Treatment and survival of 38 female breast lymphomas: a population-based study with clinical and pathological reviews.

Breast lymphomas are rare and consensus about their treatment is lacking. A population-based study of 38 breast lymphomas, registered in the databases of two Comprehensive Dutch Cancer Centers from 1981 to 1999, was performed. The median age of all female patients was 65 years (20-92): 25 patients had localized and 13 patients had disseminated lymphoma. The most common type was diffuse large B-cell lymphoma (DLBCL), which accounted for 17 of the localized and 4 of the disseminated cases. Burkitt's lymphoma (BL), three being disseminated, was found in four patients. There were six extranodal marginal zone lymphomas (ENMZL), three being localized. Seven DLBCL and one BL showed additional histological features of mucosa-associated lymphoid tissue (MALT) lymphoma. Localized aggressive lymphomas treated with surgery and/or radiation therapy had relapse rates of 100% and 67%, respectively. Cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP)-like chemotherapy with or without local irradiation led to 17% relapses in patients with localized aggressive lymphoma. Median follow-up time was 32 months (0.6-218); 37% of the patients relapsed and 24% had progressive disease. Response to salvage regimens, given to 91% of the patients with recurrent disease, was poor. The 2-year overall survival rate was 63%, 72% for patients with localized disease, and 46% for patients with disseminated lymphoma. The majority of breast lymphomas are localized aggressive lymphomas that should be treated initially with CHOP-like chemotherapy with or without irradiation. The initial choice of treatment is very important because response to salvage regimens is poor.

The role of molecular analysis of immunoglobulin and T cell receptor gene rearrangements in the diagnosis of lymphoproliferative disorders.

AIMS: To investigate whether the analysis of immunoglobulin (Ig)/T cell receptor (TCR) rearrangements is useful in the diagnosis of lymphoproliferative disorders. METHODS: In a series of 107 consecutive cases with initial suspicion of non-Hodgkin's lymphoma (NHL), Southern blot (SB) analysis of Ig/TCR rearrangements was performed. RESULTS: In 98 of 100 histopathologically conclusive cases, Ig/TCR gene results were concordant. In one presumed diffuse large B cell lymphoma (DLCL) and one follicular lymphoma (FL) case no clonality could be detected by SB analysis, or by polymerase chain reaction (PCR) at second stage. In the DLCL, sampling error might have occurred; the FL was revised after an initial diagnosis of reactivity. In many of the histopathologically inconclusive cases Ig/TCR gene SB analysis was helpful, giving support for the histopathological suspicion. However, because of a lack of (clinical) follow up data this could not be confirmed in a few cases. CONCLUSIONS: Experienced haematopathologists or a pathologist panel can diagnose malignant versus reactive lesions in most cases without the need for Ig/TCR gene analysis and can select the 5-10% of cases that might benefit from molecular clonality studies.

Clinical drug-resistant nodular sclerosing Hodgkin's lymphoma is associated with decreased bcl-2 expression in the surrounding lymphocytes and with increased bcl-2 expression in the Reed-Sternberg cells.

UNLABELLED: Identification of patients with Hodgkin's lymphoma who are primary refractory to chemotherapy will have great impact on treatment planning. Several studies have indicated that up-regulation of the bcl-2 proto-oncogene expression in non-Hodgkin's lymphoma can cause resistance to chemotherapeutic drugs. For this reason we investigated the relationship between expression of bcl-2, the pro-apoptotic protein Bax and MIB-1 with clinical drug-resistance in Hodgkin's lymphoma. METHODS AND RESULTS: Seven patients with nodular sclerosis Hodgkin's lymphoma under 40 years of age, who failed to achieve complete remission upon primary chemotherapy and 10 matched patients who did achieve complete response were selected from the Eindhoven Cancer Registry. Tissue sections from both groups of patients were stained for bcl-2, Bax and MIB-1. In the non-responding patients Reed-Sternberg cells expressed bcl-2 more frequently using a cut-off point of <25% to indicate negative cells (P = 0.04), whereas no differences were observed in the expression of Bax and MIB-1. In non-responding patients the lymphocytes surrounding Reed-Sternberg cells expressed bcl-2 less frequently (P = 0.002), using a cut-off point of < 25%, whereas no difference was observed in the expression of Bax and MIB-1. CONCLUSION: A high percentage of Reed-Sternberg cells expressing bcl-2 protein and a low expression of bcl-2 proteifi in the surrounding lymphocytes is associated with treatment-failure, and subsequent poor survival in young patients with nodular sclerosing Hodgkin's lymphoma. These results need further validation in larger studies.

