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Follicular lymphoma (FL) typically presents as a systemic disease (stages III/IV). We repeatedly observed in cases with conserved reactive follicle structures (so-called partial infiltration) an association with a limited clinical stage (I/II). In this study, we analyzed 53 lymph node biopsies of FL with conserved reactive follicle structures. In 44 cases (83%) of the patients with partial infiltration, a limited stage of disease (Ann Arbor stage I/II) was found, whereas only 9 of 53 cases (17%) suffered from a systemic disease. In those cases with at least one follicle totally spared by lymphoma, 95% of the patients (38 of 40 cases) presented with a limited stage (I/II) of disease, compared with only 20% (10 of 49 cases) in a control group with full-blown infiltration (P < 0.001). Analyzing systematically all 321 FL cases sent to the Reference Center Wurzburg in the year 2001, reactive follicle remnants were detected in 34 of 321 (10.6%) cases with 26 of 34 (76%) tumors showing limited stage (I/II) disease, including all 18 cases with at least one totally spared follicle. Our results therefore show a clear association between the occurrence of preserved reactive follicles in FL and limited disease stage.

We describe the clinicopathologic findings in a so far unrecognized thymic tumor. The tumor occurred in a 70-year-old woman with respiratory distress but neither myasthenia gravis nor other symptoms. Metastases or another primary tumor were absent. The well-circumscribed neoplasm was located in the thymic region, measured 18 x 12 x 8 cm, and showed a homogeneous, tan-colored, soft cut surface. By histology, the tumor lacked a true capsule and a lobular growth pattern, was almost devoid of stroma, and infiltrated among remnant thymus lobules. The polygonal tumor cells formed solid sheets, trabeculae, or occurred as single cells that resembled hepatocytes. Proliferative activity was low. Portal structures, sinuses, and bile were absent as were areas of conventional thymoma, adenocarcinoma, or germ cell tumor. The tumor expressed cytokeratins 7 and 19, alpha1-antitrypsin, alpha1-antichymotrypsin, and hep-Par-1. Alpha-fetoprotein (AFP), human beta-chorionic gonadotropin (beta-HCG), placental alkaline phosphatase, CD5, CD30, CD31, CD34, CD45, CD68, CD99, S-100, HMB45, desmin, actin, or neuroendocrine markers were not expressed, and intratumorous CD1a+ or TdT+ immature T cells were absent. AFP was repeatedly undetectable in the blood. Mediastinal tumor recurrence was detected 6 months after surgery. Following radiochemotherapy, the patient has remained free of disease for 26 months. We conclude that this tumor is a thymic carcinoma (WHO type C thymoma). A diagnosis of hepatoid yolk sack tumor appears unlikely considering absence of a bona fide germ cell component, lack of AFP expression, and the patient's female gender. Because of its morphologic and immunohistochemical features, we propose the term "hepatoid thymic carcinoma" for this new type of thymic carcinoma.

We describe the morphology and comparative genomic hybridization findings in a tumor for which we propose the term "spiradenocylindroma" of the kidney. The tumor arose in the wall of a renal cyst in an otherwise healthy male patient who had a favorable clinical course after nephrectomy. Tumor cells formed either large nodules exhibiting a solid or trabecular architecture with conspicuous perivascular spaces or cylindromatous small tumor cell islands arranged in a jigsaw pattern. Focally, there were interspersed tubular structures and tumor cell rosettes with central deposits of periodic acid-Schiff-positive material. A minor tumor component showed epidermoid differentiation. The tumor cells were strongly positive for cytokeratins 5/6, high molecular weight cytokeratins 34betaE12 and AE1/3, and E-cadherin, but only weakly positive for cytokeratins 7, 8, 18, 19, and epithelial membrane antigen. Focal reactivity for actin, vimentin, and S-100 protein or lysozyme and alpha 1 -antichymotrypsin within tubular and cylindromatous areas suggested myoepithelial and apocrine differentiation, respectively. By comparative genomic hybridization, the only abnormality was loss of the long arm of chromosome 16 and gain of genetic material on the short arm of chromosome 16, suggesting isochromosome i(16p). This finding is unique among renal neoplasms and implies loss of heterozygosity at 16q12-13 of the CYLD1 gene that is critically involved in the oncogenesis of familial cylindromatosis and some sporadic spiradenocylindromas. We conclude that somatic mutation of the CYLD1 gene outside the skin can have a role in the oncogenesis of tumors with cylindromatous features.

