Partial PTEN deletion is linked to poor prognosis in breast cancer.

BACKGROUND: Deletions of chromosome 10q23, including the PTEN (phosphatase and tensin homolog) locus, are known to occur in breast cancer, but systematic analyses of its clinical relevance are lacking. METHODS: We thus analyzed a tissue microarray (TMA) with 2,197 breast cancers by fluorescence in-situ hybridization (FISH) using a PTEN-specific probe. RESULTS: PTEN deletions were detected in 19% of no special type, 9% of lobular, 4% of tubular cancers and 46% in carcinomas with medullary features. 98.7% of deletions were heterozygous and only 1.3% were homozygous. PTEN deletion was significantly linked to advanced tumor stage (p=0.0054), high-grade (p<0.0001), high tumor cell proliferation (Ki67 Labeling Index; p<0.0001), and shortened overall survival (p=0.0090). PTEN deletions were inversely associated with features of luminal type breast cancers (ER/PR positivity; p<0.0001 each, and CCND1 amplification; p=0.0020). PTEN deletions were also strongly linked to amplification of genes involved in the PTEN/AKT pathway such as MYC (p=0.0430) and HER2 (p=0.0065). Remarkably the combined analysis of MYC, HER2, CCND1 and PTEN aberrations suggested that aberrations of multiple PTEN/AKT pathway genes have a strong additive effect on breast cancer prognosis. While cancers with one of these aberrations behaved only marginally different from cancers with none, disease outcome was markedly worse in cancers with two or more aberrations as compared to those with only one aberration (p=0.0002). In addition, the particularly poor prognosis of patients with HER2 amplification and PTEN deletions challenges the concept of PTEN deletions interfering with trastuzumab therapy. CONCLUSION: PTEN deletion occurs in a relevant fraction of breast cancers, and is linked to aggressive tumor behavior. Reduced PTEN function cooperates with MYC and HER2 activation in conferring aggressive phenotype to cancer cells.

8p deletion is strongly linked to poor prognosis in breast cancer.

Deletions of chromosome 8p occur frequently in breast cancers, but analyses of its clinical relevance have been limited to small patient cohorts and provided controversial results. A tissue microarray with 2,197 breast cancers was thus analyzed by fluorescence in-situ hybridization using an 8p21 probe in combination with a centromere 8 reference probe. 8p deletions were found in 50% of carcinomas with no special type, 67% of papillary, 28% of tubular, 37% of lobular cancers and 56% of cancers with medullary features. Deletions were always heterozygous. 8p deletion was significantly linked to advanced tumor stage (P < 0.0001), high-grade (P < 0.0001), high tumor cell proliferation (Ki67 Labeling Index; P < 0.0001), and shortened overall survival (P < 0.0001). For example, 8p deletion was seen in 32% of 290 grade 1, 43% of 438 grade 2, and 65% of 427 grade 3 cancers. In addition, 8p deletions were strongly linked to amplification of MYC (P < 0.0001), HER2 (P < 0.0001), and CCND1 (p = 0.001), but inversely associated with ER receptor expression (p = 0.0001). Remarkably, 46.5% of 8p-deleted cancers harbored amplification of at least one of the analyzed genes as compared to 27.5% amplifications in 8p-non-deleted cancers (P < 0.0001). In conclusion, 8p deletion characterizes a subset of particularly aggressive breast cancers. As 8p deletions are easy to analyze, this feature appears to be highly suited for future DNA based prognostic breast cancer panels. The strong link of 8p deletion with various gene amplifications raises the possibility of a role for regulating genomic stability.

Tissue microarrays: a new approach for quality control in immunohistochemistry.

AIMS: To improve the interpretation of immunohistochemistry (IHC) staining results the use of a tissue microarray technique was established in a routine setting. METHODS: A tissue microarray was constructed by harvesting 600 microm tissue cores from paraffin wax embedded samples available in a routine pathology department. The punches originating from non-tumorous tissue were placed on host paraffin wax blocks. The microarray contained 12 different tissue samples, with a wide antigen profile and a dimension of 3.5 x 3 mm. One section of the multitissue array was placed as an "internal" positive control on each slide of the patient tissue to undergo identical immunohistochemical procedures. RESULTS: Using the tissue microarray technique as a tool for internal quality control, the interpretation of immunohistochemical staining of more than 20 different antigens in routine IHC was improved. The tissue microarray did not influence the staining results in conventional IHC or in different automated IHC settings. CONCLUSION: The regular use of an institution adapted tissue microarray would be useful for internal positive control in IHC to enable different laboratory demands. Furthermore, this technique improves the evaluation of staining results in IHC.

