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BACKGROUND Studies have shown telomerase activity to be present in some B-cell non-Hodgkin lymphomas (B-NHLs). However, no large studies have assayed telomerase activity in a systematic and quantitative manner. Furthermore, the relation between telomerase and proliferation suggested by in vitro studies has not been adequately tested in B-NHLs in vivo. This information is necessary to understand the relation between proliferation and telomerase and to predict the efficacy of antitelomerase drugs currently in development. METHODS Eighteen benign biopsies and 111 B-NHLs of varying types were classified according to the revised European-American classification of lymphoid neoplasms (REAL classification) and assayed for telomerase activity and proliferation index (PI). RESULTS All B-NHLs contained telomerase activity except for low grade marginal zone B-cell lymphomas (MZBCLs) (96 of 111, 86%) (χ2 95.90, P < 0.001). Telomerase activity correlated with PI (r = 0.7536, r2 = 0.5678, t = 10.51, P < 0.001) and showed a threshold whereby telomerase activity was not present below a PI of 9.2% (t = 4.875, P < 0.001). CONCLUSIONS The level of telomerase activity fell within characteristic ranges and generally correlated with the clinical aggressiveness of each B-NHL category. Low grade MZBCLs of extranodal, nodal, and splenic types were unique among the categories of B-NHL in lacking or containing very little telomerase activity. The association between telomerase activity and PI is evidence that telomerase is controlled in vivo along with the cell cycle and is not constitutively active in B-NHL. These data provide evidence that antitelomerase drugs may be efficacious in most types of B-NHL. Cancer 2000;89:445–52. © 2000 American Cancer Society.

BACKGROUND Posttransplantation lymphoproliferative disorders (PT-LPDs) are a well-known complication of immunosuppression associated with solid organ transplantation. The clinical course of PT-LPDs is unpredictable; some patients experience regression of all lesions with a reduction in immunosuppression, whereas other patients, despite chemotherapy, radiation therapy, or surgery, rapidly die of their disease. In this study, the authors attempted to establish whether the previously described morphologic and molecular genetic categories of PT-LPD-plasmacytic hyperplasia (PH), polymorphic PT-LPD (polymorphic), and malignant lymphoma/multiple myeloma (ML/MM)-are clinically relevant and helpful in predicting the clinical outcome of patients who develop these lesions. METHODS To determine the clinical significance of the morphologic and molecular genetic categories of PT-LPDs, the clinical characteristics of 32 solid organ transplant recipients (26 heart, 5 kidney, and 1 lung), including age, time from transplantation to development of PT-LPD, stage of disease, and clinical outcome, were compared with the morphologic and molecular genetic features of the 41 PT-LPDs that they developed (15 PH in 12 patients, 19 polymorphic in 16 patients, and 7 ML/MM in 6 patients). Clinical outcome was defined by the following categories: 1) regression (after a reduction in immunosuppression) and surgical resolution (by surgical excision, with or without a reduction in immunosuppression); 2) medical resolution (by chemotherapy and/or radiation therapy); and 3) no response. RESULTS Although there was no difference in the time from transplantation to PT-LPD development among patients belonging to the three morphologic and molecular genetic categories, there was a significant difference in patient age at the time of PT-LPD development (P < 0.0098). Younger patients developed PH (mean age of 19 years), whereas older patients developed polymorphic PT-LPD (mean age of 35 years) and ML/MM (mean age of 56 years). Patients with PH presented with lower stages of disease (Stages I-II) than patients with ML/MM (P < 0.0004). Furthermore, there was a statistically significant trend between morphologic and molecular genetic category and clinical outcome, with decreased likelihood that lesions categorized as PH, polymorphic, or ML/MM would regress with a reduction in immunosuppression or be resolved by surgery, whereas those classified as ML/MM were more likely to exhibit no response to aggressive clinical intervention (P< 0.00006). Furthermore, no patients with PH died, whereas 20% with polymorphic PT-LPD and 67% with ML/MM died as a direct result of their PT-LPDs. CONCLUSIONS This study strongly suggests that classification of PT-LPDs into the morphologic and molecular genetic categories PH, polymorphic, PT-LPD and ML/MM is clinically relevant. Cancer 1998;82:1978-87. © 1998 American Cancer Society.

