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Im Kopf-Hals-Bereich kommen auch extranodale Lymphome vor. Diese machen 12–15 % aller malignen Kopf-Hals-Tumoren aus. In seltenen Fallen treten klassische Hodgkin-Lymphome (cHL) auf. Im Waldeyer-Rachenring ist das cHL mit einem Anteil von 1 % aller dort auftretenden Lymphome selten. Im Referenzzentrum fur Lymphknotenpathologie des Pathologischen Instituts der Universitat Wurzburg diagnostizierte Falle wurden naher analysiert. Von 21 Fallen wurden histologischer Subtyp und EBV-Assoziation uberpruft sowie klinische Angaben zusammengetragen. Zwolf Patienten waren mannlich, 9 weiblich. Das Durchschnittsalter lag bei 51 Jahren (Median 45; 35–72). Alle Proben stammten aus dem Waldeyer-Rachenring (Nasopharynx n = 15, Gaumentonsillen n = 5, Tonsilla lingualis n = 1). Meist fuhrten Symptome wie Otalgie, Schwellungen oder Nasenatmungsbehinderung zur HNO-arztlichen Vorstellung und Probenentnahme. Nur 4 Patienten zeigten eine B‑Symptomatik. In 6 Fallen (29 %) lag ein isolierter extranodaler Befall vor. Bei 15 Patienten (71 %) wurde im Rahmen des Stagings ein zeitgleicher zervikaler Lymphknotenbefall nachgewiesen. 6 Falle (29 %) waren EBV-assoziiert. Ausschlieslich extranodale Manifestationen des cHL im Waldeyer-Rachenring sind sehr selten. Eine Infiltration des extranodalen Gewebes bei einer primaren Lymphommanifestation in den zervikalen Lymphknoten kann haufiger vorkommen und wird moglicherweise oft nicht diagnostiziert. Daher kann die HNO-arztliche Untersuchung eine sinnvolle Erganzung der Stagingmasnahmen zur Festlegung des Tumorstadiums sein.

Zwischen einem Krankenhaus in Tansania und einem deutschen Institut fur Pathologie wurde 2007 eine Telepathologieverbindung eingerichtet. Uber die internetbasierte Plattform iPath wurden Falle anhand statischer histologischer Bilder begutachtet. Die Arbeit soll das diagnostische Spektrum bei einem Hilfsprojekt in einem afrikanischen Land skizzieren. Analysiert wurden 5230 Diagnosen, darunter Falle, die erst bei einer Zweitbegutachtung in Deutschland am ubersandten Paraffinblock geklart werden konnten. Es wurden von insgesamt 17 anatomischen Entnahmelokalisationen die fuhrenden Diagnosen in den 5 fallzahlstarksten Gruppen betrachtet. Ferner wurden Falle von Kindern/Jugendlichen und besondere Erkrankungen bewertet. Diagnostiziert wurden 2934 (56,1 %) benigne und 2134 (40,8 %) maligne Erkrankungen. Fur eine Zweitbegutachtung mussten 734 (14 %) Falle nach Deutschland geschickt werden. Die haufigsten Lokalisationen waren Cervix uteri (n = 1211), Prostata (n = 728), Haut (n = 626), Mamma (n = 524) und Lymphknoten (n = 340). In 504 Falle (9,6 %) waren Kinder/Jugendliche betroffen. Afrikatypische Erkrankungen kamen selten vor. Mittels Telepathologie konnten histopathologische Diagnosen zeitnah zur Verfugung gestellt werden. Probleme ergaben sich vor allem durch die instabile personelle Situation vor Ort. Die Materialqualitat entsprach oft nicht den Anforderungen fur eine weiterfuhrende Zweituntersuchung. Es wurde deutlich, dass im Rahmen dieses Hilfsprojektes nicht vordergrundig mit exotischen Krankheiten, sondern mehrheitlich mit Standardbefunden aus der Tumor- und Infektionspathologie zu rechnen ist.

Summary In this study, the authors report on the activity of Juan Rosai, one of the pathologists most engaged in the definition of cells, diseases and tumors occurring in the thymus and in the mediastinum during the last 60 years. With his morphological skills and tireless interest in clarification of disease patterns, he contributed extraordinarily to expand our knowledge of the mediastinal diseases and to improve our diagnostic approach. He determined extraordinary advances also in trasmission electron microscopy and in immunohistochemistry as powerful diagnostic tools. Moreover, he proposed and promoted, together with an international panel of Pathologists, the World Health Classification of Thymic tumors as a definite progress in our comprehension and diagnostics of thymic epithelial tumors (TET). Our purpose is to review J. Rosai’s achievements in thymic normal structure, in TET and particularly in the entity now definied as “thymoma”, in distinction from the thymic carcinoma. To do this, our narrative will also be based on personal memories, longstanding collaborations and/or friendship with J. Rosai.

Dysregulation of extracellular signal-regulated kinases (ERK1/2) is linked to several diseases including heart failure, genetic syndromes and cancer. Inhibition of ERK1/2, however, can cause severe cardiac side-effects, precluding its wide therapeutic application. ERKT188-autophosphorylation was identified to cause pathological cardiac hypertrophy. Here we report that interference with ERK-dimerization, a prerequisite for ERKT188-phosphorylation, minimizes cardiac hypertrophy without inducing cardiac adverse effects: an ERK-dimerization inhibitory peptide (EDI) prevents ERKT188-phosphorylation, nuclear ERK1/2-signaling and cardiomyocyte hypertrophy, protecting from pressure-overload-induced heart failure in mice whilst preserving ERK1/2-activity and cytosolic survival signaling. We also examine this alternative ERK1/2-targeting strategy in cancer: indeed, ERKT188-phosphorylation is strongly upregulated in cancer and EDI efficiently suppresses cancer cell proliferation without causing cardiotoxicity. This powerful cardio-safe strategy of interfering with ERK-dimerization thus combats pathological ERK1/2-signaling in heart and cancer, and may potentially expand therapeutic options for ERK1/2-related diseases, such as heart failure and genetic syndromes., Drugs targeting dysregulated ERK1/2 signaling can cause severe cardiac side effects, precluding their wide therapeutic application. Here, a new and cardio-safe targeting strategy is presented that interferes with ERK dimerization to prevent pathological ERK1/2 signaling in the heart and cancer.