[Typical forms of choriocarcinoma in clinical practice--diagnosis and therapeutic course in four patients]. / Typische Erscheinungsformen des Chorionkarzinoms in der klinischen Praxis--Diagnosestellung und therapeutischer Verlauf bei vier Patientinnen.

The paper reports on four patients with choriocarcinoma. In two of them, the choriocarcinoma was found after abortion, in one of them following termination of pregnancy, and in the last patient a hydatidiform mole was present. In all patients increased beta-HCG was found. One patient had lung metastasis at the time of diagnosis. In another patient, choriocarcinoma was suspected owing to ultrasonographic vaginal examination. According to the Bagshawe Score, 3 patients were low-risk and were subjected to methotrexate. One patient was medium-risk and received PEB chemotherapy. All four patients are regarded as cured.

[The value of qualitative regression grading as a prognostic factor for survival after preoperative radiochemotherapy in patients with advanced head and neck cancer]. / Wertigkeit eines qualitativen Regressionsgradings als prognostischer Faktor für das Uberleben bei präoperativ radiochemotherapierten Patienten mit fortgeschrittenen Kopf-Hals-Karzinomen.

BACKGROUND: Multimodal therapeutic strategies gain importance in locally advanced squamous cell carcinoma of the head and neck. Quantitative regression grading can be traced as an independent prognostic parameter in the histological examination in many neoadjuvantly treated cancers. Various regression systems have been suggested. We propose an easy to apply and economical score that seems to have a significant prognostic value in squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: 43 patients with Stage IV squamous cell carcinoma of the head and neck have been treated neoadjuvantly with two cycles chemotherapy (ifosfamide 1.5 g/m2 day 1-5 with mesna [300 mg/m2], cisplatin 60 mg/m2 day 5, second cycle day 22). Hyperfractionated accelerated radiotherapy (30 Gy) was given from day 29 on. We divided the resected tumors histologically as follows: Grade I--no tumor cells to be identified, Grade II--necrosis, Grade III--partial destruction of the carcinoma, Grade IV--vital carcinoma. RESULTS: After 1 year the overall survival amounted to 79%, after 2 years 56%. A significant correlation could be established between qualitative tumor regression and survival. The 1-year survival depended on the regression of the primary as follows: 94% in Grade I, 80% in Grade II, 60% in Grade III and 56% in Grade IV. For the 2-year survival: 76%, 40%, 40%, 11% (p < 0.01). The results were similar regarding the neck dissections. CONCLUSIONS: After radiochemotherapy the histological regression is a significant prognostic factor of survival. A simple system with four subgroups is suggested which seems to be of a high prognostic value. We discuss to intensify the treatment for patients with good regression after neoadjuvant therapy for a further reduction of recurrence.

Cytokeratin 5/6 immunohistochemistry assists the differential diagnosis of atypical proliferations of the breast.

AIMS: This study was performed to determine the diagnostic value of keratin 5/6 (CK 5/6) immunophenotyping on routinely processed breast tissues. METHODS AND RESULTS: Six hundred and ninety-nine breast lesions, including normal tissues as well as benign and malignant lesions in 321 formalin-fixed, paraffin-embedded samples from 158 different patients were investigated immunohistochemically, following wet autoclave pre-treatment for antigen retrieval. In normal breast tissues, both myoepithelial and luminal epithelial cells expressed CK 5/6 in varying amounts. While myoepithelial immunoreactivity was most pronounced in the duct system, luminal epithelial immunoreactivity was strongest in the terminal duct lobular units. In ductal hyperplasias (DH), luminal epithelial cells predominantly revealed CK 5/6 immunoreaction. In contrast, neoplastic epithelial cells in atypical ductal and lobular hyperplasias (ADH and ALH) lacked such an expression, whereas in ductal in-situ carcinomas (DCIS) and in infiltrating ductal carcinomas 3.7% and 7.7%, of the cases respectively, showed positive immunostaining for CK 5/6. CONCLUSIONS: Immunophenotyping of keratin 5/6 expression can be helpful in the diagnosis of atypical hyperplasias and in-situ carcinomas of the breast. It is particularly valuable in the differential diagnosis between benign and atypical proliferative lesions.

