To develop cervical cancer, it is necessary (although not sufficient) to have a persistent infection of the cervix with a high risk or oncogenic HPV (hrHPV). Virtually all cervical cancers test positive for HPV DNA. Whilst HPV infection is necessary, other associated co-factors are required that may include smoking, long-term oral contraceptive pill (OCP) use, human immunodeficiency virus (HIV) co-infection, high parity, herpes simplex virus (HSV) and chlamydia trachomatis (CT) infection, absence of male circumcision, immune suppression as well as nutritional and dietary factors.
HPV is a circular double-stranded DNA virus belonging to the family Papillomaviridae. There are over 150 genotypes of which 40 infect the moist squamous epithelium of the anogenital tract. Of these, 15 cause cervical cancer. Types 16 and 18 cause 60-80% of all cervical cancers. There is wide variation in the prevalence of the lesser HPV types throughout the Africa/Asia and other parts of the world that also includes types 31 and 45.
Although HPV is most commonly associated with disease in the cervix, HPV also causes benign genital condyloma, low and high grade dysplasia and a subset of cancers throughout the anogenital tracts of both men and women. HPV is also responsible for recurrent respiratory tract papillomatosis and for warty lesions occurring on the mucosal surfaces of the oral cavity and oropharynx.
HPV is usually acquired through sexual intercourse and most HPV infections are subclinical and transient, most cleared by cell mediated immunity within 6 months. High risk HPV infections may take longer to clear. Whilst condoms may reduce the risk of HPV acquisition, they are not fully protective against the transference of HPV infection. HPV infection is a very common in sexually active young women with a point prevalence of about 25% and a cumulative prevalence of greater than 80%. After the age of 30, the prevalence of HPV infection declines dramatically to about 5%, and the key determinants of infection remain the age of coitarche, recent and total sexual partners and male sexual behaviour.
It was originally believed that there was a natural and orderly progression of cervical disease from CIN I to CIN II to CIN III and then the development of invasive cervical cancer. Through a much greater understanding of the natural history of HPV infection and CIN we know this is not the case with the majority of low grade lesions regressing without treatment, and a significant proportion of high grade lesions progressing to invasive cancer if left untreated.
B. Squamous Abnormalities
- Possible low grade squamous intraepithelial lesion
- Low grade squamous intraepithelial lesion
- Possible high grade squamous intraepithelial lesion
- High grade squamous intraepithelial lesion
- Squamous cell carcinoma
C. Glandular abnormalities
- Atypical endocervical cells of uncertain significance
- Atypical glandular cells of uncertain significance
- Possible high grade glandular lesion
- Endocervical adenocarcinoma-in-situ
- Recurrent low grade SIL smears
- Women under the age of 30 years, whose smear is suggestive of a LSIL should undergo colposcopy if there are 3 consecutive smears over at least a 24-month period suggesting LSIL.
- It is recommended that a woman be referred for colposcopy only if she has two consecutive LSIL reports during a three year period (at least 12 months apart) if she is over the age of 30 years or three consecutive LSIL reports (all at least 12 months apart) if she is under the age of 30 years.
- Possible high grade SIL smear
- High grade SIL smear
- Glandular lesions
- Abnormal bleeding
- Abnormal appearing cervix
An adequate colposcopy is defined as one where the cervix (and upper vagina) is satisfactorily visualized. That if a lesion is present is seen in its entirety, including its upper extent. An assessment of grade is performed and volume of disease estimated.
Low grade lesions are flat, shiny acetowhite epithelium, borders not necessarily sharp, usually semitransparent with or without fine caliber, regularly shaped vessels, often with ill-defined patterns; small intercapillary distance.
High grade lesions are flat, more opaque acetowhite epithelium with more severe lesions appearing very white or grey opaque with sharp borders, with or without dilated caliber vessels exhibiting a defined pattern of punctation or mosaicism with increased intercapillary distance.
Disease volume is estimated by the number of cervical quadrants affected by disease.
Colposcopy allows for a directed biopsy(s) to be performed from the highest grade region.
Histological confirmation of a high-grade lesion is required before definitive treatment is undertaken. ‘See and treat’ is not recommended. An exception is when a woman, usually over age 30, who has completed her family, is referred with a smear predicting CIN 3, colposcopy is adequate, ie the squamocolumnar junction is fully visible and the lesion is fully visible and there is no colposcopic evidence of invasion.
