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.