Primary CNS Lymphoma Arising from the 4th Ventricle: A Case Report and Review of the Literature

A 65-year-old male with a history of ischemic strokes, seizures, and subarachnoid hemorrhage presented with a 4-week history of progressive diplopia, vertigo, nausea, and vomiting. Magnetic resonance imaging (MRI) revealed a 2.5 × 1.8 × 1.7 cm posterior fossa mass arising from the roof of the 4th ventricle extending into the cerebellar vermis. Posterior fossa craniotomy with stereotactic biopsy confirmed a locally invasive diffuse large B-cell lymphoma (DLBCL). Primary central nervous system lymphoma (PCNSL) arising from the 4th ventricle is a rare extranodal manifestation of non-Hodgkin lymphoma (NHL), with few cases documented in the literature. Review of available cases lends support that lymphoma arising from the 4th ventricle has a variable clinical presentation, occurs most commonly in immunocompetent males, and should be on the differential of any immunocompetent adult presenting with a posterior fossa mass. Optimal treatment modalities are based largely on phase 2 clinical trials, and recommended guidelines regardless of anatomic location should be adhered to.


Case
A 65-year-old Caucasian male with a pertinent history of ischemic stroke, subarachnoid hemorrhage, and recent onset of simple partial seizures 2 months prior to admission presented with a 4 week history of worsening diplopia, vertigo, nausea, and vomiting. These symptoms were initially intermittent but had become unremitting during his initial presentation. The patient denied focal neurologic deficits, ataxia, hallucinations, headaches, fevers, chills, or night sweats. The patient underwent an MRI and magnetic resonance venography (MRV) upon seizure onset that revealed 2 areas of chronic hemorrhage but was otherwise unremarkable (Figure 1).
On admission, vital signs were stable. Physical exam demonstrated rightward horizontal nystagmus, 20/40 visual acuity bilaterally, and subtle bilateral dysmetria on finger-tonose test. A complete neurologic exam was otherwise normal. Labs were unremarkable.
An MRI showed a 2 5 × 1 8 × 1 7 cm homogenously enhancing mass that extended from the roof of the 4 th ventricle ( Figure 1). Perilesional edema was present without mass effect or obstructive hydrocephalus. The patient was started on dexamethasone and underwent a posterior fossa craniotomy with stereotactic biopsy that showed locally invasive disease extending from the roof of the 4 th ventricle into the cerebellar vermis. Intraoperative frozen sectioning revealed sheet-like arrangements of highly pleomorphic lymphoid tumor cells with atypical mitotic figures and focal necrosis, suggestive of lymphoma. Permanent sections confirmed the findings and highlighted the diffuse and angiocentric nature of the lymphoma, which was comprised primarily of largesized lymphoma cells ( Figure 2). Relevant immunohistochemical staining was positive for CD45, CD20, CD79a, MUM-1, MIB-1 (Ki-67: 80% proliferation rate), Bcl-6, and Bcl-2 and negative for CD3, CD5, CD10, CD30, C-MYC, and EBER in situ hybridization. The final histopathologic diagnosis was DLBCL with a postgerminal center phenotype. The patient had peripheral blood flow cytometry with 1% clonal B cells coexpressing CD5 with surface kappa light chain restriction, possibly representing a monoclonal B cell lymphocytosis. Cerebrospinal fluid (CSF) flow cytometry was negative for malignancy. Lactate dehydrogenase (LDH) was within normal limits. Positron emission tomography (PET) indicated increased uptake (SUV of 19.3) in the 4 th ventricular mass as well as a small focus of uptake in the right pituitary gland ( Figure 3). Staging workup with computed tomography (CT) of the chest, abdomen, and pelvis, as well as whole body PET scan, was otherwise negative for metastasis.
The patient was initiated on rituximab, methotrexate, and cytarabine, followed by intrathecal methotrexate and a combination of cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), with plans for subsequent treatment with temozolomide and wholebrain radiation. After receiving his first dose of rituximab and methotrexate, he noted significant improvement in his symptoms. After his second cycle of Hyper-CVAD, repeat imaging showed resolution of the masses; he has been on single agent ibrutinib as maintenance therapy since and without recurrence for 10 months.
