Interleukin 12 gene therapy of cancer by peritumoral injection of transduced autologous fibroblasts: outcome of a phase I study.

A phase I dose-escalation clinical trial of peritumoral injections of interleukin 12 (IL-12)-transduced autologous fibroblasts was performed in patients with disseminated cancer for whom effective treatment does not exist. The goals of this study were to assess the safety and toxicities as well as the efficacy, and ancillarily the immunomodulatory effects, of peritumoral IL-12 gene transfer. Primary dermal fibroblasts cultured from the patients were transduced with retroviral vector carrying human IL-12 genes (p35 and p40) as well as the neomycin phosphotransferase gene (TFG-hIL-12-Neo). Patients received four injections at intervals of 7 days. Nine patients were enrolled in this dose-escalation study, with secreted IL-12 doses ranging from 300 ng/24 hr for the first three patients to 1000, 3000, and 5000 ng/24 hr for two patients in each subsequent dosage level. Although a definite statement cannot be made, there appears to be perturbation of systemic immunity. Also, the locoregional effects mediated by tumor necrosis factor alpha (TNF-alpha) and CD8+ T cells were observed with tumor regression. Treatment-related adverse events were limited to mild to moderate pain at the injection site; clinically significant toxicities were not encountered. Transient but clear reductions of tumor sizes were observed at the injected sites in four of nine cases, and at noninjected distant sites in one melanoma patient. Hemorrhagic necrosis of tumors was observed in two melanoma patients. These data indicate that gene therapy by peritumoral injection of IL-12-producing autologous fibroblasts is feasible, and promising in patients with advanced cancer.

Clinical features of peripheral T-cell lymphomas in 78 patients diagnosed according to the Revised European-American lymphoma (REAL) classification.

The aim of this study was to analyse the clinical characteristics and prognostic factors of peripheral T-cell lymphomas (PTCLs) according to the Revised European-American Lymphoma (REAL) classification. From 1994 to 1999, 78 patients were diagnosed with PTCLs, excluding cutaneous T-cell lymphomas and T-cell chronic lymphocytic leukaemia. The distribution of the histological subgroups were: PTCL unspecified (PTCL-U), 40%; angiocentric lymphoma, 32%; anaplastic large cell lymphoma (ALCL), 17%; angioimmunoblastic T-cell lymphoma (AILD), 6%; intestinal T-cell lymphoma, 3%; and panniculitic T-cell lymphoma, 3%. Patients with angiocentric lymphoma presented with favourable prognostic factors, whereas those with AILD presented with unfavourable prognostic factors. Most patients were treated with doxorubicin-containing combination chemotherapy (with or without radiation therapy). The overall complete remission rate was 61.2% (95% Confidence Interval (CI): 48.5-72.8%) and the 5-year probability of failure-free survival was 33.5%. Median survival of all patients was 45 months (range 0-64+ months) and the 5-year probability of survival was 36.2%. In the multivariate analysis, only the International Prognosis Index (IPI) was an independent prognostic factor for overall survival (P<0.01). Taken together, the proportion of angiocentric lymphoma in this study was higher than that in the studies of Western countries. PTCL responds poorly to treatment with low survival rates and the IPI is a useful prognostic factor for PTCL.

Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers.

Angioimmunoblastic T-cell lymphoma (or angioimmunoblastic lymphadenopathy with dysgammaglobulinemia [AILD]) was originally considered to be an abnormal immune reaction in which reactive follicles with germinal centers (GCs) are usually absent. When hyperplastic GCs are present along with an angioimmunoblastic reaction, the lesion has been interpreted as a benign hyperimmune reaction. We report seven patients with angioimmunoblastic T-cell lymphoma (AITL) who initially had hyperplastic GCs, shown to be malignant lymphoma by further studies and clinical follow-up. Clonal T-cell populations were observed in all specimens evaluated, and sequential biopsies showed histologic progression to typical AITL in two patients. Clinical presentation was characterized by generalized lymphadenopathy of acute onset, constitutional symptoms, hepatosplenomegaly, skin rash, and polyclonal hypergammaglobulinemia in five patients; regional adenopathy preceded generalized adenopathy in two patients. Five patients had rapid progression of disease, and three patients whose treatment was delayed due to inadequate evidence to diagnose lymphoma died of infection. The initial biopsy findings of each patient were similar and showed angioimmunoblastic proliferation, hyperplastic GCs with ill-defined borders, and interfollicular tingible-body macrophages. These GCs differed from occasional residual follicles of typical AITL in that the GCs were enlarged and hyperplasia of follicular dendritic cells was not seen. Diagnostic clear cells were not observed. Apoptotic bodies were markedly increased and bcl-2+ lymphocytes were sparse compared with typical AITL. Results of in situ hybridization for Epstein-Barr virus were positive in each case. We conclude that hyperplastic germinal centers with ill-defined borders and frequent interfollicular tingible-body macrophages occur in a histologic variant of AITL that is necessary to recognize for early diagnosis and treatment.

