Clinical and prognostic relevance of the Kiel classification of non-Hodgkin lymphomas results of a prospective multicenter study by the Kiel Lymphoma Study Group

Clinical and prognostic relevance of the Kiel classification of non-Hodgkin lymphomas (NHL) was investigated in 1127 patients entering a prospective multicenter observation study. Survival of the 782 (69–4 per cent) patients with low-grade malignant NHL (lymphocytic lymphomas, predominantly B-CLL, LP immunocytoma, centrocytic lymphoma, centroblastic-centrocytic lymphoma) exceeded that of the 341 patients (30–2 per cent) with high-grade malignant NHL (centroblastic, immunoblastic, lymphoblastic lymphomas). Prognosis was best in centroblastic-centrocytic lymphoma and in B-CLL and least favorable in immunoblastic and lymphoblastic lymphomas. Survival of LP immunocytoma and centrocytic lymphoma patients was intermediate after 2 to 2·5 years of follow-up. Corresponding to histopathology, pattern of survival curves of low-grade malignant NHL (slow decline, no plateauing) differed from that of high-grade malignant NHL (rapid decline, subsequent plateauing). Prognosis of B-CLL was superior to that of LP immunocytoma. Stages I and II were more frequent in centroblastic-centrocytic lymphoma (21 per cent) than in LP immunocytoma (2·5 per cent) and centrocytic lymphoma (11 per cent). Ability of radiotherapy to induce stable complete remissions in stage III of centroblastic-centrocytic lymphoma indicates prolonged restriction of lymphoma to the lymphatic system. In immunoblastic and centroblastic lymphomas, stages I and II were diagnosed in 34 and 38 per cent of cases, respectively, but only in stage I/I_E of centroblastic lymphoma prolonged remissions were achieved by radiotherapy. In advanced high-grade malignant NHL marked improvement of prognosis was solely possible by induction of complete remissions whereas in corresponding low-grade malignant lymphomas also partial remissions were prognostically relevant.     

Management of non-Hodgkin lymphoma in adults in Scandinavia, United Kingdom, and The Netherlands. Report from the European School of Oncology intercity meeting at Huddinge Hospital, 3rd June, 1988

Current treatment strategies in northern Europe of non-Hodgkin lymphoma are presented. High-grade malignant lymphomas have been treated with doxorubicin-containing polychemotherapy in various modes. The advantage of six-drug regimens over CHOP-like therapy is as yet not proven. Patients with the ability to tolerate the calculated dose have good prognosis. High-dose therapy and bone marrow transplantation should be considered in poor-risk patients with lymphoblastic lymphomas in first remission, patients with all high-grade histologies in partial remission after first-line therapy and patients with relapse that are still responsive to therapy. Preliminary results from autologous bone marrow transplantation in follicular lymphoma are also encouraging. Chlorambucil induces multiple remissions in follicular lymphoma, with a median duration of the 1st, 2nd and 3rd remission being the same. The watch and wait strategy seems justified initially in most asymptomatic generalized low-grade malignant lymphomas. Systemic therapy is required in aggressive stage II-IV lymphomas. A meticulous investigation is needed for stage I patients before giving local treatment only. Immune phenotyping is of great value for diagnosis and staging. Liver, but not bone marrow involvement seems to be an adverse prognostic factor. Follicular lymphoma is an example of a dynamic tumour with gradual cellular changes associated with new and more malignant clinical signs.     

Blood lymphocyte clonal excess in advanced non-Hodgkin's lymphoma. Relation to clinical data and prognosis

