We have amplified by the polymerase chain reaction, cloned, and sequenced genomic segments of 118 human papillomavirus type 16 (HPV-16) isolates from 76 cervical biopsy, 14 cervical smear, 3 vulval biopsy, 2 penile biopsy, 2 anal biopsy, and 1 vaginal biopsy sample and two cell lines. The specimens were taken from patients in four countries--Singapore, Brazil, Tanzania, and Germany. The sequence of a 364-bp fragment of the long control region of the virus revealed 38 variants, most of which differed by one or several point mutations. Phylogenetic trees were constructed by distance matrix methods and a transformation series approach. The trees based on the long control region were supported by another set based on the complete E5 protein-coding region. Both sets had two main branches. Nearly all of the variants from Tanzania were assigned to one (African) branch, and all of the German and most of the Singaporean variants were assigned to the other (Eurasian) branch. While some German and Singaporean variants were identical, each group also contained variants that formed unique branches. In contrast to the group-internal homogeneity of the Singaporean, German, and Tanzanian variants, the Brazilian variants were clearly divided between the two branches. Exceptions to this were the seven Singaporean isolates with mutational patterns typical of the Tanzanian isolates. The data suggest that HPV-16 evolved separately for a long period in Africa and Eurasia. Representatives of both branches may have been transferred to Brazil via past colonial immigration. The comparable efficiencies of transfer of the African and the Eurasian variants to the New World suggest pandemic spread of HPV-16 in past centuries. Representatives of the African branch were possibly transferred to the Far East along old Arab and Indonesian sailing routes. Our data also support the view that HPV-16 is a well-defined virus type, since the variants show only a maximal genomic divergence of about 5%. The small amount of divergence in any one geographic location and the lack of marked divergence between the Tanzanian and Brazilian African genome variants two centuries after their likely introduction into the New World suggest a very slow rate of viral evolution. The phylogenetic tree therefore probably represents a minimum of several centuries of evolution, if not an age equal to that of the respective human races.

PMCID: PMC288996 PMID: 1312620

2. Biopsy and selective recall compared with immediate large loop excision in management of women with low grade abnormal cervical cytology referred for colposcopy: multicentre randomised controlled trial

BMJ : British Medical Journal 2009;339:b2548.

Objectives To compare the effectiveness of punch biopsy and selective recall for treatment versus a policy of immediate treatment by large loop excision in the management of women with low grade abnormal cervical cytology referred for colposcopy.

Design Multicentre individually randomised controlled trial, nested within the NHS cervical screening programmes.

Setting Grampian, Tayside, and Nottingham.

Participants 1983 women, aged 20-59, with cytology showing borderline nuclear abnormalities or mild dyskaryosis, October 1999-October 2002.

Interventions Immediate large loop excision or up to four targeted punch biopsies taken immediately with recall for treatment (by large loop excision) if these showed cervical intraepithelial neoplasia grade II or III or worse. Participants were followed for three years, concluding with an exit colposcopy.

Main outcome measures Clinical end points: cumulative incidence of cervical intraepithelial neoplasia grade II or worse and grade III or worse at three years. Clinically significant anxiety and depression and self reported after effects assessed six weeks after colposcopy, biopsies, or large loop excision.

Results 879 women (44%) had a normal transformation zone at colposcopy and had no further procedures at that time. Colposcopists were less likely to classify the transformation zone as abnormal when the allocation was large loop excision (603 (60%) in the biopsy and selective recall group; 501 (51%) in the immediate large loop excision group). Of women randomised to biopsy and recall, 157 (16%) required a second clinic visit for treatment. Specimens from almost 60% (n=296) of women who underwent immediate large loop excision showed no cervical intraepithelial neoplasia (31%; n=156) or showed cervical intraepithelial neoplasia grade I (28%; n=140). The percentages of women diagnosed with grade II or worse up to and including the exit examination were 22% (n=216) in the biopsy and recall arm and 23% (n=228) in the immediate large loop excision arm. There was no significant difference between the arms in cumulative incidence of cervical intraepithelial neoplasia grade II or worse (adjusted relative for risk large loop excision v biopsy 1.04, 95% confidence interval 0.86 to 1.25) or grade III or worse (1.03, 0.79 to 1.34). A greater proportion of disease was detected at initial investigation and less during follow-up and at exit in the immediate large loop excision arm, but time of detection did not differ significantly between arms. Levels of anxiety and depression and reported pain did not differ between arms. Higher proportions of women randomised to large loop excision reported moderate or more severe bleeding and discharge.

Conclusion A policy of targeted punch biopsies with subsequent treatment for cervical intraepithelial neoplasia grade II or III and cytological surveillance for grade I or less provides the best balance between benefits and harms for the management of women with low grade abnormal cytology referred for colposcopy. Immediate large loop excision results in overtreatment and more after effects and should not be recommended.

Trial Registration ISRCTN 34841617.

doi:10.1136/bmj.b2548

PMCID: PMC2718084 PMID: 19638647

3. Sequence variants of human papillomavirus type 16 in clinical samples permit verification and extension of epidemiological studies and construction of a phylogenetic tree.

Journal of Clinical Microbiology 1991;29(9):1765-1772.

