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Pseudocapsules of artificial hip joints with ceramic- and metal on polyethylene combination of the articulating surfaces from 126 revision arthroplasties and 41 autopsies were studied histologically with semiquantitative evaluation of the polyethylene wear. The results were compared with reports of laboratory tests in the literature. We found in the autopsy specimens as well as in the biopsies from revision arthroplasties of prostheses implanted for 4 to 8 years three times less polyethylene wear particles released from the ceramic on polyethylene prostheses. The newly established synovium surrounding prostheses with ceramic heads appeared 20% reduced in thickness with minor villous transformation. Different types of metal on polyethylene prostheses revealed no differences in wear behaviour with the exception of the bipolar prostheses which showed a markedly increased polyethylene wear.

Aseptic loosening of joint prostheses is a quantitatively increasing problem. For evaluation of the pathogenesis of prosthesis loosening joint capsules and tissue membranes taken from the femoral and acetabular bone-cement-interface of 23 hips revised for aseptic loosening were examined. In all cases we found an excessive inflammatory histiocytic reaction with intracytoplasmatic incorporation of a small granular foreign material. This could be identified to be zirconium oxide by LAMMA-analysis. Zirconium oxide and polymethylmethacrylate (PMMA) wear particles could be shown in the cytoplasm of histiocytes by transmission electron microscopy. By quantitative grading of the histiocytic reaction and the intracellular granular wear particles we found that both were evenly distributed around the loosened prosthesis. Chronic inflammation due to bone cement abrasion is regarded as a leading cause of aseptic prosthesis loosening.

To gain insight into the tissue reactions leading to non-infectious loosening 25 autopsy specimens of femurs with well-fixed cemented femoral components of hip prostheses were analysed histomorphologically and morphometrically. The implant duration ranged from one month to 15 years. With the exception of some focal bone-cement contacts bone and cement were separated by a fibrohistiocytic soft tissue membrane. This membrane contained wear particles predominantly of the bone cement mantle and--less abundant--of the polyethylene cups. The amount of wear particles as well as histiocytes and necroses within the membrane statistically significantly increased with advancing time in situ. The cancellous bone adjacent to the soft tissue membrane often revealed a mainly histiocytic infiltration too, accompanied by bone remodeling in this area. The histiocytic inflammatory reaction at the bone cement interface, which is mainly caused by the accumulation of wear particles is considered to be of major importance for the non infectious late loosening of cemented prostheses.

Adenomatoid tumors are uncommon, benign tumors of the genital tract which have also been reported to occur extragenitally. Case reports on adenomatoid tumors of the adrenal gland exist. Most of these are incidentally discovered at autopsy or after the resection of incidentalomas. We report on the case of a young man with epigastic pain and with the finding of a 4 cm heterogeneous right adrenal mass on abdominal CT scan. After endocrine activity had been ruled out, an inactive, benign adrenal tumor was suspected and laparoscopic right adrenalectomy performed. The specimen was found to be an adenomatoid tumor. We discuss the differential diagnosis and the possible embryological origin of these tumors. The feature of 'local invasive ability' does not imply malignancy. All cases discovered surgically and at autopsy have been benign. Local resection seems to be the appropriate therapy.

In spite of intense diagnostic testing, no cause for the chronically aggressive hepatitis of a 48-year old male patient was found. Evidence for an autoimmune process, however, could be derived from a high titer of pANCA. Only according to the revised criteria of the working group on autoimmune hepatitis, but not to the first version, it was possible to classify this as an autoimmune hepatitis. Despite of high-dose steroid treatment and accelerated preparation for liver transplantation the patient died of the complications of rapid liver failure. Thus, in case of unclear rapid progressive hepatitis, the revised criteria of autoimmune hepatitis should be reviewed early and with high priority and consequent high-dose steroid therapy and preparation for liver transplantation should be initiated. The prognostic impact of a high titer of pANCA in patients with autoimmune hepatitis remains to be established.

Hintergrund. Fur das Tumor- und Metastasenmonitoring des uvealen Melanoms steht bisher kein spezifischer, serologischer Tumormarker zur Verfugung. Das neue tumorassoziierte Antigen Melanoma inhibitory activity (MIA) wird im uvealen Melanom und seinen Metastasen exprimiert und ist immunhistochemisch nachweisbar. Patienten und Methode. Wir berichten uber unsere serologischen Untersuchungen von MIA bei 38 Patienten mit uvealem Melanom. 4 Patienten wiesen bereits eine systemische Metastasierung auf. Zur Bestimmung der MIA-Serumspiegel wurde ein ELISA verwendet. Resultat. Bei den 34 Patienten ohne systemische Metastasierung betrug der Mittelwert (±1 Standardabweichung [SD]) der MIA-Serumkonzentration 3,6±1,0 ng/ml. Bei den 4 Patienten mit systemischer Metastasierung betrug der Mittelwert (±1 SD) 27,7±3,0 ng/ml. Die Differenz war statistisch hochsignifikant (/ldquo;student t test”: p=0,0001). Ergebnisse. MIA wird von uvealen Melanomen und deren Metastasen exprimiert. Patienten mit systemischer Metastasierung weisen signifikant erhohte MIA-Serumspiegel auf, sodass MIA eine viel versprechende Rolle als Tumormarker bei der Uberwachung und Nachsorge von Patienten mit uvealem Melanom spielen konnte.

