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Objective: To identify predictive factors for residual disease in hysterectomy specimens after a loop electrical excision procedure (LEEP) or cold knife conization in early-stage cervical cancer., Study Design: A retrospective review was undertaken of the clinical records and pathology reports of 108 consecutive patients who were diagnosed with early invasive cervical cancer stage IA1 to IB1 by cold knife conization or LEEP, and underwent subsequent hysterectomy or radical hysterectomy at the Gynae-oncology Unit, Queen Elizabeth Hospital between 2000 and 2012. Residual disease was defined as the presence of cervical intra-epithelial neoplasia (CIN) 2-3 or invasive carcinoma in hysterectomy specimens. Clinicopathological factors associated with residual disease were analyzed. Risk factors for the prediction of residual disease were identified by univariate and multivariate analysis., Results: Residual disease was found in 32 (29.7%) patients. Stage, tumour size, depth of invasion, lymphovascular space invasion, ectocervical margin, endocervical margin, and combined ectocervical and endocervical margin were significantly associated with residual disease in hysterectomy specimens on univariate analysis. On multivariate analysis, depth of invasion (odds ratio 2.1, p=0.033) and combined margin status (odds ratio 10.8, p≤0.001) were independent risk factors for residual disease. In a subgroup analysis using depth of invasion ≤5mm and a negative combined margin, none (0%) of the 52 patients who met the criteria had residual disease., Conclusions: Conization (combined ectocervical and endocervical) margin and tumour depth of invasion are independent predictors of residual disease in hysterectomy specimens. A negative conization margin and depth of invasion ≤5mm are associated with low risk of residual disease in patients with early-stage cervical cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The E6 and E7 proteins encoded by human papillomaviruses (HPV) are prime targets for therapeutic vaccine development. Ninety-five women with HPV 52 infection (33 transient infections, 17 cervical intraepithelial neoplasia grade II, 15 cervical intraepithelial neoplasia grade III, and 30 invasive cervical cancers) were examined for T-cell responses using interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT) assay. Of the 29 peptides (13 L1, 10 E6, and 6 E7) screened positive by an in vitro peptide-binding assay, 14 were positive by the IFN-γ ELISPOT assay. Positive epitopes for HLA A11 were located at amino acid positions 103-111, 332-340, 342-350, and 373-381 of the L1 protein; and at 27-35 and 86-94 of the E6 protein; and at 1-9 and 27-35 of the E7 protein. A24-specific epitopes included 60-68 and 98-106 of the L1 protein, 42-50 and 59-67 of the E6 protein, and 24-32 of the E7 protein. Only one epitope (99-107) of the E6 protein showed positive responses for HLA A2 subjects. Overall, T-cell responses against L1 were observed mainly in subjects who had cleared infection; whereas responses against E6 and E7 were confined mainly to subjects who had developed cervical neoplasia. The proportion of subjects showing detectable T-cell responses was low across all grades of cervical neoplasia suggesting that immune evasion mechanisms had set on early in the course of disease progression. This study provides the first set of T-cell epitopes mapped for HPV 52, which can be considered for further evaluation as targets for immunotherapy., (Copyright © 2011 Wiley-Liss, Inc.)

Human papillomavirus type 58 (HPV-58) exists in a relatively high prevalence in certain parts of the world, including East Asia. This study examined the T-cell response to HPV-58 L1, E6, and E7 peptides among women with cleared infection, cervical intraepithelial neoplasia grade 2 (CIN2) or CIN3, or invasive cervical cancer (ICC). Peptides found to be reactive in the in vitro peptide binding assay or mouse-stimulating study were tested with a gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay to detect peptide-specific responses from the peripheral blood mononuclear cells (PBMC) collected from 91 HPV-58-infected women (32 with cleared infection, 16 CIN2, 15 CIN3, and 28 ICC). Four HLA-A11-restricted HPV-58 L1 peptides, located at amino acid positions 296 to 304, 327 to 335, 101 to 109, and 469 to 477, showed positive IFN-gamma ELISPOT results and were mainly from women with cleared infection. Two HLA-A11-restricted E6 peptides (amino acid positions 64 to 72 and 94 to 102) and three HLA-A11-restricted E7 peptides (amino acid positions 78 to 86, 74 to 82, and 88 to 96) showed a positive response. A response to E6 and E7 peptides was mainly observed from subjects with CIN2 or above. One HLA-A2-restricted E6 peptide, located at amino acid position 99 to 107, elicited a positive response in two CIN2 subjects. One HLA-A24-restricted L1 peptide, located at amino acid position 468 to 476, also elicited a positive response in two CIN2 subjects. In summary, this study has identified a few immunogenic epitopes for HPV-58 E6 and E7 proteins. It is worthwhile to further investigate whether responses to these epitopes have a role in clearing an established cervical lesion.

