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Utility of flow cytometry of cerebrospinal fluid as a screening tool in the diagnosis of central nervous system lymphoma.

Involvement of the central nervous system (CNS) by lymphoma, whether primary or systemic, is uncommon but has a dismal prognosis. (1) Primary CNS lymphoma accounts for ~3% of all primary CNS tumors and can involve the brain, leptomeninges, spinal cord, and eyes. (2,3) Human immunodeficiency virus infection is an established risk factor for developing this type of lymphoma. (4) Secondary CNS involvement occurs in approximately 5% of patients with non-Hodgkin lymphoma and may present synchronously to the initial lymphoma diagnosis, as a relapse, or during the course of progressive disease. Non-Hodgkin lymphoma may involve the CNS either by forming intraparenchymal masses or, more commonly, by infiltrating the leptomeninges. (5) The incidence of secondary involvement varies with the aggressiveness of the lymphoma, and ranges from 3% for indolent lymphomas to 27% for high-grade lymphomas. (1) Given the potential side effects of intrathecal chemotherapy and CNS irradiation for CNS lymphoma, the diagnosis needs to be unequivocal. (6)

Although long regarded as the gold standard for diagnosing CNS lymphoma, cytologic examination of cerebrospinal fluid (CSF) yields a low sensitivity with a false-negative rate between 20% and 60%. (1) Paucity of lymphoma cells due to small sample size, difficulties differentiating lymphoma cells from reactive CSF lymphocytes, frequent upfront use of corticosteroids in symptomatic patients, and inability to sample near the anatomic location of the lymphoma all contribute to the poor sensitivity. (7) Recent studies have shown that CSF flow cytometry greatly improves the diagnostic accuracy of CNS involvement by lymphoma, a technique that can detect clonal B cells at as low as 0.9%, compared with a sensitivity of 5% by morphology alone. (8-10) In patients with high clinical suspicion for CNS lymphoma, submission of CSF for both cytology and flow cytometry analysis (FCA) is now recommended by the National Comprehensive Cancer Network. (3) Neurologic symptoms often prompt the clinician to order multiple and simultaneous diagnostic tests to determine the etiology of CNS lymphoma in a timely manner. Consequently, at our institution, FCA of CSF has become a routine screening method in the workup of patients with altered mental status, even when CNS lymphoma ranks low on the list of potential etiologies.

Understanding that this procedure is likely considered beneficial for the patient (fewer lumbar punctures, quicker diagnosis, etc), we set out to assess the utility of flow cytometry in an unselected patient population with neurologic symptoms, including patients with no history of lymphoma or no radiologic findings. We chose to compare the findings of FCA and cytology to histology from a brain biopsy as well as to clinical follow-up, where available. Finally, we describe the most appropriate clinical circumstances that may justify simultaneous ordering of both cytology and flow cytometry over the more-traditional approach of cytology evaluation alone.

MATERIALS AND METHODS

Case Selection

The study protocol was reviewed and approved by the Institutional Review Board of Washington University (St Louis, Missouri). For this retrospective cohort study, a search of the database of the Division of Anatomic and Molecular Pathology at the Washington University School of Medicine was conducted for all CSF samples sent for FCA between June 2001 and June 2011, for which clinicians had requested a lymphoma screen. A total of 501 samples from 373 patients met the inclusion criteria. Cerebrospinal fluid samples that had been obtained during the same procedure and sent for cytologic examination were matched to the samples submitted for flow cytometry using the pathology database. Clinical and pathology records were reviewed retrospectively to collect data on patient age, medical history, radiologic imaging studies, final pathologic diagnosis, and subsequent clinical management.

Flow Cytometry and Cytology of CSF

Before July 5, 2008, flow cytometric analysis was run on a CSF sample only if the cell count was greater than 0.1 x [10.sup.6]/[mu]L. Instead, a Wright-Giemsa-stained cytospin was prepared for morphologic evaluation. After that date, FCA was attempted on all CSF specimens regardless of the cell count.

Specimens submitted to rule out "lymphoma" received a 5-color staining (FITC/PE/ECD/PC5/PC7) screening monoclonal antibody combination of s[lambda]/s[kappa]/sCD3/CD10/CD19. If the cell count was less than 0.1 x [10.sup.6]/[mu]L, no additional tubes were prepared for more complete immunophenotyping. With a cell count between 0.1 and 0.4 x [10.sup.6]/[mu]L, an additional tube, besides the screening tube, was prepared for more complete immunophenotyping. If a clonal B-cell population was detected, CD5, CD23, and CD20 were added to the panel. If a mature T-cell lymphoma or acute lymphoblastic leukemia/lymphoma was suspected, the panel could be expanded to include some of the T-cell or blast markers: CD1, CD2, CD4, CD5, CD7, CD8, CD30, CD56/CD16, TCR [alpha]/[beta], TCR[gamma]/[delta], TdT, or CD34. A cell count of 1 x [10.sup.6]/[mu]L or greater yielded a total of 6 tubes for flow cytometry and provided the opportunity for the most complete antibody panels when indicated.

