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Paraneoplastic cerebellar degeneration in a patient with ovarian cancer
Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 313e315
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Case Report
Paraneoplastic cerebellar degeneration in a patient with ovarian cancer Hung-Ju Chien a, 1, Chuo-Yu Lee b, 1, Lu-An Chen b, Chao-Chih Wu c, Chih-Long Chang a, c, d, * a
Department of Obstetrics and Gynecology, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan Department of Neurology, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan Department of Medical Research, Mackay Memorial Hospital, Taipei City, Taiwan d Department of Medicine, Mackay Medical College, Shanchi, New Taipei City, Taiwan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 13 March 2014
Objective: Herein, we report a case of ovarian serous carcinoma with paraneoplastic cerebellar degeneration. Case report: A 44-year-old female presented to our hospital with dizziness, slurred speech, and ataxic gait. Brain magnetic resonance imaging was normal. A lumbar puncture revealed a normal cell count in the cerebrospinal fluid, but slightly elevated protein. Her serum cancer antigen -125 level was high (2126.4 U/mL), and abdominal computed tomography disclosed a pelvic mass measuring 11 cm in diameter. Exploratory laparotomy was then performed, and a frozen section of the tumor revealed serous carcinoma. Conclusion: According to the surgical findings and pathological report, The International Federation of Gynecology and Obstetrics (FIGO) Stage IIIC, Grade 3, serous-type ovarian cancer was diagnosed. Due to the abovementioned symptoms and signs, we performed a serial test to document the presence of antiYo antibody in this patient. Copyright © 2015, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: anti-Yo antibody paraneoplastic cerebellar degeneration ovarian cancer
Case report A 44-year-old previously healthy female experienced an episode of slurred speech and dizziness 3 months previously. Two weeks later, she suffered from lightheadedness, unsteady gait, and bilateral clumsiness of the hands. Her symptoms gradually worsened until she was unable to sit, stand, or walk without help. No cognitive decline, headache, fever, nausea, vomiting, double vision, sensory loss, or sphincter dysfunction was noted. She denied any history of smoking, drinking alcohol, or taking illicit drugs. There was no family history of movement or gait disorders. Initially, she visited our otolaryngology outpatient clinic where a Hallpike procedure for Benign paroxysmal positional vertigo (BPPV) was performed with negative results. Mild dysmetria on the finger-to-nose test and also a mildly ataxic gait were noted. No nystagmus or loss of hearing function was identified. She was * Corresponding author. Mackay Memorial Hospital, Number 92, Section 2, Zhongshan North Road, Taipei City 10449, Taiwan. E-mail address: [email protected] (C.-L. Chang). 1 Hung-Ju Chien and Chuo-Yu Lee are cofirst authors.
admitted for further evaluation of the dizziness and possible central vertigo. During admission, a physical examination was unremarkable except for the neurological tests. She was alert and oriented, and had normal cognitive function. Severe dysarthria was noted; however, the other cranial nerves were grossly unremarkable. Her extraocular movements were full, and no nystagmus or KaysereFleischer rings were noted. Muscle power, sensory examination, and deep tendon reflexes were normal, and no Babinski sign was noted. She had dysmetria and dysdiadochokinesia of both arms, which was more severe in the left side. She also had a wide-based gait, truncal ataxia, and bilateral dysmetria on the heelekneeeshin test. The presentation was consistent with progressive cerebellar dysfunction. Magnetic resonance imaging of the brain and cervical spinal cord did not show any specific findings. Cerebrospinal fluid obtained from lumbar puncture revealed a normal cell count, but slightly elevated protein (64 mg/dL), indicating an inflammatory process or autoimmune disease. In addition, autoimmune profile, thyroid profile, and ceruloplasmin level were all within the normal ranges; however, serum tumor markers were elevated, including cancer antigen (CA)-153 level of 132.6 U/mL and CA-125 level of
http://dx.doi.org/10.1016/j.tjog.2014.03.012 1028-4559/Copyright © 2015, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.
314
H.-J. Chien et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 313e315
ascending colon, and omentum) was found, and optimal debulking surgery was subsequently performed. Permanent pathology revealed ovarian serous carcinoma, and she was diagnosed with FIGO Stage IIIC (pT3cNxMb), Grade 3 serous ovarian carcinoma. She then received consecutive adjuvant chemotherapy. We then performed a series of examinations on her serum and tumor specimen. All Western blotting results indicated the presence of anti-cerebellar degeneration-related protein 2 (CDR2) (Yo) protein in her plasma (Figs. 1 and 2). To further confirm the presence of anti-Yo antibodies targeting neural elements, immunohistochemical staining on mouse cerebellar tissue was performed (Fig. 3). Microscopically, the findings revealed positive staining of Purkinje cells in the mouse cerebellar tissue with the patient's plasma, but not with the plasma from a healthy patient. Discussion
Fig. 1. Western blot of lysates from mouse cerebellar tissues probed by plasma from this patient, other cancer patients, and healthy donors. The first lane revealed a specific band (arrow) indicating a specific protein in the cerebellar tissue detected by the patient's plasma.
