Rare case of diffuse large B-cell lymphoma presenting with central pontine myelinolysis

Abstract

Central pontine myelinolysis (CPM) is commonly associated with osmotic stress and rapid correction of hyponatraemia. It has rarely been reported in conjunction with malignancies. We report a case where CPM was not only associated with a new diagnosis of diffuse large B-cell lymphoma but was also a key presenting feature.

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma accounting for approximately a quarter of cases.¹ Clinically aggressive, it typically presents with symptomatic nodal disease, systemic ‘B’ symptoms and an elevated lactate dehydrogenase (LDH).² Central pontine myelinolysis (CPM) is a neurological disorder characterised by non-inflammatory demyelination of the basis pontis, with degeneration and loss of oligodendrocytes while sparing nerve cell bodies and axons.³ It is the classic manifestation of osmotic demyelination syndrome caused by the rapid correction of hyponatraemia.^4–6

We report a case of DLBCL associated with CPM. This has rarely been described with only a few brief reports in the literature.^{7 8} CPM has also been reported in two cases of Hodgkin’s lymphoma.^{9 10} Our case report is therefore an important addition to the literature. We also discuss potential mechanisms of CPM in the setting of DLBCL. This is currently unknown, with no rapid shifts in serum sodium reported in published case studies to date.^{7 8} Additionally, our case is further distinguished by the uncommon presentation and difficult diagnosis. While extranodal involvement is observed in up to 40% of DLBCL cases,¹¹ the pattern of disease was unusual in our case where the disease was primarily in multiple subcentimetre subcutaneous nodules with no nodal involvement.

Case presentation

An 83-year-old man presented to our hospital with a 3-month history of progressive fatigue, lower limb oedema and functional decline. He was previously well and living independently at home alone. His medical history consisted of mild thrombocytopenia (platelets approximately 100×10⁹/L) identified 8 months prior, hypertension and previous choledocholithiasis. Clinical examination identified large volume third spacing with significant peripheral oedema, ascites and pleural effusions. Additionally, neurological signs were elicited including dysarthria and subtle dysmetria. No other signs were noted on full neurological examination. There was no palpable lymphadenopathy or organomegaly.

Investigations

Laboratory investigations on admission showed anaemia (haemoglobin 78 g/L) and thrombocytopenia (platelets 64×10⁹/L), with a normal differential count and blood film. Biochemistry results were notable for severe hypoalbuminaemia (albumin 16 g/L) and an elevated LDH (412 U/L, reference range: 120–250 U/L). Coagulopathy was also present with an international normalised ratio (INR) of 1.9 and activated partial thromboplastin time of 42 s (reference range 22–32 s), both fully correcting on mixing studies. Subsequent factor (F) levels (IU/mL) were globally reduced: FV 0.51, FVII 0.22, FVIII 1.16, FIX 0.72, FX 0.42 and FXI 0.35. Protein C and S were also reduced at 0.35 U/mL and 0.28 IU/mL, respectively. Markers of malnutrition and sarcopenia were present with transthyretin <30 mg/L (reference range: 170–340 mg/L) and creatine kinase of 16 U/L (reference range: 40–200 U/L).

Liver pathology was initially suspected. Abdominal ultrasound identified an enlarged spleen measuring 1025 cc, however there was no evidence of liver cirrhosis or portal hypertension. Transient elastography identified no cirrhosis with a median liver stiffness of 8.6 kPa (IQR 1.0). Upper endoscopy was unremarkable.

MRI of the brain was performed ~1 week into admission. This demonstrated characteristic changes of CPM in the central pons, with diffusion-weighted imaging (DWI) restriction, symmetrical T1 hypointensity and T2 hyperintensity (figure 1A). There was no gadolinium enhancement to suggest central nervous system (CNS) malignancy. Additional CNS investigations (MRI of the spine, lumbar puncture) were normal.

Figure 1.

(A) T2-weighted MRI brain image demonstrating hyperintensity in the pons consistent with pontine myelinolysis at diagnosis. (B) Maximal intensity projection of Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan demonstrating small avid lesions in bone and soft tissue (blue arrows). (C). Axial fused views of FDG-PET scan demonstrating avid lesions in bone and soft tissue (green arrows).