BACKGROUND Kaposi's sarcoma-associated herpesvirus (KSHV) DNA sequences have been identified in approximately 95% of Kaposi's sarcoma (KS) lesions and primary effusion lymphomas (PELs), suggesting a pathogenetic role for this virus in these lesions. However, KSHV has also been identified in a variety of specimens, including lymph nodes, peripheral blood B cells, semen, and prostate tissue, with varying frequencies. This suggests that KSHV, like Epstein-Barr virus, may be ubiquitously distributed. To evaluate further the clinical spectrum of KSHV infection and define better the prevalence of this virus in lymphoid tissues in the general population, the authors examined a wide spectrum of benign lymphoid proliferations occurring in human immunodeficiency virus (HIV)-negative individuals. METHODS One hundred eight lymphoid lesions were examined for the presence of KSHV by polymerase chain reaction (PCR) amplification using primers to open reading frame (ORF) 26. Positive cases were confirmed by Southern blot hybridization using an internal oligonucleotide probe and by PCR amplification using primers to ORF 74 and ORF 75 of the virus. RESULTS Only 4 (4%) of 108 specimens were KSHV positive. Three positive lymph node specimens were taken from patients with multicentric Castleman's disease (3 of 11 total cases of Castleman's disease; 3 of 5 total cases of multicentric Castleman's disease). The remaining case was a lymph node showing paracortical hyperplasia, taken from a patient with systemic lupus erythematosus. CONCLUSIONS KSHV is not detectable by PCR technology in a wide range of lymphoid proliferations occurring outside of HIV infection. These studies further support the contention that KSHV is preferentially associated with KS, PEL, and some cases of multicentric Castleman's disease. Cancer 1997; 80:788-97. © 1997 American Cancer Society.

Background. Posttransplantation lymphoproliferative disorders (PT-LPDs) are a clinicopathologically heterogeneous group of lymphoid proliferations of varied clonal composition, the majority of which are associated with Epstein-Barr virus (EBV) infection. The clonal content and clonal relatedness of 24 separate PT-LPD lesions occurring synchronously in one organ in a single patient were investigated. Methods. Twenty-four separate PT-LPD lesions from the colon and mesentery of a 15-year-old male, developing 4 months after cardiac transplantation, were studied for clonality based on immunoglobulin heavy chain (IgH) gene rearrangements for the presence, clonality, and type of EBV infection and for the presence of c-myc, ras, and p53 gene alterations. Southern blot hybridization, poly-merase chain reaction, and single strand conformation polymorphism assays were employed. Results. All 24 lesions were histologically similar (polymorphic B-cell lymphomas) but exhibited varied clonality and were clonally distinct with respect to both IgH gene rearrangements and EBV infection. All lesions were infected with EBV type A. Structural alterations of oncogenes or tumor suppressor genes were not identified. Conclusions. Separate PT-LPD lesions occurring synchronously in a single organ or patient may be clonally distinct, suggesting that they represent multiple distinct primary lymphoid proliferations rather than metastatic disease as in conventional malignant lymphomas. This may explain partially the rapid development in some patients of a large PT-LPD tumor burden that may regress rapidly after reduction of immunosuppression. Cancer 1995;75:2747–56.

