Primary large cell lymphoma of the mediastinum.

Primary mediastinal (thymic) large B-cell lymphoma is a discrete clinicopathologic subtype of diffuse large cell lymphoma recognized in the revised European-American lymphoma classification. It is an uncommon but not rare tumor with worldwide distribution. For the clinician, the occurrence of this aggressive, invasive, yet localized neoplasm arising in an unusual site in a cohort of young adult patients (frequently women) in whom large cell lymphoma is infrequent is noteworthy. The pathologist is impressed both by the characteristic sclerosis and the unusual surface immunoglobulin (SIg)-negative B-cell phenotype of a tumor arising in a T-cell organ (thymus). The phenotype is that of a B-cell subset resident in the thymic medulla. The pattern of spread resembling that of extranodal lymphoma and the excellent response to appropriate combination chemotherapy and irradiation further support the discrete character of mediastinal large cell lymphoma, and provide a practical reason for recognizing the entity. Poorly chosen or executed primary therapy can lead to rapid tumor growth or regrowth with treatment failure and death, but a reassuringly high cure rate follows appropriate management.

High risk of breast carcinoma after irradiation of young women with Hodgkin's disease.

BACKGROUND: Treatment-associated second neoplasms have emerged as a major threat to the continued survival of patients cured of Hodgkin's disease. In this study, the authors investigated the risk of breast carcinoma in an irradiated Hodgkin's disease population. METHODS: One hundred and eleven women younger than 60 years presenting between 1964 and 1984 with Stage I and II Hodgkin's disease who received mantle irradiation were retrospectively analyzed and compared with an age specific population. Median follow-up was 18 years (range, 10-30 years), and the median age at initiation of therapy was 24 years. Kaplan-Meier actuarial risks, relative risks (RRs) (the ratio of the observed to the expected cases) with 95% confidence intervals (CIs), and the log rank test for trends were calculated. RESULTS: Fourteen women developed breast carcinoma: 8 of 33 patients younger than 20 years at the time of irradiation, 5 of 48 patients age 20 to 29 years, and 1 of 30 patients age 30 years or older. Actuarial calculation predicted a 34.0% (CI, 14.2-53.8) risk of breast carcinoma at 25 years after therapy for the youngest group, 22.3% (CI, 4.1-40.5) for the group of intermediate age, and 3.5% (CI, 0-10.1) for the oldest group. The RR of breast carcinoma was 56 (CI, 23.3-107) for those 19 years or younger at the time of treatment, 7.0 (CI, 2.3-16.4) for those age 20-29 years, and 0.9 (CI, 0-5.3) for those 30 years and older. Excluding 1 patient who was age 38 years at the time of irradiation, the remaining 13 breast carcinomas were tightly clustered in women irradiated between the ages of 14 through 25, and were detected in years 11 through 25 after treatment, with 7 occurring in years 15 through 18. CONCLUSIONS: Women younger than 30 years, particularly those younger than 20 years, who have received mantle irradiation for Hodgkin's disease require meticulous follow-up for breast carcinoma. The high incidence of breast carcinoma in this patient population should be considered when making treatment decisions in young women with early stage Hodgkin's disease.

Hodgkin's disease presenting as a solitary bone tumor. A report of four cases and review of the literature.

BACKGROUND: Hodgkin's disease (HD) rarely presents as a solitary bone tumor. Fewer than 20 such cases have been reported in the English literature; many of these were reported prior to the development of immunohistologic markers for HD and T- and B-cell lymphomas. In this report, we describe four cases of HD that presented as a localized solitary mass in bone; the diagnosis was confirmed by immunohistochemical studies in all cases. METHODS: The biopsy specimens of four cases identified in our files were studied by conventional histopathology and immunohistochemistry. Clinical data and follow-up information were obtained for all patients. RESULTS: Three cases presented as a localized, solitary mass in the ilium and one case in the vertebra (T12). Three patients were female and one male. The average age was 43 years. Three of the patients presented with lower back pain without constitutional symptoms. All had solitary osteoblastic lesions. All four cases were diagnostic problems, and the diagnosis was confirmed in each case only after finding lymph node involvement. Bone biopsies showed fibrosis and a mixed inflammatory infiltrate with rare atypical cells. All four patients were subsequently found to have nodal involvement by HD. The histology of the associated nodal disease was mixed cellularity in two cases and nodular sclerosis in two. On immunohistochemical staining, the neoplastic cells in all cases expressed CD15 and CD30 and lacked CD45 and other B- and T-cell antigens. Three patients who were treated for HD are alive and well, 1, 6, and 14 years later. CONCLUSIONS: Although rare, HD should be considered in the differential diagnosis of solitary bone lesions. Most patients who present with apparently solitary HD of bone prove to have nodal involvement. Long-term survival is possible with aggressive treatment.

