Histological aspects of lesions of the cervix uteri correlated with different types of human papillomavirus

Cervical biopsies from 66 women presenting an abnormal smear, with HPV related features were studied and histologic features were correlated to the HPV type, as determined by molecular hybridisation studies. HPV DNA sequences were evidenced in 13 of 19 lesions corresponding to exophytic or flat condyloma (HPV type 16 in seven cases, HPV type 11 in four cases, as yet uncharacterized HPV types, HPV X, in two cases). Fourty biopsies were histologically interpreted as CIN, on the basis of atypical mitotic figures (AMF) and/or basal-parabasal cell atypia. HPV type 16 was evidenced in 20 cases (3 cases of double infection: HPV types 16 and 18, HPV types 16 and 33, HPV types 16 and X). In 10 other cases, HPV DNA sequences corresponding to HPV type 11 (one case), HPV 18 (one case) and HPV X (8 cases) were evidenced. In this study, potentially oncogenic HPV types (HPV 16, HPV 18, HPV 33) have been found only in CIN lesions defined on the presence of AMFs and/or basal-parabasal cells atypia. These histologic criteria seem to allow a distinction between low and high risk cervical lesions.     

Human papillomavirus types and localization in adenocarcinoma and adenosquamous carcinoma of the uterine cervix: a study by in situ DNA hybridization

Formalin-fixed, paraffin-embedded tissues from 108 cases of invasive carcinoma of the uterine cervix, consisting of 40 cases of adenocarcinoma, 44 cases of adenosquamous carcinoma, and, as a control, 24 cases of squamous cell carcinoma were examined for the presence of human papillomavirus (HPV) DNA by in situ hybridization of high sensitivity using tritium-labeled HPV-2, HPV-6, HPV-16, and HPV-18 DNA probes. This method detects five genome copies of homologous HPV DNA per cell. HPV DNA was detected with mixed HPV DNA probes in 17 cases (42.5%) of adenocarcinoma, 16 cases (36.4%) of adenosquamous carcinoma, and in 13 cases (54.2%) of squamous cell carcinoma. The types of HPV DNA in the HPV-positive tissues were also analyzed with each individual probe under high stringency conditions. HPV-18 DNA was detected in all but one case of the HPV DNA-positive adenocarcinoma and one-half of the HPV DNA-positive adenosquamous carcinoma. HPV-16 DNA was detected in one case of the HPV DNA-positive adenocarcinoma, one-half of the HPV DNA-positive adenosquamous carcinoma, and all cases of the HPV DNA-positive squamous cell carcinoma. HPV DNA was confined to the areas of carcinoma and squamous cervical intraepithelial neoplasia (CIN) associated with carcinoma. Among 36 cases in which CIN was associated with adenocarcinoma (9 cases), adenosquamous carcinoma (19 cases), and squamous cell carcinoma (8 cases), the same type of HPV DNA was present in the carcinoma and the associated CIN that constituted 12 cases (3 adenocarcinoma, 5 adenosquamous carcinoma, and 4 squamous cell carcinoma). Two cases (one adenocarcinoma and one adenosquamous carcinoma) contained HPV DNA in the carcinoma but not in the associated CIN. The incidence of HPV DNA did not show a significant correlation with the existence of CIN or histological differentiation of carcinoma.     

Cytologic and histologic manifestations of human papillomavirus infection of the uterine cervix

The role of human papillomaviruses (HPV) as possible agents in the genesis of cervical cancer is reviewed. Several types of HPV (mainly 6, 11, 16, 18, 31, and 33) have been shown to be associated with precancerous processes and cancer of the uterine cervix. HPV also induces pathognomonic abnormality of squamous cells, known as koilocytosis, that may precede or accompany various manifestations of cancerogenesis including invasive cancer. Still, recent studies suggest that HPV infection is quite common in normal people and may prove to be ubiquitous. Hence, the activation of the virus and its ability to interact with cervical epithelium is likely to be due to "patient factors" rather than the presence of the virus per se. The possible mechanisms of virus-epithelial interaction and of the factors that may put a woman at risk for cervical carcinoma are discussed.     

