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[Mutation and expression of p53 gene in nasopharyngeal carcinoma, cervical carcinoma and lung cancer].

OBJECTIVE: To investigate the mutation and expression of p53 tumor suppressor gene in nasopharyngeal carcinoma (NPC), cervical carcinoma and lung cancer. METHODS: 24 NPCs, 9 cervical carcinomas and 10 lung cancers were examined by immunohistochemical and PCR-SSCP techniques. RESULTS: 23/24 (90.1%) NPCs, 6/9 (66.7%) cervical carcinomas and 9/10 (90.0%) lung cancers showed p53 overexpression. No NPC or cervical carcinoma had p53 mutations in exons 5-8 of the gene, whereas mutations were found in 5 lung cancers, one in exon 8 and four in exon 5. All five cases showed p53 overexpression. CONCLUSIONS: Overexpression of p53 exists in NPC, cervical carcinoma and lung cancer. It is related to gene mutation in lung cancer, but not in NPC or cervical carcinoma. The DNA tumor viruses may be involved in the overexpression of p53 in NPC and cervical carcinoma.

Exons↗

Scalene lymph node metastases with the negative pelvic nodes in invasive cervical carcinoma.

Cervical carcinoma spreads predominantly by lymphatic routes and lymph node metastases may occur even in early stages of disease. Metastases usually first appear in pelvic lymph nodes, then disseminate along the efferent lymphatic chain to the extrapelvic lymph nodes. Cases of positive lymph node metastases with negative pelvic nodes in invasive cervical carcinoma are extremely rare. We report a 50-year-old woman with bulky stage IIA cervical carcinoma who had scalene lymph node metastases in the absence of pelvic lymph node metastases after radical hysterectomy and postoperative pelvic irradiation. This rare "skipping" nodal metastasis was probably via posterior trunk lymphatic drainage of the bulky cervical carcinoma which mainly invaded the posterior vaginal cuff. Neoadjuvant or adjuvant chemotherapy is recommended to prolong survival of patients in such cases.

Carcinoma, Squamous Cell↗

Effects of short-term tamoxifen administration in patients with invasive cervical carcinoma.

Cervical cancer is not considered a hormone-responsive tumor in spite of the presence of estrogen receptors (ER) and progesterone receptors (PgR) in some of them. Endocrine treatments have not achieved clinical responses, however, tamoxifen has been reported to induce PgR and to inhibit cell growth of many cervical carcinoma cell lines. In this study we investigated whether tamoxifen administration affects the histopathological characteristics of cervical cancer and the expression of ER, PgR, HER-2/neu and p53 protein. Nineteen patients with invasive cervical cancer free of previous treatments were studied. The triphenylethylene antiestrogen tamoxifen was given orally during 10 days (20 or 40 mg/day). Pre- and post-tamoxifen biopsies were evaluated using slides stained with hematoxylin and eosin and immunostained (ER, PgR, HER-2/neu, p53, PCNA, keratin, heat shock protein 27,000 daltons). Estrogen receptors were present in 37% and PgR in 16% of the biopsies from untreated patients. Only one case that was PgR-negative before tamoxifen administration showed weak PgR-positivity following antiestrogen administration. No obvious changes were observed in ER, HER-2/neu and p53 proteins. A statistically significant decrease in the number of mitotic figures was obtained in 16% (3/19) of the post-tamoxifen biopsies and two of them showed higher differentiation. The results showed that tamoxifen did not induce changes in estrogen-regulated proteins in cervical cancer. However, the data showed that certain cervical carcinomas had changes in their proliferation and differentiation levels following tamoxifen administration. These findings suggest that tamoxifen may affect some cervical cancer tissues by a hormone-independent mechanism(s).

Administration, Oral↗

[Preliminary study on the relationship between loads of human papillomavirus in cervical carcinoma and cervical intraepithelial neoplasia].

