- Email: [email protected]
Diagnosis of leptomeningeal metastasis without a history of malignancy in the absence of cerebrospinal fluid abnormalities
Accepted Manuscript Title: Diagnosis of leptomeningeal metastasis without a history of malignancy in the absence of cerebrospinal fluid abnormalities: Case report Authors: Yokote Akiyoshi M.D. Takemasa Kawamoto M.D., Ph.D. Namioka Takahiro M.D. Moteki Yosuke M.D. Takakazu Kawamata M.D., Ph.D. PII: DOI: Reference:
S0303-8467(14)00036-5 http://dx.doi.org/doi:10.1016/j.clineuro.2014.01.022 CLINEU 3610
To appear in:
Clinical Neurology and Neurosurgery
Received date: Revised date: Accepted date:
25-10-2013 13-12-2013 19-1-2014
Please cite this article as: Akiyoshi Yokote, Kawamoto Takemasa, Takahiro Namioka, Yosuke Moteki, Kawamata Takakazu.Diagnosis of leptomeningeal metastasis without a history of malignancy in the absence of cerebrospinal fluid abnormalities: Case report.Clinical Neurology and Neurosurgery http://dx.doi.org/10.1016/j.clineuro.2014.01.022 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Diagnosis of leptomeningeal metastasis without a history of malignancy in the absence of cerebrospinal fluid abnormalities: Case report
ip t
Akiyoshi Yokote, M.D., Takemasa Kawamoto, M.D., Ph.D., Takahiro Namioka, M.D.,
cr
Yosuke Moteki, M.D., Takakazu Kawamata, M.D., Ph.D.
us
Department of Neurosurgery, Tokyo Women’s Medical University Yachiyo Medical Center,
an
Chiba, Japan
M
Running head: Leptomeningeal metastasis without a history of malignancy
d
Key words: cerebrospinal fluid, cytology, intracranial hypertension, leptomeningeal
Ac ce pt e
metastasis, meningeal carcinomatosis
Address correspondence and reprint requests to: Takakazu Kawamata, M.D., Ph.D. Department of Neurosurgery
Tokyo Women’s Medical University
8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan Phone: +81-3-3353-8111 (ext.25114) Fax: +81-3-5269-7438
E-mail: [email protected]
1 Page 1 of 9
1. Introduction Leptomeningeal metastasis (LM) occurs in approximately 5% of patients with malignant tumors [1,2]. The standard treatment for LM consists of radiation therapy and chemotherapy,
ip t
but the efficacy of these treatments for LM is sometimes limited. The goals of treatment of LM also include palliating symptoms. Clinical manifestations of LM, such as nerve palsies
cr
(75%) and headaches (66%) [3], are caused by elevated intracranial pressure (ICP). A
ventriculoperitoneal (VP) shunt often reduces patients’ complaints and improves Karnofsky
us
Performance Status (KPS) scores and performance status (PS). The prognosis vary depending on the extent of neurological deficits, progression of systemic cancer, KPS score, and PS. It
an
goes without saying that an early diagnosis is very important.
M
Standard examinations of cerebrospinal fluid (CSF) cytology and gadolinium-enhanced magnetic resonance imaging (Gd-MRI) may not be sensitive enough to make a diagnosis of
d
LM even in a patient with a history of systemic malignant disease. Here, we report a patient
Ac ce pt e
without a medical history of systemic malignancy, who was diagnosed with LM after a delay because of negative early clinical findings, except intracranial hypertension.