Genomic variability between different viral isolates provides a powerful epidemiological tool for verifying ultrasensitive diagnostic procedures, understanding infectious pathways in individuals and human populations, and studying viral evolution. The potential of this approach has not yet been exploited for the diagnosis of human papillomaviruses (HPVs) like HPV type 16 (HPV-16), which are involved in genital cancer. Toward this end, we amplified by polymerase chain reaction, cloned, and sequenced a 364-bp noncoding segment of the HPV-16 genome from cell lines, cervical biopsy specimens, and cervical smears. The HPV-16 genomes in the cell lines SiHa and CaSki showed an identical point mutation, and in the SiHa cell line it had an additional 38-bp deletion. Only 4 of 22 cervical lesions biopsied from patients at several hospitals in Singapore contained HPV-16 DNA with the prototype sequence, while the DNAs of the other 18 cervical lesions differed by 1 to 10 mutations. This excludes contaminations with cloned HPV-16 DNA as the source of this DNA. To test whether this diversity was a geographic idiosyncrasy, we analyzed 25 cervical biopsy specimens from Brazil. Eight of these contained the prototype sequence, while 17 were mutated. Altogether, 11 genomic variants were found in the Singaporean samples and 12 genomic variants were found in the Brazilian samples, and only 5 of these occurred identically in both cohorts. All variants could be connected to form a phylogenetic tree, with some branches being specific for each cohort. This suggests that the variants did not originate over a short period in the individual patient but, rather, evolved consecutively while spreading throughout humankind.(ABSTRACT TRUNCATED AT 250 WORDS)

PMCID: PMC270207 PMID: 1663516

4. p16 as a diagnostic marker of cervical neoplasia: a tissue microarray study of 796 archival specimens

Lesnikova, Iana | Lidang, Marianne | Hamilton-Dutoit, Stephen | Koch, Jørn

Diagnostic Pathology 2009;4:22.

Background

To evaluate the usefulness of this biomarker in the diagnosis of cases of cervical neoplasia we studied the immunohistochemical expression of p16INK4a in a large series of archival cervical biopsies arranged into tissue microarray format.

Methods

TMAs were constructed with tissue cores from archival formalin fixed, paraffin-embedded donor tissues from 796 patients, and included cases of cervical intraepithelial neoplasia (CIN)1 (n = 249), CIN2 (n = 233), CIN3 (n = 181), and invasive cervical carcinoma (n = 133). p16INK4a expression was scored using two different protocols: 1) positive vs negative p16INK4a staining; 2) a semi-quantitative immunohistochemical score (0 to 8 points) according to the intensity of staining and the proportion of stained cells

Results

p16INK4A expression was not seen in normal cervix tissue, but was found with increasing frequency in the sequence: CIN1 (180/249; 72.3%) – CIN2 (212/233; 91.0%) – CIN3 (178/181; 98.3%) – invasive carcinoma (131/133; 98.5%). Using semi-quantitative scoring, all normal cervical samples had low scores (from 0 to 2 points), whilst the number of specimens with high scores was proportional to the degree of cervical dysplasia or the presence of invasive carcinoma.

Conclusion

Immunohistochemical analysis of p16INK4a expression is a useful diagnostic tool. Expression is related to the degree of histological dysplasia, suggesting that it may have prognostic and predicative value in the management of cervical neoplasia.

doi:10.1186/1746-1596-4-22

PMCID: PMC2714065 PMID: 19589135

5. Anal intraepithelial neoplasia in a multisite study of HIV-infected and high-risk HIV-uninfected women

AIDS (London, England) 2009;23(1):59-70.

Objectives

To study anal intraepithelial neoplasia (AIN) and its associations with anal and cervical human papillomavirus (HPV), cervical neoplasia, host immune status, and demographic and behavioral risk factors in women with and at risk for HIV infection.

Design

Point-prevalence analysis nested within a prospective study of women seen at three clinical centers of the Women’s Interagency HIV Study.

Methods

In 2001-2003 participants were interviewed, received a gynecological examination, anal and cervical cytology testing and, if abnormal, colposcopy or anoscopy-guided biopsy of visible lesions. Exfoliated cervical and anal specimens were assessed for HPV using PCR and type-specific HPV probing. Logistic regression analyses were performed and odds ratios (OR) estimated risks for AIN.

Results

470 HIV-infected and 185 HIV-uninfected women were enrolled. Low-grade AIN (LGAIN) was present in 12% of HIV-infected and 5% of HIV-uninfected women. High-grade AIN (HGAIN) was present in 9% of HIV-infected and 1% of HIV-uninfected women. In adjusted analyses among HIV-infected women, the risk factors for LGAIN were younger age (OR=0.59, 95%CI=0.36-0.97), history of receptive anal intercourse (OR=3.2, 95%CI=1.5-6.8), anal HPV (oncogenic types only OR=11, 95%CI=1.2-103; oncogenic and non-oncogenic types OR=11, 95%CI=1.3-96), and cervical HPV (oncogenic and non-oncogenic types OR=3.5, 95%CI=1.1-11). In multivariable analyses among HIV-infected women, the only significant risk factor for HGAIN was anal HPV infection (oncogenic and non-oncogenic types OR=7.6, 95%CI=1.5-38).

