To have a good grasp of clinical colposcopy, it is necessary to understand the histopathologic structure of the normal and dysplastic cervical epithelium. Previous meta-analyses had indicated high overall sensitivity of colposcopy in detecting dysplastic lesions, but recent studies have suggested that the technique has much lower sensitivity in detecting high-grade intraepithelial neoplasia. The best practice in colposcopy relies on accurately taking a biopsy from the correct (i.e. most morphological abnormal) site, and by taking more than one biopsy, the sensitivity for detection of high-grade cervical intraepithelial neoplasia can be increased. Cytological screening programmes of proven and maintained high quality will enhance the predictive colposcopic accuracy for high-grade cervical intraepithelial neoplasia after referral. With the advent of computerised colposcopy and the Internet, digital imaging can be transmitted in real-time for instant viewing, facilitating distant consultation and education. This form of ‘telemedicine’ will allow family practice and remote areas to have access to colposcopy expertise. Of all the currently available technological adjuncts to colposcopy, spectroscopy devices have demonstrated relatively high sensitivities, and seem to have the best potential to become the technique of choice in future routine clinical practice in developed countries following the human papillomavirus vaccination. Other alternatives may need to be used in parts of the globe with high disease incidence and without organised screening or vaccination programmes. Opportunities remain for global collaboration in research, education and training to promote more effective and affordable cervical screening, and to enhance the skills of colposcopists worldwide.
Principles of colposcopy
The first description of the colposcope was by Hinselmann in 1925. It was a fixed binocular instrument mounted on a tripod and equipped with a light source and a mirror to centre the light on the field to be examined. Modern colposcopic equipment now includes electrical zoom capability, photographic, video and analytic facilities for clinical, research and teaching purposes. The basic colposcope with adjustable magnification, however, will still fulfil the role adequately for most clinical colposcopists, as long as its limitations are understood.
Histopathologic basis of colposcopy
Meaningful interpretation of the colposcopic appearance is impossible without a firm grasp of the histological changes that take place in the cervix. We need to understand how the fixed and stained tissue artefact seen under the pathologist’s microscope can be translated into the living biologic image afforded by direct magnification, and how the histomorphologic alteration that occurs in dysplasia gives rise to the well-described ‘abnormal’ colposcopic patterns. The magnified image of the colposcope is based on the reciprocal relationship between the epithelium and the stroma. The epithelium acts as a filter through which both the incident and reflected light must pass. The epithelium itself is colourless. The stroma is red because it contains blood vessels. The nature and intensity of this colouration depends on the thickness and architecture of the epithelium and the nature of the stroma. The colposcopic surface configuration is determined by the interplay of the following factors: the surface of the cervix, the planes between different epithelia, and the thickness of the epithelium.
The colposcopic image hinges on these three basic characteristics: the colour of the epithelium, the surface contour of the epithelium and the arrangements of the terminal vascular bed, the angioarchitecture.
Colposcopic examination
The formal sequence of a colposcopic examination of the cervical epithelium follows application of saline solution, then 5% acetic acid and finally Lugol’s iodine solution (Schiller’s test) in successive steps.
Saline application
Saline application allows the initial study of the vascular pattern of the cervix, most effectively under a green filter.
Five per cent acetic acid application
Five per cent acetic acid application helps in coagulating and clearing the mucus. Acetic acid is thought to cause swelling of the epithelial tissue, columnar and any abnormal squamous epithelial areas in particular. It causes a reversible coagulation or precipitation of the nuclear proteins and cytokeratins. With low-grade cervical intraepithelial neoplasia (CIN), the acetic acid must penetrate into the lower one-third of the epithelium (where most of the abnormal cells with high nuclear density are located). Hence, the appearance of the whiteness is delayed and less intense owing to the smaller amount of nuclear protein compared with areas with high-grade CIN or pre-clinical invasive cancer. Aceto-whitening associated with CIN and invasive cancer quickly appears and persists for more than 1 minute. The acetic acid effect reverses much more slowly in high-grade CIN lesions and in early pre-clinical invasive cancer than in low-grade lesions, immature metaplasia and sub-clinical human papillomavirus (HPV) changes. It may last for 2–4 mins in the case of high-grade lesions and invasive cancer.
