Assessment of bone marrow involvement in non‐Hodgkin’s lymphomas: comparison between histology and flow cytometry

Bone marrow (BM) examination is essential in the staging of non‐Hodgkin’s lymphoma (NHL) patients. Few studies have compared BM histologic findings with results of flow cytometric (FC) analysis. We analyzed the incidence and patterns of histologic BM involvement in a series of 753 patients with NHL. For 498 patients, a concurrent FC analysis on BM was available. Histologic involvement was detected at diagnosis in 311/753 (41%) patients. By FC, BM involvement was clearly detected in 150/498 (30%). After excluding 12 cases with equivocal histology, concordance between the two methods was detected in 411 (85%) cases (27% BMB+/FC+; 58% BMB?/FC?), while discordance was present in 75 (15%) (P < 0.001): 58 cases (12%) were BMB+/FC? and 17 (3%) were BMB?/FC+. Discordance was more frequent in FL and in lymphoplasmacytic lymphoma (LPL). These data demonstrate that the two methods are comparable in qualitative assessment of BM involvement in NHL, with the exception of FL and LPL. In FL, diffuse large B‐cell lymphoma (DLBCL) and LPL, FC underestimates the extent of infiltrate with respect to histology.     

Diagnosis of leptomeningeal disease in diffuse large B‐cell lymphomas of the central nervous system by flow cytometry and cytopathology

Reliable detection of leptomeningeal disease has the potential of facilitating the diagnosis of central nervous system (CNS) lymphoma and is important for therapeutic considerations. Currently, the standard diagnostic procedure for the detection of lymphoma in the cerebrospinal fluid is cytopathology. To improve the limited specificity and sensitivity of cytopathology, flow cytometry has been suggested as an alternative. Here, we evaluated multi‐parameter flow cytometry in combination with conventional cytopathology in cerebrospinal fluid (CSF) samples from 30 patients with primary CNS lymphoma and seven patients with secondary CNS lymphoma. Overall, in 11 of 37 (29.7%) patients with CNS lymphoma, lymphoma cells were detected in CSF by flow cytometry, while cytopathology was less sensitive displaying unequivocally malignant CSF cells in only seven of all 37 (18.9%) patients. Six (16.2%) patients showed cytopathological results suspicious of lymphoma; however, in only one of these patients, the diagnosis of CSF lymphoma cells could be confirmed by flow cytometry. In primary CNS lymphomas (PCNSL), seven of 30 (23.3%) patients were positive for CSF lymphoma cells in flow cytometry, in contrast to four (13.3%) patients with PCNSL with definitely positive cytopathology. In summary, our results suggest that multi‐parameter flow cytometry increases the sensitivity and specificity of leptomeningeal disease detection in CNS lymphomas. Both methods should be applied concurrently for complementary diagnostic assessment in patients with CNS lymphoma.     

Standardised uptake value of 18F‐FDG on staging PET/CT in newly diagnosed patients with different subtypes of non‐Hodgkin’s lymphoma

Objectives: Positron emission tomography using 2‐[fluorine‐18]‐fluoro‐2‐deoxy‐d ‐glucose (¹⁸F‐FDG) is considered to be the most beneficial imaging method for staging patients with non‐Hodgkin’s lymphoma (NHL). The intensity of ¹⁸F‐FDG accumulation may be determined by calculating the so‐called standardised uptake value (SUV). The study aimed at assessing the benefit of SUV_max determination in staging ¹⁸F‐FDG PET/CT in untreated patients with NHL. Methods: One hundred and forty‐nine initial staging ¹⁸F‐FDG PET/CT scans performed in patients with NHL between January 2007 and August 2009 were assessed, and the SUV_max was determined. Results: The highest mean and median values of SUV_max were observed in patients with diffuse large B‐cell lymphoma (DLBCL), the lowest mean and median values were found in small lymphocytic lymphoma. The overlap in SUV_max < 10 between DLBCL and the other subgroups of NHL was very significant. Statistically, no correlation was found between the lactate dehydrogenase and SUV_max values. On the other hand, a correlation of the Ki‐67 proliferative index of tumour cells and SUV_max was revealed (r = 0.409, P < 0.001). The geometric mean of SUV_max in patients with Ki‐67 ≤ 60 and those with Ki‐67 > 60 was 8.8 and 14.3, respectively (P < 0.001). Conclusions: The results confirm that SUV_max is not beneficial for making a more precise diagnosis in most patients with NHL. Correlation of SUV_max with the Ki‐67 values suggests that SUV_max might have a prognostic values in NHL.     

