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Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation. The Kiel Lymphoma Study Group.

BACKGROUND: In order to establish the clinico-pathological properties of angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma, we evaluated the type, incidence and prognostic significance of clinical and laboratory symptoms. PATIENTS AND METHODS: Sixty-two consecutive patients diagnosed at the Kiel lymph node registry participated in the study. The median patient age was 64 years (range 21-87 years) and the female to male ratio was 1:1.4. Ninety percent of the patients were in stage III and IV and B-symptoms were observed in 68%. At diagnosis patients presented with skin rash (49%), pruritus (32%), edema (38%), pleural effusion (37%), arthritis (18%) and ascites (23%). Furthermore, they exhibited autoimmune phenomena such as cold agglutinines, circulating immune complexes, a positive Coombs test, smooth muscle antibodies, rheumatoid factors, immune hemolysis, a paraprotein, antinuclear antibodies and cryoglobulins. RESULTS: In univariate analysis, survival was significantly related to age (p=0.032), stage (p=0.037), B symptoms (p=0.007), rash/pruritus (p=0.038), edema (p=0.030), ascites (p=0.013), number of clinical symptoms including B symptoms (p=0.004) and excluding B symptoms (p=0.017), lactate dehydrogenase (p=0.007) and hemoglobin (p=0.020). CONCLUSIONS: AILD type T-cell lymphoma characteristically differs from other non-Hodgkin's lymphomas in its clinical signs and laboratory symptoms.

Adult↗

Primary thyroid lymphoma: a retrospective analysis of prognostic factors and treatment outcome for localized intermediate and high grade lymphoma.

Non-Hodgkin's lymphoma presenting in the thyroid gland is uncommon. A review of the King Faisal Specialist Hospital and Research Centre (KFSH & RC) experience was performed to assess treatment outcome and prognostic factors in this rare extranodal presentation of localized lymphoma. Sixty patients treated at KFSH & RC between 1975 and 1995 were identified, and their records were reviewed retrospectively. Eight patients who had stage III or IV disease, low grade, or did not complete their prescribed treatment were excluded from the study. There were 38 female and 14 male patients with a median age of 59.5 years at the time of diagnosis (range: 10-87 years). Thirty-five of the 52 patients underwent diagnostic partial or total thyroidectomy at other institutions based on a preoperative assumption of thyroid carcinoma. All 52 patients had non-Hodgkin's lymphoma of intermediate (94%) or high (6%) grade. Detailed staging was carried out in all patients; 16 patients (31%) had disease confined to the thyroid gland (stage IE), whereas 36 (69%) had associated disease in cervical lymph nodes and/or the mediastinum (stage IIE) disease. All patients were treated with curative intent. A total of 18 patients (35%) were treated with a single-modality treatment--radiotherapy alone in 2, chemotherapy alone in 13, and surgery alone in the remaining 3 patients. The majority of patients (34/52; 65%) were treated with a combined-modality approach. The overall relapse-free survival (RFS) and overall survival (OS) at 5 years were 72% and 88%, respectively. There were no significant differences in outcome between those treated with single-modality and those with combined-modality therapy. A univariate analysis showed that the presence of mediastinal lymph node involvement was the most important prognostic factor affecting both RFS and OS. Patients with Hashimoto thyroiditis and without "B" symptoms were found to have a significantly higher RFS without influence on the OS. However, patients who had a good performance status (PS) of 0, 1, and 2 were found to have a significantly higher overall survival in comparison to those with poor performance status. Age, sex, stage, histology, lactic acid dehydrogenase level, tumor bulk, and the treatment modality were not found to correlate with RFS or OS. Mediastinal involvement and PS were found to be the most important independent prognostic factors influencing RFS and OS.

Female↗

Epstein-Barr virus-associated gastric lymphomas are distinct from mucosa-associated lymphoid tissue-type lymphomas: genetic abnormalities of p53 gene.