Background Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on ‘double-hit’ MYC and BCL2 transformed lymphomas. Conclusions The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities. Electronic supplementary material The online version of this article (10.1186/s13073-019-0637-7) contains supplementary material, which is available to authorized users.

Dieses Kapitel gibt eine kurzgefasste Ubersicht uber die zahlreichen angeborenen Immundefekte, der Zahl vor dem Hintergrung der kompletten genetischen Analysen durch NGS standig zunimmt. Die wichtigsten Klassen werden vorgestellt und einige Syndrome und Befunde, die in der taglichen Diagnostik auftreten und an Lymphknotenveranderungen diagnostiziert oder zumindest in der Differenzialdiagnose erwahnt werden sollten, ausfuhrlich und detailliert beschrieben. Hierzu zahlen das Antikorpermangel Syndrom, das autoimmune lymphoproliferative Syndrom, die hamophagozytische Lymphohistiozytose, die chronische infantile Granulomatose und genetische Dispositionen fur bestimmte Erreger wie EBV und Tuberkulose.

In diesem Kapitel werden die haufigen Befunde von Ablagerungen exogener Fremdmaterialien nach Materialklassen und klinischem Kontext und die endogen entstandenen Speicherungen und extrazellularen Ablagerungen und deren Folgen besprochen. Zu der letzteren Gruppe gehoren seltene Befunde, wie die perivaskular hyalinisierende Lymphadenopathie, aber auch die Lipogranulomatose, massive Immunglobulinablagerungen, die Lymphknotenamyloidose und die hamophagozytischen Syndrome. Exogene Ablagerungen sind auserst vielfaltig, von den Stauberkrankungen, der Ablagerung von Tatowierungspigmenten, bis zu Lymphadenopathien bei Drogenabusus und Injektionsfolgen und verschiedenen Reaktionen auf Prothesenabriebmaterialien.

In diesem Kapitel werden alle nicht von Lymphozyten abgeleiteten Neoplasien, die primar im Lymphknoten auftreten, behandelt. Es sind einerseits seltene spezifische Neoplasien, wie das palisadenformige Myofibroblastom, Neoplasien der nicht-lymphozytaren Zellen des Lymphknotens, wie verschiedene Formen der malignen Histiozytosen, der Mastozytosen, der Tumoren der dendritischen Zellarten und unterschiedliche Neoplasien der Blut- und Lymphgefase des Lymphknotens. Diese Tumoren sind zwar selten, erfordern aber wegen ihrer besonderen Auspragung im Lymphknoten als wichtige Differenzialdiagnosen eine spezielle Beachtung.

Dieses Kapitel enthalt eine auserst breite und detaillierte Darstellung der speziellen Pathologie der Milz bei den unterschiedlichen Erregerbedingten Alterationen, wobei alle wichtigen Befunde auf dem Boden der lebenslangen Erfahrung des Erstautors mit ausgezeichneten Bilddokumenten versehen sind. Hierzu zahlt auch eine genaue Diskussion und Zuordnung histiozytarer und granulomatoser Erkrankungen nach pathogenetischen Gesichtspunkten und die Darstellung seltener mykotischer, protozoaler und metazoaler Infektionen. Weiterhin werden die Organveranderungen bei definierten autoimmunologischen Syndromen und tumorartigen Lymphoproliferationen sowie entzundliche Pseudotumoren besprochen.

Maligne Non Hodgkin Lymphome (NHL) des T- und NK-Zell Systems machen zwar in westlichen Landern nur rund 9 % aller NHL aus. Aufgrund der vielen morphologisch, klinisch und genetisch unterschiedlichen Entitaten erfordern sie jedoch trotz der relativen Seltenheit eine komplexe und detaillierte Diagnostik. Erst in der heute gultigen WHO Klassifikation wurde ihre Beziehung und Ableitung von unterschiedlichen T- und NK-Zell Populationen systematisch molekular und phanotypisch begrundet und diagnostische und differenzialdiagnostische Strategien realisiert. Dieses Kapitel bietet einen funktionell begrundeten Einstieg in die pathologische Diagnostik dieser Lymphome und setzt den Schwerpunkt auf die primar im Lymphknoten lokalisierten Entitaten, da verschiedene extranodale Entitaten mit primar intestinalem, lienalem oder kutanem Organbefall oder mit primar leukamischem Bild in den jeweiligen Organkapiteln behandelt werden.

In diesem Kapitel werden viele wichtige aber in ihrer Atiologie und Pathogenese oft unklare reaktive Lymphknotenveranderungen und -hyperplasien diskutiert. Dazu zahlen die Kikuchi Lymphadenitis, die hyperergischen und medikamenten-assoziierten Lymphadenopathien, die Lymphadenopathien bei Autoimmunerkrankungen, die Sarkoidose und weitere granulomatose Lymphadenopathien, die verschiedenen Formen der IgG 4- assoziierten Lymphadenopathie, das Rosai-Dorfman Syndrom, Vaskulitiden des Lymphknotens und die dermatopathische Lymphadenitis. Die diagnostischen Befunde sind reich in Bilddokumenten dargestellt und der diagnostische Zugang wird ausfuhrlich diskutiert.

