E. Kunze

Life style and occupational risk factors for bladder cancer in Germany. A case‐control study

A hospital‐based, case‐control study of 531 male and 144 female matched pairs was conducted in Germany to analyze the role of nonoccupational and occupational risk factors in the etiology of tumors of the lower urinary tract (bladder cancer). Smoking of cigarettes was associated with an odds ratio (OR) of 3.6 for men and 3.2 for women, compared with not smoking and showed a significant dose‐ and time‐response relationship for both sexes. Heavy pipe smoking significantly increased the risk (OR = 1.9 in men), and smoking of cigars did not alter the risk of bladder cancer. Controlling for smoking, a significantly twofold or more increase in risk was found for heavy consumption of coffee in both sexes and for heavy intake of beer in males. Increasing levels of total fluid intake were associated with increasing, smoking‐adjusted risks in men. Significant associations were found for chronic infection of the lower urinary tract (OR = 1.8), familial history of bladder cancer (OR = 2.5), and frequent consumption of high fat meals (OR = 1.4) among men and for frequent consumption of canned food in both sexes (OR = 1.7 for males, 2.4 for females). With regard to occupational history, significantly elevated odds ratios were found for ever‐employment in the printing (5.0), plastics and synthetics (2.6), rubber (2.5), mining (2.0), and dyestuffs (1.9) industries, for exposure to spray paints (2.9), zinc (2.3), chromium/chromate (2.2), oils (1.5), petroleum (1.4), stone dust (1.4) and metal dust/fumes (1.3), and for occupation as mining worker (2.0) and truck driver (1.8) among men. Multivariate logistic regression analysis showed significant contribution of coffee and beer drinking, ingestion of canned food, and familial occurrence of urothelial tumors to the risk of bladder cancer in men after accounting for the effects of tobacco smoking, occupational exposures, and a history of bladder infection. These other variables did not influence the risk attributable to occupational exposures.

Histology and histogenesis of two different types of inverted urothelial papillomas

Inverted papillomas are rare tumors of the lower urinary tract. Among 1829 reclassified tumors of the urinary bladder, renal pelves, ureters, and urethra, there were 40 (2.2%) inverted papillomas. The great majority of these were localized in the bladder. Because of distinctive histologic features and patterns of growth it is possible to differentiate between two basic types of inverted papillomas which were termed “trabecular” and “glandular.” The trabecular type consists of widely branched, anastomosing cords of urothelial cells originating directly from the overlying transitional epithelium. The trabeculae are arranged horizontally or perpendicularly to the surface epithelium and occasionally exhibit peripheral palisading of the cells. The glandular type is characterized by multiple round to oval islands of proliferated urothelial cells together with pseudoglandular and true glandular structures which are often still connected with the surface urothelium. The gland‐like structures are lined by stratified urothelium, the true glands by mucus secreting columnar epithelium. Sometimes glandular metaplasia of an intestinal type with goblet cell formation could be observed. Inverted papillomas of the trabecular type arise histogenetically from a proliferation of the basal cells of the urothelium. The glandular type develops apparently from a proliferative cystitis cystica and glandularis which, therefore, should be considered a potentially preneoplastic lesion. The predominant view of the biological behavior of inverted papillomas is that of a benign neoplastic lesion. Morphologic findings supplied some arguments in favor of a low grade malignant potential of these tumors. However, their malignant transformation seemed to be much lower than that of exophytic papillomas.

Development of Urinary Bladder Cancer in the Rat

As early as 1895 — long before any clues to the etiology of tumors in other organs were apparent — Rehn reported his observations of the increased occurrence of tumors of the urinary bladder in laborers who had daily contact with basic fuchsin over a long period. He suspected a causal connection between aniline, nitrobenzol, toluidine, and basic fuchsin and the development of the observed tumors. The years immediately following this report did not see confirmation of the suspected carcinogenicity of these substances (for a review of the literature see Temkin, 1963; Sarma, 1969; Price, 1971). Nevertheless, Rehn’s observations did initiate an early intensive search for substances that could induce tumors in the human bladder.

Stages of transformation in the development of N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced transitional cell carcinomas in the urinary bladder of rats.