2126.4 U/mL (normal range <30 U/mL and <35 U/mL, respectively). Unexpectedly, an abdominal computed tomography scan revealed a pelvic mass with solid components, measuring 11 cm in diameter, with suspected liver surface and diaphragm tumor seeding. Due to the above gynecologic findings, exploratory laparotomy was arranged, during which an ovarian serous carcinoma with peritoneal seeding (including the liver surface, diaphragm, right
Paraneoplastic cerebellar degeneration (PCD) is a rare disorder affecting the neurological system, which is neither metastasis nor direct tumor invasion to the nervous system, caused by the immune-mediated effects of cancer [1]. Cerebellar dysfunction is one of the most common paraneoplastic presentations of cancer. The following symptoms are necessary to define classical cerebellar syndrome: development of a severe pancerebellar syndrome in <12 weeks, with no magnetic resonance imaging evidence of cerebellar atrophy [2]. The associated symptoms are ataxia, diplopia, dysphagia, dysarthria, and the prodrome of dizziness, nausea, and vomiting [3]. The most commonly associated antibodies with tumors are Hodgkin's lymphoma (anti-Tr and anti-mGluR1), lung cancer (antiHu), and gynecological and breast cancers (anti-Yo and anti-Ri,
Fig. 2. Western blot of lysates from this patient's ovarian cancer tissue probed by plasma from this patient, other cancer patients, and healthy donors. (A) The first lane revealed a specific band (arrow) indicating a specific protein in the ovarian tissue detected by the patient's plasma. (B) Western blot of human CDR2 (Yo) recombinant protein probed by plasma from this patient, other cancer patients, and healthy donors. The first lane showed a specific band (arrow) indicating anti-CDR2 (Yo) antibody within the patient's plasma. CDR2 ¼ cerebellar degeneration-related protein 2.
Fig. 3. Immunohistochemical staining on mouse cerebellar tissue. Microscopically, it revealed: (A) positive staining of Purkinje cells stained by this patient's plasma, and (B) no staining in the tissue stained by the healthy donor's plasma.
H.-J. Chien et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 313e315
respectively) [4,5]. Yo antibodies are directed against human CDR2, leading to apoptosis of Purkinje cells, which is associated with PCD [6]. PCD is an immune-mediated syndrome, and initial removal of the source of the antigens by treating the underlying tumor should be performed [1]. Besides antitumor treatment, immunotherapy such as plasmapheresis, intravenous immunoglobulin, corticosteroids, cyclophosphamide, tacrolimus, or rituximab could be considered [7]. This patient received four courses of plasmapheresis and complete courses of chemotherapy, after which her CA-125 level returned to normal range but her cerebellar symptoms persisted. Some studies have reported that PCD with anti-Yo antibodies has a better outcome with reversal of neurological symptoms than other types of antibodies [4,8]. In some cases, complete antitumor and immune treatment could prevent disease progression but not reverse the neurological disorders, as in our patient. In conclusion, we report PCD in a patient with advanced ovarian cancer. We also provide direct evidence showing the presence of an anti-Yo antibody in the patient's plasma targeting cerebellar Purkinje cells. This report will help diagnose such cases of paraneoplastic syndrome in the future.
315
Conflicts of interest The authors have no conflicts of interest relevant to this article. References [1] Santillan A, Bristow RE. Paraneoplastic cerebellar degeneration in a woman with ovarian cancer. Nat Clin Pract Oncol 2006;3:108e12. quiz 1 p following 112. [2] Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004;75:1135e40. [3] Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc 2010;85:838e54. [4] Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008;7:327e40. [5] Shams'ili S, Grefkens J, de Leeuw B, van den Bent M, Hooijkaas H, van der Holt B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 2003;126:1409e18. [6] Totland C, Aarskog NK, Eichler TW, Haugen M, Nostbakken JK, Monstad SE, et al. CDR2 antigen and Yo antibodies. Cancer Immunol Immunother 2011;60:283e9. [7] Storstein A, Vedeler C. Treatment of paraneoplastic neurological syndromes. Adv Clin Neurosci Rehabil 2009;8:12e4. [8] De Beukelaar JW, Smitt PAS. Managing paraneoplastic neurological disorders. Oncologist 2006;11:292e305.
