Intermediate Lymphocytic Lymphoma Research Articles

Autopsy case of primary central nervous system lymphoma with subacute mental deterioration and progressive white matter lesions in an elderly man

An autopsy case is reported here of a 70‐year‐old Japanese man with primary central nervous system lymphoma (PCNSL) manifesting subacute mental deterioration and progressive white matter lesions. Brain magnetic resonance imaging (MRI) revealed irregular hyperintense lesions on T2‐weighted images of the white matter of the bilateral frontal lobes. The hyperintense lesions then spread to the corpus callosum, internal capsule, globus pallidus and along the pyramidal tract in the brainstem without a mass effect. The U‐fibers were also involved in some regions. Neither brain swelling nor a significant atrophy was observed. The clinical manifestations and imaging findings of PCNSL are diverse. Recently, some reports have revealed atypical MR imaging of PCNSL exhibiting diffuse infiltration in the brain parenchyma without mass formation and enhancement of the lesions after the administration of a contrast medium. The authors also encountered an interesting case of PCNSL presenting as progressive white matter lesions without brain swelling. It is now possible to finely observe white matter lesions by brain MRI, particularly in T2‐weighted images. Recently the number of immunocompetent elderly patients with PCNSL appears to be increasing in Japan. Autopsy of the present case revealed an intermediate lymphocytic malignant lymphoma. Because imaging and laboratory findings are not completely specific for the diagnosis of PCNSL at present, brain biopsy is more strongly recommended for the final diagnosis of PCNSL even in elderly patients, based on which appropriate treatment is administered.

"Small" B-cell non-Hodgkin's lymphomas with splenomegaly at presentation are either mantle cell lymphoma or marginal zone cell lymphoma. A study based on histology, cytology, immunohistochemistry, and cytogenetic analysis.

Only 1 to 2% of all non-Hodgkin's lymphomas (NHL) present with an enlarged spleen, most of them "small B-cell lymphomas." Recently, several reports have identified these lymphomas as marginal zone B-cell lymphomas. We reviewed 39 cases of NHL presenting with an enlarged spleen without lymphadenopathy, documented by fixed and frozen material. Two were peripheral T-cell lymphomas, four diffuse large B-cell lymphomas, and 14 hairy cell leukemias. The remaining 19 belonged to the "small B-cell" category and constitute the focus of our study. Subtyping was achieved by combining morphology, immunophenotype, and cytogenetic features according to the proposal of the International Lymphoma Study Group; in addition, analysis of the peripheral blood and bone marrow smears was performed adopting the French-American-British (FAB) criteria. From this study, we can conclude that most "small B-cell" NHL of the spleen were either mantle cell lymphomas or marginal zone cell lymphomas and, by peripheral blood analysis, that the mantle cell lymphomas corresponded to intermediate lymphocytic lymphoma and the marginal zone cell lymphomas to splenic lymphomas with villous lymphocytes. As a result, several diagnostic criteria can be proposed that may be helpful in differentiating mantle cell lymphoma from marginal zone cell lymphoma in the spleen.

Patterns of survival in mantle cell lymphoma

The term mantle cell lymphoma (MCL) describes a subtype of non-Hodgkin's lymphoma that includes those lymphomas previously defined as centrocytic lymphoma, intermediate lymphocytic lymphoma, and mantle zone lymphoma. Since MCL has only recently been recognised as a distinct entity, the clinical literature is sparse and very little information is available about its treatment. We retrospectively attempted to analyse the clinical features and outcome of 65 patients with mantle cell lymphoma (MCL) treated from 1979 to 1993 at two institutions in the same geographic area. Univariate (Log-rank test) and multivariate (Cox regression) analyses of the major prognostic factors were performed. At the time of analysis the median follow-up was 49 months. Median age was 64 years with a range of 27-85 years. The male to female ratio was 2:1. Forty-seven patients (72%) had stage IV at presentation and 20 (31%) had B-symptoms at presentation. The patients usually presented with generalised adenopathy (78% of cases) and bone marrow involvement (58%). Serum LDH were analysed at diagnosis in 61 patients and found to be elevated in 30%. beta 2-Microglobulin was determined at presentation in 42 patients and was higher than normal in 54% of them. In comparison with the other subtypes of NHLs in our series, MCL appears to have a very poor survival pattern. The median overall survival was 42 months. The CR rate was 51% with a median DFS of 44 months. Good performance status, normal LDH, normal beta 2-microglobulin, younger age (< 65 years), and a low prognostic risk according to the International Index were significantly associated (p < 0.05) with a better outcome. The characteristics of the patients in this study appear to be in general agreement with those in most of the previously reported series except for the somewhat lower rate of bone marrow infiltration observed in this series. Despite the limitations of a retrospective analysis and the lack of randomization between the treatment options, this study seems to suggest a survival advantage with anthracycline-containing regimens in some patients with MCL. However, this benefit was evident only for the patients with favourable International Index prognostic scores (i.e., low- and to low-intermediate-risk disease) who may already have a better prognosis. Patients with intermediate-high and high-risk disease according to the International Index have a poor prognosis regardless of the type of therapy given.

