Follicular Mixed Lymphoma Research Articles

The Percentage of Tumor-Infiltrating T Cells Is Not Correlated with Overall Survival in Follicular B-Cell Lymphomas.

Introduction: The function of tumor-infiltrating T cells in lymphoma is unknown. Previous studies have shown that an increased percentage of tumor-infiltrating CD4+ T cells was associated with a better overall survival in diffuse large B-cell lymphoma (Ansell S. et al. JCO 2001; Xu et al., British Journal of Haematology 2001). Furthermore, the CD4+ T cells observed in one study was associated with a CD3+/HLA-DR + phenotype, suggesting that they were activated T helper cells. Recently, a molecular predictor model for follicular lymphoma was reported based on microarray analysis of gene expression within the cell populations of biopsy specimens. Three groups of “predictor genes” were identified: one representing B-cell differentiation and two groups representing genes expressed by T cells and macrophages, respectively (ASH abstract, 2003). This raised the question of whether it was simply the presence of tumor-infiltrating T cells that correlated with clinical outcome as opposed to specific activation pathways within those cells.Purpose: The purpose of this study was to examine whether the percentage of tumor-infiltrating T cells is correlated with prognosis of follicular lymphoma.Patients and Methods: We identified 293 follicular lymphoma patients with clinical outcomes available within the Stanford lymphoma database, who had undergone an excisional biopsy, and whose tumor biopsy specimens had been analyzed by flow cytometry. These patients were diagnosed between 1977 and 2003. Among these patients, 167 (57%) had follicular small cleaved lymphoma, 112 (38%) had follicular mixed lymphoma, and 14 (5%) had follicular large cell lymphoma. A total of 66 deaths were documented. The overall survival was estimated from the time of diagnosis to the time of death or last follow-up. Biopsies had been analyzed for cell surface marker expression by single parameter flow cytometry. The percentage of CD3+, CD4+, CD8+, CD20+, and HLA−DR+ cells was determined directly. We also estimated activated T cells, defined by HLA−DR+ T cells, by subtracting the value for total B cells from the value for HLA + cells. Cell population percentages were treated as continuous variables and related to overall survival, each in a univariate analysis.Results: We found no statistically significant correlation between the percentage of any cell population and overall survival. For each group (CD3+, CD4+, CD8+, and estimated HLA−DR+ T cells), we used the percentage of the cell population to divide patients into 3 subgroups of equal number of patients: low-, medium-, and high-percentage. We then compared Kaplan-Meier curves of the 3 subgroups for each cell population. We found no significant differences in survival among the 3 subgroups for each of the cell populations, CD3+, CD4+, CD8+, and the estimated activated T cells, after correcting for multiple hypotheses testing.Conclusion: The percentage of tumor-infiltrating T cells or T cell subsets was not correlated with survival outcome in patients with follicular lymphoma. This finding provides the basis for building molecular predictive models based on gene expression analysis, which represents not only the presence of certain cells but their physiologic state as well.

Treatment of multicentric Castleman’s disease complicated by the development of non-Hodgkin’s lymphoma with high-dose chemotherapy and autologous peripheral stem-cell support

Castleman's disease or angiofollicular lymph node hyperplasia is a rare entity with a localized/unicentric or a generalized/multicentric presentation. While surgery is curable for most localized presentations, there is limited information regarding the optimal management of the multicentric type. The latter type is associated with a poor prognoses and can be associated with the development of lymphoma and infections. In this report we describe a case of multicentric Castleman's disease who failed steroids and chemotherapy and developed a follicular mixed lymphoma. He was treated with high-dose chemotherapy with autologous stem-cell support and remains disease at four years of follow-up. A long-term durable remission may be possible with high dose chemotherapy with stem-cell support. This treatment modality should be considered an option in the management of multicentric Castleman's disease.

Primary laryngeal lymphoma.

Primary laryngeal lymphoma is a very rare entity, with fewer than 50 cases reported in the English literature in the past 60 years. Close scrutiny of some of these case reports reveals that the larynx was not always the only site of involvement, thereby diminishing the total number of patients with primary laryngeal lymphoma to fewer than 35. The authors report a series of six patients, who were seen and evaluated at the Mayo Clinic between 1952 and 1995, with stage IAE non-Hodgkin's lymphoma of the larynx. Three patients had large-cell lymphomas according to the REAL (Revised European-American Lymphoid) classification. The other three had a small lymphocytic lymphoma, follicular small cleaved lymphoma, and follicular mixed lymphoma. All patients received radiation therapy alone as initial therapy for their disease and all patients had a complete remission to initial therapy. Four patients subsequently relapsed and the histology at relapse was the same as the initial histology in all four patients. Five patients have died, three of lymphoma, with a median survival of 67 months (range, 40 to 228 months). In view of the heterogeneity of histologies in this group of lymphomas, the variability in duration of response, and the significant number of patients who died of their disease, it is more likely that primary laryngeal lymphoma is an unusual presentation of non-Hodgkin's lymphoma than a separate disease entity. Despite the small number of patients in this study, the data would suggest that patients are best treated according to the histology of the lymphoma, rather than the limited stage and location of the disease.

High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin's lymphoma.