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Case Report
Paraneoplastic cerebellar degeneration in a patient with ovarian cancer Hung-Ju Chien a, 1, Chuo-Yu Lee b, 1, Lu-An Chen b, Chao-Chih Wu c, Chih-Long Chang a, c, d, * a
Department of Obstetrics and Gynecology, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan Department of Neurology, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan Department of Medical Research, Mackay Memorial Hospital, Taipei City, Taiwan d Department of Medicine, Mackay Medical College, Shanchi, New Taipei City, Taiwan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 13 March 2014
Objective: Herein, we report a case of ovarian serous carcinoma with paraneoplastic cerebellar degeneration. Case report: A 44-year-old female presented to our hospital with dizziness, slurred speech, and ataxic gait. Brain magnetic resonance imaging was normal. A lumbar puncture revealed a normal cell count in the cerebrospinal fluid, but slightly elevated protein. Her serum cancer antigen -125 level was high (2126.4 U/mL), and abdominal computed tomography disclosed a pelvic mass measuring 11 cm in diameter. Exploratory laparotomy was then performed, and a frozen section of the tumor revealed serous carcinoma. Conclusion: According to the surgical findings and pathological report, The International Federation of Gynecology and Obstetrics (FIGO) Stage IIIC, Grade 3, serous-type ovarian cancer was diagnosed. Due to the abovementioned symptoms and signs, we performed a serial test to document the presence of antiYo antibody in this patient. Copyright © 2015, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: anti-Yo antibody paraneoplastic cerebellar degeneration ovarian cancer
Case report A 44-year-old previously healthy female experienced an episode of slurred speech and dizziness 3 months previously. Two weeks later, she suffered from lightheadedness, unsteady gait, and bilateral clumsiness of the hands. Her symptoms gradually worsened until she was unable to sit, stand, or walk without help. No cognitive decline, headache, fever, nausea, vomiting, double vision, sensory loss, or sphincter dysfunction was noted. She denied any history of smoking, drinking alcohol, or taking illicit drugs. There was no family history of movement or gait disorders. Initially, she visited our otolaryngology outpatient clinic where a Hallpike procedure for Benign paroxysmal positional vertigo (BPPV) was performed with negative results. Mild dysmetria on the finger-to-nose test and also a mildly ataxic gait were noted. No nystagmus or loss of hearing function was identified. She was * Corresponding author. Mackay Memorial Hospital, Number 92, Section 2, Zhongshan North Road, Taipei City 10449, Taiwan. E-mail address: [email protected] (C.-L. Chang). 1 Hung-Ju Chien and Chuo-Yu Lee are cofirst authors.
admitted for further evaluation of the dizziness and possible central vertigo. During admission, a physical examination was unremarkable except for the neurological tests. She was alert and oriented, and had normal cognitive function. Severe dysarthria was noted; however, the other cranial nerves were grossly unremarkable. Her extraocular movements were full, and no nystagmus or KaysereFleischer rings were noted. Muscle power, sensory examination, and deep tendon reflexes were normal, and no Babinski sign was noted. She had dysmetria and dysdiadochokinesia of both arms, which was more severe in the left side. She also had a wide-based gait, truncal ataxia, and bilateral dysmetria on the heelekneeeshin test. The presentation was consistent with progressive cerebellar dysfunction. Magnetic resonance imaging of the brain and cervical spinal cord did not show any specific findings. Cerebrospinal fluid obtained from lumbar puncture revealed a normal cell count, but slightly elevated protein (64 mg/dL), indicating an inflammatory process or autoimmune disease. In addition, autoimmune profile, thyroid profile, and ceruloplasmin level were all within the normal ranges; however, serum tumor markers were elevated, including cancer antigen (CA)-153 level of 132.6 U/mL and CA-125 level of
http://dx.doi.org/10.1016/j.tjog.2014.03.012 1028-4559/Copyright © 2015, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.
314
H.-J. Chien et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 313e315
ascending colon, and omentum) was found, and optimal debulking surgery was subsequently performed. Permanent pathology revealed ovarian serous carcinoma, and she was diagnosed with FIGO Stage IIIC (pT3cNxMb), Grade 3 serous ovarian carcinoma. She then received consecutive adjuvant chemotherapy. We then performed a series of examinations on her serum and tumor specimen. All Western blotting results indicated the presence of anti-cerebellar degeneration-related protein 2 (CDR2) (Yo) protein in her plasma (Figs. 1 and 2). To further confirm the presence of anti-Yo antibodies targeting neural elements, immunohistochemical staining on mouse cerebellar tissue was performed (Fig. 3). Microscopically, the findings revealed positive staining of Purkinje cells in the mouse cerebellar tissue with the patient's plasma, but not with the plasma from a healthy patient. Discussion
Fig. 1. Western blot of lysates from mouse cerebellar tissues probed by plasma from this patient, other cancer patients, and healthy donors. The first lane revealed a specific band (arrow) indicating a specific protein in the cerebellar tissue detected by the patient's plasma.
