Nodular Lymphoma Research Articles

Nodular lymphoma: bone marrow and blood manifestations.

Morphological and clinical features of 39 patients with nodular lymphoma were studied with particular reference to bone marrow and blood involvement. Twenty-one patients (54%) were found to have bone marrow involvement at the time of initial diagnosis. Thirteen (33%) also had peripheral blood involvement. A specific cell type, the small nodular lymphoma cell, was found in the bone marrow smears of 19 and the 21 patients with bone marrow involvement and in the peripheral blood smears of all patients with blood involvement. When large cells predominated in the lymph node or bone marrow sections, the bone marrow smears and the imprints of the lymph node and trephine biopsy demonstrated these large cells to have morphological qualities of lymphocytes rather than histiocytes.

Reed-Sternberg-like cells in nodular lymphoma involving the bone marrow.

McKenna, Robert W., and Brunning, Richard D. Reed-Sternberg-like cells in nodular lymphoma involving the bone marrow. Am JClin Pathol 63: 779-785, 1975. Two patients with cells indistinguishable from Reed-Sternberg cells in bone marrow lesions of nodular poorly differentiated lymphocytic lymphoma are described. Both patients had lymph node biopsies showing nodular lymphoma. Bone marrow and blood involvement with the lymphoma was demonstrated at the time of initial diagnosis. Reed-Sternberg-like cells were not demonstrated in either case until later in the course of the disease, after the patients had been treated with numerous chemotherapeutic agents. Other similarities of bone marrow involvement with nodular lymphoma to Hodgkin's disease of the bone marrow are noted. The origin of the Reed-Sternberg-like cells in nodular lymphoma is not clear, but they could result from morphologicalteration of lymphoma cells by chemotherapy. The finding of Reed-Sternberg cells in bone marrow lesions should be interpreted with caution unless diagnostic biopsy material from other sites is available for study. (Key words: Bone marrow lymphoma' nodular lymphoma; Reed-Sternberg cells).

Acute Myeloproliferative Disorder Following Long-Term Chlorambucil Therapy

Potent cytotoxic agents whose initial use was confined to the treatment of malignant neoplasms are now being administered in the therapy of many non-neoplastic conditions. The use of alkylating agents in diseases such as rheumatoid arthritis,1-4systemic lupus erythematosus,5-7hemolytic anemia,8and glomerulonephritis9demands a surveillance for their possible long-term toxic effects. This report concerns two patients with malignant lymphoma who were treated with chlorambucil for periods of four and seven years. They died of acute myelogenous leukemia (AML) despite excellent response of their original disease to therapy. Patient Summaries Patient 1. —A 53-year-old white woman had an eight-year history of nodular lymphoma, poorly differentiated lymphocytic type (Fig 1, top left and right). Generalized adenopathy was treated with chlorambucil at 6 mg/day from 1962 until 1969. In November 1969, the therapy with chlorambucil was discontinued because of a falling white blood cell (WBC) count and the

Malignant reticuloendothelial disease involving the ovary as a primary manifestation: a series of 19 lymphomas and 1 granulocytic sarcoma.

Lymphoma and leukemia infiltrates presenting in the ovary as the initial manifestation have been reported only rarely. This study describes the clinical and pathologic findings in 19 patients with unrecognized lymphoma and 1 patient with an extramedullary neoplasm of poorly differentiated granulocytes (granulocytic sarcoma), all presenting as ovarian tumors. of the 20 patients, 10 had Stage I lesions and 10 had lesions of Stages II through IV, according to the FIGO staging system for ovarian cancer. Survival varied with the stage, as the median survival for patients with Stage I presentation was 11 months, but only 7 months for patients with neoplasms of Stages II-IV. The poor prognosis for patients with a Stage I presentation (tumor confined to one or both ovaries) contrasts with reports of extranodal lymphoma. The explanation may lie in inadequate initial staging. The possibility of the existence of a true primary extranodal lymphoma is discussed with reference to a patient with nodular lymphoma surviving 17 years.

Incidence cytology, and histopathology of non-Hodgkin's lymphomas in the bone marrow.

