BackgroundThe ability to distinguish hepatocellular carcinoma (HCC) from metastatic carcinoma (MC) involving the liver and cholangiocarcinoma (CC) by immunohistochemistry has been limited by the lack of a reliable positive marker for hepatocellular differentiation. Arginase-1 is a marker for HCC recently described in some literature.AimTo examine the immunohistochemical staining of arginase-1 in cases of HCC, MC involving the liver and CC as compared to hepatocyte paraffin antigen -1 (HepPar-1) in an attempt to further define the diagnostic utility of arginase-1 in differentiating these tumors.Materials and methodsA comparative immunohistochemical study of arginase-1 and HepPar-1expression was performed in 50 HCC cases, 38 cases of MC to the liver from varying sites, 12 cases of CC and 10 specimens of normal liver tissues. The predictive capacity of arginase-1 and HepPar-1 staining was determined using sensitivity, specificity, positive predictive value, and negative predictive value calculations.ResultsAll normal liver tissues (no=10), non- neoplastic cirrhotic liver tissues adjacent to HCC (no=42) as well as those adjacent to MC (no= 9) showed diffuse and strong immunostaining for both arginase-1 and HepPar-1. Arginase-1 demonstrated positive immunoreactivity in 42 of 50 (84%) cases of HCC compared with 35 of 50 (70%) for HepPar-1. Only one of 38 (2.6%) cases of MC and one of 12 (8.3%) cases of CC showed positive immunoreactivity for arginase-1. In contrast, HepPar-1 immunoreactivity was detected in 6 of 38 (15.8%) cases of MC and in 2 of 12 (16.7%) cases of CC. Arginase -1 showed a significantly higher sensitivity for HCC diagnosis (84%) compared to HepPar -1(70%) (p=0.016). The specificity of arginase-1 for HCC diagnosis was higher (96%) than that of HepPar -1 (84%); nevertheless, this was not statistically significant (p=0.109). Howerver, the combination of both immunomarkers for the diagnosis of HCC, raised the specificity to 100%.ConclusionArginase-1 immunostaining has a higher sensitivity and specificity than HepPar-1 for HCC diagnosis. Furthermore, the combined use of arginase-1 and HepPar-1 can provide a potentially promising tool to improve the accuracy in distinguishing HCC from metastatic carcinoma and cholangiocarcinoma.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9991436558072434.

BackgroundThe diagnosis of uterine smooth muscle tumors depends on a combination of microscopic features. However, a small number of these tumors still pose difficult diagnostic challenges.AimTo investigate progesterone receptor (PR) and p53 expression in leiomyomas (LMs), atypical leiomyomas (ALMs), smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcomas (LMSs) and to evaluate the potential utility of the selected immunohistochemical markers in differentiating these tumors.Materials and methodsImmunohistochemical expression of PR and p53 was investigated in 41 uterine smooth muscle tumors comprising: 15 LMS, 4 STUMP, 6 ALM and 16 LM. Quantitative evaluation of PR and p53 expression was graded on a scale from 0 to 3+.ResultsLeiomyosarcomas showed reduced PR expression. All LMs as well as ALMs and STUMP were stained intensely for PR. Conversely, LMS was strongly stained with p53, while the three non-sarcomatous groups (STUMP, ALM, LM) were either entirely negative or weakly stained for p53. Regarding both PR and p53 expression, the difference between the LMS group and the three non-sarcomatous groups was highly significant (p < 0.001). Combined high PR - low p53 expression was seen in all the 26 examined cases of the non-sarcomatous group including the STUMP cases and none of the LMS cases. Therefore, it represents a "benign" profile with 100% specificity in diagnosis of a non-sarcomatous tumor.ConclusionImmunohistochemistry for PR and p53 is valuable as an adjunct tool to morphological assessment of problematic uterine smooth muscle tumors.

