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 (αß)-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 TCRß 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.

Significant non-alcoholic fatty liver disease is found in non-diabetic, pre-obese Chinese in Singapore.

INTRODUCTION: To characterise the anthropometrical and metabolic parameters of a group of non-diabetic and non-obese patients who had histologically-proven nonalcoholic steatohepatitis (NASH). METHODS: During September 1997 to November 1999, consent for liver biopsies were sought from a consecutive series of patients, whose body mass index (BMI) were equal to or less than 30 kg per square metres, and who had persistently elevated serum alanine transaminase (more than 2.5 times upper limit of normal for more than six months), with no associated viral hepatitis, alcohol or drug-induced liver disease, hereditary liver disease and diabetes mellitus. Patients who were found to have steatohepatitis histologically were further studied. Their body weight, height, waist and hip circumferences were taken, and fasting serum lipid and glucose measured. Serum insulin was measured in six patients and insulin resistance (IR) was calculated by homeostasis model assessment. Oral glucose tolerance tests were done if fasting glucose levels were greater than 6 mmol/L. All liver biopsies were reviewed by a single histopathologist. Three age- and sex-matched controls were randomly selected for each patient. RESULTS: 11 of 12 patients who underwent liver biopsies were found to have NASH. All 11 were Chinese: eight males and three females. 73 percent of them had hepatic fibrosis. Overall, compared to controls, they had significantly higher body weight, BMI, IR and triglyceridaemia. The female patients also had a higher waist-hip ratio than controls. None had diabetes mellitus, and one had impaired glucose tolerance/fasting glycaemia. Nine out of 11 had BMI between 25 and 30 kg per square metres. CONCLUSION: Significant histological changes of NASH with hepatic fibrosis were found in Singaporean Chinese non-diabetic patients with BMI of less than 30 kg per square metres.

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.

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

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.

Gastrointestinal lymphoma--a review of 54 patients in Singapore.

Primary gastrointestinal (GI) lymphoma accounts for 2% to 5% of all GI malignancies. Primary therapy in uncomplicated GI lymphoma remains controversial. Fifty-four patients (male to female ratio of 4:3, median age 56 years) with GI lymphoma were studied to evaluate complications and results of therapy. The sites involved were the stomach (31), small bowel (12), large bowel (4), gallbladder (1) and multifocal (6). Distribution by stage and grade (Working Formulation or Kiel) were: IE-30%, IIE-43%, IIIE-6%, IV-20% and unknown-1%; low grade-33%, intermediate grade-59% and high grade-8%. Majority (54%) had diffuse large cell lymphoma. Twenty-three patients (43%) underwent primary resection of the tumour followed by chemotherapy in 14 or radiotherapy in 3. Seventeen patients (31%) had primary chemotherapy and 3 (6%) had primary radiotherapy. Of the 48 patients who underwent therapy, 52% had complete response. At the last follow-up (median 21 months), 25 patients were disease-free. Overall survival was 67% at two years. Treatment strategies employing surgery, radiotherapy and chemotherapy, alone or in combination, do not appear to influence outcome. Surgical resection plus chemotherapy appear to be effective in the control of local and distant disease.

Breast lymphoma--a pathologic study of 14 cases.

Fourteen cases of malignant non-Hodgkin's lymphoma of the breast were diagnosed at the Department of Pathology, Singapore General Hospital, since 1988. All were females with an age range of 30 to 69 years. Twelve cases were B cell and 2 were T cell in immunophenotype. Of the B cell lymphomas, one was subtyped as follicular, 8 diffuse large cell (IWF) or centroblastic (Kiel) and 3 immunoblastic lymphomas. Both T cell tumours were Ki-1 positive, large cell anaplastic lymphomas. Malignant lymphoma was not clinically suspected in any patient at presentation. Histologically, 3 cases were initially diagnosed as carcinomas, one on a trucut biopsy, another during frozen section evaluation and the third was a breast excision specimen. The pathological characteristics and potential histologic problems are detailed. The rarity of the disease, lack of uniform classification and variable treatment modalities make prognostic predictions of breast lymphoma difficult.

Four cases of developmental foregut cysts.

Four patients with developmental foregut cysts were seen in the Singapore General Hospital between 1991 and 1994. Three had bronchogenic cysts while one had features consistent with both enteric and bronchogenic origin. Among those patients with bronchogenic cysts, only one was symptomatic, having presented with cough and dysphagia. Two other patients presented incidentally on chest radiographs done for pre-National Service enlistment while one patient was picked up when a repeat chest radiograph was done following a course of antibiotics. The diagnosis of our first patient with the symptomatic bronchogenic cyst was based on barium swallow and a computerised tomographic scan of the thorax. Two patients were diagnosed on histology following open thoracotomy and surgical resection of the cysts to have a bronchogenic and a cyst of mixed origin as described above respectively. The last patient who underwent video-assisted thoracoscopic surgery with resection of the cyst was confirmed histologically to have a bronchogenic cyst.