The histogenesis of papillary and nonpapillary transitional cell carcinomas were studied morphologically and autoradiographically in 177 female Wistar rats after oral application of N-butyl-N-(4-hydroxybutyl)-nitrosamine with varying exposure and induction times. By far the largest proportion of carcinomas developed by a malignant transformation of preexisting papillomas or their precursors, the papillary hyperplasias. The transition into a focally malignant growth did not take place abruptly, but occurred stepwise through different successive stages of transformation, each having its own distinct morphological character. The first stage consisted of a focal, sharpely defined cellular atypia. In a further stage carcinomata in situ developed out of the atypical foci and progressed finally in a last stage of transformation into a circumscript infiltrative growth. The successive development of each stage occurred independent of any further carcinogen application after transformation was initiated at the molecular level. The number of papillomas with transformation stages increased with a lengthening of the exposure and induction time. 74.4% of all the registered papillomas had been transformed. Consequently papillomas must be considered potentially highly malignant. The 3H-TdR index was 4.2 times higher in atypical urothelial areas (7.6%) and 7.5 times higher in carcinomata in situ (14.3%) than in the surrounding papillomatous structures which appeared light microscopically benign. The latter demonstrated a rather constant 3H-TdR index, whether they bordered on atypical foci (1.8%) or carcinomata in situ (1.9%). The length of exposure and induction time exercised no significant influence on the degree of proliferative activity. Es wurde die Histiogenese papillärer und und nicht-papillärer Transitionalzellcarcinome nach oraler Applikation von N-Butyl-N-(4-hydroxybutyl)-Nitrosamin bei 177 weiblichen Wistar Ratten nach unterschiedlich langer Expositions- und Induktionszeit morphologisch und autoradiographisch untersucht. Der bei weitem größte Teil der Carcinome entwikkelte sich durch eine maligne Entartung präexistenter Papillome bzw. deren Vorstufen, den papillären Hyperplasien. Der Umschlag in ein herdförmig bösartiges Wachstum erfolgte nicht plötzlich, sondern schrittweise progredient über mehrere aufeinanderfolgende Transformationsstadien. Als erstes Stadium waren fokal scharf begrenzte atypische Urothelbezirke nachweisbar. Aus den Atypien entwickelten sich in einem weiteren Transformationsstadium Carcinomata in situ, die schließlich in ein circumscript invasives Wachstum übergingen. Die successive Entwicklung eines Stadiums aus dem anderen fand nach einmal vollzogener Transformation im molekularen Bereich unabhängig von einer weiteren Cancerogenzufuhr statt. Mit zunehmender Expositionsund Induktionszeit erfolgte ein kontinuierlicher Anstieg der Anzahl von Papillomen mit Transformationsstadien. Insgesamt waren 74,4% aller registrierten Papillome transformiert. Papillome sind somit in hohem Maß als potentiell maligne anszusehen. Autoradiographisch ergab sich in atypischen Urothelbezirken (7,6%) ein um durchschnittlich das 4,2fache und in Carcinomata in situ (14,3%) ein um das 7,5 fache höherer 3H-TdR-Index als in den umgebenden lichtoptisch gutartig erscheinenden Papillomstrukturen. Diese wiesen einen etwa gleichhohen 3HTdR-Index auf, gleichgültig, ob sie an atypische Urothelbezirke (1,8%) oder Carcinomata in situ (1,9%) angrenzten. Die Länge der Expositionsund Induktionszeit übte keinen signifikanten Einfluß auf die Höhe der Proliferationsaktivität aus. Die Entstehung papillärer und nicht-papillärer Transitionalzellcarcinome aus einem primären Carcinoma in situ (intraurotheliales Carcinom) spielte eine weit untergeordnete Rolle.

Primary mesenchymal tumors of the urinary bladder. A histological and immunohistochemical study of 30 cases.