In patients with a history of lymphoma, other than mature B-cell lymphoma, the initial 5-color s[lambda]/s[kappa]/sCD3/CD10/CD19 antibody screen was foregone, and antibodies were picked according to the diagnostic immunophenotype.

In general, results of less than 100 events in the gate of interest were not reported, and the sample was regarded as having "too few cells" for analysis. Additionally, cases with "too few B cells for clonality studies" were also grouped into the too-few-cells category for the purposes of this analysis, given that a definitive negative or positive diagnosis could not be rendered.

The primary hematopathologist interpreted the flow cytometry of the CSF, as well as a Wright-Giemsa-stained cytospin prepared from any remaining CSF fluid. The cytopathologist signed out the cytology report on the corresponding sample sent to cytopathology for Diff-Quik Stain Set (Siemens Healthcare Diagnostic, Deerfield, Illinois) preparation. Cytology diagnoses were benign in origin when designated "negative" or atypical, favor benign." A cytology designation of "suspicious" implied highly worrisome for lymphoid malignancy.

Statistical Analysis

Statistical analyses were performed using SPSS (Version 20; Chicago, Illinois). For categoric variables, the [[chi].sup.2] test or Fisher exact test was used. For continuous variables, the Student t test or Kruskall-Wallis test was used. All the statistical analyses were 2-sided, and P [less than or equal to] .05 was considered statistically significant.

RESULTS

Patient Characteristics

From June 2001 to June 2011, 373 patients had CSF samples submitted to pathology. Characteristics of the study population are presented in Table 1. Most of the patients presented with neurologic symptoms (78%; 291 of 373), whereas almost one-third of patients had a known history of hematologic malignancy. Brain imaging before lumbar puncture was performed in 93% (347 of 373) of the cases, and 51% (179 of 347) of those patients had abnormal imaging findings.

Flow Cytometry Results From CSF Samples

Overall, 501 CSF samples were received for immunophenotypic evaluation. The demand for flow cytometric analysis remained relatively low from 2001 to 2005 (average, ~13 cases/y submitted for analysis) but steadily increased from 2006 onward, with 149 of the 501 CSF samples (30%) submitted for FCA in 2010 alone. For most CSF samples (491 of 501; 98%) a B-cell screen was requested (Figure 1, A). A T-cell panel was performed in only 25 of the 501 samples (5%). As expected, with our policy change of performing flow cytometry on all CSF samples after June 2008 regardless of the cell count, the number of cases that were given the designation too few cells for flow cytometry" decreased (2007, 23 of 32; 74%; 2010, 39 of 148; 27%).

[FIGURE 1 OMITTED]

A lymphoid malignancy was detected by flow cytometry in 21 of 501 CSF samples (4%) from 14 of 373 patients (4%). All cases (100%) represented a B-cell malignancy. Six of these 14 patients (43%; 13 of 21 samples; 62%) were diagnosed with primary CNS lymphoma; of which, 5 of the 6 patients (83%) had large B-cell lymphoma, and one patient (17%) an extranodal, marginal zone B-cell lymphoma (Figure 1, B). A positive flow-cytometry diagnosis was more likely in patients with either histories of a hematologic malignancy or findings suspicious for CNS disease by imaging (P = .009). Flow cytometry analysis results by patient history or imaging are given in Figure 2.

[FIGURE 2 OMITTED]

Multiple flow samples were sent on the same patient in 80 of 373 cases (21%), for a total of 208 of the 501 samples (42%). In this group, 6 of the 80 patients (8%) had at least one positive result. Three of the 6 positive diagnoses (50%) were given on the first sample. Two of the 6 positive diagnoses (33%) were on the second flow sample, each of which was submitted within 1 month of the first. In those cases, the first flow diagnosis had been too few cells for flow cytometry." One patient (17%) was given a positive flow diagnosis on the third flow sample; however, that sample was drawn 1 year after the second. Again, the initial flow diagnoses had been too few cells." Overall, of the 14 patients who had a positive flow diagnosis, 11 (79%) were diagnosed on the first flow test, whereas 3 (21%) required additional testing after the first samples had too few cells.

[FIGURE 3 OMITTED]

Roughly, 19% of CSF samples (95 of 501) submitted for flow cytometry were shown to have a polytypic B-cell population. The mean CD19:CD3 ratio (0.48) of the 21 lymphoma cases (4%) was significantly higher than the mean CD19:CD3 ratio (0.09) of the polytypic cases (P = .001). None (0%) of the 25 T-cell panels revealed an overtly abnormal T-cell population.

