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Aquaporin-4 immunoglobulin-G-positive neuromyelitis optica spectrum disorder associated with small cell lung carcinoma

Published:February 27, 2020DOI:https://doi.org/10.1016/j.jcjo.2020.01.005
      Neuromyelitis optica spectrum disorders (NMOSDs) typically present with recurrent bilateral optic neuritis and longitudinally extensive transverse myelitis.
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      NMOSDs are characterized by a highly specific biomarker aquaporin-4 (AQP4) immunoglobulin-G (IgG), present in 60%–90% of NMOSD patients.
      • Jarius S.
      • Wandinger K.P.
      • Borowski K.
      • Stoecker W.
      • Wildemann B.
      Antibodies to CV2/CRMP5 in neuromyelitis optica-like disease: case report and review of the literature.
      Recent studies have reported the incidental finding of AQP4-IgG in the serum of patients with cancer, indicating a potential paraneoplastic immune response.
      • Sepulveda M.
      • Sola-Valls N.
      • Escudero D.
      • et al.
      Clinical profile of patients with paraneoplastic neuromyelitis optica spectrum disorder and aquaporin-4 antibodies.
      Here, we report a rare case of seropositive NMOSD associated with small cell lung carcinoma (SCLC) and demonstrate AQP4 immunoreactivity in SCLC tissue for the first time.
      A 66-year-old female was referred to our neuro-ophthalmology clinic with a 2-day history of vision loss OS with pain on eye movements. The patient denied any other ocular, neurologic, or systemic symptoms. The patient's active medications were Mestinon and Atorvastatin. The patient's medical history included psoriasis, hypertension, hypercholesterolemia, systemic lupus erythematosus in remission, myasthenia gravis in remission, thymoma resected 21 years prior, a lung mass that was detected on computed tomography (CT) chest 3 months prior, and intraductal carcinoma (IDC) of breast in remission for 3 months after lumpectomy, sentinel node biopsy, and radiation. Two months after her first visit to us, the lung nodule was diagnosed as SCLC.
      On examination, the patient had a best-corrected visual acuity (BCVA) of 20/20 OD and counting fingers OS. Colour vision on the Ishihara colour plates was full OD and nil OS. A relative afferent pupillary defect was present in the left eye. Pupils, efferent system, and anterior segment were normal bilaterally. The posterior segment examination demonstrated normal findings in the right eye but mild-to-moderate swelling of the optic nerve (ON) head in the left eye. The Humphrey visual field (HVF) test indicated a superior and temporal visual field defect (VFD) OD and a temporal VFD OS, suspicious for a bitemporal hemianopia. An urgent CT of the head was unremarkable aside from an incidentally detected basilar tip aneurysm. Subsequent magnetic resonance imaging of the orbits/brain with contrast demonstrated hyperintensity of both ONs, left ON enhancement, normal optic chiasm, and nonspecific subcortical white matter lesions not typical for multiple sclerosis (Fig. 1). The patient was seropositive for AQP4-IgG. Hematoxylin and eosin and immunohistochemical (anti-AQP4 antibody incubated at 4°C overnight, Sigma-Aldrich, A5971, dilution 1:250; no antigen retrieval) stainings of formalin-fixed, paraffin-embedded sections (5 μm) demonstrated AQP4 immunoreactivity in the SCLC cells but no immunoreactivity in the IDC cells (Fig. 2). The patient was diagnosed with NMOSD with a paraneoplastic association to her SCLC. She was prescribed intravenous solumedrol 1 g/day for 3 days, followed by oral prednisone 60 mg daily. The multiple sclerosis clinic was consulted to help manage her NMOSD.
      Fig 1
      Fig. 1Magnetic resonance imaging scan of orbits and brain. (A) Axial T2 fast spin echo (FSE) image of the orbits. Increased T2 signal of left optic nerve (ON) and less obvious the right ON as well. (B) Axial T2 Fluid Attenuated Inversion Recovery (FLAIR) image of the orbits with gadolinium contrast. Enhancement of left ON near orbital apex. (C) Axial T2 FLAIR image of the brain with gadolinium contrast. Multiple nonspecific T2 hyperintensities without enhancement in periventricular, deep, and subcortical white matter, indicating areas of demyelination. (D) Coronal T2 FSE image of the brain. Normal optic chiasm.
      Fig 2
      Fig. 2Biopsy specimens from the breast intraductal carcinoma (IDC) and small cell lung carcinoma (SCLC). (A) Hematoxylin and eosin (H&E) staining of breast IDC (20 ×). (B) Immunohistochemical staining of breast IDC—aquaporin-4 (AQP4) negative (20 ×). (C) H&E staining of lung SCLC (20 ×). (D) Immunohistochemical staining of lung—AQP4 positive (20 ×).
