The Pros and Cons of Cancer Registration E. Grundmann It may seem strange for somebody to hold a symposium on cancer regis tration and then submit a paper under the heading "The Pros and Cons of Cancer Registration." Indeed, this may be quite amazing to those of my colleagues who have been endeavoring for years or decades to provide a world-wide system of cancer registration. To be quite frank, this is exactly what I intended. Generally speaking, as scientists we are convinced that the work we do is worth while. We are in fact supported in this attitude by pub lic opinion, if one bears in mind that science is future-oriented. It may be said that science is a way for building the future, and that progressive-mindedness is - to use a modern word - "in." Never theless, we may somehow hesitate at this fashionable word. After all, science is not "in" in the way this word is interpreted by the younger generation. Indeed, this younger generation is much too sceptical whenever confronted with anything done by the older generation - and science is pursued primarily by the "establishment." Rather, it is "in" to criticize the system of society and, if possible, to overcome this system, which is responsible not only for many evils, but also for many illnesses."

(North American) Blastomycosis is caused by the dimorphic fungus Blastomyces dermati- tidis, first described by Gilchrist andStokes in 1896. The perfect stage was grown by Mc- Donough and Lewis in 1967 and is known as Ajellomyces dermatitidis. In the body and on appropriate media at 37 C, the organism presents itself as a round, thick-walled budding yeast cell, characteristically with a broad porus between mother and daughter cells. The yeast cell is multinucleated. For many years, North America was assumed to be the only place where blastomycosis was found, but recent demonstration of indigenous African cases changed this impression (Emmons et al., 1964). Within the United States, more cases are seen in Kentucky, Ohio, the Carolinas, Illinois, Michigan, Wisconsin, Iowa, Tennessee, Arkansas, and the Virginias than in the remainder of the country (Chick, 1971). In Mexico, occasionally, and in the provinces of Canada adjacent to the endemic areas of the United States, endemic blasto- mycosis has been recognized. Soil has been long suspected as the habitat for the fungus, but recovery from soil has seldom been successful (Denton and Di Salvo, 1964). The primary infection is, as a rule, pulmonary with frequent secondary foci in skin, bone, male genital system, and, eventually, spares no organ in widely disseminated cases. The rare cases of primary cutaneous blastomycosis are consequences of accidental percutaneous laboratory infection. These can be clinically easily differentiated from the average case of secondary hematogenous spread to the skin (Landay and Schwarz, 1971).

This second volume reports on the reaction patterns of lymph nodes in neoplastic and immunodeficient diseases. Based on the contents of volume 1, it presents a detailed survey of lymph node structures and their cellular components under these conditions. The patterns of nodal reactions to the development and spread of cancer have recently been investigated and discussed by several authors. Here, the immediate interactions between tumor tissue and the regional nodes have been assessed in experimental models and in human material. Using modern morphological methods such as im munohistochemistry on the light and electron microscopic level, new insights have been gained into the stepwise process of lymphogenous metastasis. Macrophages/reticulum cells were found to playa signifi cant role in this process, which is duly emphasized. Based on appro priate animal models, one chapter focuses on various subtypes of these cellular elements and their role in the two separate phases of tumor spread and the development of true metastases. The induction of fibronectin in lymph nodes is effected by tumor cells forming a special part of the extracellular matrix. The multifunctional fibronec tin molecule serves as a mediator between tumor cells and fibroblasts, furthering the formation of tumor stroma. This volume also contains a comprehensive survey of primary im munodeficiency syndromes and their nodal manifestations, reference being made to the most recent immunological knowledge."

Progress in science is often promoted by a new method. Diagnostic cytology, however, developed slowly over a whole century, mainly in differentiating malignant from benign cells from various tissues. The decisive step in this development was the intensive investigation of one local ization by Papanicolaou: The application of cytology for screening in the field of gynecologic oncology made it an acknowledged technique. Consequently, materials inves tigated before were tested again on a larger scale and new ones were included into the program. The possibility of a wide-range application of this diag nostic method, which carries a low risk for the patient and is low in cost, attracted the specialists of many fields. One of the problems which has resulted is the coordination of training and quality assurance for a large group of people from different fields and with different interests and whose experience in morphology varies. In this volume general problems of cytology are dis cussed, as is the question "who is a medical cytologist?" Education and training are the topics of the contributions by Coleman, Holzner, Jenny, Koss and Muller, cover ing the situation in the European Community, Germany, Austria, Switzerland, and the USA. A special contribu tion by Lange concerns the situation of cytotechnologists, paramedicals important for cytologic screening programs.

