[Tumor infiltrates suspicious of carcinoma in mediastinal lymph nodes]. / Karzinomverdächtige Tumorinfiltrate in mediastinalen Lymphknoten.

Myelosarcomas are, due to their rarity, a difficult differential diagnosis. Not infrequently, extensive immunohistochemical staining for characterization of the tumor is performed, if one does not directly think of myelosarcoma. In the present case, there was a positivity of the myeloid blasts for cytokeratin. This may complicate the discrimination of myelosarcoma from carcinoma, in particular small cell carcinoma, not only in the mediastinum, but also in the skin, e.g., Merkel cell carcinoma.

Survival and clonal expansion of mutating "forbidden" (immunoglobulin receptor-deficient) epstein-barr virus-infected b cells in angioimmunoblastic t cell lymphoma.

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a peculiar T cell lymphoma, as expanding B cell clones are often present besides the malignant T cell clones. In addition, large numbers of Epstein-Barr virus (EBV)-infected B cells are frequently observed. To analyze the differentiation status and clonal composition of EBV-harboring B cells in AILD, single EBV-infected cells were micromanipulated from lymph nodes of six patients with frequent EBV(+) cells and their rearranged immunoglobulin (Ig) genes analyzed. Most EBV-infected B cells carried mutated Ig genes, indicating that in AILD, EBV preferentially resides in memory and/or germinal center B cells. EBV(+) B cell clones observed in all six cases ranged from small polyclonal to large monoclonal expansions and often showed ongoing somatic hypermutation while EBV(-) B cells showed little tendency for clonal expansion. Surprisingly, many members of expanding B cell clones had acquired destructive mutations in originally functional V gene rearrangements and showed an unfavorable high load of replacement mutations in the framework regions, indicating that they accumulated mutations over repeated rounds of mutation and division while not being selected through their antigen receptor. This sustained selection-free accumulation of somatic mutations is unique to AILD. Moreover, the survival and clonal expansion of "forbidden" (i.e., Ig-deficient) B cells has not been observed before in vivo and thus represents a novel type of viral latency in the B cell compartment. It is likely the interplay between the microenvironment in AILD lymph nodes and the viral transformation that leads to the survival and clonal expansion of Ig-less B cells.

High expression of several tyrosine kinases and activation of the PI3K/AKT pathway in mediastinal large B cell lymphoma reveals further similarities to Hodgkin lymphoma.

Mediastinal large B-cell (MBL) and classical Hodgkin lymphoma (HL) have several pathogenic mechanisms in common. As we recently observed aberrant tyrosine kinase (TK) activities in HL, we now analysed also MBL for such activities. Indeed, MBL and HL were the only B-cell lymphomas where elevated cellular phospho-tyrosine contents were typical features. Three TKs, JAK2, RON and TIE1, not expressed in normal B cells, were each expressed in about 30% of MBL cases, and 75% of cases expressed at least one of the TKs. Among the intracellular pathways frequently triggered by TKs, the PI3K/AKT pathway was activated in about 40% of MBLs and essential for survival of MBL cell lines, whereas the RAF/mitogen-activated protein kinase pathway seemed to be inhibited. No activating mutations were detected in the three TKs in MBL cell lines and primary cases. RON and TIE1 were each also expressed in about 35% and JAK2 in about 53% of HL cases. JAK2 genomic gains are frequent in MBL and HL but we observed no strict correlation of JAK2 genomic status with JAK2 protein expression. In conclusion, aberrant TK activities are a further shared pathogenic mechanism of MBL and HL and may be interesting targets for therapeutic intervention.

[Villous adenoma of the renal pelvis and ureter]. / Villöses Adenom des Nierenbeckens und Ureters.

Villous adenomas of the urinary tract are extremely rare tumours belonging to the adenoepithelial metaplasias. They can be associated with other neoplasias, especially with carcinomas. We describe the case of an 85-year-old female patient suffering from a villous adenoma of the renal pelvis and ureter.

[A rare cause of recurrent small bowel intussusception. Case report and review of the literature]. / Eine seltene Ursache einer rezidivierenden, adulten Dünndarminvagination. Fallbericht sowie Überblick über die aktuelle Literatur.

Small bowel intussusception is a rare cause of abdominal pain in adult patients. Due to varying symptoms and different underlying causes its diagnosis and treatment is challenging for physicians. This case report describes recurrent intussusception in an adult female patient and celiac disease could only be diagnosed as the cause of these symptoms after surgery. In addition a review of the literature regarding adult intussusception is presented.

Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma.