Deoxyribonucleic acid ploidy was determined in paraffin-embedded tumor tissue from 116 patients with primary oral squamous cell carcinomas (including 5 carcinomas of the lip and 14 of the tongue) by means of flow cytometry. One hundred six cases were suitable for evaluation (91%). Sixty-eight percent of the cases (n = 72) showed a nondiploid nuclear DNA content. Nondiploidy correlated significantly with presence of lymph node metastases (p < 0.02) but not with tumor stage, grading (World Health Organization), or relapse-free and overall survival. Carcinomas of the lip and tongue turned out to be diploid more frequently than other oral squamous cell carcinomas (p = 0.002). In the 21 cases in which a comparison of DNA content of excisional biopsy specimens and subsequent resection specimens was possible a difference in DNA ploidy was found in one case only. The comparison of primary tumors and their lymph node metastases in 30 cases revealed a discrepancy of DNA content in five cases (17%), which was connected with a shift from nondiploidy to diploidy in four out of five cases. Fifty cases studied in parallel by means of image cytometry with Feulgen-stained tissue sections exhibited a concordance of the ploidy status in 87% and a significant correlation of the DNA index values obtained with both methods (p < 0.01). These results demonstrate that DNA ploidy in oral squamous cell carcinomas is distributed rather homogeneously within the tumors and remains rather stable in the lymph node metastases. Despite a significant correlation between nondiploidy and presence of lymph node metastases, ploidy failed to be a statistically significant parameter for prognosis in oral squamous cell carcinomas in our investigation.

We report on 46,XX true hermaphroditism and 46,XX maleness coexisting in the same pedigree, with maternal as well as paternal transmission of the disorder. Molecular genetic analysis showed that both hermaphrodites as well as the 46,XX male were negative for Y-chromosomal sequences. Thus, this pedigree is highly informative and allows the following conclusions: first, the maternal as well as paternal transmission of the disorder allows the possibility of an autosomal dominant as well as an X-chromosomal dominant mode of inheritance; second, testicular determination in the absence of Y-specific sequences in familial 46,XX true hermaphrodites as well as in 46,XX males seems to be due to the varying expression of the same genetic defect; and third, there is incomplete penetrance of the defect.

The processing of epidermal growth factor (EGF) and its receptor in human trophoblast during the first trimester and at term was studied using biotin-labeled EGF, an anti-EGF receptor monoclonal antibody and immunohistochemistry. In chorionic villi incubated with EGF-biotin the ligand was first bound to specific receptors on the syncytial surface, which are in contact with the maternal blood. After 2-5 min in the early gestation placenta, EGF-biotin was found at the basal plasma membrane of the syncytium accompanied by a pronounced EGF receptor immunostaining. In contrast, in the term placenta, immunostaining of EGF-biotin as well as EGF receptors was pronounced in the syncytioplasma within 30-60 min following EGF stimulation; in addition, EGF-biotin was found in some syncytial nuclei. These immunostaining reactions were enhanced after lysosomal blockage by chloroquine. The results reveal a transsyncytial, receptor-mediated transfer of EGF from the maternal blood to the cytotrophoblast, the proliferating part of the trophoblast, in the first trimester placenta. However, in the term placenta, the EGF signal seems to be directed primarily to the syncytium, thus probably influencing differentiated functions. In conclusion, the trophoblast examplifies three possible pathways of EGF processing: 1. transcytotic transfer, 2. direct intracellular signalling followed by lysosomal degradation, and 3. nuclear binding.

Immunohistochemical detection of proliferating cell nuclear antigen (PCNA) has been suggested as a new approach for determinating proliferative activity in paraffin-embedded tissue. In a prospective study PCNA immunostaining was performed in 284 colorectal biopsies using monoclonal antibodies 19F4 (Ogata et al. 1987) and PC10 (Waseem and Lane 1990) and compared with the Ki67 method. From each site three biopsies were taken and a variety of fixation regimens for frozen and paraffin-embedded samples tested. For frozen biopsies methanol fixation at −20° C proved best. In paraffin sections PCNA could be detected after methacarn fixation as well as after controled fixation at 4° C in 4% paraformaldehyde for 1 h and in most biopsies routinely fixed with 10% formalin. However, the latter fixation regimens revealed additional PCNA-positive cells in the normal superficial colonic mucosal epithelium. Although the percentage of cells positive for PCNA was generally lower than for Ki67, the rates correlated in a highly significant fashion, both in frozen methanolfixed biopsies, and in paraformaldehyde-fixed paraffinembedded samples. PCNA immunohistochemistry revealed a similar proliferative activity in different parts of the large bowel. A higher proliferative activity was found in inflamed mucosa, adenomas, carcinomas and even in normal mucosa from patients with colorectal neoplasms. In routinely fixed biopies, the monoclonal antibody PC10 was superior to 19F4 because of considerably less background staining. However, in the routine material only a rough estimate of the proliferative activity was possible by PCNA immunohistochemistry using these antibodies, because unpredictable numbers of non-S-phase cells were also stained. Thus, it was concluded that reliable results are only obtainable after careful control of the fixation conditions. Taking this reservation into account, PCNA immunohistochemistry still represents a convenient method for measurements of proliferative activity in paraffin-embedded colorectal mucosa and can be applied using methanol-containing fixatives as well as after 4% paraformaldehyde fixation.

Clear celled renal carcinomas (n = 37) were investigated by flow cytometry for intratumoural heterogeneity in DNA-ploidy and proliferation (S-phase rate). Using gross sections of the tumours, 178 regions of interest were selected and excised from the paraffin blocks. Of the tumours examined 30% (n = 11) were DNA-diploid and 70% (n = 26) were DNA-aneuploid. In six tumours (16%) homogenous DNA-aneuploidy was detected, and in 20 others (54%) there was intratumoural heterogeneity of DNA-content with a blend of either DNA-diploid and DNA-aneuploid regions (n = 16; 43%) or different aneuploid stemlines (n = 4; 11%). DNA-aneuploidy was present both in areas of the tumours composed of clear cells and in regions containing cells with cytoplasmatic eosinophilia. However, DNA-aneuploidy was correlated in a statistically highly significant manner with the degree of cytoplasmatic eosinophilia and the nuclear grading of tumour cells. The results were confirmed by comparative analysis of fresh-frozen and paraffin-embedded material. The DNA-aneuploid portions of the tumours, and the regions with increased cytoplasmatic eosinophilia, proved to have significantly higher S-phase rates than DNA-diploid and clear tumour cells. These results agreed well with the immunohistochemically determined percentage of Ki-67 (proliferation associated)-antigen positive cells. Our findings indicate that tumour cells with increased eosinophilia in renal cell carcinomas are distinct from real clear cells by virtue of their higher rates of aneuploidy and proliferative activity. These cells might therefore be regarded as a subclass with a more aggressive biological behaviour.