Further investigations were performed in search of a unifying diagnosis. Pan-scan CT confirmed splenomegaly but was otherwise unremarkable with no lymphadenopathy or evidence of solid organ malignancy. Bone marrow biopsy showed no morphologic or immunophenotypical evidence of malignancy. Finally, a positron emission tomography (PET) scan was undertaken which identified multiple focal areas of avidity. These were all subcentimetre in size and involved bone, subcutaneous tissue and muscle, with no nodal, splenic or liver uptake (figure 1B, C). These were not visualised on previous CT scan. Biopsy of a bone lesion established the diagnosis of non-germinal centre DLBCL with a Ki67 proliferation index of 95%. Immunohistochemistry showed triple positive expression of BCL2 (95%), BCL6 (80%) and C-MYC (70%) (figure 2A–C).

Figure 2.

(A) H&E sections demonstrating a diffuse infiltrate of large monomorphic lymphocytes, CD20 expression by immunohistochemistry (B) and MUM-1 expression by immunohistochemistry (C).

Differential diagnosis

The initial differential diagnoses were broad given the non-specific symptoms of fatigue and functional decline. Liver disease was initially suspected given the constellation of third spacing (pleural effusions, ascites), cerebellar findings, thrombocytopenia, hypoalbuminaemia and coagulopathy. Additionally, clotting factors (other than FVIII) and the natural anticoagulants protein C and S were decreased, a characteristic pattern in liver failure. However, the patient had no risk factors for liver disease and the ensuing FibroScan was normal. While malignancy was another major differential diagnosis, initial investigations with a pan-CT scan and bone marrow biopsy were unrewarding. The diagnosis was eventually made after a PET scan identified low-volume nodules not identified on CT scan. This case highlights the variable presentation and tumour burden of DLBCL, as well as the value of a ‘screening’ PET scan in diagnostic dilemmas.

The MRI findings were highly characteristic of CPM, consisting of a central pons lesion with hyperintensity on T2 and corresponding hypointensity on T1-weighted images. Restricted diffusion on DWI was also observed. The MRI findings typically take up to 2 weeks to develop after osmotic demyelination, however this temporal relationship could not be assessed given the sodium levels were stable (129–134 mmol/L) over the preceding months. While these findings are often diagnostic for CPM,³ we considered other possibilities given rapid correction of sodium was absent in our case. Pontine infarction was unlikely given the MRI demonstrated no evidence of prior ischaemic insults or small vessel changes elsewhere. Additionally, the lesion was central pons in location and not consistent with a vascular territory. The clinical examination (and MRI) was not consistent with Parkinsonism with only dysarthria and subtle dysmetria noted and an absence of cardinal features (bradykinesia, rigidity, tremor, postural instability). The dysarthria in our case is likely due to disruption of corticobulbar fibres from the pontine lesion. One other key differential is whether the central pontine lesion could be due to lymphoma. This was unlikely based on the MRI scan which demonstrated no gadolinium enhancement. However, further workup was performed with lumbar puncture showing normal cytology and negative flow cytometry for lymphoma involvement.

Treatment

The patient rapidly deteriorated by this point, 3 weeks into the hospital admission. He was bedbound, unable to feed himself and had an Eastern Cooperative Oncology Group Score of 4. Treatment with several weeks of high calorie/protein enteral feeding, multivitamin replacement and concentrated intravenous albumin replacement failed to improve his clinical state. His platelets had further decreased to the 25×10⁹/L and his coagulation profile remained deranged. Given his performance status, lymphoma-directed therapy was initiated with several days of prephase steroids (oral dexamethasone 20 mg daily), followed by dose-attenuated rituximab 375 mg/m², cyclophosphamide 400 mg/m², vincristine 1 mg and prednisolone 40 mg/m².

