Rare case of paraneoplastic cerebellar degeneration secondary to high-grade serous carcinoma of tubo-ovarian origin

Abstract

This case describes a 69-year-old woman, who presented with rapidly progressive cerebellar symptoms and unintentional weight loss. Full neurological assessment excluded space-occupying lesions, vascular accidents and infection. Surprisingly, a chest, abdomen and pelvis CT showed a left hemipelvis mass, which was subsequently biopsied. A high-grade serous carcinoma of tubo-ovarian origin was found, diagnosing paraneoplastic cerebellar degeneration (PCD) secondary to this. The exact mechanism is not known, but is thought to be immune-mediated. In cases of PCD, after cancer treatment, the neurological disability stabilises to a severe level and will unfortunately be lifelong. Our patient continues to make great progress with intensive rehabilitation for her ongoing balance issues. Early recognition of PCD can lead to a prompt diagnosis of the underlying malignancy and hence subsequent management. This can at least limit the extent of the neurological disability of the disease and increase the survival rate from cancer.

Background

Paraneoplastic cerebellar degeneration (PCD) is a subtype of the paraneoplastic neurological syndromes (PNS). It is an unusual manifestation of malignancy, mainly associated with lymphomas and tumours of the ovary, breast and lung. Paraneoplastic phenomena of gynaecological malignancies can span varied body systems: neurological, haematopoietic, vascular, rheumatological, dermal and endocrine. Within this, <0.005% of the population per year present with paraneoplastic neurological sequelae,¹ which are discovered before cancer is found in 80% of patients.² The mechanism of onconeural immunity is responsible, where autoantibodies recognise shared epitopes on the tumour and cerebellar tissue.³ Depending on the tumour present, different autoantibodies are produced. These include anti-Hu in small cell lung, anti-Ri/Nova in breast and anti-Yo in gynaecological cancers.³ After extensive investigations for a neurological cause of cerebellar syndrome cannot be found, PCD is considered, and full-body imaging,^{1 4–6} or sometimes a biopsy of a suspicious mass following strong clinical suspicion,³ locates the responsible tumour. In this paper, we report a case of a 69-year-old woman who presented with the cerebellar syndrome and was subsequently diagnosed with PCD as a result of tubo-ovarian carcinoma.

Case presentation

A 69-year-old woman was referred to neurology following 4 months of rapidly progressive symptoms of ataxia, dysarthria and recurrent falls. She was also noted to have an unintentional weight loss of 12 kg in the past 9 months. Her medical history included hypertension, mild asthma, gastro-oesophgeal reflux disease (GORD) and depression. She had a hysterectomy in her 30 s for endometriosis. Her family history was significant for malignancy, as her father had prostate cancer and her sister died of lung cancer in her 50 s. On examination, there was evidence of ataxia, dysdiadochokinesis, dysarthria and sustained gaze-evoked nystagmus.

Blood tests showed no evidence of nutrient deficiency, endocrine disorder or inflammation. Lumbar puncture ascertained 10 mL of a sparsely cellular sample which contained occasional lymphocytes, monocytes and red blood cells. No malignant cells were seen, confirmed immunohistochemically on a cell block sample. The cerebrospinal fluid (CSF) was analysed for oligoclonal bands, protein, glucose, haematology, culture and the presence of antibodies, all of which were within the normal laboratory parameters. An MRI head with contrast showed only signs of chronic small vessel ischaemia in the white matter of both cerebral hemispheres. However, there were no findings to suggest metastatic disease, infection or demyelination. The cerebellar hemispheres were of normal volume with no signal change. However, a cerebellar syndrome developing rapidly over days or weeks, without an identifiable intracranial occupying lesion, is most likely PCD.⁷ Thus, the normal findings in this patient led to the differential of PCD being considered.