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

BACKGROUND: Non-Hodgkin's 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. METHODS: Data from the population-based Singapore Cancer Registry for the period 1968 to 1992 were reviewed to determine time trends based on sex and ethnic group. The Poisson regression model was fitted to the cross-tabulated data to obtain the adjusted incidence density ratios. RESULTS: A total of 1988 cases of non-Hodgkin's lymphoma were included in the analysis. There was an overall increase in incidence among both Chinese and Malaysians. However, the rate of increase was greater in females (age-standardized rate from 1.8 per 100,000 in 1968-1972 to 4.5 per 100,000 in 1988-1992) than in males (3.2 per 100,000 to 5.9 per 100,000 in the same time periods). Between ethnic groups, Malay females were at higher overall risk compared with their Chinese counterparts (incidence density ratio 1.32; 95% confidence interval, 1.08-1.61). Although a substantial proportion of patients diagnosed with Hodgkin's disease between 1968 and 1972 were reclassified on review, using present criteria, as having non-Hodgkin's lymphoma, it is unlikely that this, and other recent changes in histologic interpretation, could have accounted for an increase of this magnitude. CONCLUSIONS: Non-Hodgkin's lymphoma has increased in incidence among the Chinese and Malay populations in Singapore. The pattern of increase differs from that of the common cancer sites, and suggests the need to look for environmental and genetic factors that have not yet been elucidated.

Difficulty of obtaining wide tumour to deep fascial margins in Asian women with breast cancers: implications on treatment and prognosis.

This prospective study sought to determine the width of tumour to fascial margins attainable after mastectomy in Asian women with breast cancers. The narrowest perpendicular distance from tumour to the deep fascia was measured in the mastectomy specimens of 177 consecutive Singaporean women with primary breast carcinomas. A highly significant linear correlation was present between the tumour size (P < 0.001, Pearson's R = -0.34) and the width of deep margins. Furthermore, T staging (P < 0.01, ANOVA) was inversely correlated with the width of deep margins and significant differences were observed between early (T0 to T2) and late (T3 to T4) lesions. In patients with ductal carcinoma in situ (DCIS) and T1 lesions, deep margins greater than 10 mm were achieved in only 23% and 33% of the women respectively. For patients with DCIS, 33% had either positive margins or margins less than 2 mm. The corresponding figures for women with T1 and T2 lesions were 11% and 26%, respectively. The inability to obtain negative deep margins were considerable with large tumours as 10% of the women with T3 tumours and 33% with T4 tumours had positive margins. Thus the proportion of positive or narrow deep margins following mastectomy is appreciable in Asian women and even in those with early tumours. The implications of these findings on the risk of locoregional recurrence or the need for more radical surgery or adjuvant radiotherapy remain uncertain, and will require further elucidation.

Thymoma--a study of 60 cases in Singapore.

Of 60 cases of thymomas studied in Singapore between 1988 and 1992, the histogenetic classification proposed by Müller-Hermelink was successfully applied to subtype 58 cases. There were 20 (33%) cortical, six (10%) predominantly cortical, three (5%) medullary and 12 (20%) mixed thymomas. Twelve (20%) cases were well differentiated thymic carcinomas and five (8%) were classified as other thymic carcinomas. The pathological and clinical features are presented in detail. These subtypes showed significant correlation with invasive behaviour (stage) and myasthenia gravis. We conclude that the Müller-Hermelink classification has predictive utility and represents a major step towards the understanding of the biology of thymic epithelial tumours.

Sudden postoperative death from ruptured intracranial vascular malformations in a patient receiving total parenteral nutrition.

A 30-year-old female patient underwent oesophagectomy and colonic transposition for multiple oesophageal strictures associated with epidermolysis bullosa dystrophica. On the 9th postoperative day, she had convulsions and died, whilst in a state of severe hyperglycaemia, which was presumably iatrogenically induced by total parenteral nutrition. Autopsy and subsequent histological examination revealed that the cause of death was acute subarachnoid haemorrhage from ruptured, intracranial cryptic arteriovenous malformations. Postmortem vitreous biochemistry confirmed that death had occurred in a state of hyperglycaemia. The pathology of intracranial vascular malformations and the medico-legal implications of this case are discussed.

Primary pulmonary lymphoma: report of three cases and a brief review of the literature.