A 65-year old patient, suspected to be suffering from an androgen producing ovarian tumour, was treated preoperatively with the GnRH agonist triptorelin (500 micrograms/day s.c.) for 7 days. After an initial rise, gonadotrophin levels were suppressed under this treatment. The elevated serum testosterone concentrations were reduced by approx. 50% by the triptorelin injections. After the extirpation of the tumour (histologically a Leydig cell tumour of the ovary without signs of malignancy), primary cell cultures which secreted testosterone and androstenedione were prepared. Coincubation of the tumour cells with the GnRH agonist triptorelin had no effect on their androgen secretion. Treatment of the tumour cells with high concentrations (10(-5) M) of a GnRH antagonist, however, resulted in a 100% increase of their testosterone and androstenedione secretion. GnRH-binding sites of low affinity (Ka = 0.54 x 10(5) M-1) and high capacity (B max = 1364 x 10(-12) M/mg membrane protein) were identified in the tumour. These findings suggest that GnRH analogues might modify androgen secretion of sex-cord stromal tumours of the ovary via the suppression of endogenous gonadotrophin secretion and possibly also via direct effects on the tumour cells.

Although it is now 60 years after Erdheim's (1931) detailed description of vertebral alterations in severe acromegaly, it is still unclear whether osteoporosis is a consistent feature of acromegalic bone disease or not. We studied the vertebral trabecular bone of a 44-year-old woman who had suffered active acromegaly for more than 20 years, and compared it with 17 normal as well as 2 osteoporotic controls. Histomorphometry revealed a very low trabecular bone volume and thus documented the presence of osteoporosis. The mean trabecular plate thickness was strikingly increased in acromegaly (possibly caused in part by a low-dose fluoride treatment), whereas it was normal or reduced in the osteoporotic controls. The meticulous analysis showed islands of cartilaginous tissue in the core of the acromegalic trabeculae which were not present in any other sample. In these areas collagen II was detected by immunohistochemistry. Biochemical analysis revealed that collagen II accounted for 7% of the total collagenous matrix. The degree of hydroxylation of lysyl residues of collagen I was close to the average value of all control samples studied. Our data show that osteoporosis can occur in acromegaly and that it is characterized by unusual architectural and compositional features. These findings challenge the prevailing view that the matrix of osteoporotic bone always shows a normal composition.

Since more than a century elective radical dissection of regional lymph nodes is a standard procedure in tumour surgery. We discuss whether or not this standard is still up to date.The discussion was based on evaluations from well known clinical trials and cohort studies as well as from the results of the Munich Cancer Registry (MCR).Distant metastases develop extravasally from disseminated tumour cells that originate from the primary tumour. Therefore, three categories of metastases can be described: First, regional lymph node metastases treated by surgical and/or adjuvant therapy or by watchful waiting. Although the number of positive lymph nodes is one of the most important prognostic factor in all cancer sites, treatment of lymph nodes does not affect long-term survival. The number of positive lymph nodes is therefore simply a marker, but not a cause, of distant metastases. This seems to be generally valid. Also, the major part of local recurrences can be seen as "local metastases". The frequency of local relapse can be influenced by surgery, adjuvant treatment or radiotherapy only with a small impact on survival. Distant metastases normally determine the course of disease. Whether metastases can be a source of new clinically relevant metastases that influence the prognosis has to be questioned by the presented analyses of tumour growth times.The gene-based control of metastases implies a principal process of metastatic spread for solid tumours. The hypothesis "metastases do not metastasise" has a high plausibility. Reduction of lymph node dissection and its performance only in those cases where it is necessary for treatment decisions seems to be (bio)-logically consequent.

A circumferential aortic dissection with so-called intimo-intimal intussusception is a very rare complication of a dissecting aneurysm, in which the sock-like intimal flap is upended in the true lumen by the blood stream. The few cases reported thus far are based on radiological or intraoperative findings in acute dissections. The present postmortem study documents the very rare case of long-term survival of a chronic circumferential dissection with intimo-intimal intussusception.

A number of genes are known to control the development of the testis but the transcription factor SRY encoded on the Y-chromosome is considered to play the major role in initiating the first step in determining testicular differentiation. Mutations in this gene usually result in gonadal dysgenesis, but it is interesting to note that at least three of these mutations have been found to be familial. Furthermore, fewer than 10% of true hermaphrodites carry an XY karyotype, and so far only two patients have been documented to carry a mutation in the SRY gene. We have identified a familial mutation in the SRY gene involving a previously described locus. The index patient was born with severely ambiguous genitalia and on histological examination the gonads revealed true hermaphroditism, containing ovarian as well as testicular tissue. The father, his three brothers, and his first-born son carry the identical mutation. The severely feminized XY individual was diagnosed shortly after birth, gonadectomized and raised as female. SRY was determined by PCR and subsequently sequenced using cycle sequencing. A previously published point mutation was identified at nucleotide position 680 resulting in a non-conservative exchange of the amino acid iso-leucine at position 90 into methionine. This position represents a mutational 'hot spot', which seems to retain a certain amount of protein activity, enabling normal male development in some individuals. The patient is the third one reported in whom a mutation in the SRY gene results in ovarian-like development. Since ovarian development in XY individuals is extremely rare, its mechanism is of great interest. Further studies in this family might allow the identification of factors initiating and stimulating ovarian development. How far these infantile ovaries would have developed normally, however, is merely speculative.

In spite of intense diagnostic testing, no cause for the chronically aggressive hepatitis of a 48-year old male patient was found. Evidence for an autoimmune process, however, could be derived from a high titer of pANCA. Only according to the revised criteria of the working group on autoimmune hepatitis, but not to the first version, it was possible to classify this as an autoimmune hepatitis. Despite of high-dose steroid treatment and accelerated preparation for liver transplantation the patient died of the complications of rapid liver failure. Thus, in case of unclear rapid progressive hepatitis, the revised criteria of autoimmune hepatitis should be reviewed early and with high priority and consequent high-dose steroid therapy and preparation for liver transplantation should be initiated. The prognostic impact of a high titer of pANCA in patients with autoimmune hepatitis remains to be established.

