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[Non-Hodgkin's lymphomas of low-grade malignancy with particular reference to the lymphocytic lymphomas of B-cell origin (author's transl)].

More than two thirds of all non-Hodgkin's lymphomas (NHL) are of low-grade malignancy. This group comprehends five histological types: lymphocytic, immunocytic, plasmacytic, centrocytic, and centroblastic-centrocytic lymphomas. The lymphocytic lymphomas are second in frequency among the biopsies. The most common lymphocytic lymphoma is the chronic lymphocytic leukemia (CLL). It is characterized by the proliferation of small lymphocytes. The quantity and arrangement of the constantly present paraimmunoblasts and prolymphocytes allow to distinguish three histological subtypes of CLL. CLL, prolymphocytic leukemia, and hairy cell leukemia may be composed of B- or T-cells. Mycosis fungoides, Sézary's syndrome and T-zone lymphomas are T-cell lymphomas. All NHL of low-grade malignancy show a proliferation of small to medium sized lymphoid cells. Some large blast forms may be intermingled among these smaller cells. The inhomogeneity of low-grade malignant lymphomas with regard to the size of predominant cells and the admixture of blast forms determine the higher ("intermediate") degree of malignancy of some types in the group of low-grade malignant lymphomas. The overgrowth of the intermingled blast forms probably leads to the transformation into a lymphoma of high-grade malignancy. This event happens in variable frequency in the various types of low-grade malignant lymphomas. NHL of low-grade malignancy occur almost exclusively in adults, whereas the high-grade malignant lymphomas are found in all age-groups.

Adolescent

Alkaline phosphatase-positive malignant lymphoma. A subtype of B-cell lymphomas.

Alkaline phosphatase (ALP) activity was evaluated histochemically and cytochemically in concert with immunologic technics in 60 cases of non-Hodgkin's lymphomas and lymphocytic leukemias. Surface membranes of neoplastic cells were positive for ALP only in certain B-cell malignancies: 3 of 6 lymphocytic lymphomas of intermediate differentiation, 4 of 13 nodular lymphomas, and 1 of 7 Burkett's lymphomas. All other B-cell tumors, including chronic lymphocytic leukemia, well-differentiated lymphocytic lymphoma, and diffuse "histiocytic" lymphoma, were ALP-negative. The neoplastic cells of Sezary syndrome and lymphoblastic lymphoma were also consistently negative for ALP. In control lymph nodes ALP-positive lymphocytes were present only in primary follicles and in mantle zones of secondary follicles. ALP-positive lymphomas appear to be neoplastic counterparts of these normal lymphocytes, not only cytochemically, but also with respect to their morphologic and immunologic characteristics. Furthermore, histochemical inhibition tests suggested that the ALP activity demonstrated may reflect a newly recognized, unique isoenzyme.

Alkaline Phosphatase

Signet ring cell lymphoma. A rare morphologic and functional expression of nodular (follicular) lymphoma.

Nodular lymphomas and diffuse lymphomas of corresponding cellular composition have been shown to arise from follicular center cells. This paper describes a rare functional and morphological expression of malignant lymphomas arising from follicular center cells, namely, immunoglobulin production, an observation for which no detailed description or nanlysis is available in the literature. Furthermore, the unusual signet ring-like appearance of the lymphoma cells, which is due to retention of immunoglobulins within the cytoplasm, may result in an erroneous interpretation of metastatic adenocarcinoma or liposarcoma. Therefore, we are presenting a detailed analysis of light microscopic, histochemical, immunocytochemical, and ultrastructural observations. The lymphomas of all seven patients in our series showed nodular growth patterns; in all but one, diffuse areas were also observed. Five of the lymphomas were classified as poorly differentiated lymphocytic type and two as mixed cell type, according to Rappaport's classification. In four of the seven patients, the majority of the neoplastic cells had a clear vacuolated cytoplasm, and in three of these cases, a few of the neoplastic cells showed immunoperoxidase positivity for monoclonal IgG. This group in particular closely simulated metastatic carcinoma composed of so-called signet ring cells. In the remaining three cases, most of the neoplastic cells contained PAS-positive, Russell body-like monoclonal IgM. Ultrastructurally, the monoclonal IgG appeared as even-sized electron-dense spherules or irregular electron-dense clumps, while the monoclonal IgM appeared as membrane bound, homogeneous, electron-dense material. The implications of these findings and the morphologic features which are helpful in the identification of these lymphomas are discussed.