Trephine and aspiration bone marrow biopsies were performed at time of initial diagnosis in 108 consecutive lymphoma patients. These have been evaluated to determine: 1) incidence, degree, and pattern of involvement; and 2) cytologic and histopathologic characteristics, for each type of lymphoma as classified by Rappaport. Forty cases exhibited marrow involvement. Nodular poorly-differentiated lymphocytic lymphomas (PDLL-N) more frequently exhibited marrow involvement than did diffuse poorly-differentiated lymphocytic lymphomas (PDLL-D) (p <.05). Study of cytology in blood and marrow smears and trephine imprints indicated that PDLL-D is a diverse group with two relatively distinct subgroups: an intermediate differentiated form (idll) and a more poorly-differentiated form (pdll). PDLL-N is a more homogeneous group with a distinctive cell type—the hematogone-like lymphocyte. While it may be difficult to differentiate lymphoma in the marrow from benign lymphocytic aggregates and lymphoma in the blood from lymphocytic leukemia, helpful distinguishing features exist.

Nodular lymphoma--evidence for origin from follicular B lymphocytes.

Abstract To investigate the cellular origin of nodular lymphoma, neoplastic cells from six patients with nodular lymphomas were studied both in cell suspensions and in frozen tissue sections for (1...

Malignant lymphoma diagnosed at splenectomy and idiopathic splenomegaly. A clinicopathologic comparison.

The clinical, laboratory, and histopathologic findings in 15 cases of malignant lymphoma presenting as splenomegaly and diagnosed at splenectomy were compared with 10 cases of idiopathic splenomegaly. The ages of the patients, the duration of splenomegaly, the hematologic parameters, and the weights of the spleen were similar in the two groups of patients. None of the 15 patients with malignant lymphoma initially diagnosed at splenectomy was considered cured: 8 died with disseminated disease within 2 years, 2 have survived for longer than 3 years with progression to chronic lymphosarcoma cell leukemia, and 5 have been followed for less than 12 months. Idiopathic splenomegaly, an apparently benign inflammatory lesion, may simulate lymphoma clinically and be confused with nodular lymphoma pathologically, particularly when associated with lymphocytic infiltrates of the liver and bone marrow and atypical lymphocytes in the peripheral blood. Splenectomy is indicated in patients with persistent splenomegaly without known contributing or related disease, and care must be exercised in the pathologic distinction between splenic lymphoma and idiopathic splenomegaly.

Morphological studies of 84 untreated patients subjected to laparotomy for the staging of non-Hodgkin's lymphomas.

The pathologic findings in 84 untreated patients subjected to laparotomy and open iliac crest bone marrow biopsy for the staging of malignant lymphomas other than Hodgkin's disease at Stanford University Medical Center are presented. Fifty-one (61%) of these 84 patients had lymphomatous involvement of one or more sites below the diaphragm. The applicability of the histopathologic classification of Rappaport, Winter, and Hicks was confirmed by virtue of the constancy of the histologic features in multiple lesions in 43 patients (84%) (including 1 patient with a composite lymphoma). Six patients, however, showed two different histologic patterns in two or more sites, and in two additional patients with a composite lymphoma, the initial composite pattern was not reproduced in other sites. Three patients had the remarkable association of a non-Hodgkin's lymphoma with Hodgkin's disease either within the same lymph node (composite lymphoma) or in a separate site. In the remaining 75 patients (excluding the 9 patients with multiple histologies), 43 had nodular lymphomas and 32 diffuse lymphomas. The nodular lymphomas showed a tendency for widespread dissemination by virtue of their involvement of the abdomen in 31 patients (72%) and bone marrow in 12 patients (28%). In contrast, diffuse lymphomas involved the abdomen in only 11 patients (28%). Diffuse histiocytic lymphomas showed a low incidence of early dissemination, involving the spleen and abdominal lymph nodes in only 5 (28%) and the bone marrow in 2 (11%) of 18 patients. This clearly indicates that evaluation of stage of the disease alone does not suffice in assessing response to therapy and long-term survival, in view of the poor prognosis of diffuse histiocytic lymphomas despite their initial localized involvement. It also emphasizes the importance of differentiating lymphomas according to cytologic type and architectural pattern. Occult abdominal disease was located in mesenteric lymph nodes (56%), splenic hilar lymph nodes (54%), para-aortic lymph nodes (40%), and spleen (34%). Thirteen of 25 spleens involved by lymphoma weighed less than 200 grams. Granulomas similar to those previously described by us in patients with Hodgkin's disease were observed in 5 patients.