Coherent view of non-Hodgkin's lymphoma.

PURPOSE: Even though non-Hodgkin's lymphoma is already sixth in incidence and mortality among malignant neoplasms (and the incidence was increasing at a rate of 3% to 4% per year before the advent of AIDS epidemic-associated lymphomas), most physicians and many oncologists find the disorder arcane. The problem lies in the complexity of human lymphoma, which encompasses more than a dozen neoplasms of the lymphoid system. The goal of this review is to provide user-friendly access to the condition. METHODS: The variety of inputs required for a subdivision of non-Hodgkin's lymphoma that is useful to clinicians includes lymphocyte lineage and sublineage based on microscopic appearance and immunophenotype, clinical behavior manifest in survival and early dissemination, and analysis of molecular genetic and cytogenetic abnormalities, which reflect pathogenic oncogene derangements. Epstein-Barr virus (EBV) and human T-cell leukemia virus type 1 (HTLV-1) are important in certain uncommon lymphomas. RESULTS AND CONCLUSION: The subtypes of primary B-lineage nodal lymphoma include low-grade (small lymphocytic, lymphoplasmacytic-lymphoplasmacytoid, follicular small cleaved cell, and follicular mixed small cleaved and large cell), intermediate-grade (follicular large cell, diffuse small cleaved or mixed, and intermediate lymphocytic), and high-grade (diffuse large cell, immunoblastic, and small noncleaved cell) neoplasms. The less common lymphomas of T lineage and lymphomas that arise in extranodal sites are placed in separate subdivisions. This subdivision serves as a guide to prognosis and treatment.

bcl-2 rearrangements in de novo diffuse large cell lymphoma. Association with distinctive clinical features.

BACKGROUND: The frequency and clinical significance of bcl-2 rearrangement in de novo B-cell diffuse large cell lymphoma is largely unknown. METHODS: Using Southern blot hybridization and multiple DNA probes, the status of the protooncogene bcl-2 was investigated in frozen tissue samples from 45 carefully selected cases of de novo diffuse large cell lymphoma of B-cell origin. Results were correlated with the presenting clinical and immunophenotypic features and with the subsequent clinical course. RESULTS: Rearrangements of bcl-2 were identified in nine tumor specimens (20%). The bcl-2-positive cases more often presented as early-stage, nonmucosal associated extranodal tumors (P = 0.06) and were more often HLA-DR negative (P = 0.07). Five-year failure-free survival was poor among the bcl-2-positive cases (11% versus 48%). Overall survival was no different, however, because relapses in bcl-2-positive cases tended to be responsive to further therapy. CONCLUSIONS: Analysis of bcl-2 rearrangements in de novo diffuse large cell lymphoma may identify a subset of patients with unusual clinical features.

Utility of gene rearrangements in lymphoid malignancies.

Molecular genetic study of lymphoid neoplasms by Southern blotting or polymerase chain reaction permits the ready detection of gene rearrangements. Clonal rearrangements of immunoglobulin and T-cell receptor genes identify neoplasms of B- and T-cell lineage, respectively. Additionally, lymphoma-specific chromosome translocations involving oncogenes are detected with the same molecular techniques. Probes are currently available to study the c-myc translocations of Burkitt's lymphoma, the bcl-2 translocations of follicular lymphomas, and the bcl-1 translocations of centrocytic lymphoma.

Different T-cell receptor gene configurations in T-cell neoplasms and acute lymphoblastic leukemia.