Anaplastic large cell lymphoma (ALCL) is a main type of T-cell lymphomas and comprises three distinct entities: systemic anaplastic lymphoma kinase (ALK) positive, systemic ALK(-) and cutaneous ALK(-) ALCL (cALCL). Little is known about their pathogenesis and their cellular origin, and morphological and immunophenotypical overlap exists between ALK(-) ALCL and classical Hodgkin lymphoma (cHL). We conducted gene expression profiling of microdissected lymphoma cells of five ALK(+) and four ALK(-) systemic ALCL, seven cALCL and sixteen cHL, and of eight subsets of normal T and NK cells. The analysis supports a derivation of ALCL from activated T cells, but the lymphoma cells acquired a gene expression pattern hampering an assignment to a CD4(+), CD8(+) or CD30(+) T-cell origin. Indeed, ALCL display a down-modulation of many T-cell characteristic molecules. All ALCL types show significant expression of NFkappaB target genes and upregulation of genes involved in oncogenesis (e.g. EZH2). Surprisingly, few genes are differentially expressed between systemic and cALCL despite their different clinical behaviour, and between ALK(-) ALCL and cHL despite their different cellular origin. ALK(+) ALCL are characterized by expression of genes regulated by pathways constitutively activated by ALK. This study provides multiple novel insights into the molecular biology and pathogenesis of ALCL.

[WHO classification of Hodgkin's lymphoma and its molecular pathological relevance]. / Die WHO-Klassifikation des Hodgkin-Lymphoms und ihre molekularpathologische Relevanz.

The current WHO classification of Hodgkin's lymphoma (HL) generally distinguishes the relatively rare variant (approximately 5% of all cases of HL) of nodular lymphocyte predominant type from a second group, which comprises classical HL and is separated into four subtypes: lymphocyte rich type, nodular sclerosis type, mixed cellularity type and lymphocyte depleted type. The classical lymphocyte rich subtype is a new entity and based on the typical morphology, can be recognized by definition only by the immunohistochemical characteristics of the Hodgkin and Reed/Sternberg cells (HRS) (CD30+, CD15+, CD20-). Molecular single cell studies are consistent with the dichotomy of HL in nodular lymphocyte predominant and classical types and stress the exceptional position of the former, which shows similarities with non-Hodgkin's lymphomas in several aspects. On the molecular biology level the tumor cells of all kinds of HL turn out to be clonal B cells derived from germinal center cells. However, tumor cells of nodular lymphocyte predominant HL differ from those of classical HL by the pattern of somatic mutations. Considering the inability of HRS cells of classical HL to express a B cell receptor, they should perish under normal conditions. However, they escape from apoptosis by mechanisms so far only partially understood, such as genomic mutations of the l-kappa B gene and the fas receptor gene or probably by down-regulation of B cell markers. In rare cases, HRS cells of HL can also be derived from T cells, as could be demonstrated by single cell analysis. Also, it could be shown by single cell PCR that HL and non-Hodgkin's lymphoma of both B and T cell types can arise from a common precursor. These results suggest that future classifications of HL will not only take into account the morphological and phenotypical profile, but also mechanisms of transformation yet to be discovered.

[Pathology of Hodgkin's lymphoma]. / Pathologie des Hodgkin-lymphoms.

Hodgkin's lymphoma can be divided with the help of morphologic and immunohistochemical techniques into classical and nodular lymphocyte predominant Hodgkin's lymphoma. By single cell analyses it could be established that the tumor cells of Hodgkin's lymphoma are clonal B-cells with germinal center origin. In rare cases (less than 5 %), the Hodgkin and Reed Sternberg cells represent clonal tumor cells that derive from T-cells. By gene expression analyses it can be shown that Hodgkin cell lines represent an entity independently of their B- or T-cell-origin. Hodgkin cell lines show similarities to EBV transformed B-cells and in vitro activated B-cells. The genes found with the help of gene expression analyses may have crucial importance in the pathogenesis and are potentially new diagnostic markers and therapeutic targets.

Detection of clonal lambda light chain gene rearrangements in frozen and paraffin-embedded tissues by polymerase chain reaction.

A method was established to detect clonal lambda light chain gene rearrangements in peripheral blood lymphocytes and frozen or paraffin-embedded tissues. V lambda-gene-family-specific primers were used together with a J lambda primer mix in separate reactions to amplify V lambda gene rearrangements by the polymerase chain reaction. Clonal lambda gene rearrangements were detected in seven of seven lambda-expressing B cell leukemias, in four of five lambda-expressing non-Hodgkin's lymphomas with frozen tissues, and in seven of nine cases of lambda-expressing non-Hodgkin's lymphomas for which formalin-fixed, paraffin-embedded specimens were available. Clonality of amplified polymerase chain reaction products was confirmed by sequence analysis for several cases. The present study shows that it is possible to amplify clonal lambda gene rearrangements in the majority of lambda-expressing B cell leukemias and lymphomas. The method described here, therefore, is a useful supplement to the previously described approach of VH and VK gene amplification to detect clonal B cell populations and allows the study of V lambda gene usage and somatic mutation in lambda-expressing normal and malignant B cells.

