Non-Hodgkin's lymphoma and occupational exposure.

A case-control study was conducted to assess the effect of occupational exposures on the risk of non-Hodgkin's lymphoma. Interviews were conducted with 303 persons with non-Hodgkin's lymphoma newly diagnosed from January 1, 1980, to May 31, 1982, among residents of the Boston, MA, metropolitan area and 303 age and gender matched controls. The study found an increased risk of disease among persons employed in the agriculture, forestry, and fishing industry [relative risk (RR) = 3.0]; the construction industry [RR = 2.1]; and the leather industry [RR = 2.1]. The particular job groupings at increased risk were plant farmers and gardeners (RR unbounded); painters and plasterers (RR = 6.0); and carpenters, brick and stone masons, plumbers, and roofers (RR = 12.0). Although other exposures may have led to these increased risks, the findings in this study are consistent with an increased risk of non-Hodgkin's lymphoma for workers who may be exposed to chlorophenols or phenoxyacetic acids.

Identification of early relapsing patients with adult acute nonlymphocytic leukemia by bone marrow biopsy after initial induction chemotherapy.

Bone marrow biopsies obtained from 69 adult patients with acute nonlymphocytic leukemia (ANLL) six to 10 days after initial induction chemotherapy were reviewed blindly to detect the presence of residual leukemia. Discrimination between the presence or absence of leukemic cells was provided by assessment of the numbers, clustering, and nuclear morphology of blasts and promyelocytes. Twenty-six patients had frank leukemia, 25 had no apparent leukemic cells, and 18 had focal residual leukemia. Of 25 patients whose bone marrow contained no detectable residual leukemic cells, 21 gained complete remission without further chemotherapy. These patients had a median duration of remission of 278 days, with five patients still remaining in remission for 578-882 days. Similarly, all of the 18 patients who had focal residual leukemia achieved complete remission without additional chemotherapy; however, all have relapsed with a median duration of remission of 163 days. This study indicates that patients with foci of residual leukemia in their one-week posttreatment bone marrow samples readily achieve remission, but carry a substantial leukemic burden that increases the likelihood of early relapse.

Pentostatin induces durable remissions in hairy cell leukemia.

Fifty patients with hairy cell leukemia were treated with pentostatin (2'-deoxycoformycin; dCF) for a median of 3 months; 32 (64%) patients achieved complete remission (CR), and 10 (20%) patients achieved partial remission (PR), for an overall response rate of 84%. After reaching maximal response, no maintenance therapy was administered. The median duration of follow-up is now 39 months, and only four of 32 patients in CR and two of 10 patients in PR have relapsed. dCF therapy produces durable long-term, disease-free survival in patients with hairy cell leukemia.

Phase II trial of pentostatin in refractory lymphomas and cutaneous T-cell disease.

Thirty-seven patients with refractory lymphoma or cutaneous T-cell lymphoma were treated with 2'-deoxycoformycin (pentostatin; dCF), 5 mg/m2 intravenous (IV) bolus for 3 consecutive days of every 3-week cycle in this Eastern Cooperative Oncology Group (ECOG) trial. Included were 25 with the diagnosis of non-Hodgkin's lymphoma, three with Hodgkin's disease, eight with cutaneous T-cell lymphoma (CTCL), and one with unknown subtype, of whom 31 were considered eligible. The majority had failed at least two, but no more, conventional chemotherapy regimens. Ten (32%) of the eligible patients had a partial response (PR), including patients with nodular poorly differentiated lymphocytic (NPDL), nodular mixed (NM), diffuse poorly differentiated lymphocytic (DPDL), or diffuse histiocytic (DH), lymphoma mixed-cellularity (MC), Hodgkin's disease, and unknown subtype, and in four patients with CTCL. The overall median time to treatment failure (TTF) was only 1.3 months, but the range extended to 57.3 months. The overall response duration was 16.0 months, and the range extended to 53.4 months. Overall median survival was 2.7 months, with the range extending to 63.2 months. The majority of patients had no toxicity, but there were some instances of severe or life-threatening events. Four fatal toxicities occurred, in two patients with underlying pulmonary conditions and two with prior cardiac histories. From this study, we conclude that dCF is active in refractory lymphomas and CTCLs, should be avoided in patients with a history of serious pulmonary or cardiac diseases, and warrants consideration for incorporation of a low-dosage schedule into conventional combination chemotherapy regimens, including its use with biologic response modifiers.