The light microscopic and immunohistochemical features of 30 primary mesenchymal neoplasms of the urinary bladder are reported. Half of the cases represented smooth and striated muscle tumors (five leiomyomas, seven leiomyosarcomas including epithelioid and myxoid subtypes, one rhabdomyoma, one embryonal rhabdomyosarcoma and one alveolar rhabdomyosarcoma). One third of the tumors were of fibrohistiocytic origin (one fibrous histiocytoma and eight malignant fibrous histiocytomas including fascicular and storiform, inflammatory and pleomorphic subtypes). In addition, a malignant epithelioid schwannoma, a round cell liposarcoma, two hemangiomas and two mixed mesodermal tumors were observed. The morphology of the vesical mesenchymal tumors was identical to that of their counterparts known to occur in other sites, particularly in the soft tissue. Muscle-specific actin, alpha-1-antichymotrypsin, S-100-protein and neuron-specific enolase proved to be useful and reliable immunomarkers for differential diagnosis of poorly differentiated leio- and rhabdomyosarcomas, malignant fibrous histiocytomas and malignant schwannomas. Since some tumors coexpressed several classes of intermediate filaments, diagnostic immunocytochemistry should only be used considering a larger panel of antibodies and in close correlation with the histological and cytological features of the neoplasms.

Early sequential lesions during development of experimental gastric cancer with special reference to dysplasias

ZusammenfassungEs wurde tierexperimentell die Entwicklung des Magencarcinoms in seinen Frühphasen untersucht und geprüft, welche Rückschlüsse auf den Cancerisierungsablauf am menschlichen Magen möglich sind. Nach limitierter oraler Zufuhr von N-Methyl-N′-Nitro-N-Nitrosoguanidin an 174 Ratten entwickelten sich Carcinome direkt aus der sonst unveränderten Schleimhaut über mehrere aufeinanderfolgende Transformationsstadien, ohne gutartig erscheinende proliferative oder neoplastische Epithelläsionen zu durchlaufen. Als erste lichtoptisch erkennbare Veränderung ergaben sich fokal Dysplasien Grad I, die mit zunehmender Versuchszeit in Dysplasien Grad II und III übergingen. Die experimentell induzierten Dysplasien sind kausalgenetisch und in ihrem biologischen Verhalten nicht mit der Mehrzahl der am menschlichen Magen auftretenden Dysplasien gleichzusetzen. Die in der Regel im oberen Schleimhautdrittel lokalisierten Dysplasien des Menschen insbesondere des Grades I und II sind größtenteils entzündungsbedingt und reversibel. Die experimentellen Dysplasien im Bereich der Proliferationszone sind dagegen als potentiell prämaligne anzusehen, da sie irreversibel waren und sich progredient weiterentwickten. Nach den tierexperimentellen Befunden kommen beim Menschen insbesondere die Dysplasien des Grades III als mögliche Vorläufer von Carcinomen in Betracht, die sich in nicht entzündlicher Schleimhaut im Bereich der Proliferationszone entwickelt haben.SummaryThe early sequential development of gastric cancer was studied with experimental animals and examined with respect to what conclusions can be drawn for understanding carcinogenesis in man. After limited oral administration of N-methyl-N′nitro-N-nitrosoguanidine to 174 rats carcinomas developed in most cases directly from the otherwise unchanged mucosa through various successive stages of transformation, without passing through a benignappearing proliferative or neoplastic epithelial lesion. Focal dysplasia grade I was the first recognizable change observed by light microscopy, followed by dysplasia grade II, and subsequently dysplasia grade III. In spite of very similar morphological characteristics, the experimentally induced dysplasias cannot be simply equated in their etiology and biological behavior with the dysplasias of the human stomach. Dysplasias of grade I and II commonly found in man are usually associated with a chronic gastritis; they are located in the upper third of the mucosa and are for the most part reversible. The experimental dysplasias occuring in the proliferative zone of an otherwise undisturbed mucosa must be considered potentially premalignant, as they are irreversible and develop progressively. This finding points out that in man dysplasias grade III within the regenerative zone of non-inflammatory mucosa should be considered particularly as possible precursors of gastric carcinomas.

Histology and biology of metastatic chondroblastoma. Report of a case with a review of the literature.