Telomerase, p53 and human papillomavirus infection in the uterine cervix

Human papillomavirus infection is postulated to be a major risk factor for cervical cancer, while more recent data have stressed the clinical significance of telomerase expression during tumorigenesis. This study therefore looked for any relationship between telomerase expression, presence of human papillomavirus (HPV) and expression of the high-risk HPV E6 protein at various phases of tumor progression in the uterine cervix. In addition, accumulation of the p53 protein and total tissue proliferative fraction were also studied. Telomerase was detected using a modified TRAP (telomerase repeat amplification protocol) assay. Expression of p53, Ki 67 and E6 protein was evaluated by immunocytochemistry. Presence of mutant p53 was detected using a mutant-specific ELISA. Type of HPV infection was determined by polymerase chain reaction and Southern blot using type-specific primers and probes. There was a significant correlation between the expression of telomerase with histological grade (r=0.646, p=0.00003). Fisher's exact test analysis revealed that the odds ratio of a tissue sample expressing telomerase being a case (high-grade squamous intraepithelial lesion or invasive cancer) was 28.93 (p=0.0001, 95% CI: 7.22, to 115.94). High-risk HPV-infected tissues and those expressing E6 showed increased telomerase expression (r=0.555, p=0.00001). Similarly, accumulation of p53 protein and increased cell proliferation (Ki 67 index) also correlated to the presence of telomerase (r=0.661, p=0.000004 for p53 and r=0.647, p=0.000003 for Ki 67). There was no correlation between telomerase expression and presence of p53 mutation. Activation of telomerase thus appears to be associated with high-risk-HPV infection, accumulation of inactive p53 protein and increased cell proliferation in cervical lesions.     

Ultrastructural observation of human papillomavirus particles in the uterine cervix intraepithelial neoplasia

Using transmission electron microscopy (TEM), twenty two cases of an intraepithelial lesion in the uterine cervix have been examined for the presence of human papillomavirus (HPV) particles. In 21 of these cases (95%), HPV particles were detected in the nucleus, and in 5 cases, in the cytoplasm. The distribution of the intranuclear HPV particles was classified into 4 types. In only 2 cases did the exhibited particles show a geometrical crystalline array (type I). In most cases, the exhibited particles were either seen to show an aggregate non-crystalline array (type II) or were concentrated around the chromatin (type III). Some cases also were found to show particles that were scattered sporadically in the nucleoplasm (type IV).     

Chromosomal insertion and amplification of human papillomavirus 16 DNA sequences in a cell line of argyrophil small cell carcinoma of the uterine cervix.

The chromosomal location of human papillomavirus (HPV) 16 DNA sequences integrated in a cell line derived from argyrophil small cell carcinoma of the uterine cervix was determined by means of fluorescence in situ hybridization (FISH). The HPV 16 DNA sequences were integrated near a fragile site and the location of the c-myc oncogene at 8q24.1. Amplification of the integrated viral sequences resulted in an abnormally banded region. The amplified HPV 16 DNA sequences were also detected in every interphase nucleus by FISH.     

Prevention of carcinoma of cervix with human papillomavirus vaccine

BACKGROUND: Carcinoma of cervix is the most common cancer found among the women of India. Though cervical cytology screening was effective in preventing carcinoma of cervix in developed nations, it is considered unsuitable in developing countries. Recent research has established an etiological link between human papillomavirus infection and carcinoma of cervix. In this review, an attempt is made to answer the question, 'whether carcinoma of cervix can be prevented with human papillomavirus vaccine?' METHODS: Literature search using Pubmed and Medline was carried out and relevant articles were reviewed. RESULTS: There is ample experimental evidence to show that DNA of human papillomavirus integrates with cervical cell genome. Viral genes E6 and E7 of HPV type 16 and 18 inactivate p53 function and Rb gene, thus immortalize the cervical epithelial cells. Recombinant vaccines blocked the function of E6 and E7 genes preventing development of papillomas in animals. Vaccination with HPV-VLPs encoding for genes of E6 and E7 neutralizes HPV integrated genome of malignant cells of uterine cervix. CONCLUSIONS: Based on experimental evidence, it is possible to prevent carcinoma of cervix with human papillomavirus vaccine, IMPLICATIONS: Further research is necessary to identify a effective and safe HPV vaccine, routes of administration and characteristics of potential beneficiaries.     

Relation between human papillomavirus (HPV) and cancer of uterine cervix

HPV-DNA fragments were detected in biopsy specimens (29 cases of cancer of uterine cervix, 2 cervical dysplasia and 9 normal cervix) using DNA hybridization technique. It was demonstrated that 52% of biopsy specimens of the cancer of uterine cervix was positive for HPV 16 DNA probe, while 9% was positive for HPV 18 DNA probe. 11% of non-cancerous biopsy specimens had a positive result for HPV 16 DNA probe. It was also demonstrated that the positive rate of HPV 16 DNA was 75% in grossly cauliflower and nodular type tumors but only 25% in erosion type. It seems that the positive rate of HPV 16 DNA is correlated to gross appearance of the tumor. The positive rates of HPV 16 DNA were different in 6 provinces in China. It was 64% in Shanxi Province, a high incidence area but 36% in Sichuan Province, a low incidence area. These results suggest that the carcinogenesis of cancer of the uterine cervix, be related to HPV infection.     

