analysis on cases 2 and 4 showed no evidence for imbalance of either 17p or 17q and a signal copy number in accordance with the tumor ploidy. Therefore, no chromosome 17 aberration was demonstrated for these cases. 4. Discussion We have performed a cytogenetic study of four new cases of PB and compared our findings with those previously described in the literature [1,8e14]. The present report adds to seven previous cytogenetic reports of PB [8e12] and a further two from established cell lines [1,13] (Tables 1 and 2). Included in the seven 3 Chromosome gain Chromosome loss 2

1

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

-1

-2

-3

Chromosome Fig. 1. Acquired abnormalities detected in 13 PB tumors: chromosome gain or loss.

21

22

X

Y

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No. of cases with chromosome arm involvement

4 p arm q arm

3

2

1

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

X

Y

Chromosome Fig. 2. Acquired abnormalities detected in 13 PB tumors: structural aberrations.

the present series (Fig. 3). This result illustrates a similarity with medulloblastoma, where unbalanced translocations, deletions, and duplications of chromosome 1 are frequent. Abnormalities of chromosome 1 are commonly seen in solid tumors, however, and are not considered to be specific for tumor subtype [18]. The most common aberration seen in medulloblastoma is an i(17)(q10), reported in <50% of cases [7]. Including cell lines, two PB cases have been reported with an i(17)(q10) and two cases had unbalanced gain of 17q. Further, rarer medulloblastoma changes (e.g., deletions of 9q, 11q, 16q; monosomy 22; and double minutes [19]) were also observed in PB. These results begin to provide evidence that the karyotypic picture of PB and medulloblastoma are related. Therefore, the fact that some events can be found in both tumor types may tentatively support the argument that PNET arise from a primitive cell common to all sites. How closely the cytogenetic picture of PB will ultimately parallel or diverge from that of medulloblastoma requires more cases to be investigated. This report

Fig. 3. Partial karyogram showing normal and aberrant chromosome 1 in case 3.

demonstrates that, with the exception of aberrations involving chromosome 1 and chromosome 17, it is not yet possible to establish a robust nonrandom cytogenetic picture for PB and given the often complex nature of the karyotypes further cases are needed before definable subgroups can be identified. References [1] Kees UR, Spagnolo D, Hallam LA, Ford J, Ranford PR, Baker DL, Callen DF, Biegel JA. A new pineoblastoma cell line, PER-480, with der(10)t(10;17), der(16)t(1;16), and enhanced MYC expression in the absence of gene amplification. Cancer Genet Cytogenet 1998;100: 159e64. [2] Russo C, Pellarin M, Tingby O, Bollen AW, Lamborn KR, Mohapatra G, Collins VP, Feuerstein BG. Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer 1999;86:331e9. [3] Reddy AT, Janss AJ, Phillips PC, Weiss HL, Packer RJ. Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 2000;88:2189e93. [4] Gururangan S, McLaughlin C, Quinn J, Rich J, Reardon D, Halperin EC, Herndon J II, Fuchs H, George T, Provenzale J, Watral M, McLendon RE, Friedman A, Friedman HS, Kurtzberg J, Vredenbergh J, Martin PL. High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas. J Clin Oncol 2003;21:2187e91. [5] Jakacki RI, Zeltzer PM, Boyett JM, Albright AL, Allen JC, Geyer JR, Rorke LB, Stanley P, Stevens KR, Wisoff J, McGuire-Cullen PL, Milstein JM, Packer RJ, Finlay JL. Survival and prognostic factors following radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: a report of the Children’s Cancer Group. J Clin Oncol 1995;13:1377e83. [6] Jakacki RI. Pineal and nonpineal supratentorial primitive neuroectodermal tumors. Childs Nerv Syst 1999;15:586e91.

A.E. Brown et al. / Cancer Genetics and Cytogenetics 170 (2006) 175e179 [7] Biegel JA, Janss AJ, Raffel C, Sutton L, Rorke LB, Harper JM, Phillips PC. Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system. Clin Cancer Res 1997;3:473e8. [8] Griffin CA, Hawkins AL, Packer RJ, Rorke LB, Emanuel BS. Chromosome abnormalities in pediatric brain tumors. Cancer Res 1988; 48:175e80. [9] Sreekantaiah C, Jockin H, Brecher ML, Sandberg AA. Interstitial deletion of chromosome 11q in a pineoblastoma. Cancer Genet Cytogenet 1989;39:125e31. [10] Bigner SH, McLendon RE, Fuchs H, McKeever PE, Friedman HS. Chromosomal characteristics of childhood brain tumors. Cancer Genet Cytogenet 1997;97:125e34. [11] Roberts P, Chumas PD, Picton S, Bridges L, Livingstone JH, Sheridan E. A review of the cytogenetics of 58 pediatric brain tumors. Cancer Genet Cytogenet 2001;131:1e12. [12] Sawyer JR, Sammartino G, Husain M, Linskey ME. Constitutional t(16;22)(p13.3;q11.2~12) in a primitive neuroectodermal tumor of the pineal region. Cancer Genet Cytogenet 2003;142:73e6. [13] Kees UR, Biegel JA, Ford J, Ranford PR, Peroni SE, Hallam LA, Parmiter AH, Willoughby ML, Spagnolo D. Enhanced MYCN

[14]

[15] [16] [17]

[18]

[19]

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