Treatment of HSIL

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HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2/3)

Not all CIN2 or CIN3 lesions will progress to cervical cancer.Based on studies on the natural history of cervical infections with oncogenic HPV types, it has been estimated that 30–50% of untreated CIN2 and approximately 30% of CIN3 regress spontaneously, and that approximately 5% of CIN2 and 14–31% of CIN3 progress to invasive cancer, although differing follow-up times for various studies need to be taken into account in interpreting these findings.[1][2][3][4][5][6] A young age (< 25 years) and pregnancy are two factors associated with higher regression rates of untreated high-grade abnormalities.[7][8][9][10][11][12][13][14][15][16][17]

For the adequate treatment of CIN2 or CIN3, the entire lesion and transformation zone (TZTransformation zoneThis region of the cervix where the columnar epithelium has been replaced and/or is being replaced by the new metaplastic squamous epithelium is referred to as the transformation zone. It corresponds to the area of cervix bound by the original squamocolumnar junction at the distal end and proximally by the furthest extent that squamous metaplasia has occurred as defined by the new squamocolumnar junction. In premenopausal women, the transformation zone is fully located on the ectocervix. After menopause through old age, the cervix shrinks with the decreasing levels of estrogen. Consequently, the transformation zone may move partially, and later fully, into the cervical canal.The transformation zone may be described as normal when it is composed of immature and/or mature squamous metaplasia along with intervening areas or islands of columnar epithelium, with no signs of cervical carcinogenesis. It is termed an abnormal or atypical transformation zone (ATZ) when evidence of cervical carcinogenesis such as dysplastic change is observed in the transformation zone. Identifying the transformation zone is of great importance in colposcopy, as almost all manifestations of cervical carcinogenesis occur in this zone.) must be destroyed or excised. This can be achieved by ablative or excisional treatments (see Chapter 7. Colposcopy). Ablative methods such as CO2 laser ablation are effective but infrequently used in modern practice. Excisional methods such a large loop excision of the TZTransformation zoneThis region of the cervix where the columnar epithelium has been replaced and/or is being replaced by the new metaplastic squamous epithelium is referred to as the transformation zone. It corresponds to the area of cervix bound by the original squamocolumnar junction at the distal end and proximally by the furthest extent that squamous metaplasia has occurred as defined by the new squamocolumnar junction. In premenopausal women, the transformation zone is fully located on the ectocervix. After menopause through old age, the cervix shrinks with the decreasing levels of estrogen. Consequently, the transformation zone may move partially, and later fully, into the cervical canal.The transformation zone may be described as normal when it is composed of immature and/or mature squamous metaplasia along with intervening areas or islands of columnar epithelium, with no signs of cervical carcinogenesis. It is termed an abnormal or atypical transformation zone (ATZ) when evidence of cervical carcinogenesis such as dysplastic change is observed in the transformation zone. Identifying the transformation zone is of great importance in colposcopy, as almost all manifestations of cervical carcinogenesis occur in this zone. (LLETZLarge loop excision of the transformation zone), loop electrosurgical excision procedure (LEEPLoop electrical excision procedureLoop electrical excision procedure) or cold-knife cone biopsy are preferred. A comparison of surgical modalities based on randomised trials reported relative equivalence in effectiveness and safety.[18] HysterectomyHysterectomy (total) is the complete surgical removal of the uterus including the cervix. as a primary treatment of CIN2 or CIN3 may also be an option for women who are not considering a future pregnancy and have an associated benign gynaecological disease.

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CIN2

Background

CIN2 was previously thought to be an intermediate state between a HPV infection and precancer.[19][20] However, following LASTLower Anogenital Squamous Terminology, CIN2 is now understood to be a morphological entity without a biological correlate.[20] LASTLower Anogenital Squamous Terminology emphasises that there are two biological states caused by HPVHuman papillomavirus; these are LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/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. (productive viral infection) and HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (transforming or neoplastic HPV infection). CIN2 lesions have been reported to be histologically heterogeneous, with some cases comparable to CIN3 and others similar to CIN1mild dysplasia. The reproducibility of CIN2 diagnoses has historically been poor and low inter-observer agreement has been reported.[21][22][23] This is the basis for the LASTLower Anogenital Squamous Terminology recommendation to use p16 positivity in lesions which would be called CIN2 on H&E histopathology, in order to confirm the presence of active oncogenic HPV DNA in these lesions. Two papers published prior to the 2012 report from the LASTLower Anogenital Squamous Terminology project, demonstrate that the risk of persistence of CIN2 lesions is influenced by the oncogenic HPV type and the persistence of the HPV infection, with lesions caused by HPV type 16 less likely to regress than lesions caused by other oncogenic HPV types or non-oncogenic types.[14][3]