Detection of human papillomavirus (HPV) DNA in carcinoma of uterine cervix and genital tract diseases in Jiangsu province, China]

Pst-1 cleaved DNA restriction fragment length polymorphism (RFLP) of biopsy samples from 41 patients with squamous cell carcinoma of uterine cervix collected in Jiangsu province, China were examined for HPVs by Southern blot hybridization using HPV 16 DNA as a probe. 20 of the 41 samples were positive for HPVs when hybridized under non-stringent condition. HPV was not detectable in samples collected in the same time period from patients with cervical adenocarcinoma (N = 2), vaginal carcinoma (N = 3), vulval carcinoma (N = 1) and benign cervicitis (N = 8). Of the 20 positive samples, 7 (17.1%) had CHPV X1, a new type of NPV previously discovered is China, 6 (14.6%) had HPV 16, 4 (9.9%) had HPV 31, and in 3 (7.2%) the HPV type is as yet undetermined. Our data indicate that HPV 16 and CHPV X1 may be more closely related to cancer of the uterine cervix in Jiangsu province.     

Prognostic significance of the presence of human papillomavirus DNA in patients with invasive carcinoma of the cervix

Cases of invasive carcinoma of the uterine cervix were analyzed to determine whether the presence or absence of human papillomavirus (HPV) DNA in the neoplasms was a contributing factor to their outcome. The presence of HPV DNA was evaluated using in situ hybridization on formalin-fixed, paraffin-embedded tissue sections. Eighty-five patients with cervical carcinoma who had been surgically evaluated were included in the study. Data from these patients was analyzed retrospectively to determine survival, recurrence, presence of nodal metastases, tumor grade, mode of therapy, peritoneal fluid cytologic results, and age in relation to presence or absence of HPV DNA. No significant statistical differences were found between the HPV-16-positive, HPV-18-positive, and HPV DNA-negative patients.     

Cancer screening of the uterine cervix papanicolaou smears versus state-of-the-art human papillomavirus testing

The article by Albrow et al in this issue describes the early cervical screening program in England as being “disorganized,” but goes on to describe significant improvements over 20 years. It has become one of the leading screening programs in the developed world. Liquid‐based technology has been embraced, but image analysis has not. The key ingredient for the NHSCSP's success is quality assurance. The scrutiny given to medical interventions has increased recently. Would the early cervical cancer cytology screening programs have passed muster if they had required this sort of validation? Using information from the Victorian Cytology Screening Services Melbourne and other Australian screening programs to guide its formulation, Australia's evidence‐based program differs from the NHSCSP in several ways. The screening interval is 2 years, liquid‐based technology is not funded, and human papillomavirus (HPV)‐DNA testing for the triage of atypical lesions has not been sanctioned in Australia. Albrow et al allude to the possible introduction in the future of HPV‐DNA testing as a primary screening tool. Cancer (Cancer Cytopathol) 2012;. © 2012 American Cancer Society.     

Histological cell type and DNA value in the prognosis of squamous cell cancer of uterine cervix

Based on the evaluation of 362 cases of squamous cell carcinoma of the uterine cervix, the distribution of the tumours in relation to their modified Broders'' grade, histological cell type as proposed by Wentz and Reagan, and the clinical stage of disease was evaluated. The morphological characteristics of the 3 cell types—large cell non-keratinizing, keratinizing, and small cell cancers—were described. The 5 year survival in relation to Broders'' grade, cell type, extent and DNA values of the malignant cells were evaluated and compared. Broders'' grading system was not useful in predicting the biological behaviour of cervical squamous cancer. The histological cell type and extent of the tumour were important factors in prognosis. The 5 year survival for large cell cancer was 51·8%, keratinizing cancer 34·7% and small cell cancer 10·0%. The 5 year survival was 63·3% for stage I neoplasms, 52·9% for stage II neoplasms, 30·7% for stage III neoplasms and 15·0% for stage IV neoplasms. When the DNA values of neoplastic cells were considered in relation to cell type and extent of disease, the biological behaviour of cervical squamous cell cancers was determined more accurately. The 5 year survival of women with cervical cancer in which the DNA values of the neoplastic cells exceeded 155 was more favourable than those with DNA values of less than 155. This difference in 5 year survival was evident for comparable cell type and clinical stage of disease.     

阴道镜在诊断宫颈人乳头瘤病毒感染中的作用

Among 6706 women screened by cytology, only 9 (0.13%) showed evidence of human papillomavirus infection (HPVI). In 133 women examined by colposcopy for abnormal cytology or/and suspected lesions on the cervix, 41 (30.8%) showed subclinical papillomavirus infection (SPI) while 17.4% and 5.3% showed HPVI by histopathology and cytology, respectively. The conformation rate between colposcopy and pathology was 69.6%. Sixty-nine specimens out of 133 colposcopy guided biopsies were assayed by HPV-DNA dot hybridization with 6B/11, 16, 18 probes to detect the presence of HPV-DNA in the cervical specimens. Thirty-nine (56.5%) gave a positive result. The colposcopic predictive value of positive result for HPVI was 76.7%. The difference between colposcopy (59%) and pathology (20.5%) is statistically significant (P less than 0.01). These results suggest that colposcopy is superior to cytology and histopathology for the detection of SPI in the cervix. In colposcopy HPV-DNA positive women, aceto-while-epithelium was most common (28.2%). As it is difficult to differentiate SPI from cervical intraepithelial neoplasia especially the Grade I lesion by colposcopy, discrimination criteria are proposed together with the chief colposcopic features of SPI.     