Subsequently, bilateral mammograms found a suspicious 15 mm × 4 mm lesion, on the right breast, with fine linear-branching microcalcifications in a grouped distribution. Core biopsy concluded it was a high-grade ductal carcinoma in situ (DCIS). Incidentally, the staging CT of the chest, abdomen and pelvis showed a worrying 43 mm left adnexal mass. Despite no evidence of peritoneal disease, this finding was a concern for primary malignancy. A gynaecological referral and correlation with cancer antigen 125 (CA-125) level were recommended. An MRI pelvis delineated the adnexal mass to have soft tissue features concerning for a primary neoplasm. Interestingly, CA-125 was not elevated at 17 (normal parameters are 0–35 kU/L). The paraneoplastic antibody profile was also negative, which tested for a panel including, neuronal nuclear antibody 2 (Ri/Nova) found in breast PCD, Purkinje cell antibody (Yo) found in gynaecological PCD, neuronal nuclear antibody 1 (Hu), MA 1 antibody, MA 2(TA) antibody, amphiphysin antibody, CV2 (CRMP5) antibody and TR antibody. But due to a high index of suspicion, management for a paraneoplastic cause of ataxia was initiated, consisting primarily of treating the underlying tumour.

It was decided at the gynaecological multidisciplinary meeting that the adnexal mass would be the focus of the initial treatment before the breast DCIS, as the former was likely causative for the patient’s symptoms. She underwent a laparoscopic bilateral salpingo-oopherectomy, where a left tubo-ovarian mass was found buried under the sigmoid colon and adherent to the left sidewall. Consequent pathology showed a stage IIA high-grade serous papillary adenocarcinoma of tubo-ovarian origin with positive peritoneal washings. Following surgical resection, the patient was started on single-agent chemotherapy of carboplatin. After adjuvant chemotherapy, completion surgery for the tubo-ovarian cancer was indicated as well as wide local excision of the right DCIS.

Investigations

Imaging

MRI of the head showed some patchy increased intensity on T2 and fluid-attenuated inversion recovery MRI (FLAIR) in the white matter of both cerebral hemispheres and in the brainstem. These findings were in keeping with chronic small-vessel ischaemia. There was no mass or enhancement to suggest metastatic disease. The cerebellar hemispheres were of normal volume with no signal change (figure 1). MRI of the cerebellum was not repeated in our patient, as although cerebellar atrophy is often seen later in the disease course, the diagnosis of PCD in this patient was definite, thus a repeat MRI was not necessary.

Figure 1.

(A) Coronal T1-weighted image postcontrast medium of the cerebellum (B). Axial FLAIR image of the cerebellum showing the cerebellar hemispheres to be of normal volume with no signal change (C). Axial FLAIR image demonstrating white matter changes in both cerebral hemispheres, likely from small vessel disease (incidental appearances). However, there were no findings to suggest metastatic disease, infection or demyelination.

CT of the chest, abdomen and pelvis identified a 43 mm left hemipelvis mass. MRI of the pelvis delineated this lesion further, showing intermediate T2 signal intensity with internal tissue of intermediate signal intensity, which demonstrated restricted diffusion. There was no evidence of enlarged lymph nodes, peritoneal deposits or free fluid. These features were concerning for an adnexal malignancy.

Histopathology findings

The right ovary and fallopian tube were grossly and microscopically normal. In comparison, the left ovary was enlarged at 50×40×30 mm. The cut surfaces of the ovary showed the parenchyma largely replaced by a pale cream papillary tumour with focal involvement of the capsular surface. Microscopy showed the tumour to be a high-grade serous papillary carcinoma, with papillary and solid architecture involving the parenchyma and surface of the left ovary and the left fallopian tube. The left fallopian tube also showed a focus of serous tubal intraepithelial carcinoma, in keeping with fallopian tube origin. This placed the Federation of Gynaecology and Obstetrics staging to IIA.⁸ Immunostaining showed the tumour cells were positive for CK7, CA-125, WT1 and p53 mutant (figure 2).

Figure 2.

(A) Low-power (20×) and (B) high-power (400×) images of a H&E-stained section showing infiltration of the ovary by a carcinoma with papillary architecture, marked nuclear atypia and brisk mitotic activity. Immunohistochemical staining demonstrating the tumour cells are positive for Wilms’ tumour 1 (C, 200×), and showing mutant immunophenotype (diffuse strong positive staining) for p53 (D, 200×), in keeping with a high-grade serous carcinoma.

At staging laparotomy no active disease was seen on the peritoneal surfaces, liver or bowel and no ascites was seen. Peritoneal washings showed 16 mL of a cloudy, dark, red fluid with atypical papillary clusters, which displayed hyperchromatic crowded epithelial cells, in keeping with the known tubo-ovarian lesion. Immunostaining showed these groups to express Ber-EP4, PAX8, ER (weak-moderate 70%), WT-1 and p53 (strong in the majority of cells) with negative staining with calretinin. The omentum was macroscopically normal, and sections from this identified no focal lesions. Lymph nodes were not harvested.