Infection load and the integration of human papillomaviruses (HPV) have been implicated as determinants for oncogenesis, but whether variation among different HPV types exists remains unclear. We investigated 91 women infected with HPV type 52 (HPV-52), a type that is rare worldwide but common in East Asia. The median viral load increased with the severity of the lesion (248 copies/cell equivalent for normal/cervical intraepithelial neoplasia [CIN] grade 1, 402 copies/cell equivalent for CIN 2, 523 copies/cell equivalent for CIN 3, and 1,435 copies/cell equivalent for invasive cancer). The proportion of specimens with integration increased significantly with the severity of the lesion (P < 0.001). The viral load was associated with the physical status of the viral genome, with higher levels for the pure episomal form (P = 0.001). Infection status should be considered when interpreting viral load data for HPV-52, as single infections with this HPV type were found to have marginally higher viral loads than coinfections (P = 0.051). All except one sample had E2 disruption restricted to only a part of the gene. Integration is a critical step in HPV-52-induced carcinogenesis. The profile of E2 disruption was different from that described for HPV-16, with the amino-terminal region being most frequently involved. Selecting the appropriate E2 region for amplification is critical in studying the integration of HPV-52. In summary, the HPV-52 viral load and the integrated proportion increased with the severity of the cervical lesions but had a different pattern than that of HPV-16.

Human Papillomavirus (HPV) and Hepatitis B virus (HBV) are known aetiology of cervical and hepatocellular carcinoma, respectively. Both diseases share a similar clinical course, that is, the vast majority of those infected by these two viruses can eradicate the viruses spontaneously. A small sub-group who fails to clear the virus becomes chronic carrier and can progress to carcinoma many years later. We postulated that patients with pre-malignant or malignant cervical lesion are at increased risk of becoming chronic HBV carrier if infected, which may be attributed to inherent immunological deficiency against viral infection. We tested HBV carrier status from 288 patients with cervical carcinoma, 242 patients with high grade cervical intra-epithelial neoplasia (CIN) and 311 women with neither of the above conditions as control subjects. The HBV carrier rate in the Cancer Group, CIN Group and Control Group was 21.4%, 24.1% and 10.6%. The carrier rate was significantly higher in both the Cancer Group (p<0.01) and the CIN Group (p<0.01), compared to the Control Group. Our study suggests that a common immunological mechanism is involved in eradication of HBV and HPV infections and inherent immuno-deficiency might lead to an association of HBV carrier status with cervical carcinoma. Further studies are needed to confirm our findings and delineate the mechanism involved.

Unlabelled: The objective of the present preliminary study was to determine if a difference in the pattern of gene expression exists between tumors that were subsequently found to be sensitive to radiotherapy and tumors found to be resistant to radiotherapy., Patients and Methods: A total of 16 patients with invasive squamous cell carcinoma of the uterine cervix were included in this study. All patients were treated with standardized radiotherapy alone. Ten of the tumors were clinically radiosensitive and six were radioresistant. Total RNA, extracted from tumor specimens obtained prior to treatment, was hybridized onto an oligonucleotide microarray with probe sets complementary to over 20,000 transcripts. The genes were first subjected to a statistical filter to identify genes with statistically significant differential expression levels between those that were radiosensitive and those that were radioresistant. A back-propagation neural network was then constructed to model the differences so that patterns could be easily identified., Results: Although a number of genes were found to express differentially between radiosensitive and radioresistant tumors; the 10 most discriminating genes were used to construct the model. Using the expressions from these 10 genes, we found that neural networks constructed from random subsets of the whole data were capable of predicting radiotherapy responses in the remaining subset, which appears stable within the dataset., Discussion: This study shows that such an approach has the potential to differentiate tumor radiosensitivity, although confirmation of such a pattern using other larger independent datasets is necessary before firm conclusions can be drawn.

Analysis of multiple proteins is thought to be essential for establishment of signature proteomic patterns that may distinguish cancer from non-cancer. Surface-enhanced laser desorption/ionization (SELDI) is an affinity-based mass spectrometric method in which proteins of interest are selectively absorbed to a chemically modified surface on a biochip. This technology may provide protein profiling of a variety of biological specimens. In this study, we explored whether the protein biochip SELDI approach could differentiate cervical cancer from non-cancer cohorts. We screened protein profiles generated by SELDI in 62 cervical epithelial cell samples microdissected from 35 invasive cervical cancer and 27 age-matched normal cervix tissue specimens, respectively. The cell lysates of pure populations of cervical cells were applied onto Ciphergen ProteinChip WCX2 Arrays. Proteins bound to the chips were analyzed on a ProteinChip Reader Model PBS II. Derived proteomic patterns were converted to a simple proteomic scoring for distinguishing cancer from non-cancer cohorts. SELDI protein profiles of cell lysates from 20 cervical cancer and 15 normal cervix tissue specimens were used to train and develop a classification scoring system that used a seven-protein mass pattern. The training samples could be correctly discriminated. When a test set of 27 samples was used for evaluation of this scoring system to distinguish cervical cancer from non-cancer, a sensitivity of 87%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 86% for the test population were obtained. All seven proteins appeared to be down regulated in cervical cancer. The results from this study indicate that the proteomics approach of SELDI mass spectrometry, in combination with a simple scoring system, may distinguish cervical cancer from its normal counterpart. If this approach is also workable in the analysis of cervical exfoliated cell lysate, it might potentially be used in the early diagnosis of invasive cervical cancer. In addition, the identification of these specific proteins in cervical cancer may also facilitate the discovery of new cervical tumor marker(s).

