Elsevier

Gynecologic Oncology

Volume 92, Issue 3, March 2004, Pages 752-760
Gynecologic Oncology

Analysis of chromosome abnormalities by comparative genomic hybridization in malignant peripheral primitive neuroectodermal tumor of the ovary

https://doi.org/10.1016/j.ygyno.2003.11.027Get rights and content

Abstract

Objective. Malignant primitive neuroectodermal tumor (PNET) originating from the ovary rather than from the central nervous system is extremely rare. The aim of this study is to demonstrate the chromosomal abnormalities in a case of peripheral primitive neuroectodermal tumor (PPNET) arising from the ovary of a girl.

Methods. The 13-year-old girl underwent exploratory laparotomy because of a huge pelvic tumor in lower abdomen and pelvis. She underwent removal of ovaries, tubes, omentum, peritoneal nodules, and portion of urinary bladder. Tumor specimens were sent for pathology, short-term tissue culture, and for storage in deep freezer for laboratory studies. Immunohistochemical stainings of the tumor with antibodies against O-13 (MIC/CD99), NSE, GFAP, S-100, cytokeratin AE1/AE3, desmin, NF, and AFP were performed. Short-term cell culture of fresh tumor was done for analysis of chromosomal aberrations by the technique of comparative genomic hybridization (CGH). Names of specific genes corresponding to the losses or gains on gene map loci were identified from OMIM (Online Mendelian Inheritance in Man) of the NCBI website, www.ncbi.nlm.nih.gov. The overexpressions of N-myc and EGFR as well as underexpressions of Rb and ARHI were detected by RT-PCR analysis. The patient expired 17 months later despite of chemotherapy, repeated surgery, and radiation therapy.

Result. The histopathology of the specimens revealed malignant neuroectodermal tumor, involving ovaries, tubes, bladder, omentum, and peritoneum. Immunohistochemical stainings of PPNET of the ovary showed positive reaction for O-13 (MIC2/CD99) and NSE, but negative for GFAP, S-100, cytokeratin AE1/AE3, desmin, NF, and AFP. Analysis of CGH revealed multiple chromosomal abnormalities including losses of chromosomes in 1p, 1q, 4q, 6p, 6q, 7q, 8q, 13q, and 19q; as well as gains of chromosomes in 1q, 2p, 7p, 9q, 18q, and Xq. Losses of 13q14.1–q14.2, 1p31, and 4q34–q35 indicated that Rb gene, ARHI, and FAT were deleted. Gains of 2p24.1, 1q23, and 7p12.3–p12.1 demonstrated that N-myc oncogene, FASL, GITRL, and EGFR were amplified. RT-PCR analysis showed that N-myc and EGFR were overexpressed, while Rb and ARHI were underexpressed.

Conclusions. This report is the first to show multiple chromosomal aberrations in PPENT arising from the ovary. The deletions of Rb, ARHI, and FAT, as well as amplification of N-myc, FASL, GITRL, and EGFR, may be the crucial factors for tumorigenesis and the aggressive biological behavior of PPNET.

Introduction

The entity of primitive neuroectodermal tumor (PNET) includes posterior fossa medulloblastoma, pineoblastoma, and cerebral neuroblastoma. Histologically, all of them arise from primitive neuroectodermal cells of neurocrest with variable degrees of differentiation. Besides, they have a similar morphological appearance, a similar clinical behavior, and the same therapeutic approach. On the other hand, primitive neuroectodermal tumor outside the central nervous system is named peripheral primitive neuroectodermal tumor (PPNET) and is similar to extraosseous Ewing's sarcoma in histogenesis and clinical behavior [1]. The cerebellum, pineal gland, leptomenings, skull, chest wall, posterior mediastinum, skin, kidney, myocardium, retroperitoneum, orbit, spinal cord, and even mandible are reported to be the primary site of PNET or PPNET [2], [3], [4], [5]. The primary site of PNET is most commonly seen in the cerebellum. PPNET, however, occurs mostly in the central axis of the trunk [6], [7]. Malignant neuroectodermal tumor originating from the ovary is a rare condition in gynecologic malignancy.

Morphologically, the cells of PNET are small, round, dark cells that have disproportional large hyperchromatin nuclei with numerous mitoses. Microscopically, they arrange in lobules demarcated by fine bands of fibrous tissue and are often clustered into rosettes (Homer-Wright or Flexner rosettes). Positive PAS (periodic acid-Schiff) stain has been found in about 40% cases of PNET. In addition, by immunocytochemical analysis, positive results of staining are often available in the analyses of neuron-specific enolase (NSE), S-100 protein, synaptophysin, vimentin, S antigen, and glial fibrillary acid protein (GFAP) in patients of PNET [8]. Compared to classic Ewing's sarcoma, the cells of primitive neuroectodermal tumor are somewhat more pleomorphic, having condensed chromatin and scanty cytoplasm. Generally, the term “Ewing's sarcoma” refers to undifferentiated small round cell tumors that lack any morphological or immunohistochemical evidence of neural differentiation [6].

Comparative genomic hybridization (CGH) technique has been used recently to study the pattern of chromosomal aberrations in many human cancers, such as ovarian carcinomas [9], [10], [11], and melanomas [12]. The present study was the first one to use CGH technique to demonstrate the chromosomal abnormalities in a case of peripheral primitive neuroectodermal tumor (PPNET) of the ovary. We also discussed the possible roles of the chromosomal gains or losses relevant to the tumorigenesis and progression of PPNET.

Section snippets

Case history and collection of tissue samples

The 13-year-old girl suffered abdominal distention and pain for 1 month. Physical examination revealed a huge pelvic tumor in the lower abdomen and pelvis. Computed axial tomography demonstrated multiple tumors in pelvis and abdomen, ascites, enlarged pelvic lymph node, and left hydroureter. CA125 was 188, AFP and hCG were normal. She underwent laparotomy, evacuation of 5 l of ascites, and removal of ovaries with tumors, tubes, bladder, omentum, peritoneal nodules, and portion of urinary

Results

The pathology report confirmed the diagnosis of malignant neuroectodermal tumor of the ovary. The results of hematoxylin–eosin staining as shown in Figs. 1A–C demonstrated that the ovarian tumor is composed of undifferentiated-looking cells. The ovarian tumor cells are arranged in solid sheets separated by fibrotic bands, or indistinct small nests or cords with formation of ependymal rosettes. Fig. 2 revealed that PPNET of the ovary shows positive reaction for MIC2/CD99 (O-13). In addition, the

Case management

The age of peak incidence in PNET is in early childhood, while that in PPNET is in teenagers. Raised intracranial pressure and cerebellar signs are the symptoms of PNET and PPNET. However, symptoms of local pain and palpable mass are often combined with elevated serum LDH level. Our previous study also showed that high level of LDH–ras p21 protein complex is expressed in primary human ovarian cancer [15]. Distant metastases at diagnosis are reported to range from 10% to 40% in the patients of

Acknowledgements

We thank the supports for this study from the National Science Council, Taipei, Taiwan (NSC 89-2314-B-010-034), and Global Vista Medical Foundation.

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