Southern blotting and multiple restriction enzymes were used to analyze T-cell receptor (TCR) and immunoglobulin heavy chain genes in 20 postthymic T-cell neoplasms, ten prethymic and thymic T-cell tumors, and 45 cases of precursor-B acute lymphoblastic leukemia (ALL). Immunoglobulin heavy chain, never rearranged in a postthymic specimen and only once in a prethymic/thymic sample, was rearranged in all but two cases of precursor-B ALL. In contrast, biallelic rearrangement of TCR beta with deletion of the first constant region germline fragment was regularly seen in T-cell neoplasms, but only twice in the 45 precursor-B ALL cases. TCR gamma was rearranged in all but one postthymic sample, in all prethymic/thymic samples, and in approximately half of precursor-B ALL specimens as well. Preferential use of V gamma regions was evident among the various disorders: V8 and V10 in postthymic neoplasms; and V3, V5, V7, and, particularly, V9 in precursor-B ALL. In all the studied conditions, TCR delta was rarely in germline configuration. Extensive biallelic deletion of J delta 1, J delta 2, and C delta, almost always (19 of 20 specimens) present in postthymic neoplasms, was observed in only a minority (14 of 45) of precursor-B ALL samples. In precursor-B ALL, rearranged antigen receptor genes were more frequently found in common acute lymphoblastic leukemia antigen-positive and terminal deoxynucleotidyl transferase-positive specimens. Furthermore, TCR gene rearrangement in that disorder was characterized by a hierarchical pattern: TCR beta was not rearranged without TCR gamma nor TCR gamma without TCR delta. Despite uncertainty of the mechanism, the various disorders can be distinguished on the basis of characteristic antigen receptor gene patterns.

Primary large cell lymphoma of the mediastinum. A histologic and immunophenotypic study of 29 cases.

We studied the morphologic and immunologic features of 29 cases of primary nonlymphoblastic non-Hodgkin's lymphoma of the mediastinum. The patients ranged in age from 15 to 73 years, with a median of 32 years. The mean age for the 11 men (50 years) was significantly higher than that for the 18 women (32 years) (p less than 0.05). All had diffuse large cell lymphomas (six immunoblastic, 14 large cell not otherwise specified, six large cell noncleaved, one large cell cleaved, and two not subclassifiable). Sclerosis was prominent in 11 cases, none of them immunoblastic, and did not correlate with superior vena cava syndrome. The mean age (54 years) of patients with immunoblastic lymphomas was higher than that for patients with other subtypes (35 years) (p less than 0.02). Frozen-section immunoperoxidase staining disclosed monotypic immunoglobulin in 13 cases, with a high frequency of heavy-chain class switching (seven IgG, two IgA, four IgM). Sixteen cases were immunoglobulin negative; 14 of 15 cases expressed B-lineage antigens, and none expressed T-lineage antigens. Three of four cases showed immunoglobulin heavy- or light-chain gene rearrangement by the Southern blot technique. None showed rearrangement of the T-cell receptor beta-chain-gene constant region. There was no correlation between immunophenotype and morphologic subtype. The immunoglobulin-negative group was predominantly female (13 of 16 cases; p less than 0.02), and younger (mean age, 34 years versus 44 years; p = NS) than the immunoglobulin-positive group; however, the difference in age was not statistically significant. The actuarial 5-year survival was 57%, and there was no correlation between survival and either histologic subtype or immunophenotype. Mediastinal large cell lymphoma is a B-cell tumor, which frequently lacks immunoglobulin, may be primary in the thymus, has a predilection for young women, and can be cured with aggressive therapy.

Humoral hypercalcemia in Hodgkin's disease. Clinical and laboratory evaluation.

To provide further understanding of humoral hypercalcemia in Hodgkin's disease (HD) the authors describe the clinical features and laboratory investigation of three patients recently treated at Massachusetts General Hospital. All were middle-aged men who presented with symptomatic hypercalcemia which led to a diagnosis of bulky intraabdominal HD. None had evidence of bone involvement or hyperparathyroidism. In the two cases tested 1,25(OH)2D3 was elevated at the time of diagnosis. These characteristics are remarkably similar to those of ten patients with HD and probable humoral hypercalcemia described in the literature. The diagnosis of HD was supported in Cases 1 and 3 by genomic blot analysis which showed no evidence of T-cell or B-cell tumor origin. In an in vitro assay, primary tumor medium from Case 1 stimulated dose-dependent bone resorption which was not entirely ascribable to 1,25(OH)2D3. The authors conclude that humoral hypercalcemia in HD predominantly affects males of middle age, that intraabdominal bulky disease is common, and that hypercalcemia appears to be mediated by tumor related production of 1,25(OH)2D3 in concert with a second factor.