[Pronounced bilateral mammary hypertrophy as a rare manifestation of acute lymphatic leukemia]. / Ausgeprägte bilaterale Mammahypertrophie als ungewöhnliche Manifestation einer akuten lymphatischen Leukämie.

A 33-year-old patient, hitherto healthy, has been admitted for clarification of bilateral mammary hypertrophy. In the course of the usual routine examination a lump of the size of a cherry was identified in the right breast. Within 6 weeks both breasts had become tight and grown symmetrically to three times their original size. A provisionary diagnosis of high malignant non-hodgkin lymphoma was made by multiple high speed needle biopsies and was later confirmed by a surgical tissue specimen of the right breast. For further classification a bone-marrow biopsy was taken from the pelvic bone and an immature acute lymphoblastic leukemia (ALL), known as preB1-ALL, diagnosed. Sonographic examination, computer tomography of the thorax and mammographical findings, as well as symptoms, outcome and differential diagnosis of a proliferative lymphatic disease with first manifestation in both breasts are presented and discussed.

Prognostic value of hemoglobin concentrations in patients with advanced head and neck cancer treated with combined radio-chemotherapy and surgery.

PURPOSE: Hemoglobin levels are currently the focus of interest as prognostic factors in patients with head and neck cancer. Most published clinical trials have confirmed hemoglobin to possess a significant influence on survival in patients treated with radiotherapy. In our study we have investigated the prognostic value of hemoglobin in a combined modality schedule. PATIENTS AND METHODS: Forty-three patients with advanced head and neck tumors were treated with combined radio-chemotherapy. The therapy comprised 2 courses of induction chemotherapy with ifosfamide (1,500 mg/m2, day 1 to 5) and cisplatin (60 mg/m2, day 5) followed by hyperfractionated accelerated radiotherapy with a total dose of only 30 Gy. Surgery involved tumor resection and neck dissection. RESULTS: The 1-year overall survival rate and the 2-year survival rate were 79% and 56%, respectively. The 1- and 2-year recurrence-free survival rates were 68% and 49%, respectively. Prognostic factors with an impact on survival were seen in tumor size (T3 vs T4, p = 0.0088), response to radio-chemotherapy at the primary site (no vital tumor rest vs vital tumor rest, p = 0.045), response to lymph node radio-chemotherapy (no vital tumor cells vs vital tumor cells, p = 0.013) and level of hemoglobin after radio-chemotherapy (Hb > or = 11.5 g/dl vs < 11.5 g/dl, p = 0.0084). CONCLUSION: In our study hemoglobin level after radio-chemotherapy was identified for the first time to be also a significant prognostic factor (univariate analysis) in head and neck cancer patients who underwent combined radio-chemotherapy. Besides chemotherapy plus low-dose irradiation achieved similar results in comparison with radical resection and high-dose radiotherapy at least for the first 2 years after therapy. Relapsing disease could be treated with 1 additional course of radiotherapy which is supposed to be well tolerated.

Routine minimal invasive vein harvesting reduces postoperative morbidity in cardiac bypass procedures. Clinical report of 1400 patients.

OBJECTIVE: Minimal invasive endoscopic vein harvesting has not gained widespread acceptance although potential improvements in wound healing and patient comfort are undebatable. The main objections to routine application have been impaired graft quality and prolonged operation time. The feasibility of introducing the minimal invasive approach to vein harvesting into a high volume cardiac bypass surgery program was to be investigated in 1400 patients. METHODS: Our preferred technique is based on standard videoscopic equipment for endoscopic surgery. No disposables are used. The subcutaneous tissue above the saphenous vein is tunnelled by exclusively sharp dissection. No shear stresses are applied to the vein graft or its side branches. Side branches are closed by clips or bipolar coagulation. The differences between endoscopic and conventional surgical vein harvesting with regard to operation time, graft quality, wound healing disturbances and postoperative pain were compared in two groups of 300 concurrently operated patients. Subsequently, a further 1100 patients underwent endoscopic vein harvesting, giving a total experience of 1400 endoscopic procedures. RESULTS: After a learning curve of approximately 100 procedures for an experienced surgeon, harvesting time using minimal invasive techniques was 16 +/- 4 min/graft vs. 10 +/- 2 min for the conventional technique (P < 0.01). Severe wound healing disturbances requiring re-intervention were observed in 0.1% following endoscopic harvesting, moderate wound healing disturbances were observed in 1.7% of patients. By comparison, conventional harvesting led to severe wound healing disturbances in 5% and to moderate disturbances in 8% (P < 0.05). Incidence of peri-operative myocardial infarction as an indirect measure of graft quality was 1.7% with endoscopic vs. 2.3% (n.s.) with conventional technique. Early postoperative mobilisation was faster, pain and need of analgesics were distinctly reduced in patients with endoscopic harvesting. Overall operation time was not significantly prolonged by the described technique. CONCLUSIONS: Minimal invasive endoscopic vein harvesting can be developed into a routine procedure resulting in a lower incidence of wound complications, less postoperative pain and much superior cosmetic results. Graft quality appears to be comparable to standard saphenectomy. There is, however, a higher demand of surgical training and expertise.