• Possible Low Grade and Low Grade Squamous Intraepithelial Lesions
A smear predicting a possible low grade lesion (PLSIL) is to be used when the reporting pathologist observes changes in squamous cells that may represent a low-grade squamous intraepithelial lesion, but the changes are not so clear-cut as to justify a ‘definite’ diagnosis. This category excludes changes that are within the scope of reactive processes. It corresponds to ‘nonspecific minor squamous cell changes’ in the previous Australian NHMRC-endorsed terminology (NHMRC 1994).
A smear predicting low grade changes (LSIL) is the morphological correlate of productive viral infection. It is to be used when the pathologist observes changes that would have been described as ‘HPV effect’ or ‘CIN 1’ in the previous Australian terminology and represents part of the previous ‘low-grade squamous epithelial abnormality’ category.
A woman with a Pap test report of LSIL should be managed in the same way irrespective of whether the abnormality is regarded as possible or definite and should be recommended for a repeat Pap test in 12 months
Pap test reports of LSIL in women aged 30+ years
A woman aged 30 years or more with a Pap test report of LSIL, without a history of negative smears in the preceding two to three years, should be offered either immediate colposcopy or a repeat Pap smear within six months.
Twelve-month repeat Pap test after index test results of LSIL
If the 12-month repeat Pap test is reported as showing high-grade changes (definite or possible), the woman should be referred for colposcopic assessment. Any woman whose repeat Pap test at 12 months is again reported as showing changes suggestive of LSIL (whether possible or definite), should be referred for colposcopic assessment. If the 12-month repeat Pap test is reported as normal, the woman should have a further repeat Pap test in 12 months (i.e. 24 months after the index smear).
Fluctuating repeat Pap test results
Referral for colposcopy should be considered for a woman if she has two LSIL/possible LSIL reports (at least 12 months apart) within a 3-year timeframe, regardless of intervening normal cytology reports.
If, at colposcopy, a high-grade lesion is seen or suspected, targeted biopsy should be performed for histological confirmation before definitive therapy. If the colposcopic assessment is normal, the woman should be referred back for annual cytological surveillance until two normal smears are obtained, and then resume routine screening according to the recommendation for the average population.
If the colposcopic assessment is satisfactory and a low-grade lesion is suspected, target biopsy can be performed to confirm this diagnosis. Treatment of histologically confirmed low-grade squamous lesions is not recommended, as such lesions are considered to be an expression of a productive HPV infection.
Histologically confirmed low-grade squamous abnormalities can be safely managed by repeat cytology at 12 and 24 months. If both smears are negative, it is recommended that the woman return to screenings at the intervals recommended for the average woman. If either repeat smear shows possible or definite LSIL, the woman should be advised to continue having annual smears until at least two are negative, at which time she can return to routine screening.
If the colposcopic assessment is unsatisfactory, consideration should be given to repeating the Pap test in 6-12 months (+/-colposcopy). In asymptomatic women and in the absence of any cytologic, colposcopic or histologic suggestion of high-grade disease, further diagnostic procedures, such as cone biopsy or loop excision, are not indicated.
Possible high-grade squamous lesion
The category of possible high-grade squamous lesion is to be used when the reporting pathologist suspects the presence of a high-grade squamous abnormality, such as possible CIN 2, CIN 3 or squamous cell carcinoma (SCC), but the changes are insufficient to justify a confident cytological prediction of a high-grade lesion. It corresponds to the ‘inconclusive possible high-grade squamous abnormality’ category in the previous Australian terminology.
A woman with a Pap test report of possible high-grade squamous lesion should be referred to a gynaecologist for colposcopic assessment and targeted biopsy where indicated.
High-grade squamous intraepithelial lesion
The high-grade squamous intraepithelial lesion (HSIL) category is the morphological correlate of a true preneoplastic change occurring in squamous cells as a result of HPV infection. It is to be used when the pathologist observes changes that would have previously been described as CIN 2 or CIN 3. A woman with a Pap test report of high-grade squamous lesion should be referred to a gynaecologist for colposcopic assessment and targeted biopsy where indicated.
Atypical glandular cells of undetermined significance
These categories encompass those changes in glandular cells that the reporting pathologist believes are outside the scope of a definite reactive process. It has been well documented that productive HPV infection does not exist in glandular cells, and therefore there is no glandular correlate to the low-grade squamous abnormality. Nevertheless, the morphological changes observed in glandular cells encompass a spectrum of changes. These categories should be used when such changes are insufficient to raise the possibility of a neoplasm, such as AIS, but are beyond those accepted as definitely representing a reactive process.