This study evaluated the results of high-dose therapy followed by autologous bone marrow or peripheral-blood stem-cell transplantation for patients with follicular low-grade non-Hodgkin's lymphoma. We performed a retrospective review of 100 patients undergoing autologous transplantation for follicular low-grade lymphoma between April 22, 1983 and December 31, 1993. Sixty-seven patients remained alive and 48 were failure-free. The median follow-up duration of surviving patients was 2.6 years (range, 1.0 to 11.7). There were eight (8%) deaths within 100 days of transplantation. Six additional patients died of nonrelapse causes up to 912 days after transplantation. Overall survival at 4 years was estimated to be 65% (95% confidence interval [CI], 54% to 75%) and failure-free survival was estimated to be 44% (95% CI, 33% to 55%). There was no definite evidence of a plateau in the failure-free survival curve. The only factor significantly associated with overall survival and failure-free survival was the number of chemotherapy regimen received before transplantation. No significant differences in outcome were observed between patients with follicular small cleaved-cell lymphoma and follicular mixed lymphoma, or between patients who received peripheral-blood stem-cell transplants and unpurged autologous bone marrow transplants. Prolonged failure-free survival is possible following high-dose therapy and autologous hematopoietic rescue for follicular low-grade lymphoma. It is unclear whether patients are cured with this therapy or if survival is prolonged.

Low-grade lymphoma: clinical and prognostic studies in a series of 143 patients from a single institution.

Clinical and prognostic studies were carried out in a series of 143 patients with low-grade (small-lymphocytic, follicular small cleaved cell, follicular mixed small- and large-cell) lymphoma. After treatment with alkylating agents (21.5% cases), combination chemotherapy (73.3%) or other therapies (5.2%), complete response (CR) was obtained in 40.7% of cases and partial response (PR) in 43.7%. The stage of the disease was the most important factor for response. With a median follow-up of 6.5 years, 48.0% (95% Cl: 37.5-58.5) of patients were alive 10 years after diagnosis. Among the initial parameters, advanced stage. B-symptoms, poor performance status, nodal involvement > 3 sites, extranodal involvement > or = 2 sites, WBC count > or = 10 x 10(9)/L, leukemic expression, high serum LDH levels, and bone marrow infiltration were all related to survival; treatment modality, however, had no influence on survival. In the multivariate analysis, stage (p = 0.008) and age (p = 0.053) were the most important prognostic factors. When considering response to therapy, both CR (p < 0.001) and PR (p = 0.003) emerged as the most important predictive variables, with only the absence of B-symptoms retaining its prognostic significance (p = 0.014) among the other parameters. In addition, in CR patients the duration of the response (< or = 1 year vs. > 1 year) was the most significant parameter for survival (p < 0.001). Finally, the initial stage (p = 0.011) and the histologic subtype (those patients with follicular mixed lymphoma relapsing less frequently than the others) (p = 0.052) were the only significant factors for relapse.

Combination Chemotherapy in the Treatment of Follicular Low-Grade Lymphoma

The therapeutic approach to patients with follicular low-grade non-Hodgkin's lymphoma is controversial and has varied over a wide spectrum. A "watch and wait" approach in asymptomatic patients has been taken in some studies. In other series, single agent therapy with alkylating agents as cyclophosphamide or chlorambucil has been employed. Response rates including complete responses are high, but relapses inevitably occur. Three-drug combination chemotherapy regimens consisting of cyclophosphamide, vincristine, and prednisone (CVP) have been utilized, in addition to more intensive regimens consisting of four or more drugs. Although responses are commonly achieved, there is no consistent survival advantage conferred by these more aggressive regimens. However, the remission duration may be prolonged in some subsets of patients as those with follicular mixed lymphoma. Due to the prolonged natural history of follicular low-grade lymphoma, a long period of follow-up is necessary to adequately evaluate the impact of a therapeutic regimen on remission duration and overall survival. Future trials may employ more aggressive therapy in combination with growth factors or biologic response modifiers in an effort to improve the outcome of patients with follicular low-grade lymphoma.

Chromosomal abnormalities in lymphoma and their correlations with nucleic acid flow cytometry

Cytogenetic studies were performed on 25 samples obtained from 25 patients with lymphoma. Fourteen of these were also simultaneously studied with nucleic acid flow cytometry to determine percent S-phase and DNA content (ploidy). In 17 cases (68%), evaluable metaphases were obtained. The evaluable metaphase rate was higher in previously untreated patients ( 15 19 or 79%). All but two cases showed abnormal karyotype. All five cases showing either the t(8;14) or t(8;22) abnormality were associated with extremely high percent S-phase values, ranging from 36% to 47%, which is in the range of high-grade lymphomas according to our previous experience. Four of these cases were diagnosed as Burkitt's lymphoma and one as diffuse large cell lymphoma. Further review of this latter case resulted in the pathologic diagnosis being changed to Burkitt's lymphoma. Three patients had either numerical or structural abnormalities of chromosome #21 [two cases of extra chromosomes and one i(21q)]. All three cases were diagnosed as diffuse large cell lymphoma. Four instances of trisomy 12 were identified. Only one of these was diagnosed as diffuse well-differentiated lymphocytic lymphoma. The remaining three were Burkitt's lymphoma in two and diffuse large cell lymphoma in one. Two instances of t(14;18) were observed. This is the characteristic abnormality of follicular lymphomas. One of these cases was a follicular large cell lymphoma. The second case had possibly originated from a follicular mixed lymphoma and had evolved into a diffuse mixed cell type. Both of these cases had low S-phase values in the range of low-grade lymphomas. The correlation between ploidy as determined by flow cytometry and cytogenetic analysis was good whenever the DNA index was elevated. However, when the DNA index was 1.0 (diploid), concordant measurements were observed in only five of eight cases. Flow cytometry detected one instance of clearly abnormal ploidy, which was thought to be diploid by cytogenetics. This case most likely represents a “false negative” cytogenetic determination.