2. Case Report
A 62-year-old woman presented with headache and double vision. The patient had abducens nerve paralysis and bilateral papilledema. She had no history of malignancy and her family history was unremarkable. Gd-MRI demonstrated no significant abnormalities (Fig. 1). Although intracranial pressure measured by a lumber puncture was higher than 600 mmH2O, a CSF sample showed normal protein (31 mg/dl) and glucose (45 mg/dl) levels, and a cell count of 5 cells/mm3, all of which were monocytes. With a tentative diagnosis of idiopathic intracranial hypertension, she underwent a ventriculoperitoneal (VP) shunt placement to reduce intracranial pressure one month after the first spinal tap. Headache and bilateral 2 Page 2 of 9
papilledema were improved after VP shunting, and abducens nerve paralysis disappeared. Her KPS score was 90 and PS was grade 1. Five months after VP shunt placement, she developed disorientation, hearing loss, and loss of light reflex of the pupil in the left eye. Gd-MRI
ip t
demonstrated diffuse leptomeningeal contrast enhancement without hydrocephalus (Fig. 2). CSF sampled from the VP shunt system revealed elevated protein (1348 mg/dl) and glucose
cr
(63 mg/dl) levels. The CSF cell count was 59 cells/mm3, 41% of which were atypical cells. Cytological examination of the CSF revealed malignant cells with enlarged nuclei and
us
nucleoli. After these results were obtained, the remaining CSF samples collected at the first lumber puncture and at VP shunt placement (performed one month after the first lumber
an
puncture) were examined cytologically; malignant cells were absent in the former sample (Fig.
M
3A) but present in the latter sample (Fig. 3B). Although LM was diagnosed, radiation therapy or chemotherapy could not be initiated because of her poor KPS and PS.
d
A contrast-enhanced abdominal computed tomography scan demonstrated urinary bladder
Ac ce pt e
carcinoma spreading to the ovary and the adrenal gland. She was given palliative care.
3. Discussion
There is a paucity of reports on patients with LM who have no history of cancer. A study on CSF analysis in patients with LM reported that 19% had normal CSF protein levels (<50 mg/dl) and 43% had normal cell counts (<5 cells/mm3). Straathof et al. [4] reported that the sensitivities of CSF cytology and Gd-MRI are 75% and 76%, respectively, which are not high rates. Kaplan et al. [5] reported that more than three CSF cytology examinations were necessary to diagnose LM in 8% of the patients. Hence, it is difficult to diagnose LM with a single examination of CSF cytology, as demonstrated in the present case. Furthermore, a correct diagnosis of LM is usually missed in patients without a history of malignancy, because LM is generally not suspected in patients without a history of malignancy and the frequency 3 Page 3 of 9
of LM is much lower in patients without a history of malignancy compared to those with a history. In our patient, CSF examinations including cytology showed no abnormalities in the
ip t
early stage. However, LM could have been suspected from the elevated intracranial pressure and presence of abducens nerve paralysis, even without a history of malignancy. One month
cr
after her initial presentation, CSF cytology became positive for malignancy (class V) indicating that it may be possible to diagnose LM at an earlier stage.
us
To date, there are no reports or guidelines on how often physicians should repeat CSF examinations including cytology in patients without a history of malignancy who have
an
negative findings in the early samples. However, CSF cytology should be examined if the
M
patients have primary ICP elevation not caused by subarachnoid hemorrhage, intraventricular hemorrhage, or obstructive hydrocephalus. Based on the present case, CSF cytology should
d
be examined repeatedly at least once a month because positive cytology for malignancy was
Ac ce pt e
found one month after the first examination.
Given the limited sensitivity of cytology, other diagnostic methods have been explored. Rhodes et al. [6] reported that polymerase chain reaction examination of CSF was practical and complemented cytology in the diagnosis of LM caused by hematological malignancy, and Nayak et al. [7] reported the utility of rare cell capture technology for detection of epithelial cell adhesion molecule in the diagnosis of LM caused by solid tumors. The applicability of these alternative approaches to all malignancies requires further examinations.
4. Conclusion We report a patient with LM who presented with no history of malignancy and showed negative CSF and Gd-MRI findings in the initial examinations. In a patient with idiopathic ICP elevation, LM should be suspected even in the absence of a history of malignancy, and 4 Page 4 of 9
ip t
CSF examination and systemic workup should be conducted repeatedly.
cr
References
[1] DeAngelis LM. Current diagnosis and treatment of leptomeningeal metastasis. J
us
Neurooncol 1998;38:245-52.
[2] Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev
an
1999;25:103-19.
M
[3] Pavlidis N. The diagnostic and therapeutic management of leptomeningeal carcinomatosis. Ann Oncol 2004;15 (Suppl 4):285-91.
d
[4] Straathof CS, de Bruin HG, Dippel DW, Vecht CJ. The diagnostic accuracy of magnetic
Ac ce pt e
resonance imaging and cerebrospinal fluid cytology in leptomeningeal metastasis. J Neurol 1999;246:810-4.
