Regional variation in the distribution of subtypes of lymphoid neoplasms in India.

Lymphoid malignancies (LM) are a heterogeneous group of tumours. The relative frequencies of the various types of LMs vary across geographic regions. The pattern in India shows significant differences from the rest of the world. As India is a vast country, we set out to investigate whether there are regional differences in the relative frequencies of the various LMs. A total of 562 LMs from three different regions in India--Barshi (western India, 102 cases), Pondicherry (southern India, 156 cases) and Jaipur (northern India, 304 cases) were analysed according to the WHO classification. The non-Hodgkin lymphoma (NHL) to Hodgkin disease (HD) ratio was 6.28 in Barshi, 1.26 in Pondicherry and 2.27 in Jaipur. The frequency of HD's various subtypes did not significantly differ among the three regions. While T-cell NHLs constituted only 12.5% of NHLs at Barshi, they accounted for 31 and 27.5% of all NHLs at Pondicherry and Jaipur, respectively. There were also notable differences in the specific subtypes of NHL between the three different geographic regions in India.

Expression of P53 and bcl-2 proteins in T-cell lymphoblastic lymphoma: prognostic implications.

In patients (pts) with non-Hodgkin's lymphoma (NHL) under 25 years, treatment with MCP-842 protocol, a short duration intense protocol, yields worse survival in pts with lymphoblastic lymphoma (LL) compared to other high grade lymphomas. In order to identify both favourable and unfavourable subgroups in pts with T-cell LL (T-LL) with respect to relapse free survival following treatment with MCP-842 protocol, we analysed the expression of p53 and bcl-2 proteins in 22 pts with T-LL treated at the Tata Memorial Hospital, Mumbai by immunohistochemistry. p53 protein overexpression was noted in 59% cases and bcl-2 overexpression was noted in 29.4% cases. p53 expression correlated with a higher rate of relapse (p = 0.03; RR 7.9). The 5-year relapse free survival (RFS) was better in p53 negative patients compared to positive patients (70 vs 38%) (log-rank sigma = 0.04). In conclusion, in this study, overexpression of p53 protein was common in patients with T-LL. T-LL pts negative for p53 are likely to benefit from the short intense protocol--MCL-842. Bcl-2 protein overexpression was not a prognostic factor in these patients.

Hodgkin's disease involving Waldeyer's ring: a study of four cases.

We report four cases of Hodgkin's disease who presented with involvement of Waldeyer's ring. Their clinical, morphological and immunohistochemical features are discussed. The patients were immuno-competent, were between 17 and 65 years of age and presented with symptoms related to swelling in the nasopharynx or oropharynx and cervical lymphadenopathy. The nasopharyngeal biopsy and the cervical lymph node in all four cases showed features of classical Hodgkin's disease. The Reed Sternberg cells expressed CD15 and CD30, and in three cases, CD20 and Epstein-Barr virus--latent membrane protein -1 (EBV-LMP-1). Extranodal involvement by Hodgkin's disease which is not in continuity with nodal disease is rare in immunocompetent patients. Morphologically, such extranodal lesions, especially in locations like the oropharynx and nasopharynx, should be differentiated from EBV-associated lymphoproliferations.

Malignant peritoneal mesothelioma deciduoid or anaplastic variant? Point to ponder.

A case of peritoneal mesothelioma displaying unusual morphology, occurring in a 53 year old woman is described. The role of immunohistochemistry and electron microscopy in the evaluation of this tumor is stressed. The appropriate terminology to be used and possible etiologic factor are also discussed.

Discrepancies in Epstein-Barr virus association at presentation and relapse of classical Hodgkin's disease: impact on pathogenesis.