Cells in this category are to be designated as follows:
- Atypical glandular cells when the reporting pathologist is not sure whether the cells are endocervical
- Atypical endocervical cells when the reporting pathologist is confident that the cells are endocervical.
Possible high-grade glandular lesion
This category is to be used when the reporting pathologist suspects the presence of a high-grade glandular abnormality such as possible AIS, possible endocervical adenocarcinoma or possible endometrial adenocarcinoma, but is unable to make a confident prediction. It corresponds to the ‘inconclusive possible high-grade glandular abnormality’ category in the previous Australian terminology.
Adenocarcinoma in situ (AIS)
The endocervical AIS category is self-explanatory. The diagnosis is to be used when the reporting pathologist is confident of the presence of AIS. If invasive carcinoma is not identified at colposcopic assessment, a cone biopsy should be undertaken. Hysterectomy should not be undertaken without prior cone biopsy to exclude invasive carcinoma. The management of women diagnosed with AIS on cone biopsy will be dependent upon the age and fertility requirements of the women and the status of excision margins. Hysterectomy may be recommended for women who have completed childbearing because of the difficulties of reliable cytological follow-up, a high recurrence rate and the reported multifocality of the disease.
An individual management plan is developed considering the referral (and repeat Pap test), HPV status, colposcopic impression and biopsy result. Other considerations include age, fertility issues, associated gynaecological pathology and reliability of returning for follow up.
There are 3 broad categories of treatment: (i) ablative (ii) excisional and (iii) definitive. Ablative methods include cryotherapy, electrocoagulation diathermy and CO2 Laser vaporization. These methods destroy the abnormal cervical epithelium by physical means and no further histology is available. Excisional modalities include the cold knife cone biopsy, Laser cone and the Loop electrosurgical excisional procedures (LEEP). Definitive treatment is hysterectomy
Ablative or physical destructive therapies are not commonly practiced nowadays. The requirements prior to physical destruction are (i) an expert colposcopist has assessed the lesion (ii) a colposcopically directed biopsy has sampled the most abnormal area (iii) the squamo-columnar junction is fully visible (iv) the upper limit of the lesion is seen i.e. the colposcopy is deemed satisfactory. In addition (v) the patient must be assessed as reliable for follow-up for at least one year and (vi) the presence of invasive cancer is thoroughly excluded by cytology, colposcopy and biopsy.
Using monopolar diathermy set at 40-50 watts, the electrode penetrates the cervical stroma and diathermy deployed Whilst having very high cure rates, it also has a very high cervical stenosis rate and is not commonly practiced
Carbon Dioxide Laser
The treatment plan includes a power density of at least 1000 watts/cm2 and using a large spot size of at least 1.5mm and energy output of 25-40 watts. A 750-2000 watts/cm2 laser beam is used to make a circular incision around the transformation zone, extending approximately 3-4 mm beyond the cervical intraepithelial neoplasia. The entire transformation zone is vaporized to a depth of about 8 mm to eradicate any lesion extending into the cervical glands
Excisional treatment is commonly practiced with the LEEP (LOOP or LLETZ) procedures predominating.
Cold Knife Cone
The most common method of evaluation and treatment of adenocarcinoma insitu. The method is quite destructive to the cervix.
Is reliant upon the availability of the Laser machine and superior Laser surgical skill. It is not commonly practiced. Using small spot size and high power, the Laser beam is able to incise tissue rather than ablate.
LEEP Excisional Cone
Is currently the preferred option for excisional treatment for the majority of patients. It is performed with either a 20x8mm or 15x7mm electrode. Ideally a single pass excision is performed but with large and irregular lesions, more than one pass may be required. Excess diathermy artifact should be avoided when using LEEPs in order to allow comprehensive pathological examination, including margin status.
In an older woman, or who has completed her family definitive treatment is an option. Factors to be considered include the coexistence of other gynecological disorders requiring hysterectomy, desire for sterilization, if the patient is considered unreliable for follow up, persistent abnormal smears after local excision or methods of physical destruction and finally unusual technical reasons, such as postmenopausal surprise positive smear with small uterus, where diagnostic conization may be more difficult and less effective than hysterectomy.
A woman previously treated for HSIL requires a colposcopy and cervical cytology at 4-6 months after treatment. Cervical cytology and HPV typing should then be carried out at 12 months after treatment and annually thereafter until the woman has tested negative by both tests on two consecutive occasions. The woman should then be screened according to the recommendation for the average population.