Adenomatoid tumors are uncommon, benign tumors of the genital tract which have also been reported to occur extragenitally. Case reports on adenomatoid tumors of the adrenal gland exist. Most of these are incidentally discovered at autopsy or after the resection of incidentalomas. We report on the case of a young man with epigastic pain and with the finding of a 4 cm heterogeneous right adrenal mass on abdominal CT scan. After endocrine activity had been ruled out, an inactive, benign adrenal tumor was suspected and laparoscopic right adrenalectomy performed. The specimen was found to be an adenomatoid tumor. We discuss the differential diagnosis and the possible embryological origin of these tumors. The feature of 'local invasive ability' does not imply malignancy. All cases discovered surgically and at autopsy have been benign. Local resection seems to be the appropriate therapy.

Within the evolutionary progress in biomedical research and clinical medicine the medical education plays a derminting role. Problem based learning (PBL) or problem oriented learning (POL), respectively, are main though not quite new topics in the international discussion about modern teaching in medicine. After shortly reviewing the principles of PBL the problems of this concept in general and in the special situation of the Medical Schools of German Universities bound to legal rules and with high numbers of students are discussed with special regard to Pathology representing a substantially central teaching discipline. At the Medical School of the University of Munich since 1997 the so-called Münchner Modell (Munich Model) has been successfully established representing a hybrid curriculum with integration of PBL courses and traditional forms of teaching. The experience with special regard to the participation of Pathology is discussed.Modern scientific medicine requires an adequate teaching and learning culture. PBL is one main concept possibly to be integrated. In the future Pathology will continuously play a central role in medical teaching because of its imminent potential. Permanent reflecting the usefulness of modern teaching proposals and critical engagement are prerequisites.

Several salivary gland diseases present with the histomorphological features of a lymphoepithelial lesion with or without cyst formation. Some of the most important differential diagnoses (Sjögren's syndrome, marginal zone B-cell lymphoma, HIV-associated cystic lymphoepithelial lesion) are systemic diseases and require further investigation and therapy. However, in small biopsy specimens and in cases without relevant clinical information an exact diagnosis may be difficult to obtain. We have recently determined that the characteristic lymphoepithelial duct lesions develop by proliferation of basal cells of striated ducts, while we could not confirm the previously postulated participation of myoepithelial cells ("epimyoepithelial lesion/sialadenitis"). Although these duct lesions are typical of Sjögren's syndrome, they manifest in several diseases of salivary glands, exhibiting characteristic patterns concerning frequency and localization. This review discusses the most important lymphoepithelial diseases of salivary glands with respect to clinical presentation and histomorphology. Particular emphasis is placed on the lymphoepithelial duct lesions.

Currently no serological marker for the monitoring of uveal melanoma and its metastases is available. The novel tumor associated antigen Melanoma inhibitory activity (MIA) is expressed in the uveal melanoma and it's metastatic lesions.We report about the serum samples of 38 patients with uveal melanomas. 4 of these patients had overt metastatic disease. A nonradioactive one step ELISA was used to quantify the MIA serum levels.In the 34 patients without overt metastatic disease the serum concentration of MIA was mean (+/- 1 SD) 3.6 +/- 1.0 ng/ml. In the 4 patients with overt metastatic disease the serum concentration of MIA was mean (+/- 1 SD) 27.7 +/- 3.0 ng/ml. The difference was statistically highly significant (student t test: p = 0.0001).MIA is expressed in primary and metastatic lesions of uveal melanomas. The elevation of MIA serum levels in patients with metastatic disease from melanomas suggests a promising role as a serum marker for monitoring patients with uveal melanoma.

In ovarian carcinomas, alterations of the chromosomal region 20q13 and the cyclin D1 gene have been described. This study has sought to determine their prognostic significance. Fluorescence in situ hybridization (FISH) on dissociated nuclei and paraffin sections with DNA probes for 20q13.2 and cyclin D1, as well as immunohistochemistry (cyclin D1), were applied to formalin-fixed tissue of 69 invasive ovarian carcinomas, mainly of serous type. On dissociated nuclei 33/47 cases (70%) and on tissue sections 13/66 cases (20%) demonstrated an increase of 20q13.2 copies. The presence ofor =4 copies per nucleus (isolated nuclei) andor =3 copies per nucleus (sections) was associated with an adverse prognosis (Kaplan-Meier for FIGO stage III after stratification for residual tumour: p=0.0049 and p=0.03, respectively). Thirty-four out of 47 cases (72%) showed an increase of cyclin D1 copies. Kaplan-Meier analysis for FIGO stage III after stratification for residual tumour2 cm oror =2 cm revealed an unfavourable outcome for cases with more than two cyclin D1 copies (p=0.04). No correlation was seen between FISH and immunohistochemistry. Multivariate analysis identified residual tumour (p=0.0002), 20q13.2 gain (p=0.0004) and cyclin D1 gain (p=0.0343) as independent prognostic factors. It is concluded that gains of chromosomal region 20q13.2 and the cyclin D1 gene are frequent and biologically important events, with prognostic relevance, in advanced ovarian carcinomas.