Familial clustering of infantile cirrhosis in Northern Germany: A clue to the etiology of idiopathic copper toxicosis.

Two cases of infantile liver cirrhosis of unknown origin occurred in a circumscribed rural area of Northern Germany. Both children had increased dietary copper exposure. The search for additional cases of what appeared to be idiopathic copper toxicosis (ICT) revealed a cluster of affected infants in this region, raising questions about the relative importance of genetic and environmental factors that are considered to be etiologic. We gathered clinical and pathologic data concerning the patients, analyzed the pedigrees of affected families, and searched for possible environmental factors contributing to the pathologic process. We encountered 8 cases of infantile liver cirrhosis in 5 families in Emsland, a circumscribed and predominantly rural area of Northern Germany; ICT was definitely proven in 2 cases. Clinical presentation and liver pathology in 6 additional cases were consistent with the diagnosis of ICT. Pedigrees of affected families revealed complex relationships with occasional consanguinity of parents, suggesting autosomal recessive inheritance. The households were served by private wells with water of low pH flowing through copper pipes, suggesting the possibility of increased alimentary copper exposure. These findings support earlier conclusions that ICT develops when an infant with a genetic predisposition is exposed to a copper-enriched diet.

[Terminal CTG as an expression of high degree fetal distress--1 case reports]. / Das terminale CTG als Ausdruck einer hochgradigen Gefährdung des Kindes--zwei Kasuistiken.

The cases of two patients, in whom conspicuous CTGs with restricted oscillation and late decelerations were registered in the final trimester of pregnancy, are presented. Following immediate hospitalisation and the rapid execution of a caesarean section, two depressed, severely acidotic neonates were born. Whilst the course of the pregnancy in the first case had been completely inconspicuous up to that point, and the acute occurrence of placental insufficiency must be assumed, the second patient was subject to pregnancy-induced hypertension with discrete foetal growth retardation. It is shown that two almost identical pathological CTG registrations may have different causes but that one must assume a high degree of sub partu risk to the child on the occurrence of a terminal CTG witch is characterised by line-shaped oscillation, possibly in combination with late decelerations.

Standardized in situ AgNOR analysis in breast pathology: diagnostic and cell kinetic implications.

The aim of the present study was to assess the diagnostic value of the recently standardized morphometric analysis of silver-stained nucleolar organizer region-associated proteins (AgNORs) [30] in a variety of 155 routinely processed benign and malignant breast lesions. 5 normal breast samples, 21 adenoses, 20 ductal hyperplasias, 10 atypical ductal hyperplasias, 20 in situ and 43 invasive ductal carcinomas, 10 in situ and 26 invasive lobular carcinomas were investigated. A statistically highly significant difference was found between normal/ordinary hyperplastic and neoplastic breast lesions with all 4 consensus AgNOR parameters (mean area, mean number, CV of area, CV of number) evaluated. AgNOR quantity was significantly related to histological grade of both in situ and invasive carcinomas. However, variable overlap was found between AgNOR values in different diagnostic groups. We conclude that standardized AgNOR analysis is a prerequisite for objective and reproductible AgNOR assessment in archival tissues. Despite its limited diagnostic utility for individual breast lesions, standardized AgNOR analysis bears a significant potential for characterizing cell kinetic and metabolical activity of breast lesions. This may give insight into the biological background of breast carcinogenesis, differentiation and tumor progression and may also underlie the independent prognostic value of AgNORs in breast cancer.

Immunophenotypic and prognostic analysis of E-cadherin and beta-catenin expression during breast carcinogenesis and tumour progression: a comparative study with CD44.