OBJECTIVE: To explore the relationship between loads of human papillomavirus in cervical carcinoma and cervical intraepithelial neoplasia. METHODS: From December 2001 to May 2002, 9075 married women aged from 35 to 50 years who lived in the areas with a high incidence of cervical carcinoma of Shanxi Province were screened high risk types of human papillomavirus (HPV) infection using hybrid capture II (HC-II). Of them, 2087 women with positive human papillomavirus further underwent colposcopy and multi-focal directed punch biopsies plus endocervical currettage. RESULTS: Two thousand and eighty-seven women were found with positive human papillomavirus infection, comprising 1402 (67.2%) women who were diagnosed as cervicitis, 663 (31.8%) women diagnosed as cervical intraepithelial neoplasia [including cervical intraepithelial neoplasia (CIN) I to III], and 22 (1.1%) women diagnosed as cervical squamous cell carcinoma (SCC). HPV-DNA loads of women with chronic and acute cervicitis were 150 +/- 11 and 108 +/- 13, respectively, with no significant difference between two groups statistically (P = 0.225). HPV-DNA loads for women with CIN I, CIN II and CIN III were 332 +/- 29, 358 +/- 35, and 370 +/- 31, respectively, all significantly higher than that of women with cervicitis (P = 0.000), but there were no significant differences among three groups (P > 0.05). HPV-DNA loads of women with cervical squamous cell carcinoma was 593 +/- 86, much higher than those of women with varied grades of cervical intraepithelial neoplasia and cervicitis (P < 0.05 and P < 0.01). CONCLUSIONS: The new technology using HC-II is an effective method to detect HPV infection in cervix. Viral loads of HPV-DNA increase with severity of cervical neoplasia. So it could be used for screening primary cervical carcinoma.

Adult↗

Chemotherapy in the management of cervical carcinoma.

Cervical carcinoma, although largely preventable, is one of the most prevalent cancers worldwide. Early-stage disease can be successfully treated with surgery alone, and women with locally advanced cervical carcinoma are treated with radiation and concurrent weekly cisplatin at a dose of 40 mg/m2 for six doses. For women with advanced, persistent, or recurrent disease not amenable to local resection or radiation, however, few treatment options exist. In this subset of patients, palliative cytotoxic chemotherapy is playing an ever-increasing role. Only the combination of topotecan and cisplatin has been shown to prolong survival in this setting and although the benefit of combination therapy is modest, there has been no decrease in quality of life when this doublet is compared to single-agent cisplatin. Newer innovative agents are needed to treat metastatic and recurrent cervical cancer.

Antineoplastic Agents↗

[Telomerase activity in cervical carcinoma and cervical intraepithelial neoplasia and its correlation to classification of koilocytosis].

OBJECTIVE: To investigate the telomerase activity in cervical tissues and exfoliated cells in patients with cervical intraepithelial neoplasia (CIN) and cervical carcinoma, and to study the correlation between telomerase activity and koilocytosis classification and between telomorase activity and human papillomavirus (HPV) infection. METHODS: Telomeric repeat amplification protocol (TRAP) was used to determine the telomerase activity in cervical tissues and exfoliated cells in 24 women with normal cervix, 34 patients with cervitis, 78 patients with CIN and 16 patients with cervical carcinoma. The patients with CIN were classified into 3 subgroups according to the abnormality of cervical cells (31 CIN(1) cases, 25 CIN(2) cases and 22 CIN(3) cases). The presence and classification of koilocyte in cervical tissues was examined by microscopy with double blind method. The telomerase activity in koilocytes of different types was investigated. RESULTS: The telomerase positive rate was 16.7% (4/24) in normal cervical tissue, 17.6% (6/34) in cervitis tissue, 51.6% (16/31) in CIN(1) tissue, 72.0% (18/25) in CIN(2) tissue, 86.4% (19/22) in CIN(3) tissue, and 100% (16/16) in cervical carcinoma tissue respectively. The telomerase positive rate in CIN cases was significantly higher than those in normal cervix and cervitis cases (all P < 0.01) and the telomerase positive rate was significantly higher in cervical carcinoma than in CIN (P < 0.01). It was also significantly higher in CIN(3) than in CIN(1) (P < 0.05), while no significant difference was found in the telomerase positive rate between normal cervix and cervitis, CIN(1) and CIN(2), and CIN(2) and CIN(3) (P > 0.05). No significant difference of telomerase positive rate was found between the cervical tissue and exfoliated cells in the same case too (P > 0.05). Koilocytes were found in sixty-four out of the 154 samples of cervical lesions. Among them koilocytes were found in 54 out of 94 samples of cervical cancer and CIN tissues (koilocytes of type I in 18 cases and type II in 36 cases). The telomerase positive rate was 100% in tissues of CIN and cervical carcinoma with type II koilocytosis, significantly higher than that in tissues with type I koilocytosis (66.7%, P < 0.05). CONCLUSION: (1) Activation of telomerase is closely associated with progression of CIN and cervical carcinoma, and telomerase might be a useful marker for cervical carcinoma and CIN. (2) Cervical exfoliated cells may be used as the substitute of cervical tissues in determining telomerase activity. (3) Activation of telomerase is correlated with type II koilocytosis and HPV 16/18 infection.

Female↗

Adjuvant high-dose chemotherapy supported by peripheral blood stem cell transplantation for high-risk cervical carcinoma.