E. GRUNDMANN On behalf of the "Gesellschaft zur Bekampfung der Krebskrankheiten Nordrhein- Westfalen e. V. " I welcome you in Dusseldorf. During these two days problems of oncogenesis have to be discussed. The participants have been selected with the inten- tion of giving a review of the various fields which have some bearing on this topic. So you see here biochemists, cytologists, pathologists, immunologists, pharmacologists, virologists, and so on. Only by extensive cooperation of all scientists concerned in this field can this difficult problem of carcinogenesis ever be cleared up. Once the causal relations have been identified, we may have a reliable basis for cancer treat- ment. Research on oncogenesis is of great interest, but it is only a part of the worldwide cancer campaign. It is our hope that this symposium will contribute towards helping the cancer patient. He is the center of all our efforts. Keeping this in mind - let us begin! General Problems of Carcinogenesis Molecular Mechanisms in Chemical Carcinogenesis P. N. MAGEE Covalent binding of metabolites of the hepatocarcinogenic azo dye p-dimethyl- aminoazobenzene (DAB) to proteins of the livers of rats to which it had been ad- ministered was observed by JAMES and ELIZABETH MILLER in 1947. Since then a large amount of work on the interaction of many other chemical carcinogens with cellular macromolecules has been reported.

Tabelle 2. Physiko-chemische Eigenschaften von onkogenen DNS-Viren a Papovaviren Adenoviren Herpesviren Papilloma- Polyoma- Virus (Sub- SV40 (Sub- gruppe A) gruppe B) Molekulargewicht des 40 17-25 175 6 Virions x 10 Dalton Durchmesser (nm) 53 43 70-90 ohne Envelope 100 mit Envelope 150 - 200 Virion ohne ohne ohne mit Envelope Envelope Envelope Envelope DNS-Anteil am Partikel 12 12 12 7 (%) Anzahl der Kapsomere 72 72 252 162 Molekulargewicht 5 2. 5-3 20-25 100 6 der DNS x 10 DNS-Struktur doppelstriingig doppelstriingig ringfiirmig linear GC-Gehalt der DNS 49 41-49 48-57 45-74 (%) a Teilweise zitiert nach GREEN 1970 gruppe hervorgerufen werden, oder solche Viren bevorzugt in Verbindung mit solchen Tumorformen vorkommen. Die Darstellung des gegenwartigen Erkennt- nisstandes iiber einige wichtige Vertreter dieser Gruppe, die von Bedeutung fUr den Menschen sind oder die als experimentelle Modellsysteme Interesse finden, bildet den AbschluB dieses Artikels iiber onkogene DNS-Viren. 1m strukturellen Aufbau des Virions besteht eine groBe Ahnlichkeit zwischen den einzelnen Virusarten. Das Virion besitzt die Symmetrie eines Ikosaeders. Durch seine GroBe bedingt wird es aus einer unterschiedlichen Anzahl von Untereinheiten aufgebaut. Mit Ausnahme der Herpesviren, die eine zusatzliche Glykolipidproteinhiille (Envelope) besitzen, fehlt den iibrigen Viren eine solche zusatzliche HUlle. Den innersten Teil des Virions bildet das Core, indem sich mit Proteinen assoziiert die DNS befindet. Das Molekulargewicht des Genoms 6 liegt zwischen 3 -100 x 10 Dalton, so daB sich die Viren der einzelnen Gruppen durch einen recht unterschiedlichen Informationsgehalt auszeichnen.