Histochemical studies on lectin binding in reactive lymphoid tissues.

Using the avidin-biotin-labeled peroxidase complex (ABC) method, the staining reaction of a panel of 12 biotin-labeled lectins was studied in formalin-fixed, paraffin-embedded reactive lymph nodes and tonsils. Varying degrees of lectin binding were observed in lymphoid cells and macrophage-histiocytes with Concanavalin ensiformis (Con A), Lens culinaris (LCA), Phaseolus vulgaris (PHA), Pisum sativum (PSA), Ricinus communis (RCA), and Triticum vulgaris (WGA) agglutinins, but no evidence of binding was observed with Dolichos biflorus (DBA), Bandieraea simplicifolia (BSA), Arachis Hypogaea (PNA), Glycine soja (SBA), Sophora japonica (SJA), and Ulex europaeus (UEA) agglutinins. Three major patterns of binding were seen: the reaction products occurred along the plasma membranes (membranous), were confined to one pole of the cell membrane (cap-like), or were present diffusely in cytoplasm (cytoplasmic). The cells showing membranous and cap-like staining patterns corresponded to the lymphoid cells, as did the cytoplasmic to plasma cell and macrophage-histiocytes. Cap-like staining was observed on the lymphocytes at B and T cell areas with all six lectins. Thus, the presence of cap-like staining may not be useful for discrimination between B and T cells. Membranous staining, in contrast, was limited to lymphocytes of follicles (B cells) with PSA and LCA, and to germinal center cells with PHA, WGA, Con A, and RCA also reacted with the membrane of T-cell. The cytoplasmic staining reaction of macrophage-histiocytes varied markedly from one lectin to the other. Our study indicates that the carbohydrate moiety of the cells retains their binding sites for lectins through routine processing, providing a means of valid retrospective studies. Furthermore, these observations suggest that each lectin, despite its identical inhibitory sugar, should be tested for its unique reaction pattern, which is not predictable from the data derived from cell suspension studies.

Diagnosis of left-ventricular mural thrombus by means of radionuclide ventriculography.

Radionuclide ventriculography was used to diagnose the presence of a left-ventricular mural thrombus in a patient with left-ventricular aneurysm. Diagnostic features of the radionuclide study are described and correlated with postmortem findings.

Occurrence and patterns of muramidase containing cells in Hodgkin's disease, non-Hodgkin's lymphomas, and reactive hyperplasia.

The occurrence and pattern of cytoplasmic muramidase containing histiocytes were studied by the unlabeled antibody peroxidase-antiperoxidase method in biopsy material from patients with Hodgkin's disease, non-Hodgkin's lymphomas, and reactive hyperplasia. The majority of lymph nodes from patients with Hodgkin's disease, nodular lymphoma, and reactive hyperplasia gave positive staining reactions when tested in this manner. Differences in the staining pattern were observed for the different conditions studied. In general, stain positive cells occurred in one of the following four patterns: nodular, dispersed, aggregating without background stain, or aggregating with background stain (mottling pattern). The nodular and aggregating without background stain patterns were not specific and were seen in various conditions. The dispersed pattern, however, was observed only in some cases of non-Hodgkin's diffuse lymphomas, suggesting a subgroup of tumors characterized by active participation of reactive histiocytes. The mottling pattern was virtually limited to Hodgkin's disease. Since the mottling pattern appeared to be produced by virtue of a large amount of extracellular muramidase, the elevation of the serum muramidase level in Hodgkin's disease may be related to enzymatically active secretory histiocytes. Moreover, the mottling staining pattern was observed frequently in the lymphocytic predominance and nodular sclerosis type of Hodgkin's disease, but relatively infrequently in the mixed cellularity or lymphocytic depletion types, suggesting that the variation in histiocytic activity may be related to the course of the disease. The decreased staining reaction observed in the latter two categories could not be accounted for by a decrease in the numbers of histiocytic cells in hematoxylin and eosin stained sections, suggesting that release or synthesis may be defective in those unfavorable types of Hodgkin's disease.

Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma.

BACKGROUND: The Bcl-6 gene product, a nuclear phosphoprotein, is expressed independently of Bcl-6 gene rearrangement. In lymph nodes, expression of Bcl-6 protein is restricted to germinal center (GC) B-cells and 10% to 15% of CD3/CD4+ intrafollicular T cells. Interfollicular cells are negative for Bcl-6 protein, except for rare CD3+/CD4+ T cells. Recently, we reported cases of angioimmunoblastic T-cell lymphoma (AITL) with hyperplastic GCs (AITL/GC), and observed that borders of enlarged GCs were ill defined, with features suggestive of an outward migration of GC cells to surrounding interfollicular zones. This prompted a study of follicular borders with Bcl-6 staining in reactive follicular hyperplasias and follicular lymphomas to compare with AITL/GC. MATERIALS AND METHODS: Formalin-fixed paraffin sections were used for immunostaining of Bcl-6. Six cases of AITL/GC, 12 nonspecific reactive follicular hyperplasia (FH), 7 HIV adenopathy, 10 follicular lymphoma (FL), and 8 typical AITL (ie, AITL without GC) were studied. Double staining for Bcl-6/CD20, Bcl-6/CD3, and Bcl-6/CD57 was performed in selected cases. RESULTS: In FH and HIV adenopathy, staining for Bcl-6 revealed densely populated GCs with well-defined and regular GC borders, whereas Bcl-6+ cells were rare in the interfollicular areas. An occasional GC with an ill-defined border was invariably surrounded by a broad mantle zone; those with indistinct mantle zones had well-defined, regular borders. In FL, follicles were densely populated, and their borders were irregular, with some Bcl-6+ cells in the interfollicular zones. In AITL/GC, GCs were less dense, GC borders were ill defined and irregular, and the number of interfollicular Bcl-6+ cells was markedly increased. Double staining revealed that these interfollicular Bcl-6+ cells in AITL/GC were Bcl6+/CD3+/CD20-/CD57- T cells. Moreover, CD3+ intrafollicular T cells were depleted in AITL/GC, whereas they were abundant in FH. Intrafollicular CD57+ cells did not stain for Bcl-6, and were also depleted in AITL/GC. In typical AITL, some neoplastic cells were positive for Bcl-6, showing variable degrees of staining. CONCLUSIONS: (1) GCs of AITL/GC differed from those of other reactive follicular hyperplasias and follicular lymphomas, and staining for Bcl-6 was useful to discern them. (2) Intrafollicular CD3+ T cells, many of which were also positive for Bcl-6, were markedly depleted in AITL/GC, with increased interfollicular Bcl-6+/CD3+ cells, suggesting an outward migration of intrafollicular T cells in this condition. (3) Interfollicular Bcl-6+/CD3+ cells in AITL/GC were too numerous to be accounted for by migration alone, suggesting local proliferation. (4) Intrafollicular CD57+ cells were negative for Bcl-6, indicating heterogeneity of the intrafollicular T-cell population. (5) Some neoplastic cells in AITL stained for Bcl-6, suggesting up-regulation of Bcl-6 expression in this tumor.

Coexpression of Bcl-6 and CD10 in diffuse large B-cell lymphomas: significance of Bcl-6 expression patterns in identifying germinal center B-cell lymphoma.