BACKGROUND: Though Epstein-Barr virus (EBV) has been linked to classical Hodgkin's disease (cHD), only a proportion of cHD cases show EBV-association. While there has been evidence to suggest a crucial role for EBV in the early phase of cHD evolution, we are unclear whether continued presence of EBV is essential for the maintenance of the neoplasm. We have addressed this issue by investigating the EBV-association in paired samples of cHD obtained at presentation and relapse. MATERIALS AND METHODS: We have analysed lymph node biopsy samples from 23 cases of cHD at presentation and relapse. In situ hybridization with EBER-1 probe and immunostaining with anti latent membrane protein-1 (LMP-1) antibody was performed on the paraffin sections. PCR for EBNA 3C gene was performed for EBV subtype analysis on the DNA extracted from paraffin sections. RESULTS: EBV-association was documented in both the presentation and relapse samples of 14 cases. One case showed loss of EBV-association at relapse. PCR analysable DNA was obtained from both presentation and relapse samples in four of the EBV-associated cases. The EBNA 3C amplimer corresponded to type A strain of EBV in all the samples. CONCLUSION: Loss of EBV-association between presentation and relapse seen in one case implies a hit and run mechanism in EBV-induced lymphomagenesis. Though EBV may be essential early in the evolution of cHD, it may not be required for maintenance of the neoplastic clone. Our study also brings out a speculation that a proportion of EBV-negative cHD could represent loss of EBV in the tumour prior to clinical presentation. Alternatively, an unidentified lymphotropic virus other than EBV might play a pathogenetic role in EBV-negative cHD.

Distribution of various subtypes of non-Hodgkin's lymphoma in India: a study of 2773 lymphomas using R.E.A.L. and WHO Classifications.

INTRODUCTION: The distribution of the major subtypes of non-Hodgkin's lymphoma (NHL) differs across geographic regions. This is the first study from India that has incorporated immunophenotypic findings while investigating the distribution of NHL subtypes. PATIENTS AND METHODS: All cases diagnosed as NHL between January 1995 and June 1998 in the Department of Pathology and in the Lymphoma Registry, Tata Memorial Hospital, Bombay, were selected for the study. The cases were reviewed by three pathologists and diagnostic problems were discussed by a panel of pathologists with a special interest in lymph node pathology. Of a total of 2831 cases, the diagnosis of NHL was accepted in 2773 cases. RESULTS: B-cell lymphomas formed 79.1% of the NHLs, whereas T-cell lymphomas formed 16.2% of the total. Diffuse large B-cell lymphoma was the most common subtype (34% of all NHLs). Follicular centre-cell lymphomas, B-cell small lymphocytic lymphoma, mantle-cell lymphoma, and marginal zone B-cell lymphomas (including MALT lymphomas) amounted to 12.6%, 5.7%, 3.4%, and 8.2%, respectively. Among the T-cell lymphomas, T-cell lymphoblastic lymphoma, anaplastic large-cell lymphomas of T/null-cell type, and other nodal peripheral T-cell lymphomas accounted for 6%, 4.3%, and 2.9% of all cases, respectively. CONCLUSIONS: The distribution of NHL subtypes in India shows important differences with those from the rest of the world. Follicular lymphoma and mantle-cell lymphoma are less common in India compared to Europe and the USA. Peripheral T-cell lymphomas and T/NK-cell lymphomas of nasal and nasal types, which are common in many other Asian countries, are also less prevalent. T-cell lymphoblastic lymphoma and anaplastic large T/null cell lymphoma are more prevalent in India.

Epstein-Barr virus association in classical Hodgkin's disease provides survival advantage to patients and correlates with higher expression of proliferation markers in Reed-Sternberg cells.

BACKGROUND: Most Epstein-Barr virus (EBV) associated lymphoproliferative disorders have high proliferation indices. However, classical Hodgkin's disease (cHD) is heterogeneous, with respect to proliferation index of the Reed-Sternberg cell (RS cell), and EBV association. Hence, we investigated whether cHD with and without EBV-association differ with respect to the proliferation index of the RS cells. Further we investigated whether this would have a bearing on patients survival. PATIENTS AND METHODS: We investigated 110 cases of cHD for: a) EBV association by immunohistochemical demonstration of EBV-latent membrane protein-1 and EBV encoded nuclear RNA 1 by mRNA in situ hybridisation; b) Proliferating cell nuclear antigen (PCNA) expression in the RS cells. RESULTS: EBV association was noted in 86 of 110 cases (78%). Higher PCNA expression (P = 0.004) and younger age (P = 0.001) correlated independently with EBV association. The 10 year relapse free survival (RFS) of EBV+ and EBV- patients were 60% and 44%, respectively (P = 0.03). The 10 year overall survival (OS) of EBV+ and EBV- patients were 85% and 64%, respectively (P = 0.03). EBV association maintained its significant impact on RFS and OS within Cox proportional hazard model. CONCLUSIONS: Our study suggests that EBV is likely to confer a higher PCNA expression and also contribute towards maintaining the RS cells of cHD in cell cycle. Hence, RS cells in EBV associated cHD would be more responsive to chemotherapy and radiotherapy associated DNA damage. Thus, EBV-association provides survival advantage to cHD patients treated with standard chemotherapy and radiotherapy protocols.

