Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251.

PURPOSE: To define the activity and feasibility of brief-duration high-intensity chemotherapy for adults with small noncleaved, non-Hodgkin's lymphoma (SNC) and the L3 variant of acute lymphocytic leukemia (L3 ALL). PATIENTS AND METHODS: Seventy-five adults with either SNC or L3 ALL (median age, 44 years) were treated with an aggressive regimen that consisted of one cycle of cyclophosphamide and prednisone followed by cycles containing either ifosfamide or cyclophosphamide; high-dose methotrexate, vincristine, dexamethasone, and either doxorubicin or etoposide/cytarabine; or intrathecal triple therapy with prophylactic CNS irradiation. RESULTS: All 24 patients with L3 ALL and the 30 of 51 patients with SNC confirmed by central histologic review were included in this analysis. Forty-three of 54 patients achieved complete response (CR) (18 of 24 with ALL and 25 of 30 with SNC), and 28 are alive and in continuous CR with a median follow-up of 5.1 years. Hematologic toxicity was profound, and nonhematologic toxicity was notable, with 10 of 75 patients treated developing significant neurologic toxicity consisting of transverse myelitis in five patients, CNS toxicity in three, and severe peripheral neuropathy in two. All patients who did not achieve CR died of the disease, and all recurrences occurred within 16 months of the end of treatment. Responses and toxicities were similar in the patients with both lymphoma and leukemia. CONCLUSION: Aggressively delivered chemotherapy is potentially curative in as many as half of patients with SNC and the L3 ALL variant. This treatment regimen had considerable neurologic toxicity and has been modified.

Interferon-alpha activity in a case of severe autoimmune lymphoproliferative disease.

Autoimmune lymphoproliferative disease (ALD) is a rare familial disorder. Clinical and laboratory features of this disease include a generalized lymphadenopathy, splenomegaly, increased levels of circulating CD3+ with low levels of CD4+, CD8+ T-cells, and autoimmune phenomena, characteristics that the autoimmune lymphoproliferative syndrome (ALPS) have in common. Treatment usually consists of different supportive therapies. We report on the case of a young man affected by ALD who became resistant to steroids and was unresponsive to cyclosporine. Nevertheless, he was successfully treated with interferon (IFN)-alpha, resulting in a long-lasting, clinically complete remission.

Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive neoplasm characterized by the deregulated expression of cyclin D1 by t(11;14). The molecular mechanisms responsible for MCL's clinical behavior remain unclear. The authors have investigated the expression of p53, E2F-1, and the CDK inhibitors p27 and p21 in 110 MCLs, relating their expression to proliferative activity (Ki-67). For comparison, they have similarly analyzed low-grade (12 MALT, 16 CLL/SLL) and high-grade (19 DLCL) lymphomas. p53 was detected more frequently in large-cell MCL (l-MCL; 5 of 7) than in classical MCL (s-MCL; 13 of 103) and DLCL (8 of 19). In MCL and DLCL, the percentage of E2F-1+ nuclei was high, correlating with high Ki-67 expression. Most MCLs (91 of 112) and DLCLs (12 of 19) showed a loss of p27; MALT and CLL/SLL, however, were p27 positive. Reverse transcription-polymerase chain reaction and in vitro protein degradation assays demonstrated that MCLs have normal p27 mRNA expression but increased p27 protein degradation activity via the proteasome pathway. Correlation of MCL p53 and p27 expression with clinical data showed an association between reduced overall survival rates and the overexpression of p53 (P =.001), the loss of p27 (P =. 002), or both. Loss of p27 identified patients with a worse clinical outcome among p53 negative cases (P =.002). These findings demonstrated that MCL has a distinct cell cycle protein expression similar to that of high-grade lymphoma. The loss of p27 and the overexpression of p53 in MCL are prognostic markers that identify patients at high risk. The demonstration that low levels of p27 in MCL result from enhanced proteasome-mediated degradation should encourage additional clinical trials. (Blood. 2000;95:619-626) (Blood. 2000;95:619-626)

Detection of immunoglobulin kappa light chain rearrangements by polymerase chain reaction. An improved method for detecting clonal B-cell lymphoproliferative disorders.