Intermediate lymphocytic lymphoma with both t(14;19)(q32.3;q13.1) and t(3;22)(q27;q11.2)

Chromosome translocations involving various chromosome sites, including the sites of immunoglobulin loci (14q32,2p12,22q11) represent recurrent aberration in non-Hodgkin lymphoma (NHL). We report a novel case of intermediate lymphocytic lymphoma (ILL) with both t(14;19)(q32.3;q13.1) and t(3;22)(q27;q11.2). The t(14;19)(q32.3;q13.1) and t(3;22) (q27;q11.2) may represent reciprocal recombinations between immunoglobulin (Ig) H chain gene (14q32.3) and bcl-3(19q13.1) and between Ig λ chain gene (22q11.2) and bcl-6 (3q27), respectively.

Scanning and transmission electron microscopy of clonal peripheral blood lymphocytes in low grade non-Hodgkin's B-cell lymphomas with predominant splenomegaly.

Peripheral blood mononuclear cells (PBLs) from 14 patients with low grade non-Hodgkin's B-cell lymphomas with predominant splenomegaly were studied by means of scanning (SEM) and transmission electron microscopy (TEM). All patients had peripheral blood and bone marrow involvement, the absence of lymphoadenopathy, and, except in one case, immunophenotypic features of a malignant proliferation of mature spleen B-cells arising from outside the germinal center, but not consistent with CLL or HCL. Several distinctive cytological features were observed in PBLs of the different subgroups. The SEM surface features of PBLs in patients with intermediate differentiation lymphocytic lymphoma (IDL) (five cases), lymphoplasmacytoid immunocytoma (LP-IC) (two cases), and mixed small and large cells malignant lymphoma (one case) were characterized by the presence of numerous well-developed microvilli. Some distinctive TEM ultrastructural features were also seen in the different cases. In the two cases of splenic lymphoma with villous lymphocytes (SLVL), SEM revealed large and elongated surface microvilli generally arising from two or three poles of the cells. This surface morphology, confirmed by TEM analysis, may be pathognomonic of this disease. Four additional cases, tentatively classified as small lymphocytic lymphoma on the basis of immunophenotypic data, were extremely heterogeneous at both SEM and TEM analysis. The ultrastructural features revealed by SEM and TEM may be useful for the more precise characterization of this heterogeneous group of diseases, which is generally difficult to define even when immunophenotypic and molecular approaches are used.

Intermediate Lymphocytic Lymphoma of the Small Intestine Mantle Cell Lymphoma

Intermediate Lymphocytic Lymphoma of the Small Intestine Mantle Cell Lymphoma

Mantle zone lymphoma: An immunohistologic study of skin lesions

Mantle zone lymphoma (MZL) is a B-cell proliferation regarded as the follicular variant of intermediate lymphocytic lymphoma (ILL). Neoplastic small lymphoid cells proliferate as wide mantles around atrophic centers of benign appearance. The clinical, histologic, and immunohistochemical features of four cases of MZL, heralded by cutaneous lesions, are described and correlated with the lymph node pattern. All specimens showed extensive nodules in the reticular dermis invading the subcutaneous tissue. They were mainly composed of a proliferation of small lymphocytes with slightly irregular nuclear contours and clumped chromatin, forming wide mantles around small atrophic germinal centers. Serial biopsy specimens in case 1 revealed evolution of the skin lesions from pseudolymphoma into MZL. Their immunohistochemistry was similar to that of lymph nodes and showed that the neoplastic cells were CD5+, CD20+, CD22+, CD25+, CD74+, Leu-8+, HLA-DR+, IgM+, IgD+ with restriction for the lambda light chain, CD10-, and CD71-, whereas the germinal center cells were polyclonal. In three cases many CD38+, PCA-1+ plasma cells were present both in the grenz zone and in bordering neoplastic nodules. The clinical course was chronic. The only death occurred from unrelated causes; one patient is still alive 17 years after onset. Skin lesions may be the only manifestation of MZL for an extended period. The differentiation between pseudolymphoma and other lymphoma subtypes is based not only on the histologic and cytologic features but also on the architecture, followed by immunohistochemical confirmation.

