Long-term survival after histologic transformation of low-grade follicular lymphoma.

PURPOSE: To describe the course of patients following histologic transformation (HT) from low-grade follicular lymphoma to intermediate- or high-grade non-Hodgkin's lymphoma. PATIENTS AND METHODS: Patients were identified from data bases in the Division of Oncology and the Department of Surgical Pathology. HT was defined as the conversion of a follicular small cleaved-cell or follicular mixed small cleaved-cell and large-cell lymphoma to a diffuse large-cell, diffuse mixed small cleaved-cell and large-cell or any high-grade lymphoma. RESULTS: We analyzed the clinical course of 74 low-grade lymphoma patients with histologically proven transformation occurring from 1965 to 1988. The median time from diagnosis to HT was 66 months, and the median age at HT was 58 years. The median duration of survival after transformation was 22 months. Anatomic extent of disease at HT (limited v extensive, P = .01), prior chemotherapy (none v any, P = .01), and response to therapy (complete v partial or none, P = .005) at time of HT were identified as significant predictors of survival after HT in backward-selection Cox regression analysis. Thirty patients attained a complete response to therapy at HT. They had a median survival duration of 81 months after HT. CONCLUSION: A subset of patients with HT from low-grade follicular lymphoma to intermediate- or high-grade lymphoma enjoys relatively long-term survival. Patients with limited disease and no previous exposure to chemotherapy have the most favorable prognosis.

Pathologic features of nodular lymphocyte predominance Hodgkin's disease in extranodal sites.

We describe the gross and histologic features of nodular lymphocyte predominance Hodgkin's disease (NLPHD) occurring in extranodal sites. Fifty-one specimens of NLPHD from 16 patients were studied. The sites of involvement were the spleen, liver, tonsil, salivary glands, skin, colon, soft tissue, and bone marrow, and the morphologic features were similar to those described in node-based NLPHD, including characteristic lymphocytic and/or histiocytic (L&H) cells that were easily identified in a background of a nodular proliferation of small lymphocytes and histiocytes. In the spleen, the normal architecture was generally preserved, and the tumor was found predominantly in the white pulp; the red pulp was rarely involved. In the liver, the tumor involved both the portal and parenchymal areas. In the tonsil, the lympohproliferation closely resembled the typical appearance of NLPHD in a lymph node. In all specimens with materials available for immunohistochemical studies, there were demonstrable L&H cells with an immunophenotype similar to node-based NLPHD, that is, CD45-positive, CD20-positive, and CD15-negative. The unique morphologic and immunologic characteristics of NLPHD are preserved in extranodal sites and allow its distinction from classic Hodgkin's disease and other lymphoproliferative malignancies that may occur in extranodal sites.

Malignant histiocytic neoplasms of the small intestine.

Immunologic studies have demonstrated that the vast majority of hematolymphoid neoplasms previously designated as "histiocytic" are lymphoid in origin. Consequently, malignancies of macrophage lineage are considered rare by most authors; indeed, their existence is doubted by some. Herein we report two cases of malignant histiocytic neoplasms (malignancies of macrophage lineage) of the small intestine. Both patients presented in the 7th decade with symptoms related to an abdominal mass. The polypoid tumors protruded into the intestinal lumen, extended through the entire thickness of the bowel wall, and involved regional lymph nodes. Microscopically, sheets of large pleomorphic histiocytic cells infiltrated around crypts and were associated with an admixture of bizarre giant cells and inflammatory cells. Mitotic figures were easily found. Ultrastructurally, the cells lacked desmosomes and had indented or kidney-shaped nuclei and cytoplasm containing mostly lysosomes and dense lipid droplets. In both cases, paraffin section immunohistochemistry revealed reactivity of tumor cells for CD45RB (LCA), CD45RO (A6), CD68 (KP1), CD15 (LeuM1), and lysozyme. Frozen section immunohistochemistry performed in one case further supported the macrophage phenotype. Southern blot studies of this case did not reveal immunoglobulin or T-cell receptor beta chain gene rearrangements. One patient initially treated by surgery only died of disease 3 years after diagnosis. The second patient is alive and disease-free 2 years following postoperative combination chemotherapy. The diagnosis of malignant histiocytic neoplasms requires the use of a panel of immunohistochemical markers and may be supported by electron-microscopic studies.