[5] Kaplan JG, DeSouza TG, Farkash A, Shafran B, Pack D, Rehman F, et al. Leptomeningeal metastases: comparison of clinical features and laboratory date of solid tumors, lymphomas and leukemias. J Neurooncol 1990;9:225-9. [6] Rhodes CH, Glantz MJ, Glantz L, Lekos A, Sorenson GD, Honsinger C, et al. A comparison of polymerase chain reaction examination of cerebrospinal fluid and conventional cytology in the diagnosis of lymphomatous meningitis. Cancer 1996;77:543-8. [7] Nayak L, Fleisher M, Gonzalez-Espinoza R, Lin O, Panageas K, Reiner A, et al. Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors. Neurology 2013;80:1598-605. 5 Page 5 of 9
Figure legends
Fig. 1. A, B, C: Axial sections of T1-weighted gadolinium-enhanced magnetic resonance
cr
venography showing normal patency of major cerebral venous systems.
ip t
(MR) imaging conducted at presentation demonstrating no definite abnormal findings. D: MR
Fig. 2. Axial sections of T1-weighted gadolinium-enhanced magnetic resonance imaging five
us
months after ventriculoperitoneal shunt placement demonstrating prominent enhancement
an
along the meninges compatible with diffuse leptomeningeal metastases.
M
Fig. 3. A: Cytology of cerebrospinal fluid (CSF) sampled at initial consultation demonstrating no malignant cells (Giemsa staining, x10). B: Cytology of CSF sampled one month after the
d
initial consultation demonstrating malignant cells with enlarged nuclei and nucleoli (x10).
Ac ce pt e
Inset is a high-power (x40) view of the malignant cells. Highlights Diagnosis of leptomeningeal metastasis (LM) is not easy. ► Diagnosis of LM without history of malignancy is much more difficult. ► The first examination of cerebrospinal fluid revealed no abnormalities. ► MRI demonstrated LM 5 months after the shunt placement. ► LM should be suspected even when there is no history of malignancy.
6 Page 6 of 9
ip t cr us an M d Ac ce pt e
Fig 1.
7 Page 7 of 9
ip t cr us an M d Ac ce pt e
Fig 2.
8 Page 8 of 9
ip t cr us an M d Ac ce pt e
Fig 3.
9 Page 9 of 9
S0303-8467(14)00036-5 http://dx.doi.org/doi:10.1016/j.clineuro.2014.01.022 CLINEU 3610
To appear in:
Clinical Neurology and Neurosurgery
Received date: Revised date: Accepted date:
25-10-2013 13-12-2013 19-1-2014
Please cite this article as: Akiyoshi Yokote, Kawamoto Takemasa, Takahiro Namioka, Yosuke Moteki, Kawamata Takakazu.Diagnosis of leptomeningeal metastasis without a history of malignancy in the absence of cerebrospinal fluid abnormalities: Case report.Clinical Neurology and Neurosurgery http://dx.doi.org/10.1016/j.clineuro.2014.01.022 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Diagnosis of leptomeningeal metastasis without a history of malignancy in the absence of cerebrospinal fluid abnormalities: Case report
ip t
Akiyoshi Yokote, M.D., Takemasa Kawamoto, M.D., Ph.D., Takahiro Namioka, M.D.,
cr
Yosuke Moteki, M.D., Takakazu Kawamata, M.D., Ph.D.
us
Department of Neurosurgery, Tokyo Women’s Medical University Yachiyo Medical Center,
an
Chiba, Japan
M
Running head: Leptomeningeal metastasis without a history of malignancy
d
Key words: cerebrospinal fluid, cytology, intracranial hypertension, leptomeningeal
Ac ce pt e
metastasis, meningeal carcinomatosis
Address correspondence and reprint requests to: Takakazu Kawamata, M.D., Ph.D. Department of Neurosurgery
Tokyo Women’s Medical University
8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan Phone: +81-3-3353-8111 (ext.25114) Fax: +81-3-5269-7438
E-mail: [email protected]
1 Page 1 of 9
1. Introduction Leptomeningeal metastasis (LM) occurs in approximately 5% of patients with malignant tumors [1,2]. The standard treatment for LM consists of radiation therapy and chemotherapy,
ip t
but the efficacy of these treatments for LM is sometimes limited. The goals of treatment of LM also include palliating symptoms. Clinical manifestations of LM, such as nerve palsies
cr
(75%) and headaches (66%) [3], are caused by elevated intracranial pressure (ICP). A
ventriculoperitoneal (VP) shunt often reduces patients’ complaints and improves Karnofsky
us
Performance Status (KPS) scores and performance status (PS). The prognosis vary depending on the extent of neurological deficits, progression of systemic cancer, KPS score, and PS. It
an
goes without saying that an early diagnosis is very important.