Outcome and follow-up

Chemotherapy was followed by rapid clinical improvement. Within several days, the functional status and neurological signs all improved. Remarkably, the coagulopathy (INR 1.1 from 1.8) and thrombocytopenia (platelets 90×10⁹/L from 28×10⁹/L) promptly resolved within 48 hours of treatment. Despite the profound decline prior to the treatment, the patient was able to transition to rehabilitation within 2 weeks. PET scan after two cycles of chemotherapy demonstrated complete metabolic remission. Repeat MRI at 3 months post chemotherapy demonstrated resolution of the CPM. The patient is currently independent at home and completing the remaining courses of chemotherapy as an outpatient.

Discussion

While CPM is typically associated with Osmotic demyelination syndrome (ODS), it has also been observed in other conditions including alcoholism, malnutrition, liver disease, burns, renal failure, hypophosphatemia, hypokalemia, anorexia and systemic lupus erythematosus.⁴ However, few reports in the literature have described CPM in association with DLBCL (table 1). Only two case reports have been previously published, both describing cases without rapid correction of the serum sodium.^{7 8} Given the paucity of data, the mechanism of this association is currently unknown. However, several similarities between these cases and our own are notable. The report by Kawata et al also demonstrated third spacing, hypoalbuminemia and mild hyponatraemia (Na 132–133 mmol/L).⁷ Mild hyponatraemia was also observed in the report by Zhou et al (Na 129–134 mmol/L).⁸ We theorise that the combination of malnutrition and mild hyponatraemia serves as triggers for CPM in the absence of rapid sodium correction. Indeed, malnutrition is a recognised cause of CPM.⁴ The pathophysiology of this relates to impaired production of intracellular osmolytes. In the setting of hyponatraemia, water osmotically flows across the blood–brain barrier, necessitating glial cells to adapt by decreasing intracellular osmoles and preventing cerebral oedema.¹² A rise in sodium may raise the tonicity faster than osmoles can be synthesised or transported back into the cell, causing cell shrinkage and death, with oligodendrocytes being particularly vulnerable.³ Malnutrition increases the susceptibility to osmotic demyelination by impairing the regeneration of intracellular osmolytes. The malnutrition in our case was marked with low creatine kinase, transthyretin and clinical sarcopenia. Further studies are required to delineate the pathophysiology of CPM in DLBCL.

Table 1.

Published case reports of non-Hodgkin’s and Hodgkin’s lymphoma presenting with CPM

Authors	Year	Disease	Age (years)	Gender	Presenting features
Kawata et al7	2015	DLBCL	62	Female	Intermittent expressive dysphasia and ‘vague’ episodes
Zhou et al8	2013	DLBCL	78	Female	Fatigue, progressive weakness, walk disturbance, severe lower limb oedema
Chintagumpala et al9	1993	Hodgkin’s lymphoma	12	Male	Ataxia and incoordination
Loiuzou et al10	1981	Hodgkin’s lymphoma	28	Male	Lower limb sensory, weakness, ataxia, dysarthria at disease relapse

CPM, central pontine myelinolysis; DLBCL, diffuse large B-cell lymphoma.

Our case had several other notable aspects. The distribution of disease was unusual and caused initial diagnostic uncertainty. PET scan finally identified multiple focal areas of avidity that were subcentimetre in size and were not apparent clinically or on CT scan. It was interesting that the albumin and coagulopathy did not improve with extensive nutritional replacement but responded rapidly after specific antilymphoma therapy. Similarly, the thrombocytopenia and coagulopathy briskly improved after chemotherapy and we speculate whether these manifestations were due to a paraneoplastic process.

Learning points.

• Clinicians should be aware of the multiple aetiologies of central pontine myelinolysis (CPM) other than osmotic demyelination, including an association with lymphoid malignancies.

• Malnutrition is a possible risk factor for CPM by impairing the regeneration of intracellular osmolytes.

• CPM can occur in the absence of rapid sodium shifts, especially if other risk factors such as malnutrition are present.

• The typical MRI findings of CPM are restricted diffusion on diffusion-weighted imaging, hypointensity on T1 and hyperintensity on T2, occurring symmetrically in the central pons.

• Diffuse large B-cell lymphoma with low tumour burden may be diagnostically challenging and a ‘screening’ positron emission tomography scan may be helpful.

Ethics statements

Patient consent for publication

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