MOPP/ABV hybrid chemotherapy for advanced Hodgkin's disease significantly improves failure-free and overall survival: the 8-year results of the intergroup trial.

PURPOSE: To compare the efficacy of sequential mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) followed by doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus the MOPP/ABV hybrid regimen in advanced-stage Hodgkin's disease. PATIENTS AND METHODS: A total of 737 patients with previously untreated stages III2A, IIIB, IVA, or IVB Hodgkin's disease and patients in first relapse after radiotherapy were prospectively randomized to sequential MOPP-ABV or MOPP/ABV hybrid. Of 691 eligible patients, 344 received the sequential regimen and 347 received the hybrid. RESULTS: The overall response rate was 95%, with complete responses (CRs) in 79%: 83% on the MOPP/ABV hybrid and 75% on the sequential MOPP-ABVD arm (P = .02). With a median follow-up time of 7.3 years, the 8-year failure-free survival (FFS) rates were 64% for MOPP/ABV hybrid and 54% far sequential MOPP-ABVD (P = .01; 0.69 relative risk of failure, comparing MOPP/ABV hybrid v MOPP-ABVD). The 8-year overall survival rate was significantly better for the MOPP/ABV hybrid (79%) as compared with sequential MOPP-ABVD (71%) (P = .02; relative risk, 0.65). MOPP/ABV hybrid had significantly more life-threatening or fatal neutropenia and pulmonary toxicity than the sequential MOPP-ABVD arm, which was associated with significantly greater thrombocytopenia. Nine cases of acute myelogenous leukemia or myelodysplasia were reported on the sequential regimen as compared with only one on the hybrid (P = .01). CONCLUSION: MOPP/ABV hybrid chemotherapy was significantly more effective than sequential MOPP-ABVD. FFS and overall survival were significantly improved on the hybrid arm, which was also associated with a lower incidence of acute leukemia or myelodysplasia.

Activity of fludarabine in previously treated non-Hodgkin's low-grade lymphoma: results of an Eastern Cooperative Oncology Group study.

PURPOSE: Fludarabine (2-fluoro-arabanoside-monophosphate) is a new antimetabolite chemotherapeutic agent. We performed a multicenter, phase II study of this drug in previously treated patients with refractory or relapsed non-Hodgkin's lymphoma (NHL) to determine its response rate by histologic classification. PATIENTS AND METHODS: Sixty-two assessable patients were given 18 mg/m2 by intravenous (IV) bolus injection daily for 5 days, every 28 days. Forty-eight percent had previously had one chemotherapy regimen, and the remainder had had two regimens; 42% had had radiation. RESULTS: Patients received 273 cycles of fludarabine chemotherapy, with a median of two cycles and ranging up to 25 cycles. Sixty patients were assessable for response, including nine complete responses (CRs; 15%) and nine partial responses (PRs; 15%). The response rate for patients with lower-grade histology was 52% (13 of 25); the greatest response rate was seen in those with follicular small cleaved-cell lymphoma, including seven of 11 treated. Five responders remain in unmaintained remission; the median survival of responders is greater than 30 months. Toxicity included mild neutropenia and a 10% incidence of grade 3 neurologic toxicity with occasional reversible visual and auditory changes. CONCLUSION: Fludarabine is active in patients with previously treated NHL (particularly low-grade histologies). Future studies will examine its activity in combination with other chemotherapeutic agents in previously untreated patients.

Prospectively randomized clinical trial of three intensive chemotherapy regimens for the treatment of advanced unfavorable histology non-Hodgkin's lymphoma.