AIMS: This study was performed to investigate whether immunohistochemical expression of E-cadherin (E-cad) and beta-catenin (beta-cat) in conjunction with CD44 may correlate with the clinical evolution and prognosis of breast cancer. METHODS AND RESULTS: One-hundred and forty-two routinely processed breast tissue samples including normal breast, benign lesions, in situ and invasive carcinomas were investigated. E-cad and beta-cat were strongly expressed by luminal and basal cells in normal glands, benign proliferative and early neoplastic intraductal lesions. Contrarily, CD44 was expressed exclusively by myoepithelial cells in normal breast, whereas different isoform expression patterns were observed in premalignant and malignant lesions. Simultaneous lack of E-cad/beta-cat expression was detected in in situ and invasive lobular carcinomas in contrast to ductal lesions, in which the differential loss of the molecules was associated with poorer differentiation, irrespective of CD44 immunophenotype. Reduced E-cad (P = 0.003), beta-cat (P = 0.03) and increased CD44v4 (P = 0.005) and v7 (P = 0.007) expression were significantly associated with positive lymph node status. Decreased E-cad and lack of CD44v6 expression correlated with poor survival. There was no difference between the expression of either molecule in in situ and invasive components within the same tumour. CONCLUSIONS: Our results indicate that changes in E-cad, beta-cat and CD44 expression occur early in breast carcinogenesis; they are involved in tumour differentiation, but events additional to their deranged expression are needed to acquire an invasive phenotype.

[Primary squamous cell carcinoma of female mammary gland]. / Primäres Plattenepithelkarzinom der weiblichen Brustdrüse.

Squamous metaplasia can be demonstrated in about 4% of all invasive carcinomas of the breast. Primary squamous cell carcinomas of the breast are rare, since they occur in less than 1% of all primary invasive breast carcinomas. In order to classify a breast tumor as a primary squamous cell carcinoma one must exclude an epidermal origin, especially from the nipple region and the possibility of metastatic infiltration of the breast by a squamous cell carcinoma from a different location. Causative and formal pathogenesis of primary squamous cell carcinoma of the breast is not clear. A pluripotent embryonal stem cell origin is discussed, considering the phylogenetic descent of the mammary gland from skin appendages. Squamous metaplasia is also suggested to be a precursor of squamous cell carcinoma. Here endocrine stimulation and chronic inflammation may both play an inductive role. The number of published cases of squamous cell carcinomas developing years and decades after implantation of silicon prostheses has increased in recent years. These tumors probably develop on top of squamous metaplasia induced by the inflammatory pseudocapsule. Estimating the prognosis and therapeutic management in patients with squamous cell carcinoma of the breast should follow the same guidelines as for other squamous cell cancers.

Gains and losses of CD44 expression during breast carcinogenesis and tumour progression.

AIMS: This study was performed to investigate whether the CD44 immunophenotype of breast lesions correlates with the clinical evolution and prognosis of breast cancer. METHODS AND RESULTS: One-hundred and fifty-two routinely processed normal, benign and malignant breast tissue samples were investigated by the following monoclonal antibodies: CD44s (F10-44-2), CD44v3 (3G5), CD44v4 (11.10), CD44v5 (VFF-8), CD44v6 (VFF-18), CD44v7 (VFF-9), CD44v9 (11-24) after wet autoclave pretreatment for antigen retrieval. We found that: (1) in normal breast tissues luminal epithelial cells lacked detectable CD44 in contrast to basal cells, which constitutionally expressed CD44s, v3, v5 v6 and v9 isoforms; (2) in the intraductal compartment of benign hyperplastic lesions, there was scattered or focal staining for CD44s, v5, v6, v7 and v9 isoforms; (3) in neoplastic lesions restricted neo-expression of CD44v3 and v4 was detected; and (4) the CD44 immunophenotype of invasive breast carcinomas was influenced largely by differentiation grade, steroid receptor status of the tumours and significantly correlated with metastatic involvement of the axillary lymph nodes. CONCLUSIONS: Qualitative and quantitative changes of CD44 expression are implicated in early stages of breast carcinogenesis. The restricted neo-expression of certain CD44 isoforms in breast neoplasias suggests that CD44 might be a potential target for future antibody-based tumour therapy.