The clonal determination of B-cell lymphoproliferative disorders by immunoglobulin heavy chain (IgH) rearrangement by polymerase chain reaction (PCR) is widely used. However, few attempts have been made to detect immunoglobulin kappa light chain (Igkappa) gene rearrangement using PCR. We studied 145 cases of B-cell neoplasms, along with 58 atypical and 18 reactive lymphoproliferative disorders, using newly designed degenerate oligoprimers recognizing the framework 3 (FR3kappa) and the joint (Jkappa) regions of the Igkappa gene. PCR products were analyzed on nondenaturing polyacrylamide gel (ndPAGE). Clonal B-cell determination was further investigated using IgH rearrangement and t(11:14) or t(14:18). By combining these methods, we detected either clonality or translocation in 117 of 137 cases (85%) in mature B-cell neoplasms. The additional analysis of Igkappa rearrangement improved sensitivity from 66% to 85%. To investigate whether the Ig gene configuration could be characterized using Igkappa PCR in B-cell neoplasms showing severe breakdown of genomic DNA, 18 selected cases were analyzed. Successful amplification was detected in 72% of the cases using either FR3/2-JH and/or FR3Jkappa oligoprimers. Finally, clonality was detected in 21 of 58 atypical B-cell proliferations, and among them, the atypical marginal cell (54%) and atypical large cell (50%) proliferations showed the highest frequency of clonal immunoglobulin gene products. We concluded that PCR/ndPAGE analysis of Igkappa is a sensitive, rapid, and efficient method for assessing clonality in conjunction with IgH and specific translocation analysis. This approach is particularly useful in the characterization of B-cell lymphoproliferative disorders in archival material with poor preservation of the genomic DNA.

Extramedullary plasmacytoma. A form of marginal zone cell lymphoma?

Extramedullary plasmacytoma (EMP), solitary plasmacytoma of bone, and multiple myeloma are related neoplasms, but EMP is clearly a distinct entity. Moreover, there are histologic and clinical similarities between EMP and marginal zone B-cell lymphomas (MZLs) displaying extensive plasma cell differentiation, suggesting a possible histogenetic relationship. The histologic and clinical features of 5 EMPs with extensive plasma cell differentiation were histologically reviewed for features of MZL. The previously diagnosed MZLs, mucosa-associated lymphoid tissue (MALT) type, of 2 patients also were reviewed. All patients were women aged 48 to 79 years. The EMPs originated in the parotid gland, lymph nodes, dura, or small bowel. The initial tumors diagnosed as MALT-type MZL were located in the lung and small bowel. All patients were treated with resection, with or without irradiation therapy. One patient also received systemic chemotherapy. All patients are alive with no evidence of disease. All tumors contained large numbers of plasma cells, constituting between 55% and 90% of the lymphoid cells. Centrocyte-like cells and monocytoid B cells each represented 0% to 25% of the infiltrate. Lymphoepithelial lesions were observed in all of the tumors in sites where epithelium was present. Reactive follicles were found in all of the tumors. EMPs may represent MZLs that have undergone an extensive degree of plasmacytic differentiation.

Pulmonary plasmacytomas: a clinicopathologic and immunohistochemical study of five cases.

Five cases of primary plasmacytoma of the lung are presented. The patients were four men and one woman between the ages of 50 and 79 years (mean age, 57 years; median age, 54 years). Two patients presented with symptoms related to their tumor; these included cough, dyspnea, and hemoptysis. In two patients, the tumor presented as a hilar mass, whereas in the remaining three patients, the tumor was located intraparenchymally. Clinically, only one patient had a reported monoclonal gammopathy (IgG, kappa). Because of the proximal location of these tumors, three patients underwent pneumonectomy; one other underwent a lobectomy, and one had a segmental resection. Grossly, the tumors ranged from 2.5 to 8 cm in maximum diameter (mean, 4.4 cm); they were either peribronchial or involved a major bronchus. Histologically, they were characterized by sheets of plasma cells that were well differentiated in two cases and moderately differentiated in three. Amyloid was present in two cases. In four tumors, there was a monoclonal population of lambda light chain-bearing plasma cells, whereas in one, the plasma cells expressed a monoclonal kappa light chain. The tumor cells predominantly expressed IgG heavy chains in two cases. Peribronchial and mediastinal lymph nodes were involved in three cases. Follow-up information ranged from 4 days to 262 months (average, 115 months; median, 36 months). Two patients survived more than 20 years before dying of non-tumor-related causes. Two patients died 28 months and 4 days after surgery with concurrent tumor in liver and mediastinal and para-aortic lymph nodes. Comparing the present cases and those reported in the literature, we noted that the patients herein presented are, on average, older than those published previously. Combining our cases with 14 other verifiable, previously published cases, the overall 2- and 5-year survivals of pulmonary plasmacytomas are 66% and 40%, respectively. Patients with pulmonary plasmacytomas can have a long-term survival, as evidenced by two of our patients who survived 20 or more years.

