Final Diagnosis

Primary Neurolymphomatosis

Patient Follow-up

The patient underwent chemotherapy with the R-MPV regimen (rituximab, methotrexate, procarbazine, and vincristine) developed for primary CNS lymphoma [1]. She also received radiation therapy to her right distal leg. She presented to our neurology clinic for follow up 15 months after the symptom onset, when she had received 7 cycles of chemotherapy and 17 radiation treatments. She showed remarkable interval improvement with the right leg pain completely resolved. Only mild weakness was detected in the right foot dorsiflexors (4+/5) and toe dorsiflexors (4/5). Pinprick sensation was slightly reduced at the lateral aspect of her right distal leg and the lateral, dorsum, and bottom of her right foot. She was able to walk without dragging her right foot. The repeat FDG-PET showed no evidence of residual lymphoma.

Discussion

Neurolymphomatosis (NL) , defined as lymphoma infiltrating the nerve, occurs both in isolation as primary neurolymphomatosis (PNL), or secondary to systemic or central nervous system (CNS) disease [2–4]. As a secondary phenomenon , it can present at initial lymphoma diagnosis, during the course of disease, or during relapse; as a primary condition, it is exceedingly rare [5]. It is typically due to non-Hodgkin’s lymphoma , most commonly diffuse large B-cell lymphoma (DLBCL) , but T-cell lymphomas are also reported [6, 7].

NL is a rare disease which can affect cranial nerves, spinal nerve roots, brachial and lumbosacral plexus, and peripheral nerves. The median age at onset is about 50 years, and the disease has male predominance [3, 8, 9]. A few cases of PNL have been reported affecting focal individual peripheral nerves, nerve roots, or both [4, 6, 9–12], with the sciatic nerve involvement being the most common [10–12]. Our case represents PNL with painful unilateral lower limb involvement caused by polyradiculoneuropathy, which is very rare. The patient had unilateral multiple lesions involving the right S1 root, sciatic nerve, common peroneal nerve, superficial peroneal nerve, and tibial nerve.

Due to the lack of systemic and CNS involvement , early diagnosis of PNL can be quite challenging, which requires a high clinical suspicion and adequate evaluation to avoid delay [4]. Comprehensive evaluation of patients is essential to achieve early diagnosis of PNL as seen in our patient. NCS/EMG is helpful to localize the lesion(s) [3, 13]. Neuroimaging study with MRI is useful to further localize and evaluate the lesion(s) and to target a lesion for biopsy. Whole body PET scan is more sensitive than MRI for staging the disease [3, 5, 9, 13–15]. MRI in PLN usually shows enhancing lesions in the affected nerves and nerve roots. But MRI enhancing nerve and root lesion(s) can also be seen in other malignancies such as nerve sheath tumors, inflammatory diseases such as inflammatory demyelinating polyradiculoneuropathy or sarcoid radiculoneuropathy, and infectious neuritis and radiculitis [16]. Blood tests and CSF study are important in the initial evaluation to address the differential diagnosis. CSF cytology may show lymphoma cells but the sensitivity is low [2, 9]. Therefore, successful nerve or nerve root lesion biopsy is often needed and is the gold standard for the diagnosis of PNL. In the present case, the definitive diagnosis was made by the superficial peroneal nerve lesion biopsy.

Histologically, tumor cells can infiltrate in an annular fashion just beneath the perineurium, can extend from the sub-perineurium into the endoneurial space, or can diffusely, confluently infiltrate the endoneurium [7]. Foci of demyelination devoid of macrophage infiltrates can occur in the region of NL, but without direct apposition of tumor cells to the demyelinated axons [7]. Distal to tumor, Wallerian degeneration of axons with macrophage infiltrates can be seen. As NL often has a proximal distribution, it is important to recognize that “false negative” biopsies with degenerative features may occur, thus, radiographic localization of lesions prior to biopsy is recommended [17]. In one recent review, histology with immunohistochemistry for lymphocyte markers was sufficient to make the diagnosis of NL on nerve biopsy in only 40% of cases; with the use of multiplex PCR to detect lymphoma gene rearrangements in the nerve tissue, close to 90% could be ascertained [18].

The pathogenesis of PNL is currently unclear. There is a high rate of extranodal primary presentations in a variety of organ systems in DLBCL. Gene expression profiling has identified two distinct forms of DLBCL, germinal centre B-like DLBCL and activated B-like DLBCL. Germinal centre B-like DLBCL cells resemble germinal centre cells in the lymph node and express CD10 and Bcl-6, while activated B-like DLBCL cells look like activated peripheral blood cells and express Bcl-2 [19]. Since the DLBCL cells in the NL lesion of our patient expressed Bcl-2 but not CD10, they appeared originated from peripheral blood. But the primary site of the extranodal generation of the lymphoma and how the activated circulating B cells preferentially home to and infiltrate the local peripheral nerves and nerve roots remain unclear. It may involve systemic tumor cells crossing the blood-nerve barrier mediated through aberrant NCAM expression on lymphocytes homing to CD56 in the nerve [4].

There is no standard treatment for NL. It is usually treated with chemotherapy alone or in combination with radiotherapy. Systemic chemotherapy is critical if multiple sites are involved. Radiotherapy is added if a focal lesion is prominent. High-dose intravenous methotrexate (MTX)-based poly-chemotherapy is the preferred treatment with encouraging results [3, 4]. Adding rituximab appears beneficial [10, 20]. The prognosis of NL is generally poor [2, 3, 9], but PNL appears to have a more favorable prognosis [9] with a median survival of 24 months in a small series treated with high-dose MTX-based poly-chemotherapy [3]. Our patient underwent chemotherapy with the R-MPV regimen (rituximab, methotrexate, procarbazine, and vincristine). She also received radiation therapy to her right distal leg for the lymphoma mass lesion in the right superficial peroneal nerve. She responded very well to the treatment with complete resolution of the PET scan lesions and marked improvement of her sensorimotor deficits.

Pearls