2126.4 U/mL (normal range <30 U/mL and <35 U/mL, respectively). Unexpectedly, an abdominal computed tomography scan revealed a pelvic mass with solid components, measuring 11 cm in diameter, with suspected liver surface and diaphragm tumor seeding. Due to the above gynecologic findings, exploratory laparotomy was arranged, during which an ovarian serous carcinoma with peritoneal seeding (including the liver surface, diaphragm, right
Paraneoplastic cerebellar degeneration (PCD) is a rare disorder affecting the neurological system, which is neither metastasis nor direct tumor invasion to the nervous system, caused by the immune-mediated effects of cancer [1]. Cerebellar dysfunction is one of the most common paraneoplastic presentations of cancer. The following symptoms are necessary to define classical cerebellar syndrome: development of a severe pancerebellar syndrome in <12 weeks, with no magnetic resonance imaging evidence of cerebellar atrophy [2]. The associated symptoms are ataxia, diplopia, dysphagia, dysarthria, and the prodrome of dizziness, nausea, and vomiting [3]. The most commonly associated antibodies with tumors are Hodgkin's lymphoma (anti-Tr and anti-mGluR1), lung cancer (antiHu), and gynecological and breast cancers (anti-Yo and anti-Ri,
Fig. 2. Western blot of lysates from this patient's ovarian cancer tissue probed by plasma from this patient, other cancer patients, and healthy donors. (A) The first lane revealed a specific band (arrow) indicating a specific protein in the ovarian tissue detected by the patient's plasma. (B) Western blot of human CDR2 (Yo) recombinant protein probed by plasma from this patient, other cancer patients, and healthy donors. The first lane showed a specific band (arrow) indicating anti-CDR2 (Yo) antibody within the patient's plasma. CDR2 ¼ cerebellar degeneration-related protein 2.
Fig. 3. Immunohistochemical staining on mouse cerebellar tissue. Microscopically, it revealed: (A) positive staining of Purkinje cells stained by this patient's plasma, and (B) no staining in the tissue stained by the healthy donor's plasma.
H.-J. Chien et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 313e315
respectively) [4,5]. Yo antibodies are directed against human CDR2, leading to apoptosis of Purkinje cells, which is associated with PCD [6]. PCD is an immune-mediated syndrome, and initial removal of the source of the antigens by treating the underlying tumor should be performed [1]. Besides antitumor treatment, immunotherapy such as plasmapheresis, intravenous immunoglobulin, corticosteroids, cyclophosphamide, tacrolimus, or rituximab could be considered [7]. This patient received four courses of plasmapheresis and complete courses of chemotherapy, after which her CA-125 level returned to normal range but her cerebellar symptoms persisted. Some studies have reported that PCD with anti-Yo antibodies has a better outcome with reversal of neurological symptoms than other types of antibodies [4,8]. In some cases, complete antitumor and immune treatment could prevent disease progression but not reverse the neurological disorders, as in our patient. In conclusion, we report PCD in a patient with advanced ovarian cancer. We also provide direct evidence showing the presence of an anti-Yo antibody in the patient's plasma targeting cerebellar Purkinje cells. This report will help diagnose such cases of paraneoplastic syndrome in the future.
315
Conflicts of interest The authors have no conflicts of interest relevant to this article. References [1] Santillan A, Bristow RE. Paraneoplastic cerebellar degeneration in a woman with ovarian cancer. Nat Clin Pract Oncol 2006;3:108e12. quiz 1 p following 112. [2] Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004;75:1135e40. [3] Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc 2010;85:838e54. [4] Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008;7:327e40. [5] Shams'ili S, Grefkens J, de Leeuw B, van den Bent M, Hooijkaas H, van der Holt B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 2003;126:1409e18. [6] Totland C, Aarskog NK, Eichler TW, Haugen M, Nostbakken JK, Monstad SE, et al. CDR2 antigen and Yo antibodies. Cancer Immunol Immunother 2011;60:283e9. [7] Storstein A, Vedeler C. Treatment of paraneoplastic neurological syndromes. Adv Clin Neurosci Rehabil 2009;8:12e4. [8] De Beukelaar JW, Smitt PAS. Managing paraneoplastic neurological disorders. Oncologist 2006;11:292e305.