M
Standard examinations of cerebrospinal fluid (CSF) cytology and gadolinium-enhanced magnetic resonance imaging (Gd-MRI) may not be sensitive enough to make a diagnosis of
d
LM even in a patient with a history of systemic malignant disease. Here, we report a patient
Ac ce pt e
without a medical history of systemic malignancy, who was diagnosed with LM after a delay because of negative early clinical findings, except intracranial hypertension.
2. Case Report
A 62-year-old woman presented with headache and double vision. The patient had abducens nerve paralysis and bilateral papilledema. She had no history of malignancy and her family history was unremarkable. Gd-MRI demonstrated no significant abnormalities (Fig. 1). Although intracranial pressure measured by a lumber puncture was higher than 600 mmH2O, a CSF sample showed normal protein (31 mg/dl) and glucose (45 mg/dl) levels, and a cell count of 5 cells/mm3, all of which were monocytes. With a tentative diagnosis of idiopathic intracranial hypertension, she underwent a ventriculoperitoneal (VP) shunt placement to reduce intracranial pressure one month after the first spinal tap. Headache and bilateral 2 Page 2 of 9
papilledema were improved after VP shunting, and abducens nerve paralysis disappeared. Her KPS score was 90 and PS was grade 1. Five months after VP shunt placement, she developed disorientation, hearing loss, and loss of light reflex of the pupil in the left eye. Gd-MRI
ip t
demonstrated diffuse leptomeningeal contrast enhancement without hydrocephalus (Fig. 2). CSF sampled from the VP shunt system revealed elevated protein (1348 mg/dl) and glucose
cr
(63 mg/dl) levels. The CSF cell count was 59 cells/mm3, 41% of which were atypical cells. Cytological examination of the CSF revealed malignant cells with enlarged nuclei and
us
nucleoli. After these results were obtained, the remaining CSF samples collected at the first lumber puncture and at VP shunt placement (performed one month after the first lumber
an
puncture) were examined cytologically; malignant cells were absent in the former sample (Fig.
M
3A) but present in the latter sample (Fig. 3B). Although LM was diagnosed, radiation therapy or chemotherapy could not be initiated because of her poor KPS and PS.
d
A contrast-enhanced abdominal computed tomography scan demonstrated urinary bladder
Ac ce pt e
carcinoma spreading to the ovary and the adrenal gland. She was given palliative care.
3. Discussion
There is a paucity of reports on patients with LM who have no history of cancer. A study on CSF analysis in patients with LM reported that 19% had normal CSF protein levels (<50 mg/dl) and 43% had normal cell counts (<5 cells/mm3). Straathof et al. [4] reported that the sensitivities of CSF cytology and Gd-MRI are 75% and 76%, respectively, which are not high rates. Kaplan et al. [5] reported that more than three CSF cytology examinations were necessary to diagnose LM in 8% of the patients. Hence, it is difficult to diagnose LM with a single examination of CSF cytology, as demonstrated in the present case. Furthermore, a correct diagnosis of LM is usually missed in patients without a history of malignancy, because LM is generally not suspected in patients without a history of malignancy and the frequency 3 Page 3 of 9
of LM is much lower in patients without a history of malignancy compared to those with a history. In our patient, CSF examinations including cytology showed no abnormalities in the
ip t
early stage. However, LM could have been suspected from the elevated intracranial pressure and presence of abducens nerve paralysis, even without a history of malignancy. One month
cr
after her initial presentation, CSF cytology became positive for malignancy (class V) indicating that it may be possible to diagnose LM at an earlier stage.
us
To date, there are no reports or guidelines on how often physicians should repeat CSF examinations including cytology in patients without a history of malignancy who have
an
negative findings in the early samples. However, CSF cytology should be examined if the
M
patients have primary ICP elevation not caused by subarachnoid hemorrhage, intraventricular hemorrhage, or obstructive hydrocephalus. Based on the present case, CSF cytology should
d
be examined repeatedly at least once a month because positive cytology for malignancy was
Ac ce pt e
found one month after the first examination.
