Co-occurrence of aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder and hepatocellular carcinoma: A case report

Abstract

Neuromyelitis optica spectrum disorder is a rare, relapsing autoimmune disease in which the immune system attacks the central nervous system, primarily the optic nerves and spinal cord. It causes inflammation and demyelination in the central nervous system. A defining feature of neuromyelitis optica spectrum disorder is the presence of antibodies targeting aquaporin-4. Although rare, some documented case reports have linked neuromyelitis optica spectrum disorder to the development of certain cancers. Herein, we report a case of a 60-year-old female patient who presented with relapsing optic neuritis and longitudinally extensive transverse myelitis, with positive aquaporin-4 antibodies in the cerebrospinal fluid. The patient was treated with methylprednisolone and prednisone. She was later diagnosed with hepatocellular carcinoma. This represents the first case report of aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder associated with hepatocellular carcinoma. In addition, this report contributes to the growing body of literature on paraneoplastic neuromyelitis optica spectrum disorder and highlights the need for comprehensive cancer screening, as this neurological syndrome may present with an underlying malignancy in older adults.

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory group of diseases affecting the central nervous system (CNS), primarily the optic nerves, spinal cord, and the brain. It is characterized by area postrema syndrome, brainstem syndrome, optic neuritis, and/or myelitis. Longitudinally extensive transverse myelitis (LETM), a form of myelitis extending over three or more vertebral segments on magnetic resonance imaging (MRI), is a core diagnostic feature of NMOSD identified. NMOSD is often associated with aquaporin-4 immunoglobulin G (AQP4–IgG) antibodies, ¹ with AQP4–IgG being identifiable in approximately 80% of patients diagnosed with NMOSD. ² Although it is usually an idiopathic condition, it can present as a rare paraneoplastic syndrome (PNS) associated with malignancies. Studies have shown that AQP4–IgG is present in patients with PNS as well, thus identifying a rare but crucial correlation between NMSOD, AQP4–IgG, and PNS.^3–6 Cancers such as lung, breast, and ovarian teratomas are often the most commonly diagnosed malignancies in this syndrome.^3,7–10 Paraneoplastic NMOSD differs from idiopathic NMOSD in clinical presentation, ¹¹ with paraneoplastic NMOSD occurring in patients aged >50 years, with a significant probability of an underlying malignancy. Case reports of NMOSD coexisting with systemic cancer suggest that the disease occasionally represents a paraneoplastic phenomenon. ⁴ However, this association is rare, and the underlying mechanisms remain poorly understood.^12,13 Herein, we describe the case of a 60-year-old patient with hepatocellular carcinoma (HCC) who presented with NMOSD.

Case report

The reporting of this study conforms to the Case Report (CARE) guidelines. ¹⁴ This case report has been approved by the Medical Ethics Committee of Wuming Hospital of Guangxi Medical University (Approval No. WM-2025(137); September 2025). Additionally, written informed consents for treatment and publication were obtained from the patient before her passing, and all patient details were de-identified to protect her anonymity.

A Chinese woman in her early 60 s with a 5-day history of bilateral vision loss was admitted to the Department of Ophthalmology, Wuming Hospital of Guangxi Medical University in August 2018. Best-corrected visual acuity (BCVA) was severely reduced in both eyes (left eye: counting fingers at 10 cm; right eye: 0.1), with otherwise unremarkable ophthalmic examinations. Additionally, fundus photography and ocular optical coherence tomography (OCT) showed no obvious lesions. She was further diagnosed with bilateral retrobulbar neuritis and received methylprednisolone pulse therapy (500 mg). Following treatment, her vision improved, with BCVA improving to 0.1 in the left eye and 0.04 in the right eye; the Expanded Disability Status Scale (EDSS) score reduced from 4.5 to 3.0 after steroid treatment.