PCNSL should be considered in any adult presenting with a 4 th ventricular mass. Imaging may allude towards a PCNSL. CT may demonstrate hyper or isoattenuated lesions with marked contrast enhancement in immunocompetent PCNSL, whereas MRI may demonstrate isodense to hyperintense enhancement on T2-weighted imaging, with homogenous enhancement on postcontrast imaging [25,26]. In addition to neuroimaging, the PCNSL Collaborative Group recommends ruling out non-CNS disease with full-body PET imaging and bone marrow biopsy. The confirmatory diagnostic test of choice is a stereotactic biopsy. Macroscopically, PCNSL is often identified as a well-circumscribed mass [27]. Microscopically, the tumor has highly proliferative tumor cells with an angiocentric pattern with centroblastic or immunoblastic tumor cells within and around the cerebral blood vessels [24]. The majority of PCNSL are DLBCL (90%) and less commonly Burkitt's lymphoma or T-cell lymphoma [6,28]. Immunohistochemically, PCNSL cells stain positive for CD20 and Bcl-2 [24]. PCNSL cells are less frequently involved in translocations with IGH, BCL6, and MYC compared to systemic lymphomas [24].
While treatment of PCNSL has evolved in the past decade, many recommendations are derived from phase II clinical trials. In general, high-dose methotrexate (HD-MTX) and rituximab are recommended for initial induction agents due to improved overall response rates (ORR) and progression-free survival (PFS) [29]. Recently, the IELSG32 trial demonstrated that induction therapy with HD-MTX/leucovorin and rituximab with cytarabine improved the ORR (73 vs. 53%) and median PFS (20 months vs. 6 months) [30]. The multicenter cancer and leukemia group B study 50202 used rituximab, HD-MTX, and temozolomide followed by consolidation with high-dose etoposide and cytarabine with a reported ORR of 72% and PFS of 48 months, which is comparable to combination chemoradiation [28]. The Radiation Therapy Oncology Group 0227 trial (RTOG) used induction chemotherapy with rituximab, HD-MTX, and temozolomide followed by whole-brain radiation therapy (WBRT) and postirradiation temozolomide with an ORR of 86% and PFS of 90 months [31].
Both intrathecal chemotherapy (ITC) and surgical resection have been studied for the treatment of PCNSL, though routine use of either modality remains controversial. Despite the concern that CSF can harbor lymphoma cells and contribute to treatment failure or disease relapse [29], there has been no observed benefit of ITC on PFS or ORR in retrospective trials [32,33]. In addition, surgical resection is not a recommended treatment modality due to the degree of tumor infiltration and risk of both postoperative neurologic damage and implantation metastasis associated with resection. Retrospective studies have not demonstrated a mortality benefit [23,34], except for the German PCNSL study group 1 trial which reported improved OS in patients undergoing gross subtotal or total resection [35]. However, this advantage was lost when controlling for the total number of lesions [35]. Of patients with 4 th ventricular PCNSL, 35.3% of patients received ITC [8-11, 14, 16], and 52.9% of patients with 4 th ventricular PCNSL had gross subtotal or total resection [8,[11][12][13][14][15][16][17]22]. These patients also received  various combinations of chemotherapy and chemoradiation so whether either of these treatment modalities conferred a survival benefit in this select patient population is not known.

Conclusion
PCNSL arising from the 4 th ventricle is a rare occurrence that is seldom described in the literature. This case provides further evidence that PCNSL is often a malignancy of immunocompetent males. Due to its uncommon occurrence, it is unknown if commonly utilized treatment modalities that are employed in other anatomic variants of PCNSL will have similar impact on overall survival and progression-free survival. While surgical resection has been used in over half of 4 th ventricular PCNSL, it is unknown how this impacted OS or PFS. Further research is needed to determine the optimal treatment for the many variants of PCNSL, which may vary by location or tumor subtype.