Most follicular lymphomas (FLs) transform to diffuse lymphoma eventually, comprising a significant proportion of diffuse large B-cell lymphoma (DLBCL). Judging by bcl-2 rearrangement (bcl-2R), one third of DLBCLs are believed to be of FL derivation in the Western population. However, bcl-2R is not specific and is not detectable in every case of FL. In East Asia, FL is uncommon but DLBCL is not. The proportion of tumors of FL origin in DLBCL is not known in this region. The coexpression of Bcl-6 and CD10 proteins, a reliable marker to identify germinal center (GC) B-cell lymphoma including FL, was analyzed in primary nodal DLBCLs (n = 104) diagnosed at major hospitals in Seoul during a recent 2-year period, along with well-defined cases (n = 17) of nodal FL as controls. Bcl-2 protein expression (n = 77) was also studied along with bcl-2R (n = 64), by polymerase chain reaction. Formalin-fixed archival specimens were used in all these assays. The Bcl-6/CD10 coexpression was observed in 35 DLBCLs (34%) and 14 FLs (82%), and most of them showed a pattern of Bcl-6 expression similar to that of the GC. Bcl-2 expression or bcl-2R did not correlate with Bcl-6/CD10 coexpression. Histologically, compartmentalizing sclerosis was associated with a high rate of the coexpression (8 of 10). In conclusion, to detect GC B-cell lymphoma in routine biopsy specimens, a pattern of Bcl-6 staining similar to the GC must be identified. Bcl-6+/CD10+ GC B-cell lymphomas thus defined comprised one third of primary nodal DLBCLs in Korea. The incidence rate is similar to that in the West. The reasons for the discrepancy between the incidence of GC B-cell lymphoma and the paucity of the follicular pattern in East Asian subjects warrant further studies.

Self-sandwich method. An improved immunoperoxidase technic for the detection of small amounts of antigens.

The unlabeled antibody peroxidase-antiperoxidase (PAP) sequence has been widely accepted as the most sensitive method for demonstrating antigens in paraffin sections. However, the results have been unpredictable in routine surgical specimens, with frequent false-negative stains. In order to amplify the staining reactions a self-sandwich method was used. The amplifier (antigen itself) was added after the application of specific antibody. The procedure may be repeated several times before the application of the bridge antiserum followed by PAP complexes. The method was designed to increase the number of antigen-antibody layers without increasing the number of heteroantisera in the system. Specimens derived from routine tonsillectomy were studied semi-quantitatively. Based on the number of positively stained Ig-containing cells in germinal centers, the sensitivity of the self-sandwich method was estimated to be 20 to 50 times that of the PAP method. In addition, extracellular Ig (reticular staining) and surface Ig were also stained positively in the germinal centers and lymphocytic mantles, respectively, but were not demonstrated by the PAP method. The enhancement of the sensitivity was achieved without compromising the specificity.

Non-Hodgkin's lymphomas of the gastrointestinal tract. An evaluation of paraffin section immunostaining.

Although the gastrointestinal (GI) tract is the most common site of primary extranodal lymphomas, the lineage of these tumors has been controversial. The authors used paraffin-reactive antibodies detecting markers of B-, T-, histiocytic, and epithelial cells to study 34 non-Hodgkin's lymphomas of the GI tract for which unequivocal frozen-section immunophenotypine was available as a control to determine whether these antibodies are reliable in the study of these tumors. Frozen-section studies revealed 31 tumors of B-cell origin and three T-cell tumors. Paraffin-reactive antibodies confirmed B-cell lineage in 28 of the 31 cases, with equivocal results in the remaining three. Only one of the T-cell lymphomas was identified in paraffin studies. Our results indicate that paraffin-reactive antibodies can reliably identify most B-cell lymphomas in the GI tract but may be unreliable in the detection of lymphomas of T-cell origin.

Expression of sialylated Leu-M1 antigen in histiocytosis X.

The purpose of this study is to determine the versatility of the monoclonal antibody anti-Leu-M1 in histiocytosis X diagnosis. This antibody recognizes an unsialylated lacto-N-fucopentaose III (hapen X) carbohydrate moiety that is linked to the cell membrane protein in interdigitating reticulum cells and Langerhans' cells. Previously, the authors have shown that anti-Leu-M1 can be used to stain Reed-Sternberg cells, which are likely related to interdigitating reticulum cells. In this study, the authors tested the usefulness of anti-Leu-M1 in staining formalin-fixed and paraffin-embedded tissue sections from eight patients with histiocytosis X. For staining of histiocytosis X cells, unlike Reed-Sternberg cells in Hodgkin's disease, neuraminidase treatment was required for removal of sialic acid residues from the Leu-M1 antigen. The staining characteristics of anti-Leu-M1 in histiocytosis X cells resembled those of normal Langerhans' cells and lymphocyte and histiocyte variants (L & H cells) in the lymphocyte-predominant type of Hodgkin's disease. The significance of sialylation of Leu-M1 antigen in histiocytosis X cells has yet to be determined in order to correlate the prognosis of the disease. The authors suggest that anti-Leu-M1 used together with neuraminidase treatment is a valuable tool in the diagnosis of histiocytosis X when electron microscopy or frozen sections for OKT6 immunostaining are not available.