Like sporadic colorectal cancers, ulcerative colitis (UC)-related cancers are thought to evolve through a multistep progression pathway. The genomic alterations important in sporadic colorectal carcinogenesis are well characterized, with loss of APC function being a frequent and early event. However, the genomic alterations in UC-related carcinogenesis are yet unclear and the role of APC is controversial. In this study genomic alterations in UC-related cancers, dysplasias and nondysplasias were assessed by comparative genomic hybridization (CGH). Alterations of the APC/beta-catenin pathway were evaluated by immunohistochemistry. 32 cases of UC-related cancers (14 with synchronous dysplasias and nondysplasias) and 42 sporadic cancers were matched by UICC stage. CGH was performed using DOP-PCR amplification after microdissection. Expression of beta-catenin, E-cadherin and APC were detected by immunohistochemistry in paraffin sections. Chromosomal alterations were present in 90% of the sporadic and 94% of the UC-related cancers. 86% of the UC-related dysplasias and 36% of the nondysplasias showed changes by CGH. Chromosome 5q was lost in 56% of UC-related cancers and 36% of the dysplasias but in only 26% of the sporadic cancers. Other frequent alterations in both cancer groups were loss of 18q, 8p, 17p, and gain of 8q and 20q. Immunohistochemistry showed a decrease of membranous and an increase of cytoplasmic expression of E-cadherin and beta-catenin in UC-related and sporadic cancers. APC expression was significantly decreased in both tumor types. Clonal chromosomal alterations occur early in UC-related tumor progression. UC-related and sporadic cancers share a set of common clonal abnormalities. The frequent loss of 5q and the altered expression of APC, beta-catenin, and E-cadherin proteins in UC-related cancers indicate a critical role of the APC/beta-catenin pathway in UC-related carcinogenesis.

In a prospective multicenter trial, it was our intention to elucidate clinical prognostic factors of seminomas with special reference to the importance of human chorionic gonadotropin (HCG) elevations in histologically pure seminomas.Together with 96 participating urological departments in Germany, Austria, and Switzerland, we recruited 803 seminoma patients between 1986 and 1991. Out of 726 evaluable cases, 378 had elevated, while 348 had normal HCG values in the cubital vein. Histology was reviewed by two reference pathologists. HCG levels were determined in local laboratories and in a study laboratory. Standard therapy was defined as radiotherapy in stages I (30 Gy) and IIA/B (36 Gy) to the paraaortal and the ispilateral (stage I) and bilateral (stage IIA/B) iliac lymph nodes; higher stages received polychemotherapy and surgery in case of residual tumor masses. Statistics included chi-square tests, linear Cox regression, and log-rank test.The HCG elevation is associated with a larger tumor mass (primary tumor and/or metastases). HCG-positive and HCG-negative seminomas had no different prognostic outcome after standard therapy. The overall relapse rate of 6% and the survival rate of 98% after 36 months (median) indicate an excellent prognosis. The calculation of the relative risk of developing a relapse discovered only stage of the disease and elevation of the lactate dehydrogenase concentration and its prolonged marker decay as independent prognostic factors for seminomas. A more detailed analysis of the prognostic significance of the stage revealed that the high relapse rate in stage IIB seminomas after radiotherapy (24%) is responsible for this result.We conclude that HCG-positive seminomas do not represent a special entity. Provided standard therapy is applied, HCG has no influence on the prognosis. Patients with stage IIB disease should be treated with chemotherapy because of the demonstrated higher relapse rate outside the retroperitoneum.

The molecular mechanisms leading to prostate cancer progression are poorly understood. In particular, those changes which are responsible for androgen-independent growth and metastatic spread in prostate cancer are an issue of current investigations.To gain more insight into these processes, paired microdissected samples from both untreated, locally advanced primary tumors (n = 20) and recurrences (n = 20) after conventional androgen-deprivation therapy (ADT) were analyzed retrospectively for microsatellite instability (MSI) and loss of heterozygosity (LOH) at nine loci on chromosomes 8, 18, and X by polymerase chain reaction. In parallel, 12 prostatic carcinomas treated by radical prostatectomy and nine corresponding lymph-node metastases were analyzed in the same way.The group treated with ADT showed a total of 10 MSI in 7 of the primary tumors (35%): 4 of these (20%) at one locus, and 3 of these (15%) at two loci. In the recurrences, MSI was observed in 4 cases (20%): 3 of these at one locus (15%), and 1 of these (5%) at two loci. LOH was found in 8 cases (40%) before as well as after ADT. In the radically resected carcinomas, MSI could be detected at two chromosomal loci in one of the primary tumors (8%) and in one of the metastases (11%); LOH was found in 2 primaries (16%) and 3 metastases (33%).Although MSI can be found in advanced prostatic carcinomas, it apparently does not play a major role in the progression of prostate cancer regarding androgen-independent growth or lymphogenous spread.

Histological differentiation between chondroma and chondrosarcoma is a common problem in surgical pathology. In a former study (3) we were able to show, that immuno-histochemical p53-accumulation in chondromatous neoplasias might be an additional hint for malignancy. Now we tried to find out, whether p53-accumulation is caused by TP53-aberrations or functional inactivation of p53-wildtype protein by MDM2. For this purpose, paraffin-embedded material of 80 chondromatous neoplasms (18 chondromas, 18 chondromatous neoplasms of uncertain dignity (i.e. cytologically suspicious but without definite invasive growth), and 44 chondrosarcomas (24 GI, 13 GII, 7 GIII)) were screened for TP53 gene-aberrations by means of DGGE (denaturing gradient gel electrophoresis; exons 5-8). The results were correlated with immunohistochemical p53-accumulation (DO-7, DAKO) and MDM2-expression (AB-1, Oncogene). A total of 43% of all chondromatous neoplasms showed TP53-aberrations in DGGE-analysis, i.e. 27% of chondromas, 50% of chondromatous neoplasms of uncertain dignity, 46% of GI-, 46% of GII- and 71% of GIII-chondrosarcomas. Exon 6 (58% of all cases with aberrations) and exon 8 (47%) were affected most frequently. No significant correlation between TP53-aberration and either p53-accumulation or MDM2-expression was present. A statistically significant correlation could be found between p53-accumulation and MDM2-expression (p0.0001). Regarding histological tumor-classification, p53-accumulation and MDM2-expression discriminated between chondromas/chondromatous neoplasms of uncertain dignity and well differentiated chondrosarcomas in a statistically significant manner. In the subgroup of p53-positive and MDM2-negative cases significantly more TP53-aberrations were detected by DGGE-analysis than in the other groups. Interestingly, the subgroup of p53- and MDM2-negative cases showed the second highest rate of TP53-DGGE-aberrations. Nearly 50% of these aberrations, however, were localized in exon 8, a mutation that is known to cause no p53-protein-accumulation. In conclusion, TP53-aberrations occur frequently in chondromatous neoplasms and show no significant association to either immunohistochemical p53-accumulation or MDM2-expression. Functional inactivation of p53 wildtype protein by MDM2-expression seems to be the major cause of p53-accumulation in chondromatous neoplasms and emphasizes the role of these parameters as additional hint for malignancy.

