Correspondence *The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, The Johns Hopkins Medical Institutions, 600 North Wolfe Street, Phipps #281, Baltimore, MD 21287, USA

Email rbristo@jhmi.edu

The Case

A 52-year-old postmenopausal white female presented to her local emergency department 4 days after onset of light-headedness followed by diplopia, horizontal vertigo, headaches and severe nystagmus with oscillopsia. She had previously been in good health. Family history was negative for hereditary, endocrinologic, infectious, cardiovascular and oncological conditions. MRI of the brain, with and without contrast, was normal. Spinal fluid revealed monocytic pleocytosis, but laboratory tests were otherwise normal. During the initial admission, the patient improved to some degree and was discharged after 2 days with a possible diagnosis of viral meningitis, treated only with supportive care. After 2 weeks, the patient's headaches and double vision increased in severity, and further inpatient evaluation was initiated. Examination revealed normal funduscopy without papilledema. Neurological examination was notable for an unusual nystagmus, which was present when the patient looked up and down, an unsteady widespread gait, and mild dysarthria. Cognition was unaffected. A general and gynecological examination was otherwise unremarkable. Repeat spinal-fluid examination showed increasing pleocytosis, and repeat MRI of the brain was unchanged. An electroencephalogram was normal. Based on these inconclusive findings, investigations for paraneoplastic cerebellar degeneration (PCD) syndrome were undertaken. A whole-body positron emission tomography scan revealed a small focal glucose-avid lesion in the pelvis in the region of the left adnexa (Figure 1). Transvaginal ultrasound showed a diffuse fibroid uterus, but the ovaries were normal in appearance. Both mammography and colonoscopy were unremarkable. Serum tumor markers (cancer antigen [CA] 19-9, CA 15-3, carcinoembryonic antigen [CEA] and leukemia cell marker) were within normal limits, except for CA 125, which was found to be elevated to 350 U/ml (normal range 0–35 U/ml). Anti-neuronal antibody testing (anti-Yo, anti-Ri and anti-Hu) was positive only for anti-Yo.

Figure 1 Whole-body positron emission tomography scan showing a small glucose-avid lesion in the pelvis just superior to the bladder in the region of the left adnexa.

 

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Based on the suspicion of a gynecological malignancy, the patient underwent a diagnostic laparoscopy with multiple biopsies, which showed small uterine fibroids, bilateral hydrosalpinges, pelvic adhesions, and signs of endometriosis involving the left ovary. No evidence of peritoneal or abdominal carcinomatosis was noted. Pathology of the left ovarian and anterior uterine serosal biopsies, however, revealed a poorly differentiated carcinoma with endometrioid features. Two weeks later, by which point the patient had become confined to a wheelchair, she underwent a staging exploratory laparotomy with a total abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic and para-aortic lymph-node dissection, and total omentectomy. Final pathology revealed a poorly differentiated carcinoma involving the pelvic organs and a 3 cm omental nodule consistent with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC endometrioid adenocarcinoma of the ovary. Two days before staging exploratory laparotomy surgery, the patient had completed three treatments of plasmapheresis, administered 2 days apart, with some improvement in her speech. After surgery, six cycles of intravenous chemotherapy were administered every 3 weeks with 175 mg/m² of paclitaxel over 3 h, followed by carboplatin at an area under the curve of 6–7.5, resulting in a complete clinical, biochemical (CA 125) and radiographic (CT scan) response. During and after chemotherapy, the patient also underwent physical therapy and speech therapy, with mild improvement of her PCD symptoms, but she continued to be wheelchair bound. She experienced disease recurrence 8 months after completion of primary treatment, with worsening of her neurological syndrome. Initial salvage therapy consisted of multiple cycles of single-agent carboplatin. Unfortunately, the patient had no response to this treatment and experienced disease progression with further deterioration of her PCD symptoms. Ultimately, the patient died 3 years after her initial ovarian carcinoma diagnosis.