Background CD30 (Ki-1) positive anaplastic large cell lymphoma (ALCL) has been only rarely described in HIV-positive patients. Methods The clinicopathologic features of eight ALCLs occurring in four AIDS and four HIV-positive patients were investigated. The phenotype of each neoplasm was determined by immunohistochemical methods. In three cases fresh tissue was available for molecular analysis. Results The ALCLs are a clinically heterogeneous group of T (4), B (1) and indeterminate (3) cell malignant lymphomas which presented in the skin (4), liver (1), lung (1), nasal cavity (1; also with bone marrow involvement) and peritoneal fluid (1). While most of the patients had aggressive disease, dying in a median of three months, two patients had either localized or regressing skin lesions. Molecular studies showed that two ALCLs, one of B cell and one of indeterminate cell lineage, contained clonal Epstein-Barr virus sequences. None of the ALCLs examined contained evidence of HTLV-1 or HIV integration nor did they exhibit c-myc or bcl-2 proto-oncogene rearrangements. No mutations or deletions of the p53 tumor suppressor gene were identified in the three cases studied. Conclusions HIV-related ALCL represents a clinically heterogeneous group of T cell, B cell and null cell malignant lymphomas, distinct from the previously described categories of AIDS-associated NHL, that may expand the spectrum of lymphoid neoplasms associated with HIV-infection. Identification and investigation of other cases of HIV-associated ALCL is important to determine the nature of the relationship between HIV infection and the development of ALCL.

Background. Posttransplantation lymphoproliferative disorders after solid organ transplantation are a serious complication occurring in 1–10% of patients. Different therapies have been used, but the optimal treatment is unknown. There is relatively little information in the literature on the experience with cytotoxic chemotherapy. Methods. The disease stage of patients with biopsydocumented posttransplantation lymphoproliferative was determined with standard methods to establish the extent of the disease. Patients in whom the disease failed to regress after initial management, which included reduction in immunosuppression, were treated with a combination chemotherapy regimen consisting of six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Response to therapy was determined by following previously defined sites of disease with appropriate tests. Patients were maintained on a reduced dose of immunosuppressants. Results. In the four patients studied, lymphoproliferative disorders developed after heart (three cases) or lung (one case) transplantation, which did not regress after immunosuppression was reduced. All four experienced a complete remission with CHOP chemotherapy, which continued at 3, 13+, 20 and 30+ months after completion of treatment. One patient died of sepsis after completing therapy at a point when his leukocyte count was normal, and no evidence of posttransplantation lymphoproliferative disorder was found at autopsy. A second patient died of liver failure with no clinical evidence of lymphoproliferative disorder. Conclusion. Although this is a small series, it demonstrates that patients with posttransplantation lymphoproliferative disorders may respond to cytotoxic chemotherapy. The duration of response is undetermined.

BACKGROUND: Lymphocytes that display a phenotype of mature B-cells, T-cells, natural killer (NK) cells, or a combination of T-cells and NK cells can be found in patients with lymphoproliferations that manifest as expansions of peripheral blood lymphocytes (PBL). If these PBL expansions exhibit clonality, they can be classified as chronic lymphocytic leukemia (CLL). METHODS/RESULTS: A patient who had two simultaneous, clonal lymphoproliferative disorders manifested as an unusual T-cell CLL in conjunction with systemic light chain amyloidosis is described. Gene rearrangement studies of the PBL of the patient showed clonal rearrangements of both the T-cell receptor beta (T beta) chain and the immunoglobulin genes. Additional immunologic and microscopic studies of the T-cells of the patient showed that they were large, agranular, CD4+ T-cells that also expressed the NK cell marker CD57. Cytogenetics disclosed an unusual karyotype in the PBL. CONCLUSIONS: The pathogenesis of this T-cell CLL and whether it truly represents a malignant disorder, as well as its relation to amyloidosis, is discussed.

Intracerebral involvement of Hodgkin's disease (HD) is rarely described, with only 42 cases in the literature. Since the outbreak of the acquired immune deficiency syndrome (AIDS) epidemic, there has been an increasing number of human immunodeficiency virus (HIV)-infected (HIV+) persons who have diffuse non-Hodgkin's lymphoma and, more recently, atypical aggressive HD. The authors report the case of a patient with a history of intravenous drug abuse (IVDA) and Stage IVB HD who, after a drug-induced clinical remission, had intracerebral mixed-cellularity HD. This appears to be the first report of intracerebral HD in a person who is HIV+.