Aged

Nodular lymphocytic lymphoma eventuating into diffuse histiocytic lymphoma: immunoperoxidase demonstration of monoclonality.

The patient described here had a nodular, poorly differentiated lymphocytic lymphoma associated with a serum monoclonal protein, IgG lambda. Following a three year period of radiation-induced clinical remission she developed generalized diffuse histiocytic lymphoma. Direct immunoperoxidase staining of the tissue sections demonstrated that the neoplastic cells of each biopsy only contained IgG lambda immunoglobulin, identical to the serum monoclonal protein. This is presumptive evidence that these two histopathologically distinctive malignant lymphomas, occurring consecutively in the same patient, were responsible for the synthesis and secretion of the same serum M component. This strongly suggests that both lymphoid neoplasms arose from the same malignant clone. The results 1) confirm the light microscopic observation that nodular lymphocytic lymphoma may progress to diffuse histiocytic lymphoma and 2) offer further evidence that histiocytic lymphomas arising in patients with previous B cell malignancies are most probably related to the original B cell proliferation and do not represent the emergence of a second, separate malignant clone.

Female

Sister chromatid exchange in cell lines from malignant lymphomas (lymphoma lines).

The frequency of sister chromatid exchanges (SCEs) was studied in cells from three freshly established lymphoma lines, derived from two patients with Hodgkin's disease and one patient with non-Hodgkin lymphoma. These values were compared to SCE rates found in cells from two long-established lymphoma lines (Raji and BJAB) and to those recorded in control cell lines of normal human donors. The highest SCE levels were demonstrated in the freshly established lymphoma lines, the lowest SCE values separated the lymphoblastoid cell lines from healthy controls, and the older lymphoma lines Raji and BJAB presented rates in between. The influences of BUDR concentration and of the duration of BUDR treatment on the frequency of SCEs were tested. Furthermore, the dependence of the SCE rate on the time interval between establishment of the cell line and its SCE investigation was considered. The connection between elevated SCE rates and the neoplastic nature of lymphoma lines is discussed.

Animals

Primary lymphomas of bone (so-called ("Parker and Jackson's reticulum cell sarcoma") : histological review of 75 cases according to the new classifications of non Hodgkin's lymphomas.

75 cases of primary lymphomas of bone ("reticulum cell sarcoma" described by Parker and Jackson) were reviewed. Biopsy specimens were classified according to several histological classifications, including Lukes' classification for nodal lymphomas. Among 24 tumors described as "histiocytic lymphomas" in Rappaport's classification of 1966, only one case remains as "true histiocytic sarcoma". The others were reclassified as follows : 6 tumors with a predominance of large cleaved cells, 13 tumors with large non-cleaved cells, 2 as immunoblastic tumors and 2 as unclassifiable. In non Hodgkin's lymphomas, the histological diagnosis and the results of the initial staging have been shown to be greater aids in the prediction of survival than the primary site of the disease. Therefore, the clinical and therapeutical approach to the patients with lymphomas of bone must be modified to be similar to that of patients with nodal localisations of the disease.

Adolescent

Malignant lymphomas and undifferentiated small cell carcinoma of the thyroid: a clinicopathological review in the light of the Kiel classification for malignant lymphomas.

