A 58-year-old man with a history of rheumatoid arthritis and stage IV diffuse large B-cell lymphoma, in complete remission with no evidence of residual disease on positron emission tomography/CT after completing six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy, presented with acute onset of dysphagia to solids and liquids. On further evaluation, his dysphagia was attributed to a vagus nerve palsy, and later during his admission, he developed rapidly progressing left facial and vestibulocochlear nerve palsies. Imaging studies displayed pathological enhancement of bilateral seventh and eighth cranial nerves, concerning for leptomeningeal recurrence of lymphoma. Cerebrospinal fluid analysis and flow cytometry were confirmatory, revealing markedly atypical monotypic CD19 positive B cells.
- cranial nerves
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This report describes the broad differential and diagnostic challenge in the rare case of a leptomeningeal recurrence of diffuse large B-cell lymphoma (DLBCL), an aggressive cancer characterised by a proliferation of mature B cells.1 DLBCL is the most common subtype of non-Hodgkin’s lymphoma (NHL), comprising 30% of cases worldwide.2 It commonly presents as a rapidly enlarging mass of the gastrointestinal organs, bone or testes and occasionally with ‘B symptoms’ of fever and drenching night sweats. One rarer presentation of DLBCL is manifestation via leptomeningeal disease (LMD), the presence of cancer in the meninges surrounding the central nervous system (CNS). LMD of any malignancy is an uncommon complication, occurring in 5% of all malignancies and 10% of lymphomas.3 In the case of DLBCL, involvement of the CNS via LMD is rare, but often fatal, resulting in progression to death within 4–6 weeks without therapy.4 Prophylaxis against CNS relapse is available, but often toxic with only a small benefit to the patient, and is therefore rarely used. Hence, LMD still occurs in patients with DLBCL and portends a poor prognosis.
Detection of LMD in DLBCL is challenging due to variability in presentation. Because lymphoma cells in the subarachnoid space have access to multiple areas of the CNS, the presentation is variable and usually without classic meningeal signs of neck stiffness or headache.5 The most common presenting symptoms are multiple focal neurological deficits, often cranial nerve palsies of nerves II, III, V, VI and VII, although it is unknown why these nerves in particular are more affected.6 Other presenting symptoms include headaches, encephalopathy, diplopia, hearing loss, paraesthesias and weakness.6 Given these challenges, one must begin with a broad differential diagnosis. We present a case of a DLBCL recurrence with LMD that illustrates an uncommon presentation and diagnostic challenge, emphasising that there should be a high index of suspicion for LMD in any patient with a history of malignancy and acute neurological symptoms.
A 58-year-old man with a history of hypertension, rheumatoid arthritis and treated stage IV DLBCL with no evidence of residual disease on positron emission tomography (PET)/CT presented with acute-onset dysphagia to solids and liquids. He reported choking and regurgitation while attempting to eat a spoonful of cereal with milk at breakfast 2 days prior to admission and a similar occurrence when attempting only a sip of milk. Furthermore, he had eaten a full dinner the night prior without any difficulty. Along with these complaints, he also reported sudden change in voice and choking on saliva that began concurrently with his dysphagia. He had no prior history of dysphagia, peptic ulcer disease, alcohol abuse or smoking. He denied any recent fevers, chills, night sweats or weight loss but noted some painless lymphadenopathy throughout his right leg for the last few days. Otherwise, he felt well and in his usual state of health.
His medications included lisinopril and chronic prednisone 10 mg every other day for rheumatoid arthritis, with no non-steroidal anti-inflammatory drug use. Nine months prior to admission, he was diagnosed with stage IV DLBCL,but achieved complete remission 2 months ago, after six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy. Three months prior, during treatment for febrile neutropaenia, he had a throat culture resulting in ‘presumptive Candida albicans’, with no oropharyngeal lesions seen on physical examination or symptoms of dysphagia or odynophagia at that time. He lived independently at home with his wife and children, endorsed occasional alcohol use and never smoked tobacco. Family history was significant for colon cancer in his mother.
