VOLUME
32
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NUMBER
12
䡠
APRIL
20
2015
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
I N
O N C O L O G Y
diagnosis. However, the symptoms fluctuated and were not satisfactorily responsive to treatment for aseptic meningitis. Because of treatment failure, open meningeal biopsy was performed, and the pathologic diagnosis was primary leptomeningeal melanoma. This case report illustrates the diagnostic dilemma in obtaining an accurate diagnosis of such a rare cancer.
Primary Leptomeningeal Melanoma Mimicking Meningitis: A Case Report and Literature Review Introduction Primary leptomeningeal melanoma is a rare cancer and is difficult to diagnose initially because the symptoms and relevant findings are often not characteristic. Although cytopathologic analysis of CSF may be helpful, it is not always conclusive. Herein, we report a 41-yearold man who experienced repeated headaches and dizziness for 1 week; he was diagnosed with aseptic meningitis and treated accordingly. Relevant imaging studies and laboratory tests supported the
Case Report A 41-year-old man who was previously robust experienced dizziness and headaches for approximately 1 week. The dizziness increased in severity when he stood up or rotated his head. The headache involved both sides of the head. The patient visited a medical center in northern Taiwan, where viral meningitis was diagnosed on the basis of
A
B
Fig 1. Journal of Clinical Oncology, Vol 32, No 12 (April 20), 2015: pp e57-e61
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e57
Hsieh et al
have resolved but soon reappeared. Additional studies, including lumbar puncture for CSF cytology and brain MRI, were performed for differential diagnoses between systemic lupus erythematous with CNS involvement, cytomegalovirus meningitis, herpes simplex encephalitis, HIV-associated encephalopathy, Lyme disease, and neurologic syphilis. Repeated CSF examinations showed pleocytosis with a predominance of monocytes and histiocytes. No other findings that are characteristic of systemic lupus erythematous, bacterial infection, or viral infection were observed. Repeat brain MRI showed a diffuse leptomeningeal contrast-enhancing process and a hyperintense cerebral sulcus, as was seen in the initial image. Open craniotomy with meningeal biopsy was performed, revealing diffuse black-colored masses along with cerebral sulci in the subarachnoid space (Fig 2A, arrow). Microscopic analysis of the biopsy specimen showed mixed epithelioid and spindle tumor cells displaying hyperchromatic nuclei with strong positive immunostaining for S-100 and HMB-45 and negative staining for BCL2, leukocyte common antigen, CD3, and CD20 (Figs 2B through 2F). A repeat physical examination showed no abnormal skin lesions or intraocular lesions. Subsequent positron emission tomography (PET) revealed a hypermetabolic nodule in the
lumbar puncture findings. Physical examination revealed no specific findings. After an initial response to treatment for viral meningitis, the symptoms recurred. The patient was transferred to our neurology department, while symptoms of meningitis were still present, and treatment with ibuprofen was prescribed. However, after a short period of alleviation, the symptoms recurred. Magnetic resonance imaging (MRI) of the brain showed a hyperintense sulcus on a T1-weighted image and diffuse leptomeningeal enhancement involving bilateral cerebral sulci, findings that were compatible with meningitis (Fig 1A, arrows, and Fig 1B). Repeated lumbar puncture showed nonspecific abnormalities, including CSF cytology. The patient’s symptoms resolved after glycerol treatment. Follow-up brain MRI showed subtle temporary regression of meningitis. However, short-term memory impairment developed 1 month after glycerol treatment. Progressive deterioration of neurologic symptoms including paraphasia, anomia, and self-isolation, and visual and auditory hallucination were noted as well. The patient also had a mildly unsteady gait but could still walk without assistance. No other motor deficits were noted. Physical examination did not reveal any other symptoms beyond those mentioned. Corticosteroids were prescribed, and the symptoms seemed to
A
B
D
E
C
HMB-45
F
S-100
Ki-67 Fig 2. e58
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
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Fig 3.
