Background/Aim: Proliferative bile ductular reactions occur in a variety of liver diseases in humans. It is a matter of debate whether such reactions result from progenitor cell proliferation with biliary and hepatocytic differentiation, versus biliary metaplasia of damaged hepatocytes. We investigated bile ductular reactions in liver diseases, paying particular attention to the presence of cells with intermediate (hepatocytic/ biliary) features (oval-like cells). Methods: Five specimens each were selected of submassive hepatic necrosis and cirrhosis due to hepatitis B, hepatitis C, autoimmune hepatitis, alcohol injury, primary biliary cirrhosis and primary sclerosing cholangitis. Immunohistochemical stains were performed for biliary markers (cytokeratins [CKs] 7 and 19), as well as hepatocytic markers (HepParl and alpha-fetoprotein [AFP]) in sequential sections. The degree of staining of each cell type (biliary, hepatocytic, intermediate) was graded semiquantitatively. Results: Hepatocytes always stained diffusely for HepParl, occasionally for CK7, and rarely for CK19. Biliary cells were always diffusely positive for CK7 and CK19, and rarely for HepParl. Intermediate cells were identi®ed in all cases and showed widespread staining for both HepParl and CK7, and less commonly for CK19. AFP was not expressed in any cell type. The morphologic and immunohistochemical features of bile ductular reactions were similar in the different diseases. Conclusions: Proliferating hepatic parenchymal cells with intermediate (hepatocytic/biliary) morphologic features and combined immunophenotype can be identi®ed in a variety of acute and chronic liver diseases. The similarity of bile ductular reactions among chronic hepatitic, alcoholic and biliary diseases suggests that they result from proliferation of oval-like progenitor cells.

The difficulty in distinguishing between smooth muscle and endometrial stromal-derived neoplasms of the uterine corpus is a notorious and clinically relevant problem in pathology of the female genital tract. Immunohistochemistry offers some aid in resolving this difficulty, because the expression of smooth muscle markers is reputed to indicate smooth muscle derivation. This expression, however, is not entirely specific, and difficult cases may still present in which immunohistochemistry is of little help. To explore this problem, the authors evaluated the expression of traditional muscle markers and high-molecular-weight caldesmon (h-cal), an actin and tropomyosin binding protein that has recently been described as a useful muscle marker, in uterine leiomyosarcoma (LMS), cellular leiomyomata (CL), and endometrial stromal sarcoma (ESS). Formalin-fixed and paraffin-embedded tissue sections from nine LMSs, 11 CLs, and 12 ESSs were evaluated with commercially available monoclonal antibodies against smooth muscle actin (SMA), desmin, and h-cal. Established morphologic criteria were used to classify the neoplasms. We found that there was, as expected, a significant difference in the expression of traditional smooth muscle markers (SMA and desmin) between tumors derived from smooth muscle and those derived from endometrial stroma (p = 0.005 for LMS and 0.013 for CL). We further found that h-cal was most useful in distinguishing between CL and ESS (p = 0.01). A significant difference between h-cal expression in LMS versus ESS was not found. Of note, one ESS expressed both SMA and desmin but lacked h-cal expression. Our findings confirm the most useful immunohistochemical data to date; smooth muscle neoplasms are generally distinguishable from endometrial stromal tumors by the expression of conventional muscle markers. We also report here that h-cal is useful more specifically in the differentiation of CL from ESS.

Purpose: Prostaglandin E 2 (PGE 2 ) promotes malignant growth. Cyclooxygenase (COX) catalyzes the synthesis of PGH 2 , which is converted, in turn, by microsomal prostaglandin E synthase (mPGES-1) to PGE 2 . One strategy for inhibiting carcinogenesis is to prevent PGE 2 production in premalignant and malignant tissues. It is important, therefore, to determine whether enzymes involved in PGE 2 biosynthesis are deregulated in neoplasia. The main purpose of this study was to determine whether amounts of COX-2 or mPGES-1 were increased in intraepithelial neoplasia or squamous cell carcinoma (SCC) of the penis. Because human papillomavirus (HPV) has been linked to the development of penile SCC, a secondary objective was to determine whether COX-2 was overexpressed in SCC arising in an HPV16 transgenic mouse.Experimental Design: Immunohistochemistry and immunoblotting were used to evaluate the expression of COX-2 and mPGES-1 in benign and malignant lesions including metastases to lymph nodes. Amounts of intratumoral PGE 2 were quantified by enzyme immunoassay. Reverse transcription-PCR was used to determine the expression of each of the four known receptors (EP 1-4 ) for PGE 2.Results: Immunohistochemistry demonstrated increased expression of COX-2 and mPGES-1 in dysplasia, carcinoma in situ, invasive SCC, and metastases to lymph nodes. Immunoblot analysis confirmed that COX-2 and mPGES-1 were consistently overexpressed in SCC. PGE 2 and all four of the PGE 2 receptor subtypes were detected in each of the tumor samples.Elevated levels of COX-2 were also detected in SCC arising in an HPV16 transgenic mouse.Conclusions: Increased amounts of COX-2 and mPGES-1 were detected in penile intraepithelial neoplasia and carcinoma. These findings provide the basis for evaluating whether inhibiting COX-2 will be useful in the prevention or treatment of penile SCC.