Family medicine and gynaecologic pathology

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Cervical cancer screening by enhanced cytology: application of novel markers

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Mixed low grade and high grade endometrial stromal sarcoma of uterus: Differences on immunohistochemistry and chromosome in situ hybridisation

A case of a 64 year old woman with a tumour of the uterus is reported. The patient presented with postmenopausal bleeding and subsequently underwent total hysterectomy and bilateral salpingooophorectomy. Sections of the tumour showed a low grade endometrial stromal sarcoma coexisting with areas consistent with high grade sarcoma. The sarcoma cells, in both the low and high grade areas, were positive for vimentin and negative for desmin and cytokeratin on immunohistochemistry. While the sarcoma cells in the low grade region showed immunoreactivity for oestrogen and progestogen receptors, those in the high grade region did not. Using chromosome in situ hybridisation, the low grade portion of the sarcoma was diploid for chromosomes X, 11, 12, and 17, whereas the more anaplastic areas were aneuploid for these chromosomes. This case may represent an example of high grade endometrial stromal sarcoma arising by dedifferentiation from a low grade stromal sarcoma. Adequate sampling is important in identifying such anaplastic changes as the origin of the tumour will affect patient management.published_or_final_versio

Assessment of cell proliferation in hydatidiform mole using monoclonal antibody MIB1 to Ki-67 antigen

Aims - To assess the role of Ki67 immunoreactivity in predicting the clinical progress of hydatidiform mole. Methods - Tissue from 87 hydatidiform moles, 11 normal first trimester placentas, 11 normal term placentas and 17 spontaneous abortions were examined for expression of Ki67 antigen, using the monoclonal antibody MIB1. Results - Ki67 immunoreactivity was significantly higher in the tissue from normal first trimester placentas than in that from normal term placentas and spontaneous abortions. Among the 87 patients with hydatidiform moles studied, 20 developed persistent gestational trophoblastic disease and required subsequent treatment. There was no statistically significant difference in the Ki67 index between the 20 patients who developed persistent disease and those who did not. Conclusion-Hydatidiform moles which give rise to persistent trophoblastic disease do not have a higher proliferative rate than those which do not. The Ki67 index is not useful for predicting the prognosis of molar pregnancies.published_or_final_versio

Preliminary report on the rate of apoptosis in human first and third trimester placentae

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p21(WAF1/CIP1) expression in gestational trophoblastic disease: correlation with clinicopathological parameters, and Ki67 and p53 gene expression

Background--The p21(WAF1/CIP1) gene mediates growth arrest by inhibiting G 1 cyclin dependent kinases and has been considered as a downstream effector of the tumour suppressor gene p53. Aim--To analyse the role of p21(WAF1/CIP1) in gestational trophoblastic disease. Methods--The immunohistochemical expression of p21(WAF1/CIP1) gene was measured in 33 placentas, 28 partial hydatidiform moles, 54 complete hydatidiform moles, and 13 choriocarcinomas in paraffin wax embedded tissue. The results were correlated with p53 (DO7) and Ki67 (MIB1) immunoreactivity as well as clinical progress. Results--p21(WAF1/CIP1) immunoreactivity was found predominantly in the nuclei of the syncytiotrophoblasts. p21(WAF1/CIP1) protein expression correlated with gestational age in normal placentas (p = 0.0001) but not in hydatidiform moles (p = 0.89). Complete hydatidiform moles and choriocarcinomas had a significantly higher p21(WAF1/CIP1) expression compared with normal placentas and partial hydatiform moles (p 0.05) in p21(WAF1/CIP1) expression between the 17 patients who developed persistent gestational trophoblastic disease and those who did not. Conclusions--This study suggests that p21(WAF1/CIP1) expression in trophoblastic disease may be induced by a p53 independent pathway. The proliferative activity of gestational trophoblastic diseases might not be determined solely by the control of the cell cycle operated by p21(WAF1/CIP1). p21(WAF1/CIP1) expression is not an accurate prognostic indicator of gestational trophoblastic disease.published_or_final_versio

Granulin-epithelin precursor is an oncofetal protein defining hepatic cancer stem cells

