Primary central nervous system lymphoma (PCNSL) is an uncommon type of extranodal non-Hodgkin’s lymphoma, which involves the brain, leptomeninges, eyes, or spinal cord without evidence of systemic disease [1]. It accounts for 1.5% of non-Hodgkin’s lymphomas, and lymphoma of the brain stem and spinal cord is extremely rare, accounting for 1-3% of PCNSLs [2-4]. The very low incidence of this tumor and its diverse imaging presentation makes its diagnosis difficult.

Here, we report a case of primary lymphoma occurring from the medulla oblongata to the cervical spinal cord, which was considered inflammation before the pathologic report was revealed.

A 56-year-old male, with no medical history, presented with disequilibrium and sensory changes in the arm and leg, which was more severe in the left hemibody, 1 month previously. He had felt left-sided weakness 10 days prior to his visit to our hospital. On physical examination, sensations of touch on the left side were diminished and motor weakness was grade 4+. The deep tendon reflex of the left leg was hyperactive and the other limbs were normoactive. He tested positive for the Romberg test. Magnetic resonance imaging (MRI) of the cervical spine at the time showed a diffuse T2/fluid attenuated inversion recovery hyperintense infiltrative lesion in the medulla oblongata to C2 spinal cord with multifocal patchy enhancement in the periphery of the lesion, and mild diffusion restriction in the anterior aspect of the medulla (Fig. 1). The initial suspicion was a tumorous condition including high-grade glioma and diffuse midline glioma or demyelinating disease. Laboratory tests including infection markers and peripheral blood cell counts were within the normal range. A serologic test for human immunodeficiency virus was negative. A cerebrospinal fluid (CSF) exam showed white blood cell count 5/μL, red blood cell count 5/μL, protein 76 mg/dL, glucose 75 mg/dL, and lactate dehydrogenase 17 IU/L, which had a non-specific pattern. CSF culture revealed no growth of tuberculosis, bacteria, or virus, and there were no malignant cells in the cytology of CSF. The patient underwent open biopsy of the lesion under general anesthesia. The spinal cord was swollen from the central region to the left, so the posterior median sulcus was not clear. There were black, diffuse, and minute pigmentations on the pial membrane similar to finely-spread pepper. Small pieces of the spinal cord were obtained on the left side of the C1 area, which was enhanced in the MRI and thought to correspond to the posterior column.

In the biopsy report, hematoxylin and eosin staining showed the diffuse proliferation of round cells with a hyperchromatic nucleus that was larger than that of a normal histiocyte nucleus. Immunohistochemistry was positive for cluster differentiation (CD) 20, CD79a, B-cell lymphoma 2, and CD10, and 40% of tumor cells were Ki-67 positive. The confirmatory result of the biopsy was diffuse large B-cell lymphoma (Fig. 2). The patient had an enhanced computerized tomography scan of the chest, abdomen and pelvis, and a positron emission tomography scan to assess the presence of a lymphoid tumor. There was no malignancy in other organs, which confirmed primary intramedullary lymphoma in the brainstem to high cervical spinal cord. He was started on chemotherapy. Five 14-day cycles of induction chemotherapy with rituximab, methotrexate, procarbazine, and vincristine were given as follows: day 1, rituximab 500 mg/m²; day 2, methotrexate 3.5 mg/m² (over 2 hours), vincristine 1.4 mg/m²; day 1-7, procarbazine 100 mg/m²/d (odd cycles only). After the 2nd cycle, there was a partial response on c-spine MRI (Fig. 3). He received a 3rd cycle of chemotherapy, and is going to receive reduced-dose whole brain radiotherapy. After radiotherapy, he is going to receive two consolidation high-dose cytarabine cycles (one cycle=28 days). Currently, he is alive 20 months after his neurologic symptoms presented.

We reviewed recent case reports of PCNSL in the brain stem (Table 1) [5-9] and spinal cord (Table 2) [10-28]. For brain stem lesions, patients developed diplopia and dysarthria suggesting cranial nerve dysfunction as well as hemibody weakness. Symptom progression tended to be fast from 2 weeks to 2 months.