Conclusions

Even in the era of highly active antiviral therapy, the prevalence of AIN was 16% in HIV-infected women. After controlling for potential confounders, several risk factors for LGAIN differed from risk factors for HGAIN.

doi:10.1097/QAD.0b013e32831cc101

PMCID: PMC2614220 PMID: 19050387

anal intraepithelial neoplasia; HIV-infection; human papillomavirus; women

6. Relative Accuracy of Cervical and Anal Cytology for Detection of High Grade Lesions by Colposcope Guided Biopsy: A Cut-Point Meta-Analytic Comparison

Cachay, Edward R. | Agmas, Wollelaw | Mathews, William C. | Lo, Anthony W.I.

PLoS ONE 2012;7(7):e38956.

Background

We recently reported, using a receiver operating characteristic area metric, the first meta-analytic comparison of the relative accuracy of cervical and anal cytology in detecting moderate or severe histopathologic lesions by magnification directed punch biopsy. The aim of the present research was to meta-analytically examine cut-point specific operating characteristics (sensitivity, specificity) of cervical and anal cytology in detecting high grade squamous intraepithelial lesion (HSIL) histopathology by colposcope directed punch biopsy.

Methodology/Principal Findings

The primary eligibility requirement was availability of tabulated cytology (normal, atypical cells of unclear significance [ASCUS], low grade squamous intraepithelial lesion, HSIL or atypical squamous cells cannot rule out high grade [ASC-H]) and biopsy (

Conclusions/Significance

Using a cytology cut-point of HSIL or ASC-H, anal cytology is less sensitive but comparably specific to cervical cytology. However, using a cut-point of ASCUS, differences in accuracy were of borderline significance.

doi:10.1371/journal.pone.0038956

PMCID: PMC3405082 PMID: 22848345

7. Early Invasive Cervical Cancer

Gynecologic oncology 2008;112(1):95-103.

Purpose

To compare MRI, CT, clinical exam and histopathological analysis for predicting lymph node involvement in women with cervical carcinoma, verified by lymphadenectomy.

Methods

A 25-center ACRIN/GOG study enrolled 208 patients with biopsy-proven invasive cervical cancer for MRI and CT prior to attempted curative radical hysterectomy. Each imaging study was interpreted prospectively by one onsite radiologist, and retrospectively by 4 independent offsite radiologists, all blinded to surgical, histopathological and other imaging findings. Likelihood of parametrial and uterine body involvement was rated on a 5-point scale. Tumor size measurements were attempted in 3 axes. Association with histologic lymph node involvement, scored as absent, pelvic only and common iliac or paraaortic, was evaluated using Cochran-Mantel Haenszel statistics, univariate and multivariate logistic regression, generalized estimating equations, accuracy statistics and ROC analysis.

Results

Lymphatic metastases were found in 34% of women; 13% had common iliac nodal metastases, and 9% had paraortic nodal metastases. Based on the retrospective multi-observer re-reads, average AUC for predicting histologic lymph node involvement between MRI and CT for tumor size were higher for MRI versus CT, although formal statistic comparisons could not be conducted. Multivariate analysis showed improved model fit incorporating predictors from MRI, but not CT, over and above the initial clinical and biopsy predictors, although the increase in discriminatory ability was not statistically significant.

Conclusion

MRI findings may help predict the presence of histologic lymph node involvement in women with early invasive cervical carcinoma, thus providing important prognostic information.

doi:10.1016/j.ygyno.2008.10.005

PMCID: PMC2606919 PMID: 19019414

8. Changes in Gene Expression Predicting Local Control in Cervical Cancer: Results from Radiation Therapy Oncology Group 0128

Clinical cancer research : an official journal of the American Association for Cancer Research 2009;15(12):4199-4206.

Purpose

To evaluate the potential of gene expression signatures to predict response to treatment in locally advanced cervical cancer treated with definitive chemotherapy and radiation.

Experimental Design

Tissue biopsies were collected from patients participating in Radiation Therapy Oncology Group (RTOG) 0128, a phase II trial evaluating the benefit of celecoxib in addition to cisplatin chemotherapy and radiation for locally advanced cervical cancer. Gene expression profiling was done and signatures of pretreatment, mid-treatment (before the first implant), and “changed” gene expression patterns between pre- and mid-treatment samples were determined. The ability of the gene signatures to predict local control versus local failure was evaluated. Two-group t test was done to identify the initial gene set separating these end points. Supervised classification methods were used to enrich the gene sets. The results were further validated by leave-one-out and 2-fold cross-validation.

Results

Twenty-two patients had suitable material from pretreatment samples for analysis, and 13 paired pre- and mid-treatment samples were obtained. The changed gene expression signatures between the pre- and mid-treatment biopsies predicted response to treatment, separating patients with local failures from those who achieved local control with a seven-gene signature. The in-sample prediction rate, leave-one-out prediction rate, and 2-fold prediction rate are 100% for this seven-gene signature. This signature was enriched for cell cycle genes.

Conclusions

Changed gene expression signatures during therapy in cervical cancer can predict outcome as measured by local control. After further validation, such findings could be applied to direct additional therapy for cervical cancer patients treated with chemotherapy and radiation.

doi:10.1158/1078-0432.CCR-08-2257

PMCID: PMC2758917 PMID: 19509178

9. Paravertebral muscles in disease of the cervical spine.

Wharton, S B | Chan, K K | Pickard, J D | Anderson, J R

Journal of Neurology, Neurosurgery, and Psychiatry 1996;61(5):461-465.

