1,000
Views
12
CrossRef citations to date
0
Altmetric
Letters to the Editor

Papillary serous carcinomas of the uterine cervix and paraneoplastic cerebellar degeneration: A report of two cases

, , , , , & show all
Pages 1590-1593 | Received 30 Sep 2007, Published online: 08 Jul 2009

To the Editor

Paraneoplastic cerebellar degeneration (PCD) is a debilitating neurodegenerative disease and is a rare complication of cancer. Its association with gynaecological malignancies is well described. Papillary serous carcinomas are aggressive neoplasms more commonly of ovarian and endometrial origin, but primary endocervical papillary serous carcinomas are recognised, and should be distinguished from metastases from common primary sites, though this is not always possible Citation[1]. Endometrial serous carcinomas display a high incidence of abnormal p53 expression and a low incidence of PTEN mutations when compared to conventional endometrial carcinoma Citation[2]. Similarly, many primary cervical papillary serous carcinomas exhibit abnormal p53 expression when compared to more conventional adenocarcinomas of cervical origin, which may account for the more aggressive nature of these tumours Citation[1]. The two cases described here demonstrate the aggressive and unpredictable course of papillary serous carcinomas and a rare association with PCD.

A 59-year-old female presented with a two month history of post-menopausal bleeding and abdominal fullness, and was diagnosed with a bulky grade II papillary serous adenocarcinoma of the endometrial cervix (A, B). Magnetic resonance imaging (MRI) showed parametrial extension, a left adnexal/ovarian mass and pelvic bone metastases (A, B). The cancer antigen (CA) 12–5 level was 242 units (normal <34 units/ml). After six cycles of paclitaxel and carboplatin chemotherapy the CA 12–5 fell to 13 units/ml and radiology showed stable disease by response evaluation criteria in solid tumours (RECIST). A gynaecology opinion recommended an expectant approach. Progressive lower limb dysfunction developed leading to cerebellar ataxia and dysarthria six months from completion of chemotherapy and CA 12–5 rose to 141 units/ml. MRI brain showed marked cerebellar atrophy (). Computed tomography (CT) scan showed enlargement of the adnexal mass and a reduction in the size of the cervical mass. Work up for this abnormal neurology included thyroid function tests, vitamin B12 levels, folate levels, serum protein electrophoresis, autoimmune screen and infectious screen, all of which were negative. The patient had never consumed alcohol and was a non-smoker. A lumbar puncture was attempted but was unsuccessful. Paraneoplastic anti-onconeruonal antibodies, including anti-Yo, anti-Ri, and anti-Hu were negative. Debulking surgery was performed and the histology confirmed our previous finding. Post-operative CA 12–5 fell to 36 units/ml, but rose to 132 units/ml within five months. Neurological symptoms worsened and radiology showed disease progression in bone. The patient died ten months after her initial uterine cervix carcinoma diagnosis.

Figure 1.  A – low power view of normal cervix on the left and endocervical adenocarcinoma on the right. B – papillary serous adenocarcinoma of uterine cervix with psamomma body formation.

Figure 1.  A – low power view of normal cervix on the left and endocervical adenocarcinoma on the right. B – papillary serous adenocarcinoma of uterine cervix with psamomma body formation.

Figure 2.  A – saggital T2-weighted pelvic MRI showing a mass in the lower third of the uterus relatively hyperintense to myometrium. B – saggital oblique T2-weighted sequence demonstrating a relatively hyperintense left adnexal mass medial to the left ovary.

Figure 2.  A – saggital T2-weighted pelvic MRI showing a mass in the lower third of the uterus relatively hyperintense to myometrium. B – saggital oblique T2-weighted sequence demonstrating a relatively hyperintense left adnexal mass medial to the left ovary.

Figure 3.  T2-weighted axial MRI-brain. CSF lies within the folia of the cerebellum secondary to parenchymal cerebellar loss.

Figure 3.  T2-weighted axial MRI-brain. CSF lies within the folia of the cerebellum secondary to parenchymal cerebellar loss.