Objective: To evaluate the use of laparoscopic ultrasound (USG) to detect pelvic nodal metastasis in patients with early stage cervical carcinoma., Methods: Laparoscopic USG was used to search for pelvic lymph node metastasis in stage Ia2 to IIa cervical carcinoma patients before radical hysterectomy. Suspicious lymph nodes identified by laparoscopic USG were removed laparoscopically for pathological confirmation by frozen section. If nodal metastasis was diagnosed, radical hysterectomy would be cancelled but enlarged lymph nodes were removed preferably by laparoscopic approach before closing the abdomen. These patients were treated with radiotherapy after recovering from the surgery. By comparing the laparoscopic USG and pathological findings of lymph nodes removed with or without radical hysterectomy, diagnostic accuracy of laparoscopic USG was determined., Results: Ninety-three patients were recruited and the final analysis included 90 patients. Laparoscopic USG found suspicious lymph nodes in 17 patients and nodal metastases were confirmed pathologically in 14 of them. Three patients with macroscopic and five patients with microscopic pelvic nodal metastases were missed by laparoscopic USG. The accuracy, sensitivity, specificity, positive and negative predictive value of laparoscopic USG in detecting pelvic lymph node metastasis were 87.8%, 63.6%, 95.6%, 82.4%, and 89%, respectively. Macroscopic metastatic nodes were successfully removed laparoscopically in 11 out of 14 patients and laparotomy was required for the other three patients., Conclusions: Laparoscopic USG can be performed with no major morbidity. This technique is sensitive in detecting macroscopic but not microscopic metastatic pelvic lymph nodes. Removal of macroscopic metastatic nodes identified via laparoscopic USG via laparoscopic approach could be accomplished in majority of patients.

Chronic infections with the hepatitis B virus (HBV) and high-risk human papillomaviruses (HPVs) are important risk factors for hepatocellular carcinoma (HCC) and cervical cancer (CC), respectively. HBV and HPV are DNA viruses that almost invariably integrate into the host genome in invasive tumors. The viral integration sites occur throughout the genome, leading to the presumption that there are no preferred sites of integration. A number of viral integrations have been shown to occur within the vicinity of important cancer-related genes. In studies of HBV-induced HCC and HPV-induced CC, we have identified two HBV and three HPV integrations into the human telomerase reverse transcriptase (hTERT) gene. Detailed characterization of the integrations revealed that four integrations occurred within the hTERT promoter and upstream region and the fifth integration occurred in intron 3 of the hTERT gene. None of the integrations altered the hTERT coding sequence and all resulted in juxtaposition of viral enhancers near hTERT, with potential activation of hTERT expression. Our work supports the hypothesis that the sites of oncogenic viral integration are nonrandom and that genes at the sites of viral integration may play important roles in carcinogenesis.

A large-scale epidemiologic survey on the prevalence of different types of human papillomavirus (HPV) in cervical cancer in China is indicated because of the implications for the development of diagnostic probes and vaccines against cervical cancer. A total of 809 cervical cancer specimens were collected from 5 regions in China including Shanghai, Guangzhou, Sichuan, Beijing and Hong Kong. HPV DNA was detected in 83.7% of the specimens. HPV-16 was present in 79.6%, HPV-18 in 7.5%, HPV-52 in 2.6% and HPV-58 in 3.8% of all HPV-positive specimens. The prevalences of HPV-16 and HPV-18 in Hong Kong were 61.7 and 14.8%, respectively, representing a lower HPV-16 and a higher HPV-18 proportion compared with the other regions. HPV-16 remained the most common HPV infection in both squamous cell carcinoma (SCC) and adenocarcinoma (AC). The proportion of HPV-18 infection was significantly higher in AC than in SCC., (Copyright 2002 Wiley-Liss, Inc.)