E. GRUNDMANN, and W. VAHLENSIECK In recent years tumors of the male genital system have acquired a new scientific importance in many respects: First, epidemiologic studies have revealed a striking increase of prostate carcinoma in northwestern Europe and in the USA; it is now counted among the most frequent malig nant tumors in males. Geographic and ethnic distributions suggest that this tumor, too, may be triggered by exogenous factors of a still unknown nature. Histologic classification of malignant tumors of the prostate and testes has attained a certain finality, and the clinical relevance of the stages is recognized. Diagnosis by histology is now supplemented by aspiration biopsy cytology which offers a ready and reliable diagnostic potential. Its safety even surpasses that of punch biopsy histology and supports the qualification of cytology as a screening method. In the Federal Republic of Germany prostate carcinoma was recently included in the cancer prophylaxis program of the social insurance sys tem: Every man over 45 is entitled to one prophylactic free examination per year. Although the number of patients profiting from this opportu nity is still rather small, the number of patients is steadily growing who, as a result of this prophylactic examination, received medical treatment at an early stage of the disease and with a relatively better prognosis1 . Topical problems of social medicine are discussed in this context, as well as plans and developments of the social health service and of the supporting organizations, the federal societies for cancer campaign."

Due to the topology and structure of the lymph nodes, their role in the pathogenesis and development of diseases is a very special one. Each organ and even each organ-related region of the body has its own group of lymph nodes, specific topological reactions, such as in circumscribed inflammation or in the metastatic spread of malignant tumors. On the other hand, all the lymph nodes of an organism join in a uniform function effected by highly differentiated structures. Volume 84 of Current Topics in Pathology presents our current knowledge about the structure and reaction patterns of this "sec ondary" lymphoid organ. Despite our original intention to publish all the contributions in one book, it became necessary to divide them: Part 1 focuses on the involved nodal compartments, cell types, and functions, while Part 2 describes their reactions in inflammatory, neo plastic, and immune-deficient diseases. Even with the cooperation of more than 30 authors, the coverage cannot be exhaustive. The scope of both parts is limited to those reactions that can be described by direct and indirect morphological methods, including modern tech niques such as immune electron microscopy."

Bone Tumors - A Challenge for Cooperation E. GRUNDMANN Among the wide variety of human tumors, those of the skeletal system have an exceptional position in several respects. Above all, they are comparatively rare, and that is why reliable diagnostic criteria were compiled only recently, that is during the last three decades. It is only five years since the outlines of an international code of classi fication were traced. The code was applied and discussed critically and with varying results by several international working groups. Cer tain drawbacks are due to the broad and manifold spectrum of histolo gic manifestations in neoplastic bone. Even the best experts in dia gnostic histology would hardly be able to classify more than 85% of all bone tumors after the proposed code system. For quite a long time the osteoclastic giant cells, observed in almost any kind of bone tumor, have so much fascinated the histologist's eye that he was apt to pro claim the diagnosis "brown giant cell tumor" for almost any osteoclas tic tumor regardless of its benignity or malignancy. Nowadays the group of "giant cell tumors" though'restricted, still remains disputed in terms of malignancy and benignity. The problem will certainly not be settled in a definite way without extensive follow-up studies. In this context we may see actual progress in new regional. bone tumor registries being set up after the American example in many countries, among them the German Federal Republic."

During the past few years, a considerable number of monographs on bone tumors have been published. They are mainly restricted to bone tumors as clinical-pathological entities, since their diagnosis, more than that of other tumors, requires the interdisciplinary cooperation between orthopedic specialist, radiologist, and pathologist. However, investiga tions concerning the histogenesis of bone tumors are rather limited, although they might be helpful in explaining the unique morphological heterogeneity of tumors of the skeletal system. Furthermore, the histo genetic approach in the study of bone tumors may facilitate the inter pretation of the advanced cytobiological methods available for improv ing classification and diagnosis. Therefore, this volume presents recent pathological advances in the biological characterization of bone tumors. A major chapter deals with the differential diagnosis of Ewing's sarcoma as regards its demarcation from the so-called neuroectodermal tumor of bone. The analysis of the ground substances in bone-forming tumors may be helpful for their classification. Therefore the volume includes a chapter on the biochemical and histochemical analysis of different osteosarcoma types. Recently it has become clear that in addition to different collagen types which are not specific for bone tissue, several bone-specific proteins occur, one of which is osteonectin. Its distribu tion is obviously important for the classification and diagnosis of osteo blastic tumors. Proliferative behavior is of major importance for the diagnosis of malignant tumors.