Extranodal malignant non-Hodgkin's lymphomas account for about 40% of lymphoid neoplasms, but few data are available concerning the genetic background of primary gastric diffuse large B-cell lymphoma (DLBCL). A study was performed of 27 primary gastric DLBCLs and 5 gastric DLBCLs with a concomitant low grade component of mucosa-associated lymphoid tissue-type lymphoma using comparative genomic hybridization (CGH), microsatellite studies, classic cytogenetics, and fluorescence in situ hybridization (FISH) to search for specific genetic aberrations. The most frequent aberrations were losses of material on chromosome 6q and gains of parts of chromosome 3. In three cases, a total of six high level DNA amplifications were detected, with five of them involving chromosomal regions not having been reported before in gastric DLBCL. A high overall concordance of 91.4% between microsatellite analysis and CGH was observed using DNA extracted from the same tissue block. The concordance achieved using DNA from different tissue blocks of the same patient was 85%. Microsatellite studies, CGH, FISH, and classic cytogenetics represent complementary techniques that facilitate a comprehensive view of genetic alterations in malignancies such as primary gastric DLBCL.

There are significant difficulties in the differential diagnosis of lymphomas at the interface between classic Hodgkin's lymphoma and both paragranuloma and T-cell-rich B-cell lymphoma as well as at the interface between T-cell-rich B-cell lymphoma and paragranuloma. We therefore investigated 197 cases (155 classic Hodgkin's lymphomas, 32 T-cell-rich B-cell lymphomas, and 10 paragranulomas) by paraffin immunohistochemistry. Special interest was given to cases with a B-cell phenotype of tumor cells. The reactive inflammatory infiltrate in both classic Hodgkin's lymphoma and T-cell-rich B-cell lymphoma was rich in TIA-1-positive cytolytic lymphocytes, and CD57-positive cells were rarely encountered. In contrast, in paragranuloma CD57-positive cells and small B-lymphocytes predominated the background infiltrate. The tumor cells in cases of classic Hodgkin's lymphoma were positive for CD30 in 95%, for CD15 in 75%, and for CD20 in 22%. Apart from this, vimentin was expressed in >95% of the cases. All cases of T-cell-rich B-cell lymphoma were negative for vimentin, CD30, and CD15. The reactivity of the tumor cells for CD30, CD15, CD20, and vimentin together with the background reactivity for CD57 and TIA-1 seem to reliably discriminate between the entities and should therefore help to increase the interobserver reproducibility of diagnoses in the gray zone around Hodgkin's lymphoma.

A 28-year-old man presented with selective immunoglobulin A deficiency and severe diarrhea responding to a gliadin-free diet. Biopsy samples of the small intestine showed dense T-cell infiltrations in the lamina propria and a slight increase of intraepithelial T-lymphocytes. No clonal rearrangement of the T-cell receptor c-beta chain genes was detectable by Southern blotting. Four years later, at the age of 32, the patient was hospitalized again with liver failure, abdominal lymphadenopathy, pancytopenia, and recurrent bacterial infections. Retrospective polymerase chain reaction analysis of formalin-fixed tissues of the intestinal biopsy samples obtained 4 years earlier showed monoclonal T-cell receptor gamma-chain gene rearrangement. Lymphoid cells of the peripheral blood showed an immunophenotype of CD3-positive gamma/delta T cells with a negativity for CD4 and CD8. A clonally rearranged T-cell receptor delta chain gene and a germline configuration of the c-beta chain genes was found by Southern blotting. Cytogenetics showed an abnormal karyotype with unbalanced translocations t(1;5) and t(9;13). The patient died of extensive lung infiltrations by gamma/delta T cells; autopsy showed a peripheral T-cell lymphoma of the gamma/delta type in the enlarged abdominal lymph nodes. This is the first report of an abdominal T-cell lymphoma of the gamma/delta type in a patient with selective immunoglobulin A deficiency.