Treatment

The patient underwent five cycles of single-agent chemotherapy over 4 months with carboplatin followed by supracolic omentectomy surgery. While on chemotherapy, the patient experienced severe side effects of extreme breathlessness, nausea and vomiting and heartburn, and thus declined the addition of paclitaxel. Following this, wide local excision of the right breast DCIS was undertaken. The patient had a further three cycles of chemotherapy before completion of treatment but declined adjuvant radiotherapy. A repeat CA-125 of 11 kU/L and CT found no evidence of recurrent or residual disease. Post-treatment she is being monitored through annual mammograms and CT scans and repeat CA-125 prior to regular 3 to 6 monthly oncology appointments for the next 5 years. The patient was investigated for BRCA gene mutation, which found no evidence of a pathogenic variant.

Outcome and follow-up

Unfortunately, despite the fact there was no evidence of extra pelvic disease, the patient was left with a profound level of disability and little to no improvement noted after chemotherapy. This is often seen with PCD, with reports of cerebellar symptom regression noted mainly in small cell lung carcinomas after complete resection of tumour.⁹ The patient was not treated with plasma exchange, steroids, intravenous immunoglobulin or rituximab for her residual cerebellar symptoms. This was due to the lack of consistent evidence of their neurological benefit after the causative tumour has been successfully treated.⁷ With long-term support from community neurophysiotherapy, she is aiming to become more independent with her ongoing balance and mobility impairment. The patient has found the psychological strain of her condition difficult, in particular, the realisation that her balance problem is likely lifelong.

Discussion

The cerebellar syndrome is classically described as having associated symptoms of ataxia, diplopia, dysphagia, dysarthria and nausea and vomiting.⁴ These neurological symptoms can be apparent from months to years before the malignancy presents. The tumour itself can also be of relatively small load, despite the stark neurological changes. The consequent neurological disability eventually stabilises, even after tumour remission, but is unfortunately severe and life-long.³

The pathophysiology of PCD is through a process called onconeural immunity. The production of anti-tumour antibodies cross-react with cerebellar tissue. Histopathologically, there is an almost complete destruction of Purkinje and astrogliosis cells, as well as demyelinating changes in the cerebellum and posterior columns of the spinal cord, although these are not seen on MRI until the advanced disease is present.¹⁰ The antibodies present depend on the primary causative tumour. These most commonly include antineuronal antibodies anti-Hu, anti-Yo and anti-Ri. Anti-Yo antibodies are present almost exclusively in breast and gynaecological cancer.¹ Anti-Yo antibodies directed against the tumour travel in the CSF and serum, and cross-react with at least two cerebellar degeneration-related antigens (CDR), CDR-62 and CDR-34 found on Purkinje cells.¹¹ These shared epitopes result in these antibodies, primarily produced to suppress tumour growth, also being directed against normal tissue, such as the cerebellum. The exact mechanism is not understood, although a T-cell mediated process has been hypothesised.¹ As these antibodies are not produced by the tumour and can persist indefinitely, after successful cancer treatment the severe disability continues but no longer progresses.^{10 12} Although, in multiple cases, tumour resection leads to stabilisation of the neurological disability.^{6 12 13}

Key to the treatment of PCD is its early recognition, which leads to prompt diagnosis of the underlying malignancy and hence subsequent management. As the damage is irreversible, symptoms are not expected to improve, but this can at least limit the extent of the neurological disability of the disease, as well as increase the survival rate from cancer.¹⁴ Recent guidelines have been published, recommending diagnostic criteria for PNS,¹⁵ and management strategies by the European Federation of Neurological Societies.¹⁶ Whether the diagnosis is ‘definite’ or ‘possible’ depends on if there is cancer, classical syndrome and onconeural antibodies present.¹⁵ A classical cerebellar syndrome is defined as developing severe symptoms over less than 12 weeks, that does not correlate to the level of cerebellar atrophy found on imaging, but within 5 years of the symptoms, an underlying cancer is identified. Positive onconeural antibodies are not necessary for the diagnosis but do support it.¹⁵ Thus, using this criteria, our patient had a definite PCD.