Three hundred thirty-two eligible patients with advanced (Ann Arbor stage III or IV) non-Hodgkin's lymphoma of aggressive histologic subtype (Rappaport classification diffuse histiocytic [DH], diffuse poorly differentiated lymphocytic [DPDL], diffuse mixed [DM], or diffuse undifferentiated [DU]) were randomly assigned to receive induction chemotherapy with one of three intensive regimens in a clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG) between 1978 and 1983. Chemotherapy regimens consisted of cyclophosphamide, vincristine, prednisone, and doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) (COPA) administered in 3-week cycles; cyclophosphamide plus doxorubicin plus prednisone beginning day 1, with vincristine plus bleomycin day 15 of each 3-week cycle (COPA + Bleo); or cyclophosphamide plus doxorubicin plus procarbazine beginning day 1, and bleomycin plus vincristine plus prednisone beginning day 15 of each 4-week cycle (CAP-BOP). The median patient follow-up from study entry for patients still alive is 5 years. The three regimens were not significantly different with respect to complete response (CR) rates (43% to 46%), time to progression of malignant disease (median, 1.0 to 1.7 years), or survival (5-year survival, 34% to 45%), although duration of complete remission appeared to be shorter in patients receiving COPA (P = .03). COPA + Bleo and CAP-BOP were significantly more toxic than the COPA regimen. This study did not demonstrate any substantial therapeutic advantage associated with the addition of a fifth or sixth chemotherapy drug, or with treatment administered on a more frequent administration schedule, compared with the COPA regimen in this population of patients with advanced diffuse non-Hodgkin's lymphoma. The relatively small proportion of long-term disease-free survivors treated with COPA underscores the need for prospective clinical trials of new and more effective treatments for patients with these potentially curable tumors.

Morphology of cells grown in the CFU-GEMM tissue culture assay from mononuclear cells obtained from peripheral blood and bone marrow of normal volunteers.

In ten healthy volunteers studies were done to assess the morphology, immunocytology, and cytochemical properties of mononuclear hematopoietic stem cells isolated from normal human peripheral blood and bone marrow grown in semisolid matrix mixed lineage colony-forming unit (CFU-GEMM) culture. In three volunteers, peripheral blood and bone marrow samples were collected simultaneously; the progeny were remarkably similar in each of the three paired cultures, although macrophages were more numerous in the bone marrow cultures. Three peripheral blood samples were cultured following frozen storage with 10% DMSO at-150 degrees C for approximately 5 months. Megakaryopoiesis was present in each case, demonstrating the full hematopoietic potential of previously frozen peripheral blood mononuclear cells. Four other peripheral blood samples and one bone marrow sample were cultured and, in each case, cells of all hematopoietic cell lines were present. Bone marrow, peripheral blood mononuclear cells, and previously frozen peripheral blood mononuclear cells grown in the CFU-GEMM tissue culture assay showed the presence of granulocyte-macrophage, erythroid, and megakaryocytic cell lines.

Vasculitis and Sjögren's syndrome with IgA-IgG cryoglobulinemia terminating in immunoblastic sarcoma.

Generalized lymphadenopathy and other manifestations of Sjögren's syndrome developed in a 68 year old woman with a long history of systemic vasculitis and arthralgia. An unusual immunologic feature was hypogammaglobulinemia and immunoglobulin A (IgA) monoclonal immunoglobulinemia with mixed IgA-IgG cryoglobulin. At autopsy, the histopathologic findings were compatible with immunoblastic sarcoma. The monoclonal IgA protein, found in serum, pleural and pericardial fluids, showed rheumatoid factor activity. Immunocytes from the immunoblastic sarcoma were found to be the source of the monoclonal IgA protein.

The histologic features of hyperplastic lymphadenopathy in AIDS-related complex are nonspecific.

Follicular hyperplasia is the most common histologic finding in lymph nodes of patients with AIDS-related complex (ARC) and persistent generalized lymphadenopathy. To determine the specificity of the published features considered characteristic of this condition, we compared two sets of lymph-node biopsy specimens with follicular hyperplasia. Thirty-eight specimens were from human immunodeficiency virus (HIV/HTLV3/LAV) positive homosexual men with persistent generalized lymphadenopathy, and 87 specimens were from patients free of AIDS risk. Polykaryocytes, epithelioid histiocytes, and follicle mantle zone effacement were significantly more common in the ARC group. Dermatopathic change and so-called follicle lysis were significantly more common in control, non-ARC nodes. No statistically significant difference between the two groups could be demonstrated for the following features: irregularity of follicles, burnt-out follicles, sinus monocytoid cells, marked plasmacytosis, and the toxoplasmosis triad. Most importantly, no feature was seen exclusively in either of the two groups. Although some features considered characteristic of the hyperplastic form of ARC lymphadenopathy are seen more commonly in this condition than in lymph nodes showing follicular hyperplasia unrelated to ARC, none of these features is specific for ARC and there is no histologic picture diagnostic of this condition.

