CNS lymphoma masquerading as stroke: Cases report and literature review

Abstract Central nervous system (CNS) involvement in Hodgkins lymphoma (HL) is extremely rare. There are only two reported case series of intracranial involvement of HL. CNS HL can be presented at any point in the course of HL, most mimicking with a prominent neurological symptom. This challenges the diagnosis of CNS involvement and stroke. Here, we report four cases of patients having refractory HL with CNS involvement to garner attention among neurologists for this rare disease presents with stroke symptoms and reviews its disease characteristics, prognosis, and treatment.

We studied 689 patients diagnosed with HL.Four adult HL patients with CNS involvement were diagnosed in our center in the last 10 years.

| Case 1
A 58-year-old female patient was hospitalized for speech impairment and ataxic gait.She was initially diagnosed with ischemic stroke in the district hospital and was given Ischemic stroke therapy for 1 week.However, there was no improvement in her neurological score.The patient had a history of classical HL (mixed cellularity, EBV-negative) in clinical stage IVB with lung involvement.She was diagnosed 8 months prior to admission and was undergoing treatment with four cycles of AVDB (adriamycin, bleomycin, vinblastine and dacarbazine) chemotherapy and achieved a sustained complete remission.Moreover, 3 months prior to the admission, she had received two cycles of AVD chemotherapy due to severe lung infection.
Upon examination, vital signs were within the normal range.
The patient was alert but could not speak fluently or walk steadily.
Blood tests showed mild anaemia of 9.2 g/dL with a normal white blood cell and platelet count.Serum electrolytes, coagulation, liver and renal function tests were normal.Physical examination revealed an impairment in balanced gait experiment, normal cardiac and abdominal exam.To examine a neurovascular cause, we performed an urgent brain MRI (Figure 1), which showed an ill-defined lesion in the brain stem, cerebellum and bilateral cerebral multiple space-occupying and prominent vasogenic perilesional edema, and ischemia stroke focus in basal ganglia.Cerebrospinal fluid (CSF) analysis showed mildly elevated proteins with normal protein and glucose.
CSF also showed Reed-Sternberg (RS) cells in this patient (shown in Figure 4A) and negative in other tumour by flow cytometry analysis.However, we did not stain the cells with CD30 or CD15, because there was not enough cerebrospinal fluid to complete the immunohistochemistry.After two cycles of methotrexate + temozolomide chemotherapy, the patient achieved a partial remission.She died of infection 10 months later.

| Case 2
A 47-year-old man presented with speech impairment for 1 month, with medical history of middle-risk stage IIIA classical HL (mixed cellularity, EBV-negative) 2 years ago.He was treated with six cycles of ABVD chemotherapy in January, 2017, and achieved a complete response.Laboratory examinations revealed normal complete blood cell count and biochemical parameters.Physical examination revealed a normal flat affect, with normal cardiac and abdominal reports.Cranial MRI showed cranial meningeal carcinomatosis and left frontal space-occupying lesions, and prominent vasogenic perilesional edema considering the possibility of meningeal invasion (Figure 2).Furthermore, lymphomatic brain infiltration was considered in accordance to the medical history.
We performed a complete surgical removal of the lesion due to inconclusive neuroimaging findings.Histopathological analysis showed classical HL infiltration in CNS and RS cells, with positive immunohistochemistry staining for CD30, and CD15 (Figure 3), consistent with the diagnosis of HL.After confirmed progression to the CNS, we gave multiple treatments of eight cycles of MTX+GDP (methylamine+gemcitabine+cisplatin+dexamethasone) six cycles of lenalidomide chemotherapy on January, 2019.Up until now, the patient has had no symptoms.

| Case 3
A 37-year-old male patient was diagnosed with Hodgkin lymphoma in 2015, clinical stage IIIA.He was treated with eight cycles of ABVD chemotherapy, achieving a complete response.Seven years later, he presented with neurologic symptoms of aphasia and weakness in both limbs.He was able to repeat simple phrases with semantic paraphasia and echolalia but could not communicate fluently.The muscle strength in both the lower limbs decreased, and the muscle tension was normal; the rest of the examination was unremarkable.
Serum electrolytes, coagulation, liver and renal function tests were normal.To approach a neurovascular cause, we performed an urgent brain MRI, which showed an ill-defined, contrast-enhancing lesion on the left pons, brain stem and bilateral ventricles infiltration and perilesional edema (Figure 5A-C).The CNS involvement by HL was confirmed by CSF cytology.CSF cytology analysis was performed, and large CD30-positive cells were found (Figure 4B).
Thereafter, we started one cycle of Bv+bendamustine+MTX chemotherapy but no any response was observed.The patient then received two cycles of Teniposide+MTX+PD1 with partial response and improvement in neurologic parameters.

