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A DIFFICULT CASE
A misleading case of CSF cytology: a cautionary tale Thomas Parker,1 Colin Mahoney,1 Deborah Pencharz,2 Kate Cwynarski,3 Rebecca Liu1 1
Department of Neurology, Royal Free Hospital, London, UK 2 Department of Nuclear Medicine, Royal Free Hospital, London, UK 3 Department of Haematology, Royal Free Hospital, London, UK Correspondence to Dr Thomas Parker [email protected] Published Online First 8 April 2014
To cite: Parker T, Mahoney C, Pencharz D, et al. Pract Neurol 2014;14:429–431.
A previously healthy right-handed 48-yearold man presented initially with a 5-day history of progressive left facial weakness. He was diagnosed with Bell’s palsy and discharged home; he fully recovered over 4 weeks. As he presented relatively late, he was not prescribed oral corticosteroids. Six months later, he developed a band of pain radiating around his back that persisted for 2 weeks. There was no radiation down his legs and no bladder or bowel involvement. Several days later he noted lower limb weakness and horizontal diplopia, both of which worsened over 2 months until he re-presented to hospital. On examination, he had impaired upgaze and adduction of his left eye with diplopia, consistent with a partial left third nerve palsy, although at this point he had no ptosis and his pupils were equal and reactive. There was no other cranial nerve involvement, and upper limb examination was normal. Power was reduced (4/5) in all muscle groups in his legs with absent knee and ankle jerks, flexor plantar responses and distal sensory loss to all modalities. Nerve conductions studies showed only bilateral carpal tunnel lesions with normal motor and sensory studies. Electromyography (EMG) suggested a nerve root or upper motor neurone problem with regular firing rates in the weak leg muscles. MR scan of brain and whole spine with gadolinium showed diffuse abnormal enhancement throughout intradural leptomeningeal structures. This was particularly evident around the lumbar expansion and conus medullaris, and to a lesser extent around the cervical cord and lower brainstem. Intracranial enhancement was most obvious within bilateral cisternal segments of the oculomotor and trigeminal nerves (figure 1), and within both internal auditory canals, with involvement of the facial and vestibulocochlear nerves. Lumbar puncture showed strawcoloured cerebrospinal fluid, white cell
count of 111 per mm3 (99% lymphocytes) with a protein 5.37 g/L (0.15– 0.45) and glucose 1.7 mmol/L (serum 5.2 mmol/L); oligoclonal bands were negative. Initial cytology and flow cytometry were negative. The following were normal or negative: cerebrospinal fluid (CSF) viral and mycobacterium PCR, acid-fast bacilli, India ink staining and cryptococcal antigen; serology for HIV, Lyme and Brucella; β-human chorionic gonadotropin, α-fetoprotein, full blood count and serum lactate dehydrogenase. A testicular ultrasound showed multiple areas of reduced echogenicity within both testicles, with no mass effect, making a germ cell neoplasm unlikely. He continued to deteriorate and over 2 weeks developed left-sided ptosis, right hand weakness, dysphonia and dysphagia. Since there was no tissue diagnosis, we requested a PET (positron emission tomography) CT to identify further sites of disease amenable for biopsy. This showed increased tracer uptake bilaterally in the neural exit foramina at C4/C5, C6/C7, C7/ T1 and T1/T2, nerve roots from T11-S1, consistent with the leptomeningeal enhancement seen on MRI. There was marked uptake in the left testicle and heterogeneous abnormally increased uptake in the right testicle. There was also abnormal uptake in the right greater trochanter, both humeral heads and adrenal glands (figure 2 A and B). Given the clinical and radiological findings, we considered lymphoma as a strong possibility. A bone marrow biopsy was normal. A second lumbar puncture showed flow cytometry was again negative. CSF cytological analysis showed numerous small cells resembling lymphoid cells. Immunocytochemical staining was positive for epithelial markers (Cam 5.2, MNF116 and epithelial membrane antigen), suggesting metastatic adenocarcinoma. Clinically, we felt this was unlikely. An open left
Parker T, et al. Pract Neurol 2014;14:429–431. doi:10.1136/practneurol-2014-000840
429
Downloaded from http://pn.bmj.com/ on October 6, 2017 - Published by group.bmj.com
A DIFFICULT CASE nervous system involvement. Following this definitive diagnosis on testicular biopsy, we considered that the positive staining for epithelial markers on cells in CSF cytology probably represented aberrant expression of antigens.