Lugol’s iodine solution
The original and newly formed mature squamous metaplastic epithelium is glycogenated, whereas CIN and invasive cancer contain little or no glycogen. Columnar epithelium does not contain glycogen. Immature squamous metaplastic epithelium usually lacks glycogen or, occasionally, may be partially glycogenated. Iodine is glycophilic, and hence the application of iodine solution results in uptake of iodine in glycogen-containing epithelium. Therefore, the normal glycogen-containing squamous epithelium stains mahogany brown or black after application of iodine. Areas of CIN and invasive cancer do not take up iodine (as they lack glycogen) and appear as thick mustard yellow or saffron-coloured areas. The routine use of iodine application in colposcopic practice may help in identifying lesions overlooked during examination with saline and acetic acid, and will help in delineating the anatomical extent of abnormal areas much more clearly, thereby facilitating either immediate or delayed treatment.
Limitations of colposcopy
Colposcopy is not used as a screening tool. It is used as a diagnostic test in triage after abnormal cytology is detected by cervical screening. It is also recommended when clinical examination revealed an abnormal looking cervix suspected of being neoplastic or when there is persistent post-coital bleeding. In a review of the cytology-colposcopy programme in British Columbia over 15 years (1986–2000), the finding of high-grade CIN (CIN 2 and 3) in the histology of colposcopically directed biopsies was 70% when the colposcopic prediction was high grade. Bekkers et al. concluded that experience of colposcopists did not improve overall colposcopic performance but the sensitivity of identifying high-grade CIN was significantly higher with inexperienced colposcopists and the positive predictive value was significantly higher with experienced colposcopists.
Lack of sensitivity
A meta-analysis by Mitchell et al. in 1998 on colposcopy for the diagnosis of squamous CIN showed mean weighted sensitivity of 96% and specificity of 48% when comparing normal with all cervix abnormalities. Comparison of low-grade CIN with high-grade CIN and cancer showed that mean weighted sensitivity is 85% (range 30–99%) and specificity is 69%. Although this meta-analysis showed colposcopy in a favourable light, more recent studies have suggested much poorer sensitivity. In the Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS), the investigators carried out many ancillary analyses concentrating on enrollment of women for colposcopic examination with eventual diagnosis of CIN3. They observed poor sensitivity of enrollment colposcopic impression. In the immediate colposcopy arm in which all the women had colposcopic examination at enrollment, only 54.8% of women with a final histologic diagnosis of CIN3 from the first examination or during the 2-year follow-up had a positive colposcopic biopsy (≥ CIN2) at enrollment.
Colposcopic criteria
A scoring index to improve colposcopy prediction had been introduced with varying results: Coppleson’s Schema in the 1960s, Stafl’s schema in the 1970s, Reid’s schema in the 1980s and Strander’s schema in 2000s. A study to determine the accuracy of an abbreviated Reid Colposcopic Index using its component scores of colour, margin and vessels to detect CIN 2 and 3 during the National Cancer Institute ALTS study showed the RCI score agreement to be poor (weighted Kappa = 0.17). The sensitivity, specificity, positive and negative predictive values of a Reid Colposcopic Index score to detect CIN 3 or worse were 37.3% (95% CI 32.5% to 42.3%), 89.7% (88.6% to 90.8%), 30.8% (26.7% to 35.2%), and 92.1% (91.1% to 93.0%), respectively. Recent evaluation of the Strander’s schema indicates its high specificity for high-grade CIN may make it useful in a see-and-treat scenario.
Cervical biopsy at colposcopy
As histology is often used as the gold standard to detect high-grade CIN, the sensitivity of diagnostic colposcopy in the end relies on accurately taking the biopsy from the correctly identified site with the greatest sum of abnormal characteristics. Colposcopy, although useful in estimating the lesion grade, is generally imprecise. One study showed the association between colposcopy impression and biopsy histology was significant ( P < 0.001), but the strength of the correlation was poor (0.20). The sensitivity for high-grade CIN was 56%. Management decisions for individuals ultimately require histopathological results. It has been shown that the number of biopsies taken at colposcopy dictates the sensitivity of colposcopy, with two or more biopsies being superior to single ones at any given examination. Other studies have concluded that, in women with high-grade squamous intraepithelial neoplasia or frankly invasive cytology, and who have a negative colposcopy, random biopsies of the cervix may be more helpful in detecting CIN 2 or worse.
