Chronische myeloische Neoplasien

Myeloproliferative neoplasms (MPNs) and related chronic disorders constitute a subgroup of myeloid malignancies which are defined according to clinical, morphological and molecular features by the actual World Health Organization classification of tumors of the haematopietic system. Screening procedures for a BCR-ABL fusion gene, JAK2, thrombopoietin receptor and KIT mutations are formally included in the diagnostic approach. Myelodysplastic/MPN overlap syndromes include rare entities such as refractory anemia with ringed sideroblasts characterized by a high proportion of JAK2V617F mutated cases. The paradigm of targeted treatment of chronic myeloid leukemia with imatinib has now been extended to eosinophilia-associated myeloid neoplasms with PDGFRA, PDGFRB or FGFR1 gene mutations. Pegylated interferon-alpha has convincingly been proved to reduce the JAK2 allele burden. JAK2 inhibitor drugs are currently being tested in clinical trials. The development of pathogenesis-targeted diagnostic and therapeutic approaches to the various MPNs will continue in the future.     

Neuroendokrine Neoplasien des Mediastinums

Primary neuroendocrine tumors (NET) in the mediastinum are very rare and among them thymic NETs are the most common. They represent 5?% of all thymic and mediastinal tumors. The WHO classification from 2015 subdivides thymic NETs into three groups; low grade (typical carcinoid), intermediate grade (atypical carcinoid) and high grade (large cell neuroendocrine carcinoma and small cell carcinoma). Through this change of mediastinal/thymic NET classification into three groups of malignancy, the nomenclature was adapted to that of the lungs, while the histological criteria for each entity remained the same. Thymic NETs typically occur in middle-aged adults and predominantly in males. Approximately 30?% are asymptomatic and the rest present with symptoms caused by local tumor growth, distant metastases and/or endocrine manifestations. Carcinoids can also occur as a part of multiple endocrine neoplasia type 1 (MEN1) and at the time of diagnosis commonly present with regional lymph node or distant metastases, which most often affect the lungs and bones. For the correct diagnosis tumor cell morphology, mitotic count and/or necrosis are crucial. Patients with typical carcinoids have the best prognosis, whereas the prognosis is slightly worse for atypical carcinoids but very poor for large cell neuroendocrine carcinomas. Small cell carcinomas have the worst prognosis and the shortest median survival time of approximately 14 months.     

Myeloproliferative neoplasms

The myeloproliferative neoplasms (MPN) are a group of clonal myeloid proliferations characterised by varying combinations of increased circulating red cells, granulocytes and platelets caused by excess proliferation of haemopoietic precursors in bone marrow with retained cellular maturation. These disorders typically pursue an indolent course requiring management of the consequences of the increased circulating elements (predominantly effects of thrombosis of haemorrhage in different body organs). Patients have complex symptoms, including fatigue, which are not yet fully explained. The MPN carry varying risks of progression to an acute phase characterised by increasing bone marrow and circulating blasts cells, and/or to fibrosis characterised by falling peripheral cell counts and increasing splenomegaly. Megakaryocyte morphology in BMT samples provides essential clues for diagnosis and subtyping in MPN; high quality and consistent reticulin staining for accurate assessment is also key.     

Mastozytosen und myeloische Neoplasien mit Eosinophilie

Mastocytosis and myeloid eosinophilic neoplasms are rare diseases of the bone marrow and are often a diagnostic challenge for hematopathologists. In mastocytosis, compact mast cell infiltrates represent the main diagnostic criterion and for myeloid eosinophilic neoplasms, eosinophilic granulocytes dominate the histological picture. Both disease groups include phenotypically and prognostically very different entities which are each defined by WHO criteria. For systemic mastocytosis (SM), a differentiation between indolent and aggressive or even leukemic forms is of prognostic importance. In indolent variants of SM, a local and/or systemic, usually reactive increase in eosinophilic granulocytes (SM-eo) is often observed. In contrast, an increase in neoplastic eosinophils is often observed in advanced SM, predominantly in diseases designated SM with associated non-mastocytic hematological neoplasms (SM-AHNMD), e.g. in SM with chronic eosinophilic leukemia (SM-CEL). Apart from mastocytoses, immunophenotypically aberrant tissue mast cells are only observed in certain rare forms of myeloid neoplasms with eosinophilia, in particular in myeloproliferative neoplasms (MPN-eo) with cytogenic anomalies in the platelet-derived growth factor receptor (PDGFR). The World Health Organization (WHO) classification of eosinophilic leukemias, however, fulfils the morphological and clinical requirements in a limited way only and needs an update.     

