Prognostic value of genomic alterations in invasive cervical squamous cell carcinoma of clinical stage IB detected by comparative genomic hybridization.

The clinical behavior of invasive cervical carcinoma of clinical stage IB varies considerably in tumors presenting without regional lymph node metastases. The early identification of patients at higher risk for poor outcome may prove useful because these patients would benefit from aggressive adjuvant treatments. In this study, comparative genomic hybridization was applied to evaluate whether genomic aberrations have prognostic significance in cervical carcinoma. Genomic alterations were evaluated in 62 cervical carcinomas of clinical stage IB. DNA sequence losses were most prevalent at chromosomes 4q (53%), 3p (52%), 13q (45%), 4p (44%), Xq (44%), 5q (40%), 18q (37%), and 6q (35%). Several genomic alterations were associated with poor clinical outcome or metastasis. The total number of DNA aberrations/tumor (P < 0.02) and the number of DNA sequence losses/tumor (P < 0.04) were associated with disease-specific survival. 9p deletions were significantly more frequent in carcinomas with lymph node metastasis than in node-negative tumors (P < 0.03). Losses of chromosome 11p (P < 0.0001) and 18q (P < 0.01) were associated with poor prognosis in cervical carcinomas without lymph node metastasis. These data suggest that inactivation of tumor suppressor genes on chromosomes 9p, 11p, and 18q may play a role in the progression of cervical carcinoma.

Association of tumor induced vascularization with clinicopathological parameters in cervical neoplasm.

Angiogenic properties have been shown in preinvasive cervical lesions. Our goal was to determine the angiogenesis in cervical intraepithelial neoplasms (CIN), the relationship between microvessel counts, histopathological parameters and the clinical outcome in invasive cervical carcinoma. Comparison of microvessel counts from normal epithelium with that from CIN and invasive carcinoma showed significant increases in pre-cancerous lesions and invasive cancer (p < 0.0001). Microvessel density, assessed by CD31 immunostaining, was found to be associated with the overall survival in women with clinical stage IB cervical carcinoma (p < 0.03). There was a significant association of microvessel density (p < 0.05) with relapse-free survival in patients with regional lymph node metastasis.

Analysis of proliferative activity using Ki-67 on cervical precancerous lesions and the relationship to p53 expression.

Neoplastic cell growth rate and the p53 expression have been recently analysed in invasive cervical carcinoma. Samples of 20 specimens with normal cervical epithelium and 73 specimens of dysplasia and carcinoma in situ (CIS) were immunostained with monoclonal antibodies to p53 and Ki-67 to examine the interrelationship between p53, Ki-67 and HPV status in cervical intraepithelial neoplasm. The presence of HPV was assessed by in situ DNA hybridization. Of dysplasias and CIS 79% were HPV positive. The growth rate of neoplastic cells was significantly correlated to the histological grade and the HPV status. The highest proliferation was found in poorly differentiated HPV 16/18 positive precancerous lesions. The analysis of the p53 expression showed no difference between various histological grades. However, the p53 oncoprotein was expressed significantly lower in HPV 16/18 positive neoplasms. The assessment of neoplastic cell growth rate offers a potentially valuable approach to predicting biological behaviour in intraepithelial neoplasms.

Association of p27Kip1, cyclin E and c-myc expression with progression and prognosis in HPV-positive cervical neoplasms.

Recent studies demonstrated that a variety of human cancer cell lines express relatively high levels of p27Kip1 and that this might be associated with increased expression of Cyclin E. There is a feedback inhibitory loop between Cyclin E and p27Kip1, which can be counteracted by elevated c-myc activation. This study analyzed by immunohistochemistry the expression of p27Kip1, Cyclin E and c-myc in a series of HPV-positive cervical tissue samples representing various stages of cervical carcinogenesis, using 13 samples of normal epithelium, 24 low-grade CIN, 63 high-grade CIN, and 69 samples of invasive squamous cell carcinoma. To evaluate the cell proliferation, the Ki-67 Labelling Index (LI) was assessed. The presence of HPV was investigated by in situ DNA hybridization. We did not find any correlation between p27Kip1 expression and Ki-67 LI in normal and tumor tissue samples. There was evidence for an increase of p27Kip1 levels from low-grade to high-grade CIN. Cyclin E, c-myc and the Ki-67 LI were significantly increased during cervical carcinogenesis. Cyclin E and c-myc were positively correlated to cell proliferation in pre-cancerous lesions, but not related to overall survival in invasive carcinomas. Contrary to that, high levels of p27Kip1 are associated with poor overall survival in invasive cervical carcinomas of clinical stage IB. This may reflect the counteracting function of c-myc in blocking p27Kip1, thus representing the worst condition of a disturbed tumor cell cycle in cervical carcinoma, ultimately induced by HPV.