Limitations of colposcopy
Colposcopy is not used as a screening tool. It is used as a diagnostic test in triage after abnormal cytology is detected by cervical screening. It is also recommended when clinical examination revealed an abnormal looking cervix suspected of being neoplastic or when there is persistent post-coital bleeding. In a review of the cytology-colposcopy programme in British Columbia over 15 years (1986–2000), the finding of high-grade CIN (CIN 2 and 3) in the histology of colposcopically directed biopsies was 70% when the colposcopic prediction was high grade. Bekkers et al. concluded that experience of colposcopists did not improve overall colposcopic performance but the sensitivity of identifying high-grade CIN was significantly higher with inexperienced colposcopists and the positive predictive value was significantly higher with experienced colposcopists.
Lack of sensitivity
A meta-analysis by Mitchell et al. in 1998 on colposcopy for the diagnosis of squamous CIN showed mean weighted sensitivity of 96% and specificity of 48% when comparing normal with all cervix abnormalities. Comparison of low-grade CIN with high-grade CIN and cancer showed that mean weighted sensitivity is 85% (range 30–99%) and specificity is 69%. Although this meta-analysis showed colposcopy in a favourable light, more recent studies have suggested much poorer sensitivity. In the Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS), the investigators carried out many ancillary analyses concentrating on enrollment of women for colposcopic examination with eventual diagnosis of CIN3. They observed poor sensitivity of enrollment colposcopic impression. In the immediate colposcopy arm in which all the women had colposcopic examination at enrollment, only 54.8% of women with a final histologic diagnosis of CIN3 from the first examination or during the 2-year follow-up had a positive colposcopic biopsy (≥ CIN2) at enrollment.
Colposcopic criteria
A scoring index to improve colposcopy prediction had been introduced with varying results: Coppleson’s Schema in the 1960s, Stafl’s schema in the 1970s, Reid’s schema in the 1980s and Strander’s schema in 2000s. A study to determine the accuracy of an abbreviated Reid Colposcopic Index using its component scores of colour, margin and vessels to detect CIN 2 and 3 during the National Cancer Institute ALTS study showed the RCI score agreement to be poor (weighted Kappa = 0.17). The sensitivity, specificity, positive and negative predictive values of a Reid Colposcopic Index score to detect CIN 3 or worse were 37.3% (95% CI 32.5% to 42.3%), 89.7% (88.6% to 90.8%), 30.8% (26.7% to 35.2%), and 92.1% (91.1% to 93.0%), respectively. Recent evaluation of the Strander’s schema indicates its high specificity for high-grade CIN may make it useful in a see-and-treat scenario.
Cervical biopsy at colposcopy
As histology is often used as the gold standard to detect high-grade CIN, the sensitivity of diagnostic colposcopy in the end relies on accurately taking the biopsy from the correctly identified site with the greatest sum of abnormal characteristics. Colposcopy, although useful in estimating the lesion grade, is generally imprecise. One study showed the association between colposcopy impression and biopsy histology was significant ( P < 0.001), but the strength of the correlation was poor (0.20). The sensitivity for high-grade CIN was 56%. Management decisions for individuals ultimately require histopathological results. It has been shown that the number of biopsies taken at colposcopy dictates the sensitivity of colposcopy, with two or more biopsies being superior to single ones at any given examination. Other studies have concluded that, in women with high-grade squamous intraepithelial neoplasia or frankly invasive cytology, and who have a negative colposcopy, random biopsies of the cervix may be more helpful in detecting CIN 2 or worse.