Natural killer (NK) cell leukaemia in a patient with a B cell non‐Hodgkin’s lymphoma

Summary We describe a 74‐year‐old woman with the diagnosis of natural killer (NK)‐cell leukaemia and autoimmune pathology. Four years previously, a diffuse large B cell non‐Hodgkin’s lymphoma had been diagnosed and treated effectively. Although NK‐cell leukaemia has been thought to be a distinct highly aggressive clinicopathological entity, our case shows no further evolution at the present time. As far as we know, this association has not been previously described in the literature.     

Diffuse large B‐cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era

The addition of rituximab has improved outcomes in diffuse large B‐cell lymphoma (DLBCL ), however, there remains limited information on the impact of rituximab in those with testicular involvement. All patients with diffuse large cell lymphoma and testicular involvement treated with curative intent were identified in the British Columbia Cancer Agency Lymphoid Cancer Database. In total, 134 patients diagnosed between 1982 and 2015 with diffuse large cell lymphoma involving the testis were identified: 61 received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)‐like chemotherapy and 73 received CHOP plus rituximab (R‐CHOP ). A greater proportion of R‐CHOP treated patients had higher International Prognostic Index (IPI , P  =  0·005). In multivariate analysis, the protective effect of rituximab on progression‐free survival (hazard ratio (HR ) 0·42, P  <  0·001), overall survival (HR 0·39, P  <  0·001) and cumulative incidence of progression (HR 0·46, P  =  0·014) were independent of the IPI . However, in a competing risk multivariate analysis including central nervous system (CNS ) prophylaxis and the CNS ‐IPI , rituximab was not associated with a decreased risk of CNS relapse. The addition of rituximab has reduced the risk of lymphoma recurrence in testicular DLBCL , presumably through improved eradication of systemic disease. However, CNS relapse risk remains high and further studies evaluating effective prophylactic strategies are needed.     

Central nervous system involvement in AIDS‐related lymphomas

Central nervous system (CNS) involvement is reportedly more common in acquired immunodeficiency syndrome (AIDS)‐related lymphomas (ARL). We describe factors and outcomes associated with CNS involvement at baseline (CNS^B) and relapse (CNS^R) in 886 patients with newly diagnosed ARL. Of 886 patients, 800 received either intrathecal (IT) therapy for CNS^B or IT prophylaxis. CNS^B was found in 13%. CNS^B was not associated with reduced overall survival (OS). There was no difference in the prevalence of CNS^B between the pre‐combination antiretroviral therapy (cART) and cART eras. 5·3% of patients experienced CNS^R at a median of 4·2 months after diagnosis (12% if CNS^B; 4% if not). Median OS after CNS^R was 1·6 months. On multivariate analysis, only CNS^B [hazard ratio (HR) 3·68, P = 0·005] and complete response to initial therapy (HR 0·14, P < 0·0001) were significantly associated with CNS^R. When restricted to patients without CNS^B, IT CNS prophylaxis with 3 vs. 1 agent did not significantly impact the risk of CNS^R. Despite IT CNS prophylaxis, 5% of patients experienced CNS^R. Our data confirms that CNS^R in ARL occurs early and has a poor outcome. Complete response to initial therapy was associated with a reduced frequency of CNS^R. Although CNS^B conferred an increased risk for CNS^R, it did not impact OS.     