Mediastinal large cell lymphoma. An uncommon subset of adult lymphoma curable with combined modality therapy.

Thirty adults with large cell lymphoma predominantly localized to the mediastinum diagnosed at the Massachusetts General Hospital between 1976 and 1985 were identified. The median age of the 20 females and 10 males was 34 years. All but one presented with symptoms due to an enlarging mediastinal mass, which was localized in 22 patients (73%) and exceeded 10 cm in maximal diameter in 65%. Superior vena cava syndrome and large pleural and pericardial effusions were common. Employing CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) and consolidation radiation therapy in most cases, 80% achieved a complete remission and 59% survive failure-free at 5 years by actuarial calculation. The size of the mediastinal mass adversely affected failure-free survival (89% vs. 40%, P less than 0.05). No other pretreatment risk factor predicted outcome, but more intense chemotherapy was associated with improved survival (P = 0.035). Large cell mediastinal lymphoma is a locally invasive, often bulky malignancy with a predilection for young women; disease of low or moderate bulk is curable with full dose CHOP chemotherapy and consolidation radiation, but bulky disease requires more aggressive treatment.

The bcl-2 gene is rearranged in many diffuse B-cell lymphomas.

Southern blotting was used to detect rearrangement of the bcl-2 gene in 104 cases of non-Hodgkin's lymphoma subclassified by the Working Formulation, 24 cases of B cell chronic lymphocytic leukemia (B-CLL) and 14 cases of T cell malignancy. Earlier workers reported rearrangement of this gene (located on chromosome 18) in a major fraction of follicular lymphomas, lymphomas in which a 14;18 chromosome translocation is frequently observed. In the present study, bcl-2 was rearranged in 30% (11 of 37) of follicular lymphomas and 19% (11 of 58) of diffuse lymphomas of follicle center cell lineage. In 18 of 19 samples studied, the rearranged bcl-2 fragment also hybridized with a probe for the joining region of the immunoglobulin heavy chain gene located on chromosome 14, indicating a 14;18 translocation. In lymphomas not derived from follicle center cells, ie, diffuse lymphomas of small B lymphocytes, B-CLL and T cell neoplasms, the bcl-2 gene was always in germline configuration. The frequent rearrangement of bcl-2 in a variety of B cell lymphomas of diffuse morphology (small cleaved cell, large cell, small noncleaved cell and immunoblastic) is noteworthy.

Rearrangement of the genes for the beta and gamma chains of the T cell receptor is rarely observed in adult B cell lymphoma and chronic lymphocytic leukemia.

We determined the configuration of the genes for the beta (T beta) and gamma (T gamma) chains of the T cell receptor in DNA from 100 consecutive cases of B cell lymphoma and B cell chronic lymphocytic leukemia (B-CLL), and compared the findings with those in 18 T cell neoplasms. In 7 of the 100 B cell specimens, a single nongermline band was detected after digestion with the restriction enzyme BamHI, but the rearrangement could be confirmed with a second restriction enzyme in only two. The B cell fragments were small in size and of limited size diversity when compared with the T cell cases, and germline bands of equal intensity were present. A rearrangement of the T gamma gene was never seen in a B cell sample. In contrast, T cell specimens usually rearranged both alleles of T beta (15 of 18), the rearrangement could be confirmed with a second restriction enzyme (17 of 18), both alleles of the first constant region gene segment of T beta always underwent either rearrangement or deletion, and the T gamma gene was also rearranged or deleted (17 of 18). We conclude that ordered rearrangement of the T cell receptor is a rare event in B cell lymphoma and B-CLL. T cell receptor gene studies allow B and T cell lymphomas to be distinguished from each other and from common acute lymphoblastic leukemia antigen-positive non-T, non-B acute lymphoblastic leukemia.