Cytology Results From CSF Samples

Concurrent but independent cytologic evaluation by a cytopathologist was performed on 424 of 501 samples (85%) (Figure 3, A). Of the 77 samples that underwent FCA only, 27 samples (35%) were follow-up from patients with recent flow cytometry and cytology of a CSF sample, 7 samples (9%) were from patients after intrathecal chemotherapy, and 43 samples (56%) were not sent to cytology for unspecified clinical reasons.

Thirty-five of the 424 cases (8%) were interpreted as positive or suspicious for involvement by a lymphoid malignancy (Figure 3, A and B; Table 2). Within these 35 cases, cytologic examination was able to detect 13 lymphoid malignancies (37%) that were not detected by flow cytometry (either too few cells for meaningful analysis [10 of 13 samples; 77%] or were negative for malignancy [3 of 13 samples; 23%]). Cytologic examination also provided false-positive results in 8 of the 373 patients (2%) with no history of a hematologic malignancy, whose altered mental status was due to benign causes. False-negative results occurred in 17 of 373 patients (3%); of which, 16 of the 17 (94%) had a history of lymphoma and/or abnormal radiologic findings (Table 2). Unlike the FCA cases, a positive cytologic diagnosis was not dependent on the patients' history or radiologic findings (P = .51).

Additionally, of the 373 patients, 102 (27%), who had no history of lymphoma and no suspicious radiologic findings, had 116 negative cytology samples (23%). None (0%) of the 116 samples had a correspondingly positive flow cytometry. Only one of these patients (0.8%) was later diagnosed with a primary CNS lymphoma, and that diagnosis was made on tissue histology after 2 negative FCA, one insufficient FCA, and one negative cytology.

Brain Biopsy Results and Predictive Values

Finally, 65 of the 373 patients (17%) underwent brain biopsy, and an additional 14 patients (4%) were found to have lymphomatous involvement of the CNS that had not been detected by either FCA or cytologic examination (Table 2).

Of the 65 patients (17%) who underwent a brain biopsy, the positive predictive value (PPV) and negative predictive value (NPV) of cytology alone were 50% and 72%, respectively. With combined cytology and flow cytometry studies, where one or both were positive, the PPV increased to 92%, but the NPV was only 52%. Patients with either a history of lymphoma and/or suspicious findings on brain imaging were more likely to have a positive FCA or brain biopsy (P < .001). When limited to this higher-risk population, the positive and negative predictive values were 92% and 89%, respectively.

Clinical Follow-up and Predictive Values

Clinical follow-up was available in 306 of the 373 patients (82%). Looking at all 306 patients, the PPV and NPV of combined cytology and flow cytometry were 79% and 89%, respectively. When limited to the higher-risk population (patients with either a history of lymphoma and/or suspicious radiologic findings) the PPV increased to 89% and the NPV remained stable at 86%.

COMMENT

Patients with lymphoma of the CNS, whether primary or secondary, have decreased overall survival when matched to patients with extracerebral lymphoma only, even when the CNS disease has not yet manifested itself through symptoms. (7,11) Although the numbers of patients with primary and secondary CNS lymphomas are relatively small, the poor outcome of this group rightly gives rise to research focusing on improved detection and treatment of CNS disease. (12) Flow cytometry has established itself as a valuable tool in complementing cytology in the detection of hematologic malignancies, especially in secondary CNS lymphoma, where leptomeningeal involvement is more common than parenchymal involvement and, hence, more accessible to lumbar puncture. (5) Hedge et al (9) detected occult leptomeningeal disease by flow cytometry in 11 of the 51 newly diagnosed, aggressive B-cell lymphomas (22%), whereas only 1 of the 51 (2%) was picked up by conventional cytology (P = .002). Similarly, Quijano et al (13) demonstrated that flow cytometry was able to identify leptomeningeal involvement by aggressive B-cell lymphoma in 27 of 123 patients (22%), whereas cytology was positive in only 7 of those 27 cases (26%). Bromberg et al (8) expanded their analysis to also include patients with a known myeloid malignancy. The sensitivity of flow cytometry in the detection of leptomeningeal disease was 2 to 3 times greater than that of cytology alone, and nearly 50% of leptomeningeal involvement was diagnosed by flow cytometry in the absence of positive cytology.

[FIGURE 4 OMITTED]

Although most of the published studies comparing cytology and flow cytometry in the detection of CNS lymphoma focused on the patient group with either history of lymphoma or high clinical suspicion for CNS lymphoma, our study is the largest, to our knowledge, to include a patient population lacking a history or firm clinical suspicion. Flow cytometry has become a routine ancillary tool for the clinicians in the workup of any patient with altered mental status at our hospital. We captured all flow cytometry requests from clinicians where a lymphoma screen had been performed during 10 years and focused on the value of simultaneous cytology and flow cytometry in the patient group where clinical suspicion was low.