Floral variant of follicular lymphoma. Immunological and molecular studies support a neoplastic process.

In recent reports of the so-called "floral variant" of follicular lymphoma, an unusual variant of follicular lymphoma mimicking progressive transformation of germinal centers, questions have been raised regarding whether this process represents a malignant lymphoma. We studied 19 examples of the floral variant of follicular lymphoma and report our light microscopic, immunohistochemical, and molecular diagnostic findings. Morphologic changes consisted of effacement of normal lymph node architecture by follicles composed of atypical lymphocytes. The follicles were surrounded by prominent mantle zones that invaginated irregularly into the follicle centers, often imparting a "floral" appearance. Sufficient material was available for immunophenotypic or genotypic studies in 15 biopsies. Twelve of 15 cases studied by immunohistochemistry demonstrated phenotypes supporting a diagnosis of lymphoma. Five demonstrated light-chain restriction; one was an immunoglobulin-negative B-cell neoplasm; and six, in which only formalin-fixed, paraffin-embedded tissue was available, demonstrated overexpression of the bcl-2 protein. Southern blot analysis revealed evidence of clonal immunoglobulin heavy-chain gene rearrangement in all five cases tested. Overall, 12 of the 15 biopsies studied with these techniques showed immunologic or genotypic support for malignant lymphoma. The results of this study demonstrate that the floral variant of follicular lymphoma does indeed represent a malignant lymphoma.

Primary low-grade endometrial B-cell lymphoma.

We describe three cases of primary low-grade B-cell lymphoma of the endometrium and contrast the histological, immunohistochemical, and molecular features with two examples of benign endometrial lymphoid infiltrates. The first case was an incidental finding in a curettage specimen, confirmed on a subsequent hysterectomy. The other two cases of lymphoma were incidental findings on hysterectomy procedures performed for prolapse and cervical dysplasia, respectively. All three lymphomas occurred in patients in their sixties; none formed gross tumors. Histologic examination revealed lymphoid nodules adjacent to endometrial glands. The lymphoid cells showed mild nuclear enlargement and slight irregularities of the nuclear contour. None of the three patients had evidence of disease outside the endometrium by physical examination, bone marrow biopsy, or sampling of pelvic lymph nodes. Immunohistochemistry demonstrated a B-cell phenotype of the lymphoid cells (CD20 positive, CD79a positive) with aberrant coexpression of the T-cell-associated marker CD43. Polymerase chain reaction (PCR) amplification of the VDJ region of the immunoglobulin heavy-chain was performed on DNA isolated from paraffin sections. These studies demonstrated a clonal proliferation of B-lymphocytes in two cases. In the third case, a faint band was found superimposed on a background smear, suggesting the presence of a B-cell clone. In contrast, the two examples of histologically benign lymphoid aggregates of the endometrium consisted predominantly of T cells with rare B-lymphocytes; there was no evidence of coexpression of CD43 by B-cells. The PCR amplification from the benign lymphoid aggregates did not support a clonal process. Primary lymphoid neoplasms of the endometrium are rare, and all cases described so far have been high-stage, high-grade neoplasms. To our knowledge, this is the first report of primary low-grade B-cell lymphoma of the endometrium, presumably arising from endometrial lymphoid tissue.

Hodgkin's disease and lymphoproliferations resembling Hodgkin's disease in patients receiving long-term low-dose methotrexate therapy.