The paper reports a re-evaluation--based on the Kiel classification for non-Hodgkin lymphomas--of a group of cases initially diagnosed as undifferentiated small cell carcinomas or primary lymphomas of the thyroid. Twelve such cases were found among the 155 cases of primary malignant tumours of the thyroid recorded at the Institut Jules Bordet between 1955 and 1975. The review of the clinical charts and the histology showed that all the cases were in fact malignant lymphomas fitting easily into one of the groups described in the Kiel classification. These findings support the growing opinion that undifferentiated small cell carcinoma of the thyroid does not exist as a distinctive clinicopathological entity. Furthermore, the Kiel classification proved to be an excellent prognostic indicator, since all the cases classified as highly malignant were indeed fatal, whereas the surviving cases--three of which had shown tumoral extension beyond the thyroid capsule--fell into the group of low malignancy. Lastly, this study acknowledges the frequently observed association of malignant lymphoma of the thyroid with stigmata of Hashimoto's disease, and thus supports the concept that the continuous antigenic stimulation observed in the latter could trigger the development of a malignant lymphoma.

Aged

Baseline Plasma Cell-Free and Circulating Tumor DNA Across Lymphoma Subtypes and Its Prognostic Impact in Diffuse Large B-Cell Lymphoma.

BACKGROUND: Circulating tumor DNA (ctDNA) analysis enables real‑time assessment of the tumor burden and genomic complexity in lymphomas. However, real‑world evidence across lymphoma subtypes is limited. METHODS: We analyzed cell‑free DNA (cfDNA) and ctDNA data from 336 consecutive patients with newly diagnosed Hodgkin or non-Hodgkin lymphoma in 2022 and evaluated their prognostic impact in diffuse large B‑cell lymphoma (DLBCL). RESULTS: We detected somatic alterations in 248 of 336 patients (73.8%). DLBCL and follicular lymphoma showed the highest variant prevalences and ctDNA burdens. Epigenetic regulators, including KMT2D, CREBBP, TET2, and HIST1H1E, constituted the dominant class of genes with recurrent alterations. Plasma variant profiles closely mirrored publicly available, tissue‑based next-generation sequencing datasets. The baseline ctDNA burden correlated with adverse clinical features, and ctDNA positivity was associated with failure to achieve complete remission. In DLBCL, elevated cfDNA (top quartile) and a high International Prognostic Index (IPI) were independently associated with shorter overall and progression‑free survival. However, the total variant count per patient was not significantly associated with survival after adjustment. CONCLUSIONS: Baseline plasma cfDNA and ctDNA assessments are feasible in routine practice and recapitulate tissue-variant landscapes. Elevated cfDNA concentrations-but not the total variant count-were independently associated with survival in DLBCL, providing prognostic information beyond the IPI and supporting integration of plasma-based biomarkers into multiparameter risk models. Gene‑level ctDNA associations should be regarded as exploratory and hypothesis‑generating.

Cell-free DNA

B-cell leukemia-lymphoma with striking resemblance to Burkitt lymphoma in a 70-year-old woman.

A 70-year-old woman developed acute leukemia and a serum IgM spike. She entered complete remission with an adriamycin, vincristine, cytosine arabinoside, and prednisone combination. Bone marrow remission was maintained with intermittent cytosine arabinoside; however, she developed large skin nodules which partly remitted following adriamycin, vincristine, cyclophosphamide, and prednisone combination. They very rapidly recurred, and she died soon after. Autopsy revealed extensive tumor in the abdomen, pelvis, and thoracic cavity, but no bone marrow involvement. Histology revealed a "starry sky" appearance. Cytology showed undifferentiated cells with vacuolated cytoplasm resembling Burkitt lymphoma cells. Peroxidase and esterase stains were negative. There was strong pyroninophilia and the periodic acid-Schiff reaction showed granular activity in the cytoplasm. Electron microscopic appearances also resembled Burkitt lymphoma. Cytogenetic studies were normal, with no Ph1 chromosome. Immunofluorescence demonstrated surface IgM and a little IgA. 3H-thymidine incorporation was high, indicating rapid growth. Dibutyral cyclic adenosine monophosphate (cAMP) stimulated growth, which was further evidence of the lymphoid origin of the tumor. The close resemblance of this tumor to Burkitt lymphoma emphasizes the difficulties in systematically classifying the lymphomas.

Acute Disease

"Lennert's lymphoma" with transformation to malignant lymphoma, histiocytic type (immunoblastic sarcoma).

