Diffuse histiocytic lymphoma complicating chronic lymphocytic leukemia.

Nine patients with chronic lymphocytic leukemia (CLL) who also developed diffuse histiocytic lymphoma (DH) are described. The incidence of patients with CLL developing DH was at least 3.3%. CLL existed for a median of 2 years before the diagnosis of DH. DH presented in 8 patients with abdominal symptoms and/or enlarging lymph nodes, spleen and liver. There were no consistent laboratory abnormalities associated with the onset of DH. In 4 of the patients the DH appeared to be localized. Eight of the 9 patients have died with a median survival of 2 months from the diagnosis of DH. Whether DH occurs as a result of "blastic transformation" of pre-existing CLL or is a second, unrelated malignancy is not certain. It is hypothesized that utilizing current therapies for DH might favorably influence survival.     

Combined modality therapy for advanced, diffuse lymphocytic and histiocytic lymphomas.

Forty-six previously untreated patients with advanced aggressive non-Hodgkin's (34 poorly differentiated and mixed diffuse, 8 histiocytic and 4 undifferentiated) were treated with a 3 phase combined modality program employing cyclophosphamide (C), hydroxyl-daunomycin (H), vincristine (O), prednisone (P), procarbazine (P) [CHOP(P)] combination chemotherapy in an initial induction phase, radiotherapy and nonmarrow toxic chemotherapy as a second consolidation phase, followed by a third phase of CHOP(P) chemotherapy for four more cycles. Long-term maintenance therapy was not given. High dose involved field radiation in phase II was limited to volumes encompasing less than 50% of the marrow bearing skeleton. The large majority of patients (82%) had such widespread involvement that this limitation precluded the use of local radiation and were treated instead with a mean of 132 rad of fractionated total body irradiation (TBI). Thirty-eight patients (83%) achieved complete remission. Twenty-nine (66%) of the 44 patients evaluable for follow-up, and 22 (61%) of the 36 patients receiving TBI, remain alive in complete remission for observation periods of up to 26 months.     

Long-term survival of patients with localized diffuse histiocytic lymphoma

From January 1970 to March 1981, localized diffuse histiocytic lymphoma (DHL) was identified in 31 patients by exploratory laparotomy and splenectomy (pathologic stage I, 17 patients; pathologic stage II, 14 patients) at the University of Chicago. The median follow-up time was 72 months. All patients were previously untreated and received radiation therapy as their primary treatment modality. Chemotherapy was administered only at the time of relapse. All but two patients achieved a complete remission (CR) with radiation therapy. The actuarial disease-free survival for patients with stage I disease is 94% at 5 years and 72% at 10 years. For stage II disease, the disease-free survival is 56% at 5 years and 31% at 10 years. The difference in the disease-free survival between stage I and II is statistically significant (P = .02). The survival at 10 years is 70% for stage I disease and 46% for stage II disease. Five patients had documented relapses (four had stage II disease). Only two of those who relapsed achieved a second CR with salvage chemotherapy. Our data show an excellent outcome in patients with pathologic stage I disease, indicating that a high percentage of these cases can be cured with radiotherapy alone. Patients with clinical stage II disease might be served better with chemotherapy.     

Prognostic indicators in diffuse large-cell (histiocytic) lymphoma

Identification of prognostic groups among patients with diffuse large-cell (histiocytic) lymphoma (DHL) would help to select specific therapy for individual patients and allow comparisons among combination chemotherapy clinical trials. The Ann Arbor staging system is of limited value in predicting outcome in diffuse histiocytic lymphoma. Prognostic factors have been examined by various groups without a consensus of reliable prognostic indicators. This study was undertaken to examine the validity of a predictive model for response to treatment and survival in DHL. Eighty-six patients with the diagnosis of DHL treated with combination chemotherapy between the years 1976 and 1982 were examined for prognostic variables influencing response to treatment and survival. The variables examined included: age, sex, presence or absence of systemic symptoms, serum lactic dehydrogenase (LDH), sites of disease involvement, bulk of disease, prior therapy, stage of disease, according to the Ann Arbor classification, and pathological criteria, according to the Lukes Collins classification. Factors achieving a p-value in the 0 to 0.05 range with univariate analysis for predicting response were age and systemic symptoms. Factors significant for overall survival were age and bone marrow involvement. These factors have been found to influence survival in previous studies, but there has not been a consistency regarding the importance of these factors. Large numbers of patients must be examined for various factors in order to allow identification of prognostic groups among patients with DHL.     