Of the 102 patients who had no history of lymphoma and no suspicious radiologic findings, all (100%) had negative CSF cytology samples, and none (0%) of those patients had a correspondingly positive flow cytometry. These results are in concordance with published data from Craig et al (14) and Roma et al, (15) who included flow cytometry results from patients with no history of hematolymphoid malignancy. Craig et al (14) found only 1.4% (1 of 71) of the CSF specimens from these patients to be positive for a malignancy by flow cytometry, and Roma et al (15) reported that only 1 of the 18 patients (6%) with no history had both positive cytology and flow cytometry. (14,15)

Given these findings, Figure 4 offers an algorithm of how to preferentially use flow cytometry in the diagnosis of CNS lymphoma. First, patient history needs to be considered. Certainly, a patient with a known history of lymphoma is at risk for CNS spread, and an immunosuppressed patient is at risk for developing primary CNS lymphoma. However, even in a patient with a history of lymphoma, who now presents with typical clinical and radiologic findings of a cerebrovascular accident, likely does not require flow cytometric studies of the CSF fluid. Second, imaging results need to be incorporated into the assessment. Although less than half of patients with secondary CNS lymphoma show radiologic findings of CNS involvement, patients with primary CNS lymphoma often have discrete lesions. (12,16) In our study, patients with a positive result by flow cytometry or brain biopsy were more likely to have a lymphoma history and/or abnormal radiologic findings (P < .009). Third, only cytology needs to be sent as an initial test on patients where clinical suspicion is low, and then, subsequently, flow cytometry is sent if the pathologic result or the clinical picture evolves. In our study, flow cytometry on CSF samples of patients with negative radiologic findings, negative history of hematologic malignancy, and negative cytology did not add additional clinical information, and was an unnecessary test. In these cases, only when the cytology is interpreted as suspicious for hematologic malignancy will the flow cytometric analysis be more likely to be helpful as an adjunct test. (17) In our study, false-positive results by cytology did occur in 8 of the 373 patients (2%). None had a history of a hematologic malignancy. A positive cytologic result in patients where clinical suspicion is low should prompt a repeat cytology with submission of CSF for flow cytometry to corroborate the potential lymphoma diagnosis.

In our study, open brain biopsy identified an additional 14 of the 373 patients (4%) with lymphomatous involvement of the CNS that was not detected by either FCA or cytologic examination. Furthermore, despite the reported high sensitivity of combined flow cytometry and cytology in high-risk patients, the NPV was only 52% in our study of all patients when compared with open brain biopsy. Almost half of patients with a negative or insufficient flow cytometry and negative cytology results may actually have undetected CNS involvement. Including patients with a low probability of lymphomatous involvement caused a decrease in the overall disease prevalence in our patient population and thereby decreased the value of the test.

The most common disease found on false-negative, follow-up brain biopsy was diffuse large B-cell lymphoma. False-negative results by FCA or cytology may partially be attributed to the location of the lymphoma within the CNS. Whereas secondary CNS lymphoma more commonly involves the leptomeninges, primary CNS lymphoma may present as a parenchymal lesion not shedding malignant cells into the CSF. (3) Still, CSF involvement is common enough in primary CNS lymphomas that both FCA and cytology of CSF are recommended as part of routine workup in these patients. (18)

False-negative results in our study may also have been increased because of the high percentage of specimens classified as too few cells for flow cytometry analysis before July 2008, when analysis was not run on samples with a cell count less than 0.1 x [10.sup.6]. Some of these samples may have provided positive results if tested. Running every CSF sample for flow cytometry at our institution, regardless of the cell count, resulted in a greater proportion of specimens with classified as too few B cells for clonality studies or no B cells in sample. B cells are generally much less frequent in the CSF than are T cells, and, according to the study by Subira et al, (19) B cells could only be reliably detected by flow cytometry if there were more than 5/[mu]L. This highlights flow cytometry as having limited utility in detecting minute B-cell populations, and it may not be particularly helpful for patients with low clinical suspicion of lymphomatous involvement and only few B cells in the CSF.

This study indicates that flow cytometry is useful in the detection of hematologic malignancy in the CSF in the appropriate clinical setting; however, false-negative results can occur even with flow cytometry. Concurrent flow cytometry and cytology specimens are appropriate when clinical history and imaging point to a possible hematologic malignancy, but a stepwise approach is acceptable when clinical suspicion is low.

Caption: Figure 1. A, Flow cytometric assessment for B cells. B, Breakdown of positive results for B-cell lymphoma. Abbreviations: CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; CNS, central nervous system.