| Case 4
A 42-year-old man was diagnosed with Hodgkin lymphoma nodular sclerosing subtype in 2018, clinical stage IIIA and lymphocytic predominance subtype.He was treated with ABVD chemotherapy, achieved a complete response six cycles of treatment.However, 3 years later, the patient presented with a new relapse (abdominal lymph node enlargement, new mass in the left orbit), but he refused any treatment.One month later, he complained of weakness in double limbs with normal muscle strength.Cranial MRI showed enlarged mass in the left orbit and abdominal lymph nodes were found in MRI (Figure 5D,E).The CNS involvement by Hodgkin lymphoma was confirmed with CSF cytology, and RS cells were found (Figure 4C).
He was treated with combination of chemotherapy for two cycles of MTX+PD1, finally achieving a partial response.

| DISCUSS ION
Because of the rarity in CNS involvement, the knowledge of these patients' clinical characteristics is derived from few case reports and small case series.As far we know of, there are only two reported case series of intracranial involvement of HL.From these findings, we can partially conclude that CNS involvement in HL is slightly more frequent in male patients during the fifth decade of life and it usually is of nodular sclerosing subtype with clinical stage III-IV.In our study, the four patients had clinical stage III-IV (Table 1).
The clinical presentation of CNS involvement by HL reported with mimicking of cerebral stroke symptoms.Common presentations include pain/sensory symptoms, weakness, cranial nerve palsies, altered mental status, headache, papilledema, coma, seizures

(A) (B) (C)
and ataxia.The most common presenting feature was dural/meningeal-based lesions in CNS involvement by HL. 3,4 Less often is the involvement of brain parenchyma, leptomeninges, cortical, cerebellum, spinal cord, and brainstem and pituitary 6,7 as shown in Table 1.
Our patient showed involvement of the brainstem, cerebellum, and unexplained neurological signs should be evaluated carefully in a patient with diagnosis of HL. 4 There is conflicting information in the literature regarding other possible risk factors, including suggestions of increased risk with a family history of HL, immune compromised, and EBV infection. 6,7Pathophysiological mechanisms of CNS in HL remain incompletely understood.The proposed hypotheses include hematogenous spread through the bony skull or dura; or by direct extension meningeal involvement and metastasis. 8,9Another theory is hematogenous dissemination.It is suggested that the large size of the Reed Sternberg (RS) cells may preclude their passage to the perivascular space of the CNS, and further filtering through the lung cells led to the rarity of intracranial involvement of HL. 10 However, RS cells may secrete cytokines to weaken the blood-brain barrier, together with the other, tumour internal environment factors, contributing to CNS involvement.
Given the involvement of the skull and meninges in our patient suggested by MRI scan, as well as the location of her brain lesion, the mechanism of spread to the CNS, in this case, was likely contiguous hematogenous spread in Case 1 and Case 3, and meningeal involvement in the case two.
CNS disease in HL have been described in patients on initial presentation, after the diagnosis of disseminated disease, and, most commonly, with relapsing disease. 3,5,10,11However, CNS HL has also been seen in patients after achieving complete remission after therapy. 9In a recent review of 21 CNS involvement patients, CNS HL had a feature of relapsed/refractory disease in 11 patients (52%),  discovered simultaneously with or prior to systemic disease, with an estimated crude incidence rate of 0.03% in all cases of HL. 4 The infrequency of this disease makes information on therapeutic decision-making difficult.There is a wide variety of treatment modalities that can be used, including guided radiotherapy alone, whole-brain radiation, multiagent systemic chemotherapy and total or subtotal surgical resection. 3,4,12,13The satisfactory response can be obtained in most patients after radiotherapy combined with systemic chemotherapy and brain resection (Table 2).
Additional modalities described include intrathecal chemotherapy, and stem cell transplantation, especially in the face of meningeal involvement. 7,11However, CNS involvement as a feature of relapsed/refractory disease was adversely prognostic, with the median PFS and OS were 7.6 and 29 months, respectively. 4Recently, in a phase 3 trial, a combination of brentuximab vedotin (an anti-CD30 antibody-drug conjugate) plus standard chemotherapy showed an improvement in the risk of progression, death, or incomplete response in patients with advanced stages of HL during a 2-year follow-up. 14However, there is still insufficient data to recommend the routine use of any specific treatment modality to prevent CNS involvement at the time of initial HL treatment, and more data are required to identify specific populations in whom this could be beneficial.
In our study, all patients underwent second-line chemotherapy PD1 is now being incorporated into the frontline therapy. 15Various case series studies by Elizabeth, et al and Chan.et al, showed that more patients achieved complete response (CR) after chemotherapy and radiotherapy. 3,4Unfortunately, treatment with PD1 and radiotherapy has not been reported in the patients with CNS involvement due to the rarity of CNS involvement in HL.