Die Besprechung der Lymphknotenpathologie erfolgt an Hand einer auf embryonalen und neuen immunologischen Befunden basierenden Darstellung der Histophysiologie der Lymphknoten und der daran beteiligten Zellen. Verschiedene Gewebseinschlusse und -heterotopien werden dargestellt. Die reaktiven Veranderungen, ihre Definition, Struktur und Zytologie sowie die gewebliche Zuordnung zu den funktionellen Kompartimenten des Lymphknotens, der Follikelregion, der Marginalzone, der parakortikalen Pulpa, den Rand- und medullaren Sinus, sowie den Zellen des histiozytaren Systems stellen den wesentlichen Inhalt dieses Kapitels dar. Es folgt eine Besprechung des haufigen Befunds einer „Lymphadenitis ohne erkennbare Spezifitat“, der Lymphknoten im Abflussgebiet von Tumoren und der Lymphknotentotalnekrose.

In diesem Kapitel werden die den verschiedenen Gewebskomponenten des Organs zugeordneten Tumoren und tumorartigen Alterationen mit ihren makroskopischen und histopathologischen Befunden dargestellt. Nach einer Diskussion der zystischen Milzlasionen folgt eine detaillierte Darstellung gutartiger und maligner vaskularer Tumoren in ihren charakteristischen und milztypischen Befunden. Das grose Kapitel der speziellen hamatologischen Tumoren der Milz und des Organbefalls bei systemischen malignen Lymphomen wird auf dem Boden der neuen WHO diskutiert, wobei auch auf die heute historischen Befunde aus der Zeit, als therapeutische und diagnostische Splenektomien noch haufiger waren, zuruckgegriffen werden kann. Schlieslich folgt die Darstellung unterschiedlicher histiozytarer Tumoren in der Milz und die Diskussion von Milzmetastasen.

In diesem ersten von drei Kapiteln zur Pathologie der Milz erfolgt ein nach den pathologischen Befunden gegliederter Einblick in die Struktur und Funktion der Milz als Filter und immunologisches Uberwachungsorgan des stromenden Blutes und der hieraus resultierenden Befunde. Nach einer allgemeinen Definition und Klassifikation der makroskopischen und mikroskopischen Alterationen werden die speziellen histopathologischen Befunde reaktiver Alterationen, deren Pathogenese und Differenzialdiagnose, gegliedert nach den funktionellen Kompartimenten des Organs, der weisen und roten Pulpa, dargestellt. Die Speicherung endogener und exogener Substrate aus der Blutzellmauserung bei immunologischen Erkrankungen und metabolischen Syndromen wird detailliert besprochen. Von groser Bedeutung sind die Alterationen auf dem Boden einer gestorten Durchblutung des Organs.

Rhabdomyosarcomas are the most frequent malignant soft tissue tumors of childhood; however, because current multimodality treatments fail to improve the poor survival rate of children with metastatic rhabdomyosarcoma, new treatments are required. We previously identified the γ-subunit of the fetal acetylcholine receptor (fAChR) as a specific cell surface target in rhabdomyosarcoma. Here, we engineered human T lymphocytes to express chimeric receptors composed of the antigen-binding domain of a human anti-fAChR antibody joined to the signaling domain of the human T-cell receptor ζ-chain. The interaction of fAChRζ-transduced T cells with fAChR-positive rhabdomyosarcoma cell lines, but not with fAChR-negative control cells, induced T-cell activation characterized by strong secretion of IFN-γ and delayed lysis of tumor cells. Importantly, we found that in six of six rhabdomyosarcoma patients, chemotherapy increased fAChR expression on residual tumor cells in vivo. Our observations suggest that these fully human chimeric fAChRζ-transduced T cells, which should be well tolerated by the patient, have potential use in vivo both as a primary treatment for rhabdomyosarcoma and as a complementary approach to eradicate residual tumor cells after chemotherapy. (Cancer Res 2006; 66(1): 24-28)

In adult muscle, acetylcholine receptors (AChR) are restricted mainly to the motor endplate where the adult isoform (alphabetadeltaepsilon) is expressed. When skeletal muscle is denervated in animal models, there is atrophy of the muscle and a marked increase in expression of the AChR foetal isoform (alphabetagammadelta) containing a gamma-subunit. Similar changes in AChR expression are thought to occur in human muscle. While the role of denervation in regulating AChR gene expression has been widely studied, it has not been determined whether the transcriptional programmes responsible for defining different fibre types have an impact on the expression of AChR genes. We investigated biopsies from patients with a wide spectrum of neuromuscular diseases for expression of the AChR alpha- and gamma-subunits using RNase protection assays, alpha/gamma-duplex reverse transcriptase polymerase chain reaction, immunohistochemistry for foetal AChR and RNA in situ hybridization. Muscle from all patients with neurogenic disorders and, to a lesser extent, myogenic disorders, exhibited markedly increased transcription of the AChR gamma-subunit but, in contrast to previous animal studies, did not show increased AChR alpha-subunit. Moreover, both immunohistochemistry and RNA in situ hybridization revealed that AChR gamma-subunit hyperexpression occurred exclusively in atrophic type 1 and not in atrophic type 2 muscle fibres, irrespective of the underlying neuromuscular disease. We conclude that up-regulation of the AChR gamma-subunit in human muscle disorders is restricted to type 1 muscle fibres and, therefore, that AChR gamma-subunit expression is controlled by a muscle fibre type-restricted transcriptional programme. The factors influencing expression of this and other functional proteins should be relevant to the understanding and treatment of a range of neuromuscular disorders.