Glassy cell carcinoma of the endometrium: a case report and review of the literature.

Endometrial glassy cell carcinoma (GCC) is a rare neoplasm, with 11 cases reported in the literature. Although GCC is considered to be a poorly differentiated variant of adenosquamous carcinoma, its real nature is still debatable. We report a case of GCC of the endometrium in a 60-year-old woman and review the literature. The patient presented with vaginal bleeding, and pelvic computed tomographic scan showed a polypoid lesion in the uterine fundus. Histologically, the tumor showed 2 components: a moderately differentiated adenocarcinoma with extensive areas of squamous metaplasia (adenoacanthoma) and a GCC. The clinical stage of the patient's disease was IB as classified by the International Federation of Gynecology and Obstetrics. She was treated by a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic radiation therapy. The patient was still alive and free of disease at 5 years of follow-up.

Conservative therapy of female genuine stress incontinence with vaginal cones.

OBJECTIVE: The objective was to analyse urodynamic data before and after conservative treatment with vaginal cones. STUDY DESIGN: The design was an open clinical study and was carried out at the Urogynaecology Unit of the University women's hospital. Eighteen women with genuine urinary stress incontinence were treated with vaginal cones for 6 weeks. Cystometry was performed before and after conservative therapy. The patients' subjective improvement and the urodynamic data have been compared. The Mann-Whitney U-test was used for statistical analysis. RESULTS: Of eighteen women with cone therapy, eight were continent after 6 weeks and showed a significant increase of the dynamic urethral closure pressure. Seven patients reported a subjective improvement, and in three women no change of stress incontinence was observed Colposuspension was performed at a later date in these three cases. CONCLUSION: Vaginal cone therapy is a successful method to cure mild female stress incontinence and has the advantage of avoiding incontinence operation. Therapeutic success can be assessed by urodynamic evaluation.

[Surgical treatment of vaginal prolapse after hysterectomy]. / Zur operativen Behandlung des Scheidenvorfalls nach Hysterektomie.

Forty-five women were treated with a sacrospinous ligament fixation of the vaginal apex between 1979 and 1993. The patients had a complete vaginal prolapse following abdominal or vaginal hysterectomy or in three cases a combined uterine and vaginal prolapse. The sacrospinous ligament fixation was carried out as described by Amreich, Sederl and Richter. The fixation of the vagina was successful performed in 43 women. These results were obtained using absorbable suture material. A sciatic nerve damage was observed in two patients for a short time with spontaneous recovery, coincident with suture absorption and nerve regeneration. We consider and recommend fixation of the vaginal apex to the sacrospinous ligament as the technique preferred for the operative treatment of a vaginal prolapse and for the rare cases of uterine prolapse, which cannot be corrected otherwise.

[Septic abortion in Campylobacter jejuni infection]. / Septischer Abort bei Campylobacter-jejuni-Infektion.

Case report of a 24 year old woman II G/I P with enterocolitis and septicaemia caused by Campylobacter jejuni (C.) in the following time abortion at 16 weeks of gestation. Diagnostics, therapy, review of literature.

Expression of p150 in cervical neoplasia and its potential value in predicting survival.

BACKGROUND: A recently cloned novel p150 protein was found to be overexpressed in human breast carcinoma. To the authors' knowledge, no data on p150 expression in any other human tumors have been published previously. METHODS: To investigate whether the expression of p150 correlated with the clinicopathologic stages of cervical neoplasms or the prognoses of patients with these neoplasms, the authors conducted an immunohistochemical study of archival formalin fixed, paraffin embedded specimens. Seventy-two precancerous lesions (CIN), 75 clinical Stage IB invasive squamous carcinomas, and 20 samples of normal squamous epithelia were included. In addition to p150, the Ki-67 labeling index was assessed as a proliferation parameter. The presence of human papillomavirus was analyzed by in situ DNA hybridization. RESULTS: A significant association of p150 with the grade of atypia in cervical neoplasms was demonstrated. The highest expression of p150 was observed in low grade CIN, with subsequently decreasing expression in high grade CIN and invasive carcinoma. For patients with invasive carcinoma, p150 was significantly correlated with clinical outcome. Patients with high expression of p150 had a better prognosis than those with low p150. Those with regional lymph node metastasis and significant p150 expression had longer relapse free survival than those with insignificant p150 expression. Women whose carcinomas demonstrated vascular space invasion or high microvessel density survived longer when p150 was clearly expressed. p150 behaves as a potential tumor marker during early cervical carcinoma development and is later turned off as cells proceed to more advanced stages of their malignant phenotypes. CONCLUSIONS: p150 is a molecular parameter that might become useful in predicting disease progression and determining the prognoses of patients with invasive cervical carcinoma.

