Investigation of cytological glandular abnormalities

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Contents

Background

Atypical endocervical/glandular cells of undetermined significance

The clinical significance of atypical glandular or endocervical cells of undetermined significance cannot be clearly defined.[1] The cytological finding of atypical endocervical/glandular cells is poorly reproducible.[2] It predicts increased risk but cannot be considered a specific cancer precursor.[3]

For conventional cytology within the pre-renewal NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears., 24.2% of cases of atypical endocervical cells of undetermined significance predicted by cytology in 2012 (HPV status unknown) that were biopsied within 6 months were histologically confirmed as AISAdenocarcinoma in situ and 6.2% of those biopsied were confirmed as adenocarcinoma.[1] Among all cases of atypical endocervical cells of undetermined significance predicted by cytology in 2012, including cases where no histology was performed within 6 months, AISAdenocarcinoma in situ was confirmed in 7.0% and adenocarcinoma in 1.8%.[1]

In the Pap test-based screening era, the optimal management for women with atypical glandular or endocervical cells of undetermined significance has been uncertain.[4] Guidelines for the pre-renewal NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears. recommended colposcopy as a mandatory component of the initial investigation for women with atypical glandular or endocervical cells of undetermined significance reported on conventional cytology following a screening Pap test.[4]

With the transition to HPV-based cervical screening, it is necessary to define the roles of repeated HPV testing and liquid-based cytology in monitoring risk in women with a cytology finding of endocervical cells of undetermined significance or atypical glandular cells of undetermined significance.

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Possible high-grade glandular lesion

Guidelines for the pre-renewal NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears. recommended that women with a Pap test result of possible high-grade glandular lesion should be referred to gynaecologist with expertise in the colposcopic evaluation of suspected malignancies or a gynaecological oncologist.[4]

For conventional cytology within the pre-renewal NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears., 44.7% of cases of possible high-grade endocervical glandular lesions predicted by cytology in 2012 (HPV status unknown) were histologically confirmed as AISAdenocarcinoma in situ and 11.4% were confirmed as adenocarcinoma.[1] Among all cases of possible high-grade endocervical glandular lesions predicted by cytology in 2012, including cases where no histology was performed within 6 months, AISAdenocarcinoma in situ was confirmed in 21.5% and adenocarcinoma in 5.5%.[1]
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AISAdenocarcinoma in situ

AISAdenocarcinoma in situ is considered to be the precursor to invasive endocervical adenocarcinoma.[3] When well-defined cytological criteria are used, this category correlates well with histological outcome.[3]

For conventional cytology within the pre-renewal NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears., 63.3% of cases of AISAdenocarcinoma in situ predicted by cytology in 2012 (HPV status unknown) were histologically confirmed as AISAdenocarcinoma in situ and 26.7% were confirmed as adenocarcinoma.[1] Among all cases of AISAdenocarcinoma in situ predicted by cytology in 2012, including cases where no histology was performed within 6 months, AISAdenocarcinoma in situ was confirmed in 57.1% and adenocarcinoma in 24.1%.[1]

Guidelines for the pre-renewal NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears. recommended that women in whom AISAdenocarcinoma in situ was reported on conventional cytology following a screening Pap test should be referred to a gynaecologist with expertise in the colposcopic evaluation of suspected malignancies or a gynaecological oncologist, and if invasive carcinoma is not identified at colposcopic assessment, a cone biopsy should be undertaken.[4]

The investigation and management of a cytological prediction of AISAdenocarcinoma in situ is controversial. AISAdenocarcinoma in situ lesions can present with only minimal changes on colposcopy and can extend into the endocervical canal. As a result the full extent of AISAdenocarcinoma in situ lesions may not be evident on colposcopic examination which complicates the determination of excisional approaches.[2] As AISAdenocarcinoma in situ lesions can be multifocal, the finding of negative margins for AISAdenocarcinoma in situ on an excision specimen does not reliably indicate that the lesion has been completely excised.[2] Invasive adenocarcinoma cannot be excluded without a diagnostic excisional procedure.[2]

