Chronic inflammatory demyelinating polyneuropathy caused by hepatocellular carcinoma

Background

Paraneoplastic syndromes are a group of rare disorders that can occur in response to a neoplastic disease. They result from the secretion of specific peptides, chemokines, cytokines or hormones from tumour cells, as well as from immune cross-reactivity against tumour antigens, leading to autoimmune manifestations.1 Neurological paraneoplastic syndromes specifically consist of a constellation of neurological symptoms that may involve the central, peripheral or autonomic nervous system.2 3 These pathologies are most commonly associated with breast cancers, ovarian cancers, small cell lung cancer, gynaecological cancers and lymphomas. For instance, chronic inflammatory demyelinating polyneuropathy (CIDP) is a neurological paraneoplastic syndrome that results from an autoimmune-mediated demyelinating peripheral neuropathy. CIDP is described most frequently in the context of haematological malignancies, especially Hodgkin’s and non-Hodgkin’s lymphomas, as well as haematological gammopathies. These syndromes usually manifest prior to the diagnosis of the primary malignancy and are frequently but not exclusively associated with neuronal antibodies.4 5 To the best of our knowledge, we describe the first case of complete resolution of paraneoplastic CIDP symptoms in response to radical resection of a hepatocellular carcinoma (HCC).

Case presentation

A man in his 60s presented to the emergency department of our hospital with a 10-day history of ataxia, severe weakness in the lower and upper limbs, and decreased sensation at the tips of his fingers and toes. His symptoms were preventing him from performing activities of daily living, such as climbing stairs and handling objects. The patient started experiencing paraesthesia in his fingertips 1 year prior to his admission. He also reported a 2-month history of gradual, bilateral ascending numbness in his toes, reaching his hips. This was accompanied by progressive weakness in his shoulder muscles. The patient has a history of well-controlled diabetes, hypertension and latent tuberculosis.

On physical exam, he was found to have generalised areflexia. Decreased pinprick, vibration and position sensations were also noted. No cerebellar signs were present.

Investigations

Laboratory values at the time of admission showed normal sodium, potassium, calcium and magnesium concentrations. His liver function tests were within normal ranges. His creatinine level was stable from baseline (1.3) considering his chronic kidney disease in the setting of diabetes. Serum antibody analysis was positive for anti-SSA (Sjogren's Syndrome A), anti-beta-2 glycoprotein, and anti-ganglioside GD1a, GD1b and CQ1b antibodies, as well as ANA (Anti-Nuclear Antibody). On the other hand, anti-CCP (Cyclic Citrullinated Peptide), RF (Rheumatoid Factor) and C-ANCA/p-ANCA (AntiNeutrophil Cytoplasmic Antibody) were all negative.

Electrodiagnostic studies (electromyography and neurography) were performed and revealed a severe delay in the proximal and distal motor latencies in the peroneal, posterior tibial, median and ulnar nerves, along with a moderate decrease in motor conduction velocities in the upper and lower extremities bilaterally. This was accompanied by a drop in the compound muscle action potential amplitudes proximally compared with distally in the distribution of these nerves. There were no sensory responses in any of the examined nerves. Temporal dispersion was noticed in the median nerves. Overall, the clinical picture, laboratory findings and electrodiagnostic studies supported a diagnosis of CIDP.

Differential diagnosis

The patient was then referred to the rheumatology clinic to rule out possible rheumatological or connective tissue disease. No clinical symptoms or signs suggestive of rheumatological disorders were found. CIDP, as a paraneoplastic syndrome, became more significant on the differential diagnosis. Haematological studies were performed to rule out haematological malignancies. Serum protein electrophoresis showed non-specific findings, including mild paraproteinaemia (kappa and lambda chains slightly elevated), elevated beta-2-microglobulin and elevated total serum proteins. Urine protein electrophoresis was normal.

A positron emission tomography scan was performed and showed a large heterogenous hypodense mass in the liver with a central area of photopenia related to necrosis, measuring 10×10.9×8.6 cm at the junction of segments II and IVa, extending to segments II and III, suspicious for primary malignancy of the liver (figure 1). No metastatic lesions were detected. Ultrasound imaging showed diffuse hepatic steatosis. For further characterisation of the lesion, MRI of the abdomen was completed and showed a 10.5 cm, slightly exophytic and relatively well-demarcated lesion involving the left hepatic lobe. The features were suggestive of HCC, possibly of fibrolamellar type. A CT-guided liver core biopsy was done to confirm the diagnosis. Pathological examination reported well-differentiated HCC (Hep par-1 positive, glypican positive, CK8/18 (Cytokeratin 8/18) positive, CK7 negative) (figures 2 and 3). Alpha fetoprotein and repeated liver function tests were all normal at that time.

Figure 1

(A) Non-contrast CT and (B) positron emission tomography scan showing a large heterogenous hypodense mass in the liver and central area of photopenia related to necrosis at the junction of segments II and IVa, extending to segments II and III.

Figure 2

Histology of the liver tumour (H&E stain). (A) Medium-power view, 20×: the tumour cells resemble normal hepatocytes. They have a polygonal cytoplasm. (B) High-power view, 40×: abundant cytoplasm with round to oval vesicular nuclei and nuclear invaginations.

Figure 3

Immunohistochemistry of tumour cells: (A) Hepar-1: positive; (B) glypican: patchy positivity; (C) CK8/18: positive; (D) CD34: highlights tumour vascularity; (E) AFP (Alpha Fetoprotein): negative; and (F) CK7: negative.

Treatment

The patient was started on a course of intravenous immunoglobulin (IVIG) for 5 days. There was a significant improvement in his gait and ability to walk but no tangible improvement in the distal extremity paraesthesia. Within 2 weeks of the initial course of IVIG, his neurological symptoms recurred and became refractory to further IVIG sessions. His motor and sensory symptoms were worsening. Intravenous corticosteroid (Solu-Medrol) was then added to IVIG, leading to an improvement in both upper and lower extremity motor functions. However, such improvement was not enough to allow the patient to walk or to perform daily tasks as he was still dependent on assistance from two persons to move. Medical treatment was then stopped completely.

On reviewing the case at the hospital’s tumour board, the decision was taken to intervene surgically given that his paraneoplastic syndrome is refractory to medical intervention. Child-Pugh score was computed prior to surgery and the patient was classified as a ‘Class A’ candidate. After informed consent was obtained, the patient underwent an uncomplicated laparoscopic extended left hepatic lobectomy. Staging of the cancer following surgery showed a T1bN0M0 stage tumour.

Outcome and follow-up

Following surgery, the patient had an uncomplicated hospital course of 7 days’ duration at the end of which he was able to reach objects and to grasp them with his hands. He was also able to walk with assistance from one person. His sensory functions in both upper and lower extremities were also improving prior to discharge. Four weeks later, the patient was examined at a follow-up visit, and neurological assessment showed an exceptional improvement in paresis, numbness in the upper and lower extremity, as well as proprioceptive abnormality following resection of the hepatic tumour. The patient regained most of his motor power and was able to stand up and ambulate with limited support. Two months later, neurological assessment showed a fully functional man who can perform routine tasks of daily activity with minimal effort. One year following the surgery, the patient presented to the clinic to follow up on his condition. Physical examination showed a well-healing surgical scar and his neurological examination was negative. Repeat MRI showed no suspicious lesions in the liver or in the abdomen. The patient’s neurophysiological status was well preserved, and he was functionally independent in his daily activities. Consent was taken during this encounter. The patient recently had a virtual checkup appointment, and he reports no change in his neurological status and is fully active.