Cervical carcinoma is a common disease for which the prognosis has not been substantially improved with standard locoregional treatments. Three stage IB patients with untreated cervical carcinoma were treated with high-dose chemotherapy and refrigerated peripheral blood stem cell support using the ICE program (Ifosfamide 10 g/m2 plus mesna at 100% of the ifosfamide dose; Carboplatin at 1.5 g/m2 and Etoposide 2.1 g/m2). Patients received the treatment in an adjuvant setting after radical hysterectomy with pelvic lymph-node dissection and postoperative cisplatin-based standard-dose chemotherapy. All patients underwent postoperative radiotherapy. The treatment was well-tolerated, all patients had rapid hematologic recovery, and the most frequent complications were grade 3 mucositis and neutropenic fever. The three patients are disease-free at 58, 60, and 63 months of follow-up. Our results show that adjuvant high-dose chemotherapy could be effective to reduce the likelihood of relapse in high-risk patients. High-dose chemotherapy deserves a formal evaluation in high-risk cervical cancer.

Journal Article↗

Consanguinity as risk factor for cervical carcinoma.

Cervical carcinoma is caused by human papillomavirus (HPV). Among the risk factors for HPV infection are having multiple sex partners and sex partners who themselves had multiple sex partners. Women married to relatives are more likely to become infected with HPV and develop cervical carcinoma. Consanguineous spouses have a mild sexual aversion to each other that leads to sex avoidance and increases likelihood of satisfying sexual desire outside the marriage. Sexual aversion develops as a result of spouses growing together in early childhood, which triggers biological imprinting of Westermarck. Westermarck's effect prevents incest in nuclear family. In consanguineous family, it extends to spouses, producing mild sexual antipathy. Because of high prevalence of consanguinity worldwide, it is important to test this hypothesis.

Carcinoma↗

Human papillomavirus, human cytomegalovirus and oncogene C-myc in cervical carcinoma and cervicitis.

HPV-16 and HCMV DNA homologous sequence and the status of cellular oncogene C-myc DNA were examined in uterine cervical diseases with dot blot hybridization and Southern hybridization. The results showed a positive rate of 70.8% in HPV-16 and 38.7% in HCMV in cervical carcinoma, and that of 36.7% in HPV-16 and 16.7% in HCMV in cervicitis. C-myc DNA was widely detectable in uterine cervical carcinoma, but the manifestation of translocation, deletion or overexpression in cervical carcinoma was frequent. The value of these findings in the development of cervical carcinoma is discussed.

Blotting, Southern↗

Bronchial carcinoma after cervical carcinoma.

In a series of more than 2500 patients with cervical carcinoma who were regularly surveyed after treatment, ten cases of bronchial carcinoma confirmed by biopsy were found. The mean delay between the diagnosis of the cervical carcinoma and bronchial carcinoma was 28 months. This long interval, particularly when there was no distant metastases, raises questions about whether bronchial metastasis of cervical carcinoma or a second primary occurred. Comparisons with data of population cancer registries argue in favor of metastasis.

Adult↗

Prevention of urological complications after radical operation of cervical carcinoma.

Cervical carcinomas of stage Ib and II have been treated for extended radical therapy by radioisotope radical surgery at the First Department of Obstetrics and Gynecology, University of Vienna, Austria. This extension of a more radical surgery requires to take measures in order to prevent urological and other postoperative complications. Chromocystoscopy, intravenous urography and functional scintigraphy of the kidney are carried out as routine preoperative investigations. Preservation of the adureter and an exact drainage of the field of operation are taken as intraoperative measures. Main emphasis of postoperative prophylaxis is the stimulation of ureter activity by distigminbromide and hexoprenaline. Distigminbromide stimulates the prevesical part of the ureter and increases the number of urinary excretions into the bladder. Hexoprenaline is a betamimetic substance which increases both local blood flow and number of ureter contractions. In addition, treatment by antibiotics, thrombosis prophylaxis with heparin and marcoumar and urine drainage by catheter are performed during surgery. The results of 187 radioisotope radical operations show that an uretero vaginal fistula was observed in one patient (0.53%). Hydronephrosis was registered in 10 females (5.3%) and 42 subjects (22.5%) lack of bladder feeling was noted and incontinence was observed in 22 patients (11.8%) in the postoperative period.

Carcinoma↗

Relations between the expression of p53, c-erbB-2, Ki-67 and HPV infection in cervical carcinomas and cervical dysplasias.