thyroid gland, which was later proven to be benign, thereby excluding the possibility of metastatic melanoma from other parts of the body (Fig 3; hypermetabolic nodule indicated by red lines; Fig 3A, coronal image; Fig 3B, PET coronal image; Fig 3C, fused coronal image; Fig 3D, maximum intensity projection image). Wholespine MRI revealed abnormal leptomeningeal enhancement involving the entire spine, brainstem, cerebellum, and visible brain (Fig 4, gold arrows). Collectively, these results confirmed a diagnosis of primary leptomeningeal melanoma. An extraventricular drain was inserted to relieve intracranial pressure. Subsequent analysis of extraventricular drainage revealed malignant cells shown in Papanicolaou stain (Fig 5A) and HMB-45 stain (Fig 5B, cell with pigmentation). The patient then underwent chemotherapy with temozolomide and palliative radiotherapy and is still alive 3 months after the diagnosis. www.jco.org
Discussion Primary leptomeningeal melanoma is a rare and aggressive tumor with an annual incidence of approximately one per 10 million people.1 Because of its rarity, the related literature primarily consists of individual case reports.2-5 Peak incidence occurs in the fourth decade of life. The tumor is thought to arise from melanocytes, normally found in the pia and arachnoid, that cover the base of the brain, the caudal medulla, and the cervical spinal cord.2 The diagnosis of primary CNS melanoma was made according to criteria proposed by Hayward,6 which include an absence of melanoma outside of the CNS, an absence of lesions in other areas of the CNS, and histologic confirmation of melanoma. MRI is the imaging method of choice for diagnosis.7 On T1-weighted images, the region of melanocytosis tends to be hyperintense or isointense from T1 shortening as a result of the paramagnetic properties of melanin, and is © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e59
Hsieh et al
Fig 4.
The fluctuation of neurologic symptoms and signs on treatment also affected accurate diagnosis. Approximately 25% of patients with leptomeningeal melanoma have an associated large or giant congenital pigmented nevus. In patients who do not harbor such nevi, early diagnosis may be difficult,9 as in the case of our patient. Tosaka et al10 demonstrated the utility of immunocytochemical analysis of CSF cells using HMB-45
hypointense on T2-weighted images. However, the most striking feature is diffuse leptomeningeal enhancement with gadolinium on T1weighted images.8 In our patient, the initial imaging findings showed a subtle T1-weighted precontrast hyperintensity in a cerebral sulcus (Fig 1A). The initial symptoms were primarily neurologic, including seizures, psychiatric disturbances, and signs of increased intracranial pressure (headache, vomiting, and deterioration of consciousness).
A
B
Fig 5. e60
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
and S-100 protein antibodies in diagnosing primary leptomeningeal melanoma, given the test’s simplicity, high specificity, and sensitivity. In our patient, normal CSF cytology in repeated lumbar punctures obscured the diagnosis. Subsequent positive findings in CSF drainage were noted by collecting more than 100 mL of CSF and concentrating CFS cells by centrifugation. It is almost impossible to collect such a large volume of CSF directly from routine lumbar puncture; however, in our patient, collection of such volumes of CSF was facilitated by the extraventricular drain. Insertion of the extraventricular drainage device may disrupt the integrity of the pia mater, providing a seeding route for melanoma cells. This may result in subsequent positive CSF cytology. Prompt surgical intervention for tissue biopsy early in our patient’s case was important in making the final diagnosis. Herein, we present a case of primary leptomeningeal melanoma that mimicked meningitis. Serial examinations, including laboratory tests and imaging studies, favored a diagnosis of meningitis. Because the symptoms were refractory to standard treatment for meningitis, open meningeal biopsy was performed, facilitating an accurate diagnosis. When faced with ambiguous results from diagnostic tests and treatment failure for a presumptive diagnosis of meningitis, direct surgical intervention should be considered for pathologic diagnosis of primary leptomeningeal melanoma.