Comparison of different polymerase chain reaction-based approaches for clonality assessment of immunoglobulin heavy-chain gene rearrangements in B-cell neoplasia.

Several frequently applied polymerase chain reaction strategies for analysis of immunoglobulin heavy-chain gene rearrangements were compared by analyzing 70 B-cell lymphoproliferative disorders and 24 reactive lymphoid lesions. Southern blot analysis was used as the "gold standard" for clonality assessment. For polymerase chain reaction analysis, primers directed against framework (FR) 3 (FR3-A and FR3-B), FR2, and FR1 of the variable gene segments and against joining gene segments of the immunoglobulin heavy-chain gene were used. Polymerase chain reaction products were analyzed by high-resolution fingerprinting analysis using radiolabeled nucleotides, gene scanning using fluorochrome-labeled primers, and heteroduplex analysis. All of the assays generated polyclonal patterns in the reactive tissues. The sensitivity in detecting monoclonality as defined by Southern blotting varied between 60% (heteroduplex analysis with FR3 primers) and 77% (high-resolution fingerprinting analysis with FR2 primers). Comparison of the three FR3 assays revealed that gene scanning had the highest sensitivity (69%), probably because it could detect small aberrant monoclonal amplicons. False-negative results were especially frequent in follicular center lymphoma (n = 20), but also in diffuse large B-cell lymphoma (n = 18), both renowned for having mutated variable gene segments, potentially leading to primer mismatching. For example, in follicular center lymphoma, the FR3, FR2, and FR1 region primer sets detected clonality in only 35 to 40, 65, and 50%, respectively. Combining these techniques, 17 (85%) of 20 follicular center lymphoma samples showed monoclonality. Therefore, especially in follicular center lymphoma, diffuse large B-cell lymphoma, and, to a lesser extent, in other lymphomas, multiple variable gene segment primer sets must be used for a reliable assessment of clonality. Our results also suggest that gene scanning is somewhat more sensitive than other read-out systems. Heteroduplex analysis, however, is a reliable alternative within a diagnostic setting, avoiding the use of radioactivity or expensive automated sequencing equipment and fluorochrome-labeled (oligo)nucleotides.

High grade MALT-lymphoma of the breast.

A 65-year-old woman presented with a rapidly growing breast tumor, initially diagnosed as a carcinoma. Histology showed a breast lymphoma of high grade MALT-type. A lymphoma should always be considered in the differential diagnosis of a breast tumor, because it needs a different work-up and treatment. The subgroup of NHL of Mucosa-Associated-Lymphoid-Tissue origin has different clinical behaviour, as illustrated in this report.

An important subgroup of phyllodes tumors of the breast is characterized by rearrangements of chromosomes 1q and 10q.

From a study of 10 cases of our own and 13 cases of the literature, anomalies of chromosome 1q and 10q emerge as consistently occurring changes in an important subgroup of phyllodes tumors of the breast. Anomalies of chromosome 1 were the most frequent ones, with a gain of 1q material, and histologically the tumors in which these anomalies were found were low grade malignancies. Structural changes of 10q emerged as the second most frequent chromosome change.

Improved survival of Hodgkin's patients in south-east Netherlands since 1972.

In the past 30 years, staging and treatment of Hodgkin's disease have changed dramatically, and prolonged remission can now be induced in the majority of patients. Our purpose was to assess improvement in long-term survival, previously reported for specific patient groups, among unselected patients diagnosed and treated between 1972 and 1993 in general hospitals in South-East Netherlands. Data on all 345 Hodgkin's patients were derived from the population-based Eindhoven Cancer Registry; histopathology and clinical records were reviewed. Follow-up was attained up to 1994. Relative survival rates, i.e. the ratio of observed to expected rates, were 80% after 5, 70% after 10 and 67% after 15 years. Independent prognostic factors for lower overall survival were (in decreasing order of significance): advanced age, histology (lymphocyte depletion), advanced stage and earlier period of diagnosis. Distribution of age and stage did not change over the study period, but there was a modest increase in the incidence of the nodular sclerosis histological subtype. Crude 5-year survival rates improved from 60% in the period 1972-1976 to 81% in the period of 1987-1992 (P < 0.005). The largest improvement occurred in the 1970s and was most prominent among those aged over 50 years. As previously reported, cured Hodgkin's patients exhibit a higher mortality rate, which can be explained by treatment-related long-term complications such as second malignancies and cardiovascular diseases. The relatively high survival rates compared to other population-based studies may be attributable to the existence of a regional network within the framework of a comprehensive cancer centre. Better staging, new combinations of chemotherapy, improved radiation technology, advances in supportive care as well as more frequent intensive treatment of the elderly could explain the improvement in prognosis.