Intraepithelial neoplasia of the neovagina.

Patients who require construction of a neovagina provide an opportunity for researchers to study some of the possible factors that cause vaginal neoplasia. Intraepithelial neoplastic changes occurring in the neovagina, remote from the graft margins, cannot be attributed to preexisting disease in the vaginal site. Such changes are unlikely to represent an expression of the oncogenic potential of the transplanted tissue. The most likely cause of these changes is the presence of a local carcinogenic environmental factor. Two cases are presented to demonstrate and support this thesis. The treatment prescribed, local excision in one case and application of topical 5-fluorouracil in the other case, resulted in disease-free intervals in excess of eight years for both patients.

Detection of RET/PTC oncogene rearrangements in Korean papillary thyroid carcinomas.

The prevalence of RET/PTC rearrangement in papillary thyroid carcinomas has been found to vary widely in different populations. Recent studies, however, have reported no significant geographical difference between Asian and Western countries. In addition, there are some disagreements about the correlation of RET/PTC expression with clinical aggressiveness. We have performed this study in order to examine the prevalence of RET/PTC-1, RET/PTC-2, and RET/PTC-3 rearrangements in Korean papillary thyroid carcinomas, and to ascertain its clinical relevance. Thyroid tumors from 31 patients histologically confirmed to be papillary carcinomas were included in this study. To find rearrangements, we utilized reverse transcription-polymerase chain reaction (RT-PCR) and automated direct sequencing. Initial and follow-up clinical data were obtained from the patients' medical records. We identified two tumors containing RET/PTC-1 (2/31, 6.5%) and two containing RET/PTC-2 (2/31, 6.5%). However, we could not find RET/PTC-3 rearrangement in any patients (0/31). In conclusion, we report RET/PTC rearrangements in 4 of 31, (12.9%) Korean patients with papillary thyroid carcinomas, a higher prevalence than previously reported in this population.

Aspiration cytology of ectopic cervical thymoma mimicking a thyroid mass. A case report.

BACKGROUND: Ectopic cervical thymoma, first described in 1941 by Boman, is an uncommon tumor of the neck displaying the same histologic features as mediastinal thymoma. Since it is commonly located in the anterolateral part of the neck or is subjacent to or inside the lower pole of the thyroid, the mass is often confused as being of thyroid origin. CASE: A 68-year-old female presented with dyspnea and an anterior neck mass found on routine chest roentgenography. The thyroid scan showed a cold nodule in the lower pole of the left part of the thyroid. Fine needle aspiration (FNA) cytology revealed large numbers of small lymphocytes with hyperchromatic nuclei and frequent clumping pattern in the pale, eosinophilic, fluid background. A few clusters of epithelial cells without atypism were interpreted as thyroid follicular cells. The overall cytologic features were misinterpreted as malignant lymphoma of the thyroid. However, the histologic diagnosis was thymoma, predominantly cortical type. CONCLUSION: The ectopic cervical thymoma is sometimes misdiagnosed as Hashimoto's thyroiditis, anaplastic carcinoma and malignant lymphoma of thyroid on FNA cytology or frozen diagnosis due to its rarity. Therefore, the differential diagnosis of a neck mass showing a variable composition of lymphocyte and epithelial component in a pale, eosinophilic, fluid background should also include ectopic cervical thymoma, especially in elderly females.

Stromal macrophage-histiocytes in Hodgkin's disease. Their relation to fever.