Immunoglobulin gene rearrangements in adult non-Hodgkin's lymphoma.

Southern blotting was employed to analyze the immunoglobulin heavy and light chain genes and the gene for the T cell receptor beta chain in genomic DNA derived from the tumor specimens of 120 adults with pathologically classified and immunotyped non-Hodgkin's lymphoma and B cell chronic lymphocytic leukemia. In a consecutive series of 100 patients, one or two rearranged heavy chain genes could be detected in each of the 80 samples expressing clonal surface immunoglobulin. The kappa gene was rearranged in 70 percent of kappa-bearing tumors and in 23 percent of lambda-bearing specimens. Furthermore, a rearranged immunoglobulin gene was also observed in 21 of 29 lymphomas (nine from the consecutive series and 20 selected for surface immunoglobulin-negative status) in which B cell lineage was in doubt because of absent clonal surface immunoglobulin. These findings indicate that most cases of lymphoma and lymphocytic leukemia in adults are of B cell lineage, even when phenotypic evidence is inconclusive. The exceptional cases (only 3 percent in the consecutive series) were of either follicular lymphoma or diffuse large cell (histiocytic) lymphoma subtype; the lineage in cases of diffuse lymphocytic lymphoma or chronic lymphocytic leukemia was never in doubt. Although the convenience of surface marker analysis assures its continuing clinical application, gene study resolves indeterminate cases and extends the understanding of the pathogenesis of lymphoproliferative disease.

Results of treatment of stage IA and IIA Hodgkin's disease.

This study analyzed the 5 year actuarial survival and disease-free survival of 122 patients with Stage IA and IIA Hodgkin's disease, (108 patients laparotomy staged) treated with mantle and paraaortic irradiation from 1975 to 1981. Prognostic subgroups and patterns of treatment failure were investigated. The 5 year actuarial survival and disease-free survival was 91% and 75% respectively for the entire group. For Stage IA patients, the 5 year survival and disease-free survival was 92% and 86% respectively, whereas for those in Stage IIA the respective figures were 86% and 65%. Individuals with greater than four sites of involvement at initial presentation; extensive mediastinal adenopathy; hilar or extramediastinal extension to lung, pleura or pericardium, had a poorer 5 year actuarial disease-free survival (43%-60%) than those without these factors (70%-85%). Of the 122 patients, there were 26 relapses: nine infield failures; two concurrent infield and systemic failures; nine marginal recurrences, and three relapses occurring systemically and three in nodal groups not irradiated. Following relapse, 17 patients were salvaged with chemotherapy. Two patients are alive with disease and seven patients died of Hodgkin's disease. Patients with less extensive mediastinal adenopathy and supradiaphragmatic nonmediastinal presentations can be satisfactorily treated with mantle and paraaortic irradiation, whereas patients with extensive mediastinal adenopathy receive six cycles of multiagent chemotherapy before irradiation.

Results of treatment of stage 3A Hodgkin's disease.

From 1975 to 1981, 38 patients with Stage 3A Hodgkin's disease (35 patients pathologically staged) underwent mantle and para-aortic irradiation, and in 36 patients this was preceded or followed by at least six cycles of multiagent chemotherapy. Both the 5-year actuarial survival and disease-free survival for all 38 patients were 83%. There have been six treatment failures: two patients have relapsed within irradiated nodal groups, one patient in apical pericardial lymph nodes as a marginal recurrence, one patient concurrently infield and in unirradiated nodal groups, and two patients systemically (concurrently in unirradiated nodal groups). Of these six relapses, three patients have died of Hodgkin's disease, one patient has been salvaged, and two patients currently are under treatment for salvage. One patient has developed acute nonlymphocytic leukemia and died of this disease. Extensive disease, as estimated by the number of sites of involvement at presentation, degree of splenic involvement, extent of intra-abdominal disease or mediastinal involvement, did not reveal statistically significant prognostic subgroups for relapse. It is currently recommended that patients with Stage 3A Hodgkin's disease receive six cycles of multiagent chemotherapy and mantle and para-aortic irradiation.