OBJECTIVE: The progesterone receptor (PgR) can be detected in 60 to 70% of meningiomas using immunohistochemistry in situ. Whereas in monolayer tissue cultures the PgR is only rarely expressed, we were able recently to demonstrate the preservation of the PgR in fragment spheroid cultures of meningiomas. The aim of the present study was to evaluate the stability of PgR expression in meningioma spheroids in vitro and the correlation of PgR expression and cell proliferation in spheroids and whether meningioma cells reaggregated to spheroids from monolayer cultures to reexpress the PgR again. METHODS: Tumor fragment spheroids (Weeks 1-6) and cell monolayers (Passages 1 and 3) of 15 PgR-positive meningiomas were investigated by immunohistochemistry for the expression of PgRs and their proliferative activity, as demonstrated by positivity for the proliferation-related antigen Ki-67. To study PgR reexpression in reaggregated spheroids, Northern blots were performed. In addition, a reverse transcriptase-polymerase chain reaction technique was established and evaluated in combination with immunohistochemistry. Growth of meningioma spheroids was quantified in the presence of progesterone and the specific antagonist onapristone. RESULTS: The PgR remained stable in spheroids for 6 weeks in 9 of 13 cases that were able to be evaluated. All tumor fragment spheroids exhibited a proliferation index of 5 to 40% Ki-67-positive cells. Monolayer cell cultures, on the other hand, failed to express PgRs but revealed higher proliferation indices (40-90%) to a significant extent. The detection of PgR messenger ribonucleic acid in reaggregated spheroids by means of reverse transcriptase-polymerase chain reaction correlated to the nuclear expression of PgR in immunohistochemistry. Neither progesterone nor its antagonist onapristone altered spheroid growth in vitro. CONCLUSION: The expression of the PgR in meningiomas is preserved in spheroid cultures with low proliferation indices for at least 6 weeks, whereas monolayer cell cultures with a high proliferative activity lack PgR expression. The inverse pattern of Ki-67-positive cells in the outer regions of the spheroids and PgR-expressing tumor cells in the spheroid centers leads us to the conclusion that proliferating meningioma tumor cells do not express PgRs. This might also explain why tumor cell growth in vitro was neither affected by progesterone nor by onapristone. Monolayer cell cultures can be reaggregated to spheroids, the consequence being a reexpression of PgRs and, therefore, a down-regulation of proliferation.

Expression of the tumor suppressor gene product p53 and the cyclin-dependent kinase inhibitor p21, which is transcriptionally activated by p53, was investigated and compared with patient survival in a retrospective longitudinal study of 202 cases of endometrial carcinoma. The median duration of follow-up was 4.3 years. P53 was observed immunohistochemically in 63 (31%) of the tumors and was found by univariate analysis to be related to reduced adjusted survival (p = 0.00028) and disease-free survival (p = 0.04). However, p53 expression was not found by multivariate analysis to be an independent prognostic factor when compared with FIGO stage, histologic grade, and proliferative activity, as determined by immunoreactivity for topoisomerase IIalpha with the antibody Ki-S1. Overexpression of p53 was related to histologic grade (p < 0.00001), proliferative activity (p = 0.0071), and inversely to progesterone receptor content (p = 0.042). Immunohistochemical identification of p21 was investigated in 95 cases and found to be positive in 19 (39%) of 49 tumors with p53 overexpression and in 13 (28%) of 46 tumors without p53 overexpression (p = 0.28). Expression of p21 is therefore not related to p53 expression, nor was it found to be related to proliferative activity. Strong expression of p21 was observed in tumors negative for progesterone receptors (p = 0.0028). P53 in endometrial carcinoma is not associated with induction of the cell cycle inhibitor p21, but is associated with an enhanced proliferative activity. The findings of multivariate analysis suggest that the prognostic significance of p53 is related mainly to cell proliferation.

A supportive or causal role for human herpesvirus 6 (HHV-6) in lymphoproliferative disorders is still controversial. Different results were obtained in both tissue-based and serological investigations. We investigated 243 lymph node and salivary gland tissue biopsies for the presence of viral DNA by using a newly developed, highly sensitive nested polymerase chain reaction method. HHV-6 was detected in 39% of the non-Hodgkin's lymphomas, in 52% of Hodgkin's diseases, 64% of non-neoplastic lymph nodes, 23% of tumor metastases, and 50% of salivary gland biopsies. When correlating the patients' ages with the occurrence of HHV-6, we found a significantly higher percentage of positive samples in patients younger than 60 years of age (54%) than in older patients (35%). This age-related difference was found in all the lymphoproliferative disorders studied as well as in salivary gland biopsies. Taking patient's ages into account, we found no significant difference between the various groups of disorders concerning the percentage of HHV-6-positive samples.

Based on a study of 26 cases, the well-differentiated thymic carcinoma is described as a distinct organotypical carcinoma of the thymus with low-grade malignancy. It is characterized by a predominance of epithelial cells with usually low mitotic rate, an epidermoid differentiation with slight to moderate cytological atypia, the constant presence of interepithelial immature cortical thymocytes, lobular growth, and formation of epithelial palisades around perivascular spaces. The tumor occurs at age 14 to 76 years in both sexes. An association with myasthenia gravis is found in 77% of the patients, and 83% of the tumors show invasion of adjacent organs or endothoracic metastasis at primary operation. This rate is higher than in cortical thymomas (47%) but lower than in other thymic carcinomas (92%). Two of 18 patients with follow-up died of tumor recurrence and pleural metastasis. Well-differentiated thymic carcinoma can be related to cortical thymoma by common morphological features and a similar immunophenotype of epithelial cells. It must be differentiated from the lymphocyte-depleted cortical thymomas after corticosteroid treatment and from the benign epithelial-rich medullary thymomas.