BACKGROUND:: Increasingly sensitive methods, based on the monoclonal natureof NHL, are used to detect tumour spread and remaining disease.Since the lymphomas are thought to arise due to successive geneticchanges, clonal cells in different compartments do not necessarilyrepresent the same disease despite a common clonal origin. PATIENTS AND METHODS:: In 179 patients with advanced NHL, clonal cells in peripheralblood were identified by light chain restriction analysed inflow cytometry, i.e. clonal excess (CE) analysis. RESULTS:: CE was more common in low grade NHL (52%) than in high gradeNHL (21%). In patients with a normal lymphocyte count CE wasfound in 23%. CE was significantly correlated to small cellhistology and bone marrow involvement. In high grade NHL CEin peripheral blood was more common in those with discordantsmall or mixed cell involvement of the bone marrow. CE was significantlyrelated to failure to achieve remission in both histologic subgroups.Survival was not influenced by CE in low grade NHL but in highgrade NHL. In multivariate analyses however, CE did not emergeas an independent risk factor but age, B-symptoms and LDH werethe major factors. CONCLUSIONS:: The utility of blood CE analyses in clinical praxis has stillto be settled and the prognostic value of CE per se seem limitedin the current perspective. The existence of CE in high gradeNHL might be a clue of different biology as compared to de novohigh grade NHL. non-Hodgkin's lymphoma, flow cytometry, clonal excess, peripheral blood, staging, prognosis     

Blood transfusion as a risk factor for non-Hodgkin lymphoma.

In a case-control study of 280 out of 426 consecutive patients with a recent diagnosis of non-Hodgkin lymphoma (NHL) and 1827 control subjects, 53 (19%) and 230 (13%) respectively had received blood transfusions 1 year or more before the interview. Using an age- and sex-stratified analysis the odds ratio (OR) for transfusion was 1.74 (95% CI 1.24-2.44). ORs were also determined for transfusions received in the intervals 1-5, 6-15, 16-25 and > or = 26 years before diagnosis. In the interval 6-15 years, the OR for transfusion was 2.83 (95% CI 1.60-4.99) whereas ORs for transfusions received in other intervals were lower and not significantly elevated. Histological diagnoses (Kiel classification) and results of staging procedures were known for 185 patients. For low-grade NHL of nodal B-cell chronic lymphocytic leukaemia (B-CLL) or immunocytoma type, the OR for transfusions was 4.15 (95% CI 1.92-9.01). For low-grade nodal lymphomas of follicle centre cell type and high-grade nodal lymphomas, no relation to transfusions could be demonstrated. For high-grade extranodal lymphoma as sole manifestation, OR for transfusions was 3.27 (95% CI 1.30-8.24). It is concluded that blood transfusion may be a risk factor for NHLs especially those of B-CLL or immunocytoma type and for high-grade extranodal lymphoma.     

Blood clonal B cell excess (CBE) at diagnosis in patients with non-Hodgkin lymphoma (NHL). Relation to clinical stage,histopathology and response to treatment

Untreated non-leukemic (lymphocytes ⩽ 4.0 × 10⁹/1) patients with non-Hodgkin lymphoma (NHL) of B cell type often show an excess of B cells in peripheral blood bearing the same light chain isotype as the lymph node tumor cells which may indicate a leukemic spread of the disease. The ratio betweek κ- and λ-bearing lymphocytes (normal range 1.0–3.3) was studied to evaluate the prognostic significance of clonal B cell excess (CBE) at diagnosis in 110 NHL patients. In total 43% had a CBE in peripheral blood. Fifty-two per cent of the patients in clinically advanced stages had CBE and 30% of the patients in stages I and II. CBE was detected in 49% of all patients with low-grade malignant lymphoma and in 32% with high-grade malignancy.Patients with a normal κ: λ ratio at diagnosis entered complete remission more often than those with CBE (P < 0.01). In patients with high-grade but not with low-grade malignant lymphomas remission duration was longer for those with normal κ : λ distribution than for the patients with an abnormal ratio (P < 0.01). Survival was not statistically significantly influenced.     

Flow cytometric light chain analysis of peripheral blood lymphocytes in patients with non-Hodgkin's lymphoma

Peripheral blood lymphocytes from 96 patients with non-Hodgkin's lymphoma were studied, either at primary staging, during treatment or in follow up. The amount of surface immunoglobulin light chain per cell was determined by direct immunofluorescence staining analysed by flow cytometry. Discrepancy between kappa and lambda fluorescence profiles in the sample was considered to indicate the presence of monoclonal cells i.e., circulating lymphoma cells. The results were correlated with routine haematological findings, histopathology of the lymphoma and tumour burden. Using routine haematological methods leukaemic spread was evident in 24% of the patients in our study. Using kappa/lambda distribution analysis evidence of circulating lymphoma cells was found in an additional 27%. As expected, the major diagnostic gain was in the low grade malignant group, where 30% of the patients with normal peripheral blood according to standard procedures showed evidence of circulating lymphoma cells in the kappa/lambda distribution analysis. The corresponding gain in the high grade malignant group was 19%. In patients with active disease but without morphological evidence of leukaemia, 37% showed abnormal kappa/lambda distributions. In patients in complete remission the corresponding figure was 18%. The clinical significance of small numbers of circulating lymphoma cells is not yet understood, but a possible outlook is to use kappa/lambda distribution analysis to increase staging precision and in the early detection of relapse.     

