published_or_final_version / Pathology / Master / Master of Medical Sciences

Thesis (M Med (Anatomical Pathology))--University of Limpopo, 2010. / Background Esophageal squamous cell carcinoma (SCC) remains a disease of poor prognosis. Early diagnosis is compromised by the delayed onset of symptoms. By the time of surgical intervention metastases and organ infiltration have already occurred this reduces the prognosis significantly and the 5-year survival rate of operative advanced esophageal SCC remains poor. In order to select an appropriate therapeutic regime and guard against both over- and under treatment, reproducible prognostic markers are needed at the time of diagnosis. The study evaluates the phenotypic expression of E-cadherin and β- catenin in SCC of the esophagus. Methods: The expression patterns of both β-catenin and E-cadherin was determined using immunohistochemistry technique in patients with esophageal SCC with the application of the Broders and Brynes grading systems in assessing clinical outcome. Forty four cases were randomly selected, one case was esophagectomy, and 43 were endoscopic biopsies with one case of Broders Grade I, 37 Grade II and 6 Grade III and 9 cases had pattern 2 and 35 had pattern 3 with Brynes Grade. Results: The reduced expression of E-cadherin and β-catenin was 45.5% and 47.7% respectively. No significant level was observed with E-cadherin (P= 0.20) and for β-catenin (P= 0.18) but the low protein level of both biomarkers was associated with tumor cell differentiation with Broders classification. The reduced expression of E-cadherin on invasive tumor front was 27% and 57% for reduced expression of β-catenin. The level of significance was found to be (P=1.00) for E-cadherin expression and (P=0.02) for β-catenin. E-cadherin and β-catenin showed reduced expression on invading tumor front and β-catenin was associated with tumor cell invasiveness. Conclusion: The expression of E-cadherin and β-catenin with regard to Broders classification showed no significance on tumor cell differentiation and these expressions do not play a role in guiding nor predict the behavior or progression of the tumor. However, the assessment β-catenin on the tumor invasive front (Brynes) shows a high correlated with tumor behavior as it is involved in regulation E-cadherin function.

Inactivation of mouse tumor susceptibility gene tsg101 leads to neoplastic transformation which could reversed by restoration of tsg101 protein activity. In the varieties of human malignancies, no genomic defect could be identified questioning the role of TSG101as a classical tumor suppressor. Subsequent studies revealed presence of abnormal TSG101 transcripts in both tumor tissues and its normal counter parts, as well as in embryonic tissues. Hence, the relationship between TSG101 and human cancer development remains unclear. The previous studies have demonstrated that TSG101 has multiple biological functions, including regulations of protein degradation through ubiquitination, transcriptional, protein trafficking, cell survival and proliferation and epithelial cell differentiation. To further investigate the role of TSG101 in tumorigenesis, we employed immunohistochemistry and in situ hybridization analysis to study the expressions of TSG101 protein and mRNA in squamous cell carcinomas of different differentiation status. In addition, we scrutinized the relationship between TSG101 expression and the changs of cell cycle-related tumor suppressors and markers of epithelial differentiation, cell growth, tumor metastasis and apoptosis. The results reveal that TSG101 protein and mRNA are consistently expressed in the epidermal cells residing in the suprabasal, granular and cornified layers, but only weakly expressed in the cells of basal layer. The expressions of TSG101 are down regulated in poorly differentiated squamous cell carcinomas of various organs. Furthermore, TSG101 is also expressed in the tissue of squamous metaplasia, and the expression of TSG101 is positively related to that of cytokeratin. In addition, while TSG101 is down regulated, the expressions of p21Cip1/WAF1, p14ARF and MDM2 are also decreased ehereas that of p53 is conversely increased. Phospho-Rb and E-Cadherin were found to be down regulated in advanced cancers, but we failed to find their correlation with TSG101 on cell proliferation and tumor metastasis. Taken together, we hypothesize that TSG101 expression may influence and promote cell differentiation by regulating keratin expression, being involved in the MDM2-p53 circuit and interacting with p21Cip1/WAF1. Besides, by the integration of the studies of TSG101, keratin 10, and Rb protein expression, we infer that TSG101 may indirectly suppress expression of Rb by up-regulating keratin 10 in epithelial cells. The detailed mechanisms of the observation require further investigation. Nevertheless, our results have provided evidences to support the role of TSG101 on differentiation of squamous epithelial cells in addition to tumorigenesis.

Thesis (M. Med. Sc.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 67-76).

No description available.