A number of molecular markers, of which p16INK4a (p16) has been the most widely studied, have been investigated as an adjunct to cytology and histopathology to help resolve the diagnosis of ambiguous squamous intraepithelial lesions.[20] The LASTLower Anogenital Squamous Terminology project included a comprehensive review of biomarker data, and this underpinned the LASTLower Anogenital Squamous Terminology recommendations.[20]

The expression of p16, a cell cycle regulatory protein, is highly increased in tissues that overexpress the E7 HPV oncoprotein and reflects a transformed oncogenic HPV infection with associated pre-neoplastic epithelial change. Immunostaining for p16 has been investigated in cervical cytology (for example, in identifying women with minor cervical lesions who require further investigation following a Pap smear).[24] Its use is established in histopathology, as p16 overexpression has been reported in a high percentage of high-grade precursor squamous lesions and invasive cancers.[25][26][27] The use of p16 immunohistochemistry in histopathology as recommended by LASTLower Anogenital Squamous Terminology will help to clarify the diagnosis of CIN 2Moderate dysplasia cases and improve inter-observer variability.[28]

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Evidence

Systematic review evidence

A systematic review was performed to identify studies evaluating the safety and effectiveness of using p16 immunohistochemistry to stratify management of women with histologically confirmed CIN2 (immediate treatment or observation) compared with treating all CIN2 with excision of the TZTransformation zoneThis region of the cervix where the columnar epithelium has been replaced and/or is being replaced by the new metaplastic squamous epithelium is referred to as the transformation zone. It corresponds to the area of cervix bound by the original squamocolumnar junction at the distal end and proximally by the furthest extent that squamous metaplasia has occurred as defined by the new squamocolumnar junction. In premenopausal women, the transformation zone is fully located on the ectocervix. After menopause through old age, the cervix shrinks with the decreasing levels of estrogen. Consequently, the transformation zone may move partially, and later fully, into the cervical canal.The transformation zone may be described as normal when it is composed of immature and/or mature squamous metaplasia along with intervening areas or islands of columnar epithelium, with no signs of cervical carcinogenesis. It is termed an abnormal or atypical transformation zone (ATZ) when evidence of cervical carcinogenesis such as dysplastic change is observed in the transformation zone. Identifying the transformation zone is of great importance in colposcopy, as almost all manifestations of cervical carcinogenesis occur in this zone.. No randomised or pseudorandomised studies were found that used p16 to stratify management in histologically confirmed CIN2. Details of the LASTLower Anogenital Squamous Terminology project and recommendations are found in the Literature Review evidence section below.

Literature review evidence

In the absence of any direct evidence from the systematic review, a general review of the literature was performed to ascertain the effectiveness of p16 immunohistochemistry in clarifying a diagnosis of CIN2. A systematic review and meta-analysis of five studies[29][30][31][32][33] reported a significantly higher agreement between pathologists’ diagnosis of CIN2+ from cervical biopsy specimens based on haematoxylin and eosin (H&E) morphology and p16 immunohistochemistry combined (k=0.73; 95%CI: 0.67–0.79) when compared with H&E morphology alone (k=0.41; 95%CI: 0.17-0.65).[34] A strong association between diffuse, intense staining of cervical specimens with p16 and positivity for oncogenic HPV infections, particularly HPV 16/18Only HPV types 16 and or 18 detected using routine HPV screening tests in laboratory. has also been reported.[35][36]

Until recently, CIN2 was regarded as an intermediate biological state between CIN1mild dysplasia and CIN3. With our greater understanding of the biology and natural history of HPV infection in anogenital sites, we now know that there are only 2 biological states caused by HPVHuman papillomavirus: LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/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. (productive viral infection) and HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (transforming HPV infection). CIN2 is amorphological entity without a biological correlate. Biologically it was a mixture of LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/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. and HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology).. The Lower Anogenital Squamous Terminology (LASTLower Anogenital Squamous Terminology) project in 2011-2012 (see also Terminology section earlier) comprehensively addressed this area of diagnostic difficulty and made evidence-based recommendations.[20]LASTLower Anogenital Squamous Terminology recommended that ‘If the pathologist is entertaining an H&E morphologic interpretation of –IN 2 (under the old terminology, which is a biologically equivocal lesion falling between the morphologic changes of HPV infection (low-grade lesion) and precancer), p16 IHC is recommended to help clarify the situation. Strong and diffuse block positive p16 results support a categorization of precancer. Negative or non-block positive staining strongly favors an interpretation of low-grade disease or a non-HPV associated pathology.’

