Brain Tumor Pathol (2006) 23:83–89 DOI 10.1007/s10014-006-0205-x
© The Japan Society of Brain Tumor Pathology 2006
CASE REPORT Hideki Kamitani · Hajime Miyata · Minako Ishibashi Masamichi Kurosaki · Minoru Mizushima Keiichi Akatsuka · Eisaku Ohama · Takashi Watanabe
Mixed germ cell tumors with abundant sarcomatous component in the temporal lobe after radiochemotherapy of neurohypophyseal germinoma: a case report
Received: March 31, 2006 / Accepted: July 3, 2006
Abstract We report a case of intracranial germ cell tumor that showed pathological changes from neurohypophyseal germinoma to mixed germ cell tumors consisting exclusively of undifferentiated sarcomatous component after radiochemotherapy. Three surgical specimens and autopsied brain from the patient were histologically examined. An initial specimen from the neurohypophyseal tumor was diagnosed as germinoma with a two-cell pattern. Five years later, after repeated radiochemotherapy, the second specimen resected from the right temporal lobe showed mixed germ cell tumors consisting of the three components of germinoma, choriocarcinoma, and immature teratoma. Six months later after intensive radiotherapy, the right temporal tumor recurred and was surgically removed. The histological diagnosis was mixed germ cell tumors with abundant immature teratoma component. The patient died of uncontrollable tumor growth with repeated intratumoral hemorrhages. The autopsied brain showed sarcoma with angionecrosis. This pathological alteration indicated an increase in the sarcomatous component after undergoing various treatments. We discuss the histological changes of intracranial germ cell tumor modified by treatment.
components in the specimens. In 2000, the World Health Organization (WHO) classified central nervous system (CNS) germ cell tumors1 into the following eight histological types: germinoma, embryonal carcinoma, yolk-sac tumor, choriocarcinoma, mature teratoma, immature teratoma, teratoma with malignant transformation, and mixed germ cell tumors. The precise histological diagnosis of CNS germ cell tumors is very important because it is closely linked to the prognosis for life and indispensable for the treatment strategy; e.g., the germinoma component is highly sensitive to radiation and chemotherapy,2 and the teratoma component tends to be highly resistant to radiochemotherapy.3 Therefore, in cases showing a teratoma component, extensive surgical resection is recommended. We describe a neurohypophyseal tumor in a 15-year-old boy diagnosed as germinoma in the first biopsy specimen. After repeated radiochemotherapy, the tumor recurred as a rapidly growing mass occupying the right medial temporal lobe, histologically showing mixed germ cell tumors with abundant sarcomatous components.
Key words Germinoma · Mixed germ cell tumor · Immature teratoma
Clinical summary
Introduction The histopathology of intracranial germ cell tumors is complicated because of the mixture of various histological H. Kamitani (*) · M. Ishibashi · M. Kurosaki · M. Mizushima · K. Akatsuka · T. Watanabe Department of Neurosurgery, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan Tel: +81-859-38-6767; Fax +81-859-38-6769 e-mail:
[email protected] H. Miyata · E. Ohama Department of Neuropathology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Tottori, Japan
A 15-year-old boy was admitted to our clinic in March 1997 because of a 2-year history of diabetes insipidus. Magnetic resonance imaging (MRI) demonstrated a solid neurohypophyseal mass with gadolinium-diethylene triamino pentacetic acid (Gd-DTPA) enhancement (Fig. 1A,B). His serum human chorionic gonadotropin (hCG) level was slightly elevated to 16 mIU/ml; thus, the clinical diagnosis of germinoma with syncytiotrophoblastic giant cell (STGC) was considered. A biopsy was performed by the transsphenoidal approach. The histological diagnosis was germinoma with a two-cell pattern appearance (Fig. 2; also see the pathological findings section); however, the clinical diagnosis resulted from the high level of serum hCG (16 mIU/ml). Three courses of PE (CBDCA and etoposide) chemotherapy and radiation therapy (30 Gy for whole brain and 20 Gy for the local area) were given, resulting in the complete
84 Fig. 1A,B. Gadolinium (Gd)enhanced magnetic resonance (MR) images in March 1997, when the neurohypophyseal tumor was detected. A Coronal image; B sagittal image
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B chemotherapy, the tumor, in addition to intratumoral hemorrhages, grew rapidly, requiring additional surgical removal in April 2003 (not shown). The serum hCG had not been elevated since July 2000. In June 2003, the patient lost consciousness because of tumor invasion of the brainstem and repeated intratumoral hemorrhages; he eventually died of tumor regrowth. Brain autopsy was performed with full consent of his family members.