The role of excision modalities other than cold-knife cone biopsy in the investigation of cytology-detected glandular abnormalities has been debated. Submission of single-specimen biopsies with minimal thermal damage or disruption of resection margins permits the pathologist to make an accurate assessment. The pre-renewal NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears. guideline recommended that cold-knife cone biopsy should be considered the ‘gold standard’ for the assessment of glandular lesions, and specifically recommended against the use of large loop excision of the transformation zone (LLETZLarge loop excision of the transformation zone).[4] Current American Society for ColposcopyThe examination of the cervix and vagina with a magnifying instrument called a colposcope, to check for abnormalities. and Cervical Pathology (ASCCPAustralian Society for Colposcopy and Cervical Pathology) consensus guidelines recommend that any modality can be used for diagnostic excision of the 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.) in the treatment of AISAdenocarcinoma in situ, provided that the specimen remains intact with interpretable margins and there is no fragmentation, including fragmentation resulting from ‘top-hat’ endocervical excisions (see Modalities of treatment in Chapter 7. ColposcopyThe examination of the cervix and vagina with a magnifying instrument called a colposcope, to check for abnormalities.).[2]

Endocervical sampling at the time of an excisional procedure predicts residual disease in women with AISAdenocarcinoma in situ.[2]

In women who have undergone excisional treatment for AISAdenocarcinoma in situ, a HPV test finding of oncogenic HPV not detectedOncogenic HPV types not detected by the HPV testing platform. predicts low risk of persistent or recurrent disease.[2] Conversely, a positive oncogenic HPV (any type)Women with a positive HPV test result of any oncogenic HPV types detected using routine HPV testing in a pathology laboratory. test result at any time during follow-up was reported as the most significant independent predictor of progressive disease in women with AISAdenocarcinoma in situ undergoing conservative management.[5]
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Adenocarcinoma

Guidelines for the pre-renewal NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears. recommended that women with a cytological prediction of adenocarcinoma of either endocervical, extrauterine or unspecified origin, reported on conventional cytology following a screening Pap test, should be referred to a gynaecological oncologist or a gynaecological oncology unit.[4]
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Evidence

Immediate excision versus surveillance following a normal (negative) colposcopy for women with a positive oncogenic HPV test result andreferral cytology predicting a glandular lesion less than AISAdenocarcinoma in situ

Systematic review evidence

Systematic reviews were conducted to answer the following questions:

  • For women who have a positive oncogenic HPV (any type)Women with a positive HPV test result of any oncogenic HPV types detected using routine HPV testing in a pathology laboratory. test result with referral cytological prediction of atypical endocervical cells of undetermined significance (confirmed on review) and negative colposcopy, what is the safety and effectiveness of repeating HPV and cytology testing, compared with diagnostic excisional cone biopsy)?
  • For women who have a positive oncogenic HPV (any type)Women with a positive HPV test result of any oncogenic HPV types detected using routine HPV testing in a pathology laboratory. test result with referral cytological prediction of atypical glandular cells of undetermined significance or possible high grade glandular lesion (confirmed on review) and negative colposcopy, what is the safety and effectiveness of repeating HPV and cytology testing, compared with treatment (excisional cone biopsy)?

The systematic literature searches identified no relevant randomised or pseudorandomised controlled trials comparing surveillance with excisional cone biopsy following a normal (negative) colposcopy for HPV-positiveWomen with a positive HPV test result of any oncogenic HPV types detected using HPV testing platforms in a pathology laboratory. women with cytology suggestive of a glandular lesion less than AISAdenocarcinoma in situ. The search strategies and inclusion and exclusion criteria used are described in detail in the Technical report.

General literature review evidence

In the absence of any direct evidence from the systematic review, a general review of the literature was performed on the management of HPV-positiveWomen with a positive HPV test result of any oncogenic HPV types detected using HPV testing platforms in a pathology laboratory. women with a confirmed cytological finding of atypical endocervical cells of undetermined significance, atypical glandular cells of undetermined significance, or possible high-grade glandular lesion, and normal (negative) colposcopy to inform consensus-based recommendations.