The authors studied 46 primary gastric lymphomas for expression of the p53 gene by immunohistochemistry and screened for mutations in p53 exon 5-8 by polymerase chain reaction-single strand conformation polymorphism. Twenty-five specimens cases were also analyzed for loss of heterozygosity (LOH) of chromosomal region 17p12-13.1. In 36 lymphomas negative for Epstein-Barr virus (EBV) infection, of which 29 were of mucosa-associated lymphoid tissue (MALT) type, p53 genetic changes were found in 47.2% but correlated poorly with overexpression. Only 20% of the mutations involved exon 7. There were recurrent mutations of intron 7, intron 6, and exon 6. In contrast, the 10 EBV-positive cases, none of MALT type, had a much higher rate of mutation, and all showed both p53 overexpression and p53 mutation and/or LOH, and 87.5% had mutations involving exon 7. Four of these involved codon 242, not seen in the EBV-negative group. Splicing mutations of intron 8 were seen in three specimens, two involving the same nucleotide position. In four of five specimens, LOH analysis identified microsatellite instability, allelic loss, or both. The Helicobacter pylori infection rate in the EBV-positive group (20%) was much lower than in the EBV-negative group (91.7%). These differences between the two groups suggest involvement of different carcinogens. Mutation of codon 242 has not been specifically associated with other tumors and may represent a mutational hot spot in the EBV-positive lymphomas.

Adult↗

Anaplastic large cell lymphoma, so-called Ki-1 lymphoma: a report of a case of long course.

A 55-year-old female with a complaint of tumors on the right lower extremity was reported. The condition was diagnosed as anaplastic large cell lymphoma, so-called Ki-1 lymphoma, by its histological and immunohistochemical features. The clonal proliferation of the infiltrating cells of the skin lesions was confirmed by the analysis of T cell receptor gene rearrangement. The lesions have repeatedly occurred on the right lower extremity for more than ten years. In this report, we also discuss the prognosis of anaplastic large cell lymphoma with or without skin lesions.

Anaplasia↗

Distinct pattern of gene expression in pyothorax-associated lymphoma (PAL), a lymphoma developing in long-standing inflammation.

Pyothorax-associated lymphoma (PAL) is a unique lymphoma developing in the pleural cavity after long-standing pyothorax. They are diffuse large B-cell lymphomas (DLBCLs), frequently with immunoblastic morphology, and show a strong association with Epstein-Barr virus (EBV) infection. In this study, cDNA microarray analysis was performed in six cases with PAL and 12 with nodal DLBCL. Among 5516 informative genes, 348 displayed more than 2-fold difference (higher or lower) of expression level between PAL and nodal DLBCL (P < 0.001). These genes are known to be involved in apoptosis, interferon response, and signal transduction. One of the most differentially expressed genes, IFI27 (interferon-alpha-inducible protein 27) was subjected to quantitative RT-PCR analysis, and increased expression of IFI27 was confirmed. Overexpression of IFI27 was also found in cell lines derived from PAL, but not in other lymphoid cell lines. This study shows that PAL is a distinctive subtype of DLBCL not only in its clinical presentation, but also in its molecular profile.

Adult↗

Clinical and immunological study of non-Hodgkin T-cell lymphomas (cutaneous and lymphoblastic lymphomas excluded).

We present here the immunologic, morphologic and clinical features of 16 T-derived adult non-Hodgkin lymphomas (NHL) (lymphoblastic and cutaneous lymphomas being excluded) observed in an unselected series of 260 NHL. Malignant cells bore T cell antigens (16 cases) but formed E rosettes in 14 cases only. In nine cases studied with monoclonal antibodies to T cell antigenic subsets, the phenotype of malignant cells was homogeneous; in seven cases the cells had a clear-cut helper or suppressor/cytotoxic phenotype; in one case cells had a cortical thymocyte phenotype. No T-cell subset antigens were detected on malignant cells from the last patient. Prominent morphologic features were a striking variation in tumour cell sizes, vascular proliferation and admixture of a large number of macrophages; most often, those lymphomas with a diffuse growth pattern could not be easily assigned to a given NHL subtype. The course of the disease was aggressive in most patients, only four having experienced a sustained complete remission. Waldeyer's ring involvement, waxing and waning nodes, polyclonal hypergammaglobulinaemia and skin infiltrates may be distinctive clinical features in some patients.