Insufficient apoptosis is implicated in many human cancers, including cervical carcinoma. The objectives of this study were to explore changes of apoptosis-regulating gene expression and their clinical significance in cervical cancer. The expression of apoptosis-regulating genes, including five Bcl-2 family and two caspase family members, was evaluated in 43 cervical invasive squamous cell carcinomas, using immunohistochemistry. Specimens in which >or=10% of the neoplastic cells showed cytosolic immunoreactivity were considered to be immunopositive. Results were correlated with clinico-pathologic characteristics of the subjects. All seven apoptotic regulators examined were positive in a proportion of the tumors. The percentage of cases expressing Bax was higher in the patients without evidence of disease after treatment than in the patients alive with disease or who died of disease (P<0.05). A significant difference in disease-free survival was detected between Bax-positive and -negative groups (P<0.05), and in overall survival between Mcl-1-positive and -negative groups (P<0.05). Significant association between the seven markers tested was only found for caspase 3 and Bak immunoreactivity in cervical carcinoma (P<0.05). The results demonstrate expression of multiple apoptosis-modulating proteins in cervical cancer. There appears to be complex regulation of apoptosis protein levels in association with clinical behavior of cervical squamous cell carcinoma.

An immuno-histochemical study of p21 and p27 expression in cervical carcinoma was performed in 73 patients. Positive p21 and p27 staining was detected in 35.6 and 11% of tumour tissues, respectively. p21 expression was significantly correlated with advanced disease stage and negative human papilloma virus infection whilst positive p27 staining was not correlated with any clinical and pathological parameters studied. Kaplan-Meier estimation indicated that survival might be related to disease stage, tumour grade and p21 expression. Cox regression analysis confirmed that advanced stage disease and poorly differentiated tumour are independent prognostic factors for cervical carcinoma.

Objective: The aim of this study was to evaluate the efficacy of hysteroscopy, using normal saline (NS) or carbon dioxide (CO2) as the distention medium, in assessing tumor invasion of the uterine cervix by endometrial carcinoma., Methods: A retrospective study was conducted in 200 consecutive patients with endometrial carcinoma diagnosed from 1993 to 2000. Prior to definitive surgical treatment, hysteroscopy was performed using either NS or CO2 as the distention medium to determine whether the tumor had spread to the cervix. The uterine specimens obtained after hysterectomies were cut open for gross examination. Tumor invasion of the cervix as determined by hysteroscopy and gross examinations was compared with the pathological findings., Results: Tumor invasion of the cervix was found in 41 (20.5%) cases on pathological examination. Hysteroscopy has an accuracy of 92.5% (185/200), a sensitivity of 68.3% (28/41), and a specificity of 98.7% (157/159), with a PPV of 93.3% (28/30) and a NPV of 92.4% (157/170) in determining cervical involvement. Assessment by gross inspection had 93.0% (186/200) accuracy, 68.3% (28/41) sensitivity, 99.4% (158/159) specificity, 96.6% (28/29) PPV, and 92.4% (158/171) NPV. There was no significant difference between the two assessment methods. When the results of hysteroscopy performed with different distention mediums were compared, the use of NS had a higher accuracy in determining tumor spread to the cervix (96.8% vs 88.7%, P = 0.03) and NPV (96.4% vs 88.4%, P < 0.05) than the use of CO2., Conclusions: Hysteroscopic assessment and gross examination of the uterine specimen had similar efficacy in detecting cervical invasion by endometrial carcinoma. Hysteroscopic examination using NS is more accurate than that which uses CO2., (Copyright 2001 Academic Press.)

Amplification and overexpression of cyclin D1 and CDK4 genes in cervical carcinoma were studied by semi-quantitative differential polymerase chain reaction assay and an immunostaining technique, respectively. Amplifications of cyclin D1 and CDK4 genes were found in 24% (27/113) and 26% (29/112) of tumors, respectively. Overexpression of cyclin D1 and CDK4 was demonstrated in 32% (21/66) and 73% (45/62) of tumors, respectively. No tumor showed CDK4 gene mutation on single strand conformational polymorphism. Sixteen percent (8/49) of the tumor specimens showed neither amplification nor overexpression. Disease stage, tumor grade and overexpression of cyclin D1 were found to be independent poor prognostic factors in cervical carcinoma.

Objective: To investigate the incidence of microsatellite instability (MI) in cervical carcinoma and its relationship with clinicopathological characteristics., Study Design: A retrospective study of 100 cases of cervical carcinoma., Results: MI, defined as tumor-associated alterations in at least one of five dinucleotide microsatellite markers examined, was detected in 25% of the cervical carcinomas which were observed. There was a nonsignificant trend towards MI occurrence in higher grade tumors, more advanced stage and cases with poor clinical outcome., Conclusion: The results suggest that microsatellite instability is present in a subset of cervical carcinoma and may be an independent prognostic factor. Further research with more samples is required.