Development of new technologies to increase diagnostic accuracy
Cytology
In the British Columbia cytology–colposcopy review in Canada, the colposcopic impression correlated with the referral cytology within1degree in over 90% of cases. Cytology–histology correlation within 1 degree occurred in 82%. Women with high-grade squamous intraepithelial lesion cytology had corresponding lesions in 77%, with a further 4.9% having low-grade squamous intraepithelial disease. As the degree of cytological abnormality worsened, the predictive accuracy of colposcopic diagnosis increased. This was also reflected in the screening programme in Victoria, Australia, where women with high-grade squamous intraepithelial lesion cytology had corresponding lesions in 78.3%, with a further 10.8% having Low grade squamous intraepithelial lesion disease. A high-quality cytology screening programme will have a higher cytology–histology correlation which, in turn, will increase the predictive colposcopic accuracy of high-grade CIN. Rolling quality-assurance programmes of accredited cytology laboratories, individual screeners and pathologists are a critical component of the success and reliability of the established National cervical cancer screening programmes.
Digital imaging
Colposcopic images have evolved from still photos to high-definition video. The cervicoscope, introduced in 1981 by Stafl, is a camera with a fixed telephoto lens that takes a photograph of the cervix. These photographs, called cervicograms, are then evaluated by expert colposcopists. The efficacy of cervicograms vary, but the sensitivity of cervicography is in general lower than the sensitivity of cytology (pap smear), and the specificity is in general higher. With the advanced digital image capture technology now becoming more affordable, and with the use of secure internet connections, high-quality digital images can be transmitted in real-time for instant viewing facilitating distant consultation and education ( Fig. 1 ). This form of ‘telemedicine’ could allow family practice and remote areas to have access to centralised colposcopy expertise and reduce the need for patient travel. Studies evaluating telecolposcopy showed sensitivity for the detection of high-grade CIN lesions ranges from 40.9 to 43.2% for network-based colposcopy and from 34.1 to 40.9% for computer-based colposcopy compared with a sensitivity of about 48% for on-site colposcopy. Specificity was from 55.3% to 59% for the three modalities. Digital image colposcopy can be linked to other techniques (see below).
Spectroscopy
Spectroscopy is a non-invasive method in which light or electric current is used to study the biochemical composition as well as the metabolic and structural features of tissue. Components of the electromagnetic spectrum relevant to diagnostic spectroscopy include the ultraviolet A range (315–400 nm), the visible light range (400–700 nm) and the near infrared range (700–900 nm). When light strikes tissue, it will be absorbed with or without re-emission of the light or it is scattered by (sub)surface interactions. In 1999, Mitchell et al. presented a review concluding that fluorescence spectroscopy performs better than colposcopy and other techniques, including cervicography, speculoscopy, cytology and HPV testing in the diagnosis of squamous intraepithelial lesions. Two decades on, a comprehensive review by Louwers et al. indicated some larger trials have been carried out in the field of spectroscopy that have demonstrated relatively high sensitivities. The investigators believe that, of all currently available objective data producing alternatives or adjuncts to colposcopy, spectroscopy has the potential to emerge as the technique of choice and that one day it might become incorporated into routine clinical practice. A summary of the various modalities of spectroscopy and their efficacy has been adapted from Louwer’s publication. ( Table 1 )
| Modalities of Spectroscopy | Features | Sensitivity (%) | Specificity (%) | References |
|---|---|---|---|---|
| Low grade vs High grade CIN | ||||
| LuViva™ | Multimodal hyper-spectral imaging. Fluorescence and reflectance spectra from the cervix in vivo | 95 | 55–83 | Ferris et al. DeSantis et al. |
| LUMA™ | Combination of fluorescence, white light backscattered spectroscopy and video imaging | 92 | 50 | Huh et al. |
| DySIS™ | Measures spectroscopically the acetowhitening effect | 79 88 a | 76 __ | Soutter et al. Louwers et al. |
| Trimodal | Combination of fluorescence, diffuse reflectance and light scattering spectroscopy | 92 b | 71 b | Georgakoudi et al. |
| Impedance | Impedance spectrum is measured through a contact probe that uses electrical current | 74 | 53 | Abdul et al. |
| Truscreen ® | A probe in contact with the cervix collects spectrometric data | 70 | — | Singer et al. |
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