OBJECTIVES: Cervical spine disorders are common in the older population. The paravertebral muscles are essential to the support and stabilisation of the cervical spine but have been little studied. The aim was to determine whether pathological changes develop in these muscles in patients with severe cervical spine disease, which, if present, might contribute to the pathogenesis and symptomatology of their disorder. METHODS: Open biopsies of superficial and deep paravertebral muscles were obtained during the course of surgical procedures to alleviate cervical myelopathy. Most of these patients had cervical spondylosis or rheumatoid arthritis involving the cervical spine. The biopsies were compared with muscle obtained at necropsy from patients without a history of cervical spine or neuromuscular disorder. RESULTS: Muscle from both the study and control groups showed a similar range and severity of abnormalities. In several patients, grouped fibre atrophy suggested chronic partial denervation. Most biopsies showed type 1 fibre predominance and selective type 2 fibre atrophy. Ragged red fibres were a frequent finding and electron microscopy disclosed accumulations of mitochondria, a small proportion of which contained rounded, or longitudinally oriented, single osmiophilic inclusions. Fibres containing core-like areas were also frequent. These pathological features were seen with increasing severity and frequency with increasing age. CONCLUSIONS: The paravertebral cervical muscles develop pathological abnormalities with increasing age with both neurogenic and myopathic features, the pathogenesis of which is probably multifactorial. Such a muscle disorder would be expected to be accompanied by functional impairment which may contribute to the development and symptomatology of cervical spine disease with increasing age.

Images

PMCID: PMC1074041 PMID: 8937338

10. Using Biomarkers as Objective Standards in the Diagnosis of Cervical Biopsies

The American journal of surgical pathology 2010;34(8):1077-1087.

Histopathologic diagnosis of cervical biopsies determines clinical management of patients with an abnormal cervical cancer-screening test yet is prone to poor inter-observer reproducibility. Immunohistochemical staining for biomarkers related to the different stages of cervical carcinogenesis may provide objective standards to reduce diagnostic variability of cervical biopsy evaluations but systematic, rigorous evaluations of their potential clinical utility are lacking. To address diagnostic utility of HPV L1, p16INK4a, and Ki-67 immunohistochemical staining for improving diagnostic accuracy, we conducted a community- and population-based evaluation using 1455 consecutive cervical biopsies submitted to the Department of Pathology at the University of Virginia during a period of 14 months. Thin-sections of each biopsy from 1451 of 1455 (99.7%) biopsies underwent evaluation of immunohistochemical stains for three biomarkers, masked to the original diagnosis, and the results were compared to an adjudicated, consensus diagnosis by 3 pathologists. p16INK4a immunostaining, using the strongest staining as the cutpoint, was 86.7% sensitive and 82.8% specific for cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) diagnoses. The p16INK4a performance was more sensitive (p < 0.001), less specific (p < 0.001), and of similar overall accuracy for CIN2+ compared to the combined performance of all pathologist reviews in routine clinical diagnostic service (sensitivity = 68.9%, specificity = 97.2%). Ki-67 immunostaining was also strongly associated with a CIN2+ diagnosis but its performance at all staining intensities was inferior to p16INK4a immunostaining, and did not increase the accuracy of CIN2+ diagnosis when combined with p16INK4a immunostaining compared to p16INK4a immunostaining alone. We found no utility for L1 immunostaining in distinguishing between CIN and non-CIN. In conclusion, with a rigorous evaluation, we found immunohistochemical staining for p16INK4a to be a useful and reliable diagnostic adjunct for distinguishing biopsies with and without CIN2+.

doi:10.1097/PAS.0b013e3181e8b2c4

PMCID: PMC2921638 PMID: 20661011

11. Nuclear DNA analysis of koilocytic and premalignant lesions of the uterine cervix.

Hughes, R G | Neill, W A | Norval, M

British Medical Journal (Clinical research ed.) 1987;294(6567):267-269.

Cervical biopsy samples were taken from 79 patients who had various grades of cervical intraepithelial neoplasia or who showed evidence, in the form of koilocytosis, of human papillomavirus infection of the uterine cervix and from 10 women with normal cervices. The DNA content of the cells in the samples was analysed by flow cytometry. Analysis of the data obtained showed that the biopsy samples from women with cervical intraepithelial neoplasia and human papillomavirus lesions contained significantly more dividing cells (31.2% of cells from human papillomavirus lesions with no cervical intraepithelial neoplasia and 33.06%, 29.89%, and 31.76% of cells from cervical intraepithelial neoplasia grades I, II, and III, respectively) than those from women with normal cervices (21.6%). The proportion of aneuploid samples from the group who showed evidence of human papillomavirus infection only (18.2%) did not differ significantly from the group with cervical intraepithelial neoplasia grade III (21.2%). Aneuploidy and an increased rate of cellular proliferation are recognised characteristics of malignancy. These results therefore support the view that human papillomavirus plays an important part in the aetiology of cervical carcinoma and are relevant to the clinical management of patients.

PMCID: PMC1245291 PMID: 3101837

12. Implications of tyrosine phosphoproteomics in cervical carcinogenesis

Journal of Carcinogenesis 2008;7:2.

Background

Worldwide cervical cancer remains a leading cause of mortality from gynecologic malignancies. The link between cervical cancer and persistent infection with HPV has been established. At a molecular level little is known about the transition from the precancerous state to invasive cancer. To elucidate this process, cervical biopsies from human specimens were obtained from precancerous state to stage III disease.