Objective: To investigate the clinical and prognostic significance of human papillomavirus (HPV) in a Chinese population of cervical cancers., Methods: We studied 121 cervical cancer tissue samples from patients treated at our hospital. Identification and typing of HPV were done by polymerase chain reaction (PCR) using consensus primers MY11 and MY09 followed by direct DNA sequencing. The results were correlated with various clinical and prognostic parameters., Results: We found HPV DNA in 95 (78.5%) cases, including HPV-16 in 59 (48.8%) and HPV-18 in 14 (11.6%) cases. chi(2) analysis revealed no significant correlation between the presence of HPV DNA and age at diagnosis, clinical stage, histologic type, tumor grading, 2-year and 5-year survival rate. Of the factors evaluated, age at diagnosis and histologic type were found to have a statistically significant relationship with HPV type. The mean age of the HPV-18 group was 48.6 years compared to 57.1 years for the HPV-16 group (p = 0.045) and 58.2 years for the HPV-negative group (p = 0.04). HPV-18 was detected more often in adenocarcinomas (AC) than in squamous cell carcinomas (SCC). Conversely HPV-16 was detected significantly more often in SCC (p < 0.0001). The HPV-negative group also had a higher incidence of SCC (p = 0.007). HPV-18-positive patients seemed to have more nodal involvement than both HPV-16-positive patients (45.5 vs. 20.8%) and HPV-negative patients (45.5 vs. 18.2%); however, it did not reach statistical significance., Conclusions: These observations suggest that the presence of HPV DNA does not bear any clinical or prognostic significance in a Chinese population of cervical cancers. HPV-18 is found more often in younger patients and is associated with AC., (Copyright 2001 S. Karger AG, Basel)

Infection with specific genotypes of human papillomavirus (HPV) has been strongly implicated in cervical carcinogenesis. However, HPV infection alone is insufficient for malignant transformation of the cervical epithelium. An alteration of microsatellite repeats is the result of slippage owing to strand misalignment during DNA replication and is referred to as microsatellite instability (MSI). These defects in DNA repair pathways have been related to human carcinogenesis; however, the role of MSI in the tumorigenesis of cervical cancer remains unclear. The clinical and pathological features of cervical cancers which are MSI-positive have also not been fully characterized. This study investigated the prevalence of MSI in cervical cancer and its relationship to clinico-pathological characteristics and HPV infection. Polymerase chain reaction-based microsatellite assay combined with tissue microdissection was used to examine for MSI in 50 cervical squamous cell carcinomas in Hong Kong women. In addition, the immunohistochemical staining was performed to determine the expression of major DNA mismatch repair genes, hMSH2 and hMLH1. Six cases (12%) displayed a low frequency of MSI (MSL-L) showing MSI at one locus only in 5 loci examined. Seven cases (14%) showed a high frequency of MSI (MSI-H) having MSI at 2 or more loci. Grouping MSI-L and MSI-H cases together as MSI-positive, statistical analysis of HPV infection, tumor grade, clinical stage and clinical status failed to disclose differences between MSI-positive and MSI-negative cases (p > 0.05). However, MSI-H correlated with advanced stage of disease (p < 0.05). Individuals with MSI-H tumors appeared to have reduced overall survival compared to individuals with MSI-L and MSI-negative tumors, but the difference was not statistically significant (p = 0.059). An absence of either MSH2 or MLH1 expression was observed in 2 MSI-L and 4 MSI-H cases, respectively. The results suggest that MSI is present in a subgroup of cervical squamous cell carcinomas, and defects resulting in MSI may be related to tumor progression and possibly poor prognosis in cervical cancer., (Copyright 2001 S. Karger AG, Basel)

Objective: This study compares dynamic helical CT with dynamic MR imaging in the evaluation of pelvic lymph nodes in cervical carcinoma., Subjects and Methods: Women with biopsy-proven cervical carcinoma prospectively underwent dynamic helical CT and MR imaging before surgery. A metastatic node on CT and MR imaging was defined as a rounded soft-tissue structure greater than 10 mm in maximal axial diameter or a node with central necrosis. Imaging results were compared with pathology, and receiver operating characteristic curves for size and shape were plotted on a hemipelvis basis. Nodal density and signal intensity on CT and MR images, respectively, were reviewed for differences between benign and malignant disease., Results: A total of 949 lymph nodes were found at pathology in 76 hemipelves in 43 women, of which 69 lymph nodes (7%) in 17 hemipelves (22%) were metastatic. Sensitivity, specificity, positive and negative predictive values, and accuracy of helical CT and MR imaging in the diagnosis of lymph node metastasis on a hemipelvis basis was 64.7%, 96.6%, 84.6%, 90.5%, and 89.5% and 70.6%, 89.8%, 66. 7%, 91.4%, and 85.5%, respectively. Receiver operating characteristic curves for helical CT and MR imaging gave cutoff values of 9 and 12 mm in maximal axial diameter, respectively, in the prediction of metastasis. Central necrosis had a positive predictive value of 100% in the diagnosis of metastasis. Signal intensity on MR imaging and density-enhancement pattern on CT in patients with metastatic nodes did not differ from those in patients with negative nodes., Conclusion: Helical CT and MR imaging show similar accuracy in the evaluation of pelvic lymph nodes in patients with cervical carcinoma. Central necrosis is useful in the diagnosis of metastasis in pelvic lymph nodes in cervical cancer.

