Symptomatic leptomeningeal carcinomatosis: a rare presentation of chronic lymphocytic leukaemia relapse

Abstract

Central nervous system (CNS) involvement in patients with chronic lymphocytic leukaemia (CLL) is very rare and, when present, it is frequently asymptomatic. Rather, CNS involvement is more common in other haematological malignancies such as mantle cell lymphoma or diffuse large B cell lymphoma. The paucity of literature on CNS involvement in CLL underscores the importance of increasing awareness about its presentation, diagnosis and optimal management. We describe a case of symptomatic leptomeningeal leukaemic involvement as an atypical presentation of CLL relapse. A favourable clinical response was observed following systemic monotherapy with venetoclax.

Background

In chronic lymphocytic leukaemia (CLL), leukaemic involvement of the central nervous system (CNS) leading to neurological manifestations is very rare. Recognition of CNS involvement in patients with CLL is crucial, as delays in diagnosis and treatment may affect overall prognosis.

Case presentation

A man in his 60s with history of CLL and lumbar spinal stenosis (eventually leading to paraparesis, treated with L2-S1 posterior decompression with instrumental fusion and L5-S1 interbody fusion) presented to the emergency department for evaluation of severe pain and swelling in the right thigh. Symptoms developed abruptly on the day prior to presentation while he was transferring out of his wheelchair.

The patient’s medical history was notable for CLL for more than 10 years, which had required multiple lines of treatment. He was initially treated with bendamustine and rituximab, but bendamustine was discontinued due to an allergic reaction. He was then treated with R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine and prednisone), achieving remission. A few years later, due to disease relapse, he was started on venetoclax with excellent response. After 2 years of treatment, venetoclax was discontinued due to muscle cramps that were suspected to be due to the medication. The patient’s white blood cell (WBC) counts had remained within normal limits after discontinuation of venetoclax until approximately 4–5 months prior to his index hospital presentation. At that time, he developed leucocytosis up to 60 000/µL, but remained off treatment. At the time of his hospital presentation he was not receiving any antineoplastic treatments. The patient was a former smoker. He did not use alcohol or recreational drugs.

On presentation to the emergency department, he had blood pressure of 123/74 mm Hg, was euthermic, tachycardic to 104 beats per minute, and oxygen saturation was 97% on room air. On physical examination he looked non-toxic, not distressed, alert, oriented and with no signs of cortical dysfunction. There was adequate air entry bilaterally, normal heart rate with regular rhythm, and a protuberant but soft abdomen with normoactive bowel sounds and absence of tenderness to palpation. Palpable bilateral cervical lymphadenopathy (right greater than left) was noted, but there was no neck rigidity. The patient had bilateral lower extremity oedema, more prominent in the right. His right thigh was tender, oedematous, warm to touch, with ecchymosis extending from the upper thigh to the knee. Lower extremity pulses were present bilaterally. Neurological examination was remarkable for paraparesis (power grossly 2/5 bilaterally on hip flexion/extension, 1/5 on knee flexion/extension and 0/5 at the ankles and toes). There was an apparent T12 spinal level. Tone was decreased in the lower extremities, with absent patellar and ankle jerk reflexes. Toes were mute bilaterally. In the upper extremities, muscle power was 5/5 throughout and sensory examination was normal. Triceps, biceps and brachioradialis reflexes were 1+bilaterally. Results of laboratory tests at the time of hospital admission are shown in table 1.

Table 1.

Results of laboratory tests at the time of admission

Laboratory test	Value	Reference range
White cell count	136 × 103/µL	4–11 × 103
Haemoglobin	113 g/L	135–175
Haematocrit	34.3%	41–54
Mean corpuscular volume	97.7 fL	80–100
Red cell distribution width	24.5%	12–16
Platelet	149 × 103/µL	150–440
Neutrophils	9%	48–66
Bands	1%	≤8
Lymphocytes	90%	15–40
International normalised ratio	1.2
Prothrombin time	34.5 s	25.1–36.5
Fibrinogen	180 mg/dL	200–393
D-dimer	7079 ng/mL	0–500
Creatine phosphokinase	43 IU/L	9–200
Creatinine	0.83 mg/dL	0.8–1.3
Calcium	8.5 mg/dL	8.6–10.3
Aspartate aminotransferase	43 IU/L	11–30
Alanine aminotransferase	15 IU/L	7–30
Alkaline phosphatase	379 IU/L	16–100
Total protein	5.6 g/dL	5.8–7.7
Albumin	2.8 g/dL	3.5–5.2
Lactate dehydrogenase	711 IU/L	125–345
Uric acid	5 mg/dL	3.5–7.2

Clinical and imaging evaluation of the right lower extremity were consistent with rupture of the quadriceps tendon and haematoma of the vastus lateralis, which were treated surgically. However, during our evaluation the patient also reported that his paraparesis had been gradually worsening over the past few months despite having undergone L2-S1 posterior decompression with instrumental fusion and L5-S1 interbody fusion for management of lumbar spinal stenosis. For this reason, MRI with and without contrast of the lumbar spine was obtained, which showed leptomeningeal enhancement involving the visible conus medullaris and cauda equina, suggestive of recurrent leukaemia (figure 1). In addition, there was new retroperitoneal lymphadenopathy and progressive, complete marrow replacement signal, consistent with his history of CLL. To evaluate other potential areas of CNS involvement, precontrast and postcontrast MRIs of the brain, cervical and thoracic spine were also obtained. There were no other areas suspicious for leptomeningeal enhancement or other findings suggesting CNS involvement.

