J Neurooncol DOI 10.1007/s11060-007-9331-5
CLINICAL STUDY—PATIENT STUDIES
Gliosarcoma with primitive neuroectodermal differentiation: case report and review of the literature Keith J. Kaplan Æ Arie Perry
Received: 13 December 2006 / Accepted: 9 January 2007 Springer Science+Business Media B.V. 2007
Abstract The clinical and pathological features of a gliosarcoma with a primitive neuroectodermal component in a 52-year-old male are presented. To our knowledge, only three other cases of such an entity have been reported in the English literature. Key words FISH Glioblastoma multiforme Gliosarcoma Neuroectodermal PNET
Introduction Gliosarcomas (GSs) are primary central nervous system neoplasms composed of both malignant glial and sarcomatous components. They are World Health Organization (WHO) grade IV neoplasms, and generally considered to be a variant of glioblastoma multiforme (GBM). The tumor accounts for approximately 2–3% of all GBM cases and typically arises in patients in the sixth to seventh decade of life with a slight maleto-female predominance (1.8:1) and a predilection for the temporal lobe [1]. Since Stroebe [2] described the first case in 1895, their histogenesis and histology have
K. J. Kaplan (&) Department of Pathology, Evanston Hospital, 2650 Ridge Ave, Evanston, IL 60201, USA e-mail:
[email protected] K. J. Kaplan Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA A. Perry Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
been highly controversial. The etiology of the sarcomatous component was previously thought to arise via neoplastic transformation of hyperplastic blood vessels that are commonly present in high-grade glial neoplasms. However, recent studies have supported the contention that both elements of this biphasic neoplasm arise from a single progenitor clone rather than separately from glial and mesenchymal elements and are derived from a common neoplastic neuroectodermal progenitor cell [3–5]. We report the clinical and pathologic features of a GS with a primitive neuroectodermal component (GSPNET). To our knowledge, only three other cases of GSPNET have been described in the English literature [1, 6, 7].
Case report A 48-year-old male presented with an approximately 3-week-long history of symptoms such as decreased attention span, decreased power of concentration, some memory loss for recent events, difficulty finding words and names was diagnosed; awkwardness and weakness in his right arm, hand and leg resulting in dragging of the right leg and sensory changes in his right hand. The patient worked as an engineer without known exposure to toxic industrial substances and he denied alcohol or tobacco use. Medications included occasional acetaminophen use. Physical examination revealed a well-developed, well-nourished male appearing younger than his stated age, in no apparent distress with stable vital signs, oriented to time and place, and the ability to recall three of three objects in 5 min. There was partial graphanesthesia on the left
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palm and total graphanesthesia on the right palm. Double simultaneous tactile extinction both laterally and altitudinally and stimulation of left forehead and left dorsal hand caused the patient to say ‘‘left and right forehead.’’ Ophthalmologic examination demonstrated spontaneous venous pulsations and blurred disc margins bilaterally, particularly on the left side. Cranial nerve examination showed grossly intact function.
Figs. 1–3 Representative images of coronal and sagittal post-gadolinium MRI images showing lesion adjacent to and involving left lateral ventricle with involvement of corpus callosum with mass effect and intralesional hemorrhage and necrosis
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There was marked pronator drift with nearly full strength in the upper and lower extremities on flexion and extension. Deep tendon reflexes were 2+ and symmetrical. Gait was intact, although the patient utilized a ‘‘cautious’’ gait and looked at his feet while walking. Routine hematology and chemistry studies were within normal limits. The physical examination overall was consistent with left parietal dysfunction.
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Magnetic resonance imaging (MRI) of the brain post-contrast revealed the presence of an approximately 6.7 · 4.5 cm2 intraaxial lesion situated just above the trigone of the left lateral ventricle involving a portion of the splenium of the corpus callosum and compressing the ventricular system. The imaging characteristics of this lesion suggested the presence of considerable amount of intra-tumoral hemorrhage and necrosis. Also noted was the presence of considerable amount of mass effect (Fig. 1, 2, and 3). The patient underwent a left parietal craniotomy and microsurgical total tumor removal utilizing computer stereotactic guidance with the STEALTH technique. Medially and anteriorly, the tumor reached into the quadrigeminal cistern. The tumor was closest to the surface at the junction of the superior and inferior parietal lobes, where it was 2 cm beneath the pial surface. It was felt that a gross total resection was accomplished. Post-operatively, the patient underwent a course of radiotherapy, but died of progressive disease 10 months after diagnosis. No post-mortem examination was performed.
