Successful transplantation of a human leukemia cell line into nude mice: conditions optimizing graft acceptance.

Conditions were determined for successful subcutaneous tumor development of MOLT-4 human T-cell leukemia cells in BALB/c nude (nu/nu) female mice. MOLT-4 cells injected alone at one site resulted in tumors in none of 21 mice, whereas MOLT-4 cells injected with X-irradiated human fibrosarcoma cells (HT-1080) at another site resulted in tumors in 5 of 21 mice. When X-irradiated three times with 200 rad over a 3-week period and then inoculated with MOLT-4 cells and X-irradiated HT-1080 cells, 19 of 25 mice developed tumors, which indicated that a combination of X-irradiation of the recipients and inoculation of an admixture of the leukemia cells with X-irradiated fibrosarcoma cells markedly increases tumor incidence. The cells growing in the tumors had the characteristics of MOLT-4, as assessed by marker studies and histology.

Use of the working formulation for non-Hodgkin's lymphoma in epidemiologic studies: agreement between reported diagnoses and a panel of experienced pathologists.

Independent review of slides of 668 cases of non-Hodgkin's lymphoma (NHL) by a panel of 4 experienced pathologists using the Working Formulation (WF) allowed determination of the agreement between reported diagnoses and panel review of slides. The panel agreed with the reported diagnosis of NHL in 93% of cases, but with the NHL subtype in only 55% of cases overall. The ability of the panelists to agree among themselves, however, was only slightly better than the panelists' agreement with the reported diagnosis (60% vs. 54%, respectively). Agreement of the panel with the reported subtype diagnosis varied from 14% to over 90%. The best agreement was with small lymphocytic lymphoma and follicular subtypes. Conclusions from this study are: 1) The WF functions well as common language for translation and comparison of diagnoses of subtypes of NHL. 2) Relative to time and cost involved, panel review using only light microscopy may not be useful in epidemiologic studies of NHL. 3) Small lymphocytic and follicular subtypes of NHL can be used more confidently in epidemiologic studies than can other subtypes whether the subtyping is done from abstracted reports or by panel review.

Chromosome abnormalities in malignant lymphoma in patients from Kurashiki: histological and immunophenotypic correlations.

Clonal chromosomal abnormalities were found in tumor tissue of 43 (84%) of 51 patients with non-Hodgkin's lymphoma (B-cell, 32; T-cell, 15) from an adult T-cell leukemia/lymphoma-nonendemic area in western mainland Japan. Four tumors were tetraploid, and the other 39 had a chromosome number in the diploid range. Trisomies 3, 5, 7, 18, and X, monosomy 13, and loss of an X in female and a Y in male were found in more than three patients each. Structural abnormalities in arms 1p, 1q, 2q, 3q, 13q, 14q, and 18q were found in eight or more patients each. Clustering of breaks occurred in 3q25-29 (ten patients, nine of whom with a B-cell tumor), 11q13 (five patients), dir dup(12)(q13-15----q21-24) (four patients), 14q32 (12 patients), and 18q21 (seven patients). The 14q32 translocations were all associated with B-cell tumors. t(8;14) was seen in a small noncleaved cell lymphoma, t(11;14)(q13;q32) in one follicular and three intermediately differentiated lymphocytic lymphomas, and t(14;18)(q32;q21) in two follicular lymphomas and one diffuse small cleaved cell tumor. The translocation partner of 14q could not be determined in the other four patients, three of whom had der(18)t(18;?)(q21;?). The seven 18q21 abnormalities, including a novel translocation t(2;18)(p11;q21.3), all occurred in B-cell tumors; even in the absence of t(14;18), they were closely associated with lymphomas of follicular center cell origin (six of seven).

Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients.