Rearrangement and Overexpression of the BCL-1/PRAD-1 Gene in Intermediate Lymphocytic Lymphomas and in t(11q13)-Bearing Leukemias

The t(11;14)(q13;q32) translocation and its molecular counterpart, BCL-1 rearrangement, are consistent features of intermediate lymphocytic lymphoma (ILL). Rearrangement is thought to deregulate the nearby PRAD-1/BCL-1 proto-oncogene that is a newly identified member of the cyclin family. To characterize further the association between rearrangement of chromosome 11q13 and over-expression of BCL-1. Southern blot analysis was performed in 33 cases of ILL, 5 cases of t(11;14)-associated leukemias, and 1 case of leukemia carrying a variant translocation t(11;19)(q13;q13) using three separate BCL-1 locus probes. When RNA was available, BCL-1 expression was assessed by Northern blot analysis. DNA from 19 of 33 ILL (57%) showed BCL-1 rearrangement, 16 involving the major translocation cluster (MTC) region and 3 involving a new breakpoint cluster located in the 5' flanking region of the BCL-1 gene. DNA from 3 of 6 t(11q13)-associated leukemias demonstrated a rearrangement involving the MTC. Northern blot analysis showed that BCL-1 was overexpressed in 14 of 15 ILL and in all leukemias analyzed (included the t(11;19) leukemia) relative to normal and malignant lymphoid tissues. These results constitute additional elements in favor of the role of BCL-1 in lymphoid neoplasia and allow us to speculate about its mechanisms of activation.

Rearrangement and overexpression of the BCL-1/PRAD-1 gene in intermediate lymphocytic lymphomas and in t(11q13)-bearing leukemias

The t(11;14)(q13;q32) translocation and its molecular counterpart, BCL- 1 rearrangement, are consistent features of intermediate lymphocytic lymphoma (ILL). Rearrangement is thought to deregulate the nearby PRAD- 1/BCL-1 proto-oncogene that is a newly identified member of the cyclin family. To characterize further the association between rearrangement of chromosome 11q13 and over-expression of BCL-1. Southern blot analysis was performed in 33 cases of ILL, 5 cases of t(11;14)- associated leukemias, and 1 case of leukemia carrying a variant translocation t(11;19)(q13;q13) using three separate BCL-1 locus probes. When RNA was available, BCL-1 expression was assessed by Northern blot analysis. DNA from 19 of 33 ILL (57%) showed BCL-1 rearrangement, 16 involving the major translocation cluster (MTC) region and 3 involving a new breakpoint cluster located in the 5' flanking region of the BCL-1 gene. DNA from 3 of 6 t(11q13)-associated leukemias demonstrated a rearrangement involving the MTC. Northern blot analysis showed that BCL-1 was overexpressed in 14 of 15 ILL and in all leukemias analyzed (included the t(11;19) leukemia) relative to normal and malignant lymphoid tissues. These results constitute additional elements in favor of the role of BCL-1 in lymphoid neoplasia and allow us to speculate about its mechanisms of activation.

Intermediate lymphocytic lymphoma: clinical and pathologic features of a recently characterized subtype of non-Hodgkin's lymphoma.

We present a comprehensive review of clinical, pathologic, molecular, and prognostic features and therapy of intermediate lymphocytic (mantle cell) lymphoma (ILL/MCL), a recently characterized subtype that represents 2% to 8% of non-Hodgkin's lymphomas (NHLs), but which has not been included in most classification schemes, including the International Working Formulation. The English-language literature encompassing the above aspects, published between 1977 and 1992, is critically reviewed. ILL/MCL is a disease of proliferating B lymphocytes that is characterized by generalized lymphadenopathy and frequent, often extensive, involvement of the spleen, bone marrow, and gastrointestinal tract. The malignant cells usually express the markers CD5 and IgM with or without IgD, but not CD10, on the cell surface, and grow in one of two dominant histologic patterns: mantle zone and diffuse. The characteristic cytogenetic abnormality is a t(11;14)(q13;q32) translocation, which juxtaposes the bcl-1 locus on chromosome 11 with the immunoglobulin (Ig) heavy-chain locus on chromosome 14, and appears to result in dysregulated expression of the gene encoding cyclin D1. Median survival is in the range of 2 to 5 years. While responses to chemotherapy may be seen in up to half the patients, relapses are the rule, and longterm survival is uncommon. The optimal treatment remains undefined, although therapy may be deferred until there are symptoms or complications, at which time judicious administration of alkylating agents and glucocorticoids may result in effective palliation.