Studies have shown telomerase activity to be present in some B-cell non-Hodgkin lymphomas (B-NHLs). However, no large studies have assayed telomerase activity in a systematic and quantitative manner. Furthermore, the relation between telomerase and proliferation suggested by in vitro studies has not been adequately tested in B-NHLs in vivo. This information is necessary to understand the relation between proliferation and telomerase and to predict the efficacy of antitelomerase drugs currently in development.Eighteen benign biopsies and 111 B-NHLs of varying types were classified according to the revised European-American classification of lymphoid neoplasms (REAL classification) and assayed for telomerase activity and proliferation index (PI).All B-NHLs contained telomerase activity except for low grade marginal zone B-cell lymphomas (MZBCLs) (96 of 111, 86%) (chi(2) 95.90, P0.001). Telomerase activity correlated with PI (r = 0.7536, r(2) = 0.5678, t = 10.51, P0.001) and showed a threshold whereby telomerase activity was not present below a PI of 9.2% (t = 4.875, P0.001).The level of telomerase activity fell within characteristic ranges and generally correlated with the clinical aggressiveness of each B-NHL category. Low grade MZBCLs of extranodal, nodal, and splenic types were unique among the categories of B-NHL in lacking or containing very little telomerase activity. The association between telomerase activity and PI is evidence that telomerase is controlled in vivo along with the cell cycle and is not constitutively active in B-NHL. These data provide evidence that antitelomerase drugs may be efficacious in most types of B-NHL.

Posttransplantation lymphoproliferative disorders (PT-LPDs) are a clinicopathologically heterogeneous group of lymphoid proliferations of varied clonal composition, the majority of which are associated with Epstein-Barr virus (EBV) infection. The clonal content and clonal relatedness of 24 separate PT-LPD lesions occurring synchronously in one organ in a single patient were investigated.Twenty-four separate PT-LPD lesions from the colon and mesentery of a 15-year-old male, developing 4 months after cardiac transplantation, were studied for clonality based on immunoglobulin heavy chain (IgH) gene rearrangements for the presence, clonality, and type of EBV infection and for the presence of c-myc, ras, and p53 gene alterations. Southern blot hybridization, polymerase chain reaction, and single strand conformation polymorphism assays were employed.All 24 lesions were histologically similar (polymorphic B-cell lymphomas) but exhibited varied clonality and were clonally distinct with respect to both IgH gene rearrangements and EBV infection. All lesions were infected with EBV type A. Structural alterations of oncogenes or tumor suppressor genes were not identified.Separate PT-LPD lesions occurring synchronously in a single organ or patient may be clonally distinct, suggesting that they represent multiple distinct primary lymphoid proliferations rather than metastatic disease as in conventional malignant lymphomas. This may explain partially the rapid development in some patients of a large PT-LPD tumor burden that may regress rapidly after reduction of immunosuppression.

Lymphocytes that display a phenotype of mature B-cells, T-cells, natural killer (NK) cells, or a combination of T-cells and NK cells can be found in patients with lymphoproliferations that manifest as expansions of peripheral blood lymphocytes (PBL). If these PBL expansions exhibit clonality, they can be classified as chronic lymphocytic leukemia (CLL).A patient who had two simultaneous, clonal lymphoproliferative disorders manifested as an unusual T-cell CLL in conjunction with systemic light chain amyloidosis is described. Gene rearrangement studies of the PBL of the patient showed clonal rearrangements of both the T-cell receptor beta (T beta) chain and the immunoglobulin genes. Additional immunologic and microscopic studies of the T-cells of the patient showed that they were large, agranular, CD4+ T-cells that also expressed the NK cell marker CD57. Cytogenetics disclosed an unusual karyotype in the PBL.The pathogenesis of this T-cell CLL and whether it truly represents a malignant disorder, as well as its relation to amyloidosis, is discussed.