Analysis of T-cell subpopulations in T-cell non-Hodgkin's lymphoma of angioimmunoblastic lymphadenopathy with dysproteinemia type by single target gene amplification of T cell receptor- beta gene rearrangements.

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is defined in the current lymphoma classifications as a T-cell non-Hodgkin's lymphoma. However, in approximately one third of the cases of this lymphoproliferative disease rearrangements of T-cell receptor (TCR) genes indicating clonal expansion of T cells are not detectable. It is currently believed that these cases may represent early stages of a lymphoma with a minor oligoclonal T-cell population. In the present study, 18 lymph nodes with the characteristic histology of AILD were investigated for clonal T-cell receptor gene rearrangements by analysis of DNA extracted from whole tissue sections. Dominant T-cell clones were detected in 12 of these cases. Single CD4(+) and CD8(+) T cells and proliferating Ki67(+) cells of seven cases were micromanipulated from frozen tissue sections. TCRbeta gene rearrangements were amplified from these cells by polymerase chain reaction and sequenced. In all informative cases, the clonal gene rearrangements were only detected among CD4(+), and not among CD8(+) T cells, indicating that the tumor clones in AILD usually derive from CD4(+) T cells. Minor clonal T-cell populations in those cases in which no clone was found by whole-tissue DNA analysis were not detectable even at single cell resolution. T-cell clones in 4 of 10 cases were found to express similar TCRbeta chains, indicating a potential role of (super) antigen triggering in at least some cases of AILD.

CD8(+) T cells in Hodgkin's disease tumor tissue are a polyclonal population with limited clonal expansion but little evidence of selection by antigen.

A minor component (about 25%) of lymphocytes in Hodgkin's disease (HD) are CD8(+) T cells. It is unclear whether the presence of these cells reflects an antitumor cytotoxic response. The goal of the present study was to investigate clonal composition and the T cell receptor (TCR) beta repertoire of the CD8(+) T cell population in HD. Single CD8(+) cells were micromanipulated from frozen tissue sections of lymph nodes affected by primary HD and subjected to single target amplification of TCRbeta gene rearrangements. Sequence analysis of the V region genes revealed the presence of expanded CD8(+) T cell clones in all three cases analyzed. Most of these clonal expansions accounted for less than 10% of the CD8(+) T cell population. In one case, 30% of the CD8(+) T cells belonged to one or two clones. Comparison of V region sequences, however, did not provide evidence that the micromanipulated CD8(+) cells were sampled from a population that was selected for particular antigen specificities. No obvious biases in TCR Vbeta and Jbeta gene segment usage or CDR3 length distribution were found. Similarities of CDR3 amino acid sequences as found in selected CDR3 structures were rare. These results suggest that, like CD4(+) T cells, CD8(+) T cells may also be recruited into the tumor tissue in an antigen-nonspecific manner.

[Early detection of colorectal tumors: CT or MRI?]. / Früherkennung von kolorektalen Tumoren: CT oder MRT?

Cancer screening is currently offered for the organs breast, prostate, cervix and colorectum. With progressing technique in computerized tomography (CT) and magnetic resonance imaging (MRI) the colorectum can be increasingly better assessed. Because in CT and MRI also other organs are imaged with the colorectum, a colorectal screening automatically becomes a multiorgan screening. CT and MRI protocols designed for early detection of colorectal tumors are presented and discussed with regard to monoorganscreening (in CT: low dose, no i.v. contrast) and multiorganscreening (in CT: diagnostic dose for neighboured organs with i.v. contrast). More information under http://www.multiorganscreening.org.

Cytogenetic and molecular characterization of a patient with simultaneous B-cell chronic lymphocytic leukemia and peripheral T-cell lymphoma.

A patient is described who developed a peripheral T-cell lymphoma (PTCL) after a 6-year history of B-cell chronic lymphocytic leukemia (B-CLL). The progression of the T-cell disease spreading to pleura and skin terminated the course of the disease. A cytogenetic analysis performed six years after the first onset of the B-CLL showed the presence of two clones, one with trisomy 12 and another with inv(14)(q11q32.1) and trisomy 8. Combined immunophenotyping and fluorescence in situ hybridization demonstrated that only CD19+ cells contained a trisomy 12, whereas CD3+ cells contained a trisomy 8. Analyses of IgH and TCR rearrangements in single micromanipulated B- and T-cells lacked evidence for a clonal relation between B-CLL and PTCL cells. Based on our findings, we discuss the different hypotheses which might explain the development of simultaneous PTCL and B-CLL.