Discussion
Our patient has a very unique clinical presentation with bilateral optic neurolymphomatosis in the setting of treatment sensitive systemic ALK+ ALCL. Although she was treated promptly with radiographic complete response of CNS disease, her vision never recovered resulting in permanent blindness. It is understandable that the optic nerves and tracts were infiltrated and destroyed rather quickly and irreversibly. Our case appears to be the first case of bilateral optic neurolymphomatosis with ALCL reported in the literature as our extensive search did not turn up any such case.
Neurolymphomatosis of cranial nerves by T cell lymphoma is rare. [1] In a large study reported by International Primary CNS Lymphoma Collaborative Group (IPCG), the involvement of cranial nerves was seen in 46% of 50 patients.[1] In another large study from Massachusetts General Hospital (MGH), cranial nerves were involved in 51% of 72 patients. [2] However, a report from Mayo Clinic showed 10% (4/40) cranial nerve involvement. [3] Histologically, most cases of neurolymphomatosis are related to B cell lymphomas at 82% of cases (IPCG and MGH), [1, 2] and 97.5 % of cases (Mayo). [3] T cell lymphomas account for 10% of cases (5/46 cases, IPCG study) and 5% of cases (4/72 cases, MGH study), and 2.5 % of cases (1/40 cases, Mayo study). [1,2,3] Interestingly, one case series reported neurolymphomatosis of cranial nerves with leptomeningeal involvement in 4/5 patients with primary T cell CNS lymphoma. [4] Our patient had a similar distribution of CNS involvement.
In our patient, the diagnosis of optic neurolymphomatosis was supported by diffuse bilateral enhancement of optic nerves and tracts on MRI together with positive CSF cytology and known systemic ALK+ ALCL based on right axillary lymph node biopsy. We suggest that enhancement of cranial nerves on MRI with evidence of lymphoma in CSF or peripheral sites should be regarded as diagnostic of cranial neurolymphomatosis. The diagnosis can be quite difficult requiring meningeal and nerve biopsies when CSF studies and peripheral site biopsies are negative. [1,2,3].
Primary or secondary CNS involvement of ALK+ ALCL is not common. [5] In a retrospective analysis of 600 patients with PTCL, the 5-year cumulative incidence of CNS relapse in ALK+ALCL is 5.4% (4/74 patients). [1,2,3] There has been no standardized protocol to assess the CNS risk in patients with peripheral T cell lymphoma. Involvement of more than one extra nodal site is a significant risk factor for CNS relapse with bone, subcutaneous tissue, spleen, skin, lung, and liver regarded as high-risk sites. [6] Bone marrow involvement was reportedly associated with higher risk of CNS involvement in some reports. [7] Extra nodal involvement has a one-year cumulative incidence of 17% for CNS relapse. [6,8] Other risk factors for CNS relapse include elevated serum lactate dehydrogenase (LDH), and high International Prognostic Index (IPI) score>/=3, B symptoms, ALK+ histologic type and stage III-IV disease. [6,8] CNS prophylaxis for PTCL is controversial with little data reported. [6] Some authors advocate for evaluation of CNS at the time of diagnosis and possible CNS-directed prophylaxis in patients with ALK positivity and extra nodal involvement. [6] In our patient, the presence of ALK positivity, elevated LDH and B symptoms may have increased her risk for CNS relapse although she did not have extranodal involvement on initial diagnosis.
Interestingly she developed CNS disease after achieving complete response of systemic disease to three cycles of CHOEP chemotherapy. It is possible that CHOEP chemotherapy did not have prophylactic or therapeutic impact on CNS disease, or the damage may have already occurred. It is not surprising as chemotherapeutic agents in the regimen are known for poor CNS penetration. However, she had complete CNS response to CNS-penetrating agents, high-dose methotrexate and high-dose Ara-c. We recommend that CNS-penetrating agents should be used as early as possible in PTCL patients with high CNS risk or CNS disease. High-dose methotrexate-based treatment has been associated with improved survival in neurolymphomatosis and primary CNS T cell lymphoma. [3,9]
In conclusion, our case highlights devastating consequences secondary to CNS involvement by ALK+ ALCL. Novel biomarkers and clinical markers need to be identified for better CNS risk assessment in patients with ALCL. Early treatment with high-dose methotrexate-based regimen should be instituted in patients with CNS involvement or those at an increased CNS risk.