The lymphoproliferative processes that developed in five renal transplant recipients were studied in an attempt to characterize and classify them morphologically. Nine surgical specimens, hematological material on all patients, and autopsy specimens from three patients were available. Studies performed included: conventional histopathology; evaluation of cell markers (immunoglobulins and sheep erythrocyte, complement, and Fc receptors) and cytoplasmic immunoglobulins (peroxidase-antiperoxidase technique); ultrastructural examination; and karyotype analysis. The lymphoid lesions in our patients shared marked cytological polymorphism (small and large cells, of both follicular center and "medullary" type) and polyclonal B-cell features, which indicated a common reactive nonneoplastic origin. However, other features, such as morphological atypia of the immunoblasts, extensive necrosis, chromosomal aberrations, and an incipient monoclonal component suggested the development of lymphoma in some of these lesions. In contradistinction, the abundance of typical immunoblasts was a feature that seemed to correlate with the clinical activity of the disease rather than with the biological malignancy. The multiplicity of B-cell types and the presence of a follicular center cell component with diffuse distribution, as well as the extensive necrosis in the malignant forms, seem to differentiate morphologically the lymphoproliferative processes arising in transplant recipients from both the hyperplasias and the lymphomas developing in immunologically normal hosts. For the former, we propose the terms of "polymorphic diffuse B-cell hyperplasias" and "polymorphic B-cell lymphomas."

Clinical spectrum of lymphoproliferative disorders in renal transplant recipients and evidence for the role of Epstein-Barr virus.

Six renal transplant recipients with abnormal lymphoproliferative disorders were studied in an attempt to define their clinical features and the role of Epstein-Barr virus (EBV) in their pathogenesis. Patients were either teenage (three) or in the sixth decade (three). The younger patients presented an average of 3 months after transplantation with fever, sore throat, and lymphadenopathy; had been markedly immunosuppressed; frequently had preceding or concomitant cytomegalovirus infections; and two of three had a rapidly fatal course. The older patients presented an average of 5 years after transplantation while on maintenance immunosuppressive drugs; in two of three cases with an oropharyngeal tumor; and had a more indolent, but frequently fatal, clinical course. The most frequent sites of biopsy-proven involvement in these patients were lymph nodes (three), the oropharynx (three), liver (three), bone marrow (three), transplanted kidney (three), colon (two), and central nervous system (two). EBV-specific antibody titers including anti-viral capsid antigen IgG, anti-viral capsid antigen IgM, anti-early antigen, and anti-Epstein-Barr nuclear antigen were serially measured in all patients. Four patients demonstrated serological evidence of a primary (one) or reactivation (three) EBV infection. No patient had significant changes in anti-early antigen or anti-Epstein-Barr nuclear antigen titers. All three patients tested for oropharyngeal shedding of EBV were positive. A touch imprint of one tumor was stained for the presence of Epstein-Barr nuclear antigen, and a majority of cells were positive. EBV complementary RNA/DNA filter hybridization and/or viral DNA/DNA reassociation analysis performed on tumor biopsy specimens in five patients demonstrated multiple EBV genome equivalents per cell in all eight specimens tested. Clinical, pathological, serological, and molecular hybridization studies provide substantial evidence that EBV was the cause of these lymphoproliferative disorders occurring after renal transplantation. Impaired host defenses allow the EBV-transformed B-lymphocytes to escape normal control mechanisms. This impairment is invariable and influenced by many factors resulting in the observed spectrum of disease. Cytogenetic changes, however, may also be important.

Nonrandom chromosome abnormalities in lymphoma.

G-banded chromosomes were studied from involved lymph nodes or other tumor masses in 94 patients with malignant lymphoma. Clonal chromosome abnormalities were identified in 91 patients including all 81 B-lymphomas but only 6 of 9 T-lymphomas. Many recurring chromosome abnormalities were found. Most common numerical alterations involved gains of chromosomes 12 (19% of patients), 18 (13%), 7 (12%), and 21 (10%). Structural abnormalities, which were more frequent than numerical alterations, most commonly involved chromosome regions 14q (71% of patients), 18q (36%), 6q (31%), 1p (24%), and 8q (19%). Seven recurring translocations were identified, and all except one involved 14q32. The most frequent were t(14;18)(q32;q21) in 22 patients, t(8;14)(q24;q32) in 9 patients, and t(1;14)(q42;q32) in 3 patients. Deletions most frequently involved the long arm of chromosome 6 at band q21 (11 patients) or q23 (7 patients). The common recurring chromosome abnormalities were correlated with histology (International Working Formulation for Clinical Usage) and immunological phenotype. Four abnormalities were significantly associated with specific histologies. Eighteen (82%) patients with t(14;18)(q32;q21) were follicular. Similarly, 82% of patients with del(6)(q21) were large cell lymphomas. Lymphomas with trisomy 7 were either diffuse large cell or follicular, while patients with t(8;14)(q24;q32) were either diffuse large cell or small noncleaved cell. A significant association with immunological phenotype was seen for t(14;18) only. All patients were either B- or complement lymphomas, and the heavy chain(s) was more commonly gamma and less frequently delta mu than among the total B-lymphoma population. We conclude that essentially all lymphomas have cytogenetic abnormalities; further study is required to determine their significance. Particularly, it will be of interest to see if oncogenes are found in the regions of these chromosome abnormalities.

