Low apoptotic index & bak expression in EBV-associated childhood classical Hodgkin lymphoma.

BACKGROUND & OBJECTIVE: Association of Epstein-Barr virus (EBV) with Hodgkin lymphoma (HL) is particularly high in low-income countries, and resistance to apoptosis might play a role in pathogenesis and survival. Data from previous studies are not consistent, and none is available in children. Thus this study was undertaken on Indian children with classical Hodgkin lymphoma to assess the significance of bcl-2, bak and p53 expression, and apoptotic index in relation with EBV status and treatment outcome with chemotherapy alone. METHODS: Children (age<15 yr) with classical HL (n=143) were included in the study. Bcl-2, bak, p53, Ki67 and latent membrane protein-1 (LMP1) were detected by immunohistochemistry in pre-treatment lymph node biopsies. Apoptotic index was assessed by TdT-dUTP nick-end labelling (TUNEL). RESULTS: Bcl-2, bak, p53 were expressed above positivity threshold in 83.3, 94.0 and 7.1 per cent of the cases respectively. More than 10 per cent of apoptotic tumour cells were seen in 60.4 per cent of the cases. 131 (91.6%) cases were EBV associated. EBV-positive cases had a significantly lower mean bak expression (p=0.001) and a lower apoptotic index, without higher proliferation index. Advanced stage showed a borderline association with bcl-2 expression in >25 per cent of tumour cells and p53 negative tumours. In univariate analysis, p53 positive cases, which were significantly associated with B symptoms, had a poorer overall survival (P=0.03) while low proliferation index was associated with poorer failure-free survival. Neither EBV status nor any of the apoptotic parameters studied showed independent association with survival. INTERPRETATION & CONCLUSION: EBV detection in children with classical Hodgkin lymphoma was associated with significant lower bak expression and with lower spontaneous apoptosis of H-RS cells suggesting that EBV-LMP1 might downregulate bak pro-apoptotic protein. this needs to be substantiated further.

Proliferative index and CD15 expression in pediatric classical Hodgkin lymphoma.

BACKGROUND: This study was conducted to assess the clinical and prognostic significance of lack of CD15 expression, proliferative index (PI), and expression of tumor suppressor protein p53 in pediatric classical Hodgkin lymphoma (CHL). PROCEDURE: Pre-treatment lymph node (LN) biopsies were studied by immunohistochemistry for immunophenotyping of the lymphoma and with Ki-67 (PI) and p53 antibodies. Expression of CD15 antigen on the Hodgkin and Reed-Sternberg (H-RS) cells, proliferation, and apoptosis parameters were correlated with clinical stage, response to chemotherapy alone, overall (OS) and failure-free survival (FFS). RESULTS: One hundred and twenty-one children with CHL were studied. Expression of Ki-67 and p53 in H-RS cells was seen in 100% and 89.9% of the cases, respectively. Loss of CD15 expression, seen in 12 (9.9%) cases, was significantly associated with p53 negativity and was an independent prognostic factor for poor OS and poor FFS. PI

Hodgkin's lymphoma in Indian children: prevalence and significance of Epstein-Barr virus detection in Hodgkin's and Reed-Sternberg cells.

AIM: This study was done to document the prevalence of Epstein-Barr virus (EBV) in Hodgkin's lymphoma (HL) in children of North India. METHODS: 145 previously untreated children diagnosed with HL from 1991 to 2003 were included. Lymph node (LN) biopsies were studied and classified using World Health Organisation (WHO) classification. EBV detection was done by immunohistochemistry (IHC) and in situ hybridisation (ISH) in 145 cases and 25 age- and sex-matched controls. Patients were treated with chemotherapy alone. RESULTS: EBV was detected by IHC in 131 (90.3%) cases and by ISH in 126 (93.3%) out of 135 cases, and in none of the controls examined. With IHC and ISH combined, EBV positivity was seen in 96.6% and was significantly associated with younger age (p=0.012) and lower socioeconomic level (p=0.007). EBV status had no implication on treatment response and survival. CONCLUSION: EBV detection in 96.6% of childhood HL in a population with almost universal EBV seroconversion, and in none of the control lymph nodes, suggests a causative role of EBV in most cases of Indian childhood HL.

Epidemiology of childhood Hodgkins disease: is it different in developing countries?

Childhood Hodgkins Disease (HD) is a lymphoma that displays characteristic epidemiological, clinical and pathological features according to various geographic areas, particularly according to the socio-economic level of a given country. India presents a similar sex, age and subtype distribution as other emerging countries: high male-to-female ratio, younger age at presentation, high proportion of advanced stages and presence of constitutional symptoms, predominance of mixed cellularity type of HD. The etiology of HD is still the subject of controversy and investigation, but it may occur as a sequel of a viral infection during early childhood, such as Epstein-Barr virus (EBV). Most cases of Indian childhood HD are associated to EBV, while genetic predisposition is seen in very rare cases.

Hodgkin's disease in Indian children: outcome with chemotherapy alone.