Yao-Yu Hsieh, Shun-Tai Yang, Wei-Hua Li, Chaur-Jong Hu, and Liang-Shun Wang Taipei Medical University Shuang-Ho Hospital, New Taipei City, Taiwan
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Schreiber D, Janisch HGW (eds): Neuropathologie: Tumoren des Nervensystems [in German]. Gustav Fischer, Stuttgart, Germany, 1988, pp 347-353 2. Rosenthal G, Gomori JM, Tobias S, et al: Unusual cases involving the CNS and nasal sinuses: Case 1—Primary leptomeningeal melanoma. J Clin Oncol 21:3875-3877, 2003 3. Schneider F, Putzier M: Primary leptomeningeal melanoma. Spine (Phila Pa 1976) 27:E545-E547, 2002 4. Kounin GK, Romansky KV, Traykov LD, et al: Primary spinal melanoma with bilateral papilledema. Clin Neurol Neurosurg 107:525-527, 2005 5. Sagiuchi T, Ishii K, Utsuki S, et al: Increased uptake of technetium-99mhexamethylpropyleneamine oxime related to primary leptomeningeal melanoma. AJNR Am J Neuroradiol 23:1404-1406, 2002 6. Hayward RD: Malignant melanoma and the central nervous system: A guide for classification based on the clinical findings. J Neurol Neurosurg Psychiatry 39:526-530, 1976 7. Weindling SM, Press GA, Hesselink JR: MR characteristics of a primary melanoma of the quadrigeminal plate. AJNR Am J Neuroradiol 9:214-215, 1988 8. Atlas SW, Grossman RI, Gomori JM, et al: MR imaging of intracranial metastatic melanoma. J Comput Assist Tomogr 11:577-582, 1987 9. Hoffman HJ, Freeman A: Primary malignant leptomeningeal melanoma in association with giant hairy nevi. J Neurosurg 26:62-71, 1967 10. Tosaka M, Tamura M, Oriuchi N, et al: Cerebrospinal fluid immunocytochemical analysis and neuroimaging in the diagnosis of primary leptomeningeal melanoma: Case report. J Neurosurg 94:528-532, 2001
DOI: 10.1200/JCO.2013.50.0264; published online ahead of print at www.jco.org on March 17, 2014 ■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e61
32
䡠
NUMBER
12
䡠
APRIL
20
2015
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
I N
O N C O L O G Y
diagnosis. However, the symptoms fluctuated and were not satisfactorily responsive to treatment for aseptic meningitis. Because of treatment failure, open meningeal biopsy was performed, and the pathologic diagnosis was primary leptomeningeal melanoma. This case report illustrates the diagnostic dilemma in obtaining an accurate diagnosis of such a rare cancer.
Primary Leptomeningeal Melanoma Mimicking Meningitis: A Case Report and Literature Review Introduction Primary leptomeningeal melanoma is a rare cancer and is difficult to diagnose initially because the symptoms and relevant findings are often not characteristic. Although cytopathologic analysis of CSF may be helpful, it is not always conclusive. Herein, we report a 41-yearold man who experienced repeated headaches and dizziness for 1 week; he was diagnosed with aseptic meningitis and treated accordingly. Relevant imaging studies and laboratory tests supported the
Case Report A 41-year-old man who was previously robust experienced dizziness and headaches for approximately 1 week. The dizziness increased in severity when he stood up or rotated his head. The headache involved both sides of the head. The patient visited a medical center in northern Taiwan, where viral meningitis was diagnosed on the basis of
A
B
Fig 1. Journal of Clinical Oncology, Vol 32, No 12 (April 20), 2015: pp e57-e61
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e57
Hsieh et al
have resolved but soon reappeared. Additional studies, including lumbar puncture for CSF cytology and brain MRI, were performed for differential diagnoses between systemic lupus erythematous with CNS involvement, cytomegalovirus meningitis, herpes simplex encephalitis, HIV-associated encephalopathy, Lyme disease, and neurologic syphilis. Repeated CSF examinations showed pleocytosis with a predominance of monocytes and histiocytes. No other findings that are characteristic of systemic lupus erythematous, bacterial infection, or viral infection were observed. Repeat brain MRI showed a diffuse leptomeningeal contrast-enhancing process and a