The survival of diffuse large B-cell lymphoma patients varies considerably, reflecting the molecular diversity of tumors. In view of the controversy whether cytologic features, immunohistochemical markers or gene expression signatures may capture this molecular diversity, we investigated which features provide prognostic information in a prospective trial in the R-CHOP treatment era. Within the cohort of DLBCLs patients treated in the RICOVER-60 trial of the German High-Grade Lymphoma Study Group (DSHNHL), we tested the prognostic impact of IB morphology in 949 patients. The expression of immunohistochemical markers CD5, CD10, BCL2, BCL6, human leukocyte antigen (HLA)–DR, interferon regulatory factor-4/multiple myeloma-1 (IRF4/MUM1), and Ki-67 was assessed in 506 patients. Expression of the immunohistochemical markers tested was of modest, if any, prognostic relevance. Moreover, the Hans algorithm using the expression patterns of CD10, BCL6, and interferon regulatory factor-4/multiple myeloma-1 failed to show prognostic significance in the entire cohort as well as in patient subgroups. IB morphology, however, emerged as a robust, significantly adverse prognostic factor in multivariate analysis, and its diagnosis showed a good reproducibility among expert hematopathologists. We conclude, therefore, that IB morphology in DLBCL is likely to capture some of the adverse molecular alterations that are currently not detectable in a routine diagnostic setting, and that its recognition has significant prognostic power.

Purpose Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied. Patients and Methods Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPbaseline) + 30 Gy of IFRT; or four cycles of BEACOPPbaseline + 20 Gy of IFRT. Results With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPPbaseline was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPPbaseline and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, −3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPPbaseline, 20 Gy was not inferior to 30 Gy (5-year FFTF difference, −0.8%; 95% CI, −5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, −4.7%; 95% CI, −10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy. Conclusion Moderate dose escalation using BEACOPPbaseline did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.

Purpose The standard of care for adolescent patients with Hodgkin's lymphoma (HL) is undefined, particularly the choice between pediatric and adult protocols. Thus, we compared risk factors and outcome of adolescents and young adults treated within study protocols of the German Hodgkin Study Group (GHSG). Patients and Methods Three thousand seven hundred eighty-five patients treated within the GHSG studies HD4 to HD9 were analyzed; 557 patients were adolescents age 15 to 20 years, and 3,228 patients were young adults age 21 to 45 years. Results Large mediastinal mass and involvement of three or more lymph node areas were more frequent in adolescents (P < .001). The incidence of other risk factors did not differ significantly between age groups. With a median observation time of 81 months for freedom from treatment failure (FFTF) and 85 months for overall survival (OS), log-rank test showed no significant differences between age groups regarding FFTF (P = .305) and a superior OS (P = .008) for adolescents. Six-year estimates for FFTF and OS were 80% and 94%, respectively, for adolescents and 80% and 91%, respectively, for young adults. After adjustment for other predictive factors, Cox regression analysis revealed age as a significant predictor for OS (P = .004), with a higher mortality risk for young adults. Secondary malignancies were more common in young adults (P = .037). Conclusion Outcome of adolescent and young adult patients treated within GHSG study protocols is comparable. These data suggest that adult treatment protocols exhibit a safe and effective treatment option for adolescent patients with HL. However, longer follow-up, including assessment of late toxicity, is necessary for final conclusions.

Purpose The HD9 trial of the German Hodgkin Study Group compared two different doses (baseline and escalated) of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) chemotherapy regimen in 1,196 patients with advanced-stage Hodgkin's lymphoma (HL). The previous analysis with 5 years median follow-up had indicated improved tumor control with BEACOPP escalated. Since the long-term safety and efficacy of this regimen has been debated, we report the 10-year follow-up. Patients and Methods Patients received one of three chemotherapy regimens: eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); eight cycles of BEACOPP baseline; or eight cycles of BEACOPP escalated. Results Median follow-up was 111 months. At 10 years, freedom from treatment failure (FFTF) was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for patients treated with COPP/ABVD (arm A), BEACOPP baseline (arm B), and BEACOPP escalated (arm C), respectively (P < .001). BEACOPP escalated was significantly better than BEACOPP baseline in terms of FFTF (P < .0001) and OS (P = .0053). A total of 74 second malignancies (6.2%) were documented, including acute myeloid leukemia (0.4%, 1.5%, and 3.0%), non-Hodgkin's lymphoma (2.7%, 1.7%, and 1.0%), and solid tumors (2.7%, 3.4%, and 1.9%). The corresponding overall secondary malignancy rates were 5.7%, 6.6%, and 6.0%, respectively. Conclusion The 10-year follow-up of the HD9 trial demonstrates a stabilized significant improvement in long-term FFTF and OS for BEACOPP escalated in advanced-stage HL. These results challenge ABVD as standard of care for this patient population.