Recently, it has been shown that patients with rheumatologic diseases who are treated with methotrexate can develop immunosuppression-associated lymphoproliferative disorders. Although a variety of lymphoproliferations have been described in the setting of methotrexate therapy, only rare cases of Hodgkin's disease (HD) have been reported. In this study, we provide a more complete characterization of the spectrum of lymphoproliferations that resemble HD or show features diagnostic of HD that occur in patients receiving long-term low-dose methotrexate therapy. Eight patients were receiving methotrexate for various disorders. Four cases were considered to represent lymphoproliferations resembling HD; the other four cases were diagnosed as HD because they showed diagnostic morphologic and immunophenotypic features. All three patients with lymphoproliferations resembling HD on whom follow-up was available experienced tumor regression with methotrexate withdrawal or with methotrexate withdrawal and steroids; none of these three patients required further therapy. All three patients with HD on whom follow-up was available are alive and free of disease following chemotherapy or radiation therapy. In two of these patients, the tumor persisted or progressed despite discontinuation of methotrexate with observation; the third patient received chemotherapy at the same time methotrexate was stopped. Our findings indicate that a spectrum of lymphoproliferations resembling HD or diagnostic of HD can occur in patients receiving long-term low-dose methotrexate therapy. Recognition of these lymphoproliferative disorders is clinically important because a subset of these neoplasms will completely resolve with discontinuation of methotrexate, thereby obviating the need for chemotherapy or radiation therapy.

Detection of Epstein-Barr virus in cardiac biopsies of heart transplant patients with lymphoproliferative disorders.

We investigated whether in situ hybridization for EBV RNA on routine cardiac biopsies could be used as a predictive test for the development of posttransplant lymphoproliferative disorder (PTLD) in cardiac transplant recipients. We examined the sensitivity of the test by determining the frequency of EBV-positive cells in cardiac biopsy specimens from patients with a known history of PTLD. Biopsy specimens obtained during routine monitoring for rejection before or shortly after the diagnosis of PTLD from 10 pediatric heart transplant patients were examined. Four of 74 specimens (5.4%) demonstrated EBV-positive lymphocytes in the cardiac biopsy rejection infiltrates. The four positive specimens were obtained from 3 different patients, all before the diagnosis of PTLD. Given the low number of cardiac biopsy specimens with EBV-positive lymphocytes, as well as the low incidence of PTLD in cardiac transplant patients, we conclude that a routine screening of all cardiac biopsy specimens using in situ hybridization for EBV with the intention of predicting PTLD is not warranted. However, in situ hybridization for EBV might be used in selected cases, such as those in which the transplant patient does not respond to immunosuppressive therapy for rejection. In these patients, the presence of EBV-positive lymphocytes in biopsy specimens initially interpreted as showing rejection might instead raise the suspicion of incipient PTLD.

Mixed gangliocytoma-adenoma: a distinct neuroendocrine tumor of the pituitary fossa.

A mixed gangliocytoma-adenoma occurring in the pituitary fossa of a patient who presented with acromegaly, galactorrhea, and headaches is described. Immunohistochemical studies demonstrated the gangliocytic portion of the tumor to be composed nearly entirely of ganglion cells enmeshed in their neuritic processes and disclosed focal presence of growth hormone and prolactin-secreting cells in the adenoma. Ultrastructurally, some of the larger ganglion cells contained (and were often filled with) zebra-like bodies, while the adenoma was shown to be sparsely granulated with numerous fibrous bodies. These findings support the term of mixed gangliocytoma-adenoma for these rare intrasellar tumors and provide additional support for their nature as independent neuroendocrine units.

Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein-Barr virus and other features associated with immunosuppression.

We recently reported two cases of reversible Epstein-Barr virus (EBV)-associated lymphomas in patients undergoing methotrexate therapy for rheumatic disease. The current study was undertaken to investigate how frequently lymphoid neoplasms in patients with rheumatic disease show features of lymphoproliferations occurring in immunocompromised patients. Eighteen patients (including the two previously reported patients) with rheumatoid arthritis or dermatomyositis who developed lymphoproliferative lesions and on whom detailed clinical information was available were studied. As a group these patients developed a spectrum of lymphoproliferative lesions; however, a subset of patients developed neoplasms with features associated with immunosuppression. The neoplasms occurred in extranodal sites in 10 (56%) patients, showed a diffuse large-cell histology in nine (50%) patients, and contained EBV (EBER1) transcripts and EBV latent membrane protein in six (33%) patients. In three (17%) patients the neoplasms showed the entire constellation of features typical of immunosuppression-associated lymphoproliferations, including extranodal location, large-cell or polymorphous histology, geographic areas of necrosis, and the presence of EBV. These three patients were receiving both steroids and methotrexate at the time they developed their neoplasms. The findings of this study support the hypothesis that a subset of lymphoid neoplasms in rheumatic patients occurs in an immunocompromised setting and suggest that therapeutic immunosuppression may contribute, at least in part, to the development of these lymphoid neoplasms.