Clinical features and course of the non-Hodgkin's lymphomas

It is now quite apparent that a need exists for a uniform system of histopathologic characterisation of the non-Hodgkin's lymphomas if meaningful comparisons of the results of staging and treatment are to be established. We have employed the scheme of Rappaport, Winter and Hicks (1956) and found it to be a current and valuable method of enhancing our understanding of this diverse group of tumours. Although individual differences in clinical features exist within both the nodular and diffuse categories of non-Hodgkin's lymphoma, some useful generalisations should be kept in mind because of their implications for new clinical trials (e.g. Jones, Kaplan and Rosenberg, 1972 ). Diffuse lymphomas Nodular lymphomas

Tissue Immunoglobulins in Nodular Lymphomas as Compared With Reactive Follicular Hyperplasias

Abstract Frozen tissue sections of lymph nodes and spleens from twelve patients with nodular (follicular) lymphomas were studied with fluorescein-labeled antisera against human immunoglobulins. Immunoglobulins detected by this method in the neoplastic nodules were minimal or absent. Furthermore, in no instance could the characteristic network pattern of immunoglobulin distribution which is readily demonstrable in active germinal centers be observed within these nodules. It is suggested that the preservation of the follicular network of immunoglobulins as observed by fluorescent antihuman IgG, IgM, or polyvalent antisera indicates functionally intact germinal centers. The detection, by this rather simple method, of large amounts of immunoglobulin distributed in such a distinctive pattern may thus be very useful for the differentiation between severe benign follicular hyperplasia and malignant lymphoma with nodular pattern, which may be difficult to distinguish by routine histological methods.

Recurrence Rates Following Radiation Therapy of Nodular and Diffuse Malignant Lymphomas

Analysis of local recurrence rates after initial radiation therapy in 198 patients with nodular and diffuse lymphomas revealed an inverse relationship of recurrence rate to dose, except for patients with diffuse histiocytic lymphoma. At a dose of 4,400 rads, the recurrence rates for nodular lymphomas approached zero, while for diffuse lymphocytic and diffuse mixed lymphomas the recurrence rates were significantly higher, 15 and 12%, respectively. Recurrence rates between 21 and 37% were noted in patients with diffuse histiocytic lymphoma who received between 1,500 and 6,500 rads: however, no correlation between dose and rate of recurrence could be demonstrated. The implication of these observations for the treatment of non-Hodgkin's lymphomas is discussed.

Response and survival after sequential monochemotherapy in malignant lymphocytic and histocytic lymphoma

A retrospective analysis of 118 patients with non-Hodgkin's lymphomas who received one or more drugs of single agent chemotherapy was conducted to determine the relationship between the histopathologic category of lymphoma, based on the classification proposed by Rappaport et al., and the results (type of regression and survival) of sequential chemotherapy. In 96/118 cases, slides were available for histopathologic reclassification. Patients were selected according to the following criteria: chemotherapy with single agents administered in sequence (e.g. alkylating agents, vincristine, adriamycin, bleomycin); change in drug administration only after an adequate course and either no response or clinical resistance after prior regression; measurable disease; performance status greater than 40. Prior to chemotherapy 66 patients had diffuse (extranodal) disease, 39 adenopathies above and below the diaphragm, and 13 adenopathies only above or below the diaphragm. 49/118 patients were pretreated with radiotherapy. The data were most complete for alkylating agents which were administered as a single agent in 93 patients. Complete remission (CR) plus partial remission (PR) greater than 50% occurred in 39% of patients with lymphocytic lymphoma, in 39% with histiocytic and in 50% with mixed type lymphoma (table 4). This type of response was observed with all drugs in 70% of nodular lymphomas and in 36% of diffuse lymphomas (table 7). The overall response rate to adriamycin was 75% in nodular lymphomas, and 55% in diffuse lymphomas. These data were 40% and respectively 14% after treatment with bleomycin. Median survival of all non-Hodgkin's lymphomas was 16.2 months (fig. 1); median survival was 23.4 months for nodular lymphomas and 17.4 months for diffuse lymphomas (fig. 2). Among nodular lymphomas, no significant differences were observed between nodular histiocytic and nodular lymphocytic well differentiated (fig. 3). Diffuse lymphocytic well differentiated lymphomas showed better survival in comparison to diffuse lymphocytic poorly differentiated, diffuse histiocytic and diffuse undifferentiated types (fig. 4). Patients responding to 2 drugs or more showed a better median survival (66 months) than those responding only to one drug (22.4 months) and unresponsive patients (10.2 months) (fig. 5). This study confirms most of the data reported by the Stanford group and emphasizes the need to employ a more deteailed histopathologic classification such as that proposed by Rappaport et al. Although this retrospective analysis has a number of drawbacks, it does provide, in terms of survival, a measurable indication that the responsiveness to at least two drugs is associated with better survival in non-Hodgkin's lymphomas than little or no responsiveness.