Intracerebral involvement of Hodgkin's disease (HD) is rarely described, with only 42 cases in the literature. Since the outbreak of the acquired immune deficiency syndrome (AIDS) epidemic, there has been an increasing number of human immunodeficiency virus (HIV)-infected (HIV+) persons who have diffuse non-Hodgkin's lymphoma and, more recently, atypical aggressive HD. The authors report the case of a patient with a history of intravenous drug abuse (IVDA) and Stage IVB HD who, after a drug-induced clinical remission, had intracerebral mixed-cellularity HD. This appears to be the first report of intracerebral HD in a person who is HIV+.

Extracardiac rhabdomyomas are rare benign neoplasms that in the past have been divided by histologic criteria into adult and fetal types. In this series, 15 previously unpublished cases are presented and analyzed in combination with 51 acceptable cases from the literature. The adult type of rhabdomyoma occurs almost exclusively in the head and neck region (93% of all cases), particularly in the larynx and pharynx of adult males. The fetal type of rhabdomyoma may be subdivided on histologic grounds into myxoid and cellular variants. The fetal myxoid type usually occurs in the vulvovaginal region of middle aged women or in the postauricular region of male infants. The fetal cellular type has not been previously emphasized. This type tends to occur in the head and neck region of adult males. It may be mistaken for a sarcoma because of its high degree of cellularity. Local recurrence of a rhabdomyoma is rare and has only been occasionally reported in the adult type of rhabdomyoma. In no instance has a rhabdomyoma been shown to possess aggressive local growth or metastatic potential. Therefore, it is essential that these neoplasms be recognized histologically and that they be treated conservatively by local excision.

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

Sixty cases of orbital lymphoid neoplasms originally accessioned as malignant lymphomas were analyzed histopathologically and the follow-up data evaluated separately for each category as follows: inflammatory pseudo-tumor, 5; reactive lymphoid hyperplasia, 8; atypical lymphoid hyperplasia, 7; and malignant lymphocytic lymphoma (classified according to Rappaport), 40. Significant clinical differences were not observed among these patients, suggesting that the lesions must be distinguished by histologic rather than clinical criteria. Systematic application of the histologic criteria discussed here improved diagnostic accuracy and our ability to predict clinical outcome as substantiated by follow-up data. Two of 13 patients (15%) with benign pseudo-lymphomas, 2 of 7 patients (29%) with atypical lymphoid hyperplasia, 2 of 8 patients (25%) with well differentiated lymphocytic lymphomas, and 22 of 32 patients (68%) with less differentiated lymphocytic lymphomas either had or later developed systemic lymphomas. Thus, the degree of cytologic differentiation appears to be the single most important factor for determining the prognosis of patients with orbital lymphoid neoplasms.

The authors used E-rosette formation and OKT3 reactivity to determine the percent of T-cells in lymph nodes involved by B-cell non-Hodgkin's lymphomas (B-NHL) and by Hodgkin's disease (HD). The percent of helper and suppressor/cytotoxic T-cells was determined by reactivity with OKT4 and OKT8, respectively. T-cells were also analyzed for two signs of activation: acquisition of Ia antigens and loss of acid a-naphthyl acetate esterase (ANAE) activity. The results were compared with those of lymph nodes exhibiting benign lymphoid hyperplasia (BLH). The percentage of T-cells ranged from 50% to 82%, mean 63 +/- 13%, in 25 cases of BLH, and from 6% to 62%, mean 23 +/- 11%, in 51 cases of B-NHL. The OKT4/T8 ratio was 1.0 to 6.2, mean 3.4 +/- 2.2, in the cases of BLH, and 0.5 to 5.1, mean 2.4 +/- 1.3, in the cases of B-NHL. There was no obvious or significant correlation between the percent of T-cells or the OKT4/T8 ratio and the surface immunoglobulin isotype expressed by the neoplastic B-cells, the morphologic category of B-NHL, or the clinical stage of disease. Activated T-cells were less than or equal to 3% in the cases of BLH and B-NHL. Fifteen lymph nodes involved by HD contained 44% to 96%, mean 74%, E+ (T) cells. Five of these 15 cases contained a significant number of E-OKT3+ cells suggesting that E-rosette formation is not always a reliable T-cell marker in HD. Three other cases contained a large number of E+OKT3- cells. The OKT4/T8 ratio ranged from 0.4 to 21.7, mean 6.7 +/- 5.3, in these cases, representing the most significant T-cell subset imbalances in this series. Large numbers of Ia+E+ and/or E+ANAE- cells, presumably activated T-cells, were present in 7 of these 15 cases of HD. These studies demonstrate the wide variation in the percent of T-cells and in the T-cell subset distribution in lymph nodes exhibiting benign lymphoid hyperplasia and in lymph nodes involved by B-cell-derived non-Hodgkin's lymphomas and Hodgkin's disease.