Methods

Cervical biopsies were obtained from patients with a diagnosis of cervical cancer undergoing definitive surgery or staging operation. Biopsies were obtained from patients with precancerous lesions at the time of their excisional procedure. Control samples were obtained from patients undergoing hysterectomy for benign conditions such as fibroids. Samples were subjected to proteomic profiling using two dimensional gel electrophoresis with subsequent trypsin digestion followed by MALDI-TOF protein identification. Candidate proteins were then further studied using western blotting, immunoprecipitation and immunohistochemistry.

Results

Annexin A1 and DNA-PKcs were found to be differentially expressed. Phosphorylated annexin A1 was up regulated in diseased states in comparison to control and its level was strongly detected in the serum of cervical cancer patients compared to controls. DNA-PKcs was noted to be hyperphosphorylated and fragmented in cancer when compared to controls. By immunohistochemistry annexin A1 was noted in the vascular environment in cancer and certain precancerous samples.

Conclusion

This study suggests a probable role for protein tyrosine phosphorylation in cervical carcinogenesis. Annexin A1 and DNA-PK cs may have synergistic effects with HPV infection. Precancerous lesions that may progress to cervical cancer may be differentiated from lesions that will not base on similar immunohistochemical profile to invasive squamous cell carcinoma.

doi:10.1186/1477-3163-7-2

PMCID: PMC2483982 PMID: 18637184

13. Papillomavirus and c-myc antigen expression in normal and neoplastic cervical epithelium.

Hughes, R G | Neill, W A | Norval, M

Journal of Clinical Pathology 1989;42(1):46-51.

Cervical punch biopsy specimens or brushings were collected from 33 patients with cervical human papilloma virus (HPV) infection, cervical intraepithelial neoplasia (CIN), or invasive cervical carcinoma, and from eight control patients with recent normal cervical cytology. Prostatic chippings obtained from six men with benign prostatic hypertrophy were used as further controls. Biopsy specimens and brushings were assayed by flow cytometry for c-myc oncogene antigen and papillomavirus antigen expression and rate of cell division (by measuring DNA content). Results obtained from analysis of specimens and brushings were similar in terms of c-myc antigen and total DNA content, but when the percentages of nuclei from biopsy and brush specimens staining positively with antibody to papilloma viral antigens were compared, brush specimens gave consistently higher percentages than biopsy specimens. More specimens from normal epithelium were c-myc antigen positive (five of eight, (63%) than specimens from CIN II or III (two of 10, 20%), or invasive carcinoma (0%). No association was found between c-myc antigen expression and cell division. HPV antigen positive specimens were found to contain more dividing cells than negative specimens.

PMCID: PMC1141789 PMID: 2537854

14. Demonstration of an epitope of the transferrin receptor in human cervical epithelium--a potentially useful cell marker.

Lloyd, J M | O'Dowd, T | Driver, M | Tee, D E

Journal of Clinical Pathology 1984;37(2):131-135.

The distribution of an epitope of the transferrin receptor in the human uterine cervical epithelium has been investigated. Immunohistochemical staining, both immunofluorescent and immunoperoxidase, was performed on biopsy specimens and cytological samples from normal, dysplastic, and neoplastic cervical epithelia using the monoclonal OKT9 antibody. The results of staining 145 cervical biopsy specimens with OKT9 showed widespread staining in all malignant epithelia and most severely dysplastic epithelia. No such staining was seen in either normal epithelia or in mildly dysplastic epithelia apart from the staining of the basal cell layer in some normal epithelia. The incidence of staining in the 50 cervical cytocentrifuge preparations was not as high as that in the 145 tissue sections. The potential role of the OKT9 antibody in both the screening of cervical cytocentrifuge preparations and the prediction of malignancy is discussed. The antibody is considered to be of more value in the examination of biopsy material than of cytocentrifuge preparations.

Images

PMCID: PMC498667 PMID: 6198338

15. A comparison of three methods of orienting cervical punch biopsies.

Heatley, M K

Journal of Clinical Pathology 1999;52(2):149-150.

AIMS: To compare methods of orienting cervical punch biopsies, since well oriented biopsies are needed to optimise the diagnosis and grading of cervical intraepithelial neoplasia. METHODS: The orientation, the presence and preservation of the squamocolumnar junction, and the presence or absence of the surface layers of the squamous epithelium were compared in 345 cervical biopsies that had either been attached to paper (n = 112), floated directly into 10% formalin (n = 107), or floated into a solution of 10% formalin including 0.05% eosin (n = 126) in the colposcopy clinic. RESULTS: When the specimens were mounted on filter paper before fixation, they were more likely to be optimally oriented, to have a preserved squamocolumnar junction, and to have intact surface epithelium than specimens that were handled using the other methods, even when the specimens floated off the paper in transit. CONCLUSIONS: Cervical biopsy specimens should be mounted on paper before fixation and submission to the laboratory.

PMCID: PMC501063 PMID: 10396246

16. Subaxial cervical pedicle screw insertion with newly defined entry point and trajectory: accuracy evaluation in cadavers

Zheng, Xiujun | Chaudhari, Rahul | Wu, Chunhui | Mehbod, Amir A. | Transfeldt, Ensor E.

European Spine Journal 2009;19(1):105-112.

