Ivy Sng

Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project

Among 1153 new adult cases of peripheral/T-cell lymphoma from 1990-2002 at 22 centers in 13 countries, 136 cases (11.8%) of extranodal natural killer (NK)/T-cell lymphoma were identified (nasal 68%, extranasal 26%, aggressive/unclassifiable 6%). The disease frequency was higher in Asian than in Western countries and in Continental Asia than in Japan. There were no differences in age, sex, ethnicity, or immunophenotypic profile between the nasal and extranasal cases, but the latter had more adverse clinical features. The median overall survival (OS) was better in nasal compared with the extranasal cases in early- (2.96 vs 0.36 years, P < .001) and late-stage disease (0.8 vs 0.28 years, P = .031). The addition of radiotherapy for early-stage nasal cases yielded survival benefit (P = .045). Among nasal cases, both the International Prognostic Index (P = .006) and Korean NK/T-cell Prognostic Index (P < .001) were prognostic. In addition, Ki67 proliferation greater than 50%, transformed tumor cells greater than 40%, elevated C-reactive protein level (CRP), anemia (< 11 g/dL) and thrombocytopenia (< 150 x 10(9)/L) predicts poorer OS for nasal disease. No histologic or clinical feature was predictive in extranasal disease. We conclude that the clinical features and treatment response of extranasal NK/T-cell lymphoma are different from of those of nasal lymphoma. However, the underlying features responsible for these differences remain to be defined.

Outbreak of Nipah-virus infection among abattoir workers in Singapore

BACKGROUND In March 1999, an outbreak of encephalitis and pneumonia occurred in workers at an abattoir in Singapore. We describe the clinical presentation and the results of investigations in these patients. METHODS Clinical and laboratory data were collected by systemic review of the case records. Serum and cerebrospinal fluid (CSF) samples were tested for IgM antibodies to Nipah virus with an IgM capture ELISA. Reverse-transcriptase PCR was done on the CSF and tissue samples from one patient who died. FINDINGS Eleven patients were confirmed to have acute Nipah-virus infection based on raised IgM in serum. Nipah virus was identified by reverse transcriptase PCR in the CSF and tissue of the patient who died. The patients were all men, with a median age of 44 years. The commonest presenting symptoms were fever, headache, and drowsiness. Eight patients presented with signs of encephalitis (decreased level of consciousness or focal neurological signs). Three patients presented with atypical pneumonia, but one later developed hallucinations and had evidence of encephalitis on CSF examination. Abnormal laboratory findings included a low lymphocyte count (nine patients), low platelet count, low serum sodium, and high aspartate aminostransferase concentration (each observed in five patients). The CSF protein was high in eight patients and white-blood-cell count was high in seven. Chest radiography showed mild interstitial shadowing in eight patients. Magnetic resonance imaging (MRI) showed focal areas of increased signal intensity in the cortical white marker in all eight patients who were scanned. The nine patients with encephalitis received empirical treatment with intravenous aciclovir and eight survived. INTERPRETATION Infection with Nipah virus caused an encephalitis illness with characteristic focal areas of increased intensity seen on MRI. Lung involvement was also common, and the disease may present as an atypical pneumonia.

Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is often challenging to diagnose and classify. Gene expression profiling was performed on 144 cases of PTCL and natural killer cell lymphoma and robust molecular classifiers were constructed for angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large-cell lymphoma (ALCL), and adult T-cell leukemia/lymphoma. PTCL-unclassifiable was molecularly heterogeneous, but we were able to identify a molecular subgroup with features of cytotoxic T lymphocytes and a poor survival compared with the remaining PTCL-not otherwise specified cases. Many of the pathologic features and substantial components of the molecular signature of AITL are contributed by the follicular dendritic cells, B-cell, and other stromal components. The expression of Th17-associated molecules in ALK(+) ALCL was noted and may represent aberrant activation of Th17-cell differentiation by abnormal cytokine secretion. Adult T-cell leukemia/lymphoma has a homogeneous molecular signature demonstrating high expression of human T-lymphotropic virus type 1-induced genes. These classifiers reflect the biology of the tumor cells as well as their microenvironment. We also constructed a molecular prognosticator for AITL that appears to be largely related to the microenvironmental signature, and the high expression of 2 immunosuppressive signatures are associated with poor outcome. Oncogenic pathways and tumor-host interactions also were identified, and these findings may lead to better therapies and outcome in the future.