Intermediate Lymphocytic Lymphoma with Multiple Lymphomatous Polyposis of the Gastrointestinal Tract

Intermediate Lymphocytic Lymphoma with Multiple Lymphomatous Polyposis of the Gastrointestinal Tract

Translocation t(11;14)(q13;q32) in chronic lymphoid disorders.

The translocation t(11;14)(q13;q32) has been described in a spectrum of B-lymphoproliferative diseases and involves a putative oncogene, BCL1, which maps to chromosome band 11q13. Recent evidence indicates that this abnormality may delineate particular subtypes of lymphoma, such as intermediate lymphocytic and centrocytic lymphomas. Thus the possible significance of the t(11;14) within B-cell disorders should be reexamined in the light of a more objective approach to classifying these diseases by morphology, histology, and immunophenotype. We describe 16 patients with t(11;14)(q13;q32) from a series of 90 patients with chronic lymphoid disorders in whom clonal chromosome abnormalities were detected. All the cases were leukemic: prolymphocytic (B-PLL; 4/15 cases), chronic lymphocytic leukemia (CLL) with increase in prolymphocytes (2/9 cases), or non-Hodgkin lymphoma in leukemic phase, intermediate (3/4 cases), lymphoplasmacytic (2/2 cases), splenic lymphoma with villous lymphocytes (4/18 cases), and follicular (1 case). None of the CLL (25) or hairy cell leukemia cases (15) had t(11;14). Our findings showed that t(11;14) occurred in leukemias of mature B cells with lymphoplasmacytic features as judged by morphology and immunophenotype.

A new monoclonal antibody which binds to the cytoplasm of large cell lymphomas.

We reported a new monoclonal antibody, designated FUB-1, reacting with normal and neoplastic large lymphoid cells. FUB-1 was produced using a Burkitt's lymphoma cell line (HBL-5) as an immunogen. Its immunoglobulin subtype was IgM. The determinant was not on the surface but in the cytoplasm. Western blotting analysis revealed that the molecular weight of the antigen was 52,000 dalton. In the normal lymphoid tissue, FUB-1 reacted with large lymphoid cells, but not with small or medium-sized lymphoid cells or plasma cells. In addition, the FUB-1 antigen was not found in resting cells in the peripheral blood (PB), but it was induced on mononuclear cells of PB by addition of PWM or PMA. In the B-cell lymphomas tested, FUB-1 reacted with small cleaved cell lymphomas (3/12), large cell lymphomas (7/10), Burkitt's lymphomas (4/4) and immunoblastic lymphomas (2/2), but not with small cell lymphomas (0/3) or intermediate lymphocytic lymphomas (0/8). These findings indicate that the FUB-1 antigen appears to be expressed on normal lymphoid cells during blastoid transformation and on neoplastic large lymphoid cells. FUB-1 also reacted with normal glandular epithelium and various adenocarcinomas. FUB-1 may be useful to investigate the mechanism of in vitro blastoid transformation or activation of lymphoid cells.

Mouse rosettes and surface immunoglobulin in small lymphocytic lymphoma. Importance in immunophenotyping and differential diagnosis

Cell suspensions from lymphoid tissue of 82 small lymphocytic lymphoma (SLL), 8 intermediate lymphocytic lymphoma (ILL), 286 other B-non-Hodgkin's lymphoma (B-NHL), and 248 reactive lymphadenopathy (RLA) cases were analyzed to evaluate the diagnostic significance of mouse-rosette (M-rosette) assay, and surface immunoglobulin clonality (SIg) and level of expression. In SLL, 55 were M-rosette positive (67.07%) and 72 SIg positive (87.8%), with weak fluorescence in 63 and strong fluorescence in 9 cases. Of 10 SIg-negative cases, 9 were M-rosette positive; of 27 M-rosette-negative cases, 26 were SIg positive. Seven of the nine cases with strong fluorescence were M-rosette positive. In other B-NHL, 252 were M-rosette negative (88.11%) and 245 SIg positive (85.66%), with strong fluorescence in 211 and weak fluorescence in 34 cases. Thirty-two of the 34 cases with weak fluorescence were M-rosette negative. Of the RLA cases, 213 were M-rosette negative (85.89%) and 1 SIg positive (0.4%). The study demonstrated the independent expression of M-rosettes and SIg in SLL and their complementary role in diagnosis. It showed that positive results for M-rosettes and weak fluorescence are characteristic of SLL, that M-rosette negativity and strong fluorescence are characteristic of other B-NHL, and that M-rosette negativity and polyclonal SIg are characteristic of RLA. In 26 cases with paired data for CD5, M-rosettes, and SIg, a positive result for M-rosettes was superior to CD5 in differentiating SLL from other B-NHL. Intermediate lymphocytic lymphoma frequently showed weak SIg fluorescence and M-rosette negativity.