Non-Hodgkin's lymphomas. IV. Clinicopathologic correlation in 405 cases.

An analysis is presented of the histopathologic, clinical, and prognostic features in a series of 405 previously untreated patients with non-Hodgkin’s lymphomas referred to Stanford University Medical Center between 1960 and 1971. .411 biopsies were histologically classified according to the criteria of Rappaport et al. and clinical extent of disease was thoroughly evaluated prior to treatment and staged according to the Ann Arbor Classification. Nodular lymphomas constituted 44% of the group and diffuse lymphomas 56%. Patients under the age of 35 years and those over 60 tended to have diffuse lymphomas. Although 39% of the patients had Stage IV disease at presentation, localized forms (Stage I, I,., 11, 11,) were observed in 37%. Localized extralymphatic involvement occurred more often in patients with diffuse than nodular lymphomas (11 < 0.001). Systemic symptoms occurred in 24% of patients with diffuse and 17% of those with nodular lymphomas; however, their presence did not adversely affect survival. Mediastinal adenopathy was noted in 24% of diffuse and 18% of nodular lymphomas (P = NS), and mediastinal “skipping” was observed in 20% of diffuse and 40% of nodular lymphomas (p < 0.05). By the criteria used, 81% of evaluable patients (Stages I1 through 111,) with nodular lymphoma and 90% of those with diffuse lymphoma had contiguous sites of involvement (p = 0.07). Two frequently observed sites of initial extralymphatic involvement were bone marrow and gastrointestinal; the former was observed more often in advanced lymphocytic lymphomas, whether nodular or diffuse, and the latter in advanced, diffuse lymphomas. Actuarial survival correlated strongly with the histopathologic type of lymphoma; in each cellular category, patients with nodular lymphomas survived significantly longer than those with diffuse lymphomas (1’ < 0.05). Age at presentation also influenced survival in relation to certain histologic patterns. Patients with diffuse lymphocytic or mixed lymphomas who were less than 40 years of age had a worse prognosis than those over 40 (p = 0.02). In contrast, older patients with nodular lymphocytic and mixed lymphomas fared worse than those under 40 (p < 0.01). Patients with either initial bone marrow or gastrointestinal involvement survived longer if their lymphoma had a nodular pattern. It is concluded that histopathologic classification proposed by Rappaport et al. and the Ann Arbor Staging Classification are both useful guides to the management and prognosis of the non-Hodgkin’s lymphomas.

Proteinaceous precipitate in nodular (follicular) lymphomas.

A heretofore undescribed proteinaceous material was observed within the neoplastic nodules of malignant lymphomas with nodular patterns. The amount of this precipitate varied from case to case and from nodule to nodule. Malignant lymphoma, poorly differentiated lymphocytic type, was diagnosed in five patients, and malignant lymphoma, mixed cell type (lymphocytic-histiocytic) was seen in the remaining eight cases. No correlation was found between the amount of the proteinaceous precipitate and the clinical behavior. Of 13 patients in this study, 9 were alive, with or without clinical evidence of lymphoma from 5 to 58 months after onset of symptoms. The remaining four patients died 12, 28, 42, and 48 months after clinical onset, with clinical evidence of disseminated disease at the time of their death. Eight patients were women and five were men. Their ages ranged from 34 to 76 years. Special histochemical procedures failed to reveal the nature of the precipitate, and electron micrographs prepared from one patient showed extracellular clusters of a fine fibrillar material of unknown nature.

Pathology of splenic lymphoma.

Eleven spleens removed surgically from patients with malignant lymphoma were compared according to gross, histologic, and cytologic appearances with spleens surgically removed from patients with nonmalignant disorders. The gross comparison indicates that the lymphomatous spleens were 10 to 20 times heavier than the nonmalignant spleens. The cut sectional surfaces revealed three types: (1) diffuse-homogeneous, (2) multinodular, (3) solitary and multinodular. Histologically they presented with a diffuse or nodular pattern. Splenic trabeculae and subendothelial spaces were markedly infiltrated by malignant cells. Sinusoidal congestion was prominent. Cytologically, five cases of splenic lymphomas were classified as well-differentiated lymphocytic lymphoma, five cases as poorly-differentiated lymphoma, and one case as composite lymphoma. Although numerous homogeneous lymphoid nodules were noted in the nodular lymphomas, no primary or secondary follicles or perifollicular marginal zones were seen in any of the cases of splenic lymphoma. In one spleen there were two cytologically distinct malignant lymphomas (composite lymphoma) consisting of a focal histiocytic lymphoma and a well-differentiated lymphocytic lymphoma. To our knowledge, this unusual association in the spleen has not been reported before. This experience suggests that the gross and microscopic alterations in primary splenic lymphoma can be differentiated from those seen in benign splenic disorders.