Nasal-type extranodal natural killer/T-cell lymphomas: a clinicopathologic and genotypic study of 42 cases in Singapore

We studied the clinicopathologic features of 42 cases of nasal-type extranodal natural killer (NK)/T-cell lymphoma in Singapore and compared our findings with other series reported in the Asian and Western populations. A panel of immunohistochemical stains, which included CD2, CD3, CD4, CD8, CD56, T-cell intracellular Antigen-1 and granzyme B, and in situ hybridization for Epstein–Barr virus encoded RNA (EBER) were performed. Polymerase chain reaction for T-cell receptor-gamma gene rearrangement using both gel and capillary electrophoresis were evaluated to determine the proportion of tumors which are of true T-cell lineage. We also studied the functional status of the overexpressed p53 protein in these lymphomas by correlating p53 expression with its downstream target protein, p21. In all, 31 out of 42 cases presented in the upper aerodigestive tract. The other sites of involvement included gastrointestinal tract, skin, soft tissue, testis, liver, spleen, bone marrow and brain. The tumors displayed characteristic morphologic features. In situ hybridization for EBER was detected in 41 out of 42 cases (97.6%). The only significant adverse prognostic factor identified was an International Prognostic Index of two or more. A significantly higher proportion of the tumors (27%), compared to previous studies, demonstrated monoclonal T-cell receptor-gamma gene rearrangement. There was, however, no difference in survival or clinicopathologic features between the true NK-cell tumors and their T-cell counterparts. Overexpression of p53 was present in 40% of the cases, but no significant difference in survival rate was detected in patients with p53 overexpression and there was no association between p53 overexpression with large cell morphology, and advanced stage of disease. These findings suggest that molecular aberrations other than those of the p53 pathway may be operative in the pathogenesis of this malignancy.

Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic γδ T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro

Natural killer (NK) cell lymphomas/leukemias are rare neoplasms with an aggressive clinical behavior. The majority of the cases belong to extranodal NK/T-cell lymphoma, nasal type (ENKTL) in the current WHO classification scheme. Gene-expression profiling (GEP) of 21 ENKTL and NK-cell lymphoma/leukemia patients, 17 NK- and T-cell lines and 5 indolent NK-cell large-granular-lymphocytic proliferation was performed and compared with 125 peripheral T-cell lymphoma (PTCL) patients previously studied. The molecular classifier derived for ENKTL patients was comprised of 84 transcripts with the majority of them contributed by the neoplastic NK cells. The classifier also identified a set of γδ-PTCLs both in the ENKTL cases as well as in cases initially classified as PTCL-not otherwise specified. These γδ-PTCLs expressed transcripts associated with the T-cell receptor (TCR)/CD3 complex, suggesting T cell rather than NK-cell lineage. They were very similar to NK-cell tumors by GEP, but were distinct from cytotoxic (αβ)-PTCL and hepatosplenic T-cell lymphoma, indicating derivation from an ontogenically and functionally distinct subset of γδ T cells. They showed distinct expression of Vγ9, Vδ2 transcripts and were positive for TCRγ, but negative for TCRβ by immunohistochemistry. Targeted inhibition of two oncogenic pathways (AURKA and NOTCH-1) by small-molecular inhibitors induced significant growth arrest in NK-cell lines, thus providing a rationale for clinical trials of these inhibitors in NK-cell malignancies.

Prognostic factors in patients with diffuse large B cell lymphoma: Before and after the introduction of rituximab

This study attempted to evaluate the usefulness of the International Prognostic Index (IPI) as a prognostic model in patients treated with R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin and prednisolone) chemotherapy. We compared 279 patients with DLBCL. Among them, 183 received CHOP while 96 received R-CHOP. Results showed that there were no statistically significant differences between the two groups of patients in terms of both the patient and the lymphoma characteristics. The estimated 2-year survival was significantly higher among patients treated with R-CHOP compared to CHOP alone (85.6% vs. 64.7%, P = 0.004). Both the IPI and age-adjusted IPI were less useful as prognostic models in patients receiving R-CHOP compared to CHOP. In the multivariate analysis, age ≥ 60, elevated serum LDH, low serum albumin and advanced stages of disease were each independently associated with decreased survival in patients treated with CHOP. In contrast, among those treated with R-CHOP, only male sex and advanced stage of disease were each independently associated with decreased survival. Using these two factors, patients treated with R-CHOP could be separated into three prognostic groups with 5-year estimated survival ranging from 47% to 100% (P < 0.0001). In summary, we can conclude that with the significant improvement in survival following the use of rituximab, the relevance of previously recognized prognostic factors has to be reassessed and re-evaluated.