[Adult giant cell hepatitis with fatal outcome. Clinicopathologic case report and reflections on pathogenesis]. / Adulte Riesenzellhepatitis mit tödlichem Verlauf. Klinisch-pathologischer Fallbericht und Uberlegungen zur Pathogenese.

The occurrence of plasmodial giant cells in the liver is probably a morphological reaction pattern with the most diverse causes. In babies and infants, these changes occur in particular in neonatal hepatitis and intrahepatic and extrahepatic bile duct atresia. Viral infections and/or autoimmune reactions are discussed etiologically in giant cell hepatitis in adults (adult gaint cell hepatitis, AGCH), which is much rarer. In some of the cases, there were conspicuously high titers against paramyxoviruses. Giant cell hepatitis can occur in the course of HIV infection. These both indicate an infectious cause. However, the disease cannot be transmitted to chimpanzees. Apart from our case, only one further case is described in the literature in which a completed hepatitis A infection could be demonstrated serologically. In addition, the titer of antinuclear antibodies was raised in our patient. This autoimmune phenomenon is probably of crucial pathogenetic significance in our patient, especially since a hepatitis A infection on its own does not afford an adequate etiological explanation for the form of chronic and active hepatitis with consecutive cirrhotic transformation observed here.

Modified neoadjuvant therapy regime with low dose irradiation in advanced head and neck cancer patients: preliminary results of a pilot study to minimize side effects.

We analysed the files of 52 patients with advanced head and neck tumors who were treated in a pilot phase. The therapy consisted of two courses of induction chemotherapy with ifosfamide and cisplatin followed by hyperfractionated-accelerated radiotherapy with a total dose of only 30 Gy. Surgery was performed within the following 7 days with tumor resection and neck dissection. Histologically we found in 50% of the specimens total necrosis of the tumor. The median survival time is calculated to be 22 months. The median follow-up time thus far is 36 months. Hence, therapy results are comparable to other therapy schedules. But side effects, especially late side effects had become minor. Therefore, our therapy regime results in augmentation of the quality of life of these patients.

Effect of IFN-alpha on normal human hematopoiesis: an immunohistochemical and morphometric study on trephine biopsy specimens.

To elucidate the effects of interferon-alpha (IFN-alpha) on normal human bone marrow in vivo, an immunomorphometric study was performed using trephine biopsy specimens without hematopoietic pathology. Samples were derived from patients with mycosis fungoides but no marrow involvement, who were undergoing low-dose IFN-alpha treatment. Parameters included density of reticulin (argyrophilic) fibers, CD61+ megakaryocytes, PGM1+ macrophages, the GSA-I lectin-expressing (activated) macrophage subpopulation, proliferative activity (PCNA staining), and apoptosis. Following IFN-alpha therapy (3 x 3 x 10(6) U/week between 6 and 21 months), morphometric evaluation of sequential bone marrow examinations revealed a significant increase in the number of megakaryocytes and the amount of reticulin fibers. Additionally, there was an overall decrease in PCNA+ cells, accompanied by a reduction in the incidence of apoptotic bodies. On the other hand, total number of macrophages and their activated subfraction remained unchanged. Opposed to in vitro findings, a fibrogenetic capacity of IFN-alpha associated with megakaryocyte growth was detectable. Moreover, contrasting with effects of IFN-alpha treatment in chronic myelogenous leukemia, the incidence of apoptosis was significantly reduced. This feature was assumed to contribute to a maintenance of steady-state hematopoiesis expressed by a nonaltered bone marrow cellularity in our specimens.

Expression of biglycan, decorin and proteoglycan-100/CSF-1 in normal and fibrotic human liver.

The immunohistochemical expression of the three small chondroitin/dermatan sulphate proteoglycans biglycan, decorin and proteoglycan-100 (PG-100), the proteoglycan form of colony-stimulating factor-1 (CSF-1), was studied in normal and fibrotic human liver. In normal liver tissue biglycan and decorin were clearly seen in the space of Disse, which was in contrast to a faint staining of PG-100. Biglycan and decorin were additionally detected around small bile ducts and in vessel walls. In patients with HBs-Ag positive, chronic active hepatitis decorin as well as biglycan showed strong immunoreactivity in fibrotic areas. In contrast to normal liver, PG-100 was visualized in bile duct epithelia. Therefore, PG-100 could serve as an immunohistochemical marker of the involvement of the bile duct system in chronic active hepatitis and progressive liver fibrosis.