Successful placement of cervical pedicle screws requires accurate identification of both entry point and trajectory. However, literature has not provided consistent recommendations regarding the direction of pedicle screw insertion and entry point location. The objective of this study was to define a guideline regarding the optimal entry point and trajectory in placing subaxial cervical pedicle screws and to evaluate the screw accuracy in cadaver cervical spines. The guideline for entry point and trajectory for each vertebra was established based on the recently published morphometric data. Six fresh frozen cervical spines (C3–C7) were used. There were two men and four women. After posterior exposure, the entry point was determined and the cortical bone of the entry point was removed using a 2-mm burr. Pilot holes were created with a cervical probe based on the guideline using fluoroscopy. After tapping, 3.5-mm screws with appropriate length were inserted. After screw insertion, every vertebra was dissected and inspected for pedicle breach. The pedicle width, height, pedicle transverse angulation and actual screw insertion angle were measured. A total of 60 pedicle screws were inserted. No statistical difference in pedicle width and height was found between the left and right sides for each level. The overall accuracy of pedicle screws was 83.3%. The remaining 13.3% screws had noncritical breach, and 3.3% had critical breach. The critical breach was not caused by the guideline. There was no statistical difference between the pedicle transverse angulation and the actual screw trajectory created using the guideline. There was statistical difference in pedicle width between the breach and non-breach screws. In conclusion, high success rate of subaxial cervical pedicle screw placement can be achieved using the recently proposed operative guideline and oblique views of fluoroscopy. However, careful preoperative planning and good surgical skills are still required to ensure screw placement accuracy and to reduce the risk of neural and vascular injury.

doi:10.1007/s00586-009-1213-4

PMCID: PMC2899726 PMID: 19916031

Cervical spine; Pedicle screw; Entry point; Trajectory

17. Outcome of women with inadequate cervical smears followed up for five years

Journal of Clinical Pathology 2003;56(8):592-595.

Background: The clinical and prognostic significance of “inadequate” cervical smear is unknown, even though women with repeated inadequate smears are referred for colposcopy in the National Health Service (NHS) Cervical Screening Programme.

Aim: To follow up a cohort of women with inadequate cervical smears over the following five years to examine outcomes, including detection of high grade cervical intraepithelial neoplasia (CIN).

Methods: The study comprised 1972 women with an inadequate cervical smear reported at Walsall Hospitals NHS Trust between 1 April 1995 and 31 March 1996. Results of cervical smears and biopsies taken over the following five years were reviewed to confirm the outcome.

Findings: Within five years, 2.2% of women with an inadequate cervical smear developed histologically confirmed high grade CIN, which was higher than the 1.3% seen among all women with cervical smear tests reported at the same laboratory over the same period, although the difference was not significant at the 95% level of confidence. Where inadequacy resulted from or was contributed to by “polymorphs obscuring”, the risk of subsequent development/detection of high grade CIN was 2.6%.

Conclusions: Women with inadequate cervical smears had an increased risk of detection of high grade CIN in the following five years compared with “all women”. This increased risk was not significant, although if a larger number of women had been studied significance may have been reached, so that further studies are needed. The increased risk appeared to be at least partially dependent on the reason for inadequacy.

PMCID: PMC1770040 PMID: 12890808

National Health Service Cervical Screening Programme; cervical intraepithelial neoplasia; inadequate cervical smears; Papanicolaou smear

18. An overview of prevention and early detection of cervical cancers

Mishra, Gauravi A. | Pimple, Sharmila A. | Shastri, Surendra S.

Indian Journal of Medical and Paediatric Oncology : Official Journal of Indian Society of Medical & Paediatric Oncology 2011;32(3):125-132.

Cervical cancer still remains the most common cancer affecting the Indian women. India alone contributes 25.41% and 26.48% of the global burden of cervical cancer cases and mortality, respectively. Ironically, unlike most other cancers, cervical cancer can be prevented through screening by identifying and treating the precancerous lesions, any time during the course of its long natural history, thus preventing the potential progression to cervical carcinoma. Several screening methods, both traditional and newer technologies, are available to screen women for cervical precancers and cancers. No screening test is perfect and hence the choice of screening test will depend on the setting where it is to be used. Similarly, various methods are available for treatment of cervical precancers and the selection will depend on the cost, morbidity, requirement of reliable biopsy specimens, resources available, etc. The recommendations of screening for cervical cancer in the Indian scenario are discussed.

doi:10.4103/0971-5851.92808

PMCID: PMC3342717 PMID: 22557777

Cervix cancer; colposcopy; early detection; precancer; prevention; screening; visual examination

19. A comprehensive review on host genetic susceptibility to human papillomavirus infection and progression to cervical cancer

Chattopadhyay, Koushik

Indian Journal of Human Genetics 2011;17(3):132-144.

Cervical cancer is the second most common cancer in women worldwide. This is caused by oncogenic types of human papillomavirus (HPV) infection. Although large numbers of young sexually active women get HPV-infected, only a small fraction develop cervical cancer. This points to different co-factors for regression of HPV infection or progression to cervical cancer. Host genetic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review is to compile the advances in the field of host genetics of cervical cancer. MEDLINE database was searched using the terms, ‘HPV’, ‘cervical’, ‘CIN’, ‘polymorphism(s)’, ‘cervical’+ *the name of the gene* and ‘HPV’+ *the name of the gene*. This review focuses on the major host genes reported to affect the progression to cervical cancer in HPV infected individuals.

doi:10.4103/0971-6866.92087

PMCID: PMC3276980 PMID: 22345983

Cervical cancer; genetics; HPV; polymorphism; progression

20. Upper quarter kinetic chain response to cervical manipulation: a case report

Filipkowski, Daniel E.