Primary hepatic B-cell lymphoma in a child.

Lymphoma arising in the liver is uncommon in adults and rare in children. A 12-year-old boy with hepatomegaly and jaundice had a calcified intrahepatic large-cell lymphoma of B-cell origin that expressed bcl-2 protein and had near-tetraploid chromosome number with a t(8;14) (q24;q32) and a homogeneously staining region (HSR). This tumor, only the fourth example of primary hepatic lymphoma in a child, has the rare finding of an HSR before treatment and is the first human lymphoma with t(8;14) that expresses bcl-2 protein. In addition, the demonstration of extensive calcification in the tumor by computed tomography scan is highly unusual for lymphoma. Lymphoma must be considered in the differential diagnosis of primary liver tumors in children and adults, especially if the serum alpha-fetoprotein level is normal.

Inflammatory pseudotumor of the spleen: a clinicopathology study of three cases.

The clinical and pathologic findings of three cases of splenic inflammatory pseudotumor are described, and differential diagnostic features are discussed. This benign lesion is extremely rare, only four having been previously reported. Inflammatory pseudotumors often pose diagnostic difficulties because they form infiltrative masses which have clinical and gross pathologic features that suggest malignancy. Although these lesions are usually easily recognizable microscopically as benign processes, the admixed component of lymphoid and other hematopoietic cells may sometimes raise the question of a lymphoreticular malignancy, requiring immunohistologic studies for resolution in some cases. Alternatively, pseudotumors may be mistaken for infectious granulomatous processes, sarcoidosis, or hamartomas.

Splenic marginal zone cell lymphoma: report of an indolent variant without massive splenomegaly presumably representing an early phase of the disease.

Splenic marginal zone (MRZ) cell lymphoma is a recently described neoplasm arising in a unique compartment of splenic white pulp, producing massive splenomegaly and spreading to bone marrow and distant lymph nodes. We report three cases of splenic lymphoma that morphologically and immunohistochemically appear to originate from MRZ cells that presented as indolent neoplasms involving the spleen but with no or only moderate enlargement of the organ, presumably representing an early clinical stage of this disorder. Despite the evidence of involvement of the liver in one case, lymph nodes and bone marrow proved to be uninvolved. Histologically, the three spleens showed similar features, being characterized by the involvement of white pulp follicles and periarteriolar lymphoid sheaths by medium-sized lymphoid cells with slightly irregular nuclei and ample cytoplasm. Immunohistochemically, all the specimens expressed a series of B-lineage markers that, in contrast to specimens of monocytoid B cell lymphoma (MBCL) and hairy cell leukemia (HCL) studied for comparison, did not react with KiB3, LN1, and DBA.44 monoclonal antibodies.

Immunohistochemical localization of human immunodeficiency virus p24 antigen in placental tissue.

As human immunodeficiency virus (HIV) infection spreads into the heterosexual population, perinatally acquired HIV infection will increase in incidence, and knowledge of the mechanism of this transfer is important. We have used immunoperoxidase techniques to detect HIV p24 antigen in formalin-fixed, paraffin-embedded placental tissue from nine known HIV serologically positive mothers. In four of these cases we have detected evidence or viral antigen in placental Hofbauer cells, vascular endothelium, or intermediate trophoblast. The implications for understanding the mode of transfer of infection to the fetus are discussed.

The pathology of the spleen in steroid-treated immune thrombocytopenic purpura.