For spinal cord PCNSL (Table 2), various ages, sex, and locations were noted. Locations of PCNSL were evenly distributed throughout all levels of the spinal cord from the cervical spine to the cauda equina (9 cases of cervical spine, 8 cases of thoracic spine, and 6 cases of lumbar spine and cauda equina). The patients developed various myelopathy symptoms depending on the location of the lesions.

In an immunocompetent patient, lymphoma is classically described as a solitary mass with intense homogeneous enhancement. MRI typically reveals low signal intensity on T1-weighted images and an isointense or hypointense signal on T2-weighted images [29]. However, in an immunocompromised patient, the proportion of rim enhancement or hyperintense signal on T2-weighted images is higher than that of an immunocompetent patient [29-31], and lymphomas tend to present as multiple lesions. In the literature, most cases showed typical radiological findings, but there were quite a few different images. For example, no enhancement, inhomogeneous enhancement, and leptomeningeal enhancement were presented and inhomogeneous signal intensity in T2-weighted image, or syringomyelia [18] was reported. Because of these various radiologic findings of brain stem or spinal cord lymphoma and its rarity, misdiagnosis at the initial state is common.

The lesion in our case showed scattered enhancement, diffuse swelling, and enlargement in the lower brain stem and cervical spinal cord. Because the patient had no evidence of human immunodeficiency virus or other immune deficiency, the heterogenous enhancement was thought not related to lymphoma. In addition, the incidence of intramedullary spinal cord lymphoma is very rare and he did not present with ‘B-symptoms’ such as sweating, fever, and weight loss; therefore, the first differential diagnosis included glioma rather than lymphoma. When we reviewed several articles of PCNSL, various imaging patterns emerged indicating radiology findings are not typical or specific for differential diagnosis from other central nervous system diseases.

It is important to confirm the diagnosis histologically. In many cases, steroids were used to relieve symptoms without biopsy. Patients using steroids presented with symptom relief initially but deteriorated again for a few days or weeks [6,7,10,15,24]. This can induce disease progression and delay the diagnosis and proper treatment. There have been three reported cases of initial misdiagnosis including ependymoma, tuberculosis, and demyelinating disease [10,13,18]. Lymphocytic pleocytosis in a CSF exam is likely to lead many physicians to consider tuberculosis, and high protein levels in the CSF suggest a demyelinating disease. Malignant cells were only found in 2 cases of the reports we reviewed. In all cases, diagnoses were obtained through biopsy or CSF cytology. In many cases, CSF examination showed inconclusive results, suggesting that the specificity of CSF cytology is low and therefore is of low diagnostic value. Therefore, unless a biopsy is performed and pathologic results are checked, the specific diagnosis for PCNSL is difficult. Early biopsy should be considered for brain stem or spinal cord lesions that might be primary cancer.

The optimal treatment for PCNSL has not been established. High-dose methotrexate (HD-MTX) and rituximab is used as basic regimen for induction therapy. Combined chemical treatment with vincristine, procabazine, temozolomide, or cytarabine could be added. Reduced-dose whole brain radiation (WBRT) for minimizing neurologic side effects could be added [32]. For consolidation, radiation and conventional chemotherapy (cytarabine, etoposide) is used. High dose chemotherapy and autologous stem cell transplantation can be considered for the patients who are younger and have no organ failure [32-34].

The median survival of untreated patients with PCNSL is 3 months, and the patient who treated with methotrexate-based chemotherapy and WBRT have a median survival of 36 months to 60 months [33,35]. Prognosis of patients with primary refractory or recurrent PCNSL is poorer with median survival of 2 months without additional treatment. There is no consensus about the optimal treatment of recurrent PCNSL, however WBRT and HD-MTX rechallenge seems to be effective in small studies [32]. The patients who were treated with MTX rechallenge had median overall survival of 41 to 62 months, and the patients with WBRT had median overall survival of 10 to 16 months [32,36,37]. There is a large difference in prognosis between untreated and treated PCNSL patients, and this is another reason why early diagnosis through biopsy is important.

For lesions that might be primary cancer, early biopsy can help achieve a correct diagnosis, avoiding progression of the disease, and improving its prognosis.