F I G U R E 1 2
Pre-treatment magnetic resonance imaging with ill-defined lesion in brainstem, cerebellum (A, B T1-weighted axial; C, T2-weighted axial).T1-weighted axial (D, E) and T2-weighted axial (F) images showing enhancing lesion in the cerebral.(Red arrow means NCS involvement, green arrow means ischemia strokes).Magnetic resonance imaging show ill-defined lesion in cranial meningeal and left frontal lobe.(A, Axial T1-weighted axial; B, T1-weighted coronal, C, T1-weighted sagital planes; Red arrow means NCS involvement).

F I G U R E 4
meninges at the time of relapse.The clinical presentation in our series included dysarthria, aphasia, weakness, and focal seizures.To our surprise, one case had tumour and ischemic stroke focus simultaneously.It may be related to trousseau's syndrome, which could promote cerebral infarction.Almost all patients with CNS involvement by HL had stroke symptoms, and it could be easily misdiagnosed as stroke.However, abnormal cerebrospinal fluid reminded us of the importance to distinguish stroke and CNS involvement.Moreover, intracranial involvement should be considered in any patient with known HL, who develops neurological complications, especially if there is dissemination of disease or relapse.Diagnosis was most frequently established by either stereotactic or excisional biopsy.In Chan Y.et al study diagnostics were documented in 11 cases of which only five were considered positive and one case was diagnosed by CSF microscopy only, a spinal tap, nevertheless constitutes a feasible way of evaluating CNS involvement in symptomatic HL patients. 4In Elizabeth et al. study, CSF diagnostics was performed in nine patients and two patients had atypical cells in cerebrospinal fluid.A robust conclusion of potential strengths F I G U R E 3 A, Hodgkin (Reed-Sternberg) cells with histiocyte-rich background (haematoxylin and eosin stain).Haematoxylin & eosin stain at 400× shows a large binucleated cell with conspicuous nucleoli and prominent eosinophilic cytoplasm (arrow), the pathognomonic Hodgkin lymphoma Reed-Sternberg cell, with positive immunohistochemistry staining (arrows) for (B) CD30 and (C) CD15.Reed-Sternberg cells in the Cerebrospinal fluid (CSF), (A,C) show Reed-Sternberg (RS)cell in CSF, (B) show RS cell with positive immunohistochemistry staining for CD30 in CSF.and limitations of the different diagnostic procedures should not be drawn due to the small number of patients and lack of CSF assessment in nearly half of patients.3Due to the high cost of surgery and biopsy, there were limitations when used in patients with intracranial lesion.Lumbar puncture was performed to diagnosis in patients with CNS involvement by a cheaper and lesser invasive way in our case series.We were unable to perform a central review of cerebrospinal fluid cytology with positive immunohistochemistry staining for CD30 in two cases, because of insufficient cerebrospinal fluid Hence, it is our limitation with regards to diagnosis in these cases.Nevertheless, all the CNS histology samples were investigated by experienced hematopathologists at our academic cancer centers and were determined to be HL.Therefore, any patients presented with at least one neurological symptom or

1
the median time from initial diagnosis of HL to development of CNS involvement was 1.9 years.10/21 (48%) of patients had CNS HL F I G U R E 5 Initial brain MRI shown intracranial extra-axial lesions on brain stem (A, B) and left pons (C), both hyposignal on T1 WI, T2 WI. (C and D) show ill-defined lesion in left orbit on T1 WI, T2 WI, respectively.Characteristics of the patients described.
without radiotherapy.The third and forth case were treat with PD1 resulting in partial responses (PR).Recent research has found overexpression of programmed death-1 (PD-1) ligands, including PD-L1 on RS cells.PD-L1/PD-L2 alterations are a defining feature of HL and result in very high expression of PD-L1 or PD-L2 on the cell surface, thereby protecting RS cells from T-cell mediated killing.Hence, CNS involvement in HL is rare, and we report four patients with relapsed HL with CNS involvement.Tissue diagnosis and cerebrospinal fluid cytology analysis is essential for any patient with known HL presenting with a focal CNS lesion or a new unexplained neurological pathology.The clinical course, outcome, and treatment of patients with CNS involvement needs more attention in the clinical setting.AUTH O R CO NTR I B UTI O N S Xiping Liang: Conceptualization (equal); data curation (equal); investigation (equal); methodology (equal); validation (equal); writingoriginal draft (equal).Chaoyu Wang: Conceptualization (equal); data curation (equal); formal analysis (equal); methodology (equal); writing -original draft (equal).Yao Liu: Conceptualization (equal); data curation (equal); supervision (equal); validation (equal); writing -review and editing (equal).