A case of epithelial thymoma occurring synchronously with Philadelphia chromosome-positive chronic myelogenous leukemia and urinary bladder carcinoma in a 76-year-old man is described. Thymomas have been associated with numberous hematologic, collagen-vascular and autoimmune disease states, as well as with an increased incidence of nonthymic malignancy. Human thymoma-associated leukemia is, however, extremely unusual, despite the well-documented role of the thymus in leukemogenesis in experimental animals. No previous literature reports of thymoma associated with chronic myelogeneous leukemia were found. A review of long-term followup data of surviving thymoma patients is necessary to determine if an increased propensity to develop leukemia is present in present in patients with thymoma.

Pleomorphic reticulum cell sarcoma, a histologic variant of the histiocytic lymphomas, presented as an abdominal mass in a 52-year-old woman. Extensive amyloid deposition was present within the tumor mass and an M-component (IgG Lambda) was identified in the serum. Direct immunoperoxidase staining of tissue sections demonstrated the same monoclonal immunoglobulin to be present within the neoplastic cells, presumptive evidence of their ability to both synthesize and secrete immunoglobulin. The presence of amyloid within this patient was probably the direct result of the tissue deposition of this monoclonal immunoglobulin and may be related to the amyloidogenic nature of Lambda light chains. Immunoglobulin production is a specific property of the B lymphocyte series. Transforming B lymphocytes and their differentiating progeny are engaged in active immunoglobulin synthesis and thus may be distinguished from morphologically identical but functionally distinct cells. The demonstration of cytoplasmic monoclonal immunoglobulin within these "malignant reticulum cells" strongly supports the assertion that at least some "histiocytic lymphomas" are neoplastic analogues of transformed B lymphocytes, and are not derived from phagocytic histiocytes, as previously believed.

This study delineated the distribution of reactivity of malignant human lymphoid cells with monoclonal antibodies Leu 1 and OKT1, and correlated this expression with that of conventional lymphoid cell markers. The presence of Leu 1 on benign lymph nodal T-cells and its absence from benign lymph nodal B-cells was confirmed. Twenty-two T-cell neoplasms, expressing a variety of intrathymic and mature peripheral phenotypes, expressed Leu 1, but this expression was heterogeneous with respect to percent-positive cells and antigenic density, and appeared to correlate with stages of T-cell differentiation. This study demonstrated the expression of Leu 1 by 33 of 36 cases of B-CLL, by 10 of 15 cases of the closely allied small lymphocytic cell lymphoma, and by 9 of 29 follicular center-cell lymphomas. This included B-cell malignancies of each surface immunoglobulin isotype, and some cases associated with a monoclonal protein spike. Leu 1 was not expressed by myeloma plasma cells, and was absent from non-B, non-T acute lymphoblastic leukemia cells in each of 15 cases studied. Finally, Leu 1 and OKT1 were expressed in parallel, with respect to percent-positive cells and staining intensity, on benign and malignant T-cells, and on malignant B-cells, wherever studied. Possible explanations for this shared antigen are the existence of a minor Leu 1+ B-cell subset, a transformation-associated event, or glycosylation.