Adult↗

Multilobated B-cell lymphoma, a variant of centroblastic lymphoma. Report of four cases.

Four cases of multilobated B-cell lymphoma, one follicular and three diffuse, are described. Many of the lymphoma cells show marked lobulation of the nuclei, and possess multiple prominent nucleoli. There are admixed classical centrocytes, classical centroblasts, and cells with morphology intermediate between classical centroblasts and multilobated cells. Multilobated cells are also observed in small numbers in germinal centres of lymph nodes showing reactive follicular hyperplasia. We believe that the multilobated B-cell may represent one form of centroblast during transition between the centroblastic and centrocytic stages. Multilobated B-cell lymphoma may be its neoplastic counterpart in which the nuclear lobulation is further exaggerated.

Adult↗

Pyothorax-associated lymphoma: development of Epstein-Barr virus-associated lymphoma within the inflammatory cavity.

Pyothorax-associated lymphoma (PAL) is a B cell lymphoma that develops in Japanese patients with tuberculosis-associated chronic pyothorax (TaCP). Epstein-Barr virus (EBV) has been shown to be causally related to PAL. To clarify the developmental process of PAL, the systemic and local presence of EBV, and serum profile of anti-EBV antibodies was investigated in TaCP. EBV genome was found in peripheral blood mononuclear cells by PCR in a 10(-4)-10(-5) amount of Raji cell-DNA in three of four patients with TaCP, but was also identified in patients with pyothorax caused by other diseases (2/2) or without pulmonary diseases (2/6). EBER1 in situ hybridization and EBNA2 immunocytochemistry revealed clusters of EBV-carrying cells in the cavity content (3/18) but not at the pyothorax wall; EBV(+) histological lymphoma cells were found in two cases and EBV(+) mononuclear cells were found in one case. A simultaneous increase in serum titers of anti-EBV viral capsid antigen IgG and IgA antibodies was observed in TaCP (4/16). These results suggest that a local factor, an inflammatory cavity, has a pivotal role in the development of PAL, which might be reflected in the serum titers of anti-EBV antibodies in patients with TaCP.

Antibodies, Viral↗

Establishment and characterization of new human Burkitt's lymphoma cell lines (HBL-7 and HBL-8) that are highly metastatic in SCID mice: a metastatic SCID mouse model of human lymphoma lines.

Two newly established human Burkitt's lymphoma cell lines (HBL-7 and HBL-8) were characterized by immunophenotypic, cytogenetic and molecular studies. Both cell lines were negative for Epstein-Barr virus (EBV) genome and had chromosomal translocation: t(8;14) (q24;q32). Immunoglobulin (Ig) gene rearrangement analyses confirmed that both cell lines were derived from primary lymphoma cells. These cell lines were heterotransplanted subcutaneously into severe combined immunodeficiency (SCID) mice to investigate the metastatic capacity. The most striking feature of both cell lines was to show highly spontaneous metastasis to distant organs, particularly spleen, bone marrow and ovaries in SCID mice. To elucidate the metastatic factors involved in the process of spontaneous metastasis, cell surface adhesion molecules or extracellular matrix receptors were analyzed. However, the results did not allow a significant correlation between expression levels of those molecules or matrix receptors and spontaneous metastasis in the SCID mouse model. The HBL-7 and HBL-8 cell lines, however, may be a useful tool to elucidate the metastatic mechanisms of human lymphomas in an animal model.

Adolescent↗

Survival following combination chemotherapy in advanced high grade non-Hodgkin's lymphomas: relation to proliferative activity of the lymphoma cells.

