C.S. Chim

Primary cardiac lymphoma

Primary cardiac lymphoma is a rare entity. We report on the clinicopathological features of 2 patients with primary cardiac lymphomas: one involving the right atrium resulting in intractable right heart failure, and the other involving the pericardium with massive pericardial effusion. In the first patient, sternotomy and surgical biopsy of the tumor were performed to arrive at the diagnosis. In the second patient, CT thorax and transesophageal echocardiography helped to diagnose the pericardial tumor, and cytological examination of the pericardial fluid established the pathological diagnosis of lymphoma. Combination chemotherapy (COPP) was started in both patients. The first patient died on the first day of chemotherapy due to intractable heart failure, while the second attained a partial response to chemotherapy but died of progressive disease 8 weeks later. This is followed by a literature review of 21 patients with primary cardiac lymphoma. In conclusion, the prognosis of primary cardiac tumor remains poor. Am. J. Hematol. 54:79–83, 1997

Quantification of circulating Epstein–Barr virus DNA in NK/T-cell lymphoma treated with the SMILE protocol: diagnostic and prognostic significance

Circulating Epstein–Barr virus (EBV) DNA is a biomarker of EBV-associated malignancies. Its significance in natural killer/T-cell lymphoma treated with the novel regimen SMILE was investigated. EBV DNA was quantified with a World Health Organization EBV standard in 910 plasma samples collected during 230 courses of SMILE in 56 patients. Median presentation EBV DNA was 1900 (0–1.4 × 107) IU/ml. Presentation EBV DNA was significantly associated with tumor load and treatment response. To examine lymphoma chemosensitivity, EBV DNA changes after SMILE were evaluated. EBV DNA after SMILE (I) significantly correlated with tumor load and treatment response. Two dynamic parameters were further analyzed: negative EBV DNA after SMILE (I) and EBV DNA change patterns during treatment (A: persistently undetectable; B: persistently detectable<presentation; C: persistently detectable>presentation). Negative EBV DNA after SMILE (I) and pattern A EBV DNA change significantly correlated with lower tumor load and superior outcome. Multivariate analysis involving presentation features, international prognostic index (IPI), Korean prognostic score and EBV DNA parameters showed that negative EBV DNA after SMILE (I) had the most significant impact (P<0.001) on overall survival and pattern A EBV DNA change had the most significant impact (P=0.002) on disease-free survival. Presentation EBV DNA, IPI and Korean prognostic scores were not independent prognostic factors.

SOCS1 and SHP1 hypermethylation in mantle cell lymphoma and follicular lymphoma: implications for epigenetic activation of the Jak/STAT pathway

SOCS1 and SHP1 hypermethylation in mantle cell lymphoma and follicular lymphoma: implications for epigenetic activation of the Jak/STAT pathway

Disruption of INK4/CDK/Rb cell cycle pathway by gene hypermethylation in multiple myeloma and MGUS.

Disruption of INK4/CDK/Rb cell cycle pathway by gene hypermethylation in multiple myeloma and MGUS

Methylation of INK4 and CIP/KIP families of cyclin- dependent kinase inhibitor in chronic lymphocytic leukaemia in Chinese patients

Background: INK4 (p15, p16, p18 and p19) and CIP/KIP (p21, p27 and p57) are two families of cyclin-dependent kinase inhibitors (CKI) targeting CDK4/6 and CDK2, respectively. Aim: To study the role of methylation in the inactivation of CKI in chronic lymphocytic leukaemia (CLL). Materials and methods: Methylation-specific polymerase chain reaction was carried out on DNA obtained from the bone marrow of 56 newly diagnosed patients with CLL. Results: Similar demographic features and clinical outcome were observed in our patients when compared with Caucasian patients, including an indolent clinical course (10-year overall survival 51%) and advanced Rai stage (p = 0.006), and a high-risk karyotype such as trisomy 12 and complex aberrations (p = 0.03). In the INK4 family, methylation in p15 and p16 occurred in 20 (35.7%) and 8 (14.3%) patients, respectively. In all, 5 (8.9%) CLL samples harboured concurrent methylation of both p15 and p16. Apart from an association of p16 methylation with higher presenting leucocyte count (64.5×109/l in methylated p16 and 16.0×109/l in unmethylated p16 patients; p = 0.016), there was no association between p15 and p16 methylation and age, sex and Rai stage. No difference was observed in the overall survival for patients with and without p15 and p16 methylation. By contrast, p18 and Rb were unmethylated in all samples. In the CIP/KIP family, apart from infrequent methylation of p57 in 4 (7.1%) patients, methylation of p21 and p27 was uniformly absent. Conclusion:p15 and, less frequently, p16 of the INK4 family of CKI, instead of the CIP or KIP family, were targeted by methylation in CLL. p16 methylation was associated with a higher lymphocyte count at presentation. This is the first comprehensive study of the epigenetic dysregulation of the INK4 and CIP/KIP families of CKI in Chinese patients with CLL.

Diagnostic cues for natural killer cell lymphoma: Primary nodal presentation and the role of in situ hybridisation for Epstein-Barr virus encoded early small RNA in detecting occult bone marrow involvement

Natural killer (NK) cell lymphomas are rare, and atypical features might lead to diagnostic pitfalls. This report describes an unusual patient in whom lymphoma occurred initially as isolated lymph node involvement, an exceptional presentation of an almost exclusively extranodal disease. Furthermore, during the terminal haemophagocytosis in the bone marrow, lymphoma cells lost the expression of the NK cell marker, CD56, making the histopathological diagnosis of bone marrow involvement difficult. This was resolved by in situ hybridisation for Epstein-Barr virus encoded small RNA, which detected occult bone marrow infiltration.