In the studies described here, 40 extranodal lymphoid tumors obtained from 38 patients were evaluated by cell-marker analysis and the results correlated with the light microscopic features. These infiltrates were investigated for the present composition of cells expressing Ia antigens, surface immunoglobulin (SIg), including kappa and lambda light chains, sheep erythrocyte (E) rosette formation, and acid a-naphthyl acetate esterase (ANAE) activity. Fifteen biopsy specimens consisted of variable proportions of benign T and polyclonal B cells; these 15 lesions had the histopathologic features of benign pseudolymphomas. The remaining biopsy specimens consisted almost entirely of B cells bearing monoclonal SIg (18 cases) or a great preponderance of T cells (five cases) or non-B, non-T (null) cells (two cases); these 25 lesions were classified histopathologically as malignant lymphomas. Thus, the extranodal lymphoid infiltrates were divisible, according to their cell-marker characteristics, into two categories: lesions that are immunologically polyclonal and lesions that are immunologically monoclonal B-cell proliferations or consist of a great preponderance of T or null cells. In each case, polyclonality correlated with benign cytomorphologic features and monoclonality correlated with malignant histopathology. Cell-marker analysis appears to represent an important adjunct to light microscopy in distinguishing histologically problematic benign pseudolymphomas from malignant lymphomas that arise in the extranodal tissues. Cell marker analysis will undoubtedly provide insights into the histogenesis, natural history, and biologic behavior of the extranodal lymphoid neoplasms not attainable using light microscopy alone.

In the studies described here, 40 extranodal lymphoid tumors obtained from 38 patients were evaluated by cell-marker analysis and the results correlated with the light microscopic features. These infiltrates were investigated for the present composition of cells expressing Ia antigens, surface immunoglobulin (SIg), including kappa and lambda light chains, sheep erythrocyte (E) rosette formation, and acid a-naphthyl acetate esterase (ANAE) activity. Fifteen biopsy specimens consisted of variable proportions of benign T and polyclonal B cells; these 15 lesions had the histopathologic features of benign pseudolymphomas. The remaining biopsy specimens consisted almost entirely of B cells bearing monoclonal SIg (18 cases) or a great preponderance of T cells (five cases) or non-B, non-T (null) cells (two cases); these 25 lesions were classified histopathologically as malignant lymphomas. Thus, the extranodal lymphoid infiltrates were divisible, according to their cell-marker characteristics, into two categories: lesions that are immunologically polyclonal and lesions that are immunologically monoclonal B-cell proliferations or consist of a great preponderance of T or null cells. In each case, polyclonality correlated with benign cytomorphologic features and monoclonality correlated with malignant histopathology. Cell-marker analysis appears to represent an important adjunct to light microscopy in distinguishing histologically problematic benign pseudolymphomas from malignant lymphomas that arise in the extranodal tissues. Cell marker analysis will undoubtedly provide insights into the histogenesis, natural history, and biologic behavior of the extranodal lymphoid neoplasms not attainable using light microscopy alone.

Pleomorphic reticulum cell sarcoma, a histologic variant of the histiocytic lymphomas, presented as an abdominal mass in a 52-year-old woman. Extensive amyloid deposition was present within the tumor mass and an M-component (IgG Lambda) was identified in the serum. Direct immunoperoxidase staining of tissue sections demonstrated the same monoclonal immunoglobulin to be present within the neoplastic cells, presumptive evidence of their ability to both synthesize and secrete immunoglobulin. The presence of amyloid within this patient was probably the direct result of the tissue deposition of this monoclonal immunoglobulin and may be related to the amyloidogenic nature of Lambda light chains. Immunoglobulin production is a specific property of the B lymphocyte series. Transforming B lymphocytes and their differentiating progeny are engaged in active immunoglobulin synthesis and thus may be distinguished from morphologically identical but functionally distinct cells. The demonstration of cytoplasmic monoclonal immunoglobulin within these "malignant reticulum cells" strongly supports the assertion that at least some "histiocytic lymphomas" are neoplastic analogues of transformed B lymphocytes, and are not derived from phagocytic histiocytes, as previously believed.