The second case is that of a 64-year-old female who presented in a similar manner with a CA 12–5 of 2,580 units/ml. Optimal surgical debulking revealed a stage IIIc grade II moderately differentiated papillary serous adenocarcinoma of the uterine cervix. Intermittent chemotherapy with carboplatin alone and in combination with paclitaxel, as well as hormonal therapy, over two years ultimately resulted in a partial radiological response by RECIST and normalisation of CA 12–5. Four months later she presented with a two month history of slurred speech, ataxia, and inability to execute fine hand movements. On examination she had right gaze nystagmus, dysarthria, dysmetria, and hyporeflexia. Cognitive function, muscle tone and strength were well preserved. She had no clinical or radiological evidence of recurrence. MRI brain showed mild cerebellar atrophy. Work up was performed as in the first case, and was negative. Lumbar puncture showed a slightly raised protein level of 110 mg/dl (48–106 mg/dl), and a mild lymphocyte pleocytosis of 10×106 /ml (6–23×106 /ml. Anti-onconeuronal antibodies were looked for in serum and cerebrospinal fluid but were not found. The patient underwent comprehensive rehabilitation, but six months later she deteriorated further and was referred to the palliative care services. She died three years following the diagnosis of PCD.

The majority of PCD cases associated with gynaecologic cancer cited in the literature have ovarian adenocarcinoma with serous or endometrioid histology. We describe two cases of moderately differentiated papillary serous adenocarcinoma of the uterine cervix associated with antibody negative PCD diagnosed after an initial response to chemotherapy. PCD is a rare and unusual complication of cancer and accounts for about 10% of non-metastatic neurologic cancer-related complications Citation[3]. Diagnosis can be difficult as presentation is varied and in over two-thirds of cases can precede the diagnosis of cancer Citation[4]. PCD is a diagnosis of exclusion. Differential diagnoses include: leptomeningeal metastases, cerebrovascular disease, infectious causes, toxic causes (including alcohol and chemotherapeutic toxicity), demyelinating diseases, endocrine disorders or hereditary degeneration. Patients usually present in the sixth decade and there is a female preponderance Citation[5].

PCD usually manifests as a rapid (hours to weeks) onset of pancerebellar dysfunction with associated truncal and appendicular ataxia, dysarthria, vertigo, nystagmus and diplopia. The syndrome can lead to profound disability, leaving many patients wheelchair bound and with unintelligible speech Citation[6]. Pathological examination shows degeneration of Purkinje cells within the cerebellar cortex Citation[7]. The CSF may be normal or have an elevated protein, a lymphocyte pleocytosis (usually T-cells), increased IgG, and oligoclonal banding. Specific anti-onconeuronal antibodies have been identified both in the CSF and in the sera of patients with PCD. A recent series shows that up to 77% of cases with paraneoplastic neurologic disease have positive anti-onconeuronal antibodies Citation[5]. The anti-Yo auotoantibody can account for up to 50% of PCD patients and is associated almost exclusively (74%) with breast and pelvic cancers, i.e. ovarian and endometrial Citation[6]. Anti-Yo is directed against cerebellar degeneration related (CDR) antigens expressed by Purkinje cells and cancer cells of patients with PCD. Such an immunological anti-tumour effect is said to explain the frequent finding of a low tumour burden in antibody positive PCD Citation[7], Citation[8]. The frequency of anti-Yo in ovarian cancer patients is higher than the frequency of paraneoplastic syndromes, however it is not present in patients without cancer or with other forms of cerebellar disease and thus is a very specific marker for PCD Citation[7], Citation[9]. Patients with PCD who do not have the anti-Yo antibody tend to have either lung cancer, breast cancer, or Hodgkin lymphoma, and tend to manifest neurological symptoms after the diagnosis of cancer. Lung cancer, usually small cell, is associated with the anti-Hu antibody. Breast cancer, and to a lesser extent small cell lung cancer is usually associated with the anti-Ri antibody, and Hodgkin lymphoma is associated with the anti-Tr antibody Citation[6]. Thus, in a patient with neurological symptoms, detecting onconeuronal antibodies in serum or CSF can alert the physician to the possibility of an occult malignancy.