A systemic lymphoproliferative disorder with morphologic features of Castleman's disease: clinical findings and clinicopathologic correlations in 15 patients.

Fifteen patients (11 males, four females; median age 57) manifested a disease characterized by (1) the histopathologic features of Castleman's disease, plasma cell type, in lymph node biopsies; (2) predominantly lymphadenopathic disease, involving multiple, preferentially peripheral nodal groups; (3) varied manifestations of multisystemic involvement (such as constitutional symptoms; splenomegaly and hypergammaglobulinemia; elevated ESR, anemia, and thrombocytopenia; hepatomegaly and altered liver function tests (LFTs); signs of renal disease); and (4) idiopathic nature. Two main patterns of evolution were recognized: persistent, with sustained clinical manifestations, and episodic, with recurrent exacerbations and remissions. Seventy-three percent of patients had infectious complications, and 27% developed malignancies. Complete remissions were obtained occasionally with antineoplastic agents and with splenectomy but not with glucocorticosteroids alone. The median survival time is 30 months; 60% of patients have died. Median follow-up in the six surviving patients is 97+ months. A review of 50 cases in the literature revealed similar clinical and laboratory features. Despite some similarities with autoimmune diseases, the main features of this process seem to best fit a hyperplastic-dysplastic lymphoid disorder in a setting of immunoregulatory deficit.

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.

Alternating cycles of combination chemotherapy for patients with recurrent Hodgkin's disease following radiotherapy. A prospectively randomized study by the Cancer and Leukemia Group B.

A randomized clinical trial of combination chemotherapy for patients who relapsed following primary radiation therapy for Hodgkin's disease was conducted from 1975 to 1981 by the Cancer and Leukemia Group B (CALGB). One hundred thirteen patients were prospectively randomized to receive 12 cycles of either CVPP (CCNU, vinblastine, procarbazine, and prednisone), ABOS (bleomycin, vincristine [Oncovin; Lilly, Indianapolis], doxorubicin [Adriamycin, Adria Laboratories, Columbus, Ohio], and streptozotocin), or alternating cycles of CVPP and ABOS. The median length of observation for patients in this report is 4 years. Toxicities of the three treatment programs were primarily hematologic. Frequencies of complete response were 72% for CVPP, 70% for ABOS, and 82% for CVPP/ABOS (P = .37). Females and patients who had nodular sclerosing disease at initial diagnosis had significantly higher complete response rates. The 5-year disease-free survival for the complete responders was 55%; the 5-year overall survival was 60%. There were no significant differences among the treatments on disease-free survival (P = .78) or overall survival (P = .18). Age under 40 years was the only significant positive prognostic factor for disease-free survival (P = .095) and overall survival (P = .003). This study demonstrates no statistically significant advantage for alternating cycles of combination chemotherapy in affecting complete response frequency, disease-free survival, or overall survival as compared with therapy with CVPP or ABOS alone. However, the power to detect differences in these outcome parameters is somewhat limited by the sample sizes.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioimmunoblastic lymphadenopathy and related disorders: a retrospective look in search of definitions.