Caption: Figure 2. Flow cytometry results by clinical history and imaging. Abbreviations: ALL, acute lymphoblastic leukemia; FCA, flow cytometry analysis.

Caption: Figure 3. A, Cytologic examination for malignancy. B, Breakdown of positive/suspicious results.

Caption: Figure 4. Preferred algorithm for sending cerebrospinal fluid for flow cytometry analysis (FCA) at our institution. Abbreviations: CVA, cerebrovascular accident; LP, lumbar puncture.

This publication was supported by grant P30-CA91842 from the Division of Biostatistics, Alvin J. Siteman Cancer Center, National Cancer Institute, National Institutes of Health (St Louis, Missouri).

References

(1.) Colocci N, Glantz M, Recht L. Prevention and treatment of central nervous system involvement by non-Hodgkin's lymphoma: a review of the literature. Semin Neurol. 2004;24(4):395-404.

(2.) Gerstner ER, Batchelor TT. Primary central nervous system lymphoma. Arch Neurol. 2010;67(3):291-297.

(3.) Brem SS, Bierman PJ, Brem H, et al. National Comprehensive Cancer Network. Central nervous system cancers. J Natl Compr Canc Netw. 2011;9(4): 352-400.

(4.) Chamberlain MC, Nolan C, Abrey LE. Leukemic and lymphomatous meningitis: incidence, prognosis and treatment. J Neuro Oncol. 2005;75(1):71-83.

(5.) Bishop PC, Wilson WH, Pearson D, Janik J, Jaffe ES, Elwood PC. CNS involvement in primary mediastinal large B-cell lymphoma. J Clin Oncol. 1999; 17(8):2479-2485.

(6.) Nagpal S, Glantz MJ, Recht L. Treatment and prevention of secondary CNS lymphoma. Semin Neurol. 2010;30(3):263-272.

(7.) Kiewe P, Fischer L, Martus P, Thiel E, Korfel A. Meningeal dissemination in primary CNS lymphoma: diagnosis, treatment, and survival in a large monocenter cohort. Neuro Oncol. 2010;12(4):409-417.

(8.) Bromberg JEC, Breems DA, Kraan J, et al. CSF flow cytometry greatly improves diagnostic accuracy in CNS hematologic malignancies. Neurology. 2007;68(20):1674-1679.

(9.) Hegde U, Filie A, Little RF, et al. High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology. Blood. 2005;105(2):496-502.

(10.) Finn WG, Peterson LC, James C, Goolsby CL. Enhanced detection of malignant lymphoma in cerebrospinal fluid by multiparameter flow cytometry. Am J Clin Pathol. 1998;110(3):341-346.

(11.) Sancho JM, Orfao A, Quijano S, et al. Clinical significance of occult cerebrospinal fluid involvement assessed by flow cytometry in non-Hodgkin's lymphoma patients at high risk of central nervous system disease in the rituximab era. Eur J Heme. 2010;85(4):321-328.

(12.) Chamberlain MC, Glantz M, Groves MD, Wilson WH. Diagnostic tools for neoplastic meningitis: detecting disease, identifying patient risk, and determining benefit of treatment. Semin Oncol. 2009;36(4)(suppl 2):S35-S45.

(13.) Quijano S, Lopez A, Sancho JM, et al. Identification of leptomeningeal disease in aggressive B-cell non-Hodgkin's lymphoma: improved sensitivity of flow cytometry. J Clin Oncol. 2009;27(9):1462-1469.

(14.) Craig FE, Ohori NP, Gorrill TS, Swerdlow SH. Flow cytometric immunophenotyping of cerebrospinal fluid specimens. Am J Clin Pathol. 2011; 135(1):22-34.

(15.) Roma AA, Garcia A, Avagnina A, Rescia C, Elsner B. Lymphoid and myeloid neoplasms involving cerebrospinal fluid: comparison of morphologic examination and immunophenotyping by flow cytometry. Diagn Cytopathol. 2002;27(5):271-275.

(16.) Abrey LE, Batchelor TT, Ferreri AJM, et al. International Primary CNS Lymphoma Collaborative Group. Report of an International workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005;23(22):5034-5043.

(17.) Schinstine M, Filie AC, Wilson W, Stetler-Stevenson M, Abati A. Detection of malignant hematopoietic cells in cerebral spinal fluid previously diagnosed as atypical or suspicious. Cancer. 2006;108(3):157-162.

(18.) Abrey LE. Primary central nervous system lymphoma. Curr Opin Neurol. 2009;22(6):675-680.

(19.) Subira D, Castanon S, Aceituno E, et al. Flow cytometric analysis of cerebrospinal fluid samples and its usefulness in routine clinical practice. Am J Clin Pathol. 2002;117(6):952-958.

