BACKGROUND & AIMS:Stomach-conserving therapy in primary gastric non-Hodgkin's lymphoma (mucosa-associated lymphoid tissue [MALT]-NHL) is increasingly gaining importance as an alternative to surgery. As a consequence, surgical pathologists have to define histological criteria in pretreatment endoscopic biopsy specimen samples not only to make the diagnosis but also to recognize minor tumor components that may infer a significantly adverse impact on prognosis. The aim of this study was to define histological criteria for clinically significant tumor progression in pretreatment endoscopic biopsy specimens.METHODS:In a consecutive series of 106 patients with gastric MALT-NHL, the prognostic impact of large cell components was assessed by semiquantitative analysis of clusters and diffusely intermingled malignant blasts.RESULTS:In low-grade MALT-NHL, a category with a diffuse large cell component of 1%-10% with or without nonconfluent clusters of blasts could be separated with a significantly worse prognosis (10-year disease-specific survival, 90% vs. 75%). No clinical parameters of known prognostic significance could account for this difference.CONCLUSIONS:It is possible to define criteria in endoscopic biopsy specimens to recognize clinically relevant tumor progression. To serve as a guideline in the choice of treatment, these criteria should be validated prospectively in future clinical trials.

Although the results of treatment of Hodgkin's disease (HD) have improved considerably in the last decades, the disease remains fatal in a minority of patients. We have recently shown that numbers of activated cytotoxic T cells (CTLs), present in tumor biopsy specimens, differ considerably among individual HD patients. Because CTLs are the major effector cells in elimination of neoplastic cells, we investigated whether the number of activated CTLs is related to the clinical outcome of the individual patient with HD. Activated CTLs present in tumor biopsy specimens of patients with nodular sclerosis or mixed cellularity HD were identified by immunohistochemistry using an antibody directed against granzyme B (GrB), a major constituent of the cytotoxic granules of activated CTLs and natural killer cells, and an antibody directed against CD8. The presence of a high percentage of GrB+ lymphocytes was found to be an unfavorable prognostic marker. The large majority of GrB+ cells were also CD8+, indicating that these cells are activated CTLs. Prognosis was found to decrease with increasing percentages of GrB+ lymphocytes. Optimal discrimination between patients with good and poor prognosis was obtained when the threshold was set at 15% GrB+ cells; 6 of 10 patients with > or = 15% GrB+ lymphocytes died as a result of the disease, as compared with 6 of 70 patients with less than 15% GrB+ lymphocytes (P < .0001). In stage-2 patients, the percentage of GrB+ lymphocytes retained its predictive value in a multivariate analysis including histology, sex, age, erythrocyte sedimentation rate, and the presence of B symptoms as covariables. In addition, patients with > or = 15% GrB+ lymphocytes had a shortened progression-free survival time (P = .002). We conclude that a high percentage of activated CTLs present in biopsy material of HD patients is a strong indicator for an unfavorable clinical outcome.

Cytological examination of biopsy samples obtained by fine-needle aspiration appears to be an accurate and reliable basis for the classification of canine non-Hodgkin's lymphoma (NHL). Intra- and inter-observer reproducibility of both the original and the updated Kiel classification were assessed blindly on two occasions by two experienced cytologists who examined biopsy specimens from 78 dogs with NHL. Analysis by kappa statistics showed moderate to good intra-observer reproducibility and poor to moderate inter-observer reproducibility for the original Kiel classification. In the updated Kiel classification both intra- and inter-observer reproducibilities were good, probably due in part to the additional information provided by the immunotyping. The consensus cytological classifications were compared with those based on histology, and the association constant (Cramér's V) was 0.65 for the original Kiel classification and 0.70 for the updated Kiel classification. The results suggest that the updated Kiel classification in particular is suited to cytological classification of canine NHL.