Radiotherapy of uterine cervix carcinoma

Seventy-eight patients with uterine cervix cancer were treated radically with standardized radiation therapy at Teikyo University Hospital in Tokyo from January 1979 to December 1985. The age of these patients ranged from 32 to 88 years old (average age 66.0). The pathology and the stage of them were 71 cases of squamous cell carcinoma (1 in stage I, 11 in stage II, 58 in stage III and 1 in stage IV) and 7 cases of adenocarcinoma (6 in stage III and 1 in stage IV). The cumulative survival rates for 5 years by Kaplan-Meier method were 71.5% for squamous cell carcinoma stage II, 47.4% for squamous cell carcinoma stage III and 0% for adenocarcinoma stage III. Radiation injury was studied by the grading system of Kottmeier-NIRS in Japan. The incidence of the injuries for grade 2 and 3 was 12.8% (10/78), and the items of those were rectal injury 5.1% (4/78) and sigmoidal colonic injury 7.7% (6/78). The results of survival rate were fair for the squamous cell carcinoma compared with the other reports but poor for adenocarcinoma stage III. Concerning the therapy for advanced adenocarcinoma of the uterine cervix, special consideration should be given for irradiation doses or infusion chemotherapy.     

Analysis and clinical implications of k-ras gene mutations and infection with human papillomavirus types 16 and 18 in primary adenocarcinoma of the uterine cervix

Experimental models indicate that activated ras genes and HPV oncogenic sequences may cooperate in inducing a completely transformed phenotype in epithelial cells. We searched for K-ras gene mutations and HPV type-16 and -18 sequences in 67 primary adenocarcinomas of the uterine cervix by analyzing DNAs from formalin-fixed, paraffin-embedded tissue samples. Target sequences were amplified by PCR and analyzed by denaturing gradient gel electrophoresis (DGGE) and sequencing for the detection of K-ras gene mutations and by Southern blotting for the detection of HPV infection. We found 16 mutations in 15 cases; 14 were at codon 12 and 2 at codon 13; 11 were base transitions and 5 were transversions. Mutations were more frequent in mucin-secreting than in non-mucinous tumors. HPV oncogenic sequences were detected in 58 cases with no significant difference between K-ras-mutated and wild-type tumors. HPV oncogenic sequences were also more frequent in mucin-secreting than in non-mucinous tumors. Both molecular events were present simultaneously in 13 out of 58 cases, all of which had histologically grade-2 and grade-3 tumors. Clinico-pathological parameters of the disease and the overall survival, however, were independent of K-ras mutations and of HPV-16 and -18 infection, as shown by univariate and multivariate analysis. In contrast, stage of disease, lymph-node metastases, deep infiltration, clear-cell histology and low grade of differentiation were risk factors for tumor-related death. © 1995 Wiley-Liss, Inc.     

Newly established uterine cervical carcinoma cell line with co-amplification of human papillomavirus DNA and c-myc gene.

A new human tumor cell line, NCC-c-CX-1 (CX-1), was established from a uterine cervical cancer xenografted in nude mice. This cell line harbored approximately 50 to 100 copies of human papillomavirus (HPV) type 18 DNA per haploid genome, and contained about 16-fold-amplified c-myc gene with rearrangement. These genomic alterations found in CX-1 cells were also present in both primary tumor and xenografted tumor. Histopathologically, original and xenografted tumors were poorly differentiated cancer and were characterized by neuroendocrine features such as positive neuron-specific enolase and chromogranin A by immunohistochemistry and abundant neurosecretory-type granules in the cytoplasm by electron microscopy. However, the established cell line had lost the neuroendocrine features. This cervical cancer cell line may be a useful model for studying cervical carcinogenesis, especially the interaction between HPV and c-myc oncogene.     

Adenoid cystic carcinoma of the uterine cervix

Adenoid cystic carcinoma of the uterine cervix is a rare and peculiar variant of adenocarcinoma. This tumor represents 3% of all primary cervical adenocarcinomas, and it is locally aggressive and capable of metastasis to other organs even in its early stage. We report a case of adenoid cystic carcinoma stage IIIb that was successfully treated with radiotherapy. The patient shows no evidence of recurrent tumor at 5 years after radiotherapy. Generally, radiotherapy and chemotherapy are chosen as the first treatment, because this cancer is seen most commonly in the elderly.