Materials and methods
Fig. 2. Hematoxylin and eosin-stained section of the initial biopsy specimen shows proliferation of uniform cells with relatively large vesicular nuclei and clear cytoplasm, mixed with perivascular and parenchymal lymphocytic infiltration, consistent with the histological features of germinoma. Bar 50 µm
disappearance of the mass lesion with normalization of the serum hCG level. An additional three courses of PE chemotherapy followed. The patient remained disease free for the following 3 years, and MRI showed no neurohypophyseal mass (Fig. 3A,B). In July 2000, the tumor recurred as ventricular dissemination on MRI (not shown), and the patient showed an elevated serum hCG level (140 mIU/ml). Radiation therapy, 20 Gy to the whole lateral ventricle and 28 Gy to the whole spinal cord, was added to prevent an extensive cerebrospinal fluid (CSF) dissemination. After a 2-year disease-free period, a small mass appeared in the right medial temporal lobe adjacent to the inferior horn (Fig. 4A,B), without elevation of the serum hCG level. In May 2002, the small mass was treated by stereotactic radiosurgery (for 5.6 ml volume, MD 12 Gy, 50% isodose). In October 2002, nevertheless, the mass lesion dramatically increased in size with a midline shift to the left side on MRI (Fig. 5A,B), and subtotal removal of the tumor by craniotomy was performed. The tumor of the second specimen was histologically diagnosed as a mixed germ cell tumor (Fig. 6; also see pathological findings). Regardless of aggressive
Formalin-fixed, paraffin-embedded specimens were used in this study. Sections were stained with hematoxylin and eosin. Adjacent serial sections were subjected to immunohistochemical studies. Microwave boiling of deparaffinized sections in 0.015 M sodium citrate buffer solution (pH 6.0) for 12 min was employed as an antigen retrieval procedure if necessary. Primary antibodies used in this study include placental alkaline phosphatase (PALP, monoclonal), beta-subunit of human chorionic gonadotropin (hCG, polyclonal), glial fibrillary acidic protein (GFAP, polyclonal), vimentin (clone V9), cytokeratin (clone MNF116), Ki-67 (clone MIB-1), phosphorylated neurofilament (clone 2F11) (all purchased from Dako, Tokyo, Japan), and nonphosphorylated neurofilament (clone SMI311; Sternberger Monoclonals, Maryland, USA). Sections were incubated with primary antibodies for overnight at 4°C, followed by incubation with appropriate secondary antibodies conjugated to peroxidase-labeled dextran polymer (EnVision+; Dako) for 45 min at room temperature. Immunoreaction was visualized by 3,3′-diaminobenzidine tetrahydrochloride (DAB). Sections were counterstained with hematoxylin. Immunostaining with omission of primary antibodies was used for negative controls.