In 18 untreated adult patients (median age 62.5 yr) with advanced non-Hodgkin's lymphoma of unfavourable histology, thymidine labelling indices (LIs) of the lymphoma cells were assessed. The patients were treated with combination chemotherapy and have been followed for 29-60 (median 52) months or until death. The survival curve had a steep fall during the first 2 yr. Between 2-5 yr after treatment there was a flattening of the curve and survival seemed to be similar to the survival expected for a Swedish population matched for age and sex. 11 patients died with 2 yr and 7 patients have survived for a longer period. Age, histopathologic classification and clinical stages were comparable in short-term and long-term survivors and treatment was not more aggressive for the long-term survivors. The LIs were significantly higher (median 8.2) in short-term survivors than in the long-term survivors (median 1.4). Long-term survival following combination chemotherapy of advanced NHL of unfavourable histology seems to be achieved mainly in patients with a low proliferative activity of the lymphoma cells. It is suggested that in NHL a high proliferative activity may facilitate the generation of new mutants and that some of these are spontaneously resistant to various chemotherapeutic drugs.

Adult↗

JunB induced by constitutive CD30-extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling activates the CD30 promoter in anaplastic large cell lymphoma and reed-sternberg cells of Hodgkin lymphoma.

High expression of CD30 and JunB is characteristic of tumor cells in anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL). Possible interactions of CD30 and JunB were examined in this study. We found that the CD30 promoter in tumor cells of both nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK)-positive and NPM-ALK-negative ALCL and HL is regulated by a constitutively active CD30-extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase (MAPK). Phosphorylation of ERK1/2 MAPK was confirmed in nuclei of tumor cells in both ALCL and HL. CD30-ERK1/2 MAPK signals induce JunB expression, which maintains high activity of the CD30 promoter. JunB induction seems to be largely independent of nuclear factor kappaB in ALCL and HL. These results show a common mechanism of CD30 overexpression in ALCL and HL, although the outcome of CD30 signaling differs between NPM-ALK-positive ALCL and NPM-ALK-negative ALCL, cutaneous ALCL, and HL as we recently reported.

Cell Line, Tumor↗

Diffuse large cell lymphomas: identification of prognostic factors and validation of the International Non-Hodgkin's Lymphoma Prognostic Index. A Hellenic Cooperative Oncology Group Study.

Several clinical prognostic factors have been identified that predict treatment outcome in patients with diffuse large cell lymphomas. An International Non-Hodgkin's Lymphoma Prognostic Index (IPI) has been recently formulated. We tried to identify the clinical prognostic factors that predict treatment outcome in Greek patients with diffuse large cell lymphomas and validated the IPI in these patients. The possible prognostic variables for tumor response, relapse-free (RFS) and overall survival (OS) were analyzed in 239 consecutive patients treated with anthracycline-based chemotherapy regimens. In univariate analysis, factors associated with poor response were stages III-IV, performance status (PS) >/=2, spleen and bone marrow involvement, more than one extranodal site involved, increased lactate dehydrogenase (LDH) value, hemoglobin (Hb) <12 g/dl, albumin <3.5 g/dl, erythrocyte sedimentation rate (ESR) >50 mm/h. Multivariate analysis identified stage, PS, more than one extranodal site involved, increased LDH level, and ESR > 50 mm/h as the factors more predictive of poor response. For RFS, multiple Cox analysis found stages III-IV and bone marrow involvement to be statistically significant. For OS, multiple Cox analysis identified stage III-IV, PS >/=2, bone marrow involvement, more than one extranodal site involved, increased LDH level and ESR > 50 mm/h as negative prognostic factors. Patients stratified in the different risk groups of the IPI had a significantly different outcome regarding complete response (CR) rate, RFS and OS. In conclusion, although age >60 years was not recognized as an adverse factor in this analysis, our patients stratified in the different groups of the IPI had significant differences in CR rate, 2-year RFS and OS verifying the prognostic significance of the index. Bone marrow involvement and ESR > 50 mm/h, parameters that are not included in the IPI, adversely affected survival.

Adult↗

Anaplastic large-cell lymphoma (Ki-1 lymphoma) with expression of IL-5 mRNA and eosinophilic invasion.

