Recurrent Primary CNS Lymphoma Presenting with Central Neurogenic Hyperventilation

Background: Tumor-induced Central Neurogenic Hyperventilation (CNH) is exceedingly rare, about half resulting from Primary CNS Lymphoma (PCNSL) despite their rarity. Results: We present a 75 year-old, immunocompetent woman with recurrent PCNSL leading to CNH. She was initially diagnosed with PCNSL via biopsy of the single enhancing left caudate focus among diffuse, nonenhancing CNS infiltrative disease without diffusion restriction or CSF or intraocular dissemination. She received 5 cycles of biweekly rituximab and methotrexate, initially dosed at 3.5 gm/m2 with procarbazine and vincristine, then dosed at 8 gm/m2 with monthly temozolomide 150 mg/m2. Repeat brain MRI revealed no residual enhancement with confluent subcortical nonenhancing signal without brainstem involvement suggesting methotrexate-related leukodystrophy. Two weeks after cytarabine consolidation, she presented with intractable emesis without gastrointestinal cause. A week later, she developed marked tachypnea without cardiopulmonary etiology. Blood glasses revealed respiratory alkalosis (maximal pH=7.67, respiration=27, pO2=241; minimum pCO2=10). She remained otherwise neurologically intact. For suspicion of CNH, she was intubated and brain MRI revealed progressive nonenhancing disease without restricted diffusion extending periventricularly from dorsal midbrain to vermis. CSF profile revealed normal protein (40 mg/dL), RBC 97/μL, WBC 3/μL (88% lymphocytes) with negative bacterial cultures, toxoplasma IgG and HSV, JC, CMV, EBV and JC PCRs. Flow cytometry and cytology revealed no lymphoma cells. Brain and body PET revealed avid FDG-uptake in the new periaqueductal nonenhancing tumor, confirming lymphoma recurrence; no extracranial disease was evident. Her CNH resolved though remission was only brief following posterior fossa radiation (30Gy, 17fx), dexamethasone 40 mg/day, and off-label nivolumab 3 mg/kg q 2 weeks. Repeat brain MRI revealed diffuse cerebral nonenhancing disease progression at 4 months after recurrence. She died shortly after transfer to hospice. Conclusion: This represents the first recurrent PCNSL leading to CNH, which was a presenting symptom in all prior PCNSL cases reported and lead to death in the majority.


Case Presentation
A 75 year-old, immunocompetent woman presented with months of progressive dementia and aphasia. A brain MRI revealed diffuse cerebral, predominantly subcortical, non-enhancing disease ( Figure  1A). There was a single site of enhancement in the left caudate and negligible diffusion restriction noted ( Figures 1B-1C). Stereotactic biopsy of single enhancing lesion revealed pathology consistent with diffuse large B cell lymphoma. Hematoxylin and Eosin (H&E) showed large atypical lymphoid cells in an angiocentric pattern and with scant cytoplasm, large pleomorphic nuclei with clumped chromatin, nuclear moulding and occasionally prominent nucleoli (Figure 2A). Scattered mitoses were seen. Immunohistochemistry was positive for CD20 ( Figure 2B) and MUM1. Subsets were positive for BCL2 and BCL6 and few for CD10. Small mature CD3 T lymphocytes infiltrate was detected. The Ki67 proliferation index was as high as 80-90% ( Figure  2C).

Case Report
Open Access   involvement. She was treated with 5 cycles of biweekly intravenous rituximab (500 mg/m 2 ) and methotrexate. Methotrexate was increased from 3.5 to 8.0 gm/m 2 while the initial procarbazine (100 mg/m 2 ) and vincristine 2 mg was switched to monthly temozolomide (150 mg/m 2 ) for a total of 2.5 months of therapy. After repeat brain MRI revealed remission ( Figure 1D), she underwent consolidation therapy with cytarabine (3 gm/m 2 day 1-2, q3 weeks). Over the course of this therapy, she improved clinically with a dramatic improvement in her initial encephalopathy, once again living independently. At 4 months from diagnosis and shortly after consolidation therapy, she developed intractable emesis without clear gastrointestinal cause and hyperventilation without cardiopulmonary etiology. Serial blood glasses marked revealed respiratory alkalosis (maximal pH=7.67, respiration=27, pO 2 =241; minimum pCO 2 =10). She remained otherwise neurologically intact. For suspicion of central neurogenic hyperventilation (CNH), she was intubated and brain MRI performed. While there was no clear supratentorial disease progression ( Figure  1E), there was new non enhancing FLAIR disease extending from dorsal midbrain to the vermis ( Figure 1F). Repeat brain FDG-PET revealed high glucose uptake associated with the new FLAIR disease in the pontine tegmentum ( Figure 1G), consistent with recurrent PCNSL. CSF profile revealed normal protein (40 mg/dL), RBC 97/µL, WBC 3/µL (88% lymphocytes) with negative bacterial cultures, toxoplasma IgG and HSV, JC, CMV, EBV and JC PCRs. Flow cytometry and cytology again revealed no lymphoma cells.
To palliate and spare cognitive neurotoxicity, she was treated with involved field radiation to posterior fossa radiation (30Gy in 17 fractions), dexamethasone 40 mg/day, and off-label nivolumab 3 mg/kg q2 weeks with resolution of CNH. Disease remission was only brief. By 4 months after recurrent PCNSL presenting with CNH, brain MRI revealed diffuse non enhancing disease progression, including the brainstem but more pronounced in the cerebral hemispheres ( Figure  1H). She was transferred to hospice and died shortly after 9 months after her initial diagnosis.

Conclusion
We present the first case of recurrent primary CNS lymphoma leading to Central Neurogenic Hyperventilation (CNH). CNH was a presenting symptom in all previously reported cases of CNS lymphoma, comprising nearly 60% of reported cases of tumor-induced CNH despite their rarity. Tumor-induced CNH raises the probability of CNS lymphoma in undiagnosed cases and of recurrence in diagnosed cases. Tumor-induced CNH predicts short-interval death in most cases.

Practice Points
• Primary CNS lymphoma comprises ~1% of all CNS tumors and 2.3% of primary CNS tumors. • Tumor-induced central neurogenic hyperventilation (CNH) is exceedingly rare and uniformly fatal. • Tumor-induced CNH is caused by CNS lymphoma in nearly 60% of reported cases. • CNH should raise suspicion of CNS lymphoma in undiagnosed patients and suggest recurrence in confirmed cases of CNS lymphoma.