Pathological findings The first biopsied specimen in March 1997 consisted of uniform cells resembling primitive germ cells with large vesicular nuclei and clear cytoplasms and of perivascular
85 Fig. 3A,B. Gd-enhanced MR images in July 1997, when adjuvant therapies were performed against the germinoma. A Coronal image; B sagittal image
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B
Fig. 4A,B. Gd-enhanced MR images in May 2002. Note a small enhanced lesion in the medial temporal lobe, probably a remote recurrence of the germinoma. This lesion was targeted for stereotactic radiosurgery. A Axial image; B coronal image
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B
Fig. 5A,B. Gd-enhanced MR images in October 2002, when the right temporal enhanced mass rapidly increased in size with intratumoral hemorrhages after stereotactic radiosurgery. A Axial image; B coronal image
A lymphocytic infiltration (see Fig. 2), being consistent with the histological features of germinoma. Although the serum level was elevated, syncytiotrophoblastic giant cells (STGCs) were not observed in the small biopied specimen. The tumor resected at the second operation in October 2002 was diagnosed as mixed germ cell tumors consisting of three components: (1) immature teratoma, (2) germinoma, and (3) choriocarcinoma. The predominant component was immature teratoma, consisting of abundant vimentinpositive embryonic mesenchyme-like stroma or undifferentiated sarcomatous component of “immature teratoma” (see Fig. 6A), mixed with irregularly dilated cysts covered
B by tumor cells with or without microvilli arranged linearly on the periphery of the collagen-rich matrix (see Fig. 6B), rare immature and equivocal tubular structures surrounded by embryonic mesenchyme-like stroma (see Fig. 6C), immature cartilage-like areas (see Fig. 6D), GFAP-positive astrocytic cells, neuronal cells positive for nonphosphorylated and/or phosphorylated neurofilament, and cytokeratin-positive cells (see Fig. 6E). There were some small foci of germinoma consisting exclusively of PALPpositive uniform cells with large vesicular nuclei and clear glycogen-rich cytoplasms (see Fig. 6F,G), and occasional lymphocytic infiltration. There were also clusters of
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Fig. 6A–H. Histological findings of the resected tumor shown in Fig. 5, diagnosed as mixed germ cell tumors. A Predominant area, composed of hypercellular spindle-shaped tumor cells, shows herringbone appearance, reminiscent of embryonic mesenchymal tissue or undifferentiated sarcomatous component of immature teratoma. B Irregularly dilated cysts (asterisks) covered by tumor cells with or without microvilli arranged linearly on the periphery of the collagen-rich matrix. C Immature tubular structures (arrows) surrounded by embryonic mesenchyme-like stroma. D Tumor cells with round- to oval-shaped hyperchromatic nuclei and triangular cytoplasm scattered within the
basophilic mucinous matrix, reminiscent of fetal immature cartilage. E Scattered cytokeratin-immunoreactive cells within the tumor show epithelial differentiation. F Foci of germinoma consisting of placental alkaline phosphatase (PALP)-positive round uniform cells with large vesicular nuclei and clear cytoplasm. G Glycogen-rich cytoplasms of germinoma cells demonstrated by positive periodic acid–Schiff (PAS) reaction. H Clusters of beta-human chorionic gonadotropin (beta·hCG)-immunoreactive, relatively small, not giant, tumor cells, consistent with cytotrophoblastic elements of choriocarcinoma. Bars 100 µm
Fig. 7. Gross findings of the autopsied brain showing the lobectomized right temporal lobe A, the left uncal herniation (arrow in A), and swelling of the right optic nerve (arrowhead in A). Note the areas of gray-blue discoloration along the edge of the right lobectomized area (arrowheads in B) and mainly in the subarachnoid spaces of the
midbrain and upper pons (arrowheads in C), histologically consisting exclusively of spindle-shaped tumor cells D. Angionecrosis (arrows in E) in and around the remaining tumor tissue. Bars A–C 1 cm; in D, E 100 µm
hCG-positive, relatively small round cells consistent with cytotrophoblastic elements of choriocarcinoma (see Fig. 6H). Syncytiotrophoblastic giant cells were not observed. Ki-67 labeling index was the highest (48%) in the undifferentiated sarcomatous component. The tumor resected at the third operation in April 2003 after repeated radiochemotherapy consisted exclusively of undifferentiated sarcomatous component, resembling the remaining tumor tissue in the autopsied brain (not shown). The autopsied brain, weighing 1380 g after fixation (Fig. 7A–C), revealed left uncal herniation. The tumor tissues, consisting exclusively of hypercellular spindle-shaped cells
with frequent mitotic figures (undifferentiated sarcomatous component) (Fig. 7D), remained in the lateral ventricles, in the subarachnoid spaces of the cerebrum infiltrating along the edge of the right temporal lobectomy area, and in the cerebellum, midbrain, pons, right optic nerve, anterior lobe of the pituitary body, and the cavernous sinus. There were necrotic areas consisting of abundant round ghost cells reminiscent of germinoma; however, immunoreactivities for PALP and hCG were not detected. Fresh to recent hematomas associated with angionecrosis (Fig. 7E), putatively caused by radiation therapy, were observed in and around the remaining tumor tissues, occupying the right
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external and extreme capsules, basal ganglia, hypothalamus, and white matter of the superior temporal gyrus, extending to the right midbrain and pontine base.