Disappearance of prognostic significance of histopathological grading of nodular sclerosing Hodgkin's disease for unselected patients, 1972-92.

The importance of the subclassification of nodular sclerosing Hodgkin's disease (NSHD) according to the British National Lymphoma Investigation Group (BNLI) criteria, which had an independent prognostic value for 90 unselected patients diagnosed in our region in the period 1972-83, is still equivocal. Because survival of patients with Hodgkin's disease improved in our region during the period 1972-92 and because treatment may modify prognostic factors, we re-evaluated the prognostic value of NSHD subclassification up to 1993. A registry-based study was performed with data on all 345 Hodgkin patients diagnosed in the period 1972-92. Available histology was reviewed. The prognostic value of nodular sclerosis (NS) grading was evaluated for two periods, 1972-80 and 1981-92, designated as the seventies and the eighties, respectively. NSHD was diagnosed in 57% (n = 195) of all registered cases of Hodgkin's disease, 17 of which could not be evaluated. NS stage I (NSI; 73%) and NS stage II (NSII; 27%) patients exhibited the same distribution of stage during both periods; NSII patients were older than NSI patients in the seventies. NSII patients presented with an elevated ESR and B symptoms more frequently during the eighties and subsequently received combined modality therapy more often. The crude 5-year survival rate for grade I v grade II NSHD was 85% v 38% (P < 0.05) for the seventies and 84% v 83% for the eighties. Subclassification of NSHD was not an independent prognostic factor after adjustment for age, stage, gender, B symptoms and ESR, though it remained of independent prognostic value when ESR was left out of the Cox model. The most important factors adversely influencing survival were advanced age, advanced stage and male gender. The independent prognostic value of the subclassification of NSHD has disappeared, as reflected by the clearly improved survival of NSII patients, probably due to more intensive treatment in the eighties, whereas survival of NSI patients did not changes.

Specific detection of Helicobacter pylori and non-Helicobacter pylori flora in small- and large-cell primary gastric B-cell non-Hodgkin's lymphoma.

BACKGROUND: Primary gastric non-Hodgkin's lymphomas possibly develop in response to local infection by Helicobacter pylori (H. pylori). We investigated the presence of H. pylori and non-H. pylori flora histologically in small- and large-cell primary gastric lymphoma using a specific staining method. MATERIALS AND METHODS: Specimens of 52 cases of primary gastric lymphoma (17 small cell, 35 large cell) were stained with modified Giemsa (MG) and immunohistochemically using a polyclonal antibody against H. pylori (IHC). RESULTS: Thirty-two cases (61.5%) (small cell 76% versus large cell 53%, P > 0.05) showed immunoreactivity for H. pylori in the mucosa surrounding the tumor. Remarkably, there was localization of H. pylori in the neck of the gastric glands in 3 cases. Non-H. pylori flora was seen in 35 cases (76.3%) (small cell 53% versus large cell 74%, P > 0.05). In 20 cases, this non-H. pylori flora was mixed with H. pylori. Five cases showed no bacterial flora at all. CONCLUSIONS: (1) Using immunohistochemistry, the prevalence of gastric lymphoma cases with H. pylori (61.5%) approximates that of H. pylori in the normal population. (2) No statistical difference was found between the occurrence of H. pylori and non-H. pylori bacterial flora in small- versus large-cell lymphoma. (3) Our results suggest that H. pylori may not be the only etiologic factor in primary gastric lymphoma.

Changing trends in the incidence of non-Hodgkin's lymphoma in Europe. Biomed Study Group.