Meredith Pittman, MD; Susan Treese, MT(ASCP); Ling Chen, MSPH, PhD; John L. Prater, MD; TuDung T. Nguyen, MD, PhD; Anjum Hassan, MD; Friederike Kreisel, MD

Accepted for publication November 28, 2012.

From the Department of Pathology and Immunology (Drs Pittman, Treese, Frater, Nguyen, Hassan, and Kreisel) and the Division of Biostatistics (Dr Chen), Washington University School of Medicine, Saint Louis, Missouri.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Friederike Kreisel, MD, Department of Pathology and Immunology, Washington University Medical Center, 660 S Euclid Ave, Campus Box 8118, Saint Louis, MO 63110 (e-mail: fkreisel@path.wustl.edu).
Table 1. Patient Characteristics (n = 373)

Characteristic                               Result, No. (%)

Mean age, y                                    52
Sex
  Men                                         194      (52)
  Women                                       179      (48)
Clinical presentation
  Neurologic symptoms                         291      (78)
  Hematologic malignancy, % of all cases      115      (31)
    Mature B-cell lymphoma, % of               78      (68)
  hematologic malignancies
    Primary central nervous system B-cell      8       (8)
  lymphoma, % of hematologic
  malignancies
    Natural killer/T-cell lymphoma, % of       12      (10)
  hematologic malignancies
    Hodgkin lymphoma, % of                     6       (5)
  hematologic malignancies
    B-cell acute lymphoblastic leukemia,       4       (3)
  % of hematologic malignancies
    T-cell acute lymphoblastic leukemia,       4       (3)
  % of hematologic malignancies
    Plasma cell dyscrasia, % of                3       (3)
  hematologic malignancies
  Immunosuppressed                             45      (12)
Brain imaging                                 347      (93)
  Abnormal findings                           179      (51)
Flow cytometry samples                        501     (100)
Cytology samples                              424      (85)
Brain biopsy samples                           65      (13)

Table 2. All Positive Results, by Flow Cytometry Analysis
(FCA), Cytology, or Open-Brain Biopsy, With Clinical Follow-up

Case
No.     Sex     Clinical                        Imaging

3       56/F    Altered mental status           No lesion

9       66/M    History of "low-grade           Focal lesion
                lymphoma," now with
                neurologic symptoms

13      71/M    History of DLBCL, now           No lesion
                with neurologic
                symptoms

25      64/F    Altered mental status           Diffuse changes

28      46/M    Immunosuppressed, now           Focal lesion
                with neurologic
                symptoms

30      72/M    Altered mental status           Focal lesion

35      21/F    Altered mental status           No lesion

44      66/M    Altered mental status           Focal lesion

46      52/M    History of transformed          No lesion
                follicular lymphoma,
                now with neurologic
                symptoms

50      54/M    New diagnosis of DLBCL          No lesion

51      61/M    Immunosuppressed, now           No lesion
                with neurologic
                symptoms

57      52/F    History of colorectal           Focal lesion
                carcinoma, now with
                neurologic symptoms

                Same patient, 18 mo later       Focal lesion
                with worsening                  (nasopharynx)
                neurologic symptoms

59      62/M    History of CLL/SLL; after       Focal lesion
                bone marrow transplant,
                now with neurologic
                symptoms

60      70/M    Altered mental status           Diffuse changes

68      71/M    History of DLBCL, now           No lesion
                with neurologic
                symptoms

69      86/M    History of mantle cell          No lesion
                lymphoma, now with
                neurologic symptoms

74      71/F    Altered mental status           No lesion

77      72/M    History of B-cell               No lesion
                lymphoma, now with
                neurologic symptoms

78      65/M    History of CLL/SLL, now         Focal lesion
                with neurologic
                symptoms

82      57/M    Altered mental status,          Diffuse changes
                diagnosed with viral
                meningitis at outside
                hospital

                Same patient, 2 mo later        Diffuse changes

                Same patient, 6 mo later (8     Diffuse changes
                mo after initial visit)

                Same patient, 3 mo later        Diffuse changes
                (11 mo after initial visit)

                Same patient, 3 mo later        Diffuse changes
                (1 y, 2 mo after initial
                visit)

                Same patient, 3 mo later        Diffuse changes
                (1 y, 5 mo after initial
                visit)

                Same patient, 3 mo later        Diffuse changes
                (1 y, 8 mo after initial
                visit)

                Same patient, 3 mo later        Diffuse changes
                (1 y, 11 mo after initial
                visit)

95      63/M    Altered mental status           Diffuse changes

98      68/F    Altered mental status           Focal lesion

103     19/F    Altered mental status           Focal lesion

109     60/F    History of lymphoma,            Diffuse changes
                NOS, now with
                neurologic symptoms

111     67/F    Altered mental status           Focal lesion

115     25/M    History of precursor B-cell     Diffuse changes
                lymphoma, after bone
                marrow transplant

