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Mesothelioma and anti-Ma paraneoplastic syndrome; heterogeneity in immunogenic tumours increases
  1. Hilary Anne Archer1,
  2. Aikaterini Panopoulou2,
  3. Nidhi Bhatt3,
  4. Anthony James Edey4,
  5. Nicola Jane Giffin2
  1. 1Department of Neurosciences, Frenchay Hospital, Bristol, UK
  2. 2Department of Neurology, Royal United Hospital Bath, Bath, UK
  3. 3Department of Histopathology, Bristol Royal Infirmary, Bristol, UK
  4. 4Department of Radiology, Southmead Hospital, Southmead Hospital, Bristol, UK
  1. Correspondence to Dr Hilary Archer, Department of Neurosciences, Frenchay Hospital, Frenchay Park Road, Bristol, UK, BS16 1LE; hilary.archer{at}nbt.nhs.uk

Abstract

We present a patient with opsoclonus and diffuse cerebellar signs who had an anti-Ma2 antibody-associated paraneoplastic syndrome secondary to a sarcomatoid mesothelioma. This case highlights the importance of early tumour detection, instigation of therapeutic measures, and the heterogeneity of underlying malignancies in neurological paraneoplastic syndromes.

  • Cerebellar Disease
  • Neuroophthalmology
  • Paraneoplastic Syndrome

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Introduction

Paraneoplastic syndromes of the central nervous system comprise a range of syndromes resulting from an underlying tumour, but not due to metastases or direct tumour infiltration. These syndromes can present in many ways, but the typical neurological deficit is encephalomyelitis, cerebellar degeneration or sensory neuronopathy.1 Neuronal damage appears to be mediated by an immune reaction triggered by the underlying tumour. Six antineuronal antibodies have been identified—if present, this indicates a definite paraneoplastic syndrome.2 Detecting these antibodies has led to increasing recognition of paraneoplastic syndromes, now known to complicate up to 5% of lung cancers, 20% of thymomas and 10% of B-cell or plasma cell neoplasms.3

The anti-Ma antibody is the most recently described, with approximately 80 cases described to date.4 ,5 The anti-Ma spectrum subdivides into anti-Ma1 and anti-Ma2 positivity, each with distinct diagnostic and prognostic implications. Anti-Ma1 paraneoplastic syndromes are most commonly associated with non-small cell lung carcinomas, while anti-Ma2 syndromes are often linked with testicular tumours. Identifying the underlying tumour is crucial, as the clinical outcome directly depends upon successful cancer treatment.4 ,5 We describe a patient with an anti-Ma2-positive paraneoplastic syndrome presenting with opsoclonus and cerebellar signs, with an underlying pleural mesothelioma. This unusual case underlines the heterogeneity of tumours associated with paraneoplastic syndromes, and the need for careful assessment, investigation and timely treatment in this range of disorders.

Case report

A 66-year-old right-handed man, who worked as a carpenter, presented with a 2-month history of oscillopsia, vertigo and altered speech and gait. These symptoms first developed during a trip to Egypt, with a transient episode of acute vertigo and vomiting. This was followed by intermittent and then sustained vertigo. He had difficulty walking because of poor visual fixation and imbalance, and after 1 month could walk only with support.

Four years previously he had been diagnosed with a sensory axonal peripheral neuropathy.

On examination, there was nystagmus in all directions of gaze (see web-only file). This was downbeat in the primary position, and intensified on lateral gaze (left more than right). The eye movements were full but increasingly disordered in upgaze and alternated between downbeat and torsional components, consistent with opsoclonus. His speech was slow and deliberate with slurring. There was mild past pointing and dysdiadochokinesis bilaterally in the upper limbs. Reflexes were diminished in the lower limbs, with heel–shin ataxia. He could not stand unaided, and his gait was unsteady and broad based. Cognition was normal. There was no myoclonus.

Initial blood tests were negative or normal apart from a mildly positive antinuclear antibody and antismooth muscle antibodies. Cerebrospinal fluid was acellular with protein raised at 1.0 g/L (0.15–0.45). MR brain scan with gadolinium contrast was normal. However, CT scan of the chest, abdomen and pelvis showed an anterior mediastinal mass (see figure 1).