The morphologic and molecular genetic categories of posttransplantation lymphoproliferative disorders are clinically relevant.

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.

Recent progress in lymphoma classification.

In the Revised European-American list of lymphoid neoplasms recently proposed by the hematopathologists of the International Lymphoma Study Group, the disease entities currently recognized in the literature among the B-cell and T/natural killer (NK)-cell lymphomas and leukemias and variants of Hodgkin's disease are collected and defined. This proposal is here to stay. The main challenge for the future is to present the information in this list in a form that facilitates the understanding, learning, and teaching of these disorders. A meaningful classification for clinical use has already been built on the foundation provided by this list, through the agreement of an international group of clinicians. Newer data confirm the clinical validity of many categories in the list. Others suggest the need for additions or possible changes. To be discussed, among the latter, are: a need for a better definition of the new category of lymphoplasmacytic lymphoma; the variants of mantle-cell lymphoma and their correlation with genomic abnormalities; the need for a clarification of the relationship among the variants listed as "marginal zone B-cell" lymphomas; the subclassification of large B-cell lymphomas; and the coming of age of the NK-cell lymphomas.

Angiomyoid and follicular dendritic cell proliferative lesions in Castleman's disease of hyaline-vascular type: a study of 10 cases.

Castleman's disease of hyaline-vascular type (HV CD) may rarely be associated with a confusing variety of stromal cell overgrowths and neoplasms. We report here on the pathologic and clinical findings of 10 such cases. In addition to the usual complex histoimmunophenotype of the stroma of HV CD and some unusual features that mimicked neoplasms, we observed focal proliferations of angiomyoid (five cases) and follicular dendritic cell type (five cases). The former were nonneoplastic growths featuring compact tangles of spindle cells, exhibiting immunoreactivity for smooth muscle actin and interpreted as vessel-related pericytes and myoid cells. The latter were neoplastic growths of oval to spindle cells intermixed with lymphocytes; the tumor cells grew in long, intersecting bundles, featured various degree of atypia, and expressed the markers of follicular dendritic cells (CD21, CD35, KiM4p). The two types were clinically distinct. Four of five patients with angiomyoid proliferations were young women, who presented with an abdominal mass and were cured by surgery; that is, they had a clinical profile similar to that of patients with the stroma-rich variant of HV CD. The follicular dendritic cell proliferations were in older patients of either gender presenting with masses at various sites, recapitulating the profile of follicular dendritic cell tumors arising independently from HV CD; in three patients with long-term follow-up, recurrences or metastases developed at various intervals from the initial diagnosis (1 1/6, 3 1/2, and 11 years), and one patient died as a result. This study confirms the potential for, and the variety of, stromal cell proliferations in HV CD. Because their biologic behavior differs, correct identification of these various proliferative lesions is clinically important.

Large-cell variants of mantle cell lymphoma: cytologic characteristics and p53 anomalies may predict poor outcome.