BackgroundThe microenvironment of astrocytomas includes infiltrative inflammatory cells that are dynamic in nature, possibly reflecting tumor biology. We evaluated the inflammatory cell infiltrate in astrocytic tumors aiming for a better understanding of their immunobiology.MethodsImmunohistochemical expression of CD68, CD3, and CD20 was investigated in 21 glioblastomas, 21 anaplastic astrocytomas, 13 diffuse astrocytomas, and 18 pilocytic astrocytomas. The inflammatory infiltrate was classified based on microanatomic location as perivascular and intratumoral, and subsequently graded semiquantitatively.ResultsPerivascularly, CD68-positive infiltrate was noted in 71.4% of glioblastomas compared with 14.3% of anaplastic astrocytomas (P = 0.0001), 7.7% of diffuse astrocytomas (P = 0.0001), and 33.3% of pilocytic astrocytomas (P = 0.017). Intratumorally, 85.7% of glioblastomas exhibited CD68-positive infiltrate compared with 42.9% of anaplastic astrocytomas (P = 0.004), 38.5% of diffuse astrocytomas (P = 0.008), and 33.3% of pilocytic astrocytomas (P = 0.001). Among diffusely infiltrating astrocytomas, intratumoral CD3-positive infiltrate was only associated with glioblastoma. A CD20-positive infiltrate was only detected in the perivascular space of a single case of diffuse astrocytoma.ConclusionThese data indicate a distinct immune profile in the glioblastoma microenvironment primarily related to the prevalence of macrophages. Thus, novel glioblastoma therapies should address this key CD68-positive population and its possible role in generating an antitumor immune response.

BackgroundThe incidence of hepatocellular carcinoma (HCC) in Egypt has markedly increased in the recent years, mainly due to the high incidence of hepatitis C virus (HCV) infection. Consequently, the frequency of metastatic HCC has also increased. The current study presents a series of 47 patients who were initially diagnosed as metastatic HCC.MethodsForty seven patients with the diagnosis of extrahepatic metastases of HCC at initial presentation were included in the study. The sites of metastases were bones (17), lymph nodes (9), soft tissue (7), omentum (7), maxillary sinus (2), adrenal gland (2), brain (2) and skin (1). The diagnosis of metastatic HCC was confirmed by immunohistochemistry.ResultsThe patients included in the study were 38 males and 9 females, ranging from 40 to 80 years (median 60 years). All patients were HCV-positive and 36 were cirrhotic. The diagnosis of primary HCC was confirmed in all cases, based on the typical hypervascular radiological features and/or high serum α-fetoprotein concentration, or histologic examination of liver biopsy.ConclusionMetastasis of HCC should be put into consideration when evaluating metastatic carcinoma with unknown primary. This is of particular importance in the Egyptian population who has the highest prevalence of HCV infection in the world.

Cell-based therapy is emerging as a promising therapeutic approach for a wide range of liver diseases. This study aimed to investigate the regenerative and antifibrotic therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in an early and late experimental hepatic schistosomiasis model. BM-MSCs were isolated from 6-wk-old BALB/c donor male mice, then grown and propagated in culture until cell count was 5-8 × 10(6)/ml. MSCs were then separated and injected into Schistosoma mansoni -infected female BALB/c mice on their 6, 10, 14, and 18 wk post-infection. Mice were sacrificed on the fourth and eighth week after BM-MSCs transplantation in each group. Homing of BM-MSCs was confirmed by PCR detection of male Y-chromosome gene (sry) in the liver tissue of the recipient female mice. The regenerative and antifibrotic potential of BM-MSCs was assessed by histopathological examination, morphometric analysis, electron microscopy, and liver function tests. Schistosoma-infected mice, which were treated with BM-MSCs, showed a decrease in the granuloma size, percentage and density of the fibrotic area, formation of new hepatocytes, and improvement of the liver function tests. Immunohistochemical examination of alpha-smooth muscle actin revealed a significant decrease in the immunoreactive hepatic stellate cells in mice treated with MSCs. Early granulomas (acute infection) showed better response to MSC injection than did later granulomas (chronic infection). Dosing and timing of MSCs transplantation should undergo more investigations in long-term experiments before application to the clinical field. This study is the first to assess and compare the effect of MSCs treatment on early and late granulomas.

