Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade.

The number of genes suggested to play a role in cancer biology is rapidly increasing. To be able to test a large number of molecular parameters in sufficiently large series of primary tumours, a tissue microarray (TMA) approach has been developed where samples from up to 1000 tumours can be simultaneously analysed on one glass slide. Because of the small size of the individual arrayed tissue samples (diameter 0.6 mm), the question arises of whether these specimens are representative of their donor tumours. To investigate how representative are the results obtained on TMAs, a set of 2317 bladder tumours that had been previously analysed for histological grade and Ki67 labelling index (LI) was used to construct four replica TMAs from different areas of each tumour. Clinical follow-up information was available from 1092 patients. The histological grade and the Ki67 LI were determined for every arrayed tumour sample (4x2317 analyses each). Despite discrepancies in individual cases, the grade and Ki67 information obtained on minute arrayed samples were highly similar to the data obtained on large sections (p<0.0001). Most importantly, every individual association between grade or Ki67 LI and tumour stage or prognosis (recurrence, progression, tumour-specific survival) that was observed in large section analysis could be fully reproduced on all four replica TMAs. These results show that intra-tumour heterogeneity does not significantly affect the ability to detect clinico-pathological correlations on TMAs, probably because of the large number of tumours that can be included in TMA studies. TMAs are a powerful tool for rapid identification of the biological or clinical significance of molecular alterations in bladder cancer and other tumour types.

High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer.

Studies by comparative genomic hybridization revealed that the chromosomal regions 3p25 and 8p11-p12 are recurrently amplified in bladder cancer. To investigate the prevalence of DNA copy number alterations in these chromosomal regions and study their clinical significance, we used probes for the RAF1 (3p25) and FGFR1 (8p12) genes for fluorescence in situ hybridization. A tissue microarray containing 2317 tumors was analyzed. The analysis revealed RAF1 amplification in 4.0% and FGFR1 amplification in 3.4% of interpretable tumors. In addition, deletions were found at the 3p25 locus in 2.2% and at the 8p11-12 locus in 9.9% of interpretable tumors. Both amplifications and deletions of RAF1 and FGFR1 were significantly associated with high tumor grade (P < 0.0001), advanced stage (P < 0.0001), and poor survival (P < 0.05) if tumors of all of the stages where analyzed together. RAF1 amplifications were associated with subsequent tumor progression in pT1 carcinomas (P < 0.05). The marked differences in the frequency of all of the analyzed changes between pTa grade 1/grade 2 and pT1-4 carcinomas support the concept of these tumor groups representing different tumor entities.

High-throughput tissue microarray analysis of cyclin E gene amplification and overexpression in urinary bladder cancer.

Studies by comparative genomic hybridization revealed that the 19q13 chromosomal region is frequently amplified in bladder cancer. The cyclin E gene (CCNE), coding for a regulatory subunit of cyclin-dependent kinase 2, has been mapped to 19q13. To investigate the role of cyclin E alterations in bladder cancer, a tissue microarray of 2,317 specimens from 1,842 bladder cancer patients was constructed and analyzed for CCNE amplification by fluorescence in situ hybridization and for cyclin-E protein overexpression by immunohistochemistry. Fluorescence in situ hybridization analysis showed amplification in only 30 of the 1,561 evaluable tumors (1.9%). Amplification was significantly associated with stage and grade (P: < 0.0005 each). Immunohistochemically detectable cyclin E expression was strong in 233 (12.4%), weak in 354 (18.9%), and negative in 1, 286 of the 1,873 interpretable tumors. The majority (62.1%) of CCNE-amplified tumors were strongly immunohistochemistry-positive (P: < 0.0001). The frequency of protein expression increased from stage pTa (22.2%) to pT1 (45.5%; P: < 0.0001) but then decreased for stage pT2-4 (29.4%; P: < 0.0001 for pT1 versus pT2-4). Low cyclin E expression was associated with poor overall survival in all patients (P: < 0.0001), but had no prognostic impact independent of stage. It is concluded that cyclin E overexpression is characteristic to a subset of bladder carcinomas, especially at the stage of early invasion. This analysis of the prognostic impact of CCNE gene amplification and protein expression in >1,500 arrayed bladder cancers was accomplished in a period of 2 weeks, illustrating how the tissue microarray technology remarkably facilitates the evaluation of the clinical relevance of molecular alterations in cancer.

[From epidemiology of melanoma to prevention--facts and references]. / Von der Epidemiologie des Melanoms zur Prävention--Fakten und Hinweise.

Melanoma incidence rates in Switzerland are very high for European standards. Incidence is increasing like in other white populations; melanoma mortality has stopped its secular increase and is decreasing in people under the age of 65. The reasons for the high melanoma rates in Switzerland can only be guessed: Switzerland is a rich country (melanoma is more prevalent among the rich); the Swiss are known to spend their vacations in Southern countries, exposing themselves to the sun. The paradox of increasing incidence and decreasing mortality rates is discussed, also from the view of the histopathologist. Melanoma patients are at increased risk for subsequent skin carcinoma (basalioma/spinalioma) and vice versa. This may be explained by the common risk factor: sun exposure. The importance of primary prevention is stressed; the Swiss Cancer League is organising annual education campaigns among youngsters. Secondary prevention should focus on high risk groups: families prone to melanoma; older men.