Background and Aims: Increasing evidence has suggested that hepatocellular carcinoma (HCC) might originate from a distinct subpopulation called cancer stem cells (CSCs), which are responsible for the limited efficacy of conventional therapies. We have previously demonstrated that granulin-epithelin precursor (GEP), a pluripotent growth factor, is upregulated in HCC but not in the adjacent non-tumor, and that GEP is a potential therapeutic target for HCC. Here, we characterized its expression pattern and stem cell properties in fetal and cancerous livers. Methods: Protein expression of GEP in fetal and adult livers was examined in human and mouse models by immunohistochemical staining and flow cytometry. Liver cancer cell lines, isolated based on their GEP and/or ATP-dependent binding cassette (ABC) drug transporter ABCB5 expression, were evaluated for hepatic CSC properties in terms of colony formation, chemoresistance and tumorigenicity. Results: We demonstrated that GEP was a hepatic oncofetal protein that expressed in the fetal livers, but not in the normal adult livers. Importantly, GEP+ fetal liver cells co-expressed the embryonic stem (ES) cell-related signaling molecules including β-catenin, Oct4, Nanog, Sox2 and DLK1, and also hepatic CSC-markers CD133, EpCAM and ABCB5. Phenotypic characterization in HCC clinical specimens and cell lines revealed that GEP+ cancer cells co-expressed these stem cell markers similarly as the GEP+ fetal liver cells. Furthermore, GEP was shown to regulate the expression of ES cell-related signaling molecules β-catenin, Oct4, Nanog, and Sox2. Isolated GEP high cancer cells showed enhanced colony formation ability and chemoresistance when compared with the GEP low counterparts. Co-expression of GEP and ABCB5 better defined the CSC populations with enhanced tumorigenic ability in immunocompromised mice. Conclusions: Our findings demonstrate that GEP is a hepatic oncofetal protein regulating ES cell-related signaling molecules. Co-expression of GEP and ABCB5 further enriches a subpopulation with enhanced CSC properties. The current data provide new insight into the therapeutic strategy. © 2011 Cheung et al.published_or_final_versio

A pregnant woman with a rapidly growing breast lump

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Chromosome in situ hybridisation, Ki-67, and telomerase immunocytochemistry in liquid based cervical cytology

Aims: To assess the potential value of chromosome in situ hybridisation (CISH), Ki-67, and telomerase immunocytochemistry in liquid based cervical cytology to help detect carcinoma cells and precursors. Method: Sixty ThinPrep processed cervical cytology samples were studied: 23 cases within the normal limit, 13 low grade squamous intraepithelial lesions (LSILs), 10 high grade squamous intraepithelial lesions (HSILs), six squamous cell carcinomas, three endocervical adenocarcinomas, two cervical adenosquamous cell carcinomas, and three endometrial adenocarcinomas. CISH was performed with DNA probes specific for the pericentromeric regions of chromosome 11 and 16. Hybridisation signals were visualised with the streptavidin-biotin peroxidase technique. The monoclonal MIB1 and polyclonal TRT-H231 antibodies were used to detect Ki-67 and telomerase immunoreactivity, respectively. Results: Non-specific background staining was almost absent in CISH slides. Normal squamous and glandular cells showed a diploid chromosomal pattern. A relative gain in chromosomes 11 and 16 (aneusomy) was seen in HSIL and the carcinomas (p<0.0001 ). In MIB1 stained smears, normal cells and koilocytes showed inconspicuous immunoreactivity, whereas strongly immunoreactive nuclei were found in cancer cells and HSIL (p<0.0001). Not only carcinoma and HSIL cells, but also some normal cells, showed cytoplasmic staining for telomerase. Conclusions: These preliminary results indicate that ThinPrep processed cervical smears are suitable for CISH and immunocytochemical studies. The neoplastic squamous and glandular cells were easily identified based on nuclear aneusomy and strong Ki-67 immuoreactivity in the context of abnormal nuclear morphology. This is the first study to apply CISH in cervical cytology using an immunoenzymatic approach.published_or_final_versio