Figure 1 T1-weighted MRI with gadolinium showing oculomotor nerve enhancement.
testicular biopsy showed immunohistochemical features consistent with a B-cell lymphoma, with diffuse infiltration of the interstitium with CD20(+), CD10(+), BCL6 (+), MUM1(+) large atypical lymphoid cells containing pleomorphic nuclei. We subsequently diagnosed primary testicular lymphoma with secondary central
DISCUSSION This case provides an approach for investigating a patient with suspected leptomeningeal disease, with the key learning point being the use and interpretation of CSF cytology. False negative CSF cytology is common and should be repeated if there is a high index of suspicion of a malignant process. To increase the likelihood of a positive result, strategies such as repeated lumbar puncture, large volume samples (greater than 10 mL) and rapid sample processing (within 30 min or fixed in formalin) lead to greater yields.1 However, this case highlights that, more rarely and more crucially, false positives may occur. Although Cam 5.2, MNF116 and epithelial membrane antigen (EMA) positive cells are more typically considered epithelial markers, it was important to marry this with the radiological abnormalities and the high CSF white cell count with 99% lymphocytes, which were more in keeping with a central nervous
Figure 2 (A) MIP (maximum intensity projection) of an 18F-FDG (fludeoxyglucose) PET scan. There is abnormal, increased tracer uptake in the nerve roots of C5-T1 and T11-S1, the adrenal glands bilaterally, the right greater trochanter and both humeral heads. There is also abnormal intensely increased tracer uptake in the left testicle and low-grade, abnormal, heterogeneously increased uptake in the right testicle. (B)Sagittal, fused, PET/CT image showing abnormal increased tracer uptake in the right lumbo-sacral nerve roots.
430
Parker T, et al. Pract Neurol 2014;14:429–431. doi:10.1136/practneurol-2014-000840
Downloaded from http://pn.bmj.com/ on October 6, 2017 - Published by group.bmj.com
A DIFFICULT CASE Table 1
Causes of leptomeningeal enhancement on MRI
Neoplastic
Infections
Inflammation
Traumatic
Leptomeningeal carcinomatosis for example, breast, lung, melanoma, leukaemia, lymphoma, gastrointestinal, genitourinary, sarcoma, primary leptomeningeal gliomatosis Bacterial meningitis Viral meningitis Tuberculosis meningitis Fungal meningitis Neurosyphilis Sarcoidosis Granulomatosis with polyangiitis Langerhans histiocytosis Chemical meningitis (ruptured dermoid) Previous subarachnoid Surgical scarring from previous craniotomy Post lumbar puncture CSF leak
system (CNS) lymphoma than a metastatic adenocarcinoma. It is essential to have careful clinicopathological correlation when interpreting results. We advise caution when interpreting positive staining for epithelial markers on cells in CSF cytology, particularly in the context of a florid lymphocytosis as in our patient. Where possible, a tissue diagnosis should be sought, and ultimately a meningeal biopsy may be required. In our case, we made a histological diagnosis of secondary CNS lymphoma from a biopsy of the primary tumour site. Similarly, this case highlighted that screening tests, such as serum lactate dehydrogenase levels can be normal in lymphoma and do not exclude the diagnosis. Lactate dehydrogenase is an important test because when significantly raised, reflects high cell turnover and can suggest lymphoma. However, in confirmed cases of CNS lymphoma, it is a poor marker of prognosis. A further important lesson is the usefulness of PET/ CT scanning. This can be very useful in locating a primary tumour site or a suitable site for biopsy and, ultimately, can provide a definitive diagnosis. This case highlights an unusual cause of leptomeningeal disease (see table 1 for differential diagnosis). Although CNS lymphoma is well recognised, primary testicular lymphoma with secondary CNS involvement is much rarer and emphasises the importance of considering a primary testicular pathology in any male presenting with diffuse leptomeningeal disease. PET CT scanning, testicular ultrasound and the help of our urology colleagues for testicular biopsy were all crucial in obtaining the diagnosis in this case.