BACKGROUND:Various histological classifications developed for nodal lymphomas failed to be of value in extranodal lymphomas. More recently, gastric lymphoma is considered to represent a distinctive group derived from mucosa associated lymphoid tissue (MALT).AIM:To study the prognostic value of malignancy grading based on the concept that most gastric lymphomas are of MALT origin, the endoscopic as well as clinical characteristics in 114 patients with primary gastric non-Hodgkin's lymphoma were evaluated.RESULTS:In univariate analysis, patients with low grade lymphoma (n = 51) were younger, had less advanced stage, and less frequently bulky disease than those with high grade lymphoma (n = 63). In multivariate analysis weight loss and increased erythrocyte sedimentation rate were significantly less frequent in low grade (45% and 22%) compared with high grade lymphoma (75% and 53%). In low grade lymphoma endoscopic findings were often interpreted as a benign condition (27 of 51), in contrast with high grade lymphoma, where carcinoma was most frequently (37 of 63) suspected. In low grade lymphoma complete remission rate was 92%, and five year survival 75%, In high grade lymphoma results were significantly less favourable (p = 0.0001): complete remission in 68%, and a five year survival of 46%.CONCLUSION:Malignancy grading was strongly correlated with treatment outcome; endoscopically low grade lymphoma was often hard to distinguish from benign conditions, whereas high grade lymphoma often revealed carcinoma-like features.

T-cell rich B-cell non-Hodgkin's lymphoma (T-cell rich B-cell lymphoma) is a morphological variant of diffuse large B-cell lymphoma. It is important to recognize this variant in the differential diagnosis of T-cell non-Hodgkin's lymphoma, The main differential diagnosis of T-cell rich B-cell lymphoma, nodular and diffuse lymphocyte predominance Hodgkin's disease (lymphocyte predominance Hodgkin's disease), is, however, even more difficult and differentiating criteria are still not satisfactorily defined. Moreover, T-cell rich B-cell lymphoma may not represent a clinicopathological entity, Twelve cases of T-cell rich B-cell lymphoma, selected on the basis of morphology and limited immunohistochemistry without previous knowledge of clinical data, were studied by immunohistochemistry and polymerase chain reaction for bcl-2 rearrangements to investigate the histogenetic background. In three of 12 cases, bcl-2 rearrangements were found, strongly suggesting a follicle centre cell origin, In three other cases, a documented history of definite nodular lymphocyte predominance Hodgkin's disease 29 months to 20 years prior to the diagnosis of the lymphoma was present, No differences in growth pattern, residual nodularity, tumour cell distribution, cellular morphology and composition, or immunophenotypical differences were noted in these six cases as compared to the remaining cases. These data underscore the histogenetic diversity in T-cell rich B-cell lymphoma and identify it as a progressed form of lymphoma derived from entities as diverse as follicle centre cell lymphoma and nodular lymphocyte predominance Hodgkin's disease. Moreover, it shows a complete morphological overlap with the diffuse form of lymphocyte predominance Hodgkin's disease and may actually encompass this disease entity.

Thirteen cases of nasal lymphomas with T-cell or natural killer (NK)-cell phenotype were studied, with attention to clinical presentation and follow-up, the presence of Epstein-Barr virus (EBV) using in situ hybridization (EBER), the immunophenotype, and the presence of cytotoxic granules. All but two patients presented with stage I disease. In three cases local progression resulted in involvement of the central nervous system. When dissemination occurred, this was predominantly to extranodal localizations, in two cases to the skin. Response to therapy was highly variable, but patients treated with radiotherapy with or without additional chemotherapy had a better prognosis than patients treated with initial chemotherapy alone. All lymphomas were associated with EBV, and most cases showed cytotoxic features, ten of which were CD56 positive. In eight cases a T-cell origin was proven, but in five cases a possible NK-cell origin could not be excluded. No clinical differences were seen between true T-cell lymphomas and possible NK-cell neoplasms. Nasal T-cell lymphomas should be considered as a distinct clinicopathological entity, strongly associated with EBV, and with cytotoxic features in most cases. No prognostic parameters were detected to predict dissemination and response to therapy.

the GBV-A-like virus found in uninfected tamarins could represent genotypic differences of a naturally occurring tamarin virus.However, one cannot rule out the possibilities that GBV-A represents a human equivalent of the GBV-A- like virus found in tamarins or that these tamarins have acquired a human virus while in captivity.Nonetheless, the lack of any associated rises in liver enzymes with either the GBV-A or the GBV-A-like virus suggests that GBV-B is the putative aetiological agent associated with GB-hepatitis.