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

This study delineated the distribution of reactivity of malignant human lymphoid cells with monoclonal antibodies Leu 1 and OKT1, and correlated this expression with that of conventional lymphoid cell markers. The presence of Leu 1 on benign lymph nodal T-cells and its absence from benign lymph nodal B-cells was confirmed. Twenty-two T-cell neoplasms, expressing a variety of intrathymic and mature peripheral phenotypes, expressed Leu 1, but this expression was heterogeneous with respect to percent-positive cells and antigenic density, and appeared to correlate with stages of T-cell differentiation. This study demonstrated the expression of Leu 1 by 33 of 36 cases of B-CLL, by 10 of 15 cases of the closely allied small lymphocytic cell lymphoma, and by 9 of 29 follicular center-cell lymphomas. This included B-cell malignancies of each surface immunoglobulin isotype, and some cases associated with a monoclonal protein spike. Leu 1 was not expressed by myeloma plasma cells, and was absent from non-B, non-T acute lymphoblastic leukemia cells in each of 15 cases studied. Finally, Leu 1 and OKT1 were expressed in parallel, with respect to percent-positive cells and staining intensity, on benign and malignant T-cells, and on malignant B-cells, wherever studied. Possible explanations for this shared antigen are the existence of a minor Leu 1+ B-cell subset, a transformation-associated event, or glycosylation.

Sixty cases of orbital lymphoid neoplasms originally accessioned as malignant lymphomas were analyzed histopathologically and the follow-up data evaluated separately for each category as follows: inflammatory pseudo-tumor, 5; reactive lymphoid hyperplasia, 8; atypical lymphoid hyperplasia, 7; and malignant lymphocytic lymphoma (classified according to Rappaport), 40. Significant clinical differences were not observed among these patients, suggesting that the lesions must be distinguished by histologic rather than clinical criteria. Systematic application of the histologic criteria discussed here improved diagnostic accuracy and our ability to predict clinical outcome as substantiated by follow-up data. Two of 13 patients (15%) with benign pseudo-lymphomas, 2 of 7 patients (29%) with atypical lymphoid hyperplasia, 2 of 8 patients (25%) with well differentiated lymphocytic lymphomas, and 22 of 32 patients (68%) with less differentiated lymphocytic lymphomas either had or later developed systemic lymphomas. Thus, the degree of cytologic differentiation appears to be the single most important factor for determining the prognosis of patients with orbital lymphoid neoplasms.

A case of epithelial thymoma occurring synchronously with Philadelphia chromosome-positive chronic myelogenous leukemia and urinary bladder carcinoma in a 76-year-old man is described. Thymomas have been associated with numberous hematologic, collagen-vascular and autoimmune disease states, as well as with an increased incidence of nonthymic malignancy. Human thymoma-associated leukemia is, however, extremely unusual, despite the well-documented role of the thymus in leukemogenesis in experimental animals. No previous literature reports of thymoma associated with chronic myelogeneous leukemia were found. A review of long-term followup data of surviving thymoma patients is necessary to determine if an increased propensity to develop leukemia is present in present in patients with thymoma.

The authors describe a 63-year-old woman who developed a histologically distinctive malignant cutaneous neoplasm composed of large pleomorphic cells with abundant cytoplasm and multilobate, often clefted nuclei that occasionally contained small nucleoli. This neoplastic cell population metastasized to a regional lymph node already involved by a B-cell derived chronic lymphocytic leukemia expressing surface IgMk, BA-1, and OKT1. The large metastatic tumor cells lacked surface immunoglobulin, B-lymphocyte associated antigen BA-1, T-lymphocyte associated antigens OKT1 and OKT3, and the monocyte/macrophage markers lysozyme and alpha 1-antichymotrypsin. These tumor cells expressed HLA-DR antigens, adenosine triphosphatase (ATPase), OKT6, and contained S-100 protein, i.e., they expressed the phenotype peculiar to epidermal Langerhans cells. The typical clinical and histologic features of Histiocytosis X were absent. Thus, this case appears to represent a distinctive cutaneous neoplasm composed entirely of malignant cells of dendritic cell origin which, by immunophenotypic and histochemical analysis, appear to be related to epidermal Langerhans cells.