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10. Management of histologically confirmed high-grade squamous abnormalities
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Treatment of high-grade squamous abnormalities

Treatment of high-grade squamous abnormalities

Treatment of high-grade squamous abnormalities

Clinical question

GUIDELINE UPDATES - This guideline was last updated 7/1/2022

HSIL (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 (TZ) 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 TZ (LLETZ), loop electrosurgical excision procedure (LEEP) or cold-knife cone biopsy are preferred. A comparison of surgical modalities based on randomised trials reported relative equivalence in effectiveness and safety.[18] Hysterectomy 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 LAST, CIN2 is now understood to be a morphological entity without a biological correlate.[20] LAST emphasises that there are two biological states caused by HPV; these are LSIL (productive viral infection) and HSIL (transforming or neoplastic HPV infection). CIN2 lesions have been reported to be histologically heterogeneous, with some cases comparable to CIN3 and others similar to CIN1. 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 LAST 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 LAST 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 LAST project included a comprehensive review of biomarker data, and this underpinned the LAST 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 LAST will help to clarify the diagnosis of CIN 2 cases and improve interobserver 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 TZ. No randomised or pseudorandomised studies were found that used p16 to stratify management in histologically confirmed CIN2. Details of the LAST 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 16/18 has also been reported.[35][36] 

Until recently, CIN2 was regarded as an intermediate biological state between CIN1 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 HPV: LSIL (productive viral infection) and HSIL (transforming HPV infection). CIN2 is amorphological entity without a biological correlate. Biologically it was a mixture of LSIL and HSIL. The Lower Anogenital Squamous Terminology (LAST) project in 2011-2012 (see also Terminology section earlier) comprehensively addressed this area of diagnostic difficulty and made evidence-based recommendations.[20]LAST 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 (LAST) 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 LAST 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 LAST recommendations. 

The draft recommendations were made available for public consultation and finalized in 2012 at the LAST 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*
REC10.2: Treatment for HSIL (CIN2)
Women with a histological diagnosis of HSIL (CIN2) should be treated in order to reduce the risk of developing invasive cervical carcinoma.
Practice point
REC10.3: p16 should be used to clarify diagnosis of HSIL (CIN2)
The use of p16 immunohistochemistry is recommended to stratify the management of HSIL (CIN2) into immediate treatment or a period of observation.
Practice point

REC10.4: HSIL (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 HSIL (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 LBC prediction of pLSIL/LSIL
  • women with focal minor changes on colposcopy and HSIL (CIN2) on histology
  • women recently treated for HSIL (CIN2).

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HSIL (CIN3)

HSIL (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 HSIL (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 HSIL (CIN3) lesions progress to invasive cancer, based on current evidence, HSIL (CIN3) lesions need to be treated to reduce the risk of further progression to invasive cancer.

Recommendation

Consensus-based recommendation*
REC10.5: Treatment of HSIL (CIN3)
Women with a histological diagnosis of HSIL (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*
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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Author(s):

References

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  32. Gurrola-Díaz CM, Suárez-Rincón AE, Vázquez-Camacho G, Buonocunto-Vázquez G, Rosales-Quintana S, Wentzensen N, et al. P16INK4a immunohistochemistry improves the reproducibility of the histological diagnosis of cervical intraepithelial neoplasia in cone biopsies. Gynecol Oncol 2008 Oct;111(1):120-4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18692882.
  33. Klaes R, Benner A, Friedrich T, Ridder R, Herrington S, Jenkins D, et al. p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia. Am J Surg Pathol 2002 Nov;26(11):1389-99 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12409715.
  34. Reuschenbach M, Wentzensen N, Dijkstra MG, von Knebel Doeberitz M, Arbyn M. p16INK4a immunohistochemistry in cervical biopsy specimens: A systematic review and meta-analysis of the interobserver agreement. Am J Clin Pathol 2014 Dec;142(6):767-72 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25389329.
  35. Benevolo M, Mottolese M, Marandino F, Vocaturo G, Sindico R, Piperno G, et al. Immunohistochemical expression of p16(INK4a) is predictive of HR-HPV infection in cervical low-grade lesions. Mod Pathol 2006 Mar;19(3):384-91 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16415792.
  36. Benevolo M, Terrenato I, Mottolese M, Marandino F, Muti P, Carosi M, et al. Comparative evaluation of nm23 and p16 expression as biomarkers of high-risk human papillomavirus infection and cervical intraepithelial neoplasia 2(+) lesions of the uterine cervix. Histopathology 2010 Oct;57(4):580-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20955383.
  37. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet 2007 Sep 8;370(9590):890-907 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17826171.
  38. ↑ Vink MA, Bogaards JA, van Kemenade FJ, de Melker HE, Meijer CJ, Berkhof J. Clinical progression of high-grade cervical intraepithelial neoplasia: estimating the time to preclinical cervical cancer from doubly censored national registry data. Am J Epidemiol 2013 Oct 1;178(7):1161-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23897645.
  39. Insinga RP, Dasbach EJ, Elbasha EH. Epidemiologic natural history and clinical management of Human Papillomavirus (HPV) Disease: a critical and systematic review of the literature in the development of an HPV dynamic transmission model. BMC Infect Dis 2009 Jul 29;9:119 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19640281.
  40. Peto J, Gilham C, Fletcher O, Matthews FE. The cervical cancer epidemic that screening has prevented in the UK. Lancet 2004 Jul;364(9430):249-56 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15262102.

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