We report three patients with primary pulmonary non-Hodgkin's lymphoma which is a rare extranodal lymphoid neoplasm. In these patients, both the history and physical findings were vague and minimal. The laboratory findings were normal apart from chest radiographic abnormalities and serum gammopathy in two cases. All three patients underwent several diagnostic procedures before conclusive results were obtained from thoracotomy specimens. Histology revealed small lymphocytic infiltrate of the pulmonary parenchyma with nodal involvement in all three cases. All three patients had surgical resection and two received adjuvant chemotherapy. They are all alive and symptom-free at 92, 51 and 12 months, respectively, after diagnosis.

Palatine tonsillar metastasis from carcinoma of the colon.

Metastatic carcinoma of the palatine tonsil is rare, with only 92 cases reported in the world literature. We report a case of tonsillar metastasis from the colon. This is an unusual case not only because it is the first case report of tonsillar metastasis from this site but also because the tonsillar secondary is the first sign of the primary disease.

MACOP-B in advanced non-Hodgkin's lymphoma.

Between May 1986 and March 1991, 38 patients with previously untreated advanced intermediate and high-grade non-Hodgkin's lymphoma were treated with methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B): 73% of the patients had stages III and IV disease, 55% had "B" symptoms, and 55% had bulky disease (nodal masses > 10 cm). Histologic subtypes included diffuse large-cell and immunoblastic lymphoma. In 96% of patients clinical response was achieved (69% complete response and 27% partial response). Acturial disease-free survival and overall survival were 55% and 60%, respectively, at 2 years. Treatment-related mortality was 16%: 3 patients died from neutropenic sepsis and 3 (hepatitis B carriers) from fulminant hepatitis at the time of steroid withdrawal. The incidence of nonfatal neutropenic fever was 24% and mucocutaneous toxicity was common. The poorer overall results may be attributed to more advanced disease. Caution is advised in the use of MACOP-B among hepatitis B carriers.

T-cell lymphoma in Singapore: pathology, clinical findings and association with HTLV-1 antibodies.

Of 128 cases of malignant lymphomas studied in Singapore between 1986 and 1988, 28 were identified as peripheral T-cell lymphomas. Sera from two of the 128 cases were positive for HTLV-1 antibodies and both cases had the clinical and pathological features of adult T-cell leukaemia/lymphoma. The pathological and clinical features of the 28 cases of peripheral T-cell lymphoma are presented in detail. Survival data indicated no significant difference between the low grade and high grade histological types. Three of the patients had previous or concomitant malignancies. The percentage of T-cell lymphomas associated with HTLV-1 infection in Singapore is low compared to those areas in which HTLV-1 is endemic.

View from beneath: pathology in focus. Synovial sarcoma of hypopharynx.

Synovial sarcoma of the hypopharynx is a rare neoplasm. To date only 23 cases of synovial sarcoma of the hypopharynx have been reported in the literature. An additional case in an 18-year-old male is presented. This is the first case of synovial sarcoma in the hypopharynx to be reported in Singapore. The presentation was that of a mass in the hypopharynx; progressive dysphagia, intermittent hoarseness and gradual airway compromise. A CT scan was valuable in determining the site of origin and extent of the lesion. Histopathology was diagnostic. Treatment comprised of wide surgical excision of the tumour and post-operative radiotherapy.

Fulminant hepatic failure in non-Hodgkin lymphoma patients treated with chemotherapy.

Chemotherapy is the mainstay of therapy for patients with non-Hodgkin lymphoma. Among side-effects associated with the use of chemotherapy, immunosuppression is one which can be potentially fatal. In hepatitis B carriers, immunosuppression permits widespread infection of the hepatocytes and its subsequent withdrawal causes an "immunological rebound" leading to massive necrosis of hepatocytes. 4 patients who died of fulminant hepatitis following chemotherapy are reported. These were patients with positive hepatitis B serology. Caution is advised when treating non-Hodgkin lymphoma in patients from hepatitis B endemic regions.

Oestrogen receptors in well differentiated thyroid cancers.

Oestrogen receptor (ER) monoclonal antibody, H222 was used to study ER expression in forty-seven paraffin embedded blocks of well differentiated thyroid cancers. Trypsinisation, DNase I digestion, together with the use of labelled streptavidin biotin immuno-histochemical staining kit were adopted to increase the sensitivity of the immunoreaction. One out of twenty-seven papillary carcinomas and one out of twenty follicular carcinomas were immunoreactive. Thus, 4.3% of the well differentiated thyroid cancers were noted to express ER. The increased incidence and the better prognosis in females with well differentiated thyroid cancers is unlikely to be explained on the presence or absence of ER.

Primitive neuroectodermal tumour in the oral cavity. Case report.

Primitive neuroectodermal tumour is regarded as a rarely seen lesion as it occurs mainly within the central nervous system. However, this neoplasm does occasionally occur elsewhere in the body. One such case which occurred in the posterior part of the palate in a child is reported. Following a combined therapeutic approach comprising surgery, radiotherapy and chemotherapy, the patient has been well for nine years since treatment.