This case report of a metastasizing chondroblastoma with a review of the literature was undertaken to gain a better understanding of the biologic behavior of this exceedingly rare tumor and thus to facilitate its clinical management. The lung was by far the most frequent metastatic site. Thus, all 7 patients with a proven metastatic chondroblastoma recorded up to now including the present case had developed multiple pulmonary metastases. The interval between the initial diagnosis of the primary and manifestation of lung metastases proved to be long, with a mean of 8.4 years. The average survival time was at least 12.3 years. The mean interval between diagnosis of metastatic disease and death amounted to at least 6.3 years. The histomorphologic features of metastatic chondroblastoma, its local recurrences and of the metastatic lesions differed in no way from conventional chondroblastomas. Because of the lack of cellular criteria of malignancy it is impossible to predict the potential biologic behavior of chondroblastomas, in particular with respect to their ability to metastasize. However, the presence of tumor emboli in the primary lesion is highly suggestive of a subsequent development of metastatic disease. The delayed induction of hematogenous metastases is best explained by a limited growth potential of the tumor cells. In case of a large primary tumor--especially in flat bones--with soft tissue invasion or in the presence of tumor emboli an aggressive surgical approach is suggested. When lung metastases have developed their surgical removal is recommended to hopefully prolong live expectancy or even to obtain a curative effect.

Morphology, classification and histogenesis of n-butyl-n-(4-hydroxybutyl)-nitrosamine-induced carcinomas in the urinary bladder of rats

The aim of the experiments was to determine whether the various types of carcinomas found in the human urinary bladder were reproducible in animals. We added n-butyl-n-(4-hydroxybutyl)-nitrosamine at a dose of 20 mg/kg/day to the drinking water of 177 female Wistar rats for a period of 40 to 150 days. After a total experimental time of between 150 and 250 days the animals were sacrified. The spectrum of carcinomas induced, includes all the types known to occur in man. The various tumor types occurred with the same frequency as in man and exhibited the same growth patterns. Variously differentiated papillary and non-papillary transitional cell carcinomas comprised 88.8% of tumors registered. 5.1% were keratinized and nonkeratinized squamous cell carcinomas, 2.2% adenocarcinomas. 1.1% were undifferentiated carcinomas and 2.8% were carcinomas of the mixed type with squamous cell and transitional cell differentiation. Histogenetically adenocarcinomas were found to originate from glandular metaplasia and squamous cell carcinomas from squamous metaplasia within completely developed transitional cell carcinomas. Furthermore it was possible to induce proliferative lesions such as von Brunns nests, cystitis cystica and cystitis glandularis. However, we found no clues to substantiate the development of adenocarcinomas from these proliferative lesions, or for that matter squamous cell carcinomas from squamous metaplasia of the otherwise unchanged urothelium. The present experimental model seems particularly suited for the search of further information regarding the development of tumors in the human bladder. Um Aufschlüsse darüber zu gewinnen, ob das in der menschlichen Harnblase auftretende Carcinomspektrum im Tierversuch reproduzierbar ist, wurde 177 weiblichen Wistarratten N-Butyl-N-(4-Hydroxybutyl)-Nitrosamin im Trinkwasser (20 mg/kg/tägl.) 40–150 Tage lang verabreicht. Nach einer Gesamtversuchsdauer von 150–250 Tagen wurden die Tiere getötet. Das Spektrum der induzierten Carcinome umfaßte alle auch beim Menschen vorkommende Typen. Weitgehende Übereinstimmungen ergaben sich auch in der prozentualen Häufigkeit der verschiedenen Carcinomtypen, in ihren Wachstumsformen und in ihrem biologischen Verhalten. In der weit überwiegenden Mehrzahl wurden mit 88,8% unterschiedlich differenzierte papilläre und nicht papilläre Transitionalzellcarcinome registriert. Verhornende und nicht verhornende Plattenepithelcarinome wurden in 5,1%, Adenocarcinome in 2,2% und undifferenzierte Carcinome in 1,1% der Fälle registriert. 2,8% der Carcinome stellten einen Mischtyp mit Übergangsepithel- und Plattenepitheldifferenzierung dar. Formalgenetisch entwickelten sich Adenocarcinome von glandulären Metaplasien und Plattenepithelcarcinome von Plattenepithelmetaplasien innerhalb voll ausgebildeter Transitionalzellcarcinome. Ferner wurden proliferative Veränderungen der Harnblasen-Schleimhaut wie von Brunnsche-Zellnester, die Cystitis cystica und die Cystitis glandularis beobachtet. Anhaltspunkte für die Entstehung von Adenocarcinomen auf dem Boden der genannten proliferativen Schleimhautläsionen und von Plattenepithelcarcinomen von entsprechenden Metaplasien der sonst unveränderten Harnblasenschleimhaut ergaben sich nicht. Das angewandte Cancerisierungsmodell erscheint für die Gewinnung von Erkenntnissen über die Tumorentwicklung an der menschlichen Harnblase als besonders geeignet und wertvoll.

