Paraneoplastic cerebellar degeneration diagnosed by anti-Yo determination in a young woman with early breast cancer

Abstract

A 44-year-old woman diagnosed with a HER2 positive early breast cancer, receiving neoadjuvant treatment with paclitaxel and targeted agents, trastuzumab together with pertuzumab, presented to the emergency room with gait instability and upper right limb weakness. The neurological examination was compatible with cerebellar alteration showing right dissymmetry of the finger-nose and heel-knee manoeuvre. A head CT and a brain MRI were performed and negative. The electromyography showed alterations of the pyramidal pathway and somatosensory pathway. In order to determine the cause of the cerebellar affection, a lumbar puncture was performed. The cerebrospinal fluid analysis was non-specific, but the antineuronal anti-Yo antibody was positive, being diagnosed of a paraneoplastic cerebellar degeneration (PCD). A positron emission tomography CT ruled out metastatic disease. The patient completed four cycles of antiHER2 blockade and weekly paclitaxel, achieving a complete pathological response. One year later, she maintains a complete remission but the PCD still prevails.

Background

Paraneoplastic syndromes are characterised by an immune reaction against the tumour and secondarily to healthy tissues of the same organism.¹ One of the most frequent paraneoplastic syndromes is the paraneoplastic cerebellar degeneration (PCD), which includes several neurological disorders related to cerebellar dysfunction. The pathophysiology is based on the formation of autoantibodies against various antigens, such as cerebellar degeneration-related protein (CDR2), present in Purkinje cells. Most cases described are women with breast or pelvic malignancies, as is the case of our patient.² The low prevalence of this syndrome does not allow randomised clinical trials, so the evidence of the treatment is based on series of published cases treated with steroids and immunomodulators. Unfortunately, the neurological prognosis is devastating and less than 10% of patients are able to walk on their own.³ We present a rare case of a patient with localised HER2 positive breast cancer diagnosed with a PCD.

Case presentation

A 44-year-old woman presented to the emergency room in January 2019 with severe gait instability and a progressive difficulty in raising her upper right limb for about 5 weeks. The patient was a former smoker with a 30 pack-year history. She had no known allergies. She had suffered from anxiety–depressive syndrome in the past and was treated successfully with fluoxetine. She had attained menarche at 11 years of age. The patient was also taking oral contraceptives for the past 5 years. She had one child and her mother died at a young age of metastatic breast malignancy.

Due to her family cancer history, the patient entered an early annual mammography screening for breast cancer. In July 2018, a mammography performed presented two left breast nodules; one at the junction of the lower inferior quadrants of 10×12 mm and another one of 4×3 mm at the junction of the external quadrant. A nuclear MRI was performed, which showed multiple mass lesions, the largest at the union of lower quadrants of the left breast of 15×13×20 mm. Axillary ultrasound ruled out lymph node spread and neither the thoracic-abdominal tomography nor the bone scintigraphy showed evidence of metastatic disease. Finally, two biopsies were performed in August 2018. The histological report classified the tumour as a grade 3 infiltrating ductal carcinoma (IDC) with negative oestrogen receptors (OR), positive progesterone receptors (PR), positive HER2 (3+) by immunohistochemistry, and a Ki67 proliferation rate of 45%. The histological report was a Luminal B HER2 positive breast carcinoma. In the second biopsy performed at the union of external quadrants, an IDC grade 2, OR and PR negative, HER2 positive by immunohistochemistry (3+), and a Ki67 index of 35% was detected, being the histological report compatible with an IDC HER2 positive non-luminal breast carcinoma. Therefore, the patient was diagnosed of a multicentric IDC cT1N0M0 HER2 positive with luminal B and non-luminal foci of the left breast. With that information, neoadjuvant therapy with AC scheme (doxorubicin and cyclophosphamide) was started for four cycles from September 2018 to November 2018 with excellent tolerance. Subsequently, paclitaxel, trastuzumab and pertuzumab were started on December 2018. In addition, given the oncological family history, a panel of tumour susceptibility genes was performed, which did not show any mutation.

After receiving the first cycle of paclitaxel, trastuzumab and pertuzumab, the patient presented to the emergency room with gait instability and upper right limb weakness. Vital signs were normal on admission. The neurological examination on presentation showed preserved superior function and no cranial nerves dysfunction. No ataxic dysarthria was observed. Strength was conserved in all four members. She presented weak symmetrical reflexes, except for the right patellar reflex which was diminished with respect to the contralateral. A flexor plantar reflex was noted in both lower extremities. She had developed a mild paraesthesia of all four extremities, but no alterations of the vibration, proprioception or pain exploration were detected. Dissymmetry of the right finger-nose and right heel-knee manoeuvres were observed. A discrete right diadochokinesia was noted and the Romberg test was negative.