Epstein-Barr virus-associated natural killer-large granular lymphocyte leukemia.

We describe the first case of an Epstein-Barr virus (EBV)-associated natural killer-large granular lymphocyte (NK-LGL) leukemia in the United States to the best of our knowledge. A 29-year-old woman of Japanese descent developed EBV infection after a blood transfusion as indicated by a rise in serum antibody titers. Peripheral blood and bone marrow aspirate smears demonstrated increased LGLs. Flow cytometry showed that these cells expressed NK-associated surface antigens. Cytogenetic analysis of the bone marrow aspirate showed two distinct but related clones with multiple copies of a modified 7 marker chromosome. Death followed colonic perforation. Findings at necropsy included bone marrow lymphocytosis and erythrophagocytosis, a mononucleosis-like lymphadenitis, atypical hepatitis with a mixed, predominantly T-cell infiltrate, interstitial pneumonitis, and multiorgan system vasculitis with perforation of the transverse colon. Epstein-Barr virus transcripts were identified in lymphocytes infiltrating liver and peripheral nerve by in situ hybridization. In addition, Southern blot analyses showed monoclonal bands superimposed on oligoclonal ladders of EBV termini in liver and lymph node. The identical episomal form of EBV was found in the bone marrow, lymph node, and liver. No immunoglobulin (Ig), T-cell receptor beta, or T-cell receptor gamma chain gene rearrangements were identified. These studies support the hypothesis that the LGL population was a neoplastic EBV-related clonal proliferation of NK cells.

Frequent presence of the Epstein-Barr virus in inflammatory pseudotumor.

Inflammatory pseudotumor is a presumably nonneoplastic, hematopoietic, and spindled fibrous proliferation that may occur at a variety of anatomic sites. The origin of these proliferations is generally unknown. To evaluate the role of the Epstein-Barr virus (EBV) in inflammatory pseudotumor, 18 specimens from 17 patients were studied by in situ hybridization for EBV ribonucleic acid (RNA), and the morphological and immunologic characteristics of the infected cells were evaluated. These specimens included 10 lymph nodes, six splenic masses, and two hepatic masses. Overall, EBV RNA was detected in 41.2% (seven of 18) of the cases. These included two of 10 (20%) lymph nodes, four of six (66.7%) splenic pseudotumors, and one of two (50%) hepatic lesions. The degree of EBV infection was significantly greater within the tumors in comparison with the surrounding, uninvolved tissue. Two morphologically different EBV-positive cell types, spindled and round cells, were evident, and the infected cell type differed significantly when the nodal and extranodal cases were compared. All of the positive extranodal cases shown, numerous EBV-positive spindled cells, whereas no positive spindle cells (only positive round cells, morphologically consistent with lymphocytes) were noted in the two EBV-positive lymph node pseudotumors. Double-labeling immunohistochemical and in situ hybridization studies in some cases identified rare EBV-positive B cells and rare EBV positive T cells in four and three cases, respectively. Most EBV-positive cells in all cases failed to immunoreact with any B- or T-cell markers. Three of five cases studied, however, did show a subpopulation of smooth muscle actin/EBV-positive spindled cells, five of seven cases showed vimentin/EBV-positive spindled cells, and one of four cases had EBV-positive spindled cells that immunoreacted as follicular dendritic cells. These results suggest that EBV plays a role in a significant number of cases of inflammatory pseudotumor with differences in the incidence of EBV infection and the cell type (spindled vs round cell) infected when extranodal and nodal cases are compared, suggesting a difference in pathogenesis. The cell type infected in extranodal cases seemed to be of mesenchymal origin but could not be clearly defined.

Extranodal head and neck lymphomas in Guatemala: high frequency of Epstein-Barr virus-associated sinonasal lymphomas.