Morphologic variations of Concanavalin A-binding histiocytes were studied in biopsy specimens of 140 untreated patients with Hodgkin's disease (72 asymptomatic, and 68 with constitutional symptoms). Fever was the most common symptom, present in 57 of the 68 patients. Three morphologic types of stromal histiocytes were recognized: medium-sized cells similar to those seen in reactive follicles, characterized by distinct cytoplasm and cell borders, and uniform nuclei (Type A); damaged-appearing Type A cells marked by rarefied or ragged cytoplasm, disrupted or indistinct cell borders, and varying sized nuclei (Type B); and large spindling or stellate cells (Type C). Type A cells were predominant in 52 patients; Type B cells in 51; Type C cells in seven; and Type A cells were mixed with Type B in 30. Fever was present in one of 52 patients (1.9%) with Type A predominance; 43 of 51 (84.3%) with Type B cell predominance; none of seven (0%) with Type C predominance; and 13 of 30 (43.3%) with mixed Type A and B cells. Logistic regression analysis of the data showed that the association of fever with Type B cell predominance was highly significant, and was not attributable to the known association of fever with other variables. Morphologic evidence suggests that fever in Hodgkin's disease may be a clinical manifestation of damaged macrophage-histiocytes rather than an acute-phase response of inflammatory or immune reaction.

Concanavalin A-binding histiocytes in Hodgkin's disease. A predictor of early relapse.

Staining with Concanavalin agglutinin (Con A) reveals a far greater number of macrophage-histiocytes (M-H) in paraffin sections than any other staining method. With Con A staining, the shapes of stromal M-H are clearly visualized, thus enabling a study of their morphologic variations. Con A staining patterns were also unchanged in specimens left at room temperature for 24 to 28 hours before fixation. The appearance of Con A-binding histiocytes was studied in tumors, recurrent as well as original, of 18 patients with biopsy-proven early relapse (within 26 months of diagnosis), and compared with those of 26 patients who were in complete remission (lasting 48 months at the minimum). The early-relapse patients were diagnosed from 1977 through 1984, and all received intensive combination chemotherapy. The relapse-free patients were treated in various manners, and included six patients diagnosed in the 1960s who were treated with radiation alone. Three forms of Con A-binding histiocytes were easily recognized: medium-sized cells similar to those seen in reactive follicles, characterized by uniform nuclei and distinct, abundant cytoplasm (Type A); cells of varying size and shape with altered cytoplasm, rarefied and ragged with indistinct cell borders, or globular (Type B); and large cells, stellate or spindling (Type C). Large numbers of Type A cells were present in all tumors of the relapse-free patients but were virtually absent in the original and recurrent tumors of the early-relapse group. Conversely, Type B cells were rare in the relapse-free group, but were the most common type in the patients with early relapse. Type C cells were not seen in the former group, but were present in the latter. These observations suggest that the morphologic variations of Con A-binding histiocytes in Hodgkin's disease are associated with tumor behavior. Con A staining, which can best depict stromal histiocytes in paraffin sections, may be used to identify patients at a high risk of early relapse.

Lectin histochemistry of malignant tumors. II. Concanavalin A: a new histochemical marker for macrophage-histiocytes in follicular lymphoma.

Concanavalin agglutinin (Con A) binding sites were studied in paraffin embedded lymph node specimens of reactive follicular hyperplasia (12 cases) and follicular lymphoma (37) using the avidin-biotin-peroxidase complex method, and the results were compared with those of Peanut agglutinin (PNA) and lysozyme stains. Very similar to the PNA stain, two categories of Con A receptor sites were observed: cytoplasmic and cell surface. In the reactive lymph nodes, the cells showing cytoplasmic receptor sites (CR+ cells) corresponded to macrophage-histiocytes and possibly dendritic reticulum cells in the H & E stained sections, while those showing cell surface receptor sites (SR+) corresponded to lymphoid cells. Unlike the PNA binding, however, the staining reaction of SR+ lymphoid cells was weak, and another staining pattern, a dot-like stain, was observed in some lymphocytes, both SR+ and SR-. In follicular lymphomas, CR+ histiocytes were distinctly displayed within the follicular centers in 25 of 37 cases, including 12 cases in which PNA stains on adjacent or nearby sections were negative for intrafollicular macrophage-histiocytes. Similarly, Con A stains were positive for the intrafollicular CR+ cells in four of the five cases in which lysozyme stains were negative. Many of these intrafollicular CR+ cells contained inclusion-like cytoplasmic globules and/or vacuoles, a hallmark of the large CR+ cells of germinal centers. These observations suggest that macrophage-histiocytes of presumably germinal center origin are retained in neoplastic follicular centers in varying degrees, and Con A might be a useful marker for macrophage-histiocytes in paraffin-embedded routine pathological specimens, in addition to the currently accepted markers, PNA and lysozyme.