Contributed by Jeroen de Jong, MD1, Hans Stoop1, Martin van den Bent, MD2, Prof. Johan M. Kros, MD, PhD1, Prof. J. Wolter Oosterhuis, MD, PhD1, Prof. Leendert H.J. Looijenga PhD1
1Department of Pathology, Erasmus MC-University Medical Center Rotterdam Josephine Nefkens Institute, Daniel den Hoed, 2Department of Neuro-Oncology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands
Financially supported by Translational Research Grant Erasmus MC, and the Dutch Cancer Society
A 40-year-old female presented with blurred vision and diplopia, followed by slowly progressive left-sided motor and sensory disturbances. She also suffered from memory loss and was had mild spatial and temporal disorientation. A T2 weighted MRI showed a large area of high signal intensity in the periventricular white matter of the right more than the left occipital region and the corpus callosum, without enhancement on T1 weighted images after gadolinium administration and without mass effect. A stereotactic biopsy of the intracerebral lesion showed blast-like neoplastic cells within a mononuclear infiltrate. No diagnosis could be made based on morphology and immunohistochemistry using a large series of markers. However, based on positive OCT3/4 nuclear staining, the tumor was diagnosed as a germinoma (seminoma of the brain). The patient was treated accordingly and her condition improved, although focal deficits remained.
A 40-year-old female presented with blurred vision and diplopia, followed by slowly progressive left-sided motor and sensory disturbances. She also suffered from memory loss and mild spatial and temporal disorientation. A T2 weighted MRI (Figure 1A) showed a large area of high signal intensity (indicated by arrows) in the periventricular white matter of the right more than the left occipital region and the corpus callosum, without enhancement on T1 weighted images (Figure 1B), There was no mass effect. A tumor was considered unlikely, and acute demyelinating encephalomyelopathy (ADEM) was suspected. Repeated cerebrospinal fluid (CSF) examinations showed a mononuclear pleocytosis (10 cells per cubic mm, normal value: <3 cells), without immunohistochemical evidence of tumor cells; tumor markers HCG, AFP and CEA were not elevated. Flow cytometry showed predominantly reactive T-lymphocytes, but again no evidence of tumor cells. CT scan of thorax and abdomen did not reveal any abnormalities. The CSF-serum IgG index was normal, and oligoclonal bands were absent. No evidence of a vasculitis or an inflammatory disease was found. Treatment with steroids proved ineffective.
A stereotactic biopsy of the intracerebral lesion showed blast-like neoplastic cells within a mononuclear infiltrate (Figure 2A). The rounded tumor cells contained a large centrally located nuclei. A wide panel of markers including those for carcinoma, melanoma and primary central nervous system lymphoma was applied: CD3, CD4, CD5, ALK-1, CD19, CD20, CD79a, CD45, CD30, S-100, MELAN-A, HMB45, CD68, CD43, PLAP, hCG, AFP and CD56, all found to be negative; there was some punctuated NCL5D3 (low molecular weight keratins 8 and 18) positivity (Figure 2B). No final diagnosis could be made.
Subsequently, the marker OCT3/4 became available, which has proven to be specific for certain histological types of germ cell tumors (6), including seminomatous tumors and embryonal carcinoma. This has been confirmed in multiple independent studies (1) (for review). 100% of tumor cell nuclei present in the biopsy of the above mentioned patient clearly stained positive for OCT3/4 (Figure 2C). Because only a small number of tumor cells were present in this slide and no biopsy material was left anymore, OCT3/4 was also applied to a slide previously found to be negative by immunohistochemistry for another unrelated marker. Again all tumor nuclei stained positive for OCT3/4 without any background. Recently, the stem cell factor receptor c-KIT was also applied on a previously negative slide and the cytoplasm of some tumor cells was stained positive (Figure 2D).