Sinonasal lymphomas of T cell or natural killer cell (T/NK cell) phenotype represent a subset of extranodal head and neck lymphomas. T/NK cell sinonasal lymphomas have been described in diverse geographic settings, including China, Japan, Peru, Northern Europe, and North America. The frequency of these lymphomas is highly dependent on the geographic location in which they occur, their incidence being low in Europe and North America and relatively high in Asian countries and in Peru. Regardless of their geographic location, they are typically associated with the Epstein-Barr virus (EBV). Few studies have addressed the relative frequency of sinonasal lymphoma within the group of extranodal head and neck lymphomas. We investigated the anatomic distribution, immunophenotypical profile, and EBV status of 33 cases of extranodal head and neck lymphoma from patients in Guatemala. The anatomic distribution of these lymphomas is similar to that seen in Asian countries: 17 (52%) in the sinonasal area, five (15%) in the palate, and 11 (33%) in other locations. Fifteen (88%) of the 17 sinonasal lymphomas showed a T or null cell phenotype with a strong association with EBV by in situ hybridization. Most Guatemalan patients with these lymphomas were of Mayan descent. In Guatemala, the relative frequency of sinonasal lymphomas within the group of head and neck lymphomas is significantly higher than that reported for Western countries. In addition, the relative frequency of T/NK versus B cell sinonasal lymphomas is higher than that described in North America and similar to that observed in Asian countries and Peru.

Enhanced staining for Leu M1 (CD15) in Hodgkin's disease using a secondary antibody specific for immunoglobulin M.

The utility of staining for Leu M1 (CD15) as a diagnostic aid in Hodgkin's disease has been questioned because of a relative lack of specificity and sensitivity. Furthermore, interpretation is often made difficult by staining that tends to be weak and focal. Because the murine monoclonal anti-Leu M1 antibody is of immunoglobulin M type, it is reasonable to wonder whether improved immunohistochemical staining might result from use of a secondary goat antibody specific for the mouse mu heavy chain instead of the traditional one against mouse immunoglobulin. The two methods were compared, using a biotin-avidin detection system, on paraffin sections from 15 cases of Hodgkin's disease: 9 nodular sclerosing, 1 mixed cellularity, and 5 of nodular lymphocytic and histiocytic (L&H) type. In the nodular sclerosing/mixed cellularity group, the mu-specific detection method resulted in a greater number of cases with reactive Hodgkin's cells (7 versus 5), stained an average of more than three times as many neoplastic cells in each case (49% versus 14%), and usually produced staining that was distinctly more intense, often in a membrane and paranuclear distribution characteristic of Leu M1 in Hodgkin's cells. In the noLeu M1 in Hodgkin's cells. In the nodular L&H group, 1 case showed weak, focal staining with the newer method. None of the L&H cases stained using the traditional technique. It is concluded that use of a second-stage antibody that is directed specifically against mu heavy chains results in an improvement in immunohistochemical staining for Leu M1 in paraffin sections, which is of practical significance.

Warthin-Finkeldey polykaryocytes demonstrate a T-cell immunophenotype.

Warthin-Finkeldey polykaryocytes have been described in various benign and malignant lymphoid conditions since their initial identification in tonsils of patients in the prodromal stage of measles. However, the nature of these multinucleated giant cells is obscure. The authors studied the immunohistochemical profile of the Warthin-Finkeldey-type giant cells in three cases of lymphoid proliferations (two reactive, one neoplastic) containing many multinucleated cells using a panel of paraffin-reactive antibodies. Warthin-Finkeldey polykaryocytes demonstrated reactivity with Leu22 (CD43), anti-CD3, and OPD4, indicating that these cells are multinucleated T lymphocytes. The significance of these results with respect to the disorders in which these cells are found and their possible role in pathogenesis of disease are discussed.

Virus-associated hemophagocytic syndrome characterized by clonal Epstein-Barr virus genome.