Discussion Because the neurohypophyseal germinoma was considered to be the primary tumor in our case, the histological features of the recurrent tumors, including the autopsy sample, after repeated radiochemotherapy during the 6-year treatment period, were investigated to show sequential histological changes from germinoma to mixed germ cell tumor and eventually undifferentiated sarcoma. Cases of intracranial teratoma with abundant sarcomatous component have rarely been reported.4–6 Shokry et al.4 reported a case of immature teratoma with sarcomatous components in the right basal ganglia of an 8-year-old boy, and Preissig et al.5 reported a case of pineal teratoma with rhabdomyosarcoma component. Both cases had poor survival time regardless of intensive adjuvant therapies. Our question was why histological features changed from germinoma to a mixed germ cell tumor with abundant sarcomatous component. We speculated the following two possible mechanisms. (1) Malignant transformation from germinoma to mixed germ cell tumor; the cells consisting of germinoma were genetically transformed to the cells consisting of the malignant mixed germ cell tumors. (2) The tumor arose originally as mixed germ cell tumor consisting of abundant germinoma, which was removed at biopsy, mixed with cytotrophoblastic element of choriocarcinoma and embryonic mesenchyma-like stroma of immature teratoma. The germinoma component is sensitive to radiochemotherapy, whereas the latter two components, particularly the embryonic mesenchyma-like stroma, are strongly resistant to radiochemotherapy, resulting in the final autopsy findings. Germ cell tumors contain several differentiated primordial germinal cells that potentially possess a multilineage cell type including immortalized nongerminomatous germ cell tumors. Freilich et al.7 have reported two cases of nongerminomatous germ cell tumors of pineal region that underwent transformation into enteric-type adenocarcinoma. Another report of pineal germinoma was documented by Kon et al.8 in which a malignant transformation occurred in immature teratoma at the corpus callous and embryonal carcinoma at the lateral ventricle outside the initial radiation field. However, it is less feasible that the germ cells were replaced by the immortalized mesenchyma-derived cells by malignant transformation. The concept that teratoma components grow after treatment in the germinoma resembles the so-called growing teratoma syndrome. This syndrome has been originally defined by Logothetis et al.9 in testicular germ cell tumor by the following three criteria: (1) normalization of the previously elevated serum tumor markers; (2) an increase in the tumor size during or after chemotherapy given for nonseminomatous germ cell tumor (NSGCT); and (3) absence of any NSGCT component other than mature
teratoma at the tumor resection. Since Rustin et al.10 documented “the growing teratoma syndrome” in a suprasellar hCG-producing germ cell tumor as the first intracranial case, several cases have been reported as typical growing teratoma syndrome in the brain.11–15 All these cases, however, showed histological changes from nongerminomatous germ cell tumors to mature teratoma with rapid growth within 1 year after chemotherapy. Strictly, our case does not fit the growing teratoma syndrome because the histological features changed from germinoma to immature, but not mature, teratoma. Moreover, the 5-year tumor progression period was longer than the previously reported cases of growing teratoma syndrome. In our case, the chemotherapy- and radiotherapy-resistant components appear to have grown in the temporal lobe with repeated hemorrhages associated with radiation-induced angionecrosis, as demonstrated in the autopsy brain. Spontaneous regression16,17 of the intracranial germinoma sometimes occurs during repeated radiologic examinations such as CT scanning; this is another indication of the dynamic pathological change in germinoma. We should always pay attention to the pathological variety and dynamic pathological changes of gernimoma once we start to examine and treat intracranial germ cell tumors. Acknowledgment Tomomi Araoka, Department of Neuropathology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, provided invaluable technical assistance.
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