In April 2019, the patient was readmitted with a 3-day history of numbness and weakness in both upper limbs, accompanied with cervicoscapular pain and urinary and bowel dysfunction. She was subsequently transferred to the Department of Neurology for further evaluation. Neurological examination showed no light perception in either eye. Based on the Medical Research Council (MRC) muscle strength grading scale, her elbow flexion strength was 2/5, while strength in hip flexion, knee flexion, and ankle dorsiflexion was 3/5. Complete loss of pain and touch sensations below the neck was observed, while examinations of other cranial nerves were unremarkable. Brain MRI showed no obvious abnormalities. Sagittal T2-weighted spinal MRI showed longitudinally extensive myelitis extending from C1 to Th2 (gadolinium contrast was not administered) (Figure 1(a) and (b)). Her EDSS score increased to 8.0 due to severe limb weakness and extensive neurological impairment. Cerebrospinal fluid (CSF) examination was performed and revealed normal intracranial pressure, a white blood cell count of 8 × 10⁶/L, and normal glucose and chloride levels. Furthermore, cell-based assays for demyelinating antibodies (AQP4, myelin oligodendrocyte glycoprotein, and myelin basic protein) were conducted at KingMed Diagnostics Co., Ltd., a College of American Pathologists (CAP)-certified laboratory. Results showed that both CSF and serum AQP4–IgG were positive at a titer of 1:10. Isoelectric focusing of CSF and serum revealed identical IgG oligoclonal bands. Based on the 2015 International Panel for NMO Diagnosis Criteria, ¹ the patient was diagnosed with NMOSD. She received intravenous methylprednisolone sodium succinate (1000 mg/day for 5 days tapered every 3 days) as anti-inflammatory therapy. Oral prednisone (60 mg/day) was subsequently administered. Although no improvement was observed in visual function, limb weakness and numbness improved significantly, and the patient regained her ability to walk with assistance. The MRC scale score improved to 4/5 for elbow flexion, hip flexion, knee flexion, and ankle dorsiflexion, accompanied with generalized hypoalgesia and residual dysuria. The EDSS score also improved from 8.0 to 4.0 following steroid treatment. After discharge, oral prednisone was continued and gradually tapered to 10 mg/day.

Figure 1.

MRI of the cervical and upper thoracic spine. (a) Axial and (b) sagittal T2-weighted images demonstrate a longitudinally extensive myelitis lesion extending from C1 to Th2 (gadolinium contrast not administered). The most prominent abnormalities are observed at the cervicothoracic junction, showing extensive hyperintense signal changes on T2-weighted sequences, predominantly involving the central component. MRI: magnetic resonance imaging.

In April 2020, the patient was readmitted to the hospital due to decreased visual acuity in both eyes for 1 week. At admission, the BCVA was light perception with inaccurate localization in the right eye and no light perception in the left eye. Macular OCT showed no abnormal findings, while peripapillary OCT revealed thinning of the retinal nerve fiber layer in both eyes. Color Doppler ultrasound of the eyeballs and plain computed tomography (CT) of the optic canal showed no obvious abnormalities. MRI of the brain and cervical spine was also unremarkable. These findings indicated recurrent visual loss consistent with relapse of optic neuritis rather than progressive deterioration of past optic nerve damage. In addition, the patient concurrently developed numbness, pain, and weakness in the right limbs, suggestive of NMOSD relapse. Lumbar puncture revealed a CSF white blood cell count of 20 × 10⁶/L and normal CSF biochemistry; tests for CNS-demyelinating diseases in the CSF were negative. She was treated with methylprednisolone sodium succinate pulse therapy. After treatment, her binocular visual impairment persisted, with a right limb muscle strength graded at 5− and decreased pain and temperature sensation in the right limb.