Loss of heterozygosity (LOH) is a common genetic finding in many human neoplasms, including cervical cancer. The detection of LOH at specific loci in the precursor of cervical cancer, cervical intraepithelial neoplasia (CIN) may help in elucidating the evolution of this cancer, which has a clearly defined histological premalignant phase. However, molecular genetic investigation of CIN is difficult because many of the lesions are very small and sometimes ill defined topographically. In this study we analyzed eighteen polymorphic microsatellite repeats on chromosome 3p in CINs using a method of primer extension pre-amplification (PEP) for whole genome amplification combined with microdissection. These markers encompass chromosome region 3pter-3p12. LOH at one or more loci was detected in five (33%) out of the 15 informative cases with low grade CIN (CIN 1), while 22 (92%) out of 24 cases with high grade CIN (CIN 2 and 3) (P<0.01). The highest incidence (41%) of LOH was detected at locus D3S1038 (3p26.1-3p25.2). Frequent LOH (more than 20%) was also found at other loci including D3S1110 (3p25.3-3p25.1) (31%), D3S656 (3p25.1) (24%), D3S1076 (3p21.2-3p21.1) (29%), D3S1300 (3p21.1-3p14.2) (24%), D3S1600 (3p14.2-3p14.1) (24%), and D3S1079 (3p13) (25%). The results from this study taken together with others indicate that the genetic alterations on chromosome 3p are common in high grade of CIN and are probably early events in cervical carcinogenesis. Tumor suppressor gene(s) that play a role in cervical neoplasm may be located on the short arm of chromosome 3, likely at or near 3p26.1-25.1, 3p21.2-21.1, and 3p14.2-13.

In this study we investigated the involvement of p53 polymorphism at codon 72, the infection and typing of human papillomavirus (HPV) and the correlation of p53 polymorphism with HPV type and other clinicopathologic characteristics in 72 Hong Kong women with cervical cancer. We developed a simple and nonradioactive method for determining polymorphism at codon 72 of the p53 gene. The homozygous p53 arginine allele (Arg/Arg) was detected in 22 (31%), the homozygous p53 proline allele (Pro/Pro) in 14 (19%) and the heterozygous allele (Arg/Pro) in 36 (50%) cases, respectively. Using the consensus primers MY11 and MY09, HPV infection was detected in 55 of 72 (76%) cases. The prevalent types were HPV-16 (55%), HPV-18 (16%) and HPV-58 (9%). The number of HPV-positive cases with Arg/Arg, Pro/Pro and Arg/Pro were 17 (31%), 12 (22%) and 26 (47%), respectively. The p53 polymorphism at codon 72 was not significantly correlated with any of the HPV types (p > 0.05). No striking overrepresentation of homozygous arginine-72 p53 was observed in HPV-associated cervical cancer. The results in this study did not show that any p53 polymorphic form has a prognostic significance for cervical cancer., (Copyright 2000 S. Karger AG, Basel)

Background: Alterations in chromosome 1 are common in human malignancies. The frequency of loss of heterozygosity (LOH) on chromosome 1 in cervical carcinoma and its clinical significance are not clearly understood., Methods: LOH on chromosome 1 was studied in 100 cervical carcinomas by the polymerase chain reaction (PCR) using 29 highly polymorphic microsatellite markers spaced approximately 10 centimorgans apart. Loci with high frequencies of LOH were identified and the findings were correlated with clinicopathologic characteristics., Results: LOH on chromosome 1 at 1 or more loci was detected in 93% of tumors. The frequencies of LOH at locus D1S2829 (1p31), D1S2663 (1p36.3), and D1S2725 (1q25) exceeded 30%, and 12 other loci exhibited frequencies of LOH of 20-30%. Advanced stage tumors had a significantly higher percentage of informative microsatellite markers with LOH than early stage tumors. Of the 29 microsatellite markers studied, 4 loci had a significantly higher frequency of LOH in Stage III and IV tumors than in earlier stage tumors., Conclusions: Frequent aberrations on chromosome 1 in cervical carcinoma suggest that inactivation of tumor suppressor genes is important in cervical tumorigenesis. Higher frequencies of LOH in Stage III and IV tumors suggest that chromosome 1 changes are late events in cervical carcinoma. The findings of this study are consistent with earlier reports that suggest that tumor suppressor genes are present at 1p36.3 and 1p31. To the authors' knowledge, the high frequency of LOH mapped to 1q25 has not been reported previously. Its significance awaits further clarification., (Copyright 1999 American Cancer Society.)