Non-Hodgkin's lymphomas. II. Single agent chemotherapy.

A retrospective analysis of 110 patients with non-Hodgkin's lymphoma who received one or more courses of single agent chemotherapy was conducted to determine the relationship between the histopathologic category of lymphoma, based on the scheme of Rappaport et al., and the results of chemotherapy. The data were most complete for oral alkylating agents. Complete tumor regressions occurred significantly more often in patients with nodular lymphomas than diffuse (p < 0.01) and were of longer duration. Responses and survival after the initiation of chemotherapy correlated closely with the histopathologic category of lymphoma ranging from a 5% complete response (CR) rate in patients with diffuse histiocytic lymphoma to a 48% CR rate in patients with nodular lymphocytic poorly differentiated lymphoma. The latter group exhibited a median survival of 60+ months from the initiation of chemotherapy. This study emphasizes the need to employ the more precise histologic classification of non-Hodgkin's lymphomas according to the criteria of Rappaport et al. in the design and interpretation of future prospective chemotherapy trials in patients with non-Hodgkin's lymphomas.

Non-Hodgkin's lymphomas. I. Bone marrow involvement.

Two hundred and eighteen untreated patients with non-Hodgkin's lymphomas, classified according to the scheme of Rappaport et al., were investigated for bone marrow involvement. No pattern of pretreatment laboratory abnormalities predicted which patients would have a positive bone marrow for lymphoma. Open marrow biopsy demonstrated lymphoma after needle biopsy was negative, and both biopsy techniques were clearly superior to bone marrow aspiration in identifying marrow involvement. Bone marrow involvement correlated with advanced stage, cellular composition of the lymphoma, and, in the nodular lymphomas, splenomegaly and constitutional symptoms. Patients with histiocytic lymphomas uncommonly had initial marrow involvement whereas patients with mixed and lymphocytic types were frequently affected. Nodular or diffuse patterns did not influence the incidence of marrow involvement, but patients with nodular lymphomas and positive marrows survived significantly longer than those with diffuse lymphomas.

Malignant lymphomas of the pharynx.

Fifty-five patients with malignant lymphoma of the pharynx were studied, and the pathologic material was analyzed. It is concluded that reticulum cell sarcoma with no involvement of the cervical lymph nodes is a highly curable tumor by radiotherapy (7 out of 9 survived 5 years or more). On the other hand, almost all the patients with involvement of the cervical lymph nodes had early recurrences or metastases that failed to respond to various therapeutic measures. Well-differentiated lymphocytic lymphoma (lymphosarcoma) showed more tendency to disseminate, but recurrences were relatively easier to control by radiotherapy or chemotherapy and compatible with long survival. As expected, all 3 patients with nodular lymphoma (giant follicular lymphoma) are living 5 years or more and only one with disseminated disease. Hodgkin's disease is rare in the pharynx. Careful histologic classification and irradiation to eradicate the tumor are extremely useful measures in controlling these neoplasms.

Lymphosarcoma cell leukemia. A clinicopathological study.

Lymphosarcoma cell leukemia (LSCL) represents a poorly-differentiated lymphocytic lymphoma which has involved the peripheral blood and bone marrow (leukemic phase of poorly-differentiated lymphocytic lymphoma). the clinical, biopsy, and necropsy findings of 18 patients with LSCL were reviewed. the histologic pattern of the lymphoma in the original lymph node biopsy of 16 patients was nodular (follicular) in 10 and diffuse in 6. the differences in histologic pattern of the lymphoma were related to the clinical course and prognosis of the patients. Four of the 6 patients who had a diffuse histologic pattern were leukemic at the time of lymph node biopsy. in contrast, only one of 10 patients with a nodular lymphoma was leukemic at the onset. the total survival (preleukemic and leukemic phases) as well as the survival of the leukemic phases were considerably better in those patients who initially had a nodular type of lymphoma than in those patients with a diffuse type of lymphoma. At the time of necropsy, all patients had dissemination of lymphoma (leukemia) throughout the body, and the majority of those who originally had a nodular histologic pattern had a diffuse pattern at necropsy. Separation of LSCL from other types of lymphocytic leukemias seems to be valid on morphological grounds as well as on the basis of clinical course, response to therapy, and, especially, prognosis which is considerably worse in LSCL than in chronic lymphocytic leukemia.