Along with neurological symptoms, the patient had a history of chronic liver disease. In August 2018, screening for infectious diseases yielded positive results for hepatitis B surface antigen (HBsAg), antibody to hepatitis B e antigen (HBeAb), and antibody to hepatitis B core antigen (HBcAb), consistent with hepatitis B “small three positive.” During outpatient follow‑up in October 2018, her routine blood tests were normal. Liver function tests showed markedly elevated total bile acids, alkaline phosphatase (ALP), gamma‑glutamyl transferase (γ-GT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels. Serum hepatitis B virus (HBV) DNA load was 1.27 × 10⁸ IU/mL, indicating active viral replication. The level of hyaluronic acid, one of four liver fibrosis markers, was elevated, suggesting liver fibrosis. Tests for the hepatitis virus panel and autoantibodies for autoimmune liver disease were negative. Chest radiography and abdominal ultrasonography showed no abnormal findings. Two sets of tumor marker measurements showed elevated carbohydrate antigen 19-9 (CA19‑9) and ferritin levels; her carbohydrate antigen 72-4 (CA72‑4) was initially increased but had normalized on re‑examination. She was then formally diagnosed with chronic viral hepatitis B. In April 2019, the patient was diagnosed with liver cirrhosis. Tumor markers showed an alpha-fetoprotein (AFP) level of 20.73 U/mL and CA19-9 level of 59.04 U/mL, with the levels of other markers within normal limits. Plain and contrast‑enhanced MRIs of the liver demonstrated liver cirrhosis, and abdominal ultrasound revealed diffuse hepatic lesions. Contrast-enhanced abdominal CT identified a primary small HCC in segment 7 of the liver (Figure 2(a)). During this time, the patient’s liver function was classified as Child–Pugh class A, and the tumor was categorized as Barcelona Clinic Liver Cancer (BCLC) stage 0. Serum alpha-fetoprotein levels were elevated, consistent with the diagnosis. Following the diagnosis, the patient refused surgical treatment. Two years later, in March 2022, she was readmitted due to a spontaneous rupture and hemorrhage of the HCC mass (Figure 2(b)). Follow-up contrast-enhanced abdominal CT scan demonstrated significant tumor progression, with the lesion measuring 13.5 × 11.6 cm. The findings indicated the presence of a tumor thrombus affecting the inferior vena cava and right hepatic vein in addition to pulmonary metastasis. Her liver function had deteriorated to Child–Pugh class B, and the disease was restaged as BCLC stage C. At this point, the patient and her family declined all further oncologic treatments, including both surgical and nonsurgical options. Her clinical condition deteriorated progressively, and she eventually passed away.

Figure 2.

CT of the liver. (a) A 9 × 8-mm hypodense lesion is visible in segment 7 of the right hepatic lobe on contrast-enhanced CT. (b) The lesion has increased markedly in size compared with prior imaging, measuring approximately 116 × 135 × 99 mm. CT: computed tomography.

Discussion

NMOSD is a rare inflammatory and demyelinating disease of the CNS that can be classified as AQP4–IgG seropositive or seronegative. The median onset age is 40 years, with a strong female predilection. ¹⁵ Some patients with NMOSD may present with PNS features, and any signs of NMOSD in older adults, particularly those with subacute onset, should raise suspicion of a potentially underlying paraneoplastic cause. ¹³ The pathogenic link between PNS and NMOSD is primarily mediated by AQP4–IgG cross-reactivity, the fundamental mechanism of paraneoplastic NMOSD. AQP4 is the primary target antigen in seropositive NMOSD. When the immune system recognizes tumor-expressed AQP4 as foreign, it produces AQP4–IgG antibodies that cross the blood–brain barrier (BBB) and attack AQP4–positive astrocytes, triggering inflammatory demyelination.^16,17

Paraneoplastic NMOSD is mainly associated with breast, lung, and genitourinary (primarily ovarian) malignancies.^8,10 Shahmohammadi et al. ⁸ identified 62 cases of NMOSD that met the PNS criteria. They found that the most frequently reported associated cancers were genitourinary (n = 14, 22.3%), breast (n = 12, 19.4%), lung (n = 12, 19.4%), gastrointestinal (n = 7, 11.3%), hematological (n = 6, 9.7%), endocrine (n = 5, 8%), and lymphoid organ (n = 4, 6.4%) cancers. Makishi et al. ¹⁰ reported 26 AQP4–IgG-positive cases, most commonly associated with genitourinary (n = 9, 34.2%), breast (n = 6, 23.1%), lung (n = 5, 19.2%), hematological (n = 3, 11.5%), and gastrointestinal (n = 2, 7.7%) cancers. To our knowledge, AQP4–IgG‑positive NMOSD has not been previously linked to HCC. Although AQP4 expression has been evaluated in other gastrointestinal tumors,^18,19 its expression in HCC or normal hepatocytes is poorly documented in the literature, with most studies focusing on AQP1, 3, 7, 8, and 9 rather than on AQP4. ²⁰ This underreporting may explain the absence of documented HCC–associated paraneoplastic NMOSD cases.