For women with any glandular cytology less that AISAdenocarcinoma in situ and a normal (negative) colposcopy:

  • AISAdenocarcinoma in situ or CIN 2Moderate dysplasia+ was diagnosed in 15% of 27 women in a cohort with a cytological finding (Bethesda 2001 criteria) of atypical glandular cells (endometrial or endocervical, not otherwise specified or ‘favor neoplastic’) with a normal (negative) colposcopy followed by biopsy or cytological follow-up at 6 months.[6]
  • In contrast, in a cohort of 15 women with ‘borderline glandular cytology’ and a normal (negative) colposcopy none had CIN 2Moderate dysplasia+ on biopsy or abnormal cytology on follow-up at 6, 12, 18 and 24 months.[7]

For women with cytology predicting a possible high grade glandular lesion and a normal (negative colposcopy):

  • In a series of 27 endocervical dyskaryotic smears (considered by the investigators to be equivalent to ‘atypical glandular cells endocervical – favor neoplastic’), followed by a normal (negative) colposcopy, 85.2% had a cervical lesion (type not described) on either LLETZLarge loop excision of the transformation zone, cervical punch biopsy or laser cone biopsy.[8]

International (US, Canadian and European) guidelines recommend varying degrees of surveillance following a negative colposcopy for the management of ‘atypical glandular cells - not otherwise specified’ (or equivalent).[2][9][10] US and Canadian guidelines recommend diagnostic 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. /cone biopsy following a negative colposcopy for the management of women with ‘atypical glandular cells - favor neoplasia’.[2][9]

A summary of the literature considered can be found in the Technical report.

For women with a positive oncogenic HPV test result with atypical glandular/endocervical cells and a normal (negative) colposcopy, the risk of CIN 2Moderate dysplasia+ disease is unclear. The evidence is inconsistent and is derived from small cohorts that may have included women with possible high-grade glandular lesions and that did not consider HPV status. The difficulties associated with colposcopic prediction of glandular lesions, the high rates of CIN 2Moderate dysplasia+ associated with atypical glandular/endocervical cells in Australia,[1] and the high risk associated with atypical glandular cells in the presence of a positive oncogenic HPV test result, support a recommendation for close follow-up surveillance using a combination of oncogenic HPV testing and LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. (co-testingHPV test and LBC both requested and performed on a cervical sample.). A negative co-testHPV test and LBC both requested and performed on a cervical sample. is defined as a test in which both oncogenic HPV is not detected and LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. is reported negative.

For women with high-grade glandular abnormalities, the evidence strongly supports the use of diagnostic 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. for these women. In the pre-renewal NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears., a cytology report predicting a possible high-grade glandular abnormality was associated with a substantial risk of underlying AISAdenocarcinoma in situ (44.7% of cytology biopsied within 6 months; 21.5% of all cytology) and invasive cancer (11.4% of cytology biopsied within 6 months; 5.5% of all cytology).[1]
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Cold-knife cone biopsy versus other excisional modalities

Systematic literature review evidence

A systematic review was conducted to assess the safety and effectiveness of excision modalities in women with a positive oncogenic HPV test result with a cytological prediction of possible high-grade glandular or definite high-grade glandular lesion (AISAdenocarcinoma in situ), or histologically-confirmed AISAdenocarcinoma in situ. The systematic review compared cold-knife cone biopsy with diathermy excision procedures (loop electrosurgical excision procedure [LEEPLoop electrical excision procedureLoop electrical excision procedure], LLETZLarge loop excision of the transformation zone), Fischer coneThe Fischer cone is a conisation specimen obtained by using a Fischer cone biopsy excisor, and uses similar electrosurgical technology as used in loop excision procedures., laser cone, straight wire 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. (SWETZStraight wire excision of the transformation zone) or needle 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. (NETZNeedle Excision of the Transformation Zone).

The systematic literature searches identified no relevant randomised or pseudorandomised controlled trials addressing this question in women with a positive HPV test result. The search strategies and inclusion and exclusion criteria are described in detail in the Technical report.

General literature review evidence

In the absence of any direct evidence from the systematic review, a general review of the literature comparing excisional modalities for women with a cytological prediction of possible high-grade glandular or definite high-grade (AISAdenocarcinoma in situ) glandular lesion, or histologically-confirmed AISAdenocarcinoma in situ (irrespective of HPV status) was undertaken to inform consensus-based recommendations.