Diagnose und Graduierung zervikaler intraepithelialer Neoplasien

Diagnosing and grading of cervical intraepithelial neoplasias (CIN) are part of the routine practice of pathologists. However, discriminating between reactive changes and CIN1 and determining the different degrees of CIN may be challenging. Aim of this study was the evaluation of the proliferation markers Ki-67 and Mcm2 as well as p16 for their potential to aid in the assessment of CIN. 297 samples of normal epithelium, CIN1, CIN2, and CIN3 were assessed for expression of the above mentioned markers using tissue microarrays. There was an increase in the expression of Ki67 and Mcm2 from normal epithelium, CIN1, CIN2 to CIN3 (p<0.001 for both markers). Ki-67 was the most useful marker in differentiating between normal epithelium and CIN1. The number of p16-positive cases was 7% in CIN1, 46% in CIN2 and 86% in CIN3. There were no p16-positive cases in the group with normal epithelium. In order to grade CIN1 vs. CIN2 a combination of Ki-67 and p16 was helpful. Cases with a proliferation rate of <25% assessed with Ki-67 were most likely CIN1 (sensitivity 91.7%, specificity: 54.3%, positive predictive value: 73.3%, negative predictive value 82.6%). P16 was the most helpful marker in distinguishing between CIN2 and CIN 3 as p16 negative cases were more likely to belong into the CIN2 category. In summary, the histopathological assessment of cervical biopsies is based on H&E-stained slides. However, Ki-67 and p16 can be helpful in diagnosing and grading cervical intraepithelial neoplasia.     

Hemmung maligner Neoplasien des Menschen durch L-Asparaginase

Zusammenfassung 88 Kranke mit malignen Neoplasien wurden mit dem ausE. coli hergestellten Enzym L-Asparaginase behandelt. Das therapeutische Ergebnis konnte bei 60 Kranken ausgewertet werden. Bei 20 von 33 Kranken mit akuter Lymphoblastenleukämie, bei 1 Kranken mit Lymphosarkom in leukämischer Phase und bei 1 von 5 Kranken mit akuter Myeloblasten- oder Myelomonocytenleukämie wurde eine Knochenmarksremission erzielt. Die Remissionsdauer betrug 1–8 Monate. Von 21 Kranken mit malignen Lymphomen, Sarkomen und Carcinomen sprach nur 1 Patient mit malignem Melanom auf die Behandlung mit Asparaginase an. Die Enzympräparation bewirkte in der bisher angewandten Dosis keine Knochenmarkshemmung. Reversible Nebenwirkungen waren gekennzeichnet durch Fieber, Gewichtsverlust, abnorme Leberfunktionsproben, Hypoalbuminämie, Hypofibrinogenämie, Hypolipidämie, Hyperlipidämie und Überempfindlichkeitsreaktionen gegenüber der Enzympräparation. Die Asparaginabhängigkeit der neoplastischen Zellen ließ sich auchin vitro nachweisen. Dieser Test erlaubt jedoch noch keine absolut sichere Vorhersage des Behandlungsergebnisses. Wenn sich während der Behandlung einer primär asparaginase-empfindlichen Leukämie Resistenz entwickelte, waren die Leukämiezellen auchin vitro nicht mehr asparaginabhängig.