Evaluation of cerebrospinal fluid EBV-DNA and IL-10 as markers for in vivo diagnosis of AIDS-related primary central nervous system lymphoma

Summary. Acquired immunodeficiency syndrome (AIDS)-related primary central nervous system lymphoma (PCNSL) is almost always associated with the Epstein-Barr virus (EBV), and EBV-DNA in cerebrospinal fluid (CSF) has been indicated as a useful tumour marker for this HIV-related neoplasm. AIDS lymphomas also show an enhanced production of IL-10 which is generally associated with the presence of EBV in lymphoma cells. We performed a prospective study in 19 HIV seropositive patients with brain mass lesions, and in 21 other AIDS patients with or without other neurological disorders, to assess the in vivo diagnostic value of EBV-DNA and of IL-10 levels in the CSF for primary lymphoma of the central nervous system (CNS). EBV-DNA was detected by a nested polymerase chain reaction (PCR) in the CSF from seven of eight patients with PCNSL, diagnosed by brain biopsy (875% sensitivity) and in none of the 11 controls with brain mass lesions (100% specificity) and of the other 21 AIDS patients with or without neurological disorders. The only patient with PCNSL without detectable EBV-DNA in the CSF was also negative for EBV-DNA in the lymphoma tissue, whereas the samples of the other seven brain lymphomas were all positive for EBV-DNA by nested PCR. Therefore 100% of patients with an EBV-positive primary CNS lymphoma had detectable EBV-DNA in the CSF. No patient from the control group without PCNSL with EBV-negative CSF developed a lymphoma after a mean follow-up of 157 ± 173 d. IL-10 levels in the CSF from the patients with PCNSL were not significantly different from those in the other groups of patients with AIDS. Due to uniformly high levels in the CSF from AIDS patients, IL-10 is not a useful diagnostic marker for AIDS-related brain lymphoma. The detection of EBV-DNA from the CSF by nested PCR is an extremely sensitive and specific diagnostic tool for AIDS-related PCNSL and should be further evaluated as a possible alternative in patients from whom brain biopsy is not advisable.     

Guideline on the prevention of secondary central nervous system lymphoma: British Committee for Standards in Haematology

The guideline group was selected to be representative of UK‐based medical experts. Ovid MEDLINE, EMBASE and NCBI Pubmed were searched systematically for publications in English from 1980 to 2012 using the MeSH subheading ‘lymphoma, CNS’, ‘lymphoma, central nervous system’, ‘lymphoma, high grade’, ‘lymphoma, Burkitt's’, ‘lymphoma, lymphoblastic’ and ‘lymphoma, diffuse large B cell’ as keywords, as well as all subheadings. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato‐oncology Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of ~50 UK haematologists, the BCSH and the British Society for Haematology (BSH) Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the optimal prevention of secondary central nervous system (CNS) lymphoma. The guidance may not be appropriate to patients of all lymphoma sub‐types and in all cases individual patient circumstances may dictate an alternative approach. Acronyms are defined at time of first use.     

Similar chemokine receptor profiles in lymphomas with central nervous system involvement – possible biomarkers for patient selection for central nervous system prophylaxis,a retrospective study

Central nervous system (CNS) relapse occurs in around 5% of diffuse large B‐cell lymphoma (DLBCL) cases. No biomarkers to identify high‐risk patients have been discovered. We evaluated the expression of lymphocyte‐guiding chemokine receptors in systemic and CNS lymphomas. Immunohistochemical staining for CXCR4, CXCR5, CCR7, CXCL12, and CXCL13 was performed on 89 tissue samples, including cases of primary central nervous system lymphoma (PCNSL), secondary CNS lymphoma (sCNSL), and systemic DLBCL. Also, 10 reactive lymph node samples were included. Immunoelectron microscopy was performed on two PCNSLs, one sCNSL, one systemic DLBCL, and one reactive lymph node samples, and staining was performed for CXCR4, CXCR5, CXCL12, and CXCL13. Chi‐square test was used to determine correlations between clinical parameters, diagnostic groups, and chemokine receptor expression. Strong nuclear CXCR4 positivity correlated with systemic DLBCL, whereas strong cytoplasmic CXCR5 positivity correlated with CNS involvement (P = 0.003 and P = 0.039). Immunoelectron microscopy revealed a nuclear CXCR4 staining in reactive lymph node, compared with cytoplasmic and membranous localization seen in CNS lymphomas. We found that CNS lymphoma presented a chemokine receptor profile different from systemic disease. Our findings give new information on the CNS tropism of DLBCL and, if confirmed, may contribute to more effective targeting of CNS prophylaxis among patients with DLBCL.     