Figure 1

Contrast enhanced CT scan of thorax. Axial CT scan of thorax showing a homogeneous soft tissue mass in the right anterior mediastinum, distorting the right ventricle but without local invasion. There are also bilateral calcified pleural plaques (arrowed) in the paravertebral region from previous asbestos exposure.

The mediastinal mass was biopsied percutaneously and subsequently resected; histopathologically, it was a localised sarcomatoid mesothelioma (figure 2). Antineuronal antibody screening found positive antiparaneoplastic antigen Ma2 (Ma2/Ta) antibodies. Further investigation with testicular ultrasound and fluorodeoxyglucose positron-emission tomography (PET) scanning found no other abnormalities.

Figure 2

H&E stained section. H&E stained section showing a fairly well circumscribed spindle cell tumour infiltrating mediastinal fat and arising from the parietal pleura. The background pleura showed plaques (not demonstrated here), but the mesothelioma was otherwise localised.

Despite 3 days of 1 g intravenous methylprednisolone, followed by intravenous immunoglobulin, his symptoms only marginally improved. He underwent 5 days of plasma exchange, again without significant change. We cancelled a planned course of chemotherapy due to his rapid physical decline, and he is currently being treated supportively.

Discussion

We report a patient with opsoclonus and cerebellar signs who had positive anti-Ma antibodies, in association with a sarcomatoid mesothelioma. To our knowledge, there are no previous descriptions of this relationship. Moreover, mesothelioma only rarely causes a neurological paraneoplastic syndrome; there have been two cases with a cerebellar syndrome, but without anti-Ma antibodies.1 ,6

Anti-Ma paraneoplastic syndrome most commonly presents as a limbic–diencephalic–brainstem syndrome. Eye movement disorders, including opsoclonus, are also common, along with mild to moderate cerebellar dysfunction. In most cases, neurological signs precede detection of the underlying tumour and, as in our patient, the symptoms due to the paraneoplastic syndrome can be more debilitating than those of the cancer itself.5

Neuroimaging can also help (abnormal in two-thirds). If imaging is initially normal, reimaging at an interval may show abnormalities.4 ,5

In paraneoplastic syndromes, antineuronal antibodies serve as a marker of disease, and often point to specific underlying tumours. If a malignancy is found that is not commonly associated, the patient should be investigated for an alternative causative neoplasm: some patients have two underlying tumours.7 Further investigation of our patient with testicular ultrasound, PET imaging and reimaging with CT scanning 6 months after presentation, did not find a second malignancy. Where there is no primary, screening should continue for at least 4 years.

It is very important to identify the immunogenic tumour. Most patients do not respond to immunosuppressive treatment alone, and best response is achieved by treating the underlying tumour. Within the anti-Ma group, the outcome is better with testicular tumours. Other good prognostic factors are youth (<45 years), a tumour sensitive to therapy, limited central nervous system involvement and dominant anti-Ma2 rather than anti-Ma1 antibodies.4 The clinical course usually does not change until the underlying tumour has been treated.5 Early tumour identification and treatment may also limit neuronal damage, since this occurs subacutely and is often irreversible. Thus, immunosuppressive treatment should probably be started as early as possible, ideally within 1 month of neurological symptoms, to minimise damage.4 The main treatment options are corticosteroids, intravenous immunoglobulins, and plasma exchange; however, more aggressive immunosuppressive agents, such as cyclophosphamide, tacrolimus, cyclosporin and rituximab have also been used.8

Unfortunately, our patient's symptoms did not improve despite tumour resection, pulsed intravenous methylprednisolone, immunoglobulins and plasma exchange. This failure to respond to therapy likely mirrors the inexorable progression of mesothelioma, for which there is no curative intervention.

References

Footnotes

  • Contributors HAA was responsible for conception and design of the study, drafting and revision. AP contributed to study conception and design, drafting and revision. NB provided analysis, and helped to revise the article. AJE provided image analysis, and helped to revise the article. NJG contributed to study conception and design, drafting and revision. All authors were involved in final approval of the article.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Case report. Patient has given consent for paper and images.

  • Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Jeremy Rees, London, UK.

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