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Summary Eighty-eight patients with malignant diseases were treated with L-asparaginase prepared fromE. coli. The therapeutic result could be evaluated in 60 patients. A bone marrow remission was obtained in 20 of 33 patients with acute lymphoblastic leukemia, in one patient with lymphosarcoma in leukemic phase, and in one of five patients with acute myelo- or myelo-monoblastic leukemia. The remissions lasted from 1 to 8 months. Of 21 patients with malignant lymphomas, sarcomas or carcinomas only one patient with malignant melanoma responded to treatment with asparaginase. The enzyme preparation, at the dose levels used, did not cause bone marrow depression. Reversible side effects were fever, weight loss, abnormal liver function tests, hypoalbuminemia, hypofibrinogenemia, hypolipidemia, hyperlipidemia, and hypersensitivity reactions. The dependence on L-asparaginase of the neoplastic cells could also be demonstratedin vitro. This test, however, does not yet make possible an absolutely safe prediction of the therapeutic result. When resistance developed during the treatment of a primarily asparaginase-sensitive leukemia, the leukemia cells no longer required asparaginein vitro.

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Visiting Research Fellow, beurlaubt von der Medizinischen Klinik der Universität Köln.Mit Unterstützung des National Cancer Institute, Grants CA 08748 und CA 05826.     

Neuroendokrine Neoplasien des distalen Jejunums und Ileums

Neuroendocrine neoplasms (NEN) of the distal jejunum and ileum derive from serotonin-producing enterochromaffin (EC) cells. Due to their low proliferation rate and their infiltrative growth, they are often discovered at an advanced disease stage when metastasis has already occurred. The biology of these tumours is different from other NEN of the digestive tract. In order to standardise and improve diagnosis and therapy, the guidelines for the diagnosis and clinical management of jejuno–ileal NEN as well as for the management of patients with liver and other distant metastases from NEN were revised by the European Neuroendocrine Tumour Society (ENETS) in 2012. This review focuses on aspects relevant for surgical pathology.     

Neuroendokrine Neoplasien der Appendix und des Kolorektums

Appropriate diagnosis and treatment of neuroendocrine neoplasms (NENs) of the appendix and colorectum requires a detailed knowledge of their proper classification according to the updated WHO and TNM systems. The WHO classification distinguishes well differentiated NEN, the neuroendocrine tumors (G1 and G2 NETs), from the poorly differentiated carcinomas (G3 NECs). While NETs are common in the appendix and rectum, NECs occur predominantly in the colon. G1 appendiceal and rectal NETs of 1?cm in size or below that do not invade either the muscular wall or vessels bear almost no metastatic risk and can be treated by appendectomy or endoscopic resection. G2 appendiceal and rectal NETs larger than 1?cm in size in combination with other risk factors have an increased risk of metastasis and need to be treated more aggressively. NECs of the colon usually require chemotherapy in addition to resection. Today, most patients with NETs of the appendix and rectum have an excellent prognosis when these diagnostic and therapeutic guidelines are borne in mind.     

Klinische Relevanz von Glucocorticoid-Rezeptoren für die Behandlung lymphoider Neoplasien

Summary A generalized view on the mechanism of steroid hormone action is presented with special emphasis on glucocorticoids and their lymphocytolytic effects. The present knowledge on the structure and function of glucocorticoid receptors is reviewed. Following hormone binding, the receptor complex is activated to a form which is able to interact with chromatin or DNA. Several types of receptor mutants have been obtained in an animal cell culture system which allows selection of cell variants. The biochemical analysis of these mutants helped to establish a domain model of receptor structure. The quantitative effect of receptor numbers and hormone activity on lymphocytolysis is described in a cell culture model system and the results are discussed in view of the rational treatment of lymphoid neoplasia with glucocorticoids. The clinical experience with glucocorticoids alone and in combination therapy with cytostatic drugs is summarized. Our special emphasis is on acute lymphoblastic leukemia and malignant lymphoma as patients with these diseases can now be treated with remarkable success rates.

     

Malignant myelosclerosis. Myeloproliferative disorder or leukemia?