Given the limited sensitivity of cytology, other diagnostic methods have been explored. Rhodes et al. [6] reported that polymerase chain reaction examination of CSF was practical and complemented cytology in the diagnosis of LM caused by hematological malignancy, and Nayak et al. [7] reported the utility of rare cell capture technology for detection of epithelial cell adhesion molecule in the diagnosis of LM caused by solid tumors. The applicability of these alternative approaches to all malignancies requires further examinations.
4. Conclusion We report a patient with LM who presented with no history of malignancy and showed negative CSF and Gd-MRI findings in the initial examinations. In a patient with idiopathic ICP elevation, LM should be suspected even in the absence of a history of malignancy, and 4 Page 4 of 9
ip t
CSF examination and systemic workup should be conducted repeatedly.
cr
References
[1] DeAngelis LM. Current diagnosis and treatment of leptomeningeal metastasis. J
us
Neurooncol 1998;38:245-52.
[2] Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev
an
1999;25:103-19.
M
[3] Pavlidis N. The diagnostic and therapeutic management of leptomeningeal carcinomatosis. Ann Oncol 2004;15 (Suppl 4):285-91.
d
[4] Straathof CS, de Bruin HG, Dippel DW, Vecht CJ. The diagnostic accuracy of magnetic
Ac ce pt e
resonance imaging and cerebrospinal fluid cytology in leptomeningeal metastasis. J Neurol 1999;246:810-4.
[5] Kaplan JG, DeSouza TG, Farkash A, Shafran B, Pack D, Rehman F, et al. Leptomeningeal metastases: comparison of clinical features and laboratory date of solid tumors, lymphomas and leukemias. J Neurooncol 1990;9:225-9. [6] Rhodes CH, Glantz MJ, Glantz L, Lekos A, Sorenson GD, Honsinger C, et al. A comparison of polymerase chain reaction examination of cerebrospinal fluid and conventional cytology in the diagnosis of lymphomatous meningitis. Cancer 1996;77:543-8. [7] Nayak L, Fleisher M, Gonzalez-Espinoza R, Lin O, Panageas K, Reiner A, et al. Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors. Neurology 2013;80:1598-605. 5 Page 5 of 9
Figure legends
Fig. 1. A, B, C: Axial sections of T1-weighted gadolinium-enhanced magnetic resonance
cr
venography showing normal patency of major cerebral venous systems.
ip t
(MR) imaging conducted at presentation demonstrating no definite abnormal findings. D: MR
Fig. 2. Axial sections of T1-weighted gadolinium-enhanced magnetic resonance imaging five
us
months after ventriculoperitoneal shunt placement demonstrating prominent enhancement
an
along the meninges compatible with diffuse leptomeningeal metastases.
M
Fig. 3. A: Cytology of cerebrospinal fluid (CSF) sampled at initial consultation demonstrating no malignant cells (Giemsa staining, x10). B: Cytology of CSF sampled one month after the
d
initial consultation demonstrating malignant cells with enlarged nuclei and nucleoli (x10).
Ac ce pt e
Inset is a high-power (x40) view of the malignant cells. Highlights Diagnosis of leptomeningeal metastasis (LM) is not easy. ► Diagnosis of LM without history of malignancy is much more difficult. ► The first examination of cerebrospinal fluid revealed no abnormalities. ► MRI demonstrated LM 5 months after the shunt placement. ► LM should be suspected even when there is no history of malignancy.
6 Page 6 of 9
ip t cr us an M d Ac ce pt e
Fig 1.
7 Page 7 of 9
ip t cr us an M d Ac ce pt e
Fig 2.
8 Page 8 of 9
ip t cr us an M d Ac ce pt e
Fig 3.
9 Page 9 of 9