T-cell lymphomas with similar morphology but with different sites of origin have a different clinical behavior. The theoretical explanation for this finding originates from the hypothesis that non-Hodgkin's lymphomas (NHLs) are neoplastic equivalents of immunological reactions involving tissue-restricted lymphocytes. This hypothesis also implies that T-NHLs originating from different sites differ in their genesis, and thus may differ in oncogen expression, expression of adhesion molecules, or presence of certain DNA/RNA viral sequences. Therefore, we have investigated in T-cell lymphomas with similar morphology originating from different sites, ie, nose (n = 5; all pleomorphic small- or medium- and large-cell T-cell lymphomas [PTL]), skin (PTL, n = 6; anaplastic large-cell [ALCL], n = 11), gut (PTL, n = 8; ALCL, n = 4), and lung (PTL, n = 6), the presence of Epstein-Barr virus (EBV) at the DNA, RNA (EBER 1 and EBER 2), and protein level (LMP-1). A double- staining technique was used to detect EBER 1/2, LMP-1, and differentiation markers at the single-cell level. High numbers of EBER 1/2-positive tumor cells (> 100 per medium power field [mpf]) were found in five of five nasal T-cell lymphomas, none of 17 primary cutaneous T-cell lymphomas, one of 12 gastrointestinal T-cell lymphomas (ALCL), and two of six pulmonary T-cell lymphomas. These lymphomas are therefore called EBV-associated lymphomas. In contrast to our earlier findings in lymph nodes, no extranodal lymphomas were found, with only a few EBV-positive tumor cells. Five gastrointestinal cases positive for EBV by polymerase chain reaction (PCR) showed that EBER 1/2 was only found in sporadic nonneoplastic, ie, reactive lymphocytes. Angiocentricity was present in 18 PTL and one ALCL, but not associated with the presence of EBV. These results indicate that the presence of EBV in extranodal T-cell lymphomas is site-restricted and argues for a different pathogenesis of T-cell lymphomas with similar morphology but originating from different sites. The presence of EBV in most tumor cells in these EBV-associated lymphomas suggests that when present, EBV might be important in the pathogenesis of these lymphomas.