On initial examination, he was hypertensive with a blood pressure of 166/99 mm Hg and heart rate of 102 beats/min, afebrile and in no acute distress. Shotty lymphadenopathy from his right ankle to thigh was noted. Mouth and oropharynx were erythematous but without lesions or thrush. He exhibited full strength in all extremities and no obvious cranial nerve deficits. However, 2 days after admission, left-sided palate paralysis, uvular deviation to the right with phonation and weak gag on the left manifested. New focal neurological deficits continued to present in a progressive fashion. Within 48 hours of the noted palatal weakness, he developed a complete left facial droop, inability to close the left eye, and inability to elevate the left corner of his mouth.
On admission, a CT of the chest and neck with contrast showed no obvious masses, lesions or abnormalities. Direct flexible laryngoscopy revealed lack of palatal elevation and pharyngeal squeeze on the left side, with immobile left vocal cord and pooling of secretions but no nasopharyngeal or supraglottic lesions. The patient then underwent a modified barium swallow (MBS), which revealed decreased epiglottic movement and pharyngeal constriction. While this did not provide a definitive aetiology for the deficits, it raised concern for a neurological insult. In the continuing workup, antibodies against Lyme, ss-A and ss-B were negative, as well as rapid plasma reagin (RPR), bacterial and fungal serology. Laboratory workup was remarkable for an elevated lactate dehydrogenase (661 units/L; reference range 313–618) and positive antinuclear antibodies with a speckled pattern and titre of 1:160.
Further imaging studies were also completed. PET/CT of skull base to mid-thigh showed no evidence to suggest recurrence of or residual cancer. However, contrast-enhanced MRI of the orbits, face, neck and brain revealed pathological enhancement of the bilateral seventh and eighth cranial nerves, left greater than right, worrisome for leptomeningeal spread of lymphoma but with no abnormal enhancement of left vagus nerve, despite clear clinical symptomatology (figures 1 and 2). No comments were noted by radiology on the PET/CT or MRI regarding findings in the posterior cranial fossa or base of brain and skull. A lumbar puncture was performed, and cerebrospinal fluid (CSF) analysis was significant for large, markedly atypical lymphoid cells, 49% with monotypic lambda light chain expression and staining positive for CD19, consistent with involvement by the patient’s known prior malignancy and confirming the presence of LMD. CSF also contained 0.081×109/L white cell counts with 0/μ L polymorphonuclear neutrophils (PMNs) (reference range 0–5), 0.000013×1012/L red cell counts (reference range 0–0), low glucose (<20 mg/100 mL; reference range 50–80) and normal protein (55 mg/100 mL; reference range 15–60). CSF culture and gram stain were negative, as was serology for venereal disease research laboratory (VDRL), herpes simplex virus (HSV), Epstein-Barr virus (EBV) and cryptococcal antigen. Subsequent bone marrow biopsy revealed normocellular bone marrow with triphasic lineage and no malignant involvement.
Initially, a variety of differential diagnoses were suggested, frequently changing as the patient’s presentation progressed. We first considered infectious oesophagitis due to his history of immunosuppression from chronic prednisone use. Given his positive candidal throat culture 3 months earlier and erythematous oropharynx on initial examination, candida oesophagitis was considered likely, although no oropharyngeal thrush was seen. Oesophagitis was eventually discounted with unremarkable upper gastrointestinal endoscopy, although after the diagnosis was made. Due to the patient’s globus sensation, we considered an oesophageal stricture, ring or mass-obstructing lesion. However, we thought these to be less likely due to the rapid onset of our patient’s dysphagia to solids and liquids, which is uncommon for a mass obstruction, which usually presents as chronic dysphagia to solids and progression to liquids. Oesophageal-obstructing lesions were deemed less likely with CT negative for intrathoracic lesion obstructing the oesophagus, and no remarkable oesophageal narrowing noted on MBS, later confirmed by oesophagogastroduodenoscopy. We also considered oesophageal motility disorders, notably diffuse oesophageal spasm, given the acute-onset inability to swallow. However, manometry was not performed, as other findings, such as vocal cord immobility, pointed us towards a more likely neurological insult.