Investigations

A head CT scan was performed in first instance, which showed no abnormalities. The MRI of all the neuroaxis excluded leptomeningeal spread or new lesions (figure 1A, B). The electromyogram (EMG) showed alterations of the pyramidal pathway and somatosensory pathway (figure 2A, B). However, the alterations shown by the EMG were mild and did not translate with reduced strength at the physical exploration. In order to extend the study, a lumbar puncture was performed which presented a normal biochemical analysis, but surprisingly, the determination of antineuronal antibodies presented Purkinje's anti-cell antibodies (Yo) positive in both cerebrospinal fluid (CSF) and peripheral blood. In order to stage the disease, PET-CT was performed and no metastatic disease was identified (figure 3A, B).

Figure 1.

Complete spine and brain MRI using sequences weighted at T1 and T2 before and after intravenous contrast administration (figures shown in T2). No signs of cerebral (A) or spinal (B) carcinomatosis.

Figure 2.

The EMG showed alterations of the somatosensory pathway (A) and pyramidal pathway (B). An increased latency of the right posterior tibialis somatosensorial evoked potential was noted (43.6 ms). The EMG also showed more than 2 ms difference between the right and left anterior tibialis response (B). EMG, electromyogram.

Figure 3.

Positron emission tomography-CT study did not show metabolic lesions suggestive of malignancy, synchronous tumour or metastatic lesions in either the coronal (A) or sagittal view (B).

Differential diagnosis

This was a challenging case of a 44-year-old woman recently diagnosed with multifocal IDC breast cancer cT1N0M0 luminal B Her2 positive and no luminal HER2 positive foci, who presented with a rapidly progressive asymmetrical cerebellar syndrome which led us to the following differential diagnosis.

Initial laboratory testing excluded alteration of the thyroid function, low vitamin levels and HIV infection. Our next step was to rule out oncological progression versus leptomeningeal carcinomatosis. CSF cytology was negative for malignant cells and MRI was negative for metastasis. Patients with leptomeningeal carcinomatosis can present a subacute syndrome that includes ataxia and shows signal hyperintensity in the cerebellar sulci on T2-weighted fluid attenuation inversion recovery MRI images or enhancement in the cerebellar sulci on gadolinium-enhanced images. Our patient had a normal biochemical CSF analysis and no malignant cells were found by CSF cytology. Metastatic lesions and leptomeningeal carcinomatosis were excluded by MRI. Moreover, cerebrovascular diseases or press syndrome, a demyelinating disease, were ruled out with a normal MRI. Infections can cause acute cerebellitis directly or as a parainfectious phenomenon. However, a CSF without inflammation made this differential diagnosis very unlikely.

Considering that the cerebellum is a frequent target of paraneoplastic disease, antineuronal antibodies in serum and CSF were tested. No cerebellar parenchyma morphological alterations were seen in the MRI (figure 4). Anti-Yo antibodies were found to be positive in both serum and CSF, leading us to the diagnosis of PCD.

Figure 4.

A brain MRI using sequences weighted at T1 with intravenous contrast (A) and without contrast (B) show a preserved cerebellum structure, with no evidence of morphological alterations at diagnosis.

Treatment

Treatment was continued until four cycles of paclitaxel, trastuzumab and pertuzumab were completed, finishing on April 2019 with a complete clinical and radiological response. After 11 doses of paclitaxel, the treatment was discontinued due to taxane peripheral neuropathy. Treatment with immunogamaglobulins was administered between 8 and 12 April 2019, after completing neoadjuvant treatment. A skin and nipple sparing mastectomy were performed on 15 April 2019, showing a pCR (ypT0 and pN0 in sentinel nodes 0/7). Thus, trastuzumab was continued for a total of 18 cycles together with tamoxifen.

Outcome and follow-up

One year after diagnosis, symptoms have improved after intense rehabilitation but the balance disorder persists. Currently, the patient maintains an autonomous gait and is able to sit and lift herself unaided, probably due to intensive neurological physiotherapy. However, the asymmetry of the right side of the body still remains. From an oncological point of view, she completed 1 year of trastuzumab and continues with adjuvant tamoxifen without evidence of recurrent disease until the date.