We report on a rare case of fatal congenital alveolar capillary dysplasia. The newborn boy of a 37 weeks' normal gestation suffered from persistent pulmonary hypertension without any cardiovascular malformation and died at the age of 4 weeks despite intensive treatment. The autopsy tissue was examined histologically, immunohistochemically, and ultrastructurally. Moreover, a three-dimensional tissue reconstruction based on serial sections was performed comparing the affected lung with normal lung tissue. We observed a unique pattern of pulmonary dysplasia: An extreme decrease of capillaries was localized centrally within thickened intra-acinar septa instead of capillaries intensely neighboring pneumocytes; ectatic veins normally running in the interlobular septa were found to accompany intralobular bronchovascular bundles, denying a clear distinction between pulmonary and bronchial veins; small muscular pulmonary arteries extended to the precapillary level and type 2 pneumocytes exceeded by far the type 1 pneumocytes, inverting the normal ratio. In summary, alveolar capillary dysplasia is assumed to be a primary capillary disorder of unknown origin, which possibly involves the regular differentiation of pneumocytes, according to the close alveolocapillary relationship during pulmonary ontogenesis. We consider the venous alterations as being part of the dysplasia, whereas the arterial phenomena might occur secondarily. Recent reports on affected siblings suggest a genetic component of pathogenesis.

Extending our previous efforts to characterize ovarian neoplasms by interphase cytogenetics, we analyzed a series of 32 mucinous tumors by nonisotopic in situ hybridization with seven different centromere-specific probes as well as by flow and image DNA cytometry; we then compared the data with results of p53 and Ki67 immunohistochemistry and MYC DNA-PCR analysis and of the clinical follow-ups. Of the tumors studied, 11 of 14 (78.6%) mucinous carcinomas, 7 of 7 (100%) mucinous tumors of low malignant potential (LMP), and 7 of 11 (63.6%) mucinous cystadenomas demonstrated chromosomal aberrations. The mean number of chromosomal aberrations (+/- SD) was slightly higher in DNA cytometrically nondiploid cases than in diploid cases (2.0 +/- 1.6 versus 1.6 +/- 1.2, not significant) but did not differ significantly among the study groups (carcinomas: 1.7 +/- 1.4; tumors of LMP; 1.9 +/- 0.7; adenomas: 1.4 +/- 1.4). Aberrations affected chromosomes 1 (14 of 27 cases) and 6 (12 of 31) most frequently, followed by chromosomes 17 (7 of 28), 7 (6 of 29), and X (6 of 28). Signal gain for centromere 1, which was the most prevalent finding (13 of 27), was observed in 3 of 10 mucinous cystadenomas, 2 of 4 mucinous tumors of LMP, and 8 of 13 mucinous carcinomas. All six moderately and poorly differentiated carcinomas demonstrated this aberration. Signal gain of centromere 6 (3 of 13) and centromere 7 (4 of 13) were found only in carcinomas (p0.05 and p0.025, respectively). The interphase cytogenetic results correlated neither with proliferative activity, immunohistochemical p53 accumulation, MYC DNA amplification, nor postoperative outcome. Compared with serous ovarian neoplasms (Lab Invest 1996, 75:473-485), mucinous tumors demonstrated signal gain for chromosome 1 (p0.0001) and signal loss for chromosomes 6 (p0.001) and X (p0.01) significantly more often. Loss of centromere 17 was more characteristic for serous than for mucinous carcinomas (p0.05). Our observations show that chromosomal aberrations in mucinous ovarian neoplasms are apparently not random. These results support the notion that the molecular genetic changes in mucinous neoplasms differ from those in serous tumors.

Tumorassoziierte Proteasen, vor allem das uPA-System and interaktive Proteasesysteme, sind essentielle Parameter der Invasion und Metastasierung (J Clin Oncol 13:2084–93, 1995). Ziel der Studie war es die prognostische Bedeutung eines erweiterten Stagings einschlieslich eines biologisches Gradings und disseminierter Tumorzellen zu untersuchen. In einer prospektiven Serie an 203 operierten Magenkarzinom-Patienten wurden auf disseminierte Tumorzellen in Knochenmarksproben hin untersucht und immunhistochemisch die Expression der uPA-Aktivatoren (Plasminogen, Kollagenase 4, Cathepsin D, Antithrombin 3) und Inhibitoren (α-2-Antiplasmin, α-2-Macroglobulin, Antitrypsin, Antichymotrypsin) bestimmt. Die Kaplan-Meier-Analyse zeigte eine signifikante Prognose-Assoziation von Cathepsin D (p=0,0042), α-2-Macroglobulin (p=0,0281), Antitrypsin (p=0,0372) und Antichymotrypsin (p=0,0002). Die multivariate Cox-Analyse fand PAI-1 (p=0,002; rel Risiko 1,86; 95% KI 1,32–3,73) und Cathepsin D (p=0,020; rel Risiko 2,98; 95%KI 1,28–6,91), neben pT, pN und erweiterten Eingriffen, als eigenstandige Prognoseparameter. Die Tumorzelldissemination fand sich in fruhen Tumorstadien (pT1, pT2) und bei pN0-Patienten als unabhangiger Faktor. Durch dieses neue Staging-Modell kann eine exaktere prognostische Differenzierung erfolgen. In einer Konfirmationsstudie sollte dieses neue Konzept uberpruft werden.