Discussion of Diagnosis

The paraneoplastic syndromes represent a diverse group of disorders that reflect the remote effects of cancer arising in any specific organ system. Although fewer than 15% of cancer patients experience these syndromes, recognition is important because clinical manifestations of paraneoplastic syndrome can precede those of the underlying malignancy by months, or even years. Paraneoplastic neurological syndromes are defined by the presence of cancer and exclusion of other known causes of neurological symptoms. These criteria do not, however, separate true paraneoplastic neurological syndromes from neurological syndromes that are coincidental with malignancy (Box 1).

PCD is a rare disorder affecting the neurological system, caused by the immune-mediated remote effects of cancer, which are not due to the presence of metastasis or direct infiltration of the tumor into the nervous system. Subacute cerebellar degeneration is of paraneoplastic origin in approximately two-thirds of female patients aged 50 years.¹ The syndrome occurs mainly in patients with cancer of the ovary, uterus, fallopian tube or breast and in those with small-cell carcinoma of the lung, and occasionally in patients with Hodgkin's disease. Although PCD occurs in only 2 out of every 1,000 patients with cancer, 63% of patients with this disorder are diagnosed with cancer, and cancer progression is the cause of death in 52% of cases.²

Classical PCD is defined as the development of severe cerebellar signs and symptoms in less than 12 weeks, with no radiological evidence of cerebellar atrophy by MRI. The cerebellar syndrome will also be severe enough to interfere with the patient's lifestyle or cause major disability. In the first stage of the syndrome, predominant or isolated gait ataxia might be present, but clinical evidence of truncal and hemispheric cerebellar dysfunction is required for the diagnosis. The presence of symptoms or signs of involvement beyond the cerebellum is not uncommon and does not rule out the diagnosis.³

In this case, the acute onset of cerebellar dysfunction (diplopia and vertigo), progressing to a more disabling state (limb and truncal ataxia, lack of coordination, dysarthria and nystagmus), and the absence of risk factors for cerebellar disorders (stroke, alcoholism, primary or metastatic neoplasms of the cerebellum, or treatment with chemotherapeutic agents), underscore the hallmarks of PCD. MRI with contrast is recommended to exclude any structural, demyelinating, vascular or infectious causes. MRI findings are normal in early PCD, but can show cerebellar atrophy in advanced cases. Patients with a suspected paraneoplastic disorder should receive a complete panel of laboratory studies of blood, urine and cerebrospinal fluid (CSF). Examination of CSF can reveal pleocytosis, elevated protein levels and elevated IgG levels. Pleocytosis is usually apparent only early in the course of the disease and disappears within several weeks to months, although elevated IgG levels can persist. Analysis of CSF cells through fluorescent-activated cell sorting has revealed that T cells are the predominant cell type in 75% of the cases, with a small component of B cells and natural-killer cells. Many patients with PCD have antibodies in their serum and CSF that react with both the nervous system and the underlying cancer. Detection of these autoantibodies is very important to confirm the diagnosis of PCD and distinguish it from non-neoplastic forms. The most significant PCD antibodies and the tumors with which their occurrence is associated are summarized in Table 1.^{4, 5} As in this case, the presence of anti-Yo antibodies in the serum of a woman with cerebellar symptoms is compelling evidence that she has PCD and a gynecological, usually ovarian, cancer.⁶ It should be noted, however, that cancers of the fallopian tube, endometrium and breast might also be associated with anti-Yo antibodies^{2, 6} and that 20% of patients with ovarian cancer without neurological symptoms also express Yo antigens in their tumors.⁷

Table 1 Most significant onconeuronal antibodies associated with paraneoplastic cerebellar degeneration.

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As the onset of symptoms of cerebellar degeneration might indicate the presence of an underlying malignancy, a thorough investigation is warranted. Tumor markers are useful for the diagnosis of cancers that are clinically silent, but most markers are not specific for determining the origin of the cancer. In this case, tumor marker levels were normal, except for elevated serum CA 125. In asymptomatic postmenopausal women, abnormal CA 125 elevation has been associated with a 36-fold increase in risk of ovarian cancer.⁸ Overall, approximately 85% of patients with epithelial ovarian cancer have a serum CA 125 level >35 U/ml at the time of diagnosis. Although serum CA 125 is commonly used to distinguish malignant from benign adnexal masses, this marker lacks sufficient sensitivity and specificity to be used exclusively as a reliable triage tool in premenopausal woman. More recently, ultrasound scanning, serum CA 125 and menopausal status have been combined in a risk-of-malignancy index⁹ for the differential diagnosis of adnexal masses. This approach has greater accuracy than either individual tests or clinical assessment and can assist with adequate preoperative referral.^{8, 9, 10}