節外性の低悪性度リンパ腫 ＭＡＬＴリンパ腫を含む

Malignant lymphoma (ML) of low grade malignancy includes small lymphocytic lymphoma and follicular lymphoma other than large cell type. Recent study revealed intermediate lymphocytic lymphoma (ILL) and monocytoid B-cell lymphoma (MBCL) to be new types of ML of low grade malignancy. These two types of ML are fundamental elements of ML developing in so-called mucosa associated lymphoid tissue (MALT). In this report, results of our study on ILL and MBCL of extranodal organs were described.ILL is composed of small lymphoid cells with morphologic features between those of well-differentiated lymphocytic lymphoma and poorly differentiated lymphocytic lymphoma of follicular center cell origin. The frequency of ILL in nodal and extranodal non-Hodgkin's lymphoma was almost same. The frequency was high in salivary gland and thyroid lymphoma. Histologic features of chronic lymphocytic thyroiditis (CLTH) are constantly observed in cases with thyroid lymphoma. Histologic findings suggestive of Sjogren's syndrome such as formation of lymphoid follicles and myoepithelial islands were observed in one third of cases with salivary lymphoma. These findings suggested that autoimmune diseases such as CLTH and Sjogren's syndrome played an important role in the etiology of thyroid and salivary lymphoma.MBCL shows the proliferation of the atypical lymphoid cells with abundant and pale cytoplasm and reniform nucleus. The high incidence of Sjogren's syndrome in cases with MBCL was evident suggesting the etiologic role of Sjogern's syndrome for development of MBCL. Six cases of MBCL developing in extranodal sites such as thyroid, stomach, and rectum were described below. Two of three patients with thyroid lymphoma presented with positive serum antithyroid antibodies, and one had CLTH. In all three patients with gastric or rectal lymphoma, reactive lymphoid hyperplasia was present near the tumors. These findings suggested the important role of long-standing inflammation for development of MBCL as well as ILL.

日本人のＣＬＬならびに類縁疾患の特徴

The clinical and cytological features of 73 patients with chronic (mature) B-cell leukemias were studied. Large lymphocytes or cleft cells were often seen in patients referred to us as chronic lymphocytic leukemia (CLL). Immunophenotypical and histopathological studies were performed and the diagnosis of leukemic phase of non-Hodgkin's lymphoma (follicular lymphoma; FL and intermediate lymphocytic lymphoma; ILL) was made in a significant portion of the patients and only ten cases were diagnosed as CLL including mixed cell type.Although hairy cell leukemia (HCL) is quite rare in Japan, a disproportionally large number of patients were referred to our laboratory. Typical HCL seen in Western countries, was found in nine cases. On the other hand, most (29 cases) showed cytologic features distinct from typical HCL and were classified into HCL-Japanese Variant (HCL-J). Morphology of HCL-J cells in May-Giemsa stained films resembled large CLL lymphocytes, but several features shared by typical HCL and HCL-J including typical hairy morphology under phase contrast microscopy, CD11c+, L30- phenotype and the histology distinguished the disease from CLL and other B-cell leukemias. In two cases, the cells displayed prominent nucleoli and surface villi, the features consistent with those described for HCL Variant (prolymphocytic variant). Some patients were differentiated from HCL and were diagnosed as leukemic phase of ILL with large spleens or splenic lymphoma with villous lymphocytes (SLVL). Under phase contrast, fine cytoplasmic processes were obseved in ILL cells. Surface morphology of SLVL cells considerably varied from cell to cell; some displayed prominent cytoplasmic projections similar to those of hairy cells, while others had a few, short villi or lacked villi even by phase contrast microscopy. The spleen histology showed prominent involvement in the white pulp with the features of lymphoplasmacytic lymphoma.

Leukaemic intermediate lymphocytic lymphomas: analysis of twelve cases diagnosed by morphology.