The treatment of PCD has been very disappointing. It has been estimated that up to 30% of PCD patients develop symptoms when the primary tumour is in remission. Thus treatment of cancer alone is not enough Citation[10]. Only in small cell lung carcinomas has regression of cerebellar symptoms been reported after complete resection of tumour Citation[11]. Immunologic therapy e.g. intravenous immunoglobulin, plasmapheresis, high dose steroids, and chemotherapies such as cyclophosphamide have all been tried, but with limited success Citation[10], Citation[12]. Prompt recognition of neurological symptoms and institution of the above therapies seems to improve outcome in only a minority of cases. Recent reports using rituximab in antibody associated paraneoplastic neurological syndromes show some promise, but patient numbers are small and further studies are needed Citation[13]. Proteasome antibodies and their association with anti-Yo antibodies is currently the focus of much research in PCD Citation[14]. Reasons for such poor outcomes are unclear, however it does seem that there is a central production of autoantibodies that is unaffected by plasmapheresis, both cellular and humoral responses are involved, non-immune mechanisms play a role, and irreversible Purkinje cell death has occurred by the time neurological symptoms have developed Citation[7]. Intense rehabilitation is vital to optimise the functional status of patients. Regular physiotherapy, speech therapy, and psychological support should be integral in the management of PCD Citation[15].

References

  • Nofech-Mozes S, Rasty G, Ismiil N, Covens A, Khalifa MA. Immunohistochemical characterization of endocervical papillary serous carcinoma. Int J Gynecol Cancer 2006; 16(Suppl 1)286–92
  • Zhou C, Gilks CB, Hayes M, Clement PB. Papillary serous carcinoma of the uterine cervix: A clinicopathological study of 17 cases. Am J Surg Pathol 1998; 22: 113–20
  • Linke R, Schroeder M, Helmberger T, Voltz R. Antibody-positive Paraneoplastic neurologic syndromes. Neurology 2004; 63: 282–6
  • Hammack JE, Kimmel DW, O'Neill BP, Lennon VA. Paraneoplastic cerebellar degeneration: A clinical comparison of patients with and without Purkinje cell cytoplasmic antibodies. Mayo Clin Proc 1990; 65: 1423–31
  • Candler PM, Hart PE, Barnett M, Weil R, Rees JH. A follow up study of patients with paraneoplastic neurological disease in the United Kingdom. J Neurol Neurosurg Psychiatry 2004; 75: 1411–5
  • Johns JB, Odunsi KO, Fleischman S, Azodi M, Schwartz PE. Serous adenocarcinoma of the uterus presenting as paraneoplastic cerebellar degeneration. Gynecol Oncol 1999; 73: 326–30
  • McCrystal M, Anderson NE, Jones RW, Evans BD. Paraneoplastic cerebellar degeneration in a patient with chemotherapy-responsive ovarian cancer. Int J Gynecol Cancer 1995; 5: 396–9
  • Hetzel DJ, Stanhope CR, O'Neill BP, Lennon VA. Gynecologic cancer in patients with subacute cerebellar degeneration predicted by anti-Purkinje cell antibodies and limited in metastatic volume. Mayo Clin Proc 1990; 65: 1558–63
  • Cao Y, Abbas J, Wu X, Dooley J, van Amburg AL. Anti-Yo positive Paraneoplastic cerebellar degeneration associated with ovarian cancer: Case report and review of the literature. Gynecol Oncol 1999; 75: 178–83
  • Erez Y, Rojansky N, Shveiky D, Ben-Meir A, Benshushan A. Endometrial carcinoma first presenting as Paraneoplastic cerebellar degeneration. Gynecol Oncol 2007; 105: 826–7
  • Santillan A, Bristow RE. Paraneoplastic cerebellar degeneration in a woman with ovarian cancer. Nat Clin Oncol Pract 2006; 3: 108–12
  • Widdess-Walsh P, Tavee JO, Schuele S, Stevens GH. Response to intravenous immunoglobulin in anti-Yo associated Paraneoplastic cerebellar degeneration: Case report and review of the literature. J Neuro-Oncol 2003; 63: 187–90
  • Shams'ili S, de Beukelaar J, Gratama JW, Hooijkaas H, van den Bent M, van't Veer M, et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol 2006; 253: 16–20
  • Storstein A, Knudsen A, Vedeler CA. Proteasome antibodies in Paraneoplastic cerebellar degeneration. J Neuroimmunol 2005; 165: 172–8
  • Perimutter E, Gregory PC. Rehabilitation treatment options for a patient with paraneoplastic cerebellar degeneration. Am J Phys Med Rehabil 2003;82:158–62.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.