Primary extranodal and nodal non-Hodgkin's lymphoma: A survey of a population-based registry

In a population-based registry, there were 580 patients with non-Hodgkin's lymphoma (NHL); 236 had primary extranodal lymphoma (41%). The initial localization of the primary extranodal lymphomas varied markedly, although 36% were primary gastrointestinal lymphomas. Histological classification was performed by a regional panel of pathologists according to the Kiel Classification and the International Working Formulation. Twelve per cent of the patients with nodal NHL had a localized disease in contrast to 40% with primary extranodal NHL. Low grade lymphomas were encountered in 30 and 10% of the patients with primary nodal and extranodal NHL, respectively. Recurrence-free survival rate for patients with localized low-grade malignancy and disseminated intermediate grade NHL is significantly better for extranodal lymphoma than for nodal NHL. Patients with disseminated high-grade extranodal NHL had the worst prognosis of all. We conclude that primary nodal and primary extranodal lymphomas should be considered as distinctive and separate entities.     

Oral cyclophosphamide therapy for patients with residual or relapsed indolent-type lymphoma after initial treatment for aggressive lymphomas. A sub-group of patients with apparent transformed indolent lymphoma

Lymph node or bone marrow biopsy from sixty-one patients affected by aggressive non-Hodgkin lymphomas (NHL) were retrospectively evaluated to assess the histology at relapse. Eighteen cases (29.5%) were proven to have relapsed or persistent low-grade lymphoma after conventional therapy. In 5/18 patients association of low and high-grade lymphoma was detectable at diagnosis by bone marrow biopsy. In the remaining 13/18 no evidence of follicular lymphoma was detected at diagnosis. The outcome of these patients was compared to that of 43 patients relapsed without change in histology and treated by a second line therapy. Of these 43 patients, 13 were not responders (NR), 10 achieved a partial remission (PR) and 18 complete remission (CR). Two were lost during follow-up. The 18 patients with residual/relapsed indolent subtype received oral cyclophosphamide (100 mg/day for 15 days every month for six months): 3 of them had NR, 5 CR, and 10 PR. The overall survival (OS) median time was 39 months in low-grade resistant/relapsed patients and 20 months in patients with aggressive histology. OS at 24 months was 71 and 41%, respectively, (p < 0.02). Most of the patients with high-grade disease were refractory or relapsed after a median of five months, whereas cases with low-grade NHL showed a long lasting stable PR. We suggest that the higher grade patients with residual or relapsed low grade lymphoma were, in fact, transformed low-grade at diagnosis and, after removing the more aggressive component by chemotherapy, it is possible to manage these patients by conventional therapy for indolent lymphomas.     

Primary malignant lymphoma of the salivary glands

Five cases of primary malignant lymphomas of the salivary glands are reported. Four lymphomas arose in the parotid gland and one in the submandibular gland. All were non-Hodgkin lymphomas. In 4 cases the lymphomas were of low-grade malignancy, viz. 2 immunocytomas and 2 centroblastic/centrocytic malignant lymphomas, and 1 was a T-immunoblastic malignant lymphoma of high-grade malignancy. Four patients with localized disease were treated with radiotherapy and 1 patient with disseminated disease was treated with chemotherapy. One patient died from a disease unrelated to the malignant lymphoma, and 4 patients were alive at 66-136 months after treatment.     