The recent report of an immunoblastic lymphadenopathy (IBL)-like T cell lymphoma has rekindled questions about the nature, reactive or neoplastic, of IBL, angioimmunoblastic lymphadenopathy (AIL), and lymphogranulomatosis X (LgX) and blurred the criteria for their diagnosis. We looked in the literature and our own data for a categorization of AIL (IBL, LgX) and related disorders, needed for future prospective studies. Specific differences in the original histologic definitions and discordant immunophenotypic data may warrant the separate consideration of AIL, IBL and LgX and their subdivision into predominantly T cell or B cell lesions. DNA hybridization and cytogenetic studies of the processes sharing histologic features of AIL (IBL, LgX) demonstrate a continuum of disorders from purely reactive to frankly malignant, which may be categorized as follows: (1) those without evidence of clonality by any of three parameters (immunophenotypic, immunogenotypic, and cytogenetic), for which only the term AIL (IBL, LgX) might be reserved; (2) those with evidence of clonality by all parameters, or AIL (IBL, LgX)-like lymphomas; and (3) those that, due to any discordance among the three parameters, do not fit into either of the above categories, and for which the term AIL (IBL, LgX)-like dysplasias is proposed. This intermediate group seems to be composed of unstable lymphoproliferative conditions, in which a predominant component of normal cells coexists with clonal population(s) that may either disappear with time or selectively proliferate and develop into frank lymphoma.

Chromosomal and immunophenotypic patterns in T cell acute lymphoblastic leukemia (T ALL) and lymphoblastic lymphoma (LBL).

In this study of 33 T cell acute lymphoblastic leukemia (T ALL) and 17 lymphoblastic lymphoma (LBL) patients, no relevant differences between the two groups were observed in clinical characteristics, response to therapy, and survival. We found translocations involving 14q11, 7q35, or 7p15, where T cell receptor alpha and delta, beta, and gamma subunit genes reside, in 20 patients (40%). Most of these translocations were seen with equal frequency in T ALL and LBL, indicating that, in a large proportion, the two diseases are different manifestations of the same lymphoblastic disorder. However, other translocations, such as t(9;17)(q34;q23), occurred only in LBL, perhaps pointing to the existence of subsets of LBLs that are distinct from T ALL. On the basis of karyotype, 50 patients could be classified into three groups: 20 patients with 14q11, 7q35, or 7p15 translocations (group A); 20 with other translocations, and/or deletions (group B); and 10 with normal diploidy (group C). There was no difference in survival time between any two of the three groups.

A novel translocation, t(9;17)(q34;q23), in aggressive childhood lymphoblastic lymphoma.

In a chromosome study of childhood lymphoblastic lymphoma, we found a novel translocation, t(9;17)(q34;q23), in three patients. They presented with mediastinal mass and no bone marrow involvement. Despite intensive chemotherapy, one patient had no response, the other two relapsed after a brief remission, and all progressed to death. The 9;17 translocation may have a clinical implication for lymphoblastic lymphoma patients in predicting a poor prognosis. Since, in addition to our cases, involvement of the 9q34 breakpoint, together with 2q33, 14q11, or 7q34, has been reported in the literature in four lymphoblastic lymphoma patients, a gene located in 9q34 and referred to as tcl-3 may participate in the genesis of the T cell malignancies carrying these translocations. Furthermore, as is the case in other lymphomas, the reciprocal breakpoint, 17q23, might be the site of a yet unidentified T cell function gene.

Angio-immunoblastic lymphadenopathy. Diagnosis and clinical course.