Animal model for liver dysfunction using lomustine in Wistar rats.

AIM: To induce intrahepatic cholestasis in rats using lomustine 1(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU). METHODS: Doses of 10 mg, 20 mg and 30 mg/Kg body weight of CCNU were injected intraperitoneally in separate groups of animals. RESULTS: With 10 mg/Kg body weight of CCNU, serum bilirubin levels increased for up to 72 hours and then slowly returned to normal. With a dose of 20 mg/Kg body weight of CCNU, serum bilirubin, AST, ALT and alkaline phosphatase levels increased for 72 hours and then returned to normal over 4-5 weeks. With a dose of 30 mg/Kg body weight peak levels of serum bilirubin were reached on day 17. Pathological studies were carried out after injection of 30 mg/Kg body weight of CCNU. After 72 hours hepatocytes were normal, with minimal nonspecific inflammation and bile duct proliferation. After 16 days, triaditis was observed with deposition of collagen. Focal fibrosis was also noticed. There was no significant abnormality of hepatocytes. After 75 days, hepatocytes showed focal ballooning. Bile duct proliferation was seen invading the parenchyma. Nodules of hepatocytes separated by irregular fibrous bands indicated cirrhosis. CONCLUSIONS: An animal model of intrahepatic cholestasis has been developed using CCNU; this model may be used to assess the utility of hepatobiliary radiopharmaceuticals.

Small cell carcinoma of gall bladder.

Small cell carcinoma of the gall bladder is very rare. We report a 25-year-old woman with this tumor. These tumors typically occur in elderly women with cholelithiasis; chemotherapy is not known to improve survival.

Malignant peritoneal mesothelioma deciduoid or anaplastic variant? A point to ponder.

A case of peritoneal meosthelioma displaying unusual morphology, occurring in a 53 years old woman is described. The role of immunohistochemistry and electron microscopy in the evaluation of this tumour is stressed. The appropriate terminology to be used and possible etiologic factor are also discussed.

MALT lymphoma of nasal mucosa treated with antibiotics.

Mucosa associated lymphoid tissue (MALT) lymphomas occur in sites other than the gastrointestinal tract and in the early stages respond to treatment with antibiotics. We report a rare case of nasal mucosal MALT lymphoma which responded to treatment with antibiotics and has since then remained in remission.

Expression of Fas and Fas ligand in Hodgkin's disease.

Fas and Fas ligand expression were investigated in twenty two cases of classical Hodgkin's disease (HD) by immunohistochemistry. While Reed-Sternberg (RS) cells in 7/22 (32%) cases expressed Fas ligand, reactive lymphoid cells expressed Fas ligand in only 2 (9%) cases. In 20/22 (91%) cases, the RS cells expressed Fas. A higher proportion of RS cells in the nodular sclerosis subtype expressed Fas as compared to the mixed cellularity subtype. In 18/22 (82%) cases, Fas expression was also noted in the reactive lymphoid cells. In eight cases, the reactive lymphoid cells were also analyzed by flow cytometry and a majority of them were CD4+CD45RO+. Most of these activated T-cells expressed Fas but were negative for Fas Ligand. To investigate the co-expression of Fas and Fas Ligand in the RS cells, six cases were subjected to Fas and Fas ligand immunostaining on consecutive sections. The co-expression was documented in the RS cells in four of six cases. These six cases with expression of both Fas and Fas ligand were investigated for the incidence of apoptosis. There was no statistically significant relationship between expression of Fas on reactive cells, expression of FasL on RS cells and the proportion of apoptotic reactive cells. In all these cases apoptosis was not observed in the RS cells. Thus Fas - FasL interactions may not lead to apoptosis of the RS cells.

A randomized comparison of the efficacy and toxicity of epirubicin and doxorubicin in the treatment of patients with non-Hodgkin's lymphoma.