Central nervous system involvement in diffuse large B‐cell lymphoma

Background: Malignant lymphoma with central nervous system (CNS) involvement has an extremely poor prognosis. We retrospectively studied the risk factors for CNS involvement in patients with diffuse large B‐cell lymphoma (DLBCL) treated by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab (R) ‐CHOP chemotherapy. Patients and methods: We studied 375 consecutive patients who were newly diagnosed with DLBCL between 1996 and 2006. Patients with primary CNS involvement and patients who received CNS prophylaxis were excluded. All the patients received CHOP (n = 172) or R‐CHOP (n = 203) chemotherapy. The following variables were assessed for their potential to predict CNS involvement: gender, age, serum lactate dehydrogenase (LDH) level, performance status, clinical stage, number of extranodal involvements, International Prognostic Index (IPI), bone marrow involvement, presence of a bulky mass, presence of B symptom, and treatment. Results: CNS involvement was observed in 13 cases (3.5%). In univariate analysis, LDH more than normal range, LDH more than twice as normal range, high IPI, bone marrow involvement, and systemic relapse were the predictors for CNS involvement. In multivariate analysis, no risk factors were detected for CNS involvement. The use of rituximab did not have an impact on CNS involvement. Conclusions: The incidence of CNS involvement dose not decrease in rituximab‐era.     

Autologous haematopoietic cell transplantation for non‐Hodgkin lymphoma with secondary CNS involvement

Pre‐existing central nervous system (CNS) involvement may influence referral for autologous haematopoietic cell transplantation (AHCT) for patients with non‐Hodgkin lymphoma (NHL). The outcomes of 151 adult patients with NHL with prior secondary CNS involvement (CNS⁺) receiving an AHCT were compared to 4688 patients without prior CNS lymphoma (CNS^?). There were significant baseline differences between the cohorts. CNS⁺ patients were more likely to be younger, have lower performance scores, higher age‐adjusted international prognostic index scores, more advanced disease stage at diagnosis, more aggressive histology, more sites of extranodal disease, and a shorter interval between diagnosis and AHCT. However, no statistically significant differences were identified between the two groups by analysis of progression‐free survival (PFS) and overall survival (OS) at 5 years. A matched pair comparison of the CNS⁺ group with a subset of CNS^? patients matched on propensity score also showed no differences in outcomes. Patients with active CNS lymphoma at the time of AHCT (n = 55) had a higher relapse rate and diminished PFS and OS compared with patients whose CNS lymphoma was in remission (n = 96) at the time of AHCT. CNS⁺ patients can achieve excellent long‐term outcomes with AHCT. Active CNS lymphoma at transplant confers a worse prognosis.     

Presence of antibodies in the aqueous humour and cerebrospinal fluid during Leishmania infections in dogs. Pathological features at the central nervous system

In the present paper we show that in dogs, naturally infected with Leishmania infantum , the aqueous humour and the cerebrospinal fluid contain anti- Leishmania IgGs and that the specificity of antigen recognition of these fluids is similar to that of the sera. We also show that in the encephalon and cerebellum of these dogs there is a pathological sponge-like reaction accompanied by neuronal degeneration, mobilization of glial cells together with accumulation of amyloid deposits. The interstitial and intravascular deposition of IgGs and Leishmania antigens in choroid plexus suggest that in these animals there is a failure of the blood-cerebrospinal and ciliary bodies filtration barriers which may allow the transfer of anti- Leishmania IgGs from the blood stream to these fluids. We suggest that the failure of the blood-cerebrospinal barrier and the in situ concentration of anti- Leishmania IgGs and antigens in brain tissues may predispose to the pathological features detected in this compartment.     