Large-cell variants are uncommon in mantle cell lymphoma (MCL). Here we describe the pathologic and clinical findings in five patients with large-cell lymphoma related to MCL (L-MCL), and compare them to a group of classic small-cell MCL (s-MCL) cases. Histologically, the MC origin of the large cells was evinced by their association with a small mantle cell component in the same tissue, or their distribution in a classic mantle zone pattern, or their development in a patient with previous s-MCL. The large cells were either pleomorphic mantle cells (case 1) or transformed blast-like cells (case 2-5). The median nuclear diameter, median nuclear area and proliferation index of L-MCLs and s-MCLs, were statistically different. Immunophenotypic characterization of four specimens of L-MCL and 10 of s-MCLs with a large panel of antibodies showed the classic findings of MCL, i.e. the IgM+ D+/-, CD5+, CD10-, CD23- phenotype in all cases except two (one CD5- and one CD23+), and the association with a loose follicular dendritic cell network. Two of four L-MCLs and 5/10 s-MCLs demonstrated rearrangements of the bcl-1 gene by Southern blot or by polymerase chain reaction (PCR); 2/4 L-MCLs and 1/9 s-MCLs had p53 mutations on single-strand conformation polymorphism analysis; none of the 14 specimens showed rearrangement of bcl-2 by PCR or bcl-6 and c-myc by Southern blot. All patients with 'transformed' histology (versus 37% of all others) died of lymphoma; their survival (15-18 months; median 17) was much shorter than that of all the others (28-117+ months; median 43) (P=0.0035). All three patients with p53 anomalies, two of whom had tumours with transformed histology, died of their disease in a short time (15, 18 and 28 months). In contrast, the presence of bcl-1 rearrangements did not have prognostic implications. This study documents the existence of large-cell variants of MCL and the poor prognosis associated with the 'transformed' cytologic type and/or p53 abnormalities.

Molecular characterization of the t(2;5) (p23; q35) translocation in anaplastic large cell lymphoma (Ki-1) and Hodgkin's disease.

The precise cellular origin and the pathogenetic mechanism(s) leading to the neoplastic transformation of anaplastic large cell lymphoma (ALCL) and the Reed-Sternberg cell of Hodgkin's disease (HD) remains largely uncertain. Classical cytogenetic analysis has shown a unique translocation involving bands 2p23 and 5q35 bands in a variable number of ALCLs. It has been recently shown that the nucleophosmin/B23 (NPM) gene (5q35) and a novel anaplastic lymphoma kinase (ALK; 2p23) are the fused genes of t(2;5). To investigate the presence and the precise frequency of NPM-ALK gene products among ALCL and HD cases, a large and well-characterized panel of ALCL (n = 49) and HD (n = 72) cases was studied using multiple strategies including reverse transcriptase-polymerase chain reaction (RT-PCR), Southern blot analysis, and immunohistochemistry. Overall, 6 (3 T and 3 null) of 49 ALCL and 3 (2 nodular sclerosis and 1 mixed cellularity) of 72 HD showed the presence of NPM-ALK transcripts by RT-PCR. NPM-ALK gene rearrangements were detected in all RT-PCR, NPM-ALK-positive ALCL by Southern blot analysis. Furthermore, in all the available cases we were able to show the presence of ALK-related protein using a specific polyclonal antiserum recognizing the cytoplasmic domain of ALK by immunohistochemistry. Our data show that NPM-ALK gene transcripts are identified in a subpopulation of ALCL, almost exclusively in T or null cell in origin, and in rare cases of HD. These findings show that some HD may be closely related to ALCL, giving us new insights on the pathogenesis and possibly biologic evolution of HD.

Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas. Definitions, differential diagnosis, and epidemiology.

A workshop jointly sponsored by the University of Hong Kong and the Society for Hematopathology explored the definition, differential diagnosis, and epidemiology of angiocentric lymphomas presenting in the nose and other extranodal sites. The participants concluded that nasal T/natural killer (NK) cell lymphoma is a distinct clinicopathologic entity highly associated with Epstein-Barr virus (EBV). In situ hybridization for EBV an be very valuable in early diagnosis, especially if tissue is sparse. The cytologic spectrum is broad, ranging from small or medium-sized cells to large transformed cells. Histologic progression often occurs with time. Necrosis is nearly always present, and angioinvasion by tumor cells is seen in most cases. Nasal T/NK cell lymphoma has a characteristic immunophenotype: CD2-positive, CD56-positive, but usually negative for surface CD3. Cytoplasmic CD3 can be detected in paraffin sections. Clonal T-cell receptor gene rearrangement is not found. Tumors with an identical phenotype and genotype occur in other extranodal sites, most commonly in the skin, subcutis, and gastrointestinal tract, and should be referred to as nasal-type T/NK cell lymphomas. The differential diagnosis includes lymphomatoid granulomatosis, blastic or monomorphic NK cell lymphoma/leukemia, CD56-positive peripheral T-cell lymphoma, and enteropathy-associated T-cell lymphoma.

Hodgkin's disease of Waldeyer's ring. Clinical and histoimmunophenotypic findings and association with Epstein-Barr virus in 16 cases.