It is important to note that PCD is a diagnosis of exclusion. In a patient presenting with cerebellar symptoms, leptomeningeal metastases, cerebrovascular disease, infectious and demyelinating causes need to be ruled out first. In this case, all these possibilities were addressed. Imaging ruled out intracranial mass effects, vascular accidents, and visible degeneration. Blood chemistry and CSF examination ruled out infectious, endocrine, or demyelinating diseases. Following this, PCD should become a differential, and investigations should be started in search of underlying cancer.¹⁶ This should include a thorough history to determine risk factors, examination of the breast and pelvic areas in women, mammogram, chest X-ray, pelvic ultrasound, pelvic CT or MRI and CA-125 serology.^{14 16} If the CT is clear but onconeural antibodies are present, F-fluorodeoxyglucose positron emission tomography may be used.^{14 17–19} If no malignancy is found, repeated screening every 3 to 6 months for 2 to 3 years is recommended.¹⁴ The necessity of a paraneoplastic antibody profile is debated, due to its lack of sensitivity but high specificity, they are not found in roughly 30% of patients with PNS, and conversely, they can be present in patients without PNS.2 6 11 20 21 Thus, a strong clinical suspicion should be held even if the serology is negative, as in this case. Examination under anaesthesia or even an exploratory laparotomy may be warranted.¹³ In our patient, the process of cancer identification for PCD was different, as from national screening an abnormal mammogram identified a breast lesion, and the subsequent staging CT showed an adnexal mass.

Overall, treatment of PCD has been unsuccessful. However, reports in small cell lung cancer have shown regression of cerebellar symptoms after tumour remission.⁹ Cases have shown a trend of reporting successful treatment of underlying cancer but with a limited reversal in neurological disability. In an attempt to cure the cerebellar symptoms, methods such as immunotherapy with plasmapheresis, immunoglobulin, corticosteroids, cyclophosphamide, tacrolimus or rituximab have been considered,⁴ and some cases have shown improvement,^22–24 but others had limited success.^{5 14 24} However, the success of treatment appears difficult to predict depending on the presentation,^{20 25} as some studies note that anti-Yo-positive patients with an early diagnosis have a better treatment outcome than others,^{7 26} but the prognosis can be worse in tubo-ovarian cancer.²⁷ The poor outcome in most, is probably due to how by this stage, neuronal loss is already high and irreversible and immunotherapy is unlikely to affect intrathecal antibodies. Also, anti-Yo alone does not independently cause the condition, as the removal of anti-Yo by plasmapheresis did not improve symptoms,^{28 29} and animal models injected with anti-Yo immunoglobulin G have failed to reproduce PCD symptoms.^{6 30} The number of cases is small and new and further studies are needed in order to understand the best treatment option. Thus currently, of highest importance is the long-term management of these patients to be able to live with their neurological disability. With intensive neurorehabilitation and speech therapy, our patient has had continued improvement and confidence in her independent living.

Learning points.

• Paraneoplastic cerebellar degeneration (PCD) is classically described as having associated symptoms of ataxia, diplopia, dysphagia, dysarthria, prodrome of dizziness, nausea and vomiting,⁴ developing over <12 weeks, and within 5 years an underlying tumour is found. It is rare and its diagnosis can be difficult due to the varied presentations, and the evidence of cancer may be absent for sometimes months or years.^{1 3}

• Investigations undertaken for PCD diagnosis are focused towards the search for an underlying tumour, which include chest X-ray, mammogram, CT and pelvic ultrasound.^{13 15} Onconeural antibodies can be measured but have low sensitivity, so a strong clinical suspicion should not be ignored.2 6 11 20 21

• The mechanism of onconeural immunity is responsible, where autoantibodies recognise shared epitopes on the tumour and cerebellar tissue.² However, this is not always specific to PCD,³¹ and a strong clinical suspicion should remain if there is evidence of a suspected neoplasm but the paraneoplastic antibody profile is negative.

• Treatment of PCD has been relatively unsuccessful.4 5 9 14 24 Currently, the best strategy for management is early recognition of PCD and diagnosis of underlying cancer, followed by appropriate cancer management and aggressive rehabilitation. This should be done through a multi-disciplinary approach with an oncologist and relevant cancer surgeon depending on the type of malignancy.

• In order to develop better treatment for PCD, a better understanding of the underlying mechanism and future studies on the role of immunotherapy in paraneoplastic syndromes is needed.