Figure 1.

Non-contrast and postcontrast MRI of the lumbar spine. (A) Short tau inversion recovery, (B) T2-weighted and (C) postgadolinium T1-weighted MRI of the lumbar spine show oedema and diffuse leptomeningeal enhancement involving the visible conus medullaris and cauda equina. There is an L2-S1 metallic artefact related to prior transpedicular screw fusion.

Given concerns for leukaemic involvement of the CNS, a diagnostic lumbar puncture was obtained under fluoroscopy. Cerebrospinal fluid (CSF) analysis showed red cell count of 0/µL, white cell count of 17 599/µL with lymphocytic predominance (97%), glucose of 116 mg/dL (serum 165 mg/dL) and elevated protein at 176 mg/dL. CSF IgG index was normal and there were no oligoclonal bands. CSF cultures were negative. CSF cytopathology showed numerous atypical lymphoid cells consistent with involvement by a chronic B cell lymphoproliferative disorder. Figure 2 shows microscopic features of CSF cytology. CSF flow cytometry demonstrated B cells accounting for 98% of all lymphoid cells, with monoclonal kappa light chain restriction. Cells were positive for CD19, CD5, CD23 and CD38. CD38 was expressed by 100% of CD19 positive cells. There were also some medium-to-large sized lymphocytes suggestive of large cell transformation. Fluorescence in situ hybridisation (FISH) analysis on CLL was negative for 17p deletion and negative for t(11,14), ruling out mantle cell lymphoma (MCL). No other abnormalities were detected on FISH studies.

Figure 2.

Microscopic features of cerebrospinal fluid cytology. Numerous atypical lymphoid cells of small to medium in size. A subset of cells are medium-to-large sized with pleomorphic nuclei, less condensed chromatin, variable nucleoli and scant to moderate amount of cytoplasm (original magnification ×400).

Differential diagnosis

The patient’s clinical presentation and neuroimaging raised concerns for leptomeningeal carcinomatosis. Since the patient had signs of CLL relapse, including marked leucocytosis, pleocytosis and diffuse lymphadenopathy, CLL involvement of the CNS was the main diagnostic consideration, although this is known to be a very rare entity. Other haematological malignancies were considered. FISH analysis ruled out MCL. However, given the presence of large-sized lymphocytes in the CSF, large cell transformation of CLL could not be entirely excluded. As the patient had a history of lumbar spinal surgery with implanted hardware, the possibility of infectious myelitis or soft tissue infection causing local compression of the spinal cord was also considered. However, blood and CSF cultures were negative, and imaging did not suggest the possibility of abscesses or other infectious processes in the vicinity of the spinal cord.

Treatment

During his hospitalisation the patient developed worsening peripheral leucocytosis, up to 190 000/µL. Given worsening leucocytosis and high suspicion for leptomeningeal leukaemic invasion, the patient was started on systemic venetoclax, a selective inhibitor of B cell lymphoma-2 that restores activation of apoptosis in malignancies. Venetoclax was started at a lower dose, 20 mg daily for a week, and then ramped up weekly to 50 mg daily on week 2, 100 mg daily on week 3 and eventually to reach full dose of 400 mg daily. Due to concerns for tumour lysis syndrome while receiving venetoclax, allopurinol 300 mg two times per day was initiated concomitantly. Since there was CNS involvement with leukaemic invasion, and in order to reduce spinal cord oedema, the patient received dexamethasone 4 mg four times per day for a total of 10 days. Intrathecal treatment for CNS involvement was considered. However, it was held due to concerns about bleeding risk and the availability of literature supporting good CNS penetration and response to venetoclax.^1–3

As previously noted above, the patient also underwent surgical repair of the right quadriceps tendon and retinaculum during his hospital admission. He received inpatient rehabilitation, with substantial improvement of lower extremity weakness.

Outcome and follow-up

Significant improvement in functional status was noted at 1 month follow-up. The patient regained the ability to ambulate with assistance. WBC count returned to a normal range 8−10 × 10³/µL, and cervical lymphadenopathy was no longer identified on examination. All these findings indicated a good clinical response to venetoclax monotherapy.