We analyzed morphological and immunohistochemical features in 174 aggressive B-cell lymphomas of nodal and extranodal origin. Morphological features included presence or absence of a follicular component and cytologic criteria according to the Kiel classification, whereas immunohistochemical studies included expression of CD10, BCL-2, BCL-6, IRF4/MUM1, HLA-DR, p53, Ki-67 and the assessment of plasmacytoid differentiation. Patients were treated with a CHOP-like regimen. While the presence or absence of either CD10, BCL-6 and IRF4/MUM1 reactivity or plasmacytoid differentiation did not identify particular cytomorphologic or site-specific subtypes, we found that expression of CD10 and BCL-6, and a low reactivity for IRF4/MUM1 were favourable prognostic indicators. In contrast, BCL-2 expression and presence of a monotypic cytoplasmic immunoglobulin expression was associated with an unfavourable prognosis in univariate analyses. Meta-analysis of these data resulted in the development of a cumulative immunohistochemical outcome predictor score (CIOPS) enabling the recognition of four distinct prognostic groups. Multivariate analysis proved this score to be independent of the international prognostic index. Such a cumulative immunohistochemical scoring approach might provide a valuable alternative in the recognition of defined risk types of aggressive B-cell lymphomas.

Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) inhibits T-cell activation and interleukin-2 (IL-2) production. The PTPN22(gain-of-function)+1858T(+) genotypes predispose to multiple autoimmune diseases, including early-onset (non-thymomatous) myasthenia gravis (MG). The disease association and the requirement of IL-2/IL-2 receptor signaling for intrathymic, negative T-cell selection have suggested that these genotypes may weaken T-cell receptor (TCR) signaling and impair the deletion of autoreactive T cells. Evidence for this hypothesis is missing. Thymoma-associated MG, which depends on intratumorous generation and export of mature autoreactive CD4(+) T cells, is a model of autoimmunity because of central tolerance failure. Here, we analyzed the PTPN22 +1858C/T single nucleotide polymorphism in 426 German Caucasian individuals, including 125 thymoma patients (79 with MG), and investigated intratumorous IL-2 expression levels. Unlike two previous studies on French and Swedish patients, we found strong association of PTPN22 +1858T(+) genotypes not only with early-onset MG (P=0.00034) but also with thymoma-associated MG (P=0.0028). IL-2 expression in thymomas with PTPN22 +1858T(+) genotypes (P=0.028) was lower, implying weaker TCR signaling. We conclude that the PTPN22(gain-of-function) variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.

Chronic non-bacterial osteomyelitis (CNO) is an inflammatory, non-infectious disorder of the skeletal system with unknown etiology. Besides bone-inflammation, patients may present with inflammatory involvement of other tissues. Chronic recurrent multifocal osteomyelitis (CRMO) is the most severe form of CNO. We describe the occurrence of Crohn's disease (CD) in four patients, previously diagnosed with CRMO. Mutations in CARD15, encoding the NOD2 protein, have recently been found in patients with CD. Based on the occurence of CNO and CD in these four and several reported patients, we hypothesized that CD and CRMO might share a common autoinflammatory process. Thus, we searched for CD associated CARD15 gene variants R702W, G908R and 1007fs in 29 CNO patients, 4 of them additionally diagnosed with CD. In the latter one out of the four showed compound heterozygosity for the gene variants R702W and 1007fs. The allele frequency in the 25 patients diagnosed with CNO but not CD was not different from that already reported in healthy people (R702W 4.0%, G908R 2.0%, 1007fs 2.0%). The occurrence of non-bacterial bone inflammation and granulomatous intestinal inflammation seems to represent an extended phenotype of CD, which partly might be explained by potential disease causing mutations in CARD15. However, CNO without intestinal inflammation is not associated with common CARD15 gene variants. Therefore, other variants of genes coding for proteins involved in innate immunity and inflammation might predispose for the occurrence of CNO.

Alternative splicing of transcripts from many cancer-associated genes is believed to play a major role in carcinogenesis as well as in tumor progression. Alternative splicing of one such gene, the neural cell adhesion molecule CD56 (NCAM), impacts the progression, inadequate therapeutic response, and reduced total survival of patients who suffer from numerous malignant neoplasms. Although previous investigations have determined that CD56 exists in three major isoforms (CD56(120kD), CD56(140kD), and CD56(180kD)) with individual structural and functional properties, neither the expression profiles nor the functional relevance of these isoforms in malignant tumors have been consistently investigated. Using new quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) strategies and novel CD56 isoform-specific antibodies, CD56(140kD) was shown to be exclusively expressed in a number of highly malignant CD56(+) neoplasms and was associated with the progression of CD56(+) precursor lesions of unclear malignant potential. Moreover, only CD56(140kD) induced antiapoptotic/proliferative pathways and specifically phosphorylated calcium-dependent kinases that are relevant for tumorigenesis. We conclude, therefore, that the specific detection of CD56 isoforms will help to elucidate their individual functions in the pathogenesis and progression of malignant neoplasms and may have a positive impact on the development of CD56-based immunotherapeutic strategies.

Follicular lymphoma (FL) is a morphologically and genetically well-characterized B-cell non-Hodgkin lymphoma that can show predominantly follicular, combined follicular and diffuse, or predominantly diffuse growth patterns. Although approximately 85% of FLs harbor the translocation t(14;18)(q32;q21) and consistently display a follicular growth pattern, predominantly diffuse FLs are less well characterized on the phenotypical, molecular, and clinical level. We studied 35 predominantly diffuse FL by immunohistochemistry, classical chromosome banding analysis, fluorescence in situ hybridization (FISH), and gene expression profiling. A total of 28 of 29 analyzable cases lacked t(14;18), and 27 of 29 cases revealed a unifying chromosomal aberration, a deletion in 1p36. Morphologically, 12 FLs were grade 1 and 23 were grade 2, and the immunophenotype with frequent expression of CD10, BCL6, and CD23 was in line with a germinal center B-cell phenotype. The gene expression profiles of 4 predominantly diffuse FLs fell into the spectrum of typical FL, with a unique enrichment of specific gene signatures. Remarkably, patients with diffuse FL frequently presented with low clinical stage and large but localized inguinal tumors. These results suggest that predominantly diffuse FL represent a distinct subtype of t(14;18)-negative nodal FL with a unifying genetic alteration (deletion of 1p36) and characteristic clinical features.