Predictive model for prognosis in advanced diffuse histiocytic lymphoma

The purpose of this study was to examine the validity of a predictive model for response to treatment and survival in advanced diffuse histiocytic lymphoma. One hundred twenty-seven consecutive patients with Ann Arbor stage II-IV diffuse histiocytic lymphoma, who completed treatment between 1974 and 1984 in one of four different Memorial Hospital combination chemotherapy protocols, were reviewed. The median follow-up time was 66.9 months for survivors (range, 21-153.1 months). Factors studied included: age; sex; Ann Arbor stage; prior therapy; B symptoms; serum lactic dehydrogenase (LDH); sites of initial disease; and tumor bulk. LDH was grouped accordingly (units/liter): low, less than 225; medium, 225-500; high, greater than 500. Each patient was assigned an overall level of site involvement (LSI) from the following mutually exclusive groups: group I, peripheral lymph node (PLN) (including +/- Waldeyer ring involvement, +/- spleen); group II, extranodal disease (EN) +/- PLN; group III, retroperitoneal lymph node (RLN) +/- PLN; group IV, bulky mediastinal disease (MED) +/- any other disease; group V, EN with RLN +/- PLN. The Ann Arbor staging system failed to dissect patient groups differing significantly in their prognosis. Serum LDH, LSI, and age were the only factors important for predicting response and survival after multivariate logistic regression and a parametric Weibull survival analysis. Using three levels of serum LDH and correlating them with the different LSI, four tentative "stages" differing significantly in their survival at 48 months were defined: stage I, low LDH, any LSI (80% alive); stage II, medium LDH, PLN, and/or EN (50% alive); stage III, high LDH, PLN, and/or EN or medium LDH, RLN +/- PLN +/- EN, and/or MED (35% alive); stage IV, high LDH, RLN +/- PLN +/- EN, and/or MED (15% alive). Identification of prognostic stages on the basis of LDH level and LSI will allow more accurate comparison of clinical trials for patients with advanced diffuse histiocytic lymphoma.     

Diffuse intermediate lymphocytic lymphoma. A clinicopathologic study and comparison with small lymphocytic lymphoma and diffuse small cleaved cell lymphoma

Controversy has recently arisen as to whether diffuse intermediate lymphocytic lymphoma (ILL) should be considered a low-grade or an intermediate-grade non-Hodgkin's lymphoma for clinical purposes. Therefore, the authors performed a clinicopathologic study to determine the biologic course of diffuse ILL (40 cases) and compared it with small lymphocytic lymphoma (SLL; 51 cases) and diffuse small cleaved cell lymphoma (DSCCL; 14 cases). They found that patients with diffuse ILL having pseudofollicular proliferation centers (PC) had a significantly longer median survival (84 months) than those without PC (46.5 months; P = 0.03). The median survival of patients with SLL was 72 months, whereas those with DSCCL had a median survival of only 18 months. Based on these findings, the authors conclude that diffuse ILL with PC should be included in the low-grade category of SLL for clinical purposes, whereas diffuse ILL without PC (true diffuse ILL) should be considered an intermediate-grade non-Hodgkin's lymphoma. True diffuse ILL is similar to centrocytic lymphoma in the Kiel classification and should be accorded a similar status in a modified Working Formulation.     

Annulate in four cases of diffuse lymphocytic lymphoma

Annulate lamellae were observed in 4 cases of diffuse lymphocytic lymphoma. Two lymphomas were well differentiated and 2 were of intermediate differentiation. These lymphomas had additional abnormalities of membranes: specifically, excessive blebbing of nuclear membranes and lattice-like formations of tubular endoplasmic reticulum.     