Non-Hodgkin's lymphoma (NHL) is not a uniform disease entity, and in order to investigate the reported changes in incidence we have set up a study in seven population-based cancer registries in Europe. The study is designed to look at changes in the incidence of total NHL and disease subgroups using standard definitions and methodology. The registries are based in Leeds, Dijon, Kuopio, Odense, Florence, Eindhoven, and Ragussa. The classification system we have used is based on the REAL classification and has utility for epidemiological studies. We have used it to convert data sets which have utilized both local cases and the ICD-O classification. In order to improve data reproducibility, CLL/LL, myeloma/MGUS, lymphoblastic disease, and Hodgkin's disease have been excluded because of the difficulty in defining incident cases accurately. The preliminary results of this study show that there is still an upward trend in incidence rate and that in Yorkshire this is 3% per annum in total NHL. The subgroups which are increasing are extranodal and nodal peripheral T-cell lymphoma. Similar increases in incidence have been reported for the other registries. We conclude that there is a continued upward trend in incidence of NHL, the causes of which are uncertain.

Primary gastric non-Hodgkin's lymphoma stage IE and IIE.

The aim of this study was to evaluate retrospectively the different treatment approaches and outcome of patients with stage IE and IIE gastric non-Hodgkin's lymphoma in a cancer registry. Between 1982 and 1992, the Comprehensive Cancer Centre South (CCCS), Eastern Section, The Netherlands, registered, in a population of 1 million people, a total of 81 cases of gastric lymphoma stage IE and IIE (43 men and 38 women). Median age was 69.7 years (range 30.4-88.1). According to the Working Formulation, the malignancy grade was: 9 low, 55 intermediate and 14 high. According to the MALT classification, the malignancy grade was: 38 low and 40 high. Grade was unknown in 3 patients. Patients received the following treatment modalities: surgery alone (n = 22), locoregional radiotherapy without (n = 12) or with (n = 13) surgery; or systemic chemotherapy alone (n = 10) or with radiotherapy and/or surgery (n = 18). No treatment was given or recorded in 6 patients. For stage IE, 5-year actuarial survival and relapse-free survival rates were, respectively, 76 and 64% in 18 patients who received only surgery; 70 and 67% in 17 patients given locoregional treatment (radiotherapy with or without surgery), and 76 and 62% in 13 patients given systemic treatment (chemotherapy alone or with radiotherapy and/or surgery). Radiotherapy as sole treatment seemed to be as effective as other treatment modalities in achieving local and abdominal control. For stage IIE, none of the 4 patients who were treated with surgery alone survived 5 years. The 5-year actuarial survival and relapse-free survival rates of 8 patients who received radiotherapy with or without surgery were, respectively, 25 and 17% and 49 and 33%, for 14 patients given systemic therapy (chemotherapy alone and/or radiotherapy/surgery). In stage IIE, local, abdominal as well as distant relapse were more common, irrespective of treatment modality. In the multivariate analyses, stage (P = 0.002), grade (P = 0.02), age (P = 0.04) and gender (P = 0.04) were significant prognostic factors. This report on a limited number of patients shows that the outcome of patients with stage IIE gastric lymphoma is much worse than for patients with stage IE. Grade, age, gender and particularly stage are much stronger indicators for survival than different modes of treatment. Systemic therapy might improve outcome for stage IIE, but not for stage IE, for which radiotherapy alone seems a good option.

Porokeratotic palmoplantar keratoderma discreta--a new entity or a variant of porokeratosis plantaris discreta?

We report a family with hyperkeratotic lesions on palms and soles. The lesions became evident in the second to third decade, and there is an autosomal dominant mode of transmission. Skin biopsy specimens show a central epidermal depression filled by a compact hyperkeratotic plug of columnar parakeratosis, like a broad cornoid lamella. The lesions resemble porokeratosis plantaris discreta clinically and histologically. The cornoid lamella is a broad, solid keratin plug rather than a centrifugally enlarging annular or serpentine ridge as can been seen in other types of porokeratosis. Perhaps the lesions of porokeratosis plantaris discreta should not be classified as a true porokeratosis but as porokeratotic plantar keratoderma discreta. We have therefore called the lesions in our patients porokeratotic palmoplantar keratoderma discreta, and suggest that porokeratotic palmoplantar keratoderma discreta is a variant of porokeratosis plantaris discreta.