Two cases of a recently described lymphoproliferative disorder called "Lennert's lymphoma" are presented. In both cases, the proliferation evolved into a frank malignant lymphoma of large lymphoid cells. This phenomenon has not been previously reported to occur in this disease. Immunohistologic study of the biopsy material in both cases suggest that it may be a T-cell proliferation. The possibility that "Lennert's lymphoma" is not a neoplasm but an abnormal immune reaction with similarities to angioimmunoblastic lymphadenopathy is raised. Whatever its nature, the potential for "Lennert's lymphoma" to transform into a frankly malignant tumor is documented.

Aged

Histiocytic lymphoma with sclerosis arising from a nodular lymphoma with a special stromal reaction.

Histiocytic lymphoma with sclerosis was found together with a small nodular lymphoma in a cervical lymph node biopsy from a 48-year-old man. Since the cellular origin of this entity is unclear and its ultrastructure has not been described before, we processed formalin-fixed samples for electron microscopy, which revealed three cell types: small lymphocytes with cleaved nuclei, large lymphocytes with vesticular noncleaved nuclei, and mesenchymal stromal cells occasionally bearing desmosomes or hemidesmosomes. In addition, there was an increase of the intercellular connective tissue, which consisted of a mixture of normal and fibrous long spacing collagen fibers. The results indicate that histiocytic lymphoma with sclerosis can evolve from a nodular lymphoma, and that diagnostic information can be obtained by electron microscopy of tissue samples previously fixed in formalin.

Connective Tissue

Malignant lymphoma, small lymphocytic type: a clinicopathologic study of 84 cases with suggested criteria for intermediate lymphocytic lymphoma.

Clinical and histopathologic findings were reviewed in 84 cases of malignant lymphoma of the small (well differentiated) lymphocytic type. The slides were studied without clinical information, and the following morphologic features were evaluated: pattern of growth, number of large lymphocytes, mitotic rate, degree of capsular involvement, presence of plasma cells and/or plasmacytoid lymphocytes, and presence of residual germinal centers. Subsequently, clinical information was obtained. The minimum follow-up period on living patients was 5 years. The patients were divided into 3 clinical categories: 1) monoclonal gammopathy (MG)-11 cases, 2) chronic lymphocytic leukemia (CLL) without MG-56 cases, and 3) those without MG or CLL at the time of lymph node biopsy-17 cases. The criterion for CLL was an initial absolute lymphocyte count less than 4000/mm3. Four of the patients with MG also had CLL, and 6 of those in the third group later developed CLL, from 1 to 61 months after lymph node biopsy. Generalized lymphadenopathy was the usual presentation in all 3 groups, and bone marrow examination was positive in all but 1 of the 49 cases, representing all 3 groups, in which it was performed. Median survival for the 84 patients was 51 months. The only clinical parameters which showed a significant association with poorer survival were age above 60 and anemia (Hb. conc. less than 11.0). There was no significant relationship between morphologic characteristics and clinical categories other than the association of plasmacytoid cells with MG in 6 cases. A mitotic rate of 30 or more mitoses per 20 high power fields (HPF), found in 5 cases with at least 1 in each clinical category, showed a highly significant association with decreased survival (p = .01). Variations in mitotic rate between 0 and 29 mitoses per 20 HPF and other morphologic parameters did not show a significant relationship with prognosis. It was concluded that malignant lymphoma of the small lymphocytic type is a definite clinicopathologic entity which may or may not exhibit MG or CLL, and it is proposed that the term "intermediate lymphocytic lymphoma" be applied only to those cases showing histopathologic characteristics of small lymphocytic lymphoma and a mitotic rate of 30 or more mitoses per 20 HPF.

Adolescent

Biology of the human malignant lymphomas. IV. Functional characterization of ten diffuse histiocytic lymphoma cell lines.