There was also concern for malignancy of multiple forms. We considered that an initially isolated lower motor neuron lesion of the vagus nerve could be due to a lymphomatous mass compressing the nerve along its lengthy course in the neck or chest. However, this was ruled out with an unremarkable CT of the chest and neck. Vagus nerve palsies have also been reportedly caused by cerebellopontine angle tumours, another briefly considered aetiology.7 Finally, we considered a recurrence of the patient’s DLBCL with involvement of the CNS, although LMD in particular was not mentioned.
Other less likely diagnoses we considered included cervical dissection, undiagnosed HSV, diabetes or sarcoidosis. However, given no history of trauma, no prodrome of fevers, no history of diabetes and lack of any other overt signs or symptoms, these were unlikely. Finally, considering the patient’s long-standing history of rheumatoid arthritis and an elevated erythrocyte sedimentation rate and C reactive proteinon admission, we considered the possibility of a rheumatoid arthritis flair resulting in cranial neuropathies, although rare and unlikely.8
Once leptomeningeal recurrence of DLBCL was confirmed, the patient was ultimately transferred to our comprehensive cancer centre. He had a peripherally inserted central catheter (PICC) line inserted for total parenteral nutrition due to inability to take nutrition orally. Eventually a G tube was placed, then converted to J tube due to persistent nausea, vomiting and aspiration risk. He was started on a dexamethasone taper and immediately underwent emergency X-ray telescope radiation, given the rapid progression of his facial nerve palsy, completing six fractions over the course of 1 week. He then began a chemotherapy regimen known as MATRix, consisting of rituximab (day 1) followed by high-dose methotrexate (day 2) with leucovorin, cytarabine (days 3 and 4), thiotepa (day 5) and continuous acyclovir and trimethoprim-sulfamethoxazole prophylaxis, to be repeated every 21 days for a usual total of four cycles.
Outcome and follow-up
The patient remained hospitalised for a total of 53 days. He experienced a complicated hospital course, including chemotherapy-induced pancytopaenia, Streptococcus mitis bacteraemia and Candida fungemia, both treated successfully. He consistently had bouts of vomiting with inability to tolerate tube feeds, leading to aspiration and multilobar pneumonia, with transfer to higher level of care for partial respiratory failure. He was eventually transferred back to the cancer service after his respiratory status stabilised, with mild count recovery and resolution of sepsis. Repeat CSF cytology after one round of MATRix was negative for malignant cells. He was sent home on continuous tube feeds and medication delivery through his GJ tube, with equipment for suctioning oropharyngeal secretions at home. He went on to complete three total cycles of MATRix chemotherapy, complicated by bleeding gastric ulcers and was ultimately found to have peripheral disease with soft tissue masses from L2-L5 and at S2. He further underwent four doses of radiation and high-dose chemotherapy with rituximab, busulfan and thiotepa, as well as an autologous stem cell transplant. As of submission, he is alive and awaiting restaging scans.