Comparative analysis of extra-nodal NK/T-cell lymphoma and peripheral T-cell lymphoma: significant differences in clinical characteristics and prognosis

Aim: We aimed to compare the frequencies, clinical characteristics, and prognostic factors of peripheral T‐cell lymphoma (PTCL) vs. extra‐nodal natural killer (NK)/T‐cell lymphoma and to characterize the subtypes of extra‐nodal NK/T‐cell lymphoma. Methods: We reviewed 97 consecutive patients with PTCL and extra‐nodal NKT lymphoma from 2000 to 2006. During this period, a total of 780 patients with malignant lymphomas were treated in our center. The diagnostic criteria used were based on the WHO classification system of malignant lymphomas. Results: Extra‐nodal‐NK/T‐cell lymphoma and PTCL comprised 5.0% (39/780) and 7.4% (58/780) of all cases. Of the PTCL cases, histology was PTCL‐NOS in 25, anaplastic large cell in 11, angioimmunoblastic T cell in 18 and other subtypes in four patients. Compared with PTCL, extra‐nodal NK/T‐cell lymphoma was associated with a significantly inferior rates of complete remission (33% vs. 53%, P = 0.05) and 3 yr overall survival (29.5% vs. 47.5%, P = 0.003). On multivariate analysis, extra‐nodal NK/T‐cell histology was independently associated with decreased survival. Further analysis into this subtype showed the nasal variant (n = 25) differed significantly from extra‐nasal variant (n = 14) in terms of stage at presentation (stages III/IV, 36% vs. 79%), international prognostic index scores (high intermediate or high IPI scores, 24% vs. 64%), complete remission rates (48% vs. 7%), and median survival (10 months vs. 1 month, P < 0.0001). Conclusions: Extra‐nodal NK/T‐cell lymphoma was associated with a poorer prognosis compared with PTCL and is likely to comprise two distinct variants with different clinical behavior and prognosis.

Male breast cancer: a retrospective study with immunohistochemical analysis of hormone receptor expression

Summary Of twenty‐two cases of breast carcinoma diagnosed in men in Singapore since 1969, 17 were classified as infiltrative ductal carcinoma, three as papillary and one as mucinous carcinoma. The remaining case could not be classified and further immunohistochemical workup suggested the possibility of metastasis from an occult prostatic primary. Fourteen cases that were staged revealed a majority of seven (50%) cases in Stage II, with three (21%) Stage I, one (8%) Stage III and three (21%) Stage IV cases. Estrogen and progesterone receptor (ER and PR) expression was determined in 20 cases using immunohistochemical staining of archival paraffin embedded tissue blocks, which demonstrated ER and PR positivity in 65% of the cases respectively.

Non‐Hodgkin's lymphoma in an Asian population: 1968‐1992 time trends and ethnic differences in Singapore

Non‐Hodgkins lymphoma has increased in incidence in many countries, particularly in the West. Advances in diagnostic methods and the understanding of the disease over time pose a challenge to the interpretation of these trends. The aim of this study was to determine if the disease has increased in Singapore, a newly industrialized Asian country, and to examine the possible factors that may account for any observed changes.

Molecular diagnosis of genital HPV DNA types by polymerase chain reaction and sensitivity-standardized filter in situ hybridization in randomly sampled cohorts of Singapore women

Infection of the cervix uteri with various types of human papillomaviruses is generally considered a necessary factor in the etiology of cancer of the cervix uteri. In many human populations throughout the world, approximately 90% of cervical carcinomas are found to harbour HPV genomes, as judged by Southern blot hybridization, while only a few percent of the cervical smears of asymptomatic individuals contain viral DNA, as assessed by filter in situ hybridization. To obtain corresponding epidemiological data from Singapore, we analysed two groups of 740 and 130 individuals by filter in situ hybridization, and found 4.1% and 6.9% of them to be HPV positive, with HPV 16 and HPV 31 being the predominant types. In consideration of the limitations of filter in situ hybridization, namely low sensitivity and a tendency to suggest false positives due to contaminants, including blood, we analysed the cervical smears of two further groups of 52 and 50 individuals by the polymerase chain reaction for infection by HPV 16 and HPV 18 respectively. With this test, 61% and 14% of the cervical smears proved to be HPV 16 and HPV 18 DNA positive respectively. We conclude that in Singapore, if not worldwide, the majority of the population the population is infected by genital HPV types, suggesting that factors other than HPV infection are ultimately rate-limiting in cervical carcinogenesis.