PURPOSE To determine risk factors for the development of second primary cancers during long-term follow-up of patients with Hodgkin's disease (HD). PATIENTS AND METHODS We assessed the risk of second cancers (SCs) in 1939 HD patients, who were admitted to the Netherlands Cancer Institute (NKI; Amsterdam) or the Dr Daniel den Hoed Cancer Center (DDHK; Rotterdam) between 1966 and 1986. For 97% of the cohort, we obtained a medical status up to at least January 1989. The median follow-up duration of the patients was 9.2 years; for 17% of the patients, follow-up was longer than 15 years. For more than 98% of all second tumors, the diagnosis was confirmed through a pathology report. RESULTS In all, 146 patients developed a SC, compared with 41.9 cases expected on the basis of incidence rates in the general population (relative risk [RR], 3.5; 95% confidence interval [CI], 2.9 to 4.1). The mean 20-year actuarial risk of all SCs was 20% (95% CI, 17% to 24%). Significantly increased RRs were observed for leukemia (RR, 34.7; 95% CI, 23.6 to 49.3), non-Hodgkin's lymphoma (NHL) (RR, 20.6; 95% CI, 13.1 to 30.9), lung cancer (RR, 3.7; 95% CI, 2.5 to 5.3), all gastrointestinal cancers combined (RR, 2.0; 95% CI, 1.2 to 3.1), all urogenital cancers combined (RR, 2.4; 95% CI, 1.4 to 3.7), melanoma (RR, 4.9; 95% CI, 1.6 to 11.3), and soft tissue sarcoma (RR, 8.8; 95% CI, 1.8 to 25.8). As compared with the general population, the cohort experienced an excess of 63 cancer cases per 10,000 person-years. Cox-model analysis indicated the following as significant risk factors for developing leukemia: first-year treatment with chemotherapy (CT), follow-up treatment with CT, age at diagnosis of HD greater than 40 years, splenectomy, and advanced stage. Patients treated with CT in the 1980s had a substantially lower risk of leukemia than patients treated in the 1970s (10-year actuarial risks of 2.1% and 6.4%, respectively; P = .07). Significant risk factors for NHL were older age, male sex, and combined modality treatment as compared with either modality alone. Risk of lung cancer was strongly related to radiotherapy (RT), while an additional role of CT could not be demonstrated. After more than 15 years of follow-up, women treated with mantle-field irradiation before age 20 years had a greater than forty-fold increased risk of breast cancer (P < .001). CONCLUSION While the long-term consequences of HD treatment as administered in the 1960s and 1970s are still evolving, it is promising that patients who received the new treatment regimens introduced in the 1980s have a much lower leukemia risk than patients treated in earlier years. Beginning 10 years after initial RT, the follow-up program of women who received mantle-field irradiation before age 30 years should routinely include breast palpation and yearly mammography.

Using three different classification schemes (Rappaport, the Working Formulation, and the Kiel classification), 116 canine malignant lymphomas were classified histologically. The number of lymphomas with a completely follicular growth pattern was low (14.9%). The majority of the lymphomas (50.8%) had a diffuse type of architecture, while 34.3% were diffuse with some nodularity. In the Rappaport scheme, 69.3% of the canine lymphomas were classified as histiocytic lymphomas, but these consisted of a group of tumors with different morphologic and immunologic cell types. The Working Formulation and the Kiel classification could be applied to differentiate the canine lymphomas cytomorphologically. In both the Working Formulation and the Kiel classification, only a minority of lymphomas (16.4 and 12.0%, respectively) were low-grade malignant lymphomas. Large cell or centroblastic lymphomas were the most frequently encountered in the Working Formulation or the Kiel classification, respectively. Immunophenotyping of 95 lymphomas was performed with the aid of a panel of monoclonal and polyclonal antibodies. The majority of the lymphomas were of B cell origin (58.9%) while three were classified as non-B/non-T cell lymphomas. Contrary to the distribution pattern of human non-Hodgkin's lymphoma (NHL) in western countries, there was a high percentage of T cell lymphomas (37.9%) in the canine. However, the phenotype could not be predicted by the morphologic characteristics alone.

T-cell non-Hodgkin's lymphomas can be considered the neoplastic equivalents of immunologically functional, site-restricted T lymphocytes. Little is known about the occurrence and clinical behavior of T-cell lymphomas that are the neoplastic equivalents of different functional T-cell subsets. Here, we investigated the prevalence, preferential site, immunophenotype, and clinical behavior of the neoplastic equivalents of activated cytotoxic T cells (CTLs) in a group of 140 nodal and extranodal T-cell lymphomas. Activated CTLs were shown immunohistochemically with a monoclonal antibody against granzyme B, a major constituent of the cytotoxic granules of activated T cells. Granzyme B-positive T-cell lymphomas were mainly found in mucosa- associated lymphoid tissue (MALT; nose, 63% of the cases; gastrointestinal tract, 46%; and lung, 33%). Granzyme B-positive cases with primary localization in MALT were more often associated with angioinvasion (P = .005), necrosis (P = .002), and histologic characteristics of celiac disease in adjacent mucosa not involved with lymphoma. Eosinophilia was more often observed in granzyme B-negative cases (P = .03). Most cases belonged to the pleomorphic medium- and large-cell group of the Kiel classification. CD30 expression was more often found in granzyme B-positive lymphomas of MALT (P = .04), whereas CD56 expression was exclusively found in nasal granzyme B-positive lymphomas. Immunophenotypically, most of the cases should be considered as neoplastic equivalents of activated CTLs based on the presence of T- cell markers on tumor cells. In two cases of nasal lymphoma, tumor cells probably were the neoplastic counterparts of natural killer cells. The prognosis of the granzyme B-positive gastrointestinal T-cell lymphomas was poor but did not differ from granzyme B-negative gastrointestinal T-cell lymphomas. This indicates that, in peripheral T- cell lymphomas, site of origin is more important as a prognostic parameter than derivation of activated CTLs.