Egypt has the highest prevalence rate of hepatitis C virus (HCV) infection in the world. HCV contributes to the development of about 70% of hepatocellular carcinoma (HCC) cases. Understanding the molecular basis of hepatocarcinogenesis is important for planning the therapeutic regimen for HCC patients. To clarify the possible role of mismatch repair (MMR) genes in HCV-related HCC, we studied 50 HCV-related HCC specimens (28 of which were with adjacent non-cancerous cirrhotic liver tissue, ANCLT) and 30 specimens of chronic liver disease (CLD) with no evidence of HCC. All cases were examined immunohistochemically to demonstrate the protein expression of hMSH2 and hMLH1. Thirty-two (64%) and 35 (70%) of the HCC cases revealed reduced expression of hMSH2 and hMLH1, respectively. Reduced expression of both the proteins was obtained in 26 (52%) of the HCC cases. The expression of hMSH2 and hMLH1 was reduced in 53.6% and 64.3% of ANCLT cases, respectively, with no significant difference between HCC and ANCLT. All 30 specimens of CLD had preserved expression of hMSH2 and hMLH1. Multivariate analysis showed that the reduced expression of hMSH2 or hMLH1 was significantly associated with higher grades of the tumor (p = 0.002 and 0.02, respectively).The relationships of these MMR genes with other clinicopathologic factors were not significant. Reduced expression of hMSH2 and hMLH1 in both HCC and ANCLT suggests that this event occurs at early stages of HCV-related hepatocarcinogenesis. Moreover, the significant association between reduced expression of both MMR genes and poor histologic grades of the tumor claims that these proteins are involved in the process of cancer progression.

Helal TESA, Ehsan NA, Radwan NA, Abdelsameea E. Relationship between hepatic progenitor cells and stellate cells in chronic hepatitis C genotype 4. APMIS 2018; 126: 14-20.Hepatitis C virus (HCV) infection represents a major health problem in many areas of the world, especially Egypt. Hepatic progenitor cells (HPCs) and hepatic stellate cells (HSCs) have been implicated in fibrosis progression in chronic HCV. The aim of this study was to investigate the role of HPCs and HSCs in chronic HCV infection and the relationship between both cell types. This retrospective study was conducted on 100 chronic HCV patients. Immunohistochemistry was performed on liver tissue sections for cytokeratin 19 (progenitor cell markers), smooth muscle actin (stellate cell markers), matrix metalloproteinase-9 (MMP-9), and transforming growth factor beta (TGF-ß). The necroinflammatory activity was significantly related to the number of isolated HPCs and TGF-ß expression (p = 0.003 and p = 0.001 respectively). Advanced stages of fibrosis showed significantly increase number of HPCs (p = 0.001), higher ratio of HSCs (p = 0.004), more expression of TGF-ß (p = 0.001) and MMP-9 (p = 0.001). There was a significant direct correlation between immunoexpression of HPCs and HSCs for isolated cells (r = 0.569, p = 0.001) and ductular reaction (r = 0.519, p = 0.001). Hepatic progenitor cells and stellate cells play a significant role in the development and progression of fibrosis in chronic HCV. More interestingly, the significant direct correlation between HPCs and HSCs suggests a synergistic interrelation.

Objectives The objective of this study was to define anatomical and radiological features of the so-called Y-type urethral duplication. Methods The study included four male patients and one female patient with congenital connection between the urogenital tract and the external anal orifice. Investigations included renal sonography, urethrograms, and magnetic resonance imaging pelvis in the last patient. The urethrograms of male patients were carefully reviewed, in addition to available urethrograms of similar cases that could be obtained through searching the literature. Results Unlike cases of urethral duplication, the male patients had always a complete prepuce and a functioning anterior urethra in 25%. The accessory uroanal channel had almost always a constant origin from the posterior urethra. Some tension seems to be exerted by the urethroanal tract pulling on and causing a kink in the posterior urethra. Management was simple in patients without anterior urethral hypoplasia (one male and the female patient). Both were treated by simple excision of the communicating ano-urogenital tract through a perineal approach with an excellent outcome. Histopathological examination of excised tracts revealed stratified squamous cell in the former and transitional cell lining in the latter. In patients with hypoplastic anterior urethra, staged urethral reconstruction was performed in two, and progressive dilatation of hypoplastic anterior urethra was tried in the last patient. Conclusion Several observations would support diagnosing the congenital connection between the urinary tract and the external anal orifice in the male as a congenital fistula rather than an accessory urethra. Confirming and accepting this information may have its impact on changing the current surgical approach.