Virilizing ovarian tumor of low malignant potential associated with antecedent tamoxifen use for breast cancer.

A patient is described who was treated with tamoxifen for breast cancer and developed an androgen-producing ovarian tumor of low malignant potential, which itself is a rare condition. Clinically overt virilism was leading to the diagnosis and promptly improved after surgical removal of the tumor. A causal relationship between tamoxifen use and the tumor is discussed on the basis of the known tumor-inducing potential of tamoxifen.

Investigation of the Bcl-2 and C-myc expression in relationship to the Ki-67 labelling index in cervical intraepithelial neoplasia.

This is the investigation of the relationship between the neoplastic cell proliferation and the expression of bcl-2 and c-myc in human papillomavirus (HPV)-negative and HPV-positive cervical intraepithelial neoplasms (CIN). The expression of bcl-2 and c-myc was studied using quantitative immunohistochemistry in 20 specimens of normal cervical squamous epithelium and 73 specimens of CIN. To analyze the neoplastic cell proliferation rate, the Ki-67 labelling index was determined; the latter was significantly different between normal epithelium and various grades of CIN (p < 0.0001). The highest proliferation rate was found in high-grade CIN. In precancerous lesions, we found the number of bcl-2 positive cells lower than in normal epithelium, but with a significant difference between low-grade and high-grade CIN (p < 0.0001). The highest percentage of bcl-2 positive neoplastic cells was found in high-grade CIN. C-myc was rarely expressed in normal epithelium. Similar to the Ki-67 labelling index, c-myc immunostaining correlated with the histological grade of CIN, with the highest percentage of c-myc positive nuclei occurring in high-grade CIN (p < 0.0001). In contrast to bcl-2 immunoreactivity, the c-myc significantly was more expressed in high-risk HPV-positive than in HPV-negative lesions. The c-myc expression in CIN is closely related to the neoplastic cell proliferation rate. With progression of intraepithelial neoplasia, bcl-2 production in neoplastic cells increases with high co-expression of c-myc.

Expression of CD44 and variant isoforms in cervical intraepithelial neoplasia.

The cell adhesion molecule CD44 and its variant isoforms have been found to be related to invasive and metastatic character of cancer cells. Their expression in gynecologic precancerous lesions has not yet been reported. Mouse monoclonal antibodies directed against a common epitope (CD44s) and exons 4v, 6v, and 9v were used to study the expression of CD44 and variant isoforms by immunohistochemistry in cervical intraepithelial neoplasia (CIN). Twenty tissue samples with normal cervical epithelium and 57 samples with CIN of different histological grades and different HPV status were included in this study. The standard CD44, CD44-4v, CD44-6v, and CD44-9v were expressed in normal cervical epithelium and in precancerous lesions. In distinct contrast to the normal epithelium, however, the standard CD44, CD44-4v, and 6v showed a reduced expression in precancerous lesions, whereas CD44-9v was significantly overexpressed. Expression of CD44 standard and CD44-4v was correlated with the histological grade but not with the HPV status. Compared with mild and moderate dysplasia, severe dysplasia and carcinoma in situ are associated with low expression of CD44s (P = 0.007) and of CD44-4v (P = 0.03). These observations reveal dynamic changes in CD44 expression during neoplastic cell transformation in cervical intraepithelial neoplasia.

Assessment of EGFR and TGF-alpha expression in relationship to HPV status and Ki-67 distribution in cervical intraepithelial neoplasms.

Expression of epidermal-growth-factor receptor (EGFR), transforming growth factor alpha (TGF-alpha) and Ki-67 proliferation antigen in cervical intra-epithelial neoplasms were analyzed. To examine the interrelationship of TGF-alpha, EGFR, Ki-67 and HPV status in dysplasia and carcinoma in situ, formalin-fixed tissue sections of 92 women were immunostained with monoclonal antibodies to EGFR, TGF-alpha and Ki-67. The presence of HPV was assessed by in situ DNA hybridization. The highest positive TGF-alpha expression was seen in the group of mild dysplasia. The difference was significant between the relatively high expression in mild dysplasia and the low occurrence in severe dysplasia and carcinoma in situ as well. The same relation could be found between TGF-alpha expression in papilloma-virus-negative dysplasia and those with the presence of HPV 16/18. In contrast to these findings, the Ki-67 proliferation marker was intensely detectable in severe dysplasia and carcinoma in situ. Ki-67-stained neoplastic cell nuclei were found in a significantly higher percentage of HPV-positive than in HPV-negative lesions. TGF-alpha over-expression is obviously combined with low proliferating activity and vice versa. Irrespective of the grade of dysplasia or HPV status, EGFR was expressed abnormally as compared with normal squamous epithelium. Over-expression of TGF-alpha in mild dysplasia could be associated with the autocrine pathway of cell-growth regulation. In the presence of HPV 16/18 the EGFR/TGF-alpha pathway for growth stimulation is probably not involved.