Four patients with the picture of "malignant myelosclerosis" are described and the relationship of this condition to acute granulocytic leukemia is discussed. It is suggested that there is a leukemic process from the beginning, that the fibrosis of the marrow is reactive rather than neoplastic, and that the disease should not be regarded as an accelerated form of chronic (primary) myelosclerosis. The presence of excessive reticulin in the marrow in acute leukemia, especially when the patient is first seen, indicates a bad prognosis and poor response to chemotherapy. A systemic fungal infection in one patient is described.     

Nachweis eines kleinmolekularen Glykoproteids bei Neoplasien und die Charakterisierung seiner chemischen Besonderheiten

Zusammenfassung Bei Paraproteinämien und malignen Tumoren konnten wir ein kleinmolekulares perchlorsäurelösliches Glykoproteid aus dem Urin isolieren. Es unterscheidet sich in Peptid- und Kohlenhydratverhältnissen und seiner Kohlenhydrat-Zusammensetzung von Urin-Glykoproteiden, die wir mit der gleichen Methodik bei Normalpersonen und entzündlichen Erkrankungen fanden. Es hat ein Molekulargewicht um 20 000, elektrophoretisch wandert es auf Acetatfolie bei pH 8,6 zwischen Albumin und ₁-Globulin-Fraktion. Es ist mit Ponceau S (Protein-Färbung) und Schiffscher Reagens (Glykoproteid-Färbung) darstellbar. Immunoelektrophoretisch liegt seine Präcipitationslinie im Bereich des schnellen ₁-Glykoproteids. Neben Glucose, Galaktose, Mannose und Fucose enthält es eine nicht identifizierte Kohlenhydratkomponente, die normalerweise nicht bei den Glykoproteiden des Serums nachweisbar ist. Der Neuraminsäuregehalt beträgt 8–9%, wovon 60–70% mit Neuraminidase freizusetzen sind. Die Aminosäure-Verteilung ergibt keine sicheren Unterschiede. Die Urin-Konzentration des Glykoproteids ist von der Ausdehnung des neoplastischen Prozesses abhängig. Bei Adenocarcinom des Magen-Darmtraktes ist die Neuraminsäure-Konzentration um 20–30% niedriger als bei Tumoren anderer histologischer Struktur und Lokalisation. Es wird diskutiert, ob diese Substanz in Beziehung zu dem neoplastischen Zellstoffwechsel steht.

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Summary In cases of paraproteinemia and malignant tumors we were able to isolate a low-molecular glycoprotein, soluble in perchloric acid, from the urin. Using the same methodology we found that in its peptide and carbohydrate ratios it differs from urin glycoproteins we found in normal persons and inflammatory diseases. Its molecular weight lies around 20,000 and electrophoretically, on acetate foil with a pH of 8,6, it migrates between albumen and the ₁-globulin fraction. It may be obtained from Ponceau S (protein colouring) and Schiff's reagent (glycoprotein colouring). Immuno-electrophoretically its precipitation line lies within the range of the fast ₁-glycoproteins. Besides glucose, galactose, mannose and fucose it also contains a pentose which is not normally detectable in the glycoproteins of serum. The neuraminic acid content lies between 8–9%, of which 60–70% may be liberated with neuraminidase. The amino acid distribution shows no safe differences. The urin concentration of the glycoprotein is dependent on the expansion of the neoplastic process. The neuraminic acid concentration in the case of an adenocarcinoma of the gastro-intestinal tract is lower by 20–30% than in cases of tumours of a different histological structure and localisation. It is being discussed wether this substance is connected with the neoplastic cell metabolism.

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Mit Unterstützung der Deutschen Forschungsgemeinschaft.     

Myeloproliferative disease in children: a demographic study.

Over eight years, eight cases of childhood myeloproliferative disease were recognised in the northern region of England (population 3.1 million). Five were classic chronic myeloid leukaemia (CML) and the three others, forms of myeloproliferative disease. No case of juvenile CML was recognised. With the exception of CML, "adult" type myeloproliferative disease of children is underrepresented in the literature and its natural history remains unknown.