A variety of imaging studies (mammography, chest X-ray, CT, MRI, ultrasound and PET) can be useful in detecting the primary tumor in patients with PCD. CT scanning and MRI of the whole body allow detection of the site and the extension of the underlying primary tumor, and its metastases. If the standard radiological investigations in patients with a subacute cerebellar ataxia, together with anti-Yo, fail to produce a specific diagnosis of underlying tumor, performance of PET should be considered because of the scan's ability to localize otherwise clinically occult tumors as small as 1 cm in size. In patients with neurological paraneoplastic syndromes, the sensitivity of PET scanning to detect tumors has been estimated to be 83.33% and the specificity 25%. Positive and negative predictive values were 83.33% and 25%, respectively.¹¹

Additional diagnostic procedures can be useful as part of the initial investigation for paraneoplastic syndromes. Endoscopy is recommended to detect tumors of the respiratory system and digestive tract, and also allows the examiner to obtain biopsy samples. As highlighted by this case, in patients with high suspicion for gynecological malignancy (e.g. presence of anti-Yo, suspicious PET-CT scan and elevated CA 125), direct surgical staging or debulking might be superior to diagnostic laparoscopy. In the event that no malignancy is identified and other causes are excluded, follow-up interval imaging at 6–12 months should be considered.¹²

Treatment and Management

Because PCD is considered to be an immune-mediated syndrome, initial removal of the source of the antigen by treatment of the underlying tumor and suppression of the immune response should be attempted.

Surgery is the cornerstone of management of epithelial ovarian cancer and has broad applications throughout the clinical course of disease, from initial diagnosis to palliative care. Comprehensive surgical staging is essential for precise prognostic determination and treatment planning for patients with apparent early-stage ovarian cancer. In conjunction with primary platinum-based chemotherapy, maximal cytoreduction at the time of primary surgery has been shown to be a powerful determinant of overall survival.¹³

Regression of cerebellar symptoms after complete tumor resection has only been reported in small-cell carcinomas of the lung and has not been reported in gynecological malignancies. Effective treatment of the cancer often correlates with stabilization of the neurological disorder. Antibodies can, however, persist indefinitely, even after the underlying cancer has been cured.² In patients with ovarian cancer, only mild to moderate neurological improvement has been achieved after a combination of treatment for the underlying neoplasm, plasmapheresis, intravenous immunoglobulin, or chemotherapy.¹⁴

There are no established protocols for the treatment of most paraneoplastic syndromes, but if the patient's condition is deteriorating, the physician can employ either plasma exchange or a combination of intravenous immunoglobulin and immunosuppressive agents, such as corticosteroids or cyclophosphamide. Although there have been occasional reports of improvement with these therapies, generally there is a minimal effect, if any, because antibodies are intrathecal and unaffected by plasmapheresis or intravenous immunoglobulin.^{14, 15} Symptom relief is important in managing patients with PCD. Intensive rehabilitation, speech therapy and psychological support are also vital in optimizing functional recovery.¹⁶

Conclusion

Although fewer than 15% of patients with cancer develop a paraneoplastic syndrome, recognition is important because such clinical manifestations can precede those of the underlying malignancy. Early recognition followed by investigation of the cause of the paraneoplastic syndrome facilitates preclinical detection and early treatment of the malignancy. PCD associated with anti-Yo antibodies affects approximately 2 in every 1,000 cancer patients, and occurs most frequently in patients with breast and ovarian carcinomas. Because the presence of anti-Yo antibodies is suggestive of a gynecological malignancy, cerebellar degeneration with anti-Yo might be an indication for exploratory laparotomy in the absence of diagnostic radiographic studies. Treatment of the underlying malignancy can prevent progression of symptoms but often does not result in improvement.

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Subject areas under which this article appears: Diagnosis and Imaging | Surgical Oncology