The Lower Anogenital Squamous Terminology (LASTLower Anogenital Squamous Terminology) Standardization project was undertaken with the objective of developing evidence-based recommendations to unify and standardize the terminology used to classify HPV-associated lesions of the anogenital tract. The LASTLower Anogenital Squamous Terminology recommendations were made using a rigorous process which included conducting systematic reviews and involved a consensus process which was led by a steering committee and involved five working groups which consisted of experts in the field. One working group was responsible for framing the development of historical terminology applied to HPV-associated squamous lesions of the lower anogenital tract and the impact of terminology on clinical management. Three of the working groups performed the systematic literature reviews and developed the draft recommendations. The fifth working group will lead the ongoing implementation of the LASTLower Anogenital Squamous Terminology recommendations.

The draft recommendations were made available for public consultation and finalized in 2012 at the LASTLower Anogenital Squamous Terminology Consensus Conference. The project produced recommendations which help address the issues of variability and reproducibility, often found when reporting HPV-associated neoplasia. The final recommendations specify the biologically applicable histopathologic terminology for HPV- associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites.[20] It also specifies the use of biomarkers in resolving histopathologic interpretations and improving diagnostic accuracy.

In contrast to the use of p16 immunostaining in histological specimens, which has a strong evidence base and has been endorsed by WHO, the use of immunostaining of cervical cytology specimens remains experimental. There are no current guidelines endorsing its use in cytology preparations.

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Recommendations

Consensus-based recommendation*Question mark transparent.png

REC10.2: Treatment for HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2)
Women with a histological diagnosis of HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2) should be treated in order to reduce the risk of developing invasive cervical carcinoma.

Practice pointQuestion mark transparent.png

REC10.3: p16 should be used to clarify diagnosis of HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2)
The use of p16 immunohistochemistry is recommended to stratify the management of HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2) into immediate treatment or a period of observation.

Practice pointQuestion mark transparent.png

REC10.4: HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2) and observation
In some circumstances, it may be acceptable to offer a period of observation (generally 6–12 months) to women who have a histological diagnosis of HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2), and this would usually be supervised by an experienced colposcopist or at a tertiary centre. Observation may be considered for:

  • women who have not completed childbearing
  • women with discordant histology and LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of pLSILPossible LSIL in the Australian Modified Bethesda System is broadly equivalent to ASCUS in US Bethesda system./LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/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.
  • women with focal minor changes on colposcopy and HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2) on histology
  • women recently treated for HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2).
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HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN3)

HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN3) involves the presence of dysplastic cells in greater than two thirds of the entire thickness of the epithelium but with no signs of invasion into the stroma. Almost all HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN3) lesions can be attributed to persistent infection by high risk HPV types.[37] Based on the controversial ‘unfortunate experiment’ conducted in New Zealand, involving the long-term follow-up of a cohort of women diagnosed with CIN3 from 1955 to 1976, the cumulative risk of invasive cancer over 30 years was 31% in women who only had diagnostic biopsies and 50% in women with persistent CIN3 within 2 years after their biopsy, as opposed to 0.7% in women who were treated conventionally.[4] CIN3 is the primary endpoint in longitudinal studies of the natural history of the HPV infection pathway, therefore the only other available data on the time period from CIN3 to invasive cancer comes from statistical modelling. Such lifetime risk estimates of cervical cancer are in line with the New Zealand study data.[38][39][40] Although not all HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN3) lesions progress to invasive cancer, based on current evidence, HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN3) lesions need to be treated to reduce the risk of further progression to invasive cancer.

Recommendation

Consensus-based recommendation*Question mark transparent.png

REC10.5: Treatment of HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN3)
Women with a histological diagnosis of HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN3) should be treated in order to reduce the risk of developing invasive cervical carcinoma.

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Invasive carcinoma

When invasive or superficially invasive squamous cell carcinoma is confirmed by histopathology, prompt referral to a gynaecological oncologist is required. Factors that will inform further management will include stage of disease, age, medical history and general health.

Recommendation

Consensus-based recommendation*Question mark transparent.png

REC10.6: Referral of women with invasive disease
A woman with a histologically confirmed diagnosis of invasive or superficially invasive (squamous cell carcinoma) should be referred to a gynaecological oncologist or a gynaecological cancer centre for multidisciplinary team review.

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References

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Appendices

Jutta's magnifying glass icon.pngPICO questions 6 View Systematic review report q 6View Systematic review report q 6 View General evidence summary table q 6View General evidence summary table q 6
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