Ann-Cathrin Hellström

Human Papillomavirus Infection, Centrosome Aberration, and Genetic Stability in Cervical Lesions

DNA replication and centrosome duplication have to be strictly synchronized to guarantee genomic stability. p53, pRb, cyclin E, and cyclin A are reported to be involved in the synchronizing process. We investigated the relationship between papillomavirus infection, centrosome aberration and aneuploidy during genesis of cervical carcinoma. The number of centrosomes found in cells from normal cervical epithelium (n = 5), condyloma acuminata (n = 5), cervical intraepithelial neoplasia (CIN) I, II, and III (n = 14) and invasive cervical carcinoma (n = 5) was analyzed by γ tubulin immunofluorescence staining. The nuclear DNA content was investigated by image cytometry and human papillomavirus (HPV) infection was determined by polymerase chain reaction. Normal epithelia and condyloma acuminata showed cells with one or two centrosomes, whereas CIN lesions showed cells with an increasing number of centrosomes. This abnormality was found to be lowest in CIN I lesions, increased with advancing grade of CIN and was highest in lesions of invasive carcinomas. In parallel, an increasing number of cells with aberrant DNA content was seen. All carcinomas and all except one of the CIN III lesions showed aneuploidy. Three CIN II cases were aneuploid and two cases with CIN I were tetraploid. Normal epithelia and condyloma acuminata showed diploidy. All invasive carcinomas and lesions with CIN were positive for high-risk HPV types 16, 18, or 31, except one invasive carcinoma and one CIN II lesion positive for universal primers only. Three condyloma acuminata were HPV 16-positive and one HPV 6-positive. The results suggest that high-risk HPV infection is correlated to a progressive numerical disturbance of centrosome replication followed by progressive chromosomal aberrations in CIN lesions and invasive carcinomas.

Amplification of the telomerase reverse transcriptase (hTERT) gene in cervical carcinomas

The expression of telomerase reverse transcriptase (hTERT), the catalytic component of the telomerase complex, is required for activation of telomerase during immortalization and transformation of human cells. However, the biochemical and genetic mechanisms governing hTERT expression remain to be elucidated. In the present study, we examined hTERT amplification as a potential genetic event contributing to telomerase activation in cervical carcinomas. An amplification of the hTERT gene was found in 1/4 cervical cancer cell lines and 21/88 primary tumor samples derived from the patients with cervical carcinomas. An increase in the hTERT copy number was significantly correlated with higher levels of hTERT protein expression. Moreover, the hTERT alterations with the enhanced hTERT expression were exclusively observed in those tumors with high‐risk human papillomavirus infection. Taken together, the hTERT gene amplification, directly or indirectly targeted by human papillomavirus, may be one of the driving forces responsible for upregulation of hTERT expression and activation of telomerase in cervical cancers.

Differential tissue-specific protein markers of vaginal carcinoma

The objective was to identify proteins differentially expressed in vaginal cancer to elucidate relevant cancer-related proteins. A total of 16 fresh-frozen tissue biopsies, consisting of 5 biopsies from normal vaginal epithelium, 6 from primary vaginal carcinomas and 5 from primary cervical carcinomas, were analysed using two-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry. Of the 43 proteins identified with significant alterations in protein expression between non-tumourous and tumourous tissue, 26 were upregulated and 17 were downregulated. Some were similarly altered in vaginal and cervical carcinoma, including cytoskeletal proteins, tumour suppressor proteins, oncoproteins implicated in apoptosis and proteins in the ubiquitin–proteasome pathway. Three proteins were uniquely altered in vaginal carcinoma (DDX48, erbB3-binding protein and biliverdin reductase) and five in cervical carcinoma (peroxiredoxin 2, annexin A2, sarcomeric tropomyosin kappa, human ribonuclease inhibitor and prolyl-4-hydrolase beta). The identified proteins imply involvement of multiple different cellular pathways in the carcinogenesis of vaginal carcinoma. Similar protein alterations were found between vaginal and cervical carcinoma suggesting common tumourigenesis. However, the expression level of some of these proteins markedly differs among the three tissue specimens indicating that they might be useful molecular markers.

Abnormal expression pattern of cyclin E in tumour cells

The expression pattern of cyclin E during the cell cycle was studied in normal and tumour cells in culture and in tumour biopsies. This pattern was found to be abnormal in tumour cells. A triple immunostaining protocol, digital microscopy and image analysis were used to find the position of the individual cells in the cell cycle and to measure the nuclear cyclin E levels. In normal cells, the number of cyclin E‐positive cells decreased rapidly when the cells entered the S‐phase. In the tumour cell lines, cyclin E was not downregulated in early S‐phase, as in normal cells. Instead the number of cyclin E‐positive cells remained high throughout S‐phase, and the cyclin E staining intensity per cell often increased during S‐phase. In about half of the analysed tumour cell lines, many cells stained positive for cyclin E even in the G2‐phase. This abnormal expression over the cell cycle of cyclin E was also found in tumour biopsies from cervical, breast and prostatic carcinomas, even though it varied greatly between individual tumours. In some tumours, the expression pattern of cyclin E was similar to that of normal cells in culture, whereas in others high cyclin E levels could be seen in S‐phase cells, as in the transformed cell lines. A high percentage of cells expressing cyclin E during S‐ or G2‐phase was found to be related to poor outcome (p < 0.025) in a small group of cervical carcinoma patients (n = 12).