Clinical and prognostic relevance of the Kiel classification of non-Hodgkin lymphomas

The Kiel classification provides a new subdivision of non-Hodgkin lymphomas into distinct entities showing different clinical and prognostic properties. In comparison with earlier classifications this system defines additional types of lymphoma (e.g. CC lymphoma, LP immunocytoma) (for abbreviations see text) which are to be considered separate entities also from a clinical point of view. By data derived from a multicenter prospective observation study (1,127 patients recruited from 1975 to 1980, follow-up until 1985) a precise definition of the clinical features of each lymphoma entity (e.g. frequency, age and sex distribution, patterns of initial involvement and spread of disease) was possible. In addition, the effect of radio- and/or chemotherapeutic measures was evaluated. Strictly localized disease (stage I/IE according to the Ann Arbor classification) occurred in 1.5 to 8% of patients with NHL of low-grade malignancy (comprising 69.4% of cases studied) and in 8 to 17% of patients with high-grade malignant NHL (comprising 30.2% of cases studied). Loco-regional irradiation alone was able to induce complete remission in 86 to 89% (CB and IB lymphomas) and in 100% (LP immunocytoma, CB-CC and CC lymphomas), respectively, of stage I/IE patients. Only CC and IB lymphomas showed a relevant risk of relapse (40% and 50%, respectively). Total lymphoid irradiation as able to induce stable complete remissions in about 50% of patients with stage III of CB-CC lymphoma. Probabilities of survival of patients with initial stages III and IV treated by several types of chemotherapy reflect different prognostic features of individual lymphoma entities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bone marrow involvement by non-Hodgkin's lymphoma: the clinical significance of morphologic discordance between the lymph node and bone marrow. Nebraska Lymphoma Study Group.

Bone marrow specimens from 317 patients with non-Hodgkin's lymphoma (NHL) obtained at initial staging were evaluated for the presence of lymphoma or benign lymphoid aggregates. Thirty-two percent (102 patients) had lymphoma in their bone marrow, and 9% had benign lymphoid aggregates. Bone marrow lymphoma was present in 39% of low-grade, 36% of intermediate-grade, and 18% of high-grade lymphomas. The bone marrow was involved in 25% of patients with diffuse large-cell or immunoblastic NHL (ie, diffuse histiocytic lymphoma of Rappaport). Bone marrow involvement did not affect survival of patients with low-grade NHL, but survival was significantly shorter (P = .03) for patients with intermediate- and high-grade NHL with bone marrow involvement. Bone marrow involvement was equally common in B-cell and T-cell NHL (31% v 32%). However, patients with T-cell NHL and bone marrow involvement had shorter survival than B-cell NHL with marrow involvement (P = .02) or T-cell NHL without marrow involvement (P = .05). A high incidence of morphologic discordance between lymph node and bone marrow was observed (ie, 40%), always with a more aggressive subtype in the lymph node than in the bone marrow. Presence of large-cell lymphoma in the bone marrow predicted for short survival. Survival for patients with small-cell lymphoma in their bone marrow did not differ significantly from patients with negative bone marrows. We conclude that bone marrow involvement in large-cell NHL, especially in those of T-cell origin, portends a poor prognosis. However, the subgroup of patients with an aggressive histologic subtype of NHL in a lymph node biopsy and small-cell NHL in the bone marrow do not have a poorer outlook than those without bone marrow involvement.     

Ki67 and 4F2 antigen expression as well as DNA synthesis predict survival at relapse/tumour progression in low-grade B-cell lymphoma

Previous work has shown that parameters of cell activation studied on lymphoma biopsies can be used to discriminate between low-grade and high-grade non-Hodgkin's lymphomas and to predict prognosis in the low-grade malignancy group alone. We have now examined expression of several activation antigens and indicators of DNA synthesis in 29 patients with low-grade malignant B-cell lymphomas at the time of primary diagnosis and later at relapse and/or tumour progression. At both times, the level of 4F2 antigen expression examined by flow cytometry on cells in suspension as well as the number of Ki67 antigen-positive cells examined by immunohistochemistry were predictive of patient survival. DNA synthesis estimated by (3H-TdR) thymidine incorporation was of prognostic value at the second biopsy only. These parameters were more sensitive than histological demonstration of morphological transformation in secondary high-grade lymphomas in identifying high-risk patients at repeated biopsy. We propose that Ki67 or 4F2 expression or a marker of DNA synthesis (such as 3H-TdR incorporation or labelling index) should be evaluated when repeated biopsies are performed, in order to select patients for whom aggressive chemotherapy may be considered.     

High-grade transformation of low-grade non-Hodgkin's lymphomas: mechanisms of tumor progression.