1. Concepts on the Causal Genesis of Human Intestinal Tumors The action of chemical substances has a significant role in the genesis of human tumors. It is assumed that most human tumors are induced by exogenous chemical noxae (Schmahl, 1970;Heidelberger, 1975; and others). In the course of intensive efforts to discover the principles of tumor etiology, important insights have resulted in recent years. These are that chemical carcinogens do not only arise as products of our tech nological civilization, but that they also occur in nature as potent solitary carcinogens and cocarcinogens (e. g., as plant products). For review, see Hecker (1972) and Preuss mann (1975). Not only "complete" carcinogens are significant for the genesis of tu mors, but also substances which are first transformed to the actual carcinogenic com pound in the organism (Schmahl, 1975). The causal significance of exogenous noxae in carcinogenesis is indicated by the fact emphasized by Bauer (1963) that malignant tumors occur predilectively at those sites in the body which are in direct or indirect contact with the environment. This applies especially to the intestinal tract."

Die Entstehungsgeschichte dieses Bandes reicht weit zuriick. Schon wahrend der Arbeit an dem Cytoplasma-Teil des Handbuches in den friihen fiinfziger J ahren war unter Leitung von F. HfrCHNER ein Konzept fUr die Darstellung des Zellkernes entworfen worden, das zunachst auch ziigig ausgefiillt wurde. Indessen, mit dem Beginn der neuen, vor allem von Elektronenmikroskopie und Cytobiochemie getragenen Ara der Karyologie geriet die weitere E?-twicklung ins Stocken. Jeder Versuch, die Flut der neuen Erkenntnisse durch Anderungen oder Erganzungen des bereits Formulierten einzufangen, lief3 nur ein unerfreuliches und unhaltbares Flickwerk zuriick. Es blieb also keine andere Wahl, als auf alles bereits Fixierte zu verzichten. Einem neuen Beginn standen aber fiirs erste uniiberwindliche Schwierigkeiten entgegen: Die neuen Befunde iiberstiirzten sich und erschiitterten scheinbar festgefiigte Thesen, vermochten zunachst jedoch nur spezielle, aber keine allgemeingiiltigen Gesetzmaf3igkeiten zu vermitteln. Man muf3te also abwarten, bis eine gewisse Beruhigung der Situation eingetreten war, bis sich neue Ordnungs prinzipien abzeichneten, Verbindungsglieder zu friiheren, vielfach vergessenen Befunden sichtbar wurden und eine Zusammenschau alter und neuer Daten moglich erschien. Allerdings bedurfte es jetzt, im Ganzen und in Teilen, eines vollig F. BUCHNER, neuen Entwurfes, der wiederum dem ersten Betreuer dieses Bandes, zu danken ist, und dessen Realisation mit dem hier vorliegenden Abschnitt beginnt. Mit der detaillierten Darstellung der Chromosomen solI die Grundlage fiir das Verstandnis von Kernstruktur und Kernfunktion geliefert werden."