Fig. 4 Primitive component with sheets of small round hyperchromatic cells with minimal cytoplasm and numerous mitoses (H&E, 200·)
Pathological Findings Grossly, the specimen consisted of multiple fragments of glistening white to hemorrhagic friable tissue measuring 7.8 · 4.1 · 2.1 cm3 in aggregate. A frozen section sample was interpreted as ‘‘malignant neoplasm’’ with preponderance of malignant small round blue cells with marked increase in nuclear:cytoplasmic ratios, irregular nuclear membranes and focally stippled chromatin. Representative sections of formalinfixed paraffin embedded tissue revealed a highly cellular, relatively solid-appearing neoplasm with variable morphologic appearances. The majority of the tumor cells appeared primitive with oval, markedly hyperchromatic nuclei and minimal discernible cytoplasm (Fig. 4). The cells were predominately arranged in sheets and nests, surrounded by a desmoplasticmalignant-appearing stroma composed of spindled cells with moderate nuclear atypia and high mitotic indices (Fig. 5). Focally, Homer-Wright rosettes were identified within the primitive component (Fig. 6). Additionally, occasional clusters of astrocytic-appearing tumor cells were identified containing variable amounts of eosinophilic cytoplasm (Fig. 7). The mitotic index was brisk, with foci of both endothelial hyperplasia and necrosis evident. Histochemical and immunohistochemical studies were performed. Trichrome and reticulin stains highlighted increased intercellular collagen and reticulin
Fig. 5 GSPNET with focus of sarcoma on left and primitive element on right (H&E, 100·)
deposition within the spindled regions (Fig. 8). There was diffuse and strong reactivity for neuron specific enolase and synaptophysin (Fig. 9). A stain for glial fibrially acidic protein (GFAP) highlighted a subset of tumor cells including elongated cytoplasmic processes (Fig. 10). The spindled component was strongly positive for vimentin, whereas the more primitiveappearing tumor cells were negative (Fig. 11). Immunohistochemical stains for epithelial membrane antigen and leukocyte common antigen were negative. A small subset of tumor cells was positive for cytokeratin and Neu-N. Fluorescence in situ hybridization (FISH) was performed utilizing probes against CEP2, MYC-N, CEP 7, EGFR, CEP8, MYC-C, PTEN, and DMBT1. There was evidence of polysomies (gains) of chromosomes 2,
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Fig. 6 Homer-Wright rosettes within the primitive component (H&E, 400·)
Fig. 7 Astrocytic component of GSPNET with loose collection of cells with abundant eosinophilic cytoplasmic processes and moderate nuclear pleomorphism (H&E, 100·)
7, and 8, consistent with an overall state of polyploidy/ aneuploidy (Fig. 12). Additionally, there was evidence of chromosome 10q deletion (Fig. 13). No MYC or EGFR gene amplifications were found. The morphological and immunohistochemical features are consistent with a high-grade glioneuronal tumor, more specifically, a GS with primitive neuroectodermal differentiation. The genetic pattern of chromosome 10 loss is analogous to that encountered in conventional glioblastoma.
Discussion GS is an aggressive primary central nervous system neoplasm initially described in 1895 by Stroebe [2] as
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Fig. 8 A dense reticulin network is evident in the sarcomatous elements, whereas nodules with primitive cells are reticulin-poor (Reticulin, 100·)
Fig. 9 The primitive component strongly expressed synaptophysin, whereas the sarcomatous and astrocytic elements were negative (Synaptophysin, 100·)
having both malignant glial and sarcomatous components. Currently, GS is considered to be a variant of GBM and is a grade IV neoplasm according to the 2000 WHO grading scheme [6]. GS accounts for approximately 2–3% of all GBM cases and typically arises in older adults, with a slight male predominance and predilection for the temporal lobe [1]. The etiology of the sarcomatous component has been controversial. Previously it was thought to arise via neoplastic transformation of hyperplastic blood vessels that are commonly present in high-grade glial neoplasms. However, recent genetic analysis of the glial and sarcomatous elements have now shown that
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Fig. 10 The glial component is highlighted with a GFAP)immunostain (GFAP, 100·)
Fig. 11 The sarcomatous portion is diffusely positive for vimentin, whereas the majority of primitive cells are immunonegative (Vimentin, 100·)
their genetic alterations are similar and often identical [3]. Recent comparative genomic hybridization studies have also shown similar genetic alterations in both components, and strongly support the interpretation that both elements are derived from a common neuroectodermal progenitor [3–5]. Previous reports and series of GSs have documented metaplastic bone, cartilage, smooth muscle, and epithelial elements [1, 7]. Only three other cases of GSPNET have been reported [1, 7, 8]. Like the more commonly seen metaplastic elements that characterize GS, the presence of a PNET-like component may reflect either the capability of neuroectodermal progenitor cells to differentiate along multiple lines [8] or may represent a clonal prolifera-
Fig. 12 FISH utilizing probes against the chromosome 7 centromere (green) and the EGFR gene (red) yielded more than two signals for each in most tumor nuclei. This is consistent with polysomy 7 (chromosomal gain) (Fluorescence, 1000·)
Fig. 13 FISH utilizing probes against the PTEN (10q23.3; green) and the DMBT1 (10q25.3-q26.1; red) genes yielded only one signal for each in most tumor nuclei. This is consistent with either a chromosome 10q deletion or monosomy 10 (Fluorescence, 1000·)
tion of the stem/progenitor cell itself. The latter hypothesis would be consistent with recent data showing that a cancer stem cell can be isolated even from conventional glioblastomas [3]. Prognosis is poor for patients with GS and in most examples, the clinical behavior is indistinguishable from routine glioblastoma [7, 9, 10]. However, metastatic spread to extracranial sites has been reported more frequently than in GBM [9, 10]. Lungs, pleura, cervical lymph nodes, bones, and liver are the most frequently reported sites of metastases [1], as well as well-documented intra-axial spread [11]. In the
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majority of reported cases, the metastasis consisted of the sarcomatous component. In the case report of GSPNET by Wharton et al., [1] systemic metastases were comprised PNET alone, suggesting that this component was the most aggressive.
Conclusion Very rarely, GS may be associated with a primitive neuroepithelial component. We report a tumor with both these features. It is possible that the primitive neuroectodermal component seen in this tumor either reflects the capacity of the neoplastic neuroectodermal progenitor cell to undergo a wide range of divergent differentiation or it may represent a clonal proliferation of the progenitor cell itself. Because the latter cell type resembles cerebral PNET and the latter are highly aggressive tumors with a predilection for meningeal invasion, dissemination into the subarachnoid space, and a significantly increased risk of hematogenous spread, it is possible that patients with GSPNET may require altered, more aggressive treatment regimens. However, follow-up of additional cases is needed to definitely determine whether the presence of this component significantly alters the already aggressive biology of GS in general.
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