Parker T, et al. Pract Neurol 2014;14:429–431. doi:10.1136/practneurol-2014-000840
CNS lymphoma is an extremely important diagnosis to pursue as there are rapid advances in therapeutics which make it potentially treatable. The British Neuro-Oncology society provides expert guidelines on the diagnosis and treatment of primary CNS lymphoma (http://www.bnos.org.uk/documents/rare_ tumours_guidelines/CNS%20Lymphoma%20Guidelines. pdf). One important management point is to avoid corticosteroids before tissue biopsy, as radiographic resolution of disease can begin within 48 h of treatment, and treatment may interfere with histopathological assessment. It is interesting to hypothesise whether our patient’s presentation and diagnosis might have been delayed had he been given corticosteroids as treatment for the presumed Bell’s palsy at initial presentation. Data on the treatment of secondary CNS lymphoma is limited, and the prognosis is considered poor. However, recent research looking at novel high-dose chemotherapeutic regimens with autologous stem cell transplantation show these to be well tolerated with long-lasting remissions in some patients.2 Our patient has received four cycles of R-IVAC/CODOX-M (rituximab, etoposide, ifosfamide, cytarabine, cyclophosphamide, vincristine, doxorubicin and methotrexate) in addition to intrathecal chemotherapy with complete resolution of his neurological signs. He is now awaiting a BCNU-Thiotepa conditioned autologous haematopoietic stem cell transplant. Contributors TP, CM and RL conceived and initiated this report. TP wrote the paper and all authors commented on drafts, had access to all data, and reviewed the paper. TP, CM, KC and RL managed the patient. DP commented on the radiology images. TP is guarantor. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed. This paper was refereed by Robin Grant from Edinburgh.
REFERENCES 1 Milburn-McNulty P, Michael B, Moxham N, et al. How to do it: how to get the most out of cerebrospinal fluid cytology. Pract Neurol 2012;12:241–3. 2 Korfel A, Elter T, Thiel E, et al. Phase II study of central nervous system (CNS)-directed chemotherapy including high-dose chemotherapy with autologous stem cell transplantation for CNS relapse of aggressive lymphomas. Haematologica 2013;98:364–70.
431
Downloaded from http://pn.bmj.com/ on October 6, 2017 - Published by group.bmj.com
A misleading case of CSF cytology: a cautionary tale Thomas Parker, Colin Mahoney, Deborah Pencharz, Kate Cwynarski and Rebecca Liu Pract Neurol 2014 14: 429-431 originally published online April 8, 2014
doi: 10.1136/practneurol-2014-000840 Updated information and services can be found at: http://pn.bmj.com/content/14/6/429
These include:
References Email alerting service
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This article cites 2 articles, 2 of which you can access for free at: http://pn.bmj.com/content/14/6/429#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections Ophthalmology (130)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
A DIFFICULT CASE
A misleading case of CSF cytology: a cautionary tale Thomas Parker,1 Colin Mahoney,1 Deborah Pencharz,2 Kate Cwynarski,3 Rebecca Liu1 1
Department of Neurology, Royal Free Hospital, London, UK 2 Department of Nuclear Medicine, Royal Free Hospital, London, UK 3 Department of Haematology, Royal Free Hospital, London, UK Correspondence to Dr Thomas Parker [email protected] Published Online First 8 April 2014
To cite: Parker T, Mahoney C, Pencharz D, et al. Pract Neurol 2014;14:429–431.
A previously healthy right-handed 48-yearold man presented initially with a 5-day history of progressive left facial weakness. He was diagnosed with Bell’s palsy and discharged home; he fully recovered over 4 weeks. As he presented relatively late, he was not prescribed oral corticosteroids. Six months later, he developed a band of pain radiating around his back that persisted for 2 weeks. There was no radiation down his legs and no bladder or bowel involvement. Several days later he noted lower limb weakness and horizontal diplopia, both of which worsened over 2 months until he re-presented to hospital. On examination, he had impaired upgaze and adduction of his left eye with diplopia, consistent with a partial left third nerve palsy, although at this point he had no ptosis and his pupils were equal and reactive. There was no other cranial nerve involvement, and upper limb examination was normal. Power was reduced (4/5) in all muscle groups in his legs with absent knee and ankle jerks, flexor plantar responses and distal sensory loss to all modalities. Nerve conductions studies showed only bilateral carpal tunnel lesions with normal motor and sensory studies. Electromyography (EMG) suggested a nerve root or upper motor neurone problem with regular firing rates in the weak leg muscles. MR scan of brain and whole spine with gadolinium showed diffuse abnormal enhancement throughout intradural leptomeningeal structures. This was particularly evident around the lumbar expansion and conus medullaris, and to a lesser extent around the cervical cord and lower brainstem. Intracranial enhancement was most obvious within bilateral cisternal segments of the oculomotor and trigeminal nerves (figure 1), and within both internal auditory canals, with involvement of the facial and vestibulocochlear nerves. Lumbar puncture showed strawcoloured cerebrospinal fluid, white cell