High frequency of primary cutaneous lymphomas associated with lymphoproliferative disorders of different lineage

In patients suffering from primary cutaneous lymphomas, secondary malignancies of various origin may develop. However, the frequency of a second neoplasm deriving from another lymphoid lineage is still unclear and may be underestimated. We screened all our patients with primary cutaneous lymphomas from a 4-year recruitment period for a coexisting secondary lymphoproliferative disorder. The cohort comprised of a total of 82 patients with primary cutaneous lymphomas, 62 with primary cutaneous T-cell lymphoma (CTCL), 18 with primary cutaneous B-cell lymphomas, and two with CD4+/CD56+ hematodermic neoplasm/blastic lymphomas. Seven patients (8.5%) were identified with a coexisting lymphoma of a different lymphoid lineage. Four patients with Sézary syndrome (SS) suffered from systemic B-cell lymphoma. Two of these developed SS after chemotherapy of their B-cell lymphoma. The other three patients with various types of skin lymphomas (SS, Mycosis fungoides [MF], primary cutaneous marginal zone lymphoma) developed Hodgkin’s disease (hairy cell leukemia). Our data indicate that patients with primary cutaneous lymphomas have an elevated risk for the development of a secondary lymphoproliferative disorder even without previous chemotherapy. Possible explanations for this association include a genetic predisposition, alterations in early progenitor cells, underlying viral infections, and/or stimulation of a B-cell clone by the malignant helper T cells of the primary CTCL and vice versa.

Inability of galactoside-specific mistletoe lectin to inhibit N-methyl-N-nitrosourea-induced tumor development in the urinary bladder of rats and to mediate a local cellular immune response after long-term administration

Abstract Extracts from mistletoe (Viscum album L.) are assumed to exert an antineoplastic activity through their toxicity at high doses or by immunomodulation by nanogram quantities of a lectin. They are used as an unconventional therapy modality in the management of a wide range of cancer diseases, although no anticancer potential has yet been demonstrated. This prompted us to study the effect of galactoside-specific lectin (VAA) – a major protein constituent of mistletoe with immunomodulatory properties – on chemically induced tumor development in the urinary bladder of rats and on the local cellular immune response after long-term administration. To induce urothelial neoplasms N-methyl-N-nitrosourea (MNU) was administered in a single intravesical dose (7.5 mg/kg body weight). Highly purified VAA was given subcutaneously at its immunomodulatory dose (1 ng/kg body weight) twice a week over the total experimental period of 15 months. The incidences of epithelial bladder tumors were 25.0% following administration of MNU alone and 22.9% in the rats additionally receiving VAA, which proved not to be significantly different (P = 0.81). Quantitative immunohistochemistry analyzing a panel of immune cell types, including T lymphocytes, T helper/inducer cells (CD4), T suppressor/cytotoxic cells (CD8), T cells positive for interleukin-2 receptor (CD25), B lymphocytes and plasma cells, macrophages, natural killer cells, granulocytes and all leukocytes expressing the leukocyte common antigen (CD45), yielded no evidence for the ability of VAA to stimulate a substantial cellular immunological reaction in the wall of the normal urinary bladder or during urothelial carcinogenesis. In conclusion, the current experimental findings provide no support at all that the galactoside-specific mistletoe lectin is capable of inhibiting chemically induced bladder carcinogenesis and triggering a local cellular immune response after prolonged application. It thus seems highly improbable that commercial mistletoe preparations or VAA will be effective in the management of human bladder cancer by a cell-mediated immunological mechanism.