Impact of MRI in the management and staging of cancer of the uterine cervix

Abstract Background. Cervical carcinoma is the only gynecological tumor still being staged mainly by clinical examination and only a limited use of diagnostic radiology. Cross sectional imaging is increasingly used as an aid in the staging procedure. We wanted to assess the impact of magnetic resonance imaging (MRI) in addition to the clinical staging of patients with carcinoma of the uterine cervix. Material and methods. A retrospective single-centre analysis of 183 women referred to a tertiary referral centre for gynecological tumors (≤ 65 years old) with cervical cancer diagnosed between January 1, 2003 and December 31, 2006 who have undergone an MRI investigation before start of treatment. Patient records were retrospectively reviewed and any change of the planned treatment after the MRI examination was noted. Results. In patients with cervical carcinoma FIGO stage Ia2-IIa treated surgically, the treatment plan was altered due to MRI results in 10/125 patients. In the smaller group of patients with clinically more advanced disease receiving radio-chemotherapy, the treatment plan was altered in 12/58 patients. Reasons for changing the treatment plan after MRI were findings indicating a higher (n = 8) or lower (n = 5) local tumor stage, findings of para aortic nodal disease (n = 4) or difficulty to clinically examine the patient due to obesity (n = 2). MRI was also an aid in deciding whether or not to offer fertility preserving treatment in three cases. Conclusion. The use of MRI affects treatment planning in patients with cancer of the uterine cervix. The impact is more obvious in more advanced stages of disease and in patients who are difficult to examine clinically due to, for example body constitution. The result of MRI is also an aid in deciding whether or not a fertility preserving operation is feasible.

Diagnostic protein marker patterns in squamous cervical cancer.

Purpose: Cervical cancer is the second most prevalent malignancy of women. Our aim was to identify additional marker protein patterns for objective diagnosis of squamous cervical cancer (SCC).

Invasive Carcinoma of the Uterine Cervix Associated With Pregnancy: 90 Years of Experience

This study is a representation of 90 years of experience with carcinoma of the uterine cervix in pregnancy. The objective was to retrospectively study changes in the distribution of cervical carcinoma (CC) by age, disease stage, histopathology, survival, and the development of second primary cancers.

Value of Uterine Artery Doppler in Endometrial Cancer

Twenty-seven women with endometrial cancer were studied with Doppler ultrasound coupled with a vaginal probe. Pulsatility index of the flow velocity of the uterine artery was recorded and compared to that of a control group. The subjects and the controls did not differ in blood flow measurements. There was no correlation between severity of disease and flow velocimetry values. Eleven of the patients underwent brachytherapy prior to surgery. Administration of brachytherapy resulted in a decrease of the peripheral resistance. The results of this study indicate that Doppler velocimetry of the uterine artery is not a valuable tool in discriminating between malignant and benign endometrium.

Projected cost-effectiveness of repeat high-risk human papillomavirus testing using self-collected vaginal samples in the Swedish cervical cancer screening program.

Human papillomavirus (HPV) testing is not currently used in primary cervical cancer screening in Sweden, and corresponding cost‐effectiveness is unclear.

Cost of Preventing, Managing, and Treating Human Papillomavirus (HPV)-Related Diseases in Sweden before the Introduction of Quadrivalent HPV Vaccination

Objective Costs associated with HPV-related diseases such as cervical dysplasia, cervical cancer, and genital warts have not been evaluated in Sweden. These costs must be estimated in order to determine the potential savings if these diseases were eradicated and to assess the combined cost-effectiveness of HPV vaccination and cervical cancer screening. The present study aimed to estimate prevention, management, and treatment costs associated with cervical dysplasia, cervical cancer, and genital warts from a societal perspective in Sweden in 2009, 1 year before the quadrivalent HPV vaccination program was implemented. Methods and Materials Data from the Swedish cervical cancer screening program was used to calculate the costs associated with prevention (cytological cervical cancer screening), management (colposcopy and biopsy following inadequate/abnormal cytological results), and treatment of CIN. Swedish official statistics were used to estimate treatment costs associated with cervical cancer. Published epidemiological data were used to estimate the number of incident, recurrent, and persistent cases of genital warts; a clinical expert panel assessed management and treatment procedures. Estimated visits, procedures, and use of medications were used to calculate the annual cost associated with genital warts. Results From a societal perspective, total estimated costs associated with cervical cancer and genital warts in 2009 were €106.6 million, of which €81.4 million (76%) were direct medical costs. Costs associated with prevention, management, and treatment of CIN were €74 million; screening and management costs for women with normal and inadequate cytology alone accounted for 76% of this sum. The treatment costs associated with incident and prevalent cervical cancer and palliative care were €23 million. Estimated costs for incident, recurrent and persistent cases of genital warts were €9.8 million. Conclusion Prevention, management, and treatment costs associated with cervical dysplasia, cervical cancer, and genital warts are substantial. Defining these costs is important for future cost-effectiveness analyses of the quadrivalent HPV vaccination program in Sweden.