Journal of Chiropractic Medicine 2006;5(2):69-71.

Abstract

Objective

The purpose of this single subject case study is to examine the relationship between cervical spine manipulation and tender points located in the upper quarter.

Clinical Features

A 45-year-old female presented with cervical spine pain and corresponding pain points in the upper quarter following a motor vehicle collision occurring 7 months prior to testing. Inclusion criteria were 22 of 22 clinically significant pain points as measured by pressure algometry.

Intervention and Outcome

High velocity/low amplitude manual manipulation was administered to areas of joint restriction in the cervical spine. Pre- and post-treatment computerized algometry readings were taken in areas of the cervical spine and upper extremities to assess change in pain over time. Algometry points were chosen based on published upper quarter tender points associated with cervical joint fixation/immobilization.

Conclusion

Following a series of 15 cervical chiropractic manipulations, the patient demonstrated a significant increase in pain tolerance related to upper quarter pain points and demonstrated by pressure algometry. These findings correlate well with the literature, indicating that cervical spine joint dysfunction should be considered globally as part of a dynamic kinetic chain involving the upper quarter. Dysfunction in one part of the kinetic chain should direct treatment to other areas of the chain.

doi:10.1016/S0899-3467(07)60136-0

PMCID: PMC2647061 PMID: 19674675

Upper Extremity; Manipulation, Chiropractic; Myofascial Pain Syndrome

21. Kikuchi-Fujimoto disease

Bosch, Xavier | Guilabert, Antonio

Orphanet Journal of Rare Diseases 2006;1:18.

Kikuchi-Fujimoto disease (KFD) is a benign and self-limited disorder, characterized by regional cervical lymphadenopathy with tenderness, usually accompanied with mild fever and night sweats. Less frequent symptoms include weight loss, nausea, vomiting, sore throat. Kikuchi-Fujimoto disease is an extremely rare disease known to have a worldwide distribution with higher prevalence among Japanese and other Asiatic individuals. The clinical, histopathological and immunohistochemical features appear to point to a viral etiology, a hypothesis that still has not been proven. KFD is generally diagnosed on the basis of an excisional biopsy of affected lymph nodes. Its recognition is crucial especially because this disease can be mistaken for systemic lupus erythematosus, malignant lymphoma or even, though rarely, for adenocarcinoma. Clinicians' and pathologists' awareness of this disorder may help prevent misdiagnsois and inappropriate treatment. The diagnosis of KFD merits active consideration in any nodal biopsy showing fragmentation, necrosis and karyorrhexis, especially in young individuals presenting with posterior cervical lymphadenopathy. Treatment is symptomatic (analgesics-antipyretics, non-steroidal anti-inflammatory drugs and, rarely, corticosteroids). Spontaneous recovery occurs in 1 to 4 months. Patients with Kikuchi-Fujimoto disease should be followed-up for several years to survey the possibility of the development of systemic lupus erythematosus.

doi:10.1186/1750-1172-1-18

PMCID: PMC1481509 PMID: 16722618

22. Cytopathogenic protein in filtrates from cultures of Propionibacterium acnes isolated from patients with Kawasaki disease.

British Medical Journal (Clinical research ed.) 1987;295(6608):1229-1232.

Propionibacterium acnes may have a role in Kawasaki disease. Filtrates from cultures of P acnes isolated from cervical lymph node biopsy specimens and blood samples from patients with Kawasaki disease were studied and compared with samples from control subjects. After inoculation of human embryo liver cells with filtrates from the patients a cytopathogenic effect and vacuolation were seen. A specific cytopathogenic substance was found in only the filtrates of cultures from patients with Kawasaki disease; it was a protein of about isoelectric point 7.0 with a molecular weight of about 100,000 daltons. The amount of IgG antibody to this cytopathogenic protein was measured by enzyme linked immunosorbent assay (ELISA) in serum samples taken from 63 patients in the acute phase of Kawasaki disease (mean 5.2 (SD 1.1) days after onset of illness), 45 in the subacute phase (mean 23.6 (3.3) days), and 51 in the convalescent phase (mean 18.5 (4.1) months) and from 102 control subjects matched for age. Titres of IgG antibody were significantly raised in patients with Kawasaki disease, particularly in the acute and subacute phases of the illness, compared with in the control subjects. Titres of IgG antibodies to cytopathogenic protein were found to be low in normal children below the age of 4 years but they increased with age thereafter. This may explain why outbreaks of Kawasaki disease, which is most common in children aged under 4, occur every three years.

Images

PMCID: PMC1248303 PMID: 3120957

23. Coexistence of early microinvasive endometrioid adenocarcinoma and CIN3 in the uterine cervix in a 32-year-old Japanese woman

Terada, Tadashi

Diagnostic Pathology 2011;6:51.