Cerebrospinal fluid soluble programmed death-ligand 1 is a useful prognostic biomarker in primary central nervous system lymphoma

The increased expression of programmed death-ligands 1 and 2 (PD-L1 and PD-L2, respectively) on tumour cells contributes to immune evasion, suggesting that these proteins are attractive therapeutic targets. This study aimed to evaluate the validity of cerebrospinal fluid (CSF) soluble PD-L1 (sPD-L1) and soluble PD-L2 (sPD-L2) as biomarkers for primary central nervous system lymphoma (PCNSL). We determined the CSF concentrations of sPD-L1 and sPD-L2 in 46 patients with PCNSL using enzyme-linked immunosorbent assays (ELISAs). A control group comprised 153 patients with other brain tumours, inflammatory/infectious status, or neurodegenerative diseases. Only CSF sPD-L1 levels were significantly higher in patients with PCNSL relative to the controls. CSF sPD-L1 also exhibited superior overall discrimination performance compared to CSF sPD-L2 in diagnosing PCNSL. Compared with patients with PCNSL with low CSF sPD-L1 levels, more patients with high levels had high serum lactate dehydrogenase levels, leptomeningeal involvement, and deep-brain involvement. Furthermore, CSF sPD-L1 could predict poor survival in PCNSL but CSF sPD-L2 could not. Intriguingly, CSF sPD-L1 levels were correlated with disease status and their dynamic changes post treatment could predict time to relapse. In conclusion, this study identified CSF sPD-L1 as a promising prognostic biomarker, indicating a therapeutic potential of PD-L1 blockade in PCNSL.     

Diffuse large B-cell lymphoma with involvement of the kidney: outcome and risk of central nervous system relapse

Background

Renal involvement is uncommon in diffuse large B-cell lymphoma. Recent data suggest that it is an independent risk factor for central nervous system relapse. We reviewed the clinical features, risk of central nervous system involvement, and survival of patients with diffuse large B-cell lymphoma with involvement of the kidney at diagnosis.

Design and Methods

All patients with diffuse large B-cell lymphoma and renal involvement diagnosed from January 1, 1982 to December 31, 2008 at the British Columbia Cancer Agency were retrospectively identified in the Lymphoid Cancer Database. Patients were included if they were 16 years old or over, had advanced stage disease [stage III/IV, or stage I/II with B symptoms or bulky mass (>10 cm)] and were treated with curative intent. Central nervous system involvement was diagnosed by cerebrospinal fluid cytology, radiology or clinically.

Results

We identified 55/2656 (2%) patients with diffuse large B-cell lymphoma and renal involvement at diagnosis. The male to female ratio was 2:1. The patients’ median age was 58 years. Bilateral renal involvement was present in 24 (44%) and stage IV disease in 50 (91%). The International Prognostic Index score was 3, 4 or 5 in 52 (95%), the glomerular filtration rate was less than 30 mL/min/m² in 9 (16%) and elevated lactate dehydrogenase was recorded in 46 (84%). Twenty-five (46%) patients received CHOP plus rituximab and 30 (54%) received CHOP-like regimens without rituximab. In total, 20 (36%) patients had central nervous system involvement: four at the time of diagnosis and 16 at relapse. The median time to central nervous system relapse was 5.6 months (range, 1.2 months–4.6 years), and was not affected by the addition of rituximab (P=0.547). The 5-year overall and progression-free survival rates for the whole cohort were 29% and 25%, respectively. In patients who received rituximab, there were trends towards improved 5-year overall survival (43% versus 18%, P=0.071) and progression-free survival (40% versus 13%, P=0.057).

Conclusions

There is an exceptionally high incidence of central nervous system relapse in patients with diffuse large B-cell lymphoma and kidney involvement at diagnosis. The addition of rituximab may improve overall survival in this poor-risk population, likely through improved control of systemic disease.