Ten consecutive diffuse histiocytic lymphoma (DHL) cell lines established in our laboratory were studied for the presence of Epstein-Barr virus (EBV) genomes, lysozyme, nonspecific esterase and other cytochemical reactions, phagocytic activity, cytoplasmic immunoglobulin light and heavy chains, and surface receptors to sheep erythrocytes, complement, and the Fc fragment of immunoglobulin. In agreement with previous studies performed on biopsy specimens, our results indicate that the diffuse histiocytic lymphomas, as a histopathologic entity, represent a heterogeneous group of neoplasms, the majority of which are B-lymphocyte in origin. The cell lines appear to fall into three categories based on the following criteria: 1) presence of monoclonal cytoplasmic immunoglobulins (B-lymphocytic type, 6/10 cell lines); 2) presence of non-specific esterase, phagocytic activity, and/or lysozyme (histiocytic type, 2/10 cell lines); and 3) absence of all lymphoid and histiocytic cell characteristics (null cell type, 2/10 cell lines). Despite the fact that many of the lymphoma patients had positive serologies to EBV antigens, all of the DHL cell lines were negative for the presence of EBV genomes. Both of the two B-lymphocytic type and one of the two histiocytic type lines tested were susceptible to infection with EBV, as indicated by synthesis of early antigen and also, in a small proportion of the infected cells, of viral capsid antigen. These prototypic DHL cell lines may permit the development of new criteria for the differential diagnosis and treatment of this highly malignant and diverse group of lymphomas.

Animals

Classification of animal lymphomas: the implications of applying Rappaport's classification for human lymphomas to experimental tumors.

One hundred and seventy animal lymphomas (species ranging from molluses to monkeys) were reclassified histologically according to the modified Rappaport classification for human lymphomas. The results were correlated with the etiology of the lymphomas, their clinical course, and in selected cases with their immunological type. The study stresses the value of such a procedure for comparative reasons, allowing a more adequate selection of animal models for human lymphomas.

Animals

Stem cell (immunoblastic) lymphoma. A variant of B lymphocytic lymphoma.

From a histologic review of cases coded as Hodgkin's disease and reticulum cell sarcoma, 12 cases were selected as examples of stem cell lymphoma in which the preponderant cell has characteristics of the B immunoblast. Clinically, these lesions affect the elderly (average age 57.3 years), disseminate early, and, with a few exceptions, progress rapidly to a fatal termination. Morphologically, the neoplastic stem cells, which have pyroninophilic cytoplasm, form diffuse infiltrates with an admixture of acidophilic cells. As a regional variation, the pattern in these lesions overlaps histologically with that seen in angioimmunoblastic lymphadenopathy. The overlap in patterns is presumptive evidence that the angioimmunoblastic pattern at times may be a precursory expression of the stem cell lymphoma. On the basis of morphologic features, these tumors are interpreted as a variant of B cell lymphomas.

Adult

Histiocytic lymphoma in a patient with Lennert's lymphoma. Report of a case with unusual cytoplasmic inclusions.

The transformation of Lennert's lymphoma into histiocytic lymphoma appears to be part of the natural history of the disorder rather than therapeutically induced. Unusual paranuclear nonmembrane-bound filamentous inclusions were found in many of the neoplastic cells in the histiocytic lymphoma. We report evidence for the immunoglobulin nature of this material, indicating a B cell origin of the neoplasm.

Abdominal Neoplasms

Establishment of an Epstein-Barr virus-negative B-cell lymphoma line from a Japanese Burkitt's lymphoma and its serial passage in hamsters.

An Epstein-Barr virus (EBV)-negative lymphoma line (JBL) was established in vitro from pleural effusion of an EBV-seropositive 29-year-old Japanese female with Burkitt's lymphoma. JBL cells as well as her original lymphoma cells bore monoclonal surface IgM with lambda light chains. The JBL line grew in single cell suspension with a doubling time of 30 hours. Attempts were made to serially transplant JBL cells in antilymphocyte serum-treated newborn hamsters; intraperitoneal implantation of 1-3 X 10(7) cells gave rise to invasive tumors in all recipients with death after 10 to 14 days. The hamster-passage line, now in the 9th passage, has been converted to an ascitic form with progression to leukemia in some animals. A "starry sky" pattern closely resembling the human tumor material was preserved in every tumor through serial animal passage.

Animals