Our case describes a rare incidence of DLBCL recurrence presenting as multiple progressive, acute cranial nerve palsies. Malignant cells can access the leptomeninges via multiple routes, comprising both metastasis from a known primary site and recurrence in an additional location, as seen in this case. Haematogenous spread to the arachnoid is the most common route, especially in haematological malignancies, which was likely the route of metastasis in this patient.9 Other routes include vertebral and paravertebral metastases leading to direct spread along cranial nerves, direct spread from brain parenchymal lesions, metastases to the choroid plexus and iatrogenic spread via invasive procedures. In this case, our patient had a metastatic recurrence or involvement of the cancer at a secondary site after initial remission. The likely mechanism of recurrence was subclinical CNS involvement during his disease course and spread of existing microscopic disease burden haematogenously to the CNS, which went undetected. In addition, the CSF is an immunologically protected site due to the blood brain barrier, and the subclinical disease was likely not adequately treated by chemotherapy, leading to eventual recurrence shortly after remission.9 This is not an uncommon scenario, as the highest rates of CNS involvement in cases of aggressive NHL occur within the first 6 months of initial therapy.10
Diagnosis of LMD is confirmed with evidence of cancer in the CSF or with radiological manifestations. However, diagnosis based on imaging alone may be unreliable, given human error and difficulty visualising the cranial nerves, which is a point of contention in this case. It is unknown why vagus nerve enhancement was not seen on MRI, despite obvious clinical symptomatology. MRI visualisation of vagus nerve enhancement in cases of neuropathy has been previously reported, although there is known difficulty in imaging certain nerve segments, such as those adjacent to the jugular foramen.11 While MRI can be effective, adequate visualisation requires multiple imaging sequences with and without contrast, fine imaging slices and mastery of anatomy by the radiologist.12 MR neurography, a more advanced technique, has displayed vagal neuropathy in the past and was not used in this case.13 It’s possible that a lack of more specific and precise imaging techniques, along with inevitable human error, could have contributed to the lack of MRI evidence to correlate with the clinical vagus nerve palsy observed. The gold standard for diagnosis of LMD of DLBCL is cytomorphological examination of CSF by light microscopy. Immunocytochemistry, flow cytometry and PCR of the CSF can aid in identifying malignant cells with increased sensitivity, 40%–50% increased with flow cytometry in particular.14
Standard treatment depends on the primary source of malignancy. For treatment of neurological involvement, dexamethasone is commonly given for temporary symptomatic relief of CNS symptoms related to increased intracranial pressure and oedema, with some studies reporting symptomatic improvement in 75% of patients after administration of 4–8 mg/day.15 For DLBCL specifically, high-dose methotrexate is often effective due to optimal penetration of brain tissue. Although it increases survival, the prognosis remains poor due to high rates of progression to systemic disease.16 The role of rituximab, an anti-CD20 agent, in secondary CNS DLBCL is highly debated. CD20 is not expressed by neurons or glial cells; however, case reports and single-arm prospective trials have demonstrated ability of rituximab to cross the blood–brain barrier (BBB) and display adequate activity.17 Still, its variability in crossing the BBB and frequent use by patients during initial therapy renders its use questionable.
While the most common malignancies to result in LMD include breast, lung and melanoma, there have been various reports of LMD in the setting of DLBCL.18 In addition, neurological manifestations and cranial neuropathies due to LMD of DLBCL have been well documented, in cases not dissimilar from our patient. Some of these incidences include upper extremity weakness and acute dysphagia,19 isolated oculomotor nerve palsy,20 frontotemporal headaches and diplopia,21 and isolated abducens nerve palsy.22 Hence, the presentation of LMD in DLBCL is variable and oftentimes can be misdiagnosed.
Leptomeningeal involvement by malignancy is a rare complication, occurring in 5% of all cancer cases and 10% of all lymphomas.
Leptomeningeal disease in diffuse large B-cell lymphoma commonly presents with cranial nerve palsies, frequently in II, III, IV, VI and VII; however, there can be a wide variety of presenting symptoms.
Any patient with a history of malignancy and acute neurological deficits or symptoms should be evaluated for leptomeningeal disease.
Contributors SS is the guarantor, accepts full responsibility for the work and conduct of this case report. She was the primary attending physician caring for the patient during his admission, diagnosis and initial hospitalisation and the one who identified and managed the case. SD and ARG were the medical students responsible for assisting with this patient’s care during his initial hospitalisation. They conducted a literature review, wrote and prepared the manuscript for submission, with frequent input and editorial support by SS.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Obtained.
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