      The management of the patient's NMOSD and SCLC was complicated by poor compliance to treatment. The patient initially refused corticosteroid treatment, beginning treatment 10 days late at a lower dose of 35 mg orally daily. The patient refused the azathioprine treatment advised by her neurologist. Although the patient's BCVA returned to 20/20 OU and remained stable soon after the corticosteroid treatment, a repeat HVF after 4 months demonstrated progression of VFD into bilateral superior VFDs, indicating active disease. With regard to her cancer, the patient refused lung biopsy for 5 months after the initial CT detection of a lung mass. After the biopsy, it took the patient another 4 months to comply with the first cycle of carboplatin and etoposide. Over the course of 9 months, the patient's SCLC transitioned from a curative (2.5 cm × 2.5 cm) to a noncurative (6.2 cm × 5.7 cm) mass. Eighteen months after she tested positive for AQP-IgG, the patient DIED OF hypovolemic shock secondary to upper gastrointestinal bleed.
      The median age of onset of paraneoplastic NMOSD is 50.5 years, compared with 39 years for idiopathic NMOSD.
      • Cai G.
      • He D.
      • Chu L.
      • Dai Q.
      • Xu Z.
      • Zhang Y.
      Paraneoplastic neuromyelitis optica spectrum disorders: three new cases and a review of the literature.
      Our patient was 66 years old at the onset of her NMOSD, with recent diagnoses of multiple malignancies—IDC of breast and SCLC—suggesting paraneoplastic etiology rather than idiopathic. In contrast to the active SCLC, her IDC was in remission at the onset of her NMOSD (albeit for a short period). Lastly and most importantly, the AQP4 immunoreactivity was found exclusively in the SCLC tissue, indicating that the patient's NMOSD is a paraneoplastic neurological syndrome secondary to SCLC rather than IDC.
      In a patient with known malignancies, the distinction between paraneoplastic versus idiopathic NMOSD is an important one. Compared with idiopathic NMOSD, paraneoplastic NMOSD is thought to have a poorer response to conventional immunosuppressive treatments; hence, malignancy should be suspected in medically refractory NMOSD unresponsive to treatment.
      • Deuel L.M.
      • Bunch M.E.
      A case of paraneoplastic neuromyelitis optica associated with small cell lung carcinoma.
      Our patient's poor response, as demonstrated by the worsening of her VFD, was likely due to her lack of compliance to immunosuppressive treatment and rapid progression of SCLC. Future studies that explore the relationship between tumour progression and disease severity in the patients with paraneoplastic NMOSD may help to determine the role of oncologic therapies in management of paraneoplastic NMOSD.
      Paraneoplastic NMOSD is a rare entity, constituting of only 3.2% of all NMOSD patients.
      • Deuel L.M.
      • Bunch M.E.
      A case of paraneoplastic neuromyelitis optica associated with small cell lung carcinoma.
      As described in the study by Sepulveda et al., breast and lung adenocarcinomas are the malignancies most commonly associated with paraneoplastic NMOSD.
      • Sepulveda M.
      • Sola-Valls N.
      • Escudero D.
      • et al.
      Clinical profile of patients with paraneoplastic neuromyelitis optica spectrum disorder and aquaporin-4 antibodies.
      Only a single case of seropositive paraneoplastic NMOSD associated with SCLC has been reported to date
      • Deuel L.M.
      • Bunch M.E.
      A case of paraneoplastic neuromyelitis optica associated with small cell lung carcinoma.
      ; in that report by Deuel and Bunch, although the diagnosis of SCLC-associated NMOSD was made, the AQP4 immunoreactivity in the SCLC specimen was not tested.
      • Deuel L.M.
      • Bunch M.E.
      A case of paraneoplastic neuromyelitis optica associated with small cell lung carcinoma.
      We expand upon Deuel and Bunch's report by contributing a case of seropositive SCLC-associated NMOSD, with demonstration of AQP4 immunoreactivity in the tumour tissue.
      To conclude, we report a unique case of AQP4-IgG-positive NMOSD with paraneoplastic association to SCLC and demonstrate AQP4 immunoreactivity in the SCLC tissue for the first time. We have also highlighted the diagnostic value of immunohistochemistry in identifying the malignancy that has paraneoplastic association with NMOSD, especially in the setting of multiple malignancies. Our case adds to the growing evidence that patients with NMOSD may have underlying malignancies and AQP4-IgG may be an indicator of a paraneoplastic immune response. Further investigations should be performed to firmly establish the clinical utility of AQP4-IgG.

      Footnotes and Disclosure

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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