Simultaneous occurrence of early microinvasive endometrioid adenocarcinoma (EMEA) and CIN 3 in the uterine cervix is very rare in Japan. A 32-year-old Japanese woman was pointed out to have atypical cells in the cervical cytology. Colposcopic examination revealed irregular lesions in the cervix, and a biopsy showed simultaneous EMEA and CIN3. The EMEA was grade I and CIN3 corresponded to severe dysplasia/carcinoma in situ. Hysterectomy and lymph nodes dissection were performed. Grossly, mucosal irregularity and erosion were seen in the cervix. No tumor formation was recognized. The cervix was examined by serial sections. Microscopically, there were a tiny adenocarcinoma (0.5 cm in diameter and 0.3 cm in depth) and broad areas of CIN3. The adenocarcinoma was EMEA without mucins. The EMEA was FIGO stage 1A1. Immunohistochemically, the EMEA was positive for pancytokeratins (AE1/2 +++, CAM5.2 ++), cytokeratin (CK) 34βE12 +, CK5/6 +, CK7 +, CK18 +++, CK19 ++, CA19-9 +, CA125 +++, p53 +, ER +++, PgR +++, while it was negative for CK8, CK14, CK20, EMA, vimentin, CEA, desmin, smooth muscle actin, p63, chromogranin, synaptophysin, CD56, CD68, HER2/neu, MUC1, MUC2, MUC5AC, and MUC6. The CIN 3 was positive for pancytokeratins (AE1/2 +++, CAM5.2 +), cytokeratin (CK) 34βE12 +++, CK5/6 +++, CK7 +, EMA, CA19-9 +, CA125 +, p53 +, p63 +++, ER +++, and MUC1 +, while it was negative for CK8, CK14, CK18, CK19, CK20, vimentin, CEA, desmin, smooth muscle actin, chromogranin, synaptophysin, CD56, CD68, PgR, HER2/neu, MUC2, MUC5AC and MUC6. The lymph nodes showed no metastatic lesions (0/34). In conclusion, the author reported a rare case of simultaneous EMEA and CIN 3 with extensive immunohistochemical findings.

doi:10.1186/1746-1596-6-51

PMCID: PMC3123261 PMID: 21663603

early microinvasive adenocarcinoma; CIN3; uterine cervix; histopathology; immunohistochemistry

24. Evaluation of visual inspection as a screening test for cervical cancer.

British Journal of Cancer 1997;75(3):436-440.

Visual inspection of the uterine cervix by paramedical personnel has been proposed for the early detection of cervical cancer, as an alternative to routine cytology screening in developing countries. We evaluated the performance of this procedure in detecting precursor lesions and cancer in a study involving 2843 married women in Kerala, India. Two thresholds were used to define a positive test. In the lower one, any abnormality was considered as positive. The cut-off point for the high threshold was one or more of the high-risk findings: bleeding on touch, suspicious growth/ulcer and hard, irregular, oedematous cervix. A Pap smear was performed on all subjects, and a biopsy was done for those with moderate dysplasia and above. A combination of cytology and histology findings was used as the 'gold standard'. Using the low threshold, 1279 (45%) women were positive on visual inspection, and with the higher threshold 179 (6.3%) were positive. There were six moderate dysplasias, nine severe dysplasias, ten carcinomas in situ and 13 invasive carcinomas. With the lower threshold, sensitivity and specificity to detect moderate dysplasia and above were 65.8% and 55.3% respectively; the values for severe dysplasia and above were 71.9% and 55.3% respectively and for invasive cancer were 92.3% and 55.2% respectively. With the higher threshold, the sensitivity decreased considerably (28.9% to detect moderate dysplasia lesions, 31.3% for severe dysplasia and 53.8% for clinical cancer) and the specificity increased to approximately 94%. At a lower threshold, the sensitivity was not satisfactory, and the test was highly non-specific; at a higher threshold sensitivity was even lower. Thus, the test characteristics of visual inspection are not very promising either as a preselection procedure for cytology or as a low-technology measure for cervical cancer screening in developing countries.

PMCID: PMC2063368 PMID: 9020493

25. Correlation between the tumoral expression of β3-integrin and outcome in cervical cancer patients who had undergone radiotherapy

British Journal of Cancer 2004;92(1):41-46.

Integrins are cell-surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Besides playing an important role in tumour angiogenesis, β3-integrin is also expressed in several types of epithelial cancer cells. It was the purpose of the present study to evaluate the prognostic value of β3-integrin expression in patients with cervical cancer. Biopsies were taken from 82 patients with squamous cell or adenocarcinomas of the uterine cervix who had undergone external-beam radiotherapy with or without brachytherapy. These tissue samples were analysed immunohistochemically for the expression of β3-integrin. The impact of immunoreactivity for β3-integrin on survival end points was assessed by univariate and multivariate analyses, and its correlation with clinicopathological characteristics evaluated by crosstabulations. β3-integrin was expressed in 61% (50 of 82) of the patients. Kaplan–Meier curves revealed local progression-free survival, distant metastasis-free survival and cause-specific survival to be significantly shorter (P-values according to the log-rank test: 0.002, 0.04 and 0.01, respectively) in patients with β3-integrin expression. The prognostic impact of this parameter was even higher than for other well-known prognostic parameters and remained statistically significant in the multivariate analyses. β3-integrin, which is expressed in the majority of patients with advanced cervical cancer, has a significant prognostic impact on outcome according to univariate and multivariate analyses.

doi:10.1038/sj.bjc.6602278

PMCID: PMC2361731 PMID: 15597101

β3-integrin expression; cervical cancer; radical radiotherapy

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