In the natural history of low-grade non-Hodgkin's lymphomas (NHL) a prolonged indolent phase of the disease may be followed by clinical progression toward intermediate and high-grade disease. The abrupt appearance of diffuse large cell lymphoma (DLL) in patients with low-grade NHL is usually associated with an accelerated clinical course and shorter time of survival. The histologic transformation has been described for chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and lymphoma of mucosa-associated lymphoid tissue (MALT). Although the histological transformation of low-grade lymphomas are relatively frequent, the clonal relationship between the two neoplasms and pathogenetic mechanisms underlying the progression of the disease are widely debated. In this review, we will focus on the possible relationship between the low-grade and the transformed high-grade NHLs and genetic lesions that may be associated with the histologic transformation and clinical progression of the disease.     

Primary localized non-Hodgkin's lymphoma of the thyroid: a retrospective clinicopathological review

Primary localized non-Hodgkin's lymphomas (NHL) of the thyroid are rare. The data presented are derived from 819 consecutive patients with NHL and six patients with anaplastic thyroid carcinomas of small cell type investigated and treated at our department between 1970 and 1981. The present analyses are based on the 19 patients, who were found to have localized primary thyroid lymphomas. Four of these patients were initially considered to have undifferentiated small cell carcinomas of the thyroid but revealed to be lymphomas at re-examination supplemented with immunohistopathologic staining. Prognosis has been evaluated with regard to initial stage, histopathology according to the Kiel classification and therapy. Median follow-up was 5 years. The crude survival was 77% 5 years after diagnosis. This was not significantly less (4.2%) than the overall-survival in an age- and sex-matched population, despite the majority of patients having tumours which were locally advanced, often with spread to regional lymph nodes, and in many cases a histology showing a high-grade malignancy according to Kiel classification. The excellent prognosis in the current study compared to other studies is probably mainly attributed to more extensive staging procedures. The biologic behaviour supports the hypothesis that these lymphomas represent lymphomas of mucosa associated lymphoid tissue (MALT). According to present results anaplastic thyroid carcinoma of small cell type must be extremely rare.     

The distribution of non-Burkitt, non-Hodgkin's lymphomas in Uganda in relation to malarial endemicity

Biopsies of malignant lymphomas collected from all districts of Uganda, filed in the Kampala Cancer Registry for the 8-year period 1966-1973, were reviewed. This review confirmed a relatively low frequency of follicle-centre-cell lymphomas with a follicular growth pattern and the geographical co-distribution between malaria and Burkitt's lymphoma (BL). It also showed a similar, though less marked, association between non-Burkitt, non-Hodgkin's lymphoma (NBNHL) and malarial endemicity, and a correlation in the regional incidence between BL and NBNHL. In both comparisons, these associations were strong for high-grade lymphomas and weak for low-grade neoplasms. BL and other NHL may therefore share, to a varying degree, some common pathogenesis. The excess in frequency of NBNHL of high-grade malignancy in malarial endemic areas appears to be in contrast to Western countries where most non-Hodgkin's lymphomas are of low-grade malignancy.     

Gastric low-grade MALT lymphoma, high-grade MALT lymphoma and diffuse large B cell lymphoma show different frequencies of trisomy.

Gastric MALT lymphoma is a distinct entity related to Helicobacter pylori gastritis. Some studies suggest a role for trisomy 3 in the genesis of these lymphomas, but they mainly focused on low-grade MALT lymphoma. Gastric MALT lymphoma, however, comprises a spectrum from low- to high-grade cases. Furthermore, its exact relation to primary diffuse large B cell lymphoma (DLBCL) of the stomach is not clear. We applied in situ hybridisation (ISH) with centromeric probes on 43 samples of 39 patients with primary gastric lymphoma (13 samples with low-grade MALT lymphoma, 25 with high-grade MALT lymphoma and five with DLBCL) to detect numerical aberrations of 10 chromosomes. ISH was performed immunohistochemically on nuclei isolated from paraffin-embedded resection tissue and on whole paraffin sections using immunofluorescence. In six of 13 low-grade MALT lymphomas trisomy was detected (46%) and mostly involved chromosome 3 (33%). In high-grade MALT lymphomas, trisomies were found in 16 of 25 cases (64%), mainly involving chromosomes 12 and 18. Trisomy 3 was present in only 13% of these cases. Of five DLBCL, only one showed trisomy. Nine of the 16 aberrant high-grade MALT lymphomas (56%) showed trisomy of more than one chromosome per case vs two of six for low-grade cases. In lymphomas with separate low- and high-grade tumour components some trisomies were detected in both components, whereas others occurred only in the high-grade tumour cells. This supports the hypothesis that high-grade MALT lymphomas can develop from a low-grade type and that this progression is accompanied by the acquisition of more genetic aberrations. However, trisomy 3 probably does not play a major role in this progression.     

