Contributed by Michel Mittelbronn1+, Annika Wersebe2, Michael Weller3, Walter Hewer4, Richard Meyermann1, Edwin Kaiserling5, Rudi Beschorner1, Stefan M. Kröber5+
1Institute of Brain Research, University of Tuebingen, Tuebingen, Germany
2Department of Radiology, University of Tuebingen, Tuebingen, Germany
3Department of General Neurology Hertie Institute for Clinical Brain Research, University of Tuebingen, Germany
4Psychiatric and Neurological Hospital, Rottenm¨ınster, Germany
5Institute of Pathology, University of Tuebingen, Tuebingen, Germany
+M. Mittelbronn and S.M. Köber contributed equally to this publication and thus share first authorship
A 63 year-old man initially presented in February 2003 with 3 episodes of syncopes accompanied by nausea, vomiting and sweating. Starting June 2003, the patient became indifferent and showed a weight loss of 15 kg over a period of the following 6 months. In July 2003, beginning ataxia, visual and cognitive decline were reported. Neurological examination in October 2003 revealed a right VI nerve palsy, ataxia, dysarthria and dementia as the main clinical features. One month later, he suffered a cardiac arrest with resuscitation, but he eventually died of a cardio-respiratory insufficiency in November 2003 showing the clinical picture of brainstem encephalitis. Final clinical report suggested a metastatic neoplasm with unknown primary.
Until October 2003, no significant pathological alterations could be detected in CT and MRI scans. For the first time, in October 2003, small osteolytic zones were detected in the dorsal sella. Furthermore, at this time a 12 mm left periventricular enhancement led to the suspicion of an inflammatory disease. A CT scan in November 2003 revealed a mass with heterogeneous contrast enhancement in the sella region with partial destruction of the clivus and infiltration of the sphenoid sinus. The mass was 3.2 cm in maximum diameter (Fig. 1; arrow). Keeping in mind other suspect lesions of the left kidney and both adrenal glands (not shown), the radiological differential diagnosis favored a metastatic disease (e.g. primary tumor like renal cell cancer or melanoma) or a systemic lymphatic disease.
GROSS AND MICROSCOPIC PATHOLOGY:
The macroscopic appearance of the brain seemed to be in the age-related range of normal anatomy. However, a grayish-whitely mass of a diameter of 4 cm could be seen in the parasellar area (Fig 2a; arrows) involving the clivus and the pituitary gland.
Histological examination revealed large atypical lymphoid cells (Fig 2b) which were also found in most of the intra- and extracerebral blood vessels (Fig 2c), but very few were accompanied by fibrin thrombi. Multifocal infiltration was seen in the leptomeningeal (Fig 2d) and the ventricular space as well as in the brain parenchyma. On the right side, the VI nerve showed an infiltration by tumor cells (Fig 2e; Fig 2f for higher magnification). Here, tumor cells were both located intra- and extravascular spaces, the latter forming a mass with diffuse infiltration of adjacent tissue. The neoplastic cells presented with a high nucleoplasmic index, prominent nucleoli and atypic nuclear configuration. Brisk mitotic figures were seen.
By immunohistochemistry, the MiB-1-proliferation index focally reached 80 %. The neoplastic cells were strongly positive for LCA, CD20, CD62-L, CD79a, Pax-5, and MUM-1. In the sellar mass, CD20 immunoreactivity partially was detected only within vessels surrounded by normal pituitary gland tissue (Fig 2g). However, in other adjacent areas, the mass entirely consisted of CD20-positive neoplastic cells (Fig 2h). The tumor cells were negative for CD3, CD5, CD29, markers of germinal center (CD10, bcl-6), and CD138. About 5% of the lymphocytes were T-cells by CD3 immunostains and most of these cells were CD8 positive.
DNA was extracted from the specimens by standard methods and analysed by the polymerase chain reaction (PCR) with primers for gene rearrangements of the IgH by a standard protocol. PCR products were purified and analyzed by direct sequencing. Published sequences were used as reference for the germline IgH V genes. In the index case, the PCR revealed an identical clonal IgH rearrangement in the intravascular and extravascular component, confirming involvement by the same IVL cells. Sequence analysis of the PCR-amplified IgH gene demonstrated somatic mutations of the IgH gene.