[A normal thyroid gland upon autopsy: a relatively uncommon finding]. / Die autoptisch normale Schilddrüse: ein relativ seltener Befund.

In a series of 420 autopsies the thyroid glands have been weighed, serial sections made and examined histologically with at least one specimen per lobe. There is an age-dependent increase in mean thyroid weight. In the 7th decade the mean weight exceeds 29 g and weights above this are regarded as goitre. Between the 4th and 8th decade the incidence of goitre is 20-30%, after which the incidence rises steadily to 64% in the 10th decade. The commonest thyroid pathology is hyperplastic nodules, which are found in 39% of patients (49.4% of males and 33.4% of females). 2.4% of all patients have adenomas, 1.9% primary carcinomas and 2.8% thyroid metastases. Inflammatory infiltrates are observed in 6.6% of cases (9.4% of females and 4.4 of males). To establish the incidence of normal thyroid glands we have studied 840 serial autopsies. Only 25% of thyroids are normal (19% of females and 30% of males). The incidence of normal thyroid glands tends to decrease with age and in no decade does it reach 50%.

[Histopathological and clinical aspects of benign cutaneous fibrous histiocytoma: increased rate of recurrent histiocytomas with a proliferative tendency]. / Histopathologie und Klinik des benignen kutanen fibrösen Histiozytoms.

An investigation of 2486 benign cutaneous fibrous histiocytomas (BFH) at the institute of Pathology of Münsterlingen, Switzerland, revealed a special group of histiocytomas, proliferative benign cutaneous fibrous histiocytomas (PBFH). These tumors recur 17 times more frequently than the so-called normal benign cutaneous fibrous histocytoma (NBFH). A quantitative analysis of six histopathological parameters showed that PBFH can be differentiated from NBFH with a sensitivity of 95%.

Digital 3D image reconstruction of ventriculocapillary communication as revealed in one case after transmyocardial laser revascularization.

TMR (Transmyocardial Laserrevascularization) was performed on the partially dyskinetic left ventricular anterior wall with stenotic coronary blood supply in a 61 year old woman with a history of angina and myocardial infarction. As an ischemic aneurysm developed in the anteroapical region of the TMR treated area, it became clear that TMR did not provide a substitute for coronary blood supply in this very heart region. The aneurysm was removed surgically 7 months after TMR and showed histopathologic features of an acute aneurysm. Three-dimensional image analysis helped prove the presence of linear tracks through several serial sections which were not easily visible in routine histology sections. Also, three-dimensional vessel reconstruction showed a connection between a small endocardial pit on one serial section with the capillary network in the adjacent serial sections. The results should not be generalized, as currently aneurysmectomy is an end point not reached by the majority of TMR-treated patients.

[Spitz nevus and Reed nevus: simulating melanoma in adults]. / Naevus Spitz und Naevus Reed: bei Erwachsenen ein Melanomsimulator.

One hundred and three cases of Spitz nevi were reviewed, 36% of these patients were adults. The lesions in children occurred primarily on the face and secondarily on the trunk followed by the extremities. In adults, they affect the legs in women, and the trunk in men as does malignant melanoma. Clinically they were diagnosed more frequently as Spitz nevi in children and adolescents than in adults. Spitz nevi were most commonly mistaken clinically for "common" melanocytic nevus, hemangioma, verruca, fibrous histiocytoma, molluscum contagiosum, granuloma pyogenicum, keloid, and melanoma. Histologically, there are various expressions of Spitz nevi, but they are usually compound melanocytic nevi with little pigmentation and typically large spindle- and/or epithelioid melanocytes. There are only small histopathological differences between Spitz nevi in childhood and adulthood: one important feature rarely seen in Spitz nevi of adults is multiple mitotic figures at the dermo-epidermal junction but rarely at the base of the melanocytic nevus. Nevus Reed is considered to possibly be a distinctly pigmented variant of Spitz nevus.

[Transmyocardial laser revascularization. Histopathology of laser channels in 10 postoperatively deceased patients 1 to 18 days after treatment with a CO2 laser]. / Transmyokardiale Laserrevaskularisation. Histopathologische Befunde an Laserkanälen bei 10 postoperativ verstorbenen Patienten 1 bis 18 Tage nach Behandlung mit einem CO2-Laser.