Several lines of evidence suggest that the proliferation of ovarian carcinoma might be stimulated by gonadotrophins. A number of Phase I/Phase II clinical trials have reported that the suppression of endogenous luteinizing hormone and follicle-stimulating hormone secretion by luteinizing hormone-releasing hormone (LHRH) analogs induced objective remissions and/or disease stabilization in 10-30% of patients with advanced refractory ovarian carcinoma. The current study was performed to evaluate whether the addition of LHRH agonist treatment to standard platinum-based chemotherapy could prolong survival of patients with surgically treated Stage III or IV epithelial ovarian carcinoma.One hundred and thirty-five patients with Stage III or IV epithelial ovarian carcinoma participated in this prospective randomized double blind trial. After cytoreductive surgery, 69 patients received monthly injections of a depot preparation of the LHRH agonist [D-Trp6] LHRH (triptorelin, 3.75 mg) and 66 patients received placebo until their deaths or termination of trial, respectively. All patients were treated with a standard platinum-based chemotherapy, and, if necessary, with second- or third-line cytotoxic regimens.Endogenous gonadotrophins were reliably suppressed in patients treated with triptorelin. However, their progression free and overall survival were not significantly different from that of patients receiving placebo injections (statistical power80% for a difference between both groups ofor = 20%).The results of this trial suggest that the suppression of endogenous gonadotrophins by conventional doses of an LHRH agonist produces no relevant beneficial effects in patients with advanced ovarian carcinoma who receive standard surgical cytoreduction and cytotoxic chemotherapy.

The cytogenetic and molecular genetic changes in serous tumors of low malignant potential (LMP) of the ovary have not been well characterized so far. Therefore, we analyzed 20 serous tumors of LMP, 10 invasive serous ovarian carcinomas, and 7 benign serous cystadenomas by nonisotopic in situ hybridization (seven different centromere-specific probes) as well as by flow and image DNA cytometry and compared the data with results of p53 and Ki67 immunohistochemistry, MYC DNA PCR analysis and with the clinical follow-up. All but two tumors of LMP were DNA cytometrically diploid; 9 of 10 invasive carcinomas proved to be DNA nondiploid (p0.0001). Nonisotopic in situ hybridization revealed a mean number of 1.5 chromosomal aberrations in tumors of LMP, which differed statistically significantly from cystadenomas (mean, 0.4) and from invasive carcinomas (mean, 3.4) (rho0.01). The main changes in tumors of LMP were +6 (7 of 18 cases) and +7 (6 of 19) followed by -3 (5 of 20), -1 (4 of 17) and +X (3 of 20). In the group of invasive carcinomas, the number of cases with signal gains for chromosomes 6 (5 of 8), 7 (7 of 10) and X (4 of 10) and signal loss for chromosome 1 (4 of 9) was even larger. In addition, statistically significantly more cases showed gain of 8 (5 of 10) and loss of 17 (5 of 10) (p0.05). Proliferative activity (Ki67 index) was positively correlated with the number of chromosomal aberrations (p0.05). There was no association between changes in the centromere signal number of chromosomes 8 and 17 and MYC DNA amplification and immunohistochemical p53 accumulation, respectively. Clinical follow-up showed prognostic differences between tumors of LMP and invasive carcinomas as expected (rho0.001) but did not reveal differences within the group of tumors of LMP with regard to the number or type of the chromosomal abnormalities detected. In conclusion, the patterns of chromosomal gains and losses in serous tumors of LMP and invasive serous carcinomas of the ovary do not seem random and suggest a close relation between these neoplasms compatible with sequential stages in a multistep model of ovarian carcinogenesis.

Lymphangioleiomyomatosis is a rare disease with proliferation of smooth muscle cells within the lymphatics, mediastinal and retroperitoneal lymph nodes and in the lungs. The clinical symptoms are increasing dyspnea, chylous effusion, intestinal obstruction and thoracic or abdominal pain. The authors report the case of a 42-year-old woman who primarily suffered from thoracic pain, dyspnea and chylous effusion. In further examinations we discovered a leftsided retroperitoneal tumor and a tumor in the mesentery. The diagnostic difficulties experienced are described and the necessity of explorative laparotomy for definite diagnosis is demonstrated. Furthermore, the article provides a review of the latest developments in pathology, diagnostics and therapy.

To gain insight into the tissue reactions leading to non-infectious loosening 25 autopsy specimens of femurs with well-fixed cemented femoral components of hip prostheses were analysed histomorphologically and morphometrically. The implant duration ranged from one month to 15 years. With the exception of some focal bone-cement contacts bone and cement were separated by a fibrohistiocytic soft tissue membrane. This membrane contained wear particles predominantly of the bone cement mantle and--less abundant--of the polyethylene cups. The amount of wear particles as well as histiocytes and necroses within the membrane statistically significantly increased with advancing time in situ. The cancellous bone adjacent to the soft tissue membrane often revealed a mainly histiocytic infiltration too, accompanied by bone remodeling in this area. The histiocytic inflammatory reaction at the bone cement interface, which is mainly caused by the accumulation of wear particles is considered to be of major importance for the non infectious late loosening of cemented prostheses.

Haemopathologic changes were studied in 19 patients (13 male, six female, age 33-85 years, mean 56 years) with relapsing polychondritis (RP). Anaemia was found in eight, thrombocytopenia in two and splenomegaly in three patients. A total of 17 bone marrow biopsies were obtained from seven individuals. Bone marrow evaluation revealed myelodysplastic syndromes (MDS) with marked trilineage hyperplasia and dysplasia in three cases. Since an excess of myeloblasts or an increase of CD34 positive progenitor cells was not seen, the disorders were designated as‘refractory anaemia’or with regard to the dysplastic megakaryopoiesis‘MDS, unclassifiable'. Two of the three patients died after 10 and 55 months of follow-up due to infectious complications. In a further patient, bone marrow analysis repeatedly showed an unexplained granulopoietic hyperplasia, which, however, was not dysplastic enough to allow a diagnosis of MDS. The remaining patients had clearly reactive changes. Our findings support the notion that RP is a heterogenous disorder and suggest that RP may at times represent a paraneoplastic phenomenon of an underlying MDS. Since HLA typing revealed a significantly increased frequency of the antigen DR4 (10/17 patients positive = 59%), we hypothesize that immunological imbalances due to the MDS in conjunction with a specific immunogenetic background may play key roles in the pathogenesis of RP in these patients.