We describe the case of a 60-year-old woman with AQP4–IgG-positive NMOSD experiencing annual relapses who was subsequently diagnosed with HCC. This case is characteristic of paraneoplastic NMOSD and broadens its known manifestations. Her condition improved with intravenous methylprednisolone and oral corticosteroid tapering; however, annual relapses persisted. We speculate that the undiagnosed/untreated HCC contributed to disease recurrence. Research has confirmed that surgical resection of the primary tumor can effectively inactivate the dysregulated immune response, thereby significantly improving patient outcome and long-term prognosis. ²¹ However, the patient declined surgery, leading to rapid clinical deterioration. This case serves as a notable adverse example, highlighting the critical impact of targeted management of the primary tumor on patient prognosis.

This case links AQP4–IgG-positive NMOSD to HCC, a previously unassociated malignancy. This discovery may reflect underrecognized AQP4 expression in HCC or the rarity of both conditions. Although direct evidence of AQP4 expression in HCC is lacking in the published literature, we postulate that HCC cells express AQP4 or a cross‑reactive epitope that triggers AQP4–IgG production, targeting CNS astrocytes and driving NMOSD. This extends the classic paraneoplastic mechanism to a new tumor type and supports HCC screening in older NMOSD patients. This case highlights the need for thorough cancer screening in NMOSD patients aged >45 years, especially those with treatment-refractory relapses. Further research into AQP4 expression in HCC and understudied malignancies is needed to define the full spectrum of paraneoplastic NMOSD and improve outcomes. Future studies should characterize AQP4 expression in HCC tissues and validate the proposed cross‑reactive immune mechanism to confirm HCC as an associated malignancy.

This study has certain limitations. First, no immunohistochemical analysis was performed to confirm AQP4 expression in HCC tissue, which is required according to the 2021 PNS criteria to establish a causal paraneoplastic link. Notably, considering the patient’s history of hepatitis B and liver cirrhosis, we cannot rule out the possibility that HCC was already in a subclinical stage at the time of NMOSD onset; additionally, a direct paraneoplastic causal relationship cannot be confirmed. This further underscores the need for additional research to clarify this association. Second, the patient did not receive early antitumor treatment, which likely accelerated progression. Third, detailed ophthalmological evaluations, including formal visual field testing and orbital gadolinium contrast-enhanced MRI, were not available. Although OCT showed thinning of the retinal nerve fiber layer in both eyes, the lack of standard visual field assessment and orbital MRI limited the comprehensive and objective characterization of optic nerve involvement. Fourth, the patient and her family refused further contrast-enhanced testing; therefore, gadolinium contrast-enhanced T1-weighted MRI was not performed. Thus, we were unable to fully assess myelitis lesion activity. Finally, we could not assess the potential impact of antitumor therapy on the clinical course and outcomes of NMOSD in this patient. Further studies with larger cohorts and long-term follow-up are necessary to clarify the fundamental pathophysiology of paraneoplastic NMOSD, characterize the spectrum of ophthalmological manifestations in cancer-associated NMOSD, and establish optimal multidisciplinary management strategies for these complex patients.

Conclusions

This case report contributes to the growing body of clinical literature on paraneoplastic NMOSD and emphasizes the crucial clinical significance of conducting thorough tumor examinations for newly diagnosed older NMOSD patients. Notably, this is the first case of AQP4–IgG-positive NMOSD associated with HCC, a malignancy that has rarely been linked to paraneoplastic NMOSD in previous studies. This finding expands the known spectrum of tumors potentially associated with paraneoplastic NMOSD and lays the foundation for future exploration of potential pathogenic links between NMOSD and malignant tumors.