Contributed by Elli Kontogeorgi1, Dimitrios Papadopoulos1, Eirini Zafeiropoulou1, George Karagkounis2, Theodore Argyrakos2, George Stranjalis3, Dimitra Rontogianni2, Dimitrios Karakalos1
1Department of Neurology, Evangelismos General Hospital, 4th floor AHEPA building, 2Department of Pathology, Evangelismos General Hospital, 3rd floor Laboratory building, 3Department of Neurosurgery, University of Athens Medical School, 7th floor Patera building, Ipsilantou 45-47, Athens, 10676, GREECE
A 24 year-old white right handed woman with an otherwise unremarkable medical and family history was admitted with vertigo, hiccups, intractable vomiting, gait unsteadiness and oscillopsia that developed gradually over 9 months. Although initially relapsing and remitting, her manifestations became persistent approximately one month prior to her admission. Neurological examination revealed periodic alternating nystagmus, gait ataxia and bilaterally brisk tendon reflexes in upper and lower extremities and a right extensor plantar reflex. On admission brain MRI there were several lesions with increased T2/FLAIR (Fig. 1BCD) and low T1 signal including a space-occupying lesion in the left half of the pons, extending into the left middle cerebellar peduncle, the medulla and the lower mesencephalic tectum (Fig.1A). Lesions did not exhibit gadolinium enhancement (Fig.1A) but showed restricted diffusion in diffusion-weighted sequences (Fig.1E). Spinal cord MRI was normal. CSF analysis on admission and two months later showed normal cell counts and glucose levels, increased protein (83mg/dL and 90mg/dL, respectively), normal IgG index and no oligoclonal bands. CSF flow cytometric analysis was within normal values and CSF cytology was negative for neoplastic cells in both occasions. Full blood counts, biochemistry, serum LDH, thyroid studies, coagulation profiles, ESR, CRP, autoimmune antibody screening including anti-AQP IV antibodies, plasma folate and B12 vitamin levels, plasma protein immunoelectrophoresis, complement levels, urine analysis and serology for hepatitis and HIV were normal. Bone marrow biopsy and contrast-enhanced whole body CT, upper and lower endoscopy and abdominal ultrasonography were unremarkable. Fundoscopy and slit-lamp examination were also unremarkable. Upon magnetic resonance spectroscopy findings suggestive of tumefactive demyelinating lesions, the patient was treated with two monthly courses of mitoxantrone with no apparent clinical benefit and expansion of lesions on MRI, yet still without gadolinium enhancement. A month after the second course of mitoxantrone she developed dysphagia, voice hoarseness and cachexia. Neurological examination revealed left abducens palsy, pathological left-sided cerebellar tests in addition to previous findings and posterior laryngoscopy showed left vocal cord paresis. A new CSF analysis revealed a raised protein level (130mg/dL) with normal cell counts and glucose. CSF cytology, oligoclonal bands were negative and flow cytometric analysis was within normal ranges. A new brain MRI indicated enlargement of pre-existing lesions with peripheral gadolinium enhancement of the brainstem space-occupying lesion (Fig.1F). Stereotactic biopsy of the brainstem lesion was performed.
Histochemical and immunohistochemical examination of two paraffin-embedded stereotactic biopsy blocks showed infiltration by middle size agranular lymphocytes in perivascular spaces (Fig. 2). These exhibited a blastic chromatin and scant cytoplasm (Fig. 3) and expressed CD56 (Fig. 4) and TdT strongly (Fig. 5). All myeloid (MPO, CD13, CD33), B-cell (CD19, CD20, CD22, CD79a, Pax-5), T-cell (CD3, CD5) and plasmatocytoid differentiation markers (CD123, TCL-1) and cytotoxic enzymes (granzyme-B, perforin, TIA-1) were negative. EBV latency examined using in situ hybridization for EBERs mRNA was also negative. Genotype PCR analysis revealed a germline configuration of the immunoglobulin heavy chain (IgH) and TCR genes. What is the diagnosis?