Starting from previous methodical approaches a procedure for low temperature methyl methacrylate (MMA) embedding of bone marrow biopsies is introduced, which allows routine application of enzyme and immunohistochemistry without loss of morphological quality by retaining fixation in Schaffer's solution. Survival of enzyme activity and antigen determinants is achieved by washing the fixed specimens in 70% methanol and dehydration in acetone in ascending concentrations at 4 degrees C. Modifications of the plastic embedding technique used in this study simplify and shorten the procedure, so that embedding according to this routine method is complete after two days of preparation. Additionally, a rapid embedding variant is introduced, which enables tissue preparation within one day if necessary. Results are demonstrated using markers for myeloid, lymphoid and epithelial cells as well as immunoglobulins and the proliferation associated antigen Ki-67. The investigation of a panel of monoclonal and polyspecific antibodies in 31 cases shows the eventually reduced immunoreactivity of a few markers after prolonged fixation. As a consequence it seems essential to ensure short fixation periods, especially when the specimens are sent by mail.

To gain a better understanding of chromosomal aberrations in direct correlation with histology, we studied tumor material from 35 patients (36 regions) with primary prostate carcinoma by nonisotopic in situ hybridization. Nine biotinylated DNA probes were used on serial paraffin sections (centromer-specific probes for X, Y, 1, 7, 8, 10, 17, and 18, and a telomer-specific probe for 1p; ONCOR). Of the 324 hybridized sections, 94% were suitable for evaluation. In 34 of the 35 cases (35 of 36 regions) 1-8 chromosomal aberrations were detected. Chromosome X showed supernumerary centromer copies in 44% of cases. The probes for chromosomes 1, 1p, 10, and 18 demonstrated deletions in 25, 23, 40 and 58% of cases, respectively. Gains as well as deletions were present for Y, 7, 8, and 17 in 31, 25, 36, and 58% of cases, respectively. In 27% of cases discordant copy numbers of the centromer- and the telomer-specific probes for chromosome 1 were observed. No aberration which might be specific for prostate cancer could be established. The rate of aneusomy increased significantly with histological grade. Intratumoral heterogeneity of chromosomal aberrations was revealed in one case. Due to the higher sensitivity of nonisotopic in situ hybridization, aneusomic cases outnumbered cases with cytometrically determined DNA aneuploidy. In view of published results of metaphase preparations, the high frequency of aneusomy and some of the chromosomal aberrations detected by nonisotopic in situ hybridization were unexpected.

The aim of this investigation was to determine whether the cytometrically assessed DNA ploidy is a parameter of prognostic significance in gallbladder carcinomas. For this purpose the DNA content of tumor cells from archival tumor material from 80 patients with cholecystic cancer was analysed retrospectively by using comparatively different cytometrical methods, namely flow cytometry (FCM) and image cytometry, using tissue sections (ICM-S) and nuclear suspensions (ICM-N). Conventional tumor classifications (according to pTNM and Nevin) were able to predict the further clinical course. DNA ploidy showed a statistically significant correlation only to histological grade (P0.001), but not to tumor stage and survival. Only a trend towards a poorer outcome for patients harboring non-diploid tumors became evident especially when no residual tumor was present postoperatively (R 0-stage; P = 0.08). The different cytometrical methods discussed in detail, showed a highly significant concordance in the determination of DNA index values (DI) and in the classification of the tumors as either diploid or non-diploid. In conclusion, our results indicate that cytometrical determination of DNA ploidy provides no further prognostic informations in gallbladder carcinomas as compared to conventional tumor staging.

In order to examine the correlation of cytometric DNA ploidy in paraffin-embedded tumour material, a comparison was made of flow (FCM) and image cytometry (ICM); in the case of ICM FEULGEN-stained tissue sections (8-10 microns) and in some cases nuclear suspensions were used. Tumour tissue from seminomas (FCM: n = 50; ICM/section: n = 28), oral squamous carcinomas (FCM: n = 110; ICM/section: n = 50) and adenocarcinomas of the gallbladder (FCM: n = 50; ICM/section: n = 46; ICM/nuclear susp.: n = 40) was studied. The concordance regarding diploid/non-diploid characteristics was 96.5% in the case of seminomas, 87% in oral carcinomas and 100% in gallbladder carcinomas. A statistically significant correlation of DNA indices of FCM with ICM histograms was found in all three organ tumours examined. 6% of oral and up to 18% gallbladder carcinomas, however, could not be evaluated by means of FCM due to poor quality of the histograms (coefficient of variation (CV)6%). In the determination of DNA indices and resolution of multiploid stemlines, FCM analysis proved to be superior. Regional intratumoural differences and rare tumour populations were best detected by ICM using sections. Without correction factors being used, these sections did not show any significant deviation of DNA indices from the other methods used. Our study has revealed that in paraffin-embedded tumour material FCM and ICM usually provide well-correlating results, when standardised and controlled preparation and measuring procedures are applied.(ABSTRACT TRUNCATED AT 250 WORDS)

The significance of artificial joint pathology has become clear in view of the approximately 600 000 joint prosthesis implantations performed worldwide each year. Today the chief indications for endoprosthetic joint replacement are serious degenerative joint disease and femoral neck fracture in combination with osteoarthrosis and rheumatoid arthritis; the procedures are less liberally applied in younger patients because of their greater life expectancy and the risk of long-term complications.

A rare case of teratoma of the umbilical cord is reported. It is differentiated from acardius amorphus and compared with the nine cases reported in the literature since the first description in 1878. The clinical consequences for pregnancy of the tumour's influence on the circulation are discussed. For the first time, non-radioactive in situ hybridization of the interphase nucleus was performed in a teratoma of the umbilical cord. The results are presented and different histogenetic pathways, e.g. parthenogenetic origin of the teratoma, are debated.