Treatment of diffuse poorly differentiated lymphocytic lymphoma. An analysis of prognostic variables

Forty patients with diffuse poorly differentiated lymphocytic lymphoma (DPDL) Stages II-IV were treated with three different and successive combination chemotherapy protocols. Seventeen patients were treated with the cyclophosphamide (CTX) L2 protocol which included maintenance chemotherapy for 3 years. Only three patients were treated with the NHL-3 (non-Hodgkin's lymphoma) protocol, and 20 patients received the NHL-5 program. All protocols included radiotherapy (1500-4800 rad) to areas of initial bulky disease or persistent tumor, as well as central nervous system (CNS) prophylaxis with intrathecal methotrexate in patients with bone marrow involvement. Seventy-eight percent of local recurrences occurred in previously irradiated areas. Two-year survival rates were 55% and 70% for the CTX-L2 and NHL-5 protocols, respectively. Median disease-free survival for 24 complete response (CR) patients was 16.5 months. Of the 40 patients, 37 were evaluable for response to therapy. The CTX-L2 produced an 80% total response (TR) rate, a 60% CR, and a 20% partial response (PR). The patients on the NHL-5 achieved a TR rate of 95%, 74% CR, and 21% PR. Differences in TR and CR between the two protocols were not significant. Only 1 of 3 patients on the NHL-3 protocol achieved a CR. There was a trend for age greater than 50 years to lessen the chances of CR (P = 0.091); however, sex, symptoms, stage of disease, and LDH level were not significantly related to CR rate. Response to treatment (CR versus PR versus failure) was the most important factor influencing survival (P less than 0.001); age (greater than 50 years) was also significant (P = 0.008). Lactate dehydrogenase (LDH) was of borderline significance (P = 0.06). Cox regression model showed age (greater than 50 versus less than 50 years, P = 0.001), LDH (greater than 500 versus less than or equal to 500 U/L, P = 0.019) and symptoms (A or B) to be the best predictors of survival.     

Survival of nodular versus diffuse pattern lymphocytic poorly differentiated lymphoma

Response and survival were analyzed in 97 patients with NLPD (Nodular Lymphocytic Poorly Differentiated Lymphoma) and 77 with DLPD (Diffuse Lymphocytic Poorly Differentiated) treated by intensive versus moderate chemotherapy regimens. The complete and overall response rate in NLPD of 47% and 81% was significantly superior to 25% and 59% obtained in DLPD. The estimated two year survival of 83% in NLPD was also significantly superior to 47% two year survivorship of DLPD (p less than .001). The chemotherapy responsiveness had a significantly favorable effect on DLPD survivorship with two year survivals of 84% for CR, 58% for PR and 17% for PD. In NLPD the effect of chemotherapy responsiveness on survival was less striking (CR 91%, PR 85%, and PD 72% surviving two years). The data, in our opinion, confirm the rationale for the use of aggressive multiple agent chemotherapy regimens in DLPD where achievement of compelte response appears to be the single most important factor in improving survivorship. On the other hand NLPD, with excellent survival rates which appear to be only partially dependent on chemotherapy responsiveness might serve as an ideal model for moderate intensity or single agent chemotherapy trials.     

Primary histiocytic lymphoma of the epididymis.

The first documented case of primary histiocytic lymphoma of the epididymis is presented. The tumor showed distinct nodularity, which is unusual for extranodal lymphomas, and marked sclerosis. Extensive staging work-up showed no evidence of extraepididymal spread. Unusual features included the youth of the patient at presentation and the severe diffuse atrophy of the adjacent testicular parenchyma. Following orchiectomy and radiotherapy, there has been no subsequent clinical evidence of systemic disease.     

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.     

Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience

To study the influence of chronologic age on treatment outcome in patients with advanced, diffuse large-cell (histiocytic) lymphoma (DHL), we reviewed the results of two recent Southwest Oncology Group (SWOG) clinical trials. From 1974 to 1982, members entered 307 eligible patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without bleomycin, and CHOP with or without immunotherapy using BCG, levamisole, or both. Complete response (CR) rates declined progressively with advancing age: 65% in those under 40, 60% in the 40 to 54 age group, 55% in the 55 to 64 age group, and 37% in those 65 and older (P = .001). Likewise, survival decreased significantly in older patients: medians were 101 +, 52, 34, and 16 months, respectively (P less than .001). Treatment guidelines included an initial dose reduction of 50% for patients aged 65 or older and for younger patients with bone marrow compromise. Despite protocol specifications, 23 of 81 patients aged 65 or older received initial full-dose therapy. When these patients were compared with younger patients on whom full-dose chemotherapy was started, survival curves, but not CR rates, were still significantly different. There were no significant differences in duration of CR or frequency of treatment complications. These data suggest that older age is associated with a worse prognosis in advanced DHL. Moreover, the initial dose reduction for patients aged 65 or older may have contributed to their inferior outcomes.     

Nodular lymphoma with intracellular immunoglobulin.

A case of malignant lymphoma with vacuolated cells is presented and, as with two other recent reports, is of the nodular poorly differentiated lymphocytic type. This form of malignant lymphoma presumably is composed of neoplastic B lymphocytes, which produce intracellular immunoglobulins or fractions thereof, corresponding to various cellular vacuoles and inclusions. The vacuolated appearance of the neoplastic cells simulates mucinous or "signet ring" adenocarcinoma, which may be excluded by clinical, routine microscopic, histochemical, immunologic, and electron microscopic observations.     

Survival of patients with localized histiocytic lymphoma.

Twenty of 65 patients with diffuse histiocytic lymphoma were identified by staging laparotomy as being in pathologic stages (PS) I, I(E), II, II(E). Six of the 20 patients were treated with total nodal, 10 with extended mantle, and four with involved-field radiotherapy. The survival rate and relapse-free survival at five years were 71% and 78%, respectively. All relapses occurred within the first year and were confined to patients with PS II disease and four or more sites of involvement. Accurate pathologic staging identifies patients who are potentially curable with radiotherapy. Further studies are required to determine the treatment necessary to achieve cure in PS II patients with more than four sites of involvement.     

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.     

A morphologic study of childhood lymphoma of the diffuse "histiocytic" type. The Pediatric Oncology Group experience

Of 227 cases of pediatric non-Hodgkin's lymphoma with adequate histopathologic material for review, 72 (32%) were classified as diffuse "histiocytic" lymphoma (DHL). These cases were further divided into different morphologic subtypes according to the Lukes-Collins classification, and the National Cancer Institute Working Formulation, to ascertain whether there were any significant prognostic differences among the different subtypes. The results of our study showed that 40 patients were classified as immunoblastic lymphomas, and 32 were called large follicular center cell (FCC) tumors. Of the 40 patients with immunoblastic histology, 19 had morphologic features of the clear cell type and were interpreted as consistent with T-immunoblastic lymphomas; an additional two had polymorphous features also consistent with T-cell type: 17 had plasmacytoid features, and were morphologically classified as B-immunoblastic lymphomas; two could not be subtyped. Of the 32 patients with morphologic features of FCC lymphomas, 29 were classified as large noncleaved type, and three as large cleaved type. A clinicopathologic analysis showed that 90% of the patients obtained complete remission, and there were no significant differences in complete remission rate among the different morphologic subtypes of DHL. The estimated five year disease-free survival for all patients was over 70%, with no failure after the second year; and there were no significant differences in the disease-free survival among the different subtypes. The only clinical differences that we found, were that patients with lymphomas of FCC (large noncleaved) type were younger (P = 0.01); had less nodal involvement (P = 0.03); and had more organ involvement (P less than 0.01). We conclude that the morphologic subclassification of DHL in children currently has limited clinical prognostic significance.