Objective: This study compared laparoscopic sonography with surgical pathology in the evaluation of pelvic lymph nodes in women with cervical cancer., Subjects and Methods: Intraoperative laparoscopic sonography of pelvic lymph nodes was performed in 31 women with biopsy-proven cervical cancer. A lymph node that was rounded (longitudinal-transverse axis ratio of <2) or showed absence of central hilum was defined as positive for metastasis. For comparison, lymph nodes from each hemipelvis were grouped anatomically into paraaortic, common, internal, and external iliac chains during evaluation on laparoscopic sonography and on surgical pathologic examination., Results: Pelvic dissection in 31 women yielded 630 lymph nodes. There were 54 metastatic nodes in 12 women. Laparoscopic sonography revealed 32 (59%) of all pathologically metastatic lymph nodes. Sensitivity on laparoscopic sonography when comparing groups by hemipelves was 93.3% and by anatomic lymph node chains was 76.2%. Metastatic nodes were most commonly located in the common iliac region and were characteristically rounded, hypoechoic, showed absence of central hilum, and occasionally showed central necrosis. Nine (28%) of 32 metastatic lymph nodes revealed by laparoscopic sonography measured 1 cm or less. Six benign nodes in four patients were also visualized with laparoscopic sonography., Conclusion: Laparoscopic sonography achieved a sensitivity exceeding 90% in the detection of metastatic lymph nodes in the hemipelves of women with cervical cancer. Laparoscopic sonography is a feasible and promising technique for the evaluation of pelvic lymph nodes in women with cervical cancer and merits further evaluation.

Objectives: The objectives of this study were to evaluate the use of laparoscopic ultrasonography (USG) in combination with laparoscopic pelvic lymphadenectomy in the management of patients with cervical carcinoma., Methods: A technique for detecting pelvic and para-aortic lymph node metastases through laparoscopic USG was developed. Laparoscopic USG was done prior to pelvic lymphadenectomy performed either laparoscopically or by laparotomy. Laparoscopic USG findings were compared with pathologic findings., Results: The sensitivity and specificity of laparoscopic USG in detecting pelvic lymph node metastases were 91 and 100%, respectively. Metastatic pelvic lymph nodes could be completely removed through laparoscopes in 7 of 11 patients, with no complications., Conclusion: Laparoscopic USG is highly sensitive in detecting metastatic pelvic lymph nodes. Detection and removal of metastatic pelvic lymph nodes laparoscopically allow quick recovery from the operation and early commencement of radiotherapy., (Copyright 1998 Academic Press.)

Karyotypic studies have shown that genetic aberrations of the short arm of chromosome 3 (3p) may be involved in the pathogenesis of cervical carcinoma. In this study we analyzed nine polymorphic microsatellite repeats on 3p using a PCR-based assay for loss of heterozygosity (LOH) in 64 invasive squamous cell carcinomas of the cervix. These markers encompass chromosome region 3p13-25. LOH at one or more loci was detected in 46 (79%) out of the 58 informative cases. The incidence of LOH at locus D3S643 (3p13) was the highest among nine markers examined. The difference between the frequency of LOH at D3S643 in early stage (I-II) disease (43%) and those with advanced stage (stage III-IV) (79%) was statistically significant (P < 0.05). The results indicate that tumor suppressor gene(s) that play a role in cervical cancer may be located on the short arm of chromosome 3, likely near or at 3p13. The LOH at 3p13 appears to be a late event in tumor progression and may serve as an indicator for a less favorable clinical outcome.

To evaluate both the incidence of c-myc gene mutation and the relationship of this finding to the clinico-pathologic characteristics of patients with cervical cancer, a polymerase chain reaction (PCR)-based heteroduplex gel electrophoresis method was used to screen DNA extracted from 102 cervical invasive carcinomas referred to the Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong. C-myc mutation was detected and then characterised by sequencing of PCR products in 4 cases (4%). The incidence of c-myc mutation in patients with advanced stage tumours (stage III-IV, 11% was statistically higher than in those with early stages (stage I-II, 1%, p = 0.05). There was also a significant difference in the incidence of c-myc mutation among the patients who had died of their disease (10%), were alive with evidence of disease (25%), and those without evidence of disease (0%, p = 0.0003). These findings indicate that the c-myc mutation is not common in cervical cancer, but where it exists, it may be associated with cancer progression and poorer outcome. Whether the c-myc mutation is an adjunct prognostic indicator in cervical cancer remains to be established in a larger study.