A woman already undergoing annual cytological review for follow-up of a previously treated HSIL, as advised by the previous NHMRC guidelines (1994), may be offered HPV testing as described above. Once she has tested negative by both cytology and HPV typing on two consecutive occasions, she should be screened according to the recommendation for the average population.
Whilst classified as a high grade lesion and treatment recommended in older women, there is increasing evidence that adopting a conservative approach in women under the age of 25 with biopsy proven CIN2 is likely to be safe and would result in the avoidance of a significant number of unnecessary cervical treatments. Approximately 50-60% of CIN 2 will regress over an 18 month period and 20% of women treated for CIN 2 will have either normal or low grade histology on the excisional biopsy. Therefore, observation with colposcopy and cytology at six-month intervals for up to two years is preferable to excisional or ablative therapy for reliable adolescents with biopsy-confirmed CIN 2 as long as colposcopy is satisfactory, and the possibility of occult disease is acknowledged by the patient. Repeat biopsy is indicated if high grade disease persists at 12 months and treatment is indicated if it persists for 24 months.
- Pap Smears after Hysterectomy
Patients who have undergone hysterectomy for benign reasons and have had a normal smear history, do not in the absence of symptoms require further Pap smears. However due to the risk of development of VAIN, performance of a vault smear every 5 years is not unreasonable. Patients who have undergone subtotal hysterectomy will require 2 yearly smears. Patients whose smear history is not known or who has a history of vaginal or cervical dysplasia should have yearly vault smears.
- Abnormal Smear in Pregnancy
The principles and practice of evaluation of smear detected abnormalities is essentially the same as in the non-pregnant patient except that colposcopic evaluation is preferred in order to exclude the possibility of invasive disease. After colposcopy a decision is made whether to defer treatment until after delivery. The decision to perform a cervical biopsy in pregnancy depends upon the experience, expertise and confidence of the colposcopist. Colposcopic evaluation in pregnancy is often quite difficult and should be undertaken by an experienced colposcopist. Definitive treatment of a high-grade lesion, with the exception of invasive cancer, may be deferred safely until after the pregnancy because high grade lesions discovered during pregnancy have a high rate of regression in the postpartum period. This underscores the role for conservative antepartum management followed by careful postpartum evaluation. Furthermore, the morbidity associated with cervical conization during pregnancy is substantial. CIN 2,3 should be monitored during pregnancy with colposcopy (without endocervical curettage); there are no data on which to base a recommendation for the optimal interval, but once each trimester is a reasonable approach. Colposcopy and cervical cytology should be performed 6 to 12 weeks postpartum. Repeat biopsies are indicated only if worsening disease is suspected by cytology or colposcopic appearance, with a diagnostic excisional procedure if invasive disease is suspected and knowledge of the diagnosis will alter management.
- Immunosuppressed women
If an immunosuppressed woman has a screen-detected abnormality she should be referred for colposcopy, even if the lesion is low-grade, as cytological surveillance alone may be inadequate. Assessment and treatment should be by an experienced colposcopist. The whole of the lower genital tract will need evaluation as the same risk factors apply for cervical, vaginal, and vulval and perianal lesions. Treatment of the cervix should be by excisional methods. Follow-up after treatment should include colposcopy as well as cytology. Follow-up should be annual and indefinite.
- Postmenopausal women with normal endometrial cells
Normal endometrial cells occurring in the Pap smear of an asymptomatic postmenopausal woman should not be reported. A symptomatic postmenopausal woman requires investigation irrespective of her Pap test status.
- Women exposed to diethylstilboestrol (DES) in utero
DES-exposed women should be offered annual cytological screening and colposcopic examination of both the cervix and vagina. Screening should begin any time at the woman’s request and continue indefinitely. A balanced perspective should be maintained. DES-exposed women who have a screen-detected abnormality should be managed in a specialist centre by an experienced colposcopist.
The term cervical intraepithelial neoplasia (CIN) denotes all precursors of squamous cervical cancer and embraces a continuous spectrum through CIN I (mild dysplasia); CIN II (moderate dysplasia) and CIN III (severe dysplasia and carcinoma in situ). While the majority of CIN lesions return to normal cytology within short periods of time, the likelihood of a high grade lesion regressing is much less common, with greater propensity to progression to invasive cancer. CIN lesions in most cases occur within the transformation zone, which is usually visible in its entirety by the colposcope.