Paraneoplastic antibody panel (Blood)

Diagnostic Use

Paraneoplastic neurological syndromes (PNS) are rare disorders that are triggered by an abnormal (most likely T-cell mediated) immune response to an underlying (and usually undetected) malignant tumour. The exception found to date is anti-Amphiphysin, where, the evidence from in-vivo animal studies using intrathecal passively transferred Amphiphysin IgG implies the antibody itself is pathogenic [1]. Invariably, patients with PNS present with neurological symptoms before tumour detection. Approximately 1-3% of all cancer patients have PNS [2].

Paraneoplastic cerebellar degeneration (PCD) occurs when antibodies produced against the tumour proteins attack similar antigens present in cells within the cerebellum via an irreversible and rapid inflammatory based process accounting for both the rapid (weeks to months) progression of PNS and usual ineffectiveness of immunomodulatory treatments [3].

PCD is characterised by cerebellar dysfunction. Usually initial symptoms are loss of co-ordination initially on one side but rapidly progressing to involve both sides equally. There is severe ataxia of arms, legs, neck and trunk with afflicted patients being unable to stand without assistance. Ocular findings are often abnormal and speech can be severely affected. Mild deterioration of mental status has been reported. After several weeks, symptoms stabilize leaving the patient in a severely disabled state [4].

The most effective treatment for PNS patients is successful treatment of the tumour.

Interpretation

Although approximately 1 in 3 PNS patients do not have a well characterised intracellular onconeuronal antibody, detection of antibodies remains the most useful diagnostic tool for PNS as outlined in the Table below.

 

Antibody	Neurological Syndromes	Tumours (prevalence)
Anti-Hu (ANNA-1)	Encephalomyelitis, Limbic encephalitis, Sub-acute sensory neuropathy, Paraneoplastic cerebellar degeneration, Autonomic neuropathy	SCLC, Neuroblastoma, Prostate   (84-88%)
Anti-Ri (ANNA-2)	Opsoclonus Myoclonus Syndrome (OMS), Brainstem Encephalitis, paraneoplastic cerebellar degeneration	SCLC, Breast   (86-100%)
Anti-Yo (PCA-1)	Paraneoplastic cerebellar degeneration	Ovary, Breast   (79-95%)
Anti-CV2 (CRMP5)	Sub-acute sensory neuropathy, Autonomic neuropathy, Paraneoplastic cerebellar degeneration, Encephalomyelitis, Limbic encephalitis, Optic neuritis, Chorea	SCLC, Thymoma   (86-91%)
Anti-Ma2 (Ta)	Encephalomyelitis, Limbic encephalitis, Paraneoplastic cerebellar degeneration, Brainstem encephalitis	Testicle, Lung   (63-89%)
Anti-Amphiphysin	Stiff-Person syndrome, Encephalomyelitis, Sub-acute sensory neuropathy, Sensory motor neuropathy	SCLC, Breast   (79-100%)
Anti-DNER (Tr)	Paraneoplastic cerebellar degeneration	Hodgkin?s Lymphoma   (89%)
Anti-GAD	Stiff-person syndrome, Paraneoplastic cerebellar degeneration, Limbic encephalitis	Lung, Neuroendocrine tumours   (1-9%)

 

Yo antibodies recognise two (34 and 62kDa) proteins expressed in the cytoplasm of cerebellar Purkinje cells. Patients with Yo antibodies are typically females where the underlying tumour is usually breast or ovarian. Mortality caused by the neurological degeneration is approximately 30% of afflicted patients. Survival is poorer in patients with ovarian (median survival: 22 months) as compared to breast cancer (median survival: 100 months) [6].

Hu antibodies recognise a family of 35-40kDa proteins found in both the cytoplasm and nucleus of all neurons. Additionally, Hu antibodies bind to cells of the stomach myenteric plexus. The most prevalent tumour association is SCLC and the associated neurological syndromes are the cause of death in almost two-thirds of patients [7].

CV2 / CRMP5 antibodies recognise a 66kDa developmentally regulated brain protein expressed, in the adult brain by a subset of oligodendrocytes. Over two-thirds of patients are male with a median age of 62 years. The most frequently associated cancer is SCLC and the most commonly expressed neurological disorders are polyneuropathy and cerebellar ataxia (both seen in approximately 60% of cases) [8].

The cerebellar reactivity pattern for Ri antibodies is identical to that seen with Hu antibodies in that the nuclei of all neurons are stained, however, unlike Hu antibodies the proteins recognised by Ri antibodies are 50 and 80kDa. Additionally, and importantly for laboratory diagnosis Ri antibodies do not react with cells of the stomach myenteric plexus. OMS and SCLC are the most prevalent neurological syndromes and tumours respectively [9].

In the cerebellum, anti-DNER / Tr antibodies attach to the cytoplasm and proximal dendrites of Purkinje cells. The presentation differs from Yo antibody staining by virtue of diffuse staining of the molecular layer and presence of multiple small dots suggestive of immunoreactivity with the dendritic spines of Purkinje cells. Hodgkin?s lymphoma and PCD are the cancer and neurological syndrome associated with Tr antibodies [10].

Amphiphysin antibodies recognise a 128 kDa antigen expressed in cerebellum axonal synapses. As previously mentioned, in vivo transmission studies with rodents implies the antibodies are pathogenic. The antibodies were first identified with stiff person syndrome and breast cancer but latterly have been associated with encephalomyelitis and sensory neuropathy when the underlying tumour is SCLC [11].  

Ma2 antibodies recognise a 40kDa protein in cerebellar sub-nuclear structures giving discrete dot staining in molecular layers. The ?dot? presentation in the nucleus of Purkinje cells mimics that of ANA nucleolar staining therefore ANA testing must be performed as a quality check if Ma2 antibody is suspected. The main clinical neurological associations are limbic and / or brainstem encephalopathies. The clinical picture is often complex with short-term memory loss, seizures, confusion, excessive daytime sleepiness, hypothalamic-hormonal deficits and vertical gaze paralysis that can progress to total opthalmoplegia. The tumour most associated with Ma2 antibodies is non-seminomatous testicular cancer [12].

Reference Intervals

All newly detected paraneoplastic antibody reactive results must be immediately referred to a clinical resource.