BACKGROUND: The analysis of mutual relations between HPV infection and the expression of cancer gene products and proliferative activity in cervical carcinomas and dysplasias. MATERIALS AND METHODS: The expression of p53, c-erbB-2 oncoproteins and proliferative activity (Ki-67) was evaluated immunohistochemically in 41 cervical carcinomas and 29 dysplasias. HPV infection (type 16, 18) was assessed by in situ hybridization technique. RESULTS: HPV-positive carcinomas were found in 68.3% of cases. HPV type 16 infection were detected in 54% and HPV 18 in 39% of carcinomas. Simultaneous appearance of both virus types was shown in 25% of carcinomas. In dysplastic lesions, HPV infection was observed in 62.1% of cases. HPV type 16 was found in 34.5% and HPV 18 in 44.8% of patients. Both virus types were found in 17.2% of dysplasias. HPV infection was more extensive in cervical carcinomas than in dysplasias. Similarly the expression of oncoproteins was more intensive and referred to a higher percentage of cells in carcinomas. No relations between p53, c-erbB-2 overexpression and HPV infection were found. Ki-67 activity was found in a higher percentage of HPV-positive than in HPV-negative, both carcinomas and dysplasias. CONCLUSIONS: HPV infection, especially accompanied by increase of proliferative activity in dysplasias may define the cell subpopulation predisposed to malignant process development. The employment of in situ hybridization technique appears to be useful in detecting the viral infection in cytological smears even with no morphological changes in the cells.

Female↗

Prevention of urological complications after radical operation of cervical carcinoma.

Cervical carcinomas of stage Ib and II have been treated for extended radical therapy by radioisotope radical surgery at the First Department of Obstetrics and Gynecology, University of Vienna, Austria. This extension of a more radical surgery requires to take measures in order to prevent urological and other postoperative complications. Chromocystoscopy, intravenous urography and functional scintigraphy of the kidney are carried out as routine preoperative investigations. Preservation of the adureter and an exact drainage of the field of operation are taken as intraoperative measures. Main emphasis of postoperative prophylaxis is the stimulation of ureter activity by distigminbromide and hexoprenaline. Distigminbromide stimulates the prevesical part of the ureter and increases the number of urinary excretions into the bladder. Hexoprenaline is a betamimetic substance which increases both local blood flow and number of ureter contractions. In addition, treatment by antibiotics, thrombosis prophylaxis with heparin and marcoumar and urine drainage by catheter are performed during surgery. The results of 187 radioisotope radical operations show that an uretero vaginal fistula was observed ruly in one patient (0.53%). Hydronephrosis was registered in 10 females (5.3%) and 42 subjects (22.5%) lack of bladder feeling was noted and incontinence was observed in 22 patients (11.8%) in the postoperative period.

Anti-Infective Agents↗

The physical state of human papillomavirus 16 DNA in cervical carcinoma and cervical intraepithelial neoplasia.

Cervical carcinomas and cervical intraepithelial neoplasias (CIN) were analyzed for the presence of human papillomavirus (HPV) DNA using Southern blot hybridization. Of the five HPV types examined (HPV types 6, 11, 16, 18, and 33), HPV 16 DNA was detected most frequently. In most HPV 16-positive carcinomas examined, HPV 16 DNA was present in an integrated state in cellular DNA with or without the coexistence of episomal species. In one case, however, only episomal species were detected. Among seven cases of HPV 16-positive CIN, four contained HPV 16 DNA only in the episomal state and the rest contained HPV 16 DNA only in the integrated state, but the coexistence of both states was not found. These results suggest that the integration of HPV 16 DNA is not necessary for cells to become malignant, although it is frequently associated with malignant cells.

Blotting, Southern↗

Prediction of disease persistence after conization for microinvasive cervical carcinoma and cervical intraepithelial neoplasia grade 3.

We attempted to determine the significant variables and to predict the probability of disease persistence after conization for microinvasive cervical carcinoma and cervical intraepithelial neoplasia grade 3 (CIN3). We analyzed 133 patients from 2001 to 2002 who had a subsequent hysterectomy after conization. The histological findings of the cone specimens, together with the clinical parameters, were correlated with the presence of residual dysplasia in the hysterectomy specimen. The probability of having residual dysplasia was calculated based on the function of the significant variables obtained by logistic regression analysis. Of the 133 patients, 42 (31.6%) had residual disease in their hysterectomy specimens. Using multivariate analysis only for the postmenopausal state, positive endocervical curettage, positive margin, and microinvasive carcinoma were predictive of residual dysplasia. The probabilities of having residual dysplasia were about 0.99, 0.84, 0.4, 0.07, and 0.01 in patients with a presence of all four, any three, any two, any one, and no risk factors, respectively. The best cutoff probability determined by the receiver operating characteristic curve was 0.32, yielding a sensitivity of 81% and a specificity of 88%. Based on these results, patients with the presence of any two or more of the risk factors mentioned above should be considered as a high-risk group for having disease persistence after conization for the treatment of CIN3 and microinvasive carcinoma.