Primary cutaneous marginal zone B-cell lymphoma is considered the cutaneous counterpart of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Although its molecular pathogenesis is currently unknown, an etiological link with Borrelia burgdorferi infection has been identified in European, but not in American or Asian cases. To better understand the pathogenesis and the geographical differences of cutaneous marginal zone B-cell lymphoma, 60 cases from the East Asia, Germany, and the United States at their initial presentation were subjected to the following analyses; (1) clinicopathological comparison between the geographical regions, (2) detection of B. burgdorferi DNA, (3) detection of the API2-MALT1 fusion transcript, a gene alteration specific to mucosa-associated lymphoid tissue lymphoma, and (4) inactivation of tumor suppressor genes (death-associated protein kinase (DAPK), p16(INK4a), p14(ARF), MGMT, TIMP3, CDH1, and RARB) by hypermethylation of the CpG islands. Cases from the three geographical regions showed similar clinicopathological features. However, moderate/marked tissue eosinophilia was found in 9/25 Asian cases, but only 1/23 German cases (P=0.011) and 0/12 American cases (P=0.015). All 60 cases were negative for either Borrelia DNA or API2-MALT1 fusion. Tumors from the three regions were highly methylated for DAPK (38-50% of the cases, mean 43%) and p16(INK4a) (42-70%, mean 49%), and the positivities were significantly higher than those of nonneoplastic skin (8%, P=0.0010 and 14%, P=0.0032, respectively). Methylation of these genes had no significant association with progressive features of the tumor. Primary cutaneous marginal zone B-cell lymphomas from the three geographical regions have common clinicopathological features, however, moderate/marked tissue eosinophilia is a feature found almost exclusively in Asian cases. Borrelia infection and API2-MALT1 fusion are not significant in this tumor. Methylation of DAPK and p16(INK4a) genes is a frequent event in this lymphoma at its initial presentation, but may not be associated with tumor progression.

Purpose Despite the common underlying translocation t(11;14) involving cyclin D1 that is present in nearly all cases of mantle-cell lymphoma (MCL), the clinical course of the disease is highly variable. The aim of the present study was to develop a quantitative gene expression–based model to predict survival in newly diagnosed patients with MCL that involves a minimum number of genes and is applicable to fresh-frozen and formalin-fixed, paraffin-embedded (FFPE) tumor samples. Patients and Methods The expression of 33 genes with potential prognostic and pathogenetic impact in MCL was analyzed using quantitative reverse-transcription polymerase chain reactions (qRT-PCR) in a low-density array format in frozen tumor samples from 73 patients with MCL. Multivariate Cox methods and stepwise algorithms were applied to build gene expression-based survival predictors. An optimized five-gene model was subsequently applied to FFPE tumor samples from 13 patients with MCL from the initial series and to 42 independent MCL samples. Results The optimized survival predictor was composed of the five genes RAN, MYC, TNFRSF10B, POLE2, and SLC29A2 and was validated for application in FFPE tissue samples. It allowed the survival prediction of patients with MCL with widely disparate clinical outcome and was superior to the immunohistochemical marker Ki-67, an established prognostic factor in MCL. Conclusion We here present a validated qRT-PCR–based test for survival prediction in patients with MCL that is applicable to fresh frozen as well as to FFPE tissue specimens. This test may prove useful to guide individualized treatment approaches for patients with MCL.

In extranodalen Marginalzonen-B-Zell-Lymphomen vom MALT-Typ (eMZBCL) wurde fur verschiedene anatomische Lokalisationen eine Assoziation mit einer durch einen spezifischen Erreger verursachten chronischen Entzundung (z. B. Helicobacter pylori im Magen) beschrieben. Fur die Lunge ist eine solche Erregerassoziation bislang nicht bekannt. Mittels einer erstmalig auf diese Fragestellung angewandten sensitiven Screeningmethode (SHARP-Screening), die auf der Analyse der bakteriellen 16S-rRNA-Gene beruht, haben wir die mikrobielle Diversitat von 9 eMZBCL der Lunge analysiert und mit 9 Kontrollfallen verglichen. Interessanterweise konnten in 8 der 9 eMZBCL-Falle Bakterien der Alcaligenacea-Familie (Alcaligenes, Achromobacter, AKIW733 ) nachgewiesen werden, wahrend keiner der 9 Kontrollfalle eine Besiedlung mit diesen Keimen zeigte. Weitere Untersuchungen, z. B. mit spezifischen PRC-Assays an groseren Fallzahlen sind notig, um zu klaren, ob Betaproteobakterien der Alcaligenacea-Familie mit der Genese von eMZBCL in der Lunge assoziiert oder sogar ursachlich beteiligt sind.

Although the phosphatidylinositide 3-kinase (PI3K)/Akt pathway has been reported to contribute to the malignant growth of multiple myeloma (MM), the true relevance of Akt kinases for this disease is still unclear. In particular, functional analyses in primary tumor cells and genetic target validation experiments are missing. Here, we used combined functional and molecular analyses to determine the importance of Akt activity in a large panel of primary MM samples and in MM cell lines. Akt down-regulation with isoform-specific siRNA constructs or with an Akt1/2-specific pharmacologic inhibitor strongly induced apoptosis in approximately half of the primary MM samples analyzed. Sensitivity to Akt inhibition strongly correlated with the activation status of Akt as determined by immunohistochemistry, phospho-Akt–specific flow cytometry, and Western analysis. Additional blockade of the MAPK and the IL-6R/STAT3 pathways was often not sufficient to decrease the viability of MM cells resilient to Akt inhibition. Taken together, these experiments led to the identification of 2 myeloma subgroups: Akt-dependent and Akt-independent MM.