hyperintense cerebral sulcus, as was seen in the initial image. Open craniotomy with meningeal biopsy was performed, revealing diffuse black-colored masses along with cerebral sulci in the subarachnoid space (Fig 2A, arrow). Microscopic analysis of the biopsy specimen showed mixed epithelioid and spindle tumor cells displaying hyperchromatic nuclei with strong positive immunostaining for S-100 and HMB-45 and negative staining for BCL2, leukocyte common antigen, CD3, and CD20 (Figs 2B through 2F). A repeat physical examination showed no abnormal skin lesions or intraocular lesions. Subsequent positron emission tomography (PET) revealed a hypermetabolic nodule in the
lumbar puncture findings. Physical examination revealed no specific findings. After an initial response to treatment for viral meningitis, the symptoms recurred. The patient was transferred to our neurology department, while symptoms of meningitis were still present, and treatment with ibuprofen was prescribed. However, after a short period of alleviation, the symptoms recurred. Magnetic resonance imaging (MRI) of the brain showed a hyperintense sulcus on a T1-weighted image and diffuse leptomeningeal enhancement involving bilateral cerebral sulci, findings that were compatible with meningitis (Fig 1A, arrows, and Fig 1B). Repeated lumbar puncture showed nonspecific abnormalities, including CSF cytology. The patient’s symptoms resolved after glycerol treatment. Follow-up brain MRI showed subtle temporary regression of meningitis. However, short-term memory impairment developed 1 month after glycerol treatment. Progressive deterioration of neurologic symptoms including paraphasia, anomia, and self-isolation, and visual and auditory hallucination were noted as well. The patient also had a mildly unsteady gait but could still walk without assistance. No other motor deficits were noted. Physical examination did not reveal any other symptoms beyond those mentioned. Corticosteroids were prescribed, and the symptoms seemed to
A
B
D
E
C
HMB-45
F
S-100
Ki-67 Fig 2. e58
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
A
B
C
D
Fig 3.
thyroid gland, which was later proven to be benign, thereby excluding the possibility of metastatic melanoma from other parts of the body (Fig 3; hypermetabolic nodule indicated by red lines; Fig 3A, coronal image; Fig 3B, PET coronal image; Fig 3C, fused coronal image; Fig 3D, maximum intensity projection image). Wholespine MRI revealed abnormal leptomeningeal enhancement involving the entire spine, brainstem, cerebellum, and visible brain (Fig 4, gold arrows). Collectively, these results confirmed a diagnosis of primary leptomeningeal melanoma. An extraventricular drain was inserted to relieve intracranial pressure. Subsequent analysis of extraventricular drainage revealed malignant cells shown in Papanicolaou stain (Fig 5A) and HMB-45 stain (Fig 5B, cell with pigmentation). The patient then underwent chemotherapy with temozolomide and palliative radiotherapy and is still alive 3 months after the diagnosis. www.jco.org
Discussion Primary leptomeningeal melanoma is a rare and aggressive tumor with an annual incidence of approximately one per 10 million people.1 Because of its rarity, the related literature primarily consists of individual case reports.2-5 Peak incidence occurs in the fourth decade of life. The tumor is thought to arise from melanocytes, normally found in the pia and arachnoid, that cover the base of the brain, the caudal medulla, and the cervical spinal cord.2 The diagnosis of primary CNS melanoma was made according to criteria proposed by Hayward,6 which include an absence of melanoma outside of the CNS, an absence of lesions in other areas of the CNS, and histologic confirmation of melanoma. MRI is the imaging method of choice for diagnosis.7 On T1-weighted images, the region of melanocytosis tends to be hyperintense or isointense from T1 shortening as a result of the paramagnetic properties of melanin, and is © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e59
Hsieh et al
Fig 4.