The clinical and pathologic findings in 24 patients with "angio-immunoblastic lymphadenopathy with dysproteinemia" (AILD) are presented. The patients' ages ranged from 44 to 80 years, with a median age of 68 years. The disease has an acute onset. In many respects, the clinical presentation is suggestive of malignant lymphoma. Generalized lymphadenopathy was always present. Hepatomegaly was found in 20 patients, splenomegaly in 17, constitutional symptoms in 20 and skin rashes in nine. Twenty patients had anemia, with positive Coombs' test in eight of 14 tested. Polyclonal hypergammaglobulinemia was found in 17 of 22 patients. Two patterns of evolution were recognizable: (1) long survival (24 to 67 months) without treatment or after the administration of intensive combination chemotherapy; and (2) rapid progression (one to 19 months) regardless of the treatment given. Sixteen patients died; postmortem examination in 10 cases showed the cause of death to be attributable to severe infection in eight patients, to renal disease in one and to cardiovascular disease in one. No evidence of malignant lymphoma was seen in any of these autopsies. Histologically, the disease is systemic, with specific lesions in the lymph nodes. The spleen, liver, bone marrow, skin and lung are also involved, but the changes are less characteristic than in the lymph nodes. In the patients in whom sequential biopsies were performed, a trend toward restoration of the nodal architecture was observed. AILD is a clinical-pathologic entity in a spectrum of yet to be defined immune reactions. The clinical, laboratory and pathologic manifestations of AILD are consistent with an autoimmune disorder, in which a deficiency of the T-cell regulatory functions probably predisposes to an abnormal proliferative and autoaggressive reaction of the B-cell system. Surgical staging procedures do not appear to be indicated. Intensive cytotoxic treatment may be hazardous in some patients, precipitating their death, but long survival after such therapy has been observed in others. Supportive therapy and small doses of steroids appear to be a safer therapeutic approach.

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.

T-cell-rich large B-cell lymphoma. A study of 30 cases, supporting its histologic heterogeneity and lack of clinical distinctiveness.

To determine whether correlations existed between morphologic and immunophenotypic findings and clinical characteristics, 30 cases of T-cell-rich large B-cell lymphomas (TBL) were evaluated by histopathology, immunostaining, and polymerase chain reaction on paraffin-embedded material. All were characterized by a polymorphic cell composition, including a variable mixture of small and large lymphoid cells and reactive cell. Most cases (87%) fitted into one of three main histologic types of non-Hodgkin's lymphoma (diffuse, mixed cell; diffuse, large cell; follicular and diffuse, mixed cell), and one group of eight cases had the prototypic features described by Ramsay et al. (17). All cases showed a component of large CD20(L26)+ MB2+ B cells in a predominant back-ground of reactive T cells (> 50% of the total lymphoid forms). Clonality was demonstrated by light chain restriction in 67% of cases and by rearrangement of the immunoglobulin heavy chain gene and bcl-2 gene in 64% and 28% of cases, respectively. The patients were predominantly men (70%), ages 18-83 years (median of 62.5), and were initially seen predominantly with nodal disease (and extranodal involvement in 20%) at advanced stages (III-IV: 77%). Treatment was mostly aggressive chemotherapy, and the outcomes were favorable (84% alive and well). These features are not distinctive as compared with those of typical large-cell lymphoma, nor did subgroups within the series (prototypic cases versus others; cases with less [< or = 70%] or more [> 70%] T-cell infiltration) significantly differ in clinical presentation or outcome. Thus, this study confirms that TBL, while useful as a diagnostic variant to be distinguished from both peripheral T-cell lymphoma and Hodgkin's disease, is a heterogeneous assortment of diverse histopathologic categories rather than a clinicopathologic entity. The term "T-cell rich" might, however, be usefully retained as a morphologic specification to be added to recognized histologic categories of lymphoma.

Mediastinal diffuse large-cell lymphoma with sclerosis. A clinicopathologic study of 60 cases.

A retrospective analysis was conducted of 60 cases of mediastinal diffuse large-cell lymphoma with sclerosis (MDLLS). The study group consisted of 43 females and 17 males. Eighty-five percent were 35 years of age or younger at time of initial diagnosis. Thirty are alive and well at least 1 year after diagnosis (median: 34.5 months), six are alive with disease (median: 13 months), 20 died of disseminated disease (median: 16.5 months), and four died of other causes. Complete autopsy was performed on eight of the patients who died of disease. The most frequently involved extrathoracic organs were lymph nodes, kidney, liver, pancreas, gastrointestinal tract, and ovary. Fifty-six cases were classified according to the Lukes-Collins scheme: 35 were follicular center cell, 13 immunoblastic T (IBT), seven immunoblastic B (IBB), one a composite of IBB and nodular sclerosing Hodgkin's disease; four cases were unclassifiable. Lymphoreticular origin was proven immunohistochemically in 53 cases, including the four unclassifiable examples and eight cases typed as B-cell tumors. Unfavorable prognostic factors were age less than 25 years at diagnosis, tumor outside the thoracic cavity at presentation, disease recurrence, and IBT or IBB tumor histology. Favorable signs were good response to initial therapy and marked tumor sclerosis. MDLLS is most often mistaken for malignant thymoma, seminoma, and Hodgkin's disease. Criteria helpful for the recognition of MDLLS are discussed.