Virus-associated hemophagocytic syndromes are a heterogeneous group of disorders in which viral infection is associated with a proliferation of hemophagocytic histiocytes throughout the reticuloendothelial system. The authors report the case of a 24-year-old Vietnamese male who developed a hemophagocytic syndrome associated with Epstein-Barr virus (EBV) and who died following a rapidly progressive course. A proliferation of reactive-appearing lymphoid cells was associated with an extensive proliferation of erythrophagocytic histiocytes. Immunophenotypically, the lymphoid infiltrate consisted of CD56+ natural killer cells, predominantly CD8+ T-cells and rare B-cells (CD20+). Double-label immunohistochemical studies showed CD3+ T-cells and CD56+ natural killer cells to be distinct cell populations. Combined immunohistochemical-in situ hybridization studies localized EBV to CD43+, CD3-, CD68-, lymphoid-appearing cells, indicating the presence of EBV within natural killer cells. Southern hybridization analysis of EBV genomic termini revealed clonal EBV genome. However, there was no detectable immunoglobulin or T-cell receptor gene rearrangements. The findings indicate that this case of hemophagocytic syndrome represents a clonal proliferation of natural killer cells containing EBV and highlights the importance of the analysis of EBV genomic termini for determination of clonality in EBV-associated proliferations. It is possible that other cases of fulminant EBV-associated hemophagocytic syndromes represent clonal natural killer cell proliferations.

Clonal VDJ recombination of the immunoglobulin heavy chain gene by PCR in classical Hodgkin's disease.

Although Hodgkin's disease (HD) has been a subject of much investigation, fundamental questions remain unanswered regarding its lineage and clonality. The authors used a polymerase chain reaction (PCR) technique to investigate whether clonal Variable-Diversity-Joining recombination of the immunoglobulin heavy (IgH) chain gene, a phenomenon that characterizes clonal B-cell proliferations, exists in nodular sclerosing (NSHD) and mixed cellularity (MCHD) Hodgkin's disease (so-called "classical" Hodgkin's disease). The isolation of DNA from paraffin-embedded tissue sections allowed for direct correlation of PCR results with the cell populations that were analyzed. Thirty-two cases were studied. These included 12 cases in which the Reed-Sternberg (RS) cells expressed the B-cell antigen, CD20, and 10 cases that were classified as syncytial variant of NSHD (3 CD20+, 7 B-cell antigen negative). Overall, clonal patterns of VDJ PCR products were found in 14 of 32 (44%) cases. These clonal patterns were identified in 7 of 12 (58%) cases of CD20+ classical HD and in 7 of 20 (35%) cases of B-antigen-negative classical HD. Clonal patterns were found in 3 of 10 cases of syncytial variant of NSHD, including 2 of 3 (67%) CD20+ cases and 1 of 7 (14%) B-cell antigen-negative cases. The results of this study provide support that a subset of HD represents a clonal B-cell neoplasm, and indicate that clonal IgH VDJ sequences are more frequently found in CD20+ HD.

Immunosuppression-associated lymphoproliferative disorders in rheumatic patients.

The association between rheumatic disease and the occurrence of hematolymphoid neoplasms has been a subject of investigation for many years. Recently, we and others have reported the development in rheumatic patients of lymphoproliferative disorders that are similar to those occurring in patients with known immunocompromised states. The lymphoid neoplasms that develop in patients with immunosuppression are characterized by several features including the presence of EBV genome in the neoplastic cells. The fact that lymphomas with features of those occurring in immunosuppressed patients can occur in patients with rheumatic disease suggests that immune system impairment secondary to the rheumatic disease, the treatment given for the rheumatic disease, or to a combination of these factors, might play a role in the development of lymphoma in these patients. This review will first describe the characteristics of lymphoproliferative disorders that occur in patients with known immunocompromised states. It will then review general aspects of lymphomas in rheumatic patients with a focus on more recent reports that have described the development of immunosuppression-associated lymphoproliferative disorders in rheumatic patients. Studies that investigate the relative contribution of the rheumatic disease versus therapy for rheumatic disease in the development of lymphoma in this patient group are still needed.

True histiocytic lymphoma: a study of 12 cases based on current definition.