Mantle cell lymphoma in the Chinese: Clinicopathological features and treatment outcome

We report the clinical, molecular, and immunohistological findings of 20 Chinese patients with mantle cell lymphoma diagnosed over a 10‐year period. The disease affected mainly elderly patients (median age, 65.5 years) with a male predominance (M/F, 3/1). Eighty percent presented with advanced stage III/IV disease but only 25% had B symptoms. Eighty‐five percent had extranodal disease at presentation. Complete remission (CR) and partial remission (PR) were achieved in 45% and 40% of the patients, respectively. There was no difference in the CR rate for patients treated with anthracycline‐containing or nonanthracycline‐containing regimens (43% and 50%, P = 0.67). Disease progression or relapse was observed after a median of 26 months in patients who initially responded to treatment. Extranodal relapse occurred in the central nervous system (n = 1), bone marrow (n = 1), pleura (n = 2), orbit (n = 2), and the gastrointestinal tract (n = 3). The median overall survival (OS) was 52 months but there were no long‐term survivors. This was not different from the median OS of 53 months of patients with diffuse large cell (DLC) lymphoma treated in the same center over the same period (log rank, P = 0.76). Of the 12 patients who were tested for bcl‐1 rearrangement by polymerase chain reaction (PCR), five (42%) were positive for rearrangement in the major translocation cluster (MTC) region. The median OS rates were 45 months and 63 months for PCR positive and negative patients, respectively (P = 0.97). In conclusion, MCL is a disease mainly of the elderly in the Chinese with a male predominance and most had advanced‐stage disease and extranodal involvement at presentation. Clinicopathologic features and treatment outcome were similar to Caucasian patients, in that the disease combined the aggressive nature of DLC lymphoma and the incurability of low‐grade lymphoma. Am. J. Hematol. 59:295–301, 1998.

Aberrant gene promoter methylation marking disease progression in multiple myeloma

The pathogenesis of multiple myeloma (MM), a neoplastic proliferation of monoclonal plasma cells, is a multi-step process with progressive acquisition of genetic aberrations. Disease initiation involves the activation of oncogenes such as D-type cyclins by chromosomal translocations involving the immunoglobulin (Ig) gene. Inactivation of tumor suppressor genes, however, appears to be a late event. Clinically, the disease may progress through monoclonal gammopathy of undetermined significance, smouldering myeloma, MM and plasma cell leukemia. DNA methylation involves the addition of a methyl group to the carbon 5 position of the cytosine ring. Aberrant methylation in the CpG dinucleotide regions of gene promoters results in transcription repression, and may act as an alternative mechanism of gene inactivation. In myeloma, aberrant methylation is a frequent genetic alteration that results in perturbation of signaling pathways. For instance, we had shown previously that aberrant methylation of SHP1 was associated with absent SHP1 expression, resulting in constitutive activation of the Jak/ STAT pathway. Demethylation with 5-azacytidine led to re-expression of SHP1 and downregulation of Jak/STAT signalling, thus demonstrating that aberrant methylation was biologically relevant. Several putative tumor suppressor genes such as SHP1 (targeting interleukin-6 (IL-6) signaling), DAP kinase (targeting p53-mediated apoptosis), CDKN2A (targeting the cell cycle) and E-CAD are frequently methylated in MM, and thus might be acquired during disease evolution. Here, we describe the methylation status of multiple genes in four patients with MM, where disease evolution was punctuated by progressive gene hypermethylation.

Epigenetic dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in acute leukaemias

Background: Dysregulation of apoptosis is important in carcinogenesis. Aim and Methods: To analyse the potential inactivation of the DAP kinase/p14/HDM2/p53/Apaf-1 pathway by aberrant promoter methylation in acute leukaemias. Results: Of five leukaemic lines examined, p14 was unmethylated in Raji, HL60 and U937, but completely deleted in Jurkat and NB4. DAP kinase was totally methylated in Raji and NB4, but unmethylated in HL60, Jurkat and U937. Apaf-1 was unmethylated in all the lines. At diagnosis, DAP kinase methylation occurred in eight (25%) APL patients and none of the other AML patients (8/32 vs 0/50, p = 0.001). DAP kinase methylation was detected in four (16%) ALL patients. p14 and Apaf-1 methylation was not detected in any of the 32 cases of acute promyelocytic leukaemia (APL), 50 cases of other subtypes of acute myeloid leukaemia (AML), and 25 cases of acute lymphoblastic leukaemia. Conclusion: Among AML subtypes, DAP kinase is preferentially hypermethylated in APL.

Hemophilia B in a female carrier due to skewed inactivation of the normal X-chromosome

A novel missense mutation (codon 351, GCT (Ala) → CCT (Pro)) of the FIX gene was characterised in a young female with mild hemophilia B. She is heterozygous for the FIX mutation inherited from her carrier mother. Analysis of the methyl‐sensitive Hpa II sites at the 5′ end of the hypoxanthine phosphoribosyltransferase gene showed that skewed inactivation of the X chromosome carrying her normal FIX gene accounted for the hemophilia phenotype. Am. J. Hematol. 58:72–76, 1998.