Twelve cases of leukaemic intermediate diffuse lymphocytic lymphoma (ILL), diagnosed by morphology, were analysed. The morphology of the ILL cells was so typical that it allowed ready distinction from chronic lymphocytic leukaemia (CLL) and other related B cell disorders. All cases were of B derivation, had strong mu and chi or lambda immunoglobulin (Ig) staining, were CD5 and FMC7 positive and CD10 negative. Cytogenetic abnormalities were found in 8 patients all having t(11;14)(q13;q32). DNA analysis revealed a relatively high incidence of hypoploidy. At diagnosis all the patients (9 males, 5 females; median age 68) had a low degree of absolute lymphocytosis but the disease was advanced and mostly widespread. The course of the disease appears to be aggressive and incurable with conventional combination chemotherapy.

低悪性度リンパ腫の治療 化学療法について

We analyzed 113 cases of low-grade lymphoma including follicular medium-sized cell type, follicular mixed type and diffuse small cell type of B-cell origin in the LSG classification. Diffuse medium-sized cell type of B-cell origin corresponding to diffuse small cleaved cell in working formulation and intermediate lymphocytic lymphoma, both of which are classified in indolent lymphoma by national cancer institute, was excluded because our study showed poor prognosis of this type. Chemotherapy was done as the primary therapy in 89 patients and anthracycline was used in 63 patients. Analysis of survival rate revealed better prognosis of the chemotherapy with anthracycline from 5 -to 10-year survival, although CR ratio was less than that of the chemotherapy without anthracycline. Significant differences in prognosis were found in clinical stage (I vs II), primary sites (nodal vs exnodal), serum LDH (normal vs high) and therapeutic response (CR vs PR). Follicular medium-sized cell type showed almost the same survival as that of diffuse small cell type within 5 years after onset. Ten patients with follicular medium-sized cell type, however, died more than 5 years after onset and all of 4 patints of 10-year survival were under recurrent disease. In contrast, none of patients with diffuse small cell type died after 4-year survival and all of 4 patients of 10-year survival were disease-free. Improvement of long-term survival of follicular lymphoma is a major problem in chemotherapy of low-grade lymphoma, and a more intensive chemotherapy and/or combination with radiotherapy will be necessary in the near future.

Intermediate lymphocytic lymphoma: Its frequency and characteristics in japan

The nature of intermediate lymphocytic lymphoma (ILL) in Japan was investigated. For this purpose, we have reviewed 1,766 cases of malignant lymphoma and related diseases, and 38 cases were selected as ILL. In two cases, small lymphoid cells proliferated as a wide mantle of atrophic secondary follicles. The frequency of ILL in nodal and extranodal non-Hodgkin's lymphoma was 3.4% and 3.9%, respectively. The frequency was high in orbit and salivary gland lymphomas; two out of three cases and one out of six cases, respectively. Age range (median) and sex ratio (M:F) in nodal and extranodal cases were 34-65 (52) years and 2.1:1 and 22-82 (61) years and 1.1:1, respectively. The majority of nodal ILL presented as systemic disease, but extranodal ILL usually presented as localized disease. ILL when treated with chemotherapy and/or radiotherapy had a favorable prognosis, the 5-year survival rate was 82%.

Pathology of malignant lymphomas.

Attempts to understand the malignant lymphomas have followed two major lines of investigation: attempts to define the relationship of neoplastic lymphoid cells to stages of normal T- and B-lymphocyte differentiation, and attempts to understand the genetic abnormalities associated with malignant transformation. It is hoped that these two lines of investigation will make it possible to define clinically important entities, so that specific treatment strategies can be developed and tested, and will also point the way to new options for treatment and prevention. Despite the advances in immunology of the last two decades, our understanding of the relationships of lymphoma cells to the normal immune system remains incomplete. Techniques of molecular genetics, which initially promised to resolve questions of clonality and lineage, have proven less definitive than had been hoped. Studies in the field of molecular cytogenetics--the study of chromosomal translocations by molecular techniques--have just begun to unravel some of the mysteries surrounding neoplastic transformation and differentiation. As we enter the last decade of the century, small advances continue to chip away at the uncertainties shrouding the malignant lymphomas. Advances in the past year include the subclassification of low-grade B-cell lymphomas, including so-called intermediate lymphocytic lymphoma and extranodal lymphomas of mucosa-associated lymphoid tissue, the classification of T-cell lymphomas, the definition of Hodgkin's disease and its relationship to anaplastic large cell lymphoma, and new techniques for characterizing lymphoid cells in paraffin-embedded tissue sections.