Discussion

CNS involvement from CLL is very rare and is estimated to occur in fewer than 1% of CLL patients.^{4 5} In many of these cases, CNS involvement is asymptomatic.^5–7 Symptomatic CNS disease as the presenting symptom of CLL relapse is exceedingly rare.^8–10 However, autopsy studies in CLL patients revealed leptomeningeal involvement in 8%, suggesting that CNS involvement in patients with CLL is underdiagnosed.¹¹

The clinical manifestations of CLL involvement of the CNS are variable and heterogenous. They may include—but not limited to—headache, cranial nerve palsies, cerebellar signs, visual problems, motor or sensory deficits. Imaging studies are neither specific nor sensitive in the detection of CLL involvement of the CNS. The diagnosis is usually made and confirmed by lumbar puncture, including flow cytometric immunophenotyping^{12 13} since CSF cytology is of low sensitivity.¹⁴ Our patient presented with progressive, worsening paraparesis over a course of few months. In the present case, MRI findings of leptomeningeal enhancement along with the clinical context were suggestive of CNS involvement; therefore, a diagnostic lumbar puncture was performed which showed findings consistent with leukaemic invasion of the CNS. These included WBC count of 17 599/µL with lymphocytic predominance (97%), and numerous atypical lymphoid cells seen on the CSF cytopathology slides.

CNS involvement in early stages of CLL (stage 0–1) is very rare.¹⁵ Specific tumour markers for CNS leukaemic invasion have remained elusive. Soluble CD27 is considered a helpful marker for leptomeningeal involvement which has a good negative predictive value of approximately 92%, but the fact that it could be seen in various non-malignant inflammatory conditions makes it non-specific.¹⁶ Presence of 17p deletion is significantly associated with poor progression-free survival.¹⁷ Of note, FISH testing was negative for 17p deletion in our patient.

Confirmed CNS involvement in CLL patients should raise suspicion regarding the possibility of Richter syndrome, which implies transformation of CLL into aggressive lymphomas. This occurs approximately in 2%–10% patients with CLL.^18–20 Another consideration that should be ruled out for CLL patients with CNS involvement is MCL²¹ which has a higher tendency to involve the CNS.²² MCL is genetically characterised by a t(11,14), which results in cyclin D1 overexpression.^{23 24} CNS involvement in MCL is highly variable but ranges between 5% and 25%.^25–27 In our patient, the presence of few medium-to-large sized lymphocytes in the CSF did raise suspicion for large cell transformation. However, this would need further workup with lymph node tissue biopsy to prove conclusively, and due to need for urgent initiation of treatment, it was deferred at the time. If suspicion remained high for large cell transformation, lymph node biopsy should be recommended. Lymph node biopsy was not pursued in our patient given clinical improvement while receiving venetoclax, which was consistent with our clinical suspicion for CNS involvement due to CLL relapse. FISH analysis was negative for t(11,14) in our case which ruled out MCL as a possible diagnosis.

The optimal treatment of CLL with CNS involvement is unclear. Common modalities of treatment of leptomeningeal carcinomatosis in CLL patients are radiation and intrathecal administration of chemotherapy such as high-dose methotrexate, cytarabine and corticosteroids.9 12 16 17 Intrathecal chemotherapy with single-agent methotrexate has been shown to clear the CSF of CLL lymphocytes and resolve symptoms.²⁸ Intrathecal rituximab has proven to be effective in aggressive B cell lymphomas, but studies are lacking regarding its efficacy in treating CLL.²⁹ Ibrutinib is frequently used given its good CNS penetration.^{1 17} Our patient was treated with venetoclax monotherapy. Venetoclax is considered an acceptable modality of treatment either as single agent or as part of combination therapy.^{2 3}

Patient’s perspective.

I am doing better now, but it happened so fast it was like a nightmare. I feel like I am constantly waiting for the other shoe to drop. Things were starting to turn around, but it was two steps forwards and one step back. I noticed something different. I used to be able to push myself down the hallway in my wheelchair with my legs, but 1 day my legs could not move and that’s when I came into the emergency room. I felt overwhelmed with having back surgery then leg surgery and then to find out about the new enhancements on the MRI. When the medicine and oncology team came to see me, my wife and I felt very safe and cared for throughout the entire hospital stay. There was consistent communication about my treatment plan, and I understood what to expect. I think my team did a wonderful job.

I do not know where we go from here, but my wife and I have been married for 40 years and she has been here for me since. I was diagnosed with CLL 11 years ago and since then we have tried to educate ourselves through research and asking doctors questions. It is the good doctors that we meet along the way that keep our spirits going. We want to keep moving forwards. Our next plan of action is to continue my rehab for my legs so that I can start to walk again and to start my disability papers. Our long-term goals are to move out into a better location and travel to a sunny state!

Learning points.

• Chronic lymphocytic leukaemia (CLL) can present with central nervous system (CNS) involvement, even though this is rare. When CNS involvement occurs in CLL, patients may or may not present with acute neurological symptoms. Its diagnosis may therefore be challenging.

• Treatment for CNS involvement of CLL includes local therapies such as radiation and intrathecal chemotherapy. Newer treatments including venetoclax and ibrutinib also have shown good clinical response.

• It is important to rule out large cell transformation of CLL as well as other lymphomas such as mantle cell lymphoma as this changes treatment course and overall prognosis for patients.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).