Peripheral T-cell lymphomas (PTCLs) are biologically heterogeneous and have not been successfully correlated with specific T-cell subsets. We investigated PTCL, not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AILT), and anaplastic large cell lymphoma (ALCL) cases for FoxP3 expression to determine a potential derivation from regulatory T (Treg) cells. One PTCL-NOS case strongly expressed FoxP3 in the neoplastic T cells and showed unusual histomorphologic features with a dense infiltration of the lymph node by immunoblastic T cells and almost no reactive background infiltrate. The patient died shortly after diagnosis, suggesting that biologic properties of Treg cells may have contributed to the rapidly fatal clinical course. All remaining PTCL-NOS and AILT cases showed FoxP3 positivity only in the reactive infiltrate. Among ALCL cases, 4 of 6 ALK+ cases displayed weak and inhomogeneous FoxP3 expression in the tumor cells. FoxP3+ PTCL-NOS presumably derived from bona fide Treg cells occurs but seems rare in the Western population.

Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes ( P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB , which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a / ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17–92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways.

Aims: To report 16 cases of sclerosing angiomatoid nodular transformation (SANT) of the splenic red pulp. Methods and results: Patients were selected in two phases. An initial group of seven patients was diagnosed with SANT based on the presence of angiomatoid nodules. Sheets of inflammatory fibrosis were found in three patients, resembling inflammatory pseudotumour (IPT); nine further cases of IPT were reviewed. Angiomatoid nodules were detected, leading to the diagnosis of SANT in all cases. The splenic mass (10–150 mm in diameter) was polycyclic, composed of multiple small nodules of loose connective tissue comprising myofibroblasts and a dense network of capillaries as well as some remnants of sinuses. Collagenous fibrosis surrounded them. Bands or large sheets of fibrosis, infiltrated by various inflammatory cells, particularly polytypic plasmacytes, resembling IPT, were present in 10 cases. Conclusions: SANT of the red pulp is a distinct benign pseudotumorous lesion of the spleen characterized by the presence of angiomatoid nodules. We observed such angiomatoid nodules in all our cases of splenic IPT, which were not follicular dendritic cell or myofibroblastic tumours. We therefore recommend careful examination for angiomatoid nodules in all suspected cases of splenic IPT.

Mantle cell lymphoma (MCL) is an aggressive lymphoid tumour characterized by the translocation t(11;14)(q13;q32) and a poor clinical outcome (median survival: 3-4 years). Recent studies revealed that increased proliferation of the tumour cells and certain chromosomal aberrations, such as deletions of 17p13 and 9p21 represent major adverse biological markers in this disease, although the molecular targets of chromosomal imbalances in MCL have not been identified for the large majority of loci affected. To correlate histomorphological and proliferation features of MCL with genetic findings, we investigated 223 MCL by fluorescence in situ hybridization (FISH) (n = 157) and/or classical cytogenetic banding analysis (n = 129). FISH analysis turned out to be distinctly more sensitive in the delineation of aberrations. Complex karyotypic alterations were associated with higher proliferation indices and inferior prognosis. A comprehensive analysis of biological features including genetic alterations in MCL by hierarchical clustering resulted in the delineation of four tumour subgroups differing with respect to their genetic constitution and suggesting different transformation or progression pathways. Moreover, in one of the groups identified, a more indolent clinical behaviour was associated with few secondary aberrations and fewer known high-risk chromosomal aberrations, which points to the importance of the quality of karyotypic evolution in MCL tumours.

Molecular insights into the morphology of myeloproliferative neoplasms using an in situ PCR assay specific for the JAK2 mutation V617F

Generation of autoreactive CD4(+) effector T cells and defective production of regulatory CD4(+) T cells inside thymomas contribute to the development of myasthenia gravis (MG) in >90% of MG(+) thymomas. The molecular basis of these abnormalities is unknown. We report here that a) expression levels of class II major histocompatibility complex (MHCII) genes are variably decreased in thymomas, most prominently in histological WHO types A and AB; b) epithelial cells of type A and AB thymomas exhibit signal transducer and activator of transcription (STAT-1)-related defects of interferon-gamma (IFN-gamma) signaling and human leukocyte antigen (HLA)-DR expression in vitro; c) the promoter III (pIII)- and pIV-driven splice variants of the MHCII transactivator (CIITA) play a key role in MHCII gene expression in thymus and thymomas; and d) the pIV CIITA promoter is heavily methylated in thymomas. Recently, we also found that expression of the autoimmune regulator (AIRE) gene is absent from approximately 95% of thymomas. Among all theses abnormalities, only better preserved expression levels of MHCII (P < 0.001) in thymomas were significantly associated with the presence of MG. Taking the association of a gain-of-function polymorphism of the CTLA-4 and PTPN22 gene with MG in thymomas into account, we conclude that these acquired cellular abnormalities of the thymoma microenvironment in concert with inherited genetic high-risk polymorphisms of immunoregulatory genes have an impact on intratumorous thymopoiesis and appear to tip the balance toward central tolerance failure and development of MG. The findings imply that IFN-gamma and STAT-1 signaling play a role in MHCII expression in the human thymus and in the pathogenesis of paraneoplastic MG.