BACKGROUND: To assess the efficacy of chemotherapy alone, using four cycles of COPP alternating with four cycles of ABVD in all stages of childhood Hodgkin's disease (HD). PROCEDURE: Between January 1991 and February 2001, 148 previously untreated patients were investigated, treated, and analyzed for remission and survival. RESULTS: There were 134 boys and 14 girls with a median age of 8 years, 75% were less than 10 years old. 63.5% had advanced stage disease (IIB-IV). B symptoms were present in 54.4% of cases; bulky mediastinal mass in 18 cases (12.2%); spleen and bone marrow involvement in 22 (14.9%) and four cases (2.7%), respectively. Mixed cellularity (MC) subtype was found in 86.0%. Response to treatment was evaluated in 133 patients: complete remission (CR) was achieved in 121 patients (91.0%), partial remission (PR) in seven (5.3%), progression occurred in two (1.5%), and three (2.3%) died on therapy. Four patients with mediastinal residual disease were given additional involved field radiotherapy. Out of 111 patients analyzable, five (4.5%) have relapsed 6-30 months after completing chemotherapy, and were treated with additional cycles of ABVD and low-dose involved field radiotherapy. The 5-year actuarial overall survival (OS) and event-free survival (EFS) are 91.5 and 87.9%, respectively. Advanced stage, B symptoms, anemia, spleen, and marrow involvement were adverse prognostic factors for survival. CONCLUSIONS: Chemotherapy alone with alternating COPP/ABVD, without additional radiotherapy, provides high rates of durable remission and is an effective therapy in childhood HD, even in case of large mediastinal mass and peripheral or abdominal bulky disease.

Current strategies in the treatment of childhood Hodgkins disease.

Dramatic changes in the treatment of childhood Hodgkins disease have taken place during the past three decades. Contemporary combined modality treatment regimens produce durable disease-free survival in 90 to 100%of patients with early disease and in 70 to 85%of patients with advanced disease. Studies using chemotherapy alone also report high survival rates, and current studies are few to highlight the superiority of chemo-radiotherapy vs. chemotherapy alone. After the prodigious improvement achieved in response and survival rates, current strategies aim at reducing late effects of therapy, reserving more aggressive treatment modalities for patients with high risk features.

Significance of splenomegaly in childhood Hodgkin disease.

OBJECTIVES: Spleen involvement in childhood Hodgkin disease (HD) has not been described extensively. The authors' purpose was to study the clinicoradiologic features and prognostic significance of splenomegaly and that of splenic involvement in childhood HD. METHODS: One hundred forty-one children presenting with HD between January 1991 and February 2001 and treated with chemotherapy alone (4 COPP/4 ABVD) were included in the study. Radiotherapy was given in four patients with residual mediastinal disease. Patients were staged clinically and assessed for splenic deposits by computed tomography, ultrasonography, or both. RESULTS: Splenic involvement was seen in 22 children (15.6%). On univariate analysis, spleen deposits were significantly correlated with constitutional symptoms (P = 0.02), splenomegaly on physical examination (P < 0.001), involvement of three or more lymph node areas (P = 0.006), involvement of subdiaphragmatic lymph nodes (P = 0.01), mediastinal involvement (P = 0.001), and bulky disease (P = 0.005). Multivariate analysis retained enlarged spleen, involvement of three or more lymph node areas, and bulky disease as significant risk factors for spleen involvement. Relapse occurred significantly more in children with splenic involvement (P = 0.04) and in those with splenomegaly (P = 0.04). Presence of splenic deposits was an adverse prognostic factor for 5-year event-free survival (67.5% vs. 93.0%, P = 0.01). CONCLUSIONS: Enlarged spleen, involvement of three or more lymph node areas, and bulky disease are predictable risk factors for HD splenic deposits. Splenic involvement on computed tomography scan or ultrasonography is significantly associated with relapse and contributes to a poorer outcome of HD in children treated with chemotherapy alone.

Visual outcome in macular retinoblastoma treated with primary chemotherapy.

In this prospective clinical study, we treated 8 patients (8 eyes, 11 tumors) of macular retinoblastoma with chemotherapy alone, with the aim of avoiding visual loss because of retinal damage by radiation or adjuvant therapy and to assess their final visual outcome. The mean basal dimension of the tumor was 5.0 +/- 2.6 mm and the mean height was 2.9 +/- 1.3 mm. The fovea was involved in 4 patients (50%) and foveal detachment was present in 3 patients (37.5%). All the patients required less than 6 cycles for tumor control. Four patients (50%) obtained visual acuities ranging from 20/25 to 20/200. Two patients (25%) could gain visual acuity of 20/20. The mean follow-up of patients was 3.24 +/- 0.9 years (range 2-5). No patient developed recurrence or metastatic disease. In conclusion, recent trends for ocular salvage have favored chemoreduction followed by focal therapy for the treatment of retinoblastoma. This study supports the consideration of chemotherapy alone as the primary treatment in eyes with macular retinoblastomas, under close supervision, with satisfactory visual outcome.