We examined a patient with anaplastic large-cell lymphoma (Ki-1 lymphoma) showing eosinophilic invasion of the tumor tissues. The number of eosinophils in the peripheral blood changed as a function of the stage of the disease. The IL-5 gene was expressed in the tumor tissues, suggesting that the eosinophilic invasion and eosinophilia were caused by IL-5 derived from the lymphoma cells.

Adult↗

Lymphoepithelioid cell lymphoma (Lennert's lymphoma). Report of a case with fine needle aspiration cytology.

BACKGROUND: Lymphoepithelioid cell lymphoma (LCL) is a rare morphologic variant of peripheral T-cell lymphoma. Although their histopathologic and immunohistochemical findings are well known, the cytopathologic features have not been well documented. This report describes the fine needle aspiration cytology (FNAC) findings of a case of LCL. CASE: A 75-year-old woman presented with cervical, supraclavicular, axillary and mediastinal lymphadenopathy. FNAC of a cervical lymph node was performed. The smears contained a polymorphous infiltrate formed by abundant histiocytes disposed singly or in clusters, small and medium-sized to large atypical lymphoid cells and reactive cells, including eosinophils and plasma cells. Isolated capillary-sized vessels also were observed. Histopathologic and immunohistochemical examination confirmed the diagnosis of Lennert's lymphoma. CONCLUSION: Although histopathologic and immunohistochemical studies were required for a definitive diagnosis, the findings of FNAC in this case appeared distinctive and suggested the possibility of LCL.

Aged↗

Non-Hodgkin's lymphomas of the tonsil: a retrospective analysis of twenty-eight patients with primary tonsillary lymphoma.

AIMS: To analyze the clinical and therapeutic aspects of patients with primary tonsillary non-Hodgkin's lymphoma. METHODS: Twenty-eight patients with primary tonsillary non-Hodgkin's lymphoma who had been followed in the Hacettepe Oncology Institute between 1974 and 1992 were retrospectively analyzed. Fifteen patients were male, 13 were female. Median age was 55 years. RESULTS: Constitutional symptoms were present in 10 patients (35.7%). Stages according to the Ann Arbor classification were I and II in 12 and 16 patients, respectively. According to the Rappaport classification, poorly differentiated lymphocytic was the most common pathologic subgroup (42.9%). Grades according to the Working Formulation were low, intermediate and high in 3, 22 and 3 patients, respectively. Twenty-two patients had received chemotherapy. Cyclophosphamide, vincristine and prednisone (CVP), and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) were the regimens most commonly employed. Eighteen patients received radiotherapy to Waldeyer's ring and neck. Eight patients achieved remission with chemotherapy plus radio-therapy, 7 patients with chemotherapy alone, and 5 patients with radiotherapy alone. In addition to the 20 patients who achieved complete remission, 3 patients achieved partial remission; the overall response rate was 82.1%. The response rates and survival attained with the combined modality, chemotherapy, or radiotherapy alone were not statistically different (P > 0.05). The median follow-up was 14 months. Overall and disease-free survival at 5 years were 62.6% and 77.6%, respectively. Pathologic grade was the most important prognostic factor influencing overall survival in the Cox multivariate model. CONCLUSIONS: Poorly differentiated lymphocytic lymphomas were the most common pathologic subtype, and pathologic grade was the most important prognostic factor to influence survival in the present study. Although combined modality treatment did not appear to be superior to chemotherapy or radiotherapy alone, a larger number of patients is needed to draw definite conclusions.

Adult↗

The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome.

The Follicular Lymphoma International Prognostic Index (FLIPI) was developed to predict prognosis of patients with follicular lymphoma (FL). However, it was based on different protocols, none of which included rituximab. The current analysis aimed at evaluating the predictive value of the FLIPI for treatment outcome in 362 patients with advanced-stage FL treated front-line with rituximab/CHOP in a prospective trial of the German Low Grade Lymphoma Study Group. According to the FLIPI, 14% of the patients were classified as low-risk, 41% as intermediate-risk, and 45% as high-risk patients. With a 2-year time to treatment failure (TTF) of 67%, high-risk patients had a significantly shorter TTF as compared with low- or intermediate-risk patients (2-year TTF of 92% and 90%, respectively; P < .001). Our data demonstrate that the FLIPI is able to identify high-risk patients with advanced-stage FL after first-line treatment with rituximab/chemotherapy.

