Expanding the Concept of Paraneoplastic Neuromyelitis Optica: A Cohort Description with Histological Staining

Background: Neuromyelitis optica (NMO) is an autoimmune Central Nervous System (CNS) syndrome associated with aquaporin-4 (AQP4) antibodies, which are found in 60 to 70% of patients. NMO is frequently associated with auto-immune disorders. The co-occurrence of NMO and cancer has been previously described, but the evidences are scarce on a potential link between NMO and cancer in these rare cases.  

Objectives: To describe a large case series of paraneoplastic NMO cases. To confirm that the expression of AQP-4 by tumor cells can trigger NMO.

Methods:  10 patients were identified from a database of 155 NMO patients followed at the UBC NMO Clinic. A retrospective chart review was performed, looking at patient age, medical history, date and symptoms of the initial NMO relapse, subsequent relapses, date and histological type of cancer and blood AQP4 status done by a cell-based assay. Pathological samples of cancer, when available, were stained with AQP4.

Results:

The average age of patients is 58 years old (range: 41-68; sd: 7.8). 80% of the cohort are women. 5 patients presented with longitudinally extensive transverse myelitis (LETM), 2 with severe unilateral optic neuritis (ON), 1 with bilateral ON, 1 with simultaneous LETM and bilateral ON and 1 with an area postrema syndrome. AQP4 antibody was found in serum of 60% of the cohort.

One patient had multiples cancers (endometrium, colon and bladder) part of Lynch syndrome. The other cancer types were: breast carcinoma (2), lung adenocarcinoma (1), non-Hodgkin lymphoma (1), thymoma (1), adrenocortical carcinoma (1), multiple myeloma (1), melanoma (1) and ovarian adenocarcioma associated with BRCA1 mutation (1). Positive immunostaining for AQP4 was found on the ovarian adenocarcinoma sample.

In 3 patients, the cancer was diagnosed before NMO (3 months, 4 months and 5 years). In the remaining 7 patients, the cancer was diagnosed after NMO (6 months to 15 years). It is not unusual with paraneoplastic syndromes to find cancer months or years after the neurological manifestations. In our cohort, the higher age of patients is a confounder.

Conclusions:

We described 10 cases of paraneoplastic NMO. Ovarian adenocarcinoma and adrenocortical carcinoma are cancer histological subtypes not previously described in association with NMO.

Paraneoplastic neurological syndromes are remote effects of cancer caused by an autoimmune response initiated by neural self-antigens expressed by tumor cells. We showed in one case of ovarian cancer that tumor can express AQP4. This can suggest that AQP4 antibodies could be produced as part of the anti-neoplastic immune response, leading clinically to NMO.