Waldeyer's ring is an uncommon, rarely reported primary site for Hodgkin's disease. We report a series of 16 such cases culled from the files of the Armed Forces Institute of Pathology and the National Cancer Institute. The patients' median age was 41 years (range, 14-74), and they presented with airway obstruction or unilateral tonsillar enlargement. The disease was localized to the Waldeyer's ring (stage I) in 46% of patients and extended to the cervical lymph nodes (stage II) in 39% and to the spleen (stage III) in 15%. Local radiation therapy, with or without chemotherapy, obtained a complete response in all but two patients. There was local recurrence in one patient and distant spread in three others. All patients for whom follow-up is available are alive without evidence of disease at 9 to 216 months (median, 20 months) except two who died of widespread Hodgkin's disease and two others who died of other causes. Histologically, eight cases were classified as mixed cellularity type (50%), four as nodular sclerosis (25%), and one as lymphocyte predominance, nodular (LPn; 6.3%); three others that showed interfollicular involvement were unclassified (18.7%). The Reed-Sternberg (RS) and atypical mononuclear cells in most cases of mixed cellularity and interfollicular types and all cases of nodular sclerosis had the classic immunophenotype (CD45-, CD20- and/or CD45RO-, CD15+ and/or CD30+). In the single case of LPn, they were of B-cell lineage (CD45+, CD20+, CD45RO-, CD15-, CD30-). In situ hybridization performed on routinely processed sections revealed Epstein-Barr virus (EBV) EBER1 mRNA in RS cells of eight of 12 cases studied (67%) only in mixed cellularity and nodular sclerosis, but not in LPn. We conclude that, however rarely, Hodgkin's disease of typical morphology and immunophenotype can originate in Waldeyer's ring. The incidence of EBV detection in the RS cells in our study is greater than that usually seen in nodal Hodgkin's disease in the United States. The greater prevalence of EBV-related Hodgkin's disease at this site is probably a reflection of the fact that the Waldeyer's ring is a reservoir for EBV.

Dilantin-associated lymphadenopathy. Spectrum of histopathologic patterns.

The association of Dilantin (hydantoin) therapy and lymphadenopathy in the form of "pseudolymphoma" or malignant lymphoma has been reported primarily in the clinical literature in single case reports or small series, most of which contain very few pathologic details. We studied a series of 25 lymph node lesions collected at the Armed Forces Institute of Pathology from 1965 to 1991 that were suspected to be related to intake of the antiseizure medication Dilantin. Each case had been coded by the Environmental and Toxicology Department according to the so-called "operational degrees of certainty," which gives the possibility that a pathologic change is the result of a drug. Of the 25 cases, six were coded as probable, 17 as possible, and two as coincidental. The male:female ratio was 11:14, and patient ages ranged from 24 to 81 years (median, 53 years). Documented lymphadenopathy developed 1 week to 30 years (median, 5 years) after the start of Dilantin. The histologic features were reviewed in 25 of 25 cases, and the immunophenotypic data was available in 18 of 25. Fifteen of 25 cases showed a benign histology, which we primarily classified according to the presence or absence of immunoblastic hyperplasia. Seven cases were non-Hodgkin's lymphoma, and three were Hodgkin's disease. In two of five cases for which sequential biopsies were available for review, there was progression from paracortical hyperplasia to malignant lymphoma. Our report describes the clinicopathologic features of 25 cases of Dilantin-associated lymphadenopathy and confirms the heterogeneity and nonspecificity of these histologic patterns.

Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders.