Adult↗

MACOP-B versus ProMACE-MOPP in the treatment of advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group.

PURPOSE: The aim of our study was to compare in a multicentric randomized trial two regimens widely used in the treatment of advanced-stage intermediate- to high-grade non-Hodgkin's lymphoma and to assess whether a third-generation regimen (methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B]) was superior to a second-generation regimen (procarbazine, methotrexate with leucovorin, doxorubicin, cyclophosphamide, and etoposide [ProMACE-MOPP]). PATIENTS AND METHODS: Between January 1987 and August 1991, 221 patients with diffuse intermediate- to high-grade non-Hodgkin's lymphoma (Working Formulation groups F, G, H, and K), stage II bulky (> 10 cm), III, or IV, were randomized by the Non-Hodgkin's Lymphoma Cooperative Study Group (NHLCSG) to receive ProMACE-MOPP for six cycles or MACOP-B for 12 weeks. Survival, progression-free survival, and disease-free survival were determined, and multivariate analysis of prognostic factors was performed. RESULTS: In the two groups of patients, there was no significant difference in terms of complete remission (CR) rate (49.1% with ProMACE-MOPP and 52.3% with MACOP-B), 3-year overall survival rate (45.2% with PROMACE-MOPP and 52.3% with MACOP-B), and 3-year progression-free survival rate (36.4% with ProMACE-MOPP and 36.1% with MACOP-B). In terms of toxicity, no significantly greater toxicity occurred in either arm. Overall toxicity was acceptable. The most frequent side effects were grade II through IV leukopenia, infection, mucositis, and anemia. Treatment-related deaths were equally distributed. CONCLUSION: No significant differences in terms of efficacy and/or toxicity between ProMACE-MOPP and MACOP-B are evident. These results are consistent with recent randomized trials showing that the new-generation aggressive regimens are no better than previous ones.

Adolescent↗

Purging of bone marrow in autologous bone marrow transplantation for non-Hodgkin's lymphoma: a case-matched comparison with unpurged cases by the European Blood and Marrow Transplant Lymphoma Registry.

PURPOSE: The use of in vitro purging of bone marrow in autologous bone marrow transplantation (ABMT) for non-Hodgkin's lymphoma (NHL) has been a controversial issue; its benefit is as yet unproven. Its effect on the clinical outcome of ABMT in these patients is still unclear. We look at this issue using data from the European Blood and Marrow Transplant (EBMT) Lymphoma Registry. PATIENTS AND METHODS: Seventeen hundred twenty-six patients with NHL have been reported to the EBMT registry, of whom 270 had bone marrow purged at transplant. Two hundred twenty-four of these patients were compared with a case-matched group of 224 unpurged patients who had undergone the same procedure. The case matching was made following selection of the main prognostic factors for progression-free survival (PFS) by multivariate analysis. Response, complications, and outcome in ABMT were analyzed. RESULTS: Time to hematologic engraftment, response to ABMT, and number of procedure-related deaths were similar in purged and unpurged patients. The overall survival (OS) rate was 54% at 5 years in purged patients and 48.3% in unpurged patients (P = .1813). The PFS rate was 44.3% and 44.6%, respectively (P = .1961). Patterns of relapse, including bone marrow relapse, were similar in both groups. Patients with low-grade lymphoma did not have a significantly improved PFS if the bone marrow was purged (P = .1757); however, they did have a significantly improved OS (P = .00184). This increased OS was found to be associated with non-totalbody irradiation (TBI) conditioning and also with the purged patients undergoing transplantation at large transplant centers (P = .0016). CONCLUSION: Purging of bone marrow in ABMT for NHL does not affect the rate of hematologic engraftment or risk of procedure-related death (PRD). There is no significant difference in PFS for patients whose bone marrow is purged as compared with unpurged.

Adolescent↗