count of 111 per mm3 (99% lymphocytes) with a protein 5.37 g/L (0.15– 0.45) and glucose 1.7 mmol/L (serum 5.2 mmol/L); oligoclonal bands were negative. Initial cytology and flow cytometry were negative. The following were normal or negative: cerebrospinal fluid (CSF) viral and mycobacterium PCR, acid-fast bacilli, India ink staining and cryptococcal antigen; serology for HIV, Lyme and Brucella; β-human chorionic gonadotropin, α-fetoprotein, full blood count and serum lactate dehydrogenase. A testicular ultrasound showed multiple areas of reduced echogenicity within both testicles, with no mass effect, making a germ cell neoplasm unlikely. He continued to deteriorate and over 2 weeks developed left-sided ptosis, right hand weakness, dysphonia and dysphagia. Since there was no tissue diagnosis, we requested a PET (positron emission tomography) CT to identify further sites of disease amenable for biopsy. This showed increased tracer uptake bilaterally in the neural exit foramina at C4/C5, C6/C7, C7/ T1 and T1/T2, nerve roots from T11-S1, consistent with the leptomeningeal enhancement seen on MRI. There was marked uptake in the left testicle and heterogeneous abnormally increased uptake in the right testicle. There was also abnormal uptake in the right greater trochanter, both humeral heads and adrenal glands (figure 2 A and B). Given the clinical and radiological findings, we considered lymphoma as a strong possibility. A bone marrow biopsy was normal. A second lumbar puncture showed flow cytometry was again negative. CSF cytological analysis showed numerous small cells resembling lymphoid cells. Immunocytochemical staining was positive for epithelial markers (Cam 5.2, MNF116 and epithelial membrane antigen), suggesting metastatic adenocarcinoma. Clinically, we felt this was unlikely. An open left
Parker T, et al. Pract Neurol 2014;14:429–431. doi:10.1136/practneurol-2014-000840
429
Downloaded from http://pn.bmj.com/ on October 6, 2017 - Published by group.bmj.com
A DIFFICULT CASE nervous system involvement. Following this definitive diagnosis on testicular biopsy, we considered that the positive staining for epithelial markers on cells in CSF cytology probably represented aberrant expression of antigens.
Figure 1 T1-weighted MRI with gadolinium showing oculomotor nerve enhancement.
testicular biopsy showed immunohistochemical features consistent with a B-cell lymphoma, with diffuse infiltration of the interstitium with CD20(+), CD10(+), BCL6 (+), MUM1(+) large atypical lymphoid cells containing pleomorphic nuclei. We subsequently diagnosed primary testicular lymphoma with secondary central
DISCUSSION This case provides an approach for investigating a patient with suspected leptomeningeal disease, with the key learning point being the use and interpretation of CSF cytology. False negative CSF cytology is common and should be repeated if there is a high index of suspicion of a malignant process. To increase the likelihood of a positive result, strategies such as repeated lumbar puncture, large volume samples (greater than 10 mL) and rapid sample processing (within 30 min or fixed in formalin) lead to greater yields.1 However, this case highlights that, more rarely and more crucially, false positives may occur. Although Cam 5.2, MNF116 and epithelial membrane antigen (EMA) positive cells are more typically considered epithelial markers, it was important to marry this with the radiological abnormalities and the high CSF white cell count with 99% lymphocytes, which were more in keeping with a central nervous
Figure 2 (A) MIP (maximum intensity projection) of an 18F-FDG (fludeoxyglucose) PET scan. There is abnormal, increased tracer uptake in the nerve roots of C5-T1 and T11-S1, the adrenal glands bilaterally, the right greater trochanter and both humeral heads. There is also abnormal intensely increased tracer uptake in the left testicle and low-grade, abnormal, heterogeneously increased uptake in the right testicle. (B)Sagittal, fused, PET/CT image showing abnormal increased tracer uptake in the right lumbo-sacral nerve roots.