117     16/F    Altered mental status           No lesion

123     39/M    Altered mental status,          Diffuse changes
                history of tuberculosis

131     39/F    Altered mental status           No lesion

142     47/M    History of CLL/SLL, now         No lesion
                with neurologic
                symptoms

147     66/F    History of                      No lesion
                lymphoplasmacytic
                lymphoma, now with
                neurologic symptoms

148     23/F    Altered mental status           Focal lesion

154     78/F    History of DLBCL, now           No lesion
                with neurologic
                symptoms

159     69/F    Altered mental status           Diffuse changes

171     42/M    Altered mental status           Diffuse changes

225     24/M    History of ALCL, now with       Diffuse changes
                neurologic symptoms

231     85/M    History of marginal zone        No lesion
                lymphoma, now with
                neurologic symptoms

232     51/M    Altered mental status           Focal lesion

234     54/M    Immunosuppressed with           Diffuse changes
                new diagnosis of Burkitt
                lymphoma

236     68/M    Immunosuppressed with           Focal lesion
                history of NK/T-cell
                lymphoma, now with
                neurologic symptoms

242     36/M    Immunosuppressed, now           Diffuse changes
                with neurologic
                symptoms

260     50/F    New diagnosis of DLBCL          Focal lesion

269     80/F    Altered mental status           Focal lesion

293     40/F    Altered mental status           Focal lesion

321     71/M    History of large cell           Diffuse changes
                lymphoma of vitreous,
                now with neurologic
                symptoms

                Same patient, 5 d later         Diffuse changes

333     60/M    History of B-cell               Diffuse changes
                lymphoma, NOS, now with
                neurologic

348     58/F    symptoms Altered                Diffuse changes
                mental status

365     51/M    Altered mental status           Focal lesion

Case
No.     Sex     Cytology (a)   FCA         Biopsy

3       56/F    Suspicious     Too few     Not performed
                               cells

9       66/M    Negative       Too few     Positive
                               cells

13      71/M    Positive       Positive    Not performed

25      64/F    Negative       Negative    Positive

28      46/M    Negative       Too few     Positive
                               cells

30      72/M    Negative       Too few     Positive
                               cells

35      21/F    Positive       Too few     Not performed
                               cells

44      66/M    Positive       Positive    Not performed

46      52/M    Positive       Too few     Not performed
                               cells

50      54/M    Positive       Too few     Not performed
                               cells

51      61/M    Suspicious     Too few     Not performed
                               cells

57      52/F    Suspicious     Too few     Not performed
                               cells

                Positive       Too few     Positive
                               cells

59      62/M    Negative       Positive    Not performed

60      70/M    Atypical       Too few     Positive
                               cells

68      71/M    Suspicious     Positive    Not performed

69      86/M    Suspicious     Too few     Not performed
                               cells

74      71/F    Negative       Too few     Positive
                               cells

77      72/M    Suspicious     Too few     Not performed
                               cells

78      65/M    Positive       Too few     Not performed
                               cells

82      57/M    Not sent       Positive    Not performed

                Not sent       Positive    Positive

                Negative       Positive    Not performed

                Positive       Positive    Not performed

                Negative       Positive    Not performed

                Positive       Positive    Not performed

                Positive       Positive    Not performed

                Positive       Positive    Not performed

95      63/M    Atypical       Negative    Positive

98      68/F    Negative       Too few     Positive
                               cells

103     19/F    Suspicious     Too few     Negative
                               cells

109     60/F    Positive       Positive    Not performed

111     67/F    Atypical       Too few     Positive
                               cells

115     25/M    Positive       Positive    Not performed

117     16/F    Suspicious     Negative    Not performed

123     39/M    Suspicious     Negative    Not performed

131     39/F    Suspicious     Negative    Not performed

142     47/M    Positive       Positive    Not performed

147     66/F    Negative       Positive    Not performed

148     23/F    Suspicious     Negative    Negative

154     78/F    Positive       Too few     Not performed
                               cells

159     69/F    Suspicious     Positive    Not performed

171     42/M    Suspicious     Positive    Positive

225     24/M    Positive       Too few     Not performed
                               cells

231     85/M    Suspicious     Positive    Not performed

232     51/M    Suspicious     Negative    Not performed

234     54/M    Positive       Too few     Not performed
                               cells

236     68/M    Negative       Too few     Positive
                               cells

242     36/M    Negative       Positive    Not performed

260     50/F    Atypical       Too few     Positive
                               cells

269     80/F    Atypical       Positive    Positive

293     40/F    Atypical       Too few     Positive
                               cells

321     71/M    Suspicious     Too few     Not performed
                               cells