Pretreatment characteristics of 138 dogs with malignant lymphoma were analyzed to determine prognostic factors associated with outcome (ie, complete response rate, time to relapse after complete response, survival time). Dogs were all treated for 10 weeks, using a standard induction chemotherapy protocol, and were then given asparaginase weekly. Once the disease became progressive, second-line chemotherapy was instituted. Age, sex, weight, clinical stage, performance grade, immunophenotype, and malignancy grade assigned according to the National Cancer Institute's Working Formulation were not associated with complete response rate. However, malignancy grade assigned according to the Kiel classification was found to be associated with complete response rate; dogs with high-grade malignancies had a significantly higher complete response rate than did dogs with low-grade malignancies. By means of multivariate analysis, clinical stage and immunophenotype were found to be prognostic factors for time to relapse (among dogs that had had a complete response) and survival time. In addition, malignancy grade assigned according to the Kiel classification was found to be a prognostic factor for time to relapse; whereas, malignancy grade assigned according to the Working Formulation was determined to be a prognostic factor for survival time.

Primary oesophageal involvement by lymphoma in two patients, one with Hodgkin's disease and one with non-Hodgkin's lymphoma is reported. In both, there were no manifestations of the disease outside the oesophagus, which is exceptionally rare. In the patient with non-Hodgkin's lymphoma, the oesophageal tumour was the first manifestation of lymphoma. Shortly after admission he developed a tracheo-oesophageal fistula from which he died before treatment could be started. In the patient with Hodgkin's disease, isolated oesophageal lymphoma was the first relapse after a 13 year interval free of disease. As he had previously received mediastinal irradiation he was treated with combination chemotherapy that resulted in long term survival (> five years). Several other long term survivors have been described but only after radiotherapy or surgery. These findings suggest that systemic chemotherapy may be equally successful in treating isolated primary oesophageal lymphoma, thus offering an alternative for those patients in whom local treatment is contraindicated.

BACKGROUND:The clinical relevance of the updated Kiel classification for T-cell lymphomas is discussed. Large series with long-term follow-up are needed to investigate the clinical relevance of a separation into high- and low-grade T-cell lymphomas, based on the Kiel classification.METHODS:The clinicopathologic data of 97 consecutive noncutaneous T-cell lymphomas, diagnosed in the Comprehensive Cancer Center Amsterdam, between July 1, 1985, and December 1, 1990, were reviewed and analyzed for their prognostic significance.RESULTS:Immunohistochemistry contributed substantially in the diagnosis of T-cell lymphoma. Using the updated Kiel classification, many difficulties occurred in classifying these lymphomas. Only large cell anaplastic lymphoma (LCAL) and lymphoblastic lymphoma (LBL) were classified with a high degree of confidence. Variables associated with prolonged survival were classified as LCAL and low stage of disease (Stage I and II) at clinical presentation. Multivariate survival analysis revealed that subtype (grouped as LCAL versus non-LCAL) was selected as the most significant variable, closely followed by stage of disease at clinical presentation (grouped as Stage I/II versus Stage III/IV). LCAL was associated with a significantly better survival than were all other types of high-grade T-cell lymphoma (P = 0.018) and tended to be associated with a better survival than low-grade T-cell lymphoma (P = 0.067). No significant differences in survival were found between the other types of T-cell lymphoma or between high- and low-grade T-cell lymphomas as classified according to the updated Kiel classification. Other variables, such as sex and age (younger than 60 years versus older than 60 years) had no significant influence on survival time.CONCLUSIONS:This study indicates that the clinical relevance of classifying primary noncutaneous T-cell lymphomas according to the updated Kiel classification is limited because only a diagnosis of LCAL has prognostic relevance in predicting survival.