TMLR (Transmyocardial laser revascularization) is a disputed cardiosurgical technique available in Europe since 1994 that aims to deliver additional blood flow to ischemic myocardium from the left heart chamber. Goal of our study is morphological examination of laser channels in human hearts to answer the questions: Are there patent laser channels with communication to the left chamber and to intramural vessels? We examined hearts of 10 patients who died during the first 18 days after TMLR. Channels were examined in histological serial sections under the light microscope. Laser channels in the first days postoperatively have a lumen diameter of about 1 mm and are surrounded by coagulation necrosis about 500 microns thick. Despite phagocytic removal of necrotic tissue the lumen diameter decreases during the following two weeks. Open intramyocardial channels can be shown in all patients. These channels communicate with intramural vessels, but in no instance with chamber lumen. Our results suggest that clinical benefits are based on improved distribution of coronary blood. Additional blood is not delivered from left chamber lumen to the myocardium. However, our patients represent the small subgroup of the decreased. If similar observations can be made in the majority of patients living symptom free after TMLR remains open.

Melanoma in childhood: an EORTC-MCG multicenter study on the clinico-pathological aspects.

Melanoma in children is rare. Nevertheless, it is imperative that clinicians be aware that melanoma does occur in childhood. Yet there is very little information available on the clinico-pathologic variations, and the prognostic parameters of melanoma in children. This report presents the results of a multicenter study of 102 lesions originally diagnosed as cutaneous melanoma, conducted among 5 Western European countries and collected during the period 1961-1994. Criteria for inclusion in the study included: (1) diagnosis of cutaneous melanoma; (2) age up to 16 years at diagnosis; and (3) availability of representative microscopic slides. On the basis of the histologic review only, 60 lesions were confirmed as melanoma, and 42 lesions initially diagnosed as melanoma were reclassified as nevi; 31 of the latter contained a predominance of spindle cells. The only significant parameter associated with the development of metatases or fatal outcome was thickness of more than 2.00 mm. The 5-year survival rate observed in this study was 84%. Based on these findings we conclude that considerable over-diagnosis of melanomas in children occurs. In order, therefore, to give consistent epidemiological data on melanomas in children and to improve proper recognition of their diagnostic features, both by clinicians and by pathologists, we propose to set up a central registry of melanomas in children in Europe, under the auspices of the European Organization for Research and Treatment of Cancer.

[Pathologic-anatomic examination of prostatovesiculectomy samples in prostate carcinoma]. / Pathologisch-anatomische Untersuchung von Prostatovesikulektomiepräparaten beim Prostatakarzinom.

The incidence of the prostatic carcinoma as well as the cases treatable by radical prostatovesiculectomy with curative intention is increasing. The exact pathological examination of the specimens defines the stage of disease and subsequently the prognosis and therapeutic consequences. The compatibility of different scientific studies is made difficult by the lack of a standard in the pathological examination of the specimens. Our exactly defined rational method helps eliminate these troubles and ameliorate the interdisciplinary dialogue.

[Analysis and epidemiology of gallstones in deceased and autopsied patients of the Thurgau canton]. / Analyse und Epidemiologie von Gallensteinen anhand im Kanton Thurgau verstorbener und obduzierter Patienten.

In our postmortem examinations of patients in the canton of Thurgau from May 1989 through December 1991 we found a cholelithiasis or a condition after a cholecystectomy of gallstones in 44% of the women and 23% of the men. While gallstones were found in only 11% of the women and 7% of the men up to age 50, half of all women and every third man in the age group over 90 had gallstones. Among the gallstone carriers, 8% of the women and 2.5% of the men had developed a gall bladder--gall duct carcinoma. Where a liver cirrhosis was present, gallstones occurred at nearly the same rate in both sexes (45%/44%). 33% of the persons with gallstones had a solitary stone, and 31% had more than 10 stones. More than a third of all stones had a cholesterol content of more than 80%, and every seventh stone had a bilirubin content higher than 80%. The calcium content of more than 40% of the stones exceeded 5%. The examination for bilirubin can be easily performed with some exercise by means of the bilirubin test field on the urine sticks supplied by the Boehringer Mannheim company.

Cytokeratin expression in mucinous sweat gland carcinomas: an immunohistochemical analysis of four cases.

Four mucinous sweat gland carcinomas were examined for the distribution of cytokeratin (CK) polypeptides using immunohistochemical techniques on paraffin-embedded sections. All the tumour specimens reacted with monoclonal antibodies to CK 7, CK 8, CK 18 and CK 19. Antibodies to CK 1, CK 1/2/10/14, CK 1/5/10/11, CK 13, CK 14 and CK 20 did not stain any of the carcinomas. The results add additional support to the notion that mucinous sweat gland carcinoma represents a tumour histogenetically related to the eccrine secretory coil. Furthermore, the absence of CK 20 might significantly contribute to the differentiation of this tumour from cutaneous metastases from gastrointestinal carcinomas.

[Multiple primary melanomas of the hair follicles--a special form of malignant melanoma of the skin]. / Multiple primäre Melanome der Haarfollikel--eine Sonderform des malignen Melanoms der Haut.

Within 5 years, a 79-year-old male patient developed multiple primary melanomas, all which originated from the hair follicles. The fact that this patient was elderly, the high number of primary tumors, their follicular origin, and the lack of a history of such disorders in the patient's family caused us to postulate that multiple primary follicular melanomas represent a special form of malignant melanoma of the skin.