The posttransplantation lymphoproliferative disorders (PT-LPDs) are a morphologically heterogeneous group of Epstein-Barr virus (EBV)-driven lymphoid proliferations of varying clonal composition. Some PT-LPDs regress after a reduction in immunosuppression, while others progress in spite of aggressive therapy. Previously defined morphologic categories do not correlate with clonality, and neither morphology nor clonality has reliably predicted the clinical behavior of PT-LPDs. We investigated 28 PT-LPD lesions occurring in 22 patients for activating alterations involving the bcl-1, bcl-2, c-myc, and H-, K- and N-ras proto-oncogenes and for mutations involving the p53 tumor suppressor gene. We correlated the results of these studies with the morphology of the lesions, their clonality based on Ig heavy and light chain gene rearrangement analysis, and the presence and clonality of EBV infection. We found that the PT-LPDs are divisible into three distinct categories as follows: (1) plasmacytic hyperplasia: most commonly arise in the oropharynx or lymph nodes, are nearly always polyclonal, usually contain multiple EBV infection events or only a minor cell population infected by a single form of EBV, and lack oncogene and tumor suppressor gene alterations; (2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma: may arise in lymph nodes or various extranodal sites, are nearly always monoclonal, usually contain a single form of EBV, and lack oncogene and tumor suppressor gene alterations; and (3) immunoblastic lymphoma or multiple myeloma: present with widely disseminated disease, are monoclonal, contain a single form of EBV, and contain alterations of one or more oncogene or tumor suppressor genes (N-ras gene codon 61 point mutation, p53 gene mutation, or c-myc gene rearrangement). The PT-LPDs are divisible into three categories exhibiting distinct morphologic and molecular genetic characteristics. Alterations involving the N-ras and c-myc proto-oncogenes and the p53 tumor suppressor gene may play an important role in the development and/or progression of the PT-LPDs.

Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis.

Similarities have been noted in the histologic patterns of lymphomatoid granulomatosis and Epstein-Barr virus associated lymphoproliferative disease involving the lung. Epstein-Barr virus has also been identified by polymerase chain reaction in most cases of lymphomatoid granulomatosis; however, the precise cellular localization of Epstein-Barr virus sequences has not been extensively studied. We analyzed 10 cases of lymphomatoid granulomatosis involving the lung by immunohistochemistry and combined immunohistochemistry with in situ hybridization for Epstein-Barr virus, CD20, and CD45RO. All cases were selected from the files of the Armed Forces Institute of Pathology and met the clinical and histologic criteria for the diagnosis of lymphomatoid granulomatosis, grades 1 through 3. In all 10 cases, immunohistochemistry showed that most of the cells--small to medium-sized lymphocytes--were T cells (CD45RO+); however, a much smaller population of medium-sized to large atypical cells were B cells (CD20+). In each case, combined immunohistochemistry and in situ hybridization confirmed the presence of Epstein-Barr virus sequences within B (CD20+) cells and the absence of Epstein-Barr within T-cells (CD45RO+). Polymerase chain reaction analysis for immunoglobulin heavy-chain gene rearrangement identified a monoclonal pattern in six of nine cases tested, whereas analysis for T-cell receptor gamma-chain gene rearrangements was negative in three cases tested. On the basis of these findings, we hypothesize that most cases of lymphomatoid granulomatosis involving the lung represent a proliferation of Epstein-Barr virus infected B-cells with a prominent T-cell reaction and vasculitis, distinguishing these cases from angiocentric "T-cell lymphomas" in other sites, such as the head and neck.

Prognostic factors for therapeutic outcome of diffuse small non-cleaved cell lymphoma in adults.

Most reports of prognosis and therapy in diffuse small non-cleaved cell lymphoma (DSNCL), an aggressive high-grade non-Hodgkin's lymphoma (NHL) which appears to be of two histopathologic subtypes, have included predominantly a pediatric population and very few adults. We studied 20 newly diagnosed, previously untreated adults with DSNCL. Three patients had Ann Arbor Stage I disease, five Stage II, and 12 Stage IV. Bone marrow involvement was present in seven of 20 (35%) patients; no patient had central nervous system involvement at diagnosis. Clonal chromosomal abnormalities were found on cytogenetic analysis of all 12 cases studied. Ten patients had specific recurring translocations, including t(8;14) (q23;q32) (five patients), t(14;18) (q32;q21) (four patients), and t(2;8) (p12;q24) (one patient). Induction chemotherapy with the COMP regimen (cyclophosphamide, vincristine, methotrexate, and prednisone) or a variant schedule of the same drugs resulted in complete remission for 13 patients (65%), and partial remission for 5 patients (25%). Clinical characteristics predictive of a favorable response to induction therapy included Stage I or II disease, a normal lactic dehydrogenase (LDH), and performance status (PS) of 0 or 1. Remission duration ranged from two to 125+ (median 37+) months. Survival ranged from one to 126+ (median 23) months; ten patients (50%) remain alive, nine with no active disease. Factors predictive of longer survival included achievement of a complete remission with induction therapy, a normal LDH, and PS 0 or 1. As in children with DSNCL, long-term disease-free survival may be achieved in adults with combination chemotherapy.