Adult↗

p53 point mutation in HPV negative human cervical carcinoma cell lines.

Clinical and experimental evidence is consistent with a key role for transforming human papilloma viruses (HPVs) in the aetiology of anogenital carcinoma. Cervical carcinoma does, however, occasionally occur in the absence of HPV sequences (Riou et al., 1990). We have used a direct cDNA/PCR sequencing protocol to analyse the sequence of p53 mRNA expressed by HPV positive and negative cervical carcinoma cell lines. Six cell lines which contain HPV sequences express p53 mRNA which has wild-type sequence throughout conserved boxes 2, 3, 4 and 5. The two HPV negative cell lines (C33a and HT3) express mutant p53 mRNA. In each case the mutation occurs in an evolutionarily conserved amino acid. Our data suggest that loss of wild-type p53 function is important in development of cervical carcinoma, and that this might be achieved either by mutation within the p53 gene or the presence of a virally encoded p53 binding protein.

Base Sequence↗

Biology of cervical carcinoma.

Cervical cancer is generally a locoregional disease. The endopelvic fascia envelops the cervix in anterior-posterior fashion and serves as a natural barrier. Thus, cervical cancer preferentially grows to the parametria and involves the ureters before it infiltrates the bladder or rectum. Disease stage, grade, cell type, tumor volume, depth of stromal invasion, vascular space invasion, and lymph node status are common prognostic indicators. Irregular vaginal bleeding and discharge are the two most frequent complaints. Although cervical cancer is still staged clinically, data continue to accumulate favoring a conversion to surgical staging to improve accuracy and treatment outcome.

Female↗

Microinvasive cervical carcinoma and cervical intraepithelial neoplasia: biologic significance and clinical implications of 72-kDa metalloproteinase immunostaining.

OBJECTIVE: The immunohistochemical expression of 72-kDa metalloproteinase was evaluated in cervical intraepithelial neoplasia (CIN) and microinvasive carcinoma, with the aim to define a relationship between 72-kDa metalloproteinase expression and neoplastic invasiveness, useful to identify subsets of intraepithelial lesions with higher risk of progression. MATERIALS AND METHODS: Cervical bioptic samples were obtained consecutively from 54 women who attended our Colposcopic Service from January 1993 to July 1993 because of abnormal pap smear, suspicious for cervical dysplasia and/or human papillomavirus infection. After written consent, 29 women with CIN were included in the study. All women with CIN 3 lesion underwent conization; in 21 women with mild or moderate cervical dysplasia, we did not perform any medical or physical treatment but followed them longitudinally at close interval. After 12 months, the clinical evolution was classified as spontaneous remission, persistence, or progression depending on the absence or presence of lesion and/or HPV infection in colposcopy, histology, and polymerase chain reaction findings. In the study we also included surgical specimens from 10 women with microinvasive squamous carcinoma who underwent primary radical surgery. Seventy-two kilodalton metalloproteinase positivity was immunohistochemically stained on serial sections by using the avidin-biotin complex technique (Vector Laboratories, Burlingame, CA) and expressed as percentage of cells per 10(3) counted neoplastic cells. RESULTS: Cytoplasmatic positive 72-kDa metalloproteinase immunostaining was significantly higher in microinvasive cervical carcinomas than in CIN lesion (Student's t test; P < 0.001). Considering only cervical intraepithelial neoplasias, a significant increase in 72-kDa metalloproteinase immunostaining was observed with CIN degree increasing (one-way analysis of variance; P = 0.002). No correlation was found between 72-kDa metalloproteinase immunostaining and HPV infection and lesion size defined by quadrants of the cervix involved with colposcopically evident dysplasia. By analyzing 72-kDa metalloproteinase positivity, regressive dysplasia showed low values of 72-kDa metalloproteinase immunostaining (median 1.2%, range 0.5-1.8%), while persistent (median 2.6%, range 1.9-3.6%) and progressive lesions (median 4.6%, range 2.3-6.9%) presented a significantly higher positivity (one-way analysis of variance; P < 0.001). DISCUSSION: In conclusion, the 72-kDa metalloproteinase expression is related to invasive potential with a significant increase in staining positivity in microinvasive carcinomas; 72-kDa metalloproteinase is detectable in cervical dysplasia, and it is related to the severity of cellular atypia. A clinical implication of 72-kDa metalloproteinase immunostaining seems to be indicated, by analyzing the differences in 72-kDa metalloproteinase positivity rates between regressive and persistent or progressive disease.

Adult↗