Discussion

Paraneoplastic neurological syndromes (PNS) are a perfect example of an antitumor immune response. PNS are uncommon in breast cancer, being more frequent in high mutational burden cancer type, such as lung, melanoma or head and neck.⁴ PNS include PCD, Lambert-Eaton myasthenic syndrome, limbic encephalitis, sensory and motor neuropathy, Stiff-man syndrome and opsoclonus myoclonus ataxia.⁵ The majority of these syndromes have a subacute, progressive course and the neurological dysfunction typically precedes the detection of neoplastic disease months or years before tumour diagnosis.^{5 6}

Random mutations in cancer cells may lead to neoantigens of embryo-fetal antigens which the human immune system responds with T cell and antibody responses.⁴ Ectopic expression of neuronal antigens, such as CDR2, by the tumour in patients with breast and pelvic tumours could explain the pathophysiology of PCD.⁷ The anti-Yo antibody or Purkinje cell cytoplasmic antibody type 1, known as anti-Yo, has been associated with PCD and two other syndromes: opsoclonus myoclonus syndrome and paraneoplastic sensory peripheral neuropathy. PCD associated with anti-Yo antibody is the most common variant of PCD. It is presented with pancerebellar deficits such as ataxia, nystagmus, vertigo and dysarthria with a clinical plateau at around 6 months. The ataxia is usually severe, with an asymmetric onset in about 40% of patients, but soon becomes symmetric. Cognitive and psychiatric morbidity, especially memory loss and emotional lability, are also common, but concomitant dysarthria makes this difficult to determine.^{4 6} The persistence of the antibodies after tumour resection is common.⁶ Anti-Yo PCD syndrome has a poor prognosis and most patients end up bedridden or dependent for essential activities. It does not have an effective treatment and presents an independent evolution to the tumour response to treatment.⁷ However, it is described that patients affected by anti-Yo PCD syndrome have tumours with a better prognosis, probably due to the exalted immunological response.⁸ Likewise, case series described in the literature relates the overexpression of HER2 with an increased risk of presenting PCD.⁸

In 2004, the PNS Euronetwork established the most commonly used diagnostic criteria; which includes the development of a severe pancerebellar syndrome in less than 12 weeks, with no MRI evidence of cerebellar atrophy, other than what would be expected given the patient’s age. A classical PNS and cancer which develops within 5 years of neurological symptoms meet the criteria for definite PNS, but a neurological syndrome with a positive onconeural antibody is also considered a definite PNS.⁶ Clinical evidence of hemispheric cerebellar involvement is required, and non-cerebellar imaging findings do not rule out the diagnosis. MRI of the brain is often normal in early stages, with cerebellar atrophy seen only after the disease is well established.⁶ There have been isolated reports of MRI morphological changes in the cerebellum of patients with anti-Yo PCD.⁹

PCD remains a therapeutic challenge, based on the treatment of the neoplastic disease in conjunction with corticotherapy and immunomodulators, such as immunoglobulins. It should be noted that neurological improvements have been described in patients with HER2 positive breast cancer under treatment with trastuzumab.⁸ In paraneoplastic conditions where the antigen is intracellular, as in the present case, the effectiveness of immunoglobulins is doubtful. Both positivity and titres of antibodies have not been shown to be predictors of evolution or response to treatment.⁶ Here, we present a novel case of a patient treated with double HER2 blockade, achieving a pathological complete response, which may impact the prognosis of the paraneoplastic syndrome.

The patient achieved a complete pathological response after treatment, with no evidence of disease after 1 year and a significant neurological improvement was noted.

Patient’s perspective.

I did not understand what was happening, suddenly I could not walk straight nor raise my right arm normally. It was so frustrating. Now I am used to it and I am much better with rehabilitation.

Learning points.

• Paraneoplastic syndromes are rare disorders that are triggered by an altered immune system response to a neoplasm.

• Anti-Yo syndrome has a poor prognosis, it does not have an effective treatment and presents an independent evolution to the tumour response to treatment.

• The management of most paraneoplastic syndromes, such as paraneoplastic cerebellar degeneration, consists primarily of treating the malignancy.

• In paraneoplastic conditions where the antigen is intracellular, the effectiveness of immunoglobulins is doubtful.

• Despite the optimal treatment of the malignancy, achievement of pathological response (pCR) and intensive physiotherapy, there was not a complete neurological recovery.