Medical Case Studies: 63 Year-Old Man With Dementia

CLINICAL HISTORY

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.

NEUROIMAGING

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. 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 involving the clivus and the pituitary gland.

Histological examination revealed large atypical lymphoid cells which were also found in most of the intra- and extracerebral blood vessels, but very few were accompanied by fibrin thrombi. Multifocal infiltration was seen in the leptomeningeal and the ventricular space as well as in the brain parenchyma. On the right side, the VI nerve showed an infiltration by tumor cells. 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. However, in other adjacent areas, the mass entirely consisted of CD20-positive neoplastic cells. 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.

MOLECULAR PATHOLOGY

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.

FINAL DIAGNOSIS

DIAGNOSIS

Intravascular large b-cell lymphoma with extensive sellar involvement..

DISCUSSION

In the reported case of a 63 year-old man showing a fulminant clinical course consisting of progressive dementia, cerebellar ataxia, myoclonus, alternating hemiparesis, right VI nerve palsy and somnolence, differential diagnosis comprised primarily a metastatic disease (e.g. primary tumor like renal cell cancer or melanoma), a systemic lymphatic disease and a brain stem encephalitis. A sellar mass of 3.2 cm in maximum diameter was diagnosed one month before death. Autopsy revealed an intravascular large cell lymphoma (IVLL).

Intravascular large cell lymphoma (IVLL) is a rare neoplasm characterized by the proliferation of lymphoma cells predominantly within the blood vessels. It most likely originates from a unique subtype of B cells, their normal counterpart being of germinal center/post germinal center B-cell.

According to the WHO classification it is considered a subtype of diffuse large B-cell lymphoma. Probably, some cases previously diagnosed as primary CNS lymphomas may have included IVLL cases. PCR studies revealed that IVLL might be associated with EBV infection, but in the majority of cases such association could not be established. Clinical manifestations are typically neurologic and dermatologic, but it is often diagnosed solely at autopsy. In general, IVLL is a very aggressive lymphoma which responds poorly to chemotherapy and death occurs in most cases within a short time following presentation, according to the immunohistochemical gene expression profiles delineating IVLL as diffuse large B-cell lymphoma of activated type. Although an more or less extend extravascular tumor component is a known feature of IVLL, the peculiar phenotype of intravascular proliferation is not clarified and still controversial. Probably the tumor cells are unable to extravasate because of the disturbance of adhesion profile on the tumor cells and/or endothelial cells. Of these the ß1-integrin CD29 is documented to be lacking on IVLL. In our case, the patient presented with a mass lesion which initially could be seen only 2 months before death, but reaching a diameter of 4 cm by the time of his death. The determinant histologic feature of IVLL is the intraluminal presence of tumor cells and thus the extensive extravascular involvement of CNS with diffuse infiltration of lymphoma cells seen in our cases is remarkable since this finding is described in only 13 cases in the literature. Beside the mass in the CNS, the large tumor in the adrenal glands and surrounding tissue is a known feature of IVLL and probably contributed to the fever that is often encountered in IVLL. This is the first published case of an intravascular B-cell lymphoma to become predominantly manifest as a large sellar tumor mass.

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