True histiocytic lymphoma (THL), as it is currently defined, is a rare entity. We report 12 cases of THL seen at Stanford over the last ten years. By definition, the neoplastic cells in each case showed histological and immunological evidence of histiocytic differentiation. Seven females and five males ranged in age from 9 to 67 years. Sites of involvement included lymph node, soft tissue, bone, stomach, small intestine, mediastinum, kidney, breast and salivary gland. Lymph nodes showed diffuse architectural effacement and/or a paracortical pattern of involvement. The infiltrates involved other tissues in a diffuse pattern. Cytologically the cells were characterized by abundant eosinophilic cytoplasm and enlarged, indented eccentrically placed nuclei containing prominent nucleoli. In all cases the cytological features were sufficiently atypical to indicate a neoplastic infiltrate. Paraffin section immunophenotyping demonstrated reactivity of the atypical cells for CD15, 43, 45RO, 45RB, 68, lysozyme and/or S100. In frozen sections, the atypical cells demonstrated reactivity for CD4 (cytoplasmic), 11c, 14, 15, and/or 68. Genotypic studies were performed on 3 cases, one of which showed rearrangements of immunoglobulin heavy and light chain genes. Follow-up was available on eleven patients, six of whom died of disease 0.5 to 36 months following diagnosis.

Heterogeneity of epithelial marker expression in routinely processed, poorly differentiated carcinomas.

The application of immunohistochemical markers against epithelial antigens has proved useful for studying tumor differentiation and in aiding tumor diagnosis. However, the reactivity of various epithelial markers with poorly differentiated carcinomas (the situation in which they are most often used) has not been well established. As a result, it is unclear how negative results should be interpreted and how often more than one antibody may be needed to document the epithelial nature of poorly differentiated neoplasms. We studied 98 poorly differentiated epithelial tumors with AE1, CAM 5.2, and EMA to assess the use of these markers in their diagnosis. Both CAM 5.2 and EMA provided support for epithelial differentiation in 71% (70/98) of the cases, while AE1 stained 50% (49/98) of the tumors; CAM 5.2 was the single most useful marker in the subset of poorly differentiated neuroendocrine carcinomas, staining 20 (77%) of 26 tumors. Use of these markers in pairs increased the recognition of epithelial differentiation (at least one marker showing positive staining) as follows: AE1/CAM 5.2, 80% (78/98); AE1/EMA, 87% (85/98); and CAM 5.2/EMA, 99% (97/98). Thirty carcinomas stained with all three markers, 34 with two markers, and in 34 cases only one antibody supported epithelial differentiation. Twelve (21%) of 58 tumors showed evidence of S100 reactivity. None of the 71 cases to which PD7 was applied showed staining This study indicates that poorly differentiated carcinomas are heterogeneous in their expression of antigens recognized by AE1, CAM 5.2, and EMA. Moreover, these results quantitate the probability of reactivity with poorly differentiated carcinomas for each marker and support the use of one or more antibodies in a "backup" panel when a negative result is obtained with a single antibody and the diagnosis of carcinoma is still suspected.

Iatrogenic lymphoproliferative disorders in nontransplantation settings.

Iatrogenic (IAT) immunosuppression-related lymphoproliferative disorders (LPDs) can occur outside the solid organ transplantation setting in patients who receive immunomodulatory therapy for a variety of underlying diseases. Most frequently, these patients suffer from rheumatologic diseases and are receiving one or more therapies during the time that LPDs develop. Specific therapies include methotrexate, azathiaprine, cyclosporine, prednisone, and others as well as combinations of therapies. In a significant subset of patients, these IAT LPDs spontaneously regress when therapy is discontinued, a finding that implicates immunomodulatory therapy, at least in part, in the development of these LPDs. The morphological spectrum of IAT LPDs includes atypical polymorphous LPDs, diffuse aggressive non-Hodgkin's lymphomas, Hodgkin's disease, and lymphoproliferations resembling Hodgkin's disease. The diagnosis requires a combined morphological and immunonphenotypic approach; in situ hybridization studies for Epstein-Barr virus (EBV) provide important information in the evaluation of these lesions. Withdrawal of immunosuppressive therapy and observation for a short period should be considered in the initial treatment of IAT LPDs, especially when they are EBV positive. This approach may obviate the need for unnecessary cytotoxic chemotherapy or radiation therapy in a significant subset of patients. However, some of these IAT LPDs behave in an aggressive manner; therefore, close clinical management is warranted.