Die Orthologie und Pathologie des Wachstums und der Differenzierung waren schon Gegenstand des 1955 erschienenen Bandes VI!I dieses Handbuches. Seine von Biologen und Pathologen verfassten Kapitel stutzten sieh auf die Ergebnisse der klassischen Morphologie. Die morphologischen Probleme des Wachstums standen dabei ganz im Mittelpunkt. Mit der systematischen Anwendung biochemischer Methoden, der Histo- autoradiographie zur Markierung der Reduplikationsphase der DNS sowie der RNS- und Protein-Synthese, der Cytophotometrie zur quantitativen Messung der Nueleinsauren und schliesslich der elektronenmikroskopischen Cytologie standen in der Erforschung der Orthologie und Pathologie des Wachstums seit einem .Jahrzehnt Methoden von vorher ungeahnter Aussagekraft zur Velfugung. So wird jeder, der sich in den vorliegenden Band vertieft, feststellen, dass der Einsatz dieser Methoden zu einer sturmischen Entfaltung der Erforschung von Wachstum und Differenzierung gefuhrt hat. In der Konfrontierung dieses Bandes mit dem 1955 erschienenen wird er zugleich voller Respekt erkennen, wievieles schon in der klassischen Biologie und Pathologie zu diesem Thema grundgelegt war und bis heute fortwirkt. Im ersten Beitrag des vorliegenden Bandes vermittelt R. SCH1NDLER-Bern einen UEberblick uber die Biochemie der Regeneration. Er berichtet uber Struktur und Synthese der DNS, deren Stoerungen durch chemische Faktoren und strahlende Energie, eroertert die RNS-Synthese sowie die Synthese der Proteine und ihre Stoerungen. Ausfuhrlich stellt er dann die Regulation und den Ablauf der biochemischen Vorgange wahrend der Regenerationsprozesse am Beispiel der Oberflachenepithelien, der Zellkulturen und bei der Leberregeneration dar und behandelt schliesslich die Frage nach den Proliferations-ausloesenden bio- chemischen Faktoren.

Die Beurteilung der Krankheitsverlaufe von Tumorpatienten und deren Prognose bedarf - ebenso wie die onkologische Qualitatskontrolle - einer systematischen Dokumentation. Voraussetzung fur die Vergleichbarkeit der vom Patienten gewonnenen Daten und deren sinnvolle Auswertung ist eine nach einheitlichen Kriterien durchgefuhrte Erhebung, wie sie die Basisdokumentation vorschlagt. In der vorliegenden vierten Auflage werden die Standards fur die Dokumentation von Diagnostik, Therapie, Krankheitsverlauf und Status bei Abschluss der Betreuung definiert, die auf Empfehlung der "Arbeitsgemeinschaft Deutscher Tumorzentren" (ADT) bei jedem Tumorpatienten angewandt werden sollten.

Hypoxie als Ursache krankhafter Gewebsveranderungen - das ist heute ein unbestrittenes pathogenetisches Prinzip. Die theoretische, naturwissenschaftlich ausgerichtete Medizin erklart einen groBen Teil ihrer Phanomene tiber eine abnorme Beeintrachtigung der oxydativen Energieproduktion in den Zellen und Geweben. In der praktischen Medizin sind die Gefahren der Hypoxie dem Operateur ebenso gelaufig wie dem Arzt in der Allgemeinpraxis: der Sauerstoffmangel begrenzt die intraoperative Drosselungszeit einer Organ- durchblutung; er bedroht jeden Schock-Patienten. Die Erkrankungen des Kreis- laufs stehen statistisch an der Spitze der Todesursachen, allen voran der Herz- infarkt als lokale Myocard-Hypoxie. Die Pathologie hypoxischer Phanomene ist mit dem Namen Franz Btichners un16sbar verbunden. Ausgehend von seinen Studien tiber die Rolle des Herz- muskels bei der Angina pectoris hat er den pathophysiologischen Begriff der Coronarinsuffizienz in die Allgemeine Pathologie eingeftihrt und dabei synop- tisch Morphologie, Physiologie und Klinik erfaBt unter Einbezug der ftir Coronarinsuffizienz und Coronarinfarkt charakteristischen EKG-Verande- rung en. Diese Beobachtungen eroffneten ihm die allgemeine Bedeutung der Hypoxamie. Angeregt durch pathophysiologische Experimente entwickelten er und seine Mitarbeiter ein nahezu alle Organe umfassendes Werk, das man die "patho- physiologische Morphologie der Hypoxie" nennen konnte. Dieses Werk ist in Zeitschriften des In-und Auslandes weit verstreut. Es begann mit der "Hohen- pathologie", ausgelOst durch die sttirmische Entwicklung der Luftfahrt, und ftihrte zu subtilen Studien tiber die Veranderungen der parenchymatosen Organe beiexogenem Sauerstoffmangel, Beobachtungen, die analog auf endogene Hypoxamien zu tibertragen waren.