Angiogenesis in cervical neoplasia: microvessel quantitation in precancerous lesions and invasive carcinomas with clinicopathological correlations.

Recently, angiogenic properties have been shown in preinvasive cervical lesions. Our goal was to determine the angiogenesis in cervical intraepithelial neoplasia (CIN) and the relationship between microvessel counts, histopathological parameters, and clinical outcome in invasive cervical carcinoma. One hundred thirty-eight cervical specimens were evaluated; among these 20 were designated normal epithelium, 20 low-grade CIN, 40 high-grade CIN, and 58 invasive carcinoma. Histological sections immunostained for CD31 were quantitatively evaluated for microvessel density. The tumor proliferation rate was determined by the Ki-67 Labeling Index. Comparison of microvessel counts from normal epithelium with those from CIN and invasive carcinoma showed significant increases in precancerous lesions and invasive cancer (P < 0.0001). Microvessel density was found to be associated with the overall survival in women with invasive carcinoma (P < 0.01). There was a significant correlation of microvessel density (P < 0.05) with relapse-free survival in patients with regional lymph node metastasis. A Cox stepwise regression analysis revealed microvessel density, together with depth of invasion, regional lymph node status, and vascular invasion, to be a strong independent prognostic indicator for overall survival in patients with clinical stage IB cervical carcinoma.

Altered expression of mdm-2 and its association with p53 protein status, tumor-cell-proliferation rate and prognosis in cervical neoplasia.

Recent results suggest that p53 inactivation is required for cervical-carcinoma development. The mdm-2 oncogene, which forms an auto-regulatory feedback loop with the normal p53 protein, has been found amplified in human carcinomas, thus abolishing the anti-proliferative function of p53. To investigate whether the mdm-2/p53 interaction plays a role in cervical neoplasms, we performed an immunohistochemical study in archival fixed, embedded specimens that included 178 pre-cancerous lesions (CIN) and invasive squamous-cell carcinomas of clinical stage IB. In addition to p53, we assessed the p53-associated protein, mdm-2, and the Ki-67 labelling index (LI). The presence of HPV was assessed by in situ DNA hybridization. Tumor expression of all nuclear proteins was scored as fraction of positive CIN or cancer nuclei. The analysis demonstrated a significant association of the Ki-67 LI with grade of atypia in cervical neoplasms. p53 accumulation and mdm-2 expression are higher in invasive carcinomas than in pre-cancerous lesions. No correlation was observed with HPV status. An inverse correlation was found between increased tumor-cell proliferation and mdm-2 expression in invasive carcinomas (p < 0.0001). mdm-2 expression was significantly associated with p53 accumulation (p < 0.02). However, the investigated nuclear proteins were not associated with overall survival in patients with invasive carcinomas. Cox stepwise-regression analysis revealed regional lymph node status and depth of invasion to be independent parameters.

p53 protein expression but not mdm-2 protein expression is associated with rapid tumor cell proliferation and prognosis in renal cell carcinoma.

The clinical course of renal cell carcinoma (RCC) is highly variable. Overexpression of the p53 protein has been suggested as a possible prognostic parameter in RCC. Overexpression of the mdm-2 oncogene product has been shown to interact with the p53 function. To investigate the immunohistochemical overexpression of mdm-2 protein in comparison with that of p53 protein in RCC, 50 nonpapillary pT3 RCCs were immunostained for p53 protein (DO-7) and mdm-2 (IF2). Tumor growth fraction (Ki-67 labeling index; MIB-1) was determined by immunohistochemistry. p53 positivity was detected in 16% of tumors. mdm-2 overexpression was seen in 30% of RCCs. There was a significant association between p53 and mdm-2 immunostaining (P = 0.0006), suggesting that mdm-2 protein may contribute to p53 protein stabilization in RCC. p53 overexpression was associated with a high Ki-67 LI (P = 0.0002), suggesting that p53 overexpression is involved in growth control in RCC. Survival analysis showed that Ki-67 LI (P = 0.04) and p53 overexpression were associated with poor prognosis (P = 0.0021), whereas mdm-2 overexpression was not related to patient outcome (P = 0.73). A Cox regression analysis revealed tumor stage (P < 0.001) and p53 overexpression (P < 0.05) to be independent prognostic parameters. It is concluded that p53 but not mdm-2 may be of practical relevance in predicting patient prognosis in RCC.