Forty-six nodal T-cell lymphomas, classified according to the updated Kiel classification, were investigated for the presence of Epstein-Barr virus (EBV) DNA by polymerase chain reaction (PCR), EBER 1 and 2 (EBER 1/2) and latent membrane protein-1 (LMP-1) expression. A combination of RNA in situ hybridization and immunohistochemistry was used to establish the phenotype of the Epstein-Barr virus harbouring cells. In 21 of 45 cases Epstein-Barr virus DNA sequences could be detected with the polymerase chain reaction. In 15 cases (14 of 21 EBV PCR positive cases), EBER 1/2 positive cells could be demonstrated. As judged by morphology, EBER 1/2 expression was found in nonneoplastic and neoplastic lymphoid cells. Double staining revealed that more than 80% of the EBER 1/2 harbouring cells, lacked B-, T- or histiocytic markers, suggesting down regulation of T- and B-cell markers by Epstein-Barr virus. In eight of 15 cases some EBER 1/2 positive T-cells (CD3, CD45RO, CD43) morphologically resembling tumour cells were found. In nine of 14 cases tested EBER 1/2 positive non-neoplastic B-cells (CD20) were seen. Based on in situ hybridization results, four patterns of EBER 1/2 positive cells were found, i.e. single cells (< 1 per medium power field (mpf), n = 3), scattered (1-25/mpf, n = 4), clustered (26-100/mpf, n = 5) and diffuse (> 100/mpf, n = 3). In eight of 15 cases a clustered or diffuse pattern of EBER 1/2 positive cells was found and these lymphomas were therefore considered to be strongly associated with Epstein-Barr virus. In these lymphomas LMP-1 expression was found to be associated with an aggressive clinical course and hepatosplenomegaly.

The histological, immunophenotypic and clinical features of 19 primary cutaneous anaplastic large cell lymphomas (cutaneous ALCL) were compared with those of 18 primary nodal anaplastic large cell lymphomas (nodal ALCL) of T‐cell or null cell type. Although cutaneous ALCL and nodal ALCL had identical morphological features, differences in surface marker expression and clinical behaviour were found. Immunophenotypical differences concerned the expression of epithelial membrane antigen (82% of the nodal ALCL were positive v. none of the cutaneous ALCL) and the cutaneous lymphocyte antigen (HECA‐452), a possible skin‐homing receptor on cutaneous T‐lymphocytes (most tumour cells in 44% of cutaneous ALCL cases were positive, whereas nodal ALCL showed expression of HECA‐452 on only few tumour cells (< 25%) in 18% of cases tested). Loss of T‐cell markers was more pronounced for nodal ALCL. Patients with cutaneous ALCL were generally older (median 61 years) than patients with nodal ALCL (median 24 years) and, in contrast to the latter group, did not show bimodal age distribution. Survival after 4 years, using lymphoma‐related death as an end‐point, differed significantly between cutaneous ALCL and nodal ALCL; 92% for cutaneous ALCL and 65% for nodal ALCL ( P =0.04). The better survival of cutaneous ALCL patients could not be ascribed to differences in age, stage or initial mode of treatment. These data indicate that differences in ismmunophenotype and clinical behaviour exist between morphologically identical primary cutaneous and primary node‐based ALCL. They indicate that the primary site is an important prognostic factor in predicting the clinical outcome of ALCL.