Flow cytometric analysis of consecutive lymph node samples from patients with Hodgkin's disease: reproducible within one biopsy?

In Hodgkin's disease DNA aneuploidy is not a prognostic factor. However, the prognostic significance of DNA content in Hodgkin's disease may be missed by either intratumor DNA heterogeneity or DNA analysis of limited samples. For flow cytometry usually one section of 40-60 microns is used for the analysis. In breast cancer this proved to be insufficient. In Hodgkin's disease no data are available. Therefore, we examined if analysis of more sections does increase the yield of aneuploidy. Archival, formalin-fixed, parafin embedded tissues were used. From 13 patients four sections of 50 microns could be analysed for DNA content. In 12 of 13 patients the results were consistent in all four sections of one patient case; seven diploid, four aneuploid and one multiploid. In one case ploidy status changed: two sections were diploid and two were aneuploid. The DNA-index of the aneuploid samples ranged from 0.75 to 1.38 and varied from 0.02 to 0.14 within one case. The S-phase fraction remained constant within all evaluable cases (sd: 0.5-1.5%), except for one (sd: 4.7%). In conclusion, in Hodgkin's disease the ploidy status of the first section can be regarded to represent the whole tissue sample. Therefore, the absence of prognostic value of ploidy status is not explained by sampling errors in tissues analysed.

P53 as a marker of the malignant cell in Hodgkin's disease.

BACKGROUND: The p53 gene has a tumor-suppressor function. The mutated gene encodes for a protein which has a longer half-life than the normal p53 protein. This enables the detection of the mutated p53 protein by immunohistochemistry. MATERIALS AND METHODS: In this study we examined 53 lymph nodes of patients with Hodgkin's disease for the presence of p53. The lymph nodes were stained with DO-1 and CM-1, two antibodies directed against the p53 protein. RESULTS: DO-1 weakly stained 2/14 samples positively, and CM-1 10/25. When preincubated with Target Unmasking Fluid, CM-1 stained 51/53 samples positively. Although, only Hodgkin and Reed-Sternberg cells stained positively, p53-negative Hodgkin and Reed-Sternberg cells were also seen in the same sample. CONCLUSION: Based on these results, we conclude that the p53 mutated protein is present in a high number of cases with Hodgkin's disease, which is suggestive for an important event in the pathophysiology of the disease. In addition, because of the absence of positive staining in the surrounding lymphocytes, these cells are unlikely to be part of the malignant clone.

Trends in the incidence of non-melanoma skin cancer in the SE Netherlands 1975-1988: a registry-based study.

The trends in the incidence and the sites of primary basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin were examined in a defined population of 650,000 persons in the SE Netherlands during the period 1975-88. The data was obtained from the Cancer Registry in Eindhoven and was from the dermatological and surgical clinics of 12 community hospitals. The incidence rates for BCC during this period rose from 42 to 53/100,000 person years for males and 24 to 38/100,000 person years for females. The rate of incidence for SCC varied with an increase mainly among males. In about 80% of the cases BCC and SCC occurred on the head and neck. Allowing for some detection bias a rise in the true incidence of BCC and SCC was observed, with an increase in SCC only since 1982. There was a marked decline in the incidence of SCC on the lips of males. These rates and trends fit into a pattern observed in other parts of Europe.

Grades of nodular sclerosis (NSI-NSII) in Hodgkin's disease. Are they of independent prognostic value?

Subclassification of the nodular sclerosis (NS) type of Hodgkin's disease in Grade 1 and 2 was reported for the first time by the British National Lymphoma Investigation (BNLI). Three groups, the BNLI, Gärtner et al. and the current authors, found clearly different survival rates between Grade 1 and 2 NS patients. The authors studied retrospectively if this NS grading has an independent prognostic value in 90 NS patients, diagnosed in ten hospitals in the southeastern part of the Netherlands (1972-1983). In this study there is no significant difference in sex, age, B-symptoms, erythrocyte sedimentation rate (ESR), stage, positive laparotomy, involvement of mediastinum or spleen, lymphocyte count, and percentage of complete remissions between the NS subgroups. Multivariate analysis suggests that the subclassification of NS in Grades 1 and 2 is a prognostic factor in survival independent of age, stage and ESR. This finding and the high relative frequency of NS makes application of this NS subdivision probably clinically useful to identify patients for a risk-adapted therapy.