Inflammatory pseudotumor of lymph nodes. A distinctive pattern of nodal reaction.

We report seven cases of a previously undescribed, distinctive pattern of nodal reaction resembling inflammatory pseudotumor (IPT) of the lung and other organs. The four men and three women in the series ranged in age from 16 to 62 years (median, 33). All patients presented with prominent lymphadenopathy. Constitutional symptoms were present in five patients, and laboratory abnormalities (especially elevated erythrocyte sedimentation rate, anemia, or hypergammaglobulinemia) in four. All patients recovered (two without treatment) and are alive and well 7-40 months (median, 23) after presentation. Histologically, the process mainly involved the connective tissue framework of the node (hilum, trabeculae, capsule), secondarily spreading into the lymphoid tissue proper and the perinodal soft tissue. It was characterized by a storiform growth pattern, marked vascularity with associated vascular lesions, and a polymorphous reactive cellular infiltrate in a collagen-rich stroma. The differential diagnosis included other reactive processes (Castleman's disease, drug lymphadenopathies), malignant lymphoma (Hodgkin's, peripheral T-cell), histiocytic or reticulum cell lymphomas, and malignant fibrous histiocytoma. Some features of this process appear to be the result of an "acute phase" response; others might be accounted for by a specific target of the initial insult or alterations in the regulation of the inflammatory response to it, rather than by any specific etiologic agent.

Littoral cell angioma. A novel splenic vascular lesion demonstrating histiocytic differentiation.

Seventeen cases of a novel type of vascular tumor of the spleen are described. The lesions, whose size ranges from minute foci to large nodules almost completely replacing the splenic tissue, are composed of anastomosing vascular channels resembling splenic sinus and have irregular lumina, often featuring papillary projections and cyst-like spaces; they are lined by tall endothelial cells that slough off into the vascular lumina and show hemophagocytosis. Atypical cells are absent and mitotic activity very low. In contrast to normal sinus endothelia, which express only FVIIIag, neoplastic cells express both endothelial (FVIII-AG, BMA 120) and histiocytic (KP1, lysozyme) antigens; occasionally S-100 protein is also present. The morphologic and immunohistochemical findings in this tumor reflect the dual differentiation potential of the reticuloendothelial cells lining the splenic sinus, justifying the term littoral cell angioma, and recognize a distinct entity that is different from other vascular lesions of the spleen, notably angiosarcoma. This distinction is all the more important because the clinical behaviour of this lesion is apparently benign.

Rosai-Dorfman disease of soft tissue.

Whereas Rosai-Dorfman disease (RDD) or sinus histiocytosis with massive lymphadenopathy is well described in lymph nodes and other organs, it is frequently not recognized in soft tissue. We studied the clinical and histologic features of 23 previously unreported soft tissue lesions from 17 patients (13 females, 4 males) who were 24 to 66 years of age (mean, 46 years). These lesions involved the extremities (12, 52%), trunk (6, 26%), head and neck (3, 13%), and the retroperitoneum (2, 9%). Associated lymph node involvement was present in four cases; most patients were asymptomatic. RDD of soft tissue had more subtle histologic features than its lymph node counterpart. Emperipolesis was less conspicuous and proliferating histiocytes were frequently spindled, associated with collagen deposition, and arranged in a vague storiform pattern with scattered lymphoplasmacytic aggregates. These features led to a variety of diagnoses, including benign inflammatory and fibrohistiocytic lesions (13 cases) as well as lymphoma and malignant fibrous histiocytoma (three cases). RDD was correctly diagnosed in only one case. Diagnosis was confirmed in 16 of 18 lesions by detection of S-100 protein and histiocytic markers KP1 (12 of 13) and lysozyme (eight of 11) in the characteristic histiocytes. Recognition that RDD of soft tissue occurs in an older patient population than does nodal RDD and that it mimics fibrous and inflammatory lesions of soft tissue is important.

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.