The molecular genetics of human cervical cancer remains to be defined to a significant extent. The current study examined the prevalence and significance of proto-oncogene c-fos overexpression in cervical cancer. Immunohistochemical staining of c-fos oncoprotein was performed in 27 invasive cervical carcinomas and 30 cervical intraepithelial neoplasias (CINs) managed in our department. Eight normal cervical specimens were used as controls. In the patients with invasive cervical cancer, 8 were stage I, 12 were stage II, and 7 had stage III-IV disease. Three of the cancers were well differentiated, 18 were moderately differentiated and 6 were poorly differentiated. Twenty invasive cervical carcinomas (59%) and 3 CIN (10%) showed overexpression of c-fos. The difference is statistically significant (p < 0.001). No statistically significant relationship was found between c-fos overexpression and clinical stage, histological grade, or survival in invasive cervical cancer. In this population, c-fos overexpression appears to be common in invasive cervical cancer and correlated with the ability of the tumor to become invasive, but is not associated with the progression of cervical cancer.

38 women with biopsy proven untreated cervical carcinoma were prospectively studied with transrectal ultrasound (TRUS), spiral computed tomography (SCT) and magnetic resonance imaging (MRI). 20 women had radical hysterectomy and pelvic lymphadenectomy with detailed histological evaluation of the parametra. The echographic features of cervical carcinoma on TRUS are a hypoechoic (60%) or isoechoic (40%) (relative to normal uterine muscle/cervical stroma), poorly defined mass lesion with indistinct margins in an enlarged cervix. This relatively high percentage of isoechoic tumours and relative lack of contrast resolution may pose a problem in the identification of some tumours, and to our knowledge has not been previously reported. Further limitations of TRUS are in the evaluation of advanced cervical cancer, due to bulky tumours rendering poor access to the parametrium and pelvic sidewall. The overall accuracy in staging of early cervical cancer (less than stage 2b) was 85% for examination under anaesthesia (EUA), 75% for TRUS, 65% for MRI and 50% for SCT. The positive predictive value in evaluating the parametra in this group of patients was also lower for SCT (14%) and MRI (33%) compared with TRUS (100%). In the evaluation of advanced cervical cancer (stage 2b or higher), there was poor correlation between TRUS and EUA, with MRI showing the best correlation with EUA. We conclude that SCT is inferior to both TRUS and MRI in the staging of early stage cervical cancer.

Objective: To determine the amplification of proto-oncogene HER-2/neu in invasive cervical cancer and its relationship with the stage of disease, grade of tumor and prognosis of patients., Methods: In this retrospective study 70 women with invasive cervical squamous cell carcinoma were included. DNA was extracted from the paraffin-embedded tumor tissue. The amplification of HER-2/neu was studied using a differential polymerase reaction (PCR) technique. Assessment of significance was performed using Peason's Chi-square test and Fisher's exact test., Results: Eleven of the 70 cases (16%) showed an amplification of HER-2/neu but there was no relation between amplification and tumor histologic grading (p = 0.408) or clinical staging (p = 0.180). Follow-up information in 67 patients was available. The incidence of amplification in the patients who were alive with disease was not statistically different from that in the patients who were alive with no evidence of disease (p = 0.315). The incidence of amplification in the patients who died of disease was higher than that in the patients who were still alive, but statistical significance did not reached (p = 0.062)., Conclusion: The results suggest that HER-2/neu amplification does exist in a subgroup of invasive cervical cancer and may play a role in cervical carcinogenesis. The role as independent prognostic factor has to be evaluated by further prospective studies.

Eighty samples of cervical invasive squamous cell carcinoma were examined for ras gene mutations using polymerase chain reaction (PCR) followed by restriction enzyme digestion. We found 28 (35%) cervical cancers contained ras mutations at H-ras codon 12, 49 (61%) at K-ras codon 12, and 5 (6%) at K-ras codon 13. There were no significant differences in incidence of the ras gene mutations among different histologic grades or clinical stages of the cancer (P > 0.05). This result suggests that ras mutation may be an important step involved in a substantial number of cervical carcinoma. The interaction of ras with other genes and/or events may also be involved in pathogenesis of this malignancy.

Sarcoma botryoides rarely arises in the uterine cervix. It usually presents in the adolescent age group and is treated primarily by surgery followed by adjuvant chemotherapy. It has been reported in the literature that is possible to limit surgery to local excision in stage I cases, when the tumor is confined to the cervix. In an attempt to preserve reproductive function in a young female patient, we performed cervicectomy alone, followed by adjuvant chemotherapy. After 36 months follow-up she remains well, suggesting that limited excision with adjuvant chemotherapy may be sufficient for early-stage disease.

Ki67 immunostaining was performed on 48 cases of squamous cell carcinoma of the cervix and AgNOR silver staining on 29 cases. There was no correlation between the clinical stage of the tumor and the two methods of staining but both methods correlated with histological grade. There was no correlation between the two methods of staining in 17 case where they were done on adjacent blocks of tumor tissue. High Ki67 score but not high AgNOR count was significantly associated with early recurrence.