The spleen is a central organ in the pathophysiology of immune thrombocytopenic purpura (ITP). Splenic lymphoid tissue synthesizes anti-platelet IgG, and splenic cordal macrophages destroy platelets coated with anti-platelet antibodies. The morphologic features of the spleen in this disease reflect this splenic function: hypertrophied lymphoid follicles with secondary germinal centers in the white pulp, with perivascular plasma cells in the red pulp and evidence of increased platelet phagocytosis in cords of the Billroth. Foamy macrophages and evidence of a variable degree of extramedullary hematopoiesis also have been noted. The authors have studied 17 spleens removed for therapeutic purposes in patients with proven ITP previously treated with varying amounts of corticosteroids. In all cases there was little or no morphologic evidence of follicular hyperplasia or plasmacytosis. However, platelet sequestration and phagocytosis were demonstrated easily in all cases, both in histologic sections and in touch imprints. The authors' findings indicate that morphologic evidence of lymphoid activation characteristic in spleens from patients with ITP usually is ablated by prior corticosteroid therapy but that the characteristic platelet sequestration and phagocytosis persists.

Evidence to suggest that the human fetal spleen is not a hematopoietic organ.

The human fetal spleen commonly is regarded as an organ of hematopoiesis. Because of the authors' interest in myelofibrosis with myeloid metaplasia (MMM) and because the myeloid metaplasia commonly is regarded as a reactivation of embryonic sites of blood formation, spleens from 48 fetuses and stillborn infants were studied, in an attempt to evaluate splenic hematopoiesis (myelopoiesis). The authors employed immunohistologic and cytochemical technics to identify granulocytic, erythroid, and megakaryocytic cells, in contrast to previous studies that have relied solely on conventional morphology. The authors found surprisingly little evidence of hematopoiesis. Virtually no hematopoietic cells of the dividing cell pool were identified, in spite of the fact that the technic used is capable of detecting such immature forms. The results suggests that the spleen is not a significant organ of hematopoiesis in the human fetus but that immature hematopoietic cells found there merely reflect trapping of circulating precursors in the fetal blood. These findings have significant implications for the pathophysiology of MMM.

Peliosis of the spleen.

Peliosis of the spleen is a rare condition that accompanies peliosis hepatis. Two cases are presented, and a detailed morphologic description is given. The lesions are confined to the red pulp and appear to arise by progressive distention of splenic sinuses, with eventual thrombosis and organization. Peliotic involvement of the spleen is probably more common than realized and can have serious clinical implications.

"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.

Peripheral T-cell lymphoma: a clinicopathologic study of nine cases.

The clinicopathologic features of nine cases of peripheral T-cell lymphoma were analyzed. Although the youngest patient was 18 years old, the median age was 59.8 years. They usually presented with widespread disease and had an aggressive course. Seven have died with a median survival of 10.9 months. Five cases were of mixed cell type, sharing certain histopathologic features that we believe are characteristic of peripheral T-cell lymphomas. Three cases were of large cell type; one was a small cell (PDL) type. This latter patient lived symptom-free without treatment for over 3 years, despite stage III disease. Another patient, whose tumor had nodular sclerosis-like fibrosis, is in complete remission two years after chemotherapy for stage III B disease. Because peripheral T-cell lymphoma is morphologically heterogeneous, it may be clinically heterogeneous as well. We believe that classification according to a modified Rappaport system may clarify possible variations in biologic behavior.

Bone marrow morphology and immunology in systemic amyloidosis.

Bone marrow specimens from 45 patients presenting with signs and symptoms of systemic amyloidosis were studied to assess the degree and pattern of plasmacytosis and its clonality, using immunohistologic technics. Twenty-four of 35 patients with primary amyloidosis had monoclonal plasma cells, while 11 had polyclonal plasma cells. Five patients with secondary amyloidosis and five with familial amyloidosis had a mild polyclonal plasmacytosis. The authors' data suggest that there may be two subgroups of patients with primary amyloidosis: those with monoclonal plasmacytosis representing part of the spectrum of plasma cell dyscrasias, and those in which a monoclonal plasmacytosis cannot be documented. Immunohistologic staining of bone marrows in patients with amyloidosis may be of future value in characterizing subtypes of amyloidosis and evaluating their relationship to multiple myeloma.