Based on the light microscopical features of normal thymic epithelial cells, human thymoma was divided in different types, namely cortical, medullary, and mixed ones, according to the epithelial cell (EC) type. Lymphoid cell populations with morphological features of either cortical or medullary thymocytes were found according to different types of EC in thymoma. The histological variation of the different types of thymoma are demonstrated. In a retrospective study of 58 thymomas and 13 thymic carcinomas, malignant invasive character as well as the occurrence of myasthenia gravis were both found to be related to the neoplastic proliferation of the cortical epithelial cells, whereas in the usual mixed type of thymoma and the medullary type no gross invasion or metastases were noticed.

Objective: To investigate the association of MG with the transcription of muscular or neuronal acetylcholine receptor (AChR) subunit genes in thymomas.Background: Many steps in the pathogenesis of MG have been elucidated but, with rare exceptions, its etiology is unknown. In patients with MG with thymoma, the tumor probably elicits autoimmunity to AChR, but it is enigmatic why MG develops in some patients but not in others.Methods: Reverse transcriptase (RT)-PCR, immunohistochemistry, and immunofluorescence studies were carried out to investigate AChR expression in 35 patients with thymoma. Statistical analysis was used to specify significant differences between thymoma subtypes.Results: Considering all thymomas (n = 35), no correlation was found between MG status and AChR gene expression as detected by RT-PCR. However, when histologically defined thymoma subtypes were studied separately, transcription of the muscular AChR P3A− α-subunit gene was significantly associated (α < 0.01) with the occurrence of MG in mixed thymomas (n = 17), but not in thymomas of the cortical type. For the other muscular AChR subunits (P3A+ α isoform, β, γ, δ, and ε) and the α2 and β4 neuronal AChR subunits, no such correlation was detected.Conclusions: Expression of the P3A− AChR α-subunit gene might be important for the pathogenesis of MG in mixed thymomas, suggesting etiologic heterogeneity of paraneoplastic MG among patients with histologically different thymoma subtypes.

In 1958, a medium-sized cell was recognized in human lymph nodes and found to occur in clusters in about one out of every 10 cases of reactive hyperplasia. At first, it was interpreted as a lymphoblast. Later, electron-microscopic investigations revealed that the cell contained abundant rough endoplasmic reticulum and was apparently restricted to T-regions of lymph nodes. Recently, it was possible to analyze a malignant lymphoma uniformly composed of such cells with a panel of monoclonal antibodies. The cells proved to be Leu-1+, OKT4+, Leu-3a+, HLA-DR+, and weakly reactive with VIL-A1 (antibody to common ALL antigen) and clone F8-11-13, but negative for OKT3, OKT11, OKT8, cytoplasmic immunoglobulin, common B-cell antigen, and C3b receptors. Short-term, in vitro cultures of lymphoma cells showed weak responses to phytohemagglutinin and Interleukin 2 (IL2), but no IL2 production. Lymphoma cells had a low spontaneous proliferation rate (about 2% Ki-67+ cells). In view of these findings, the term "plasma-cytoid T-cell" is proposed. A functional relationship between these cells and the myeloid system was suggested because the patient developed a myelomonocytic leukemia 3 months after the diagnosis of malignant lymphoma was made.

Immunohistochemical, histochemical, and morphometrical studies of six gastric carcinoid tumors and their possible precursor lesions in gastric mucosa are reported. All tumors, presenting successively at our institute, occurred in the corpus mucosa of 45- to 78-year-old patients. Two neoplasms had already metastasized. Three tumors contained gastrin- and/or serotonin-positive cells. Two groups of carcinoids, one with atrophic gastritis type A [AGA (four cases)], and one without AGA (two cases) were discerned. Only cases with AGA showed antral G cell hyperplasia consistently as well as fundic endocrine cell proliferation and sometimes multifocal tumors. This confirms previous reports that hypergastrinemia might be a predisposing condition for the development of gastric carcinoids in AGA. Fundic endocrine cell increase, verified by quantitative methods, was either diffuse or nodular. Diffuse endocrine cell hyperplasia comprised G, EC, and ECl cells. The observation that endocrine cell nodules comprised a similar mixture of endocrine cells, sometimes communicating with glands of pseudopyloric metaplasia and proving to be reversible in one case, provides evidence that these nodules are hyperplastic, but finally may lead to gastric carcinoid tumors in AGA. Size less than 150 micron, basal location, and mixed hormone content may be helpful criteria for the distinction of hyperplastic endocrine cell nodules from small carcinoid tumors.