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Positive response to therapy in a patient with seropositive paraneoplastic cerebellar degeneration and an endometrioid carcinoma of the vesico- vaginal septum
  1. A P BATOCCHI,
  2. G DE ROSA,
  3. A EVOLI,
  4. P TONALI
  1. Institute of Neurology
  2. Obstetrics and Gynecology, Catholic University, Rome, Italy
  3. IRCCS, Casa Sollievo della Sofferenza, S Giovanni Rotondo, Italy
  1. Dr AP Batocchi, Institute of Neurology, Catholic University, L go F, Vito 1, 00168 Rome, Italy. Telephone 0039 06 30154435; fax 0039 06 35501909.
  1. S GREGGI,
  2. G SCAMBIA,
  3. G SALERNO
  1. Institute of Neurology
  2. Obstetrics and Gynecology, Catholic University, Rome, Italy
  3. IRCCS, Casa Sollievo della Sofferenza, S Giovanni Rotondo, Italy
  1. Dr AP Batocchi, Institute of Neurology, Catholic University, L go F, Vito 1, 00168 Rome, Italy. Telephone 0039 06 30154435; fax 0039 06 35501909.
  1. P TONALI
  1. Institute of Neurology
  2. Obstetrics and Gynecology, Catholic University, Rome, Italy
  3. IRCCS, Casa Sollievo della Sofferenza, S Giovanni Rotondo, Italy
  1. Dr AP Batocchi, Institute of Neurology, Catholic University, L go F, Vito 1, 00168 Rome, Italy. Telephone 0039 06 30154435; fax 0039 06 35501909.

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Paraneoplastic cerebellar degeneration is a rare complication of human cancer. This disorder is characterised by subacute onset of pancerebellar symptoms, often associated with dysfunction of other areas of the CNS. The onset of the degeneration may occur months before or after the detection of the primary cancer, or as a sign of its recurrence. It is usually associated with antineuronal antibodies directed against antigens coexpressed by the cells that undergo degeneration and by the associated tumour. Anti-Yo antibodies can be detected in serum and CSF of patients with paraneoplastic cerebellar degeneration with breast or gynaecological tumours. These antibodies show a coarse granular staining pattern of the cytoplasm of Purkinje cells, while the nucleus remains unstained.1 2 Patients with paraneoplastic cerebellar degeneration without anti-Yo antibodies may have other tumours, most commonly bronchial carcinoma or Hodgkin’s lymphoma, and may be positive for anti-Hu, anti-voltage gated calcium channels, or anti-Tr antibodies.1 Although the antibodies provide a diagnostic test for the associated tumours, it is generally thought that destruction of the Purkinje cells by autoreactive T cells is the major pathogenic mechanism, and previous reports suggest a lack of response to conventional immunosuppressive treatments.

A 47 year old woman had no history of neurological disease until March 1996. There was a history of surgical correction of a urethral diverticulum at the age of 34, and at 44 years she had been treated for a “vaginal cyst” (likely a Naboth cyst) by aspiration. In March 1996 she complained of blurred vision, diplopia, dysphagia, and gait ataxia with balance disturbance. Brain MRI and an ultrasound of the pelvis were reported negative, but serum anti-Yo antibody was positive by immunohistochemistry, confirmed by immunoblotting with purified antigen (DPC Biermann).2 By 29 October 1996 there was marked gait ataxia, nystagmus, diplopia, dysphagia, cerebellar dysarthria, pyramidal signs, and arm and leg dysmetria with tremor. At this time MRI demonstrated cerebellar atrophy (figure A) and CT and MRI of the pelvis (figure C, D) both revealed a 3.5 cm diameter lesion located in the vesicovaginal septum, infiltrating the bladder and vaginal wall. A transvaginal biopsy was performed and the histological examination showed the presence of malignant cells. The staging markers excluded further distant tumour localisation and the patient underwent an anterior pelvic exenteration with ileal conduit. Pathological examination disclosed a very rare endometrioid carcinoma, and confirmed extensive bladder involvement. In particular, the tumour seemed to arise from islands of endometriosis. Four cycles of adiuvant chemotherapy with carboplatinum and cyclophosphamide (respectively 300 mg/m2 and 500 mg/m2, day 1, every 3 weeks) were administered between April and September 1997. From then until the present time she has been treated monthly with cyclophosphamide at a dose of 1 g, day 1, every 4 weeks.

Four months after surgery and while still on chemotherapy, the patient began to show neurological improvement. Over subsequent months, diplopia and pyramidal signs disappeared and ataxia, tremor, and dysmetria progressively improved. However, 1 year after surgery a small vaginal tumour recurrence was diagnosed during a follow up gynaecological examination. Brain MRI demonstrated a slight progression of the cerebellar atrophy (figure B). The patient was subsequently submitted to external radiation therapy followed by intracavitary boosts. At the last follow up examination (September 1998, 21 months from primary surgery) the patient had no evident tumour, and was able to read, to eat precut meals, to sit independently, and to walk short distances by using a wheeled walking support.

It is well recognised that microscopic ovarian cancer, only detected at laparotomy, can be associated with paraneoplastic cerebellar degeneration.1 Malignant transformation of benign endometriosis is a well documented phenomenon, but it occurs most commonly in the ovaries, and cancer arising at extraovarian sites is a rare event.3 In our patient we found an endometrioid adenocarcinoma located in the vesicovaginal septum, probably arising from islands of asymptomatic endometriosis and the delay in diagnosis was due not only to the small size but also to the unusual position of the tumour. We are not aware of any previous reports of paraneoplastic cerebellar degeneration associated with malignant transformation in pelvic endometriosis arising neither from the adnexa nor from the uterus.

A striking feature of this case was the improvement in neurological symptoms on treatment of the tumour and subsequent immunosuppression. In most previous cases of paraneoplastic cerebellar degeneration, the early detection and removal of the tumour has not affected the neurological symptoms,1 nor has there been improvement or slowed progression of the disease after immunosuppressive treatment.4 There are only rare reports of successful immunosuppressive treatment with intravenous immunoglubulin therapy5 or courses of cyclophosphamide.6 In the second case, a very good response to cyclophosphamide was described but the sudden interruption of drug treatment led to a progressive reappearance of symptoms, indicating that the clinical response was related to immunosuppression rather than a long term effect of tumour therapy.

In agreement with other authors1 we think that the presence of anti-Yo antibody in patients with cerebellar symptoms warrants an aggressive diagnostic approach that must begin with careful clinical examination, then proceed with mammography, pelvic CT, and MRI. If no malignancy is found, surgical exploration should be considered, particularly in postmenopausal women. In addition, although many cases may not respond to plasma exchange, intravenous immunoglobulin or immunosuppressive drugs,4 perhaps because the neuronal damage is irreversible, the successful results in the present case indicate that continuous immunosuppressive therapy should be carefully considered.

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Figure 1

(A, B) sagittal spin echo (SE) T1 weighted images of the brain obtained in November 1996 and 1 year later: This shows cerebellar atrophy, which clearly increased after 1 year. (C, D) Unenhanced coronal and sagittal FSE T2 weighted MR images of the pelvis: the vesicovaginal septum is occupied by an infiltrating neoplastic mass (arrowheads).

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