The purpose of this study was to investigate several biological markers that may predict the response of muscle invasive transitional cell carcinoma TCC of the bladder to radical radiotherapy. The specific markers chosen were tumour angiogenesis (CD31 &CD34), tumour cell proliferation (Ki-67) and apoptosis (bcl-2), intratumour macrophage infiltration (CD68) and p53. Archival formalin fixed paraffin embedded pre treatment bladder biopsies from 101 patients with muscle invasive TCC were obtained. All patients subsequently received radical radiotherapy as their only treatment for the disease. 4µm sections were graded according to the WHO grading system and staged by the TNM classification. Angiogenesis (CD31&CD34) counts were obtained using a 25-point Chalkley eyepiece graticule. Bcl-2 scored as positive and negative, while p53, Ki-67 and CD68 were estimated using an eyepiece graticule. The medical records were examined to assess the response of the tumour at the 3-month post radiotherapy cystoscopy and the long-term outcome. Patients were classified into two groups in two sections: the first section includes (1) those free of disease (no tumour detected in the bladder at the 3-month cystoscopy), (2) those with resistant disease (tumour present at 3 months). The second section includes (1) those with persistent or recurrent cancer in the bladder (tumour recurred after an initial 3 months negative check cystoscopy together with patients with resistant disease at 3 months), (2) those free of disease at all subsequent cystoscopies. Detailed statistical analysis revealed that there were no association between any of the markers examined and the response to radiotherapy. MVD using CD34 was lower in higher stage tumours (p=0.050). Females, whilst representing only a small fraction (16) of the total of patients studied showed an inferior response to radiotherapy when compared to that of male patients (p=0.048). Higher median haemoglobin levels for the response group (p=0.031) was observed as well as a positive significant correlation between p53 (L1) expression and MIB-1 (LI) (r=0.332, p=0.001). The Kaplan-Meier survival analysis shows that the survival time is significantly better for those who were exposed longer to radiotherapy (> 33 days) (Log Rank, p=0.0246). There was a significantly higher survival time for patients who have CD68 higher than 42.4 (log rank, p=D.036). The study concluded that none of the selected markers could be used as prognostic value in determining patients most suitable for radiotherapy as primary treatment with curative intent for their bladder cancer. The finding of a poorer response in females is worthy of further study since, hormonal and anatomical influences may be important.

Thesis (M.S.)--University of Missouri-Columbia, 2007. / "May 2007" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. Includes bibliographical references.

We report two cases of combined cutaneous tumors composed of melanoma and carcinoma. The first tumor presented as a 5-mm pink-blue macule over the right zygomatic arch in an 85-year-old man. Shave biopsy and immunohistochemical studies revealed that the tumor was composed of melanoma (highlighted by SOX10 and MART-1, with high Ki-67 proliferative index) intermixed with nodular basal cell carcinoma (highlighted by pan-cytokeratin and Ber-EP4). The neoplastic melanocytes were confined to the basal cell carcinoma nodules, and a diagnosis of combined melanoma in situ and basal cell carcinoma was rendered. After therapeutic excision, the patient was disease-free at 9 months after the initial diagnosis. The second tumor presented as a 6-mm pink-brown crusted papule on the right forehead in an 89-year-old man. Shave biopsy and immunohistochemical studies revealed that the tumor was composed of malignant melanoma (MM) (highlighted by S100 and MART-1) intermixed with squamous cell carcinoma (SCC) (highlighted by cytokeratin and p63), and a diagnosis of combined MM-SCC was rendered. These two cases highlight the importance of recognizing these rare types of melanocytic-epithelial cutaneous neoplasms to arrive at an accurate diagnosis that may inform appropriate disease stage and therapy.

Penile squamous cell carcinoma (PSCC) is rare; hence little is known about its aetiology and pathogenesis. Two challenges exist in the clinical management of PSCC patients. Firstly, finding a non-invasive method to aid the detection of occult lymph node metastasis to improve patient selection for inguinal lymphadenectomy. Secondly, the development of novel treatment strategies for those with advanced PSCC, as current treatment options are limited. A high prevalence of copy number gain in the chromosome 3q arm has been identified and linked to poor cancer-specific and disease-free survival in PSCC. Within this region lies the PIK3CA oncogene, which is mutated/amplified/gained and results in the activation of the PI3K-AKT-mTOR pathway. PIK3CA copy number gain has not been fully investigated in PSCC and it has the potential to be a driver gene in penile carcinogenesis and the PI3K-AKT-mTOR pathway presents an opportunity for targeted therapeutics in PSCC. I demonstrated an increasing frequency of PIK3CA copy number gain with evolving PSCC disease state (penile intraepithelial neoplasia (10/58; 17%), primary PSCC (83/199; 42%), advanced primary PSCC (20/26; 77%); p < 0.0001) with few PIK3CA mutations in PSCC (3/51; 6%). PIK3CA copy number gain correlated with more aggressive PSCC subtypes (p=0.0028), higher tumour grade (p < 0.0001) and stage (p=0.0043) and thus could be used as a marker of high-risk disease. However, it shows no significant association with lymph node metastasis or prognostic value for cancer-specific survival in PSCC. Overall, I confirmed that the PI3K-AKT-mTOR pathway activity is primarily involved in early penile carcinogenesis and based on these findings the therapeutic targeting of this pathway in those with advanced PSCC disease is unlikely to produce significant clinical benefit. Future studies will need to focus on the identification of new clinically relevant candidate genes and signalling pathways, which offer prognostic value and the potential for targeted therapeutics in this rare cancer.

Thesis (Ph.D.)--University of Hong Kong, 2003. / Also available in print.