Background The genetic hallmark of mantle cell lymphoma is a t(11;14)(q13;q32). However, additional genomic alterations are likely involved in the pathogenesis of this lymphoma.Design and Methods To determine the incidence and clinical relevance of these aberrations, we analyzed 103 well-characterized samples of mantle cell lymphoma by fluorescence in situ hybridization for the most common recurrent additional genomic findings.Results Screening 16 different regions we detected additional genomic aberrations in 92% of the cases of mantle cell lymphoma. Common gains included 3q26, 8q24, 15q23, 7p15, and common losses 13q14, 11q22–q23, 9p21, 1p22, 17p13, 6q27, and 8p22. Deletions 8p22, 9p21, 13q14, and gain of 7p15 were associated with evidence of clonal heterogeneity. While there was no correlation of additional genomic aberrations and VH-mutation status, gain of 15q23 and deletion 6q27 were associated with lower disease stage (p=0.01 and p=0.04, respectively). Patients with deletion 13q14 had shorter overall survival times (p=0.01), and there was a strong trend towards inferior outcome in patients with deletion 9p21 (p=0.07). In multivariable analysis, loss of 13q14 and an International Prognosis Index score ≥ 3 turned out to be significantly associated with inferior clinical outcome (p=0.002 and p

Background Development and growth of extranodal marginal zone B-cell lymphomas (eMZBCLs) of mucosa-associated lymphoid tissue (MALT) type are thought to be highly dependent on Helicobacter pylori and autoantigens. Receptors mediating these effects are not characterised so far. Toll-like receptors (TLRs) recognise bacterial proteins and autoantigens, which results in inflammatory reactions and influences tumour development and growth. Materials and methods TLR4, 5 and 9 expressions were evaluated by immunohistology and confocal microscopy in gastric eMZBCL in comparison to other lymphomas infiltrating the stomach. Results TLR4 was exclusively expressed on the cell surface in all eMZBCL (n = 19) and not in chronic lymphocytic leukaemia (CLL, n = 12) or mantle cell lymphoma (MCL, n = 10). TLR5 was strongly expressed in CLL and weak in some eMZBCL (15 of 19), but not in MCL. TLR4, 5 and 9 were negative in all the three lymphoma entities. Conclusions Exclusive TLR4 expression may enable eMZBCL to interact with H. pylori and autoantigens. Blockade of TLR4 might be a new approach for therapy of eMZBCL of MALT type.

Summary In Helicobacter pylori gastritis gastric epithelium plays a central role in the innate immunity to H. pylori. However, epithelial receptors interacting with H. pylori have been poorly characterized so far. Recently a new triggering receptor expressed on myeloid cells-1 (TREM-1) has been identified on human neutrophils and monocytes. On these cells TREM-1 triggers innate immunity by stimulating the secretion of interleukin (IL)-8 and tumour necrosis factor (TNF)-α and thus amplifies bacterial-induced inflammation. In this study expression and function of TREM-1 in gastric epithelium exposed to H. pylori has been investigated. TREM-1 mRNA and protein were expressed on gastric epithelial cell lines as demonstrated by reverse transcription–polymerase chain reaction (RT–PCR) and fluorescence activated cell sorter analysis. Gastric epithelial TREM-1 expression was up-regulated directly by H. pylori and was independent of epithelial IL-8 induced by H. pylori. Immunohistochemistry and tissue RT–PCR demonstrated significantly stronger TREM-1 expression in H. pylori gastritis compared with the non-inflamed gastric mucosa supporting in vivo that epithelial TREM-1 is up-regulated during H. pylori infection. Stimulation of gastric epithelial TREM-1 receptor resulted in IL-8 up-regulation on mRNA and protein level, as shown by real-time PCR and immunoassay. This is the first study localizing TREM-1 on gastric epithelium. Functional data suggest that TREM-1 expressed on gastric epithelium amplifies inflammation of the underlying gastric mucosa by up-regulation of IL-8.

Kreislaufstorungen der Milz betreffen im Wesentlichen die rote Pulpa, die aufgrund ihrer Filterfunktion besonders in diese Storungen involviert ist. Die venosen Stauungen fuhren zu weiten Milzsinus, wahrend Kongestionen des arteriellen Schenkels zu engen Milzsinus fuhren. Hier sind insbesondere Erythrozytenanomalien und Hamolysen zu bedenken. Milzinfarkte sind zumeist durch Embolien verursacht.

Vaskulare Tumoren der Milz spiegeln die Vielfaltigkeit der Endothelformen in der Milz wider. So gibt es neben Hamangiomen auch milzspezifische Sinuswandzellangiome, die oft paraneoplastisch auftreten konnen und daher differenzialdiagnostisch gegenuber Metastasen abzugrenzen sind. Als maligner Tumor ist in erster Linie das Angiosarkom der Milz zu nennen. Als relativ neu beschriebene Entitat wird die sklerosierende angiomatose nodulare Transformation (SANT) vorgestellt, die haufig als Zufallsbefund bei bildgebenden Untersuchungen gefunden wird.

The spleen is commonly affected by malignant lymphomas and the macroscopic findings of the spleen correlate with different lymphoma entities. However, most lymphomas are not primarily diagnosed in splenectomy specimens. Exceptions include splenic marginal zone lymphomas and hepatosplenic T-cell lymphomas that are typically diagnosed from histological findings. In addition, hairy-cell leukemia, LGL leukemia and T-cell prolymphocytic leukemia typically show characteristic patterns of infiltration in the spleen which may be diagnostically useful. The different infiltration patterns of these tumors are discussed here.