                Suspicious     Negative    Not performed

333     60/M    Suspicious     Negative    Not performed

348     58/F    Negative       Negative    Positive

365     51/M    Atypical       Negative    Positive

Case
No.     Sex     Follow-up

3       56/F    Meningoencephalitis

9       66/M    Treated for CNS
                involvement by
                DLBCL

13      71/M    Treated for CNS
                involvement by
                DLBCL

25      64/F    Treated for CNS
                involvement by
                DLBCL

28      46/M    Treated for CNS
                involvement by
                DLBCL

30      72/M    Treated for CNS
                involvement by
                DLBCL

35      21/F    Aseptic meningitis

44      66/M    Treated for CNS B-cell
                lymphoma, not
                otherwise classified

46      52/M    Treated for CNS
                involvement by
                follicular lymphoma

50      54/M    Treated for CNS
                involvement by
                DLBCL

51      61/M    Altered mental status
                resolved after
                normalization of
                electrolytes

57      52/F    Treated for
                leptomeningeal
                carcinomatosis of
                unknown primary

                Treated for CNS
                involvement by
                nasopharyngeal T-cell
                lymphoma

59      62/M    Lost to clinical follow-up
                before initiating
                treatment

60      70/M    Died from disease
                (DLBCL) before
                treatment initiated

68      71/M    Treated for CNS
                involvement by
                DLBCL

69      86/M    Treated for CNS
                involvement by B-cell
                lymphoma, NOS

74      71/F    Treated for CNS
                involvement by
                DLBCL

77      72/M    Negative PET scan,
                patient not treated

78      65/M    Treated for CNS
                involvement by CLL/
                SLL

82      57/M    Infectious workup with
                repeat lumbar
                puncture and biopsy

                Treated for CNS
                involvement by
                extranodal marginal
                B-cell lymphoma

                Continued intrathecal
                treatment

                Continued intrathecal
                treatment

                Continued intrathecal
                treatment

                Continued intrathecal
                treatment

                Continued intrathecal
                treatment

                Continued intrathecal
                treatment

95      63/M    Treated for CNS
                involvement by B cell
                lymphoma, NOS

98      68/F    Treated for CNS
                involvement by
                DLBCL

103     19/F    Diagnosed with acute
                demyelinating disease

109     60/F    Treated for CNS
                involvement by B-cell
                lymphoma, NOS

111     67/F    Treated for CNS
                involvement by
                DLBCL

115     25/M    Treated for CNS
                involvement by
                precursor B cell
                lymphoblastic
                lymphoma

117     16/F    PET scan and repeat CSF
                cytology normal

123     39/M    Chronic granulomatous
                meningitis

131     39/F    PET scan and all workup
                negative

142     47/M    Treated for CNS
                involvement by CLL/
                SLL

147     66/F    Treated for CNS
                involvement by
                lymphoplasmacytic
                lymphoma

148     23/F    Acute demyelinating
                encephalomyelitis

154     78/F    Treated for CNS
                involvement by
                DLBCL

159     69/F    Treated for CNS
                involvement by B cell
                non-Hodgkin
                lymphoma

171     42/M    Treated for CNS
                involvement by
                DLBCL

225     24/M    Treated for CNS
                involvement by ALCL

231     85/M    Treated for CNS
                involvement by
                marginal zone
                lymphoma

232     51/M    Treated for CNS
                involvement by
                lymphoma, NOS

234     54/M    Treated for CNS
                involvement by Burkitt
                lymphoma

236     68/M    Treated for CNS
                involvement by
                NK/T-cell lymphoma

242     36/M    Died from disease (B-cell
                lymphoma, NOS)
                before treatment
                initiated

260     50/F    Treated for CNS
                involvement by
                DLBCL

269     80/F    Treated for CNS
                involvement by
                DLBCL

293     40/F    Treated for CNS
                involvement by
                DLBCL

321     71/M    Repeat lumbar puncture

                Treated for CNS
                involvement by B cell
                lymphoma, NOS

333     60/M    Died of disease before
                treatment initiated

348     58/F    Treated for CNS
                involvement by
                DLBCL

365     51/M    Treated for CNS
                involvement by
                DLBCL

Abbreviations: ALCL, anaplastic large cell lymphoma;
CLL/SLL, chronic lymphocytic leukemia/small lymphocytic
lymphoma; CNS, central nervous system; CSF, cerebrospinal
fluid; DLBCL, diffuse large B-cell lymphoma; NK/T-cell lymphoma,
natural killer/T-cell lymphoma; NOS, not otherwise
specified; PET, positron emission tomography.

(a) Results considered false positives are shown
in bold. False-negative results are underlined.
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Author:Pittman, Meredith; Treese, Susan; Chen, Ling; Frater, John L.; Nguyen, TuDung T.; Hassan, Anjum; Kre
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Geographic Code:1USA
Date:Nov 1, 2013
Words:5809
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