BACKGROUND: Combination chemotherapy consisting of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisolone, and bleomycin (MACOP-B) has been frequently used for the treatment of non-Hodgkin's lymphoma. This randomized study was undertaken to assess the efficacy and toxicity of this regimen when either doxorubicin or epirubicin was used as the anthracycline drug. METHODS: Between April 1989 and December 1993, 211 previously untreated patients with intermediate grade and high grade non-Hodgkin's lymphoma were randomized to receive either doxorubicin (n=106) or epirubicin (n=105) with the MACOP-B regimen. These patients were followed through December 1996. Numerous clinical features predictive of response and survival were analyzed. Cardiac and noncardiac toxicity in the two treatment arms were compared. RESULTS: The median age of the patients was 48 years. Complete remission was experienced by 122 patients (58.3%); 62 patients (58.5%) achieved complete remission in the doxorubicin arm and 60 (58.1%) in the epirubicin arm. Response rates, time to treatment failure, relapse data, and overall survival were comparable between the two arms. Morbidity due to mucositis, vomiting, peripheral neuropathy, and cardiotoxicity were also comparable. The overall mortality was 10%. Mortality due to neutropenic sepsis was considerably higher among patients who received epirubicin (10 patients) than among those who received doxorubicin (5 patients). Cardiac evaluation revealed no difference in toxicity between the two arms. CONCLUSIONS: Epirubicin was as effective as doxorubicin in terms of patients' responses to therapy. There was no difference in cardiotoxicity between the two treatment arms. However, in this study, the mortality due to neutropenic sepsis was significantly higher among patients treated with epirubicin.

Restriction fragment length polymorphism of the L-myc oncogene in non-Hodgkin's lymphoma patients from India.

We examined 89 non-Hodgkin's lymphoma (NHL) patients of Indian origin for EcoRI restriction fragment length polymorphism (RFLP) of the L-myc gene with a view to testing the hypothesis that the presence of the L-myc S-allele predisposes towards NHL. We found no significant difference either in the distribution of the LL, LS and SS genotypes or in the allelic frequencies between the patient group and the control group with the frequencies of L-myc alleles, L (10.0 kb) and S (6.6 kb), being 0.56 and 0.44, respectively, in the patient group and 0.54 and 0.46, respectively, in the control group. However, a higher proportion (70%) of the S-allele was observed in our control group of normal healthy volunteers. Thus, the presence of L-myc S-allele did not indicate increased susceptibility or predisposition to the malignancy.

Pseudolymphomatous phase of Kikuchi-Fujimoto disease.

Kikuchi-Fujimoto lymphadenitis is a distinctive entity which is easily recognised in its classical histology. However, cases which are biopsied in the early stage of the disease, before entering the necrotic phase may be misdiagnosed as non-Hodgkin's lymphoma. Ten cases of Kikuchi-Fujimoto disease which mimicked non-Hodgkin's lymphoma and in which less than 10% of the lymph node was occupied by necrosis were chosen for this study. The patients included 4 males and 6 females with an age range of 15-40 years. Eight patients presented with cervical lymphadenopathy. The pathologic areas ranged from 70% to 95% of the total nodal area. The features that helped distinguish this lesion from non-Hodgkin's lymphoma were: 1) a sprinkling of karyorrhectic debris throughout the node 2) plasmacytoid monocytes as well as "histiocytes" in the company of transformed lymphocytes (immunoblasts) 3) enlarged mottled T-zone areas, and 4) presence of residual lymphoid follicles. Follow up on six patients revealed no evidence of disease.

Reactive oxygen species involvement in ricin-induced thyroid toxicity in rat.

Ricin is known to have diverse effects on the cells of different organs like liver, kidney, pancreas, intestines and parathyroid. Acute decrease in serum thyroid hormone level 24 h after ricin administration (1.5 micrograms/100 g) led us to suspect the toxic action of ricin on the thyroid. We monitored the lipid peroxidation (LP) and anti-oxidant status of the thyroid tissue to determine the role, if any, played by reactive oxygen species (ROS) in this pathology. An increase of 39% in LP and 47% in superoxide dismutase, along with a 8.5% decrease in catalase points to the imbalance in the antioxidant defence involving hydrogen peroxide and its univalent reduction product, the hydroxyl radical. Thyroid histopathology shows destruction of thyroid follicles and necrosis, which may be due to ROS and may partly explain the 50% reduction in circulating thyroid hormones seen after ricin administration.