The fluctuation of neurologic symptoms and signs on treatment also affected accurate diagnosis. Approximately 25% of patients with leptomeningeal melanoma have an associated large or giant congenital pigmented nevus. In patients who do not harbor such nevi, early diagnosis may be difficult,9 as in the case of our patient. Tosaka et al10 demonstrated the utility of immunocytochemical analysis of CSF cells using HMB-45
hypointense on T2-weighted images. However, the most striking feature is diffuse leptomeningeal enhancement with gadolinium on T1weighted images.8 In our patient, the initial imaging findings showed a subtle T1-weighted precontrast hyperintensity in a cerebral sulcus (Fig 1A). The initial symptoms were primarily neurologic, including seizures, psychiatric disturbances, and signs of increased intracranial pressure (headache, vomiting, and deterioration of consciousness).
A
B
Fig 5. e60
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
and S-100 protein antibodies in diagnosing primary leptomeningeal melanoma, given the test’s simplicity, high specificity, and sensitivity. In our patient, normal CSF cytology in repeated lumbar punctures obscured the diagnosis. Subsequent positive findings in CSF drainage were noted by collecting more than 100 mL of CSF and concentrating CFS cells by centrifugation. It is almost impossible to collect such a large volume of CSF directly from routine lumbar puncture; however, in our patient, collection of such volumes of CSF was facilitated by the extraventricular drain. Insertion of the extraventricular drainage device may disrupt the integrity of the pia mater, providing a seeding route for melanoma cells. This may result in subsequent positive CSF cytology. Prompt surgical intervention for tissue biopsy early in our patient’s case was important in making the final diagnosis. Herein, we present a case of primary leptomeningeal melanoma that mimicked meningitis. Serial examinations, including laboratory tests and imaging studies, favored a diagnosis of meningitis. Because the symptoms were refractory to standard treatment for meningitis, open meningeal biopsy was performed, facilitating an accurate diagnosis. When faced with ambiguous results from diagnostic tests and treatment failure for a presumptive diagnosis of meningitis, direct surgical intervention should be considered for pathologic diagnosis of primary leptomeningeal melanoma.
Yao-Yu Hsieh, Shun-Tai Yang, Wei-Hua Li, Chaur-Jong Hu, and Liang-Shun Wang Taipei Medical University Shuang-Ho Hospital, New Taipei City, Taiwan
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Schreiber D, Janisch HGW (eds): Neuropathologie: Tumoren des Nervensystems [in German]. Gustav Fischer, Stuttgart, Germany, 1988, pp 347-353 2. Rosenthal G, Gomori JM, Tobias S, et al: Unusual cases involving the CNS and nasal sinuses: Case 1—Primary leptomeningeal melanoma. J Clin Oncol 21:3875-3877, 2003 3. Schneider F, Putzier M: Primary leptomeningeal melanoma. Spine (Phila Pa 1976) 27:E545-E547, 2002 4. Kounin GK, Romansky KV, Traykov LD, et al: Primary spinal melanoma with bilateral papilledema. Clin Neurol Neurosurg 107:525-527, 2005 5. Sagiuchi T, Ishii K, Utsuki S, et al: Increased uptake of technetium-99mhexamethylpropyleneamine oxime related to primary leptomeningeal melanoma. AJNR Am J Neuroradiol 23:1404-1406, 2002 6. Hayward RD: Malignant melanoma and the central nervous system: A guide for classification based on the clinical findings. J Neurol Neurosurg Psychiatry 39:526-530, 1976 7. Weindling SM, Press GA, Hesselink JR: MR characteristics of a primary melanoma of the quadrigeminal plate. AJNR Am J Neuroradiol 9:214-215, 1988 8. Atlas SW, Grossman RI, Gomori JM, et al: MR imaging of intracranial metastatic melanoma. J Comput Assist Tomogr 11:577-582, 1987 9. Hoffman HJ, Freeman A: Primary malignant leptomeningeal melanoma in association with giant hairy nevi. J Neurosurg 26:62-71, 1967 10. Tosaka M, Tamura M, Oriuchi N, et al: Cerebrospinal fluid immunocytochemical analysis and neuroimaging in the diagnosis of primary leptomeningeal melanoma: Case report. J Neurosurg 94:528-532, 2001
DOI: 10.1200/JCO.2013.50.0264; published online ahead of print at www.jco.org on March 17, 2014 ■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e61