430
Parker T, et al. Pract Neurol 2014;14:429–431. doi:10.1136/practneurol-2014-000840
Downloaded from http://pn.bmj.com/ on October 6, 2017 - Published by group.bmj.com
A DIFFICULT CASE Table 1
Causes of leptomeningeal enhancement on MRI
Neoplastic
Infections
Inflammation
Traumatic
Leptomeningeal carcinomatosis for example, breast, lung, melanoma, leukaemia, lymphoma, gastrointestinal, genitourinary, sarcoma, primary leptomeningeal gliomatosis Bacterial meningitis Viral meningitis Tuberculosis meningitis Fungal meningitis Neurosyphilis Sarcoidosis Granulomatosis with polyangiitis Langerhans histiocytosis Chemical meningitis (ruptured dermoid) Previous subarachnoid Surgical scarring from previous craniotomy Post lumbar puncture CSF leak
system (CNS) lymphoma than a metastatic adenocarcinoma. It is essential to have careful clinicopathological correlation when interpreting results. We advise caution when interpreting positive staining for epithelial markers on cells in CSF cytology, particularly in the context of a florid lymphocytosis as in our patient. Where possible, a tissue diagnosis should be sought, and ultimately a meningeal biopsy may be required. In our case, we made a histological diagnosis of secondary CNS lymphoma from a biopsy of the primary tumour site. Similarly, this case highlighted that screening tests, such as serum lactate dehydrogenase levels can be normal in lymphoma and do not exclude the diagnosis. Lactate dehydrogenase is an important test because when significantly raised, reflects high cell turnover and can suggest lymphoma. However, in confirmed cases of CNS lymphoma, it is a poor marker of prognosis. A further important lesson is the usefulness of PET/ CT scanning. This can be very useful in locating a primary tumour site or a suitable site for biopsy and, ultimately, can provide a definitive diagnosis. This case highlights an unusual cause of leptomeningeal disease (see table 1 for differential diagnosis). Although CNS lymphoma is well recognised, primary testicular lymphoma with secondary CNS involvement is much rarer and emphasises the importance of considering a primary testicular pathology in any male presenting with diffuse leptomeningeal disease. PET CT scanning, testicular ultrasound and the help of our urology colleagues for testicular biopsy were all crucial in obtaining the diagnosis in this case.
Parker T, et al. Pract Neurol 2014;14:429–431. doi:10.1136/practneurol-2014-000840
CNS lymphoma is an extremely important diagnosis to pursue as there are rapid advances in therapeutics which make it potentially treatable. The British Neuro-Oncology society provides expert guidelines on the diagnosis and treatment of primary CNS lymphoma (http://www.bnos.org.uk/documents/rare_ tumours_guidelines/CNS%20Lymphoma%20Guidelines. pdf). One important management point is to avoid corticosteroids before tissue biopsy, as radiographic resolution of disease can begin within 48 h of treatment, and treatment may interfere with histopathological assessment. It is interesting to hypothesise whether our patient’s presentation and diagnosis might have been delayed had he been given corticosteroids as treatment for the presumed Bell’s palsy at initial presentation. Data on the treatment of secondary CNS lymphoma is limited, and the prognosis is considered poor. However, recent research looking at novel high-dose chemotherapeutic regimens with autologous stem cell transplantation show these to be well tolerated with long-lasting remissions in some patients.2 Our patient has received four cycles of R-IVAC/CODOX-M (rituximab, etoposide, ifosfamide, cytarabine, cyclophosphamide, vincristine, doxorubicin and methotrexate) in addition to intrathecal chemotherapy with complete resolution of his neurological signs. He is now awaiting a BCNU-Thiotepa conditioned autologous haematopoietic stem cell transplant. Contributors TP, CM and RL conceived and initiated this report. TP wrote the paper and all authors commented on drafts, had access to all data, and reviewed the paper. TP, CM, KC and RL managed the patient. DP commented on the radiology images. TP is guarantor. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed. This paper was refereed by Robin Grant from Edinburgh.
REFERENCES 1 Milburn-McNulty P, Michael B, Moxham N, et al. How to do it: how to get the most out of cerebrospinal fluid cytology. Pract Neurol 2012;12:241–3. 2 Korfel A, Elter T, Thiel E, et al. Phase II study of central nervous system (CNS)-directed chemotherapy including high-dose chemotherapy with autologous stem cell transplantation for CNS relapse of aggressive lymphomas. Haematologica 2013;98:364–70.
431
Downloaded from http://pn.bmj.com/ on October 6, 2017 - Published by group.bmj.com
A misleading case of CSF cytology: a cautionary tale Thomas Parker, Colin Mahoney, Deborah Pencharz, Kate Cwynarski and Rebecca Liu Pract Neurol 2014 14: 429-431 originally published online April 8, 2014
doi: 10.1136/practneurol-2014-000840 Updated information and services can be found at: http://pn.bmj.com/content/14/6/429
These include:
References Email alerting service
Topic Collections
This article cites 2 articles, 2 of which you can access for free at: http://pn.bmj.com/content/14/6/429#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections Ophthalmology (130)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