The use of serum deoxythymidine kinase as a prognostic marker, and in the monitoring of patients with non-Hodgkin's lymphoma.

A recently developed enzyme assay, utilizing [125I]-iododeoxyuridine as substrate, and capable of detecting normal levels of serum deoxythymidine kinase (s-dTk), was used in an investigation of sera from 155 untreated patients with non-Hodgkin''s lymphoma (NHL). The patients were classified at the discovery of disease, both according to spread (stages I-IV according to the Ann Arbor classification) and to tumour histology (the Kiel classification). The results showed a significant correlation between s-dTk level and the extent of disease, as well as to the malignancy; i.e. the more advanced the disease or the more aggressive the tumour, the higher the s-dTk values. Greater than 100-fold increases in s-dTk levels were found in some patients compared to those reported for healthy individuals. A high pretreatment level of s-dTk for patients in stages III-IV correlated with a poor prognosis for the patient in terms of survival. This was consistent even when only patients in stages III-IV with "high-grade" malignant lymphomas were included in the analysis. Longitudinal studies of s-dTk levels in 19 NHL patients showed that s-dTk increases with progression of the disease, decreases during successful therapy, and finally increases during relapse. It is concluded that s-dTk could be used both as a prognostic marker and to monitor the effect of therapy in NHL patients.     

造血干细胞移植治疗中高度恶性非霍奇金淋巴瘤5例

造血干细胞移植治疗非霍奇淋巴瘤５例,包括４例第 完全缓中,高度恶性ＮＨＬ;１例高度恶性ＮＨＬ合并淋巴瘤白血病。其中自体骨髓移植４例,异基因外周血干细胞移植１例。所有病例的移植成功。４例ＡＢＭＴ患者已无病生存５０,４８,３９和３个月,１例ａｌｌｏ－ＰＢＳＣＴ发生慢性移植物抗宿主病,移植后１２人月死于白血病复发。结果显示ＡＢＭＴ是治疗中,高度恶性ＮＨＬ有效手段。     

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) for the staging of low-grade non-Hodgkin's lymphoma (NHL).

Background:Although PET has been shown to be highlysensitive in the primary staging of lymphoma, previous studies withsmall numbers of patients indicated that low-grade NHL may not always beadequately detected by PET. We undertook this study to determine factorsinfluencing the detection of lesions by PET in low-grade NHL and toevaluate the utility of PET in this indication. Patients and methods:Forty-two patients underwentconventional staging procedures (clinical examination,oto-rhino-laryngologic examination, computed tomography of the chest,abdomen and pelvis, gastroscopy and bone marrow biopsy as well aswhole-body non-attenuation corrected ¹⁸F-FDG-PET. Results:PET detected 40% more abnormal lymph nodeareas than conventional staging in follicular lymphoma but wasinappropriate for the staging of small lymphocytic lymphoma where itdetected less than 58% of abnormal lymph node areas. PET showedmore lesions than conventional staging for peripheral (34% morelymph node areas detected) and thoracic lymph node (39% more)areas but not for abdominal or pelvic lymph nodes (26% fewerareas detected). The sensitivity to detect bone marrow infiltration wasunacceptably low for PET. In contrast, PET was as effective as standardprocedures for the detection of other extranodal localizations, althougha few localizations were detected only by PET and a few others only byconventional procedures. Conclusions:PET may contribute to the management ofpatients with low-grade follicular NHL. For the other low-grade lymphomasubtypes, the role of PET is less evident. Further studies using PET toevaluate the results of treatment or to diagnose disease recurrence arewarranted in low-grade follicular NHL.