Generally, positive or close margins were associated with an increased risk of disease persistence and recurrence and were more likely with LLETZLarge loop excision of the transformation zone.[11][12][13][14][15]

A 2014 systematic review[15] using pooled data from cohort and case series studies found that positive margins were associated with a higher risk of residual and recurrent disease, and that higher rates of incomplete excision were associated with LLETZLarge loop excision of the transformation zone (51%) than with cold-knife cone biopsy (30%) or laser cone (28%). This review reported rates of recurrence of AISAdenocarcinoma in situ ranging from 9% to 29% after LLETZLarge loop excision of the transformation zone and from 6% to 11% after cold-knife cone biopsy and concluded that the safety of LLETZLarge loop excision of the transformation zone was comparable to that of cold-knife cone biopsy when negative margins were achieved.[15]
In Australia

The findings included two Australian studies:

  • A retrospective population based cohort study of 338 women (Cervical Screening RegisterA database of identifiable persons containing defined demographic and health information, established for a specific purpose. In the case of cervical screening or other cancer screening registers, the purpose includes inviting eligible persons for screening, sending reminders when they are overdue for screening, follow up of abnormalities, statistical reporting and research. of WA) Munro 2015[11] reported that after adjusting for margin status, no significant differences in cancer outcomes between women with AISAdenocarcinoma in situ who underwent LEEPLoop electrical excision procedureLoop electrical excision procedure or cold-knife cone biopsy after a median follow-up of 3.6 years. In this study LEEPLoop electrical excision procedureLoop electrical excision procedure was associated with a greater likelihood of more than one surgical specimen being excised during the procedure compared to cold-knife cone biopsy. The authors noted the need for prospective studies to confirm these findings.
  • A retrospective cohort study based on review of hospital records (Royal Prince Alfred Hospital, Sydney)[16] reported no significant differences in cancer outcomes after 9–10 years of post-treatment surveillance between women with AISAdenocarcinoma in situ who underwent laser cone or cold-knife biopsy.

This body of evidence should be interpreted with caution: at best, it is based on small retrospective cohort studies in which the decision to perform a particular procedure was likely based on the clinical judgement or preference of the treating physician, and the possible inclusion of procedures undertaken for diagnostic rather than therapeutic reasons – a scenario in which positive surgical margins are not a consideration. On the basis of this evidence, it remains unclear as to whether any electrosurgical techniques are as effective and safe as cold-knife cone biopsy. Randomised controlled trials are required to provide a definitive answer.

A summary of the literature considered can be found in the Technical report.

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Recommendations

Atypical glandular/endocervical cells of undetermined significance recommendations

Flowchart 11.1. Management of LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. predicting atypical glandular/endocervical cells of undetermined significance

Mx LBC predicting atypical glandular endo of u.significance.PNG








Consensus-based recommendation*Question mark transparent.png

REC11.1: ColposcopyThe examination of the cervix and vagina with a magnifying instrument called a colposcope, to check for abnormalities. referral for atypical glandular/endocervical cells
Women who have a positive oncogenic HPV (any type)Women with a positive HPV test result of any oncogenic HPV types detected using routine HPV testing in a pathology laboratory. test result with a LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. report of atypical glandular/endocervical cells of undetermined significance should be referred to a gynaecologist with expertise in the colposcopic evaluation of suspected malignancies or a gynaecological oncologist.

Consensus-based recommendation*Question mark transparent.png

REC11.2: Follow-up after normal colposcopy and LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of atypical glandular/endocervical cells
Women who have a positive oncogenic HPV test result (any type) with a LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of atypical glandular/endocervical cells of undetermined significance and normal colposcopy can be offered repeat co-testingHPV test and LBC both requested and performed on a cervical sample. (HPV and LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory.) at 6–12 months:

  • If the follow-up co-testHPV test and LBC both requested and performed on a cervical sample. is negative, co-testingHPV test and LBC both requested and performed on a cervical sample. should be repeated annually until the woman has two consecutive negative co-tests, after which she can return to 5-yearly screening.
  • If there is either a positive oncogenic HPV (any type)Women with a positive HPV test result of any oncogenic HPV types detected using routine HPV testing in a pathology laboratory. test result or an abnormal LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. (any report other than negative), the woman should be referred for colposcopic assessment, and diagnostic 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. should be considered.
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REC11.3: Exclusion of upper genital tract disease before diagnostic excision
For women who have a positive oncogenic HPV test result (any type) and who have atypical glandular/endocervical cells of undetermined significance on cytology, investigation of the upper genital tract (endometrium, fallopian tube or ovary) using endometrial sampling and/or pelvic ultrasound should be considered, before diagnostic 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. is performed or the woman is advised to return for colposcopy and further tests in 6–12 months, in these groups of women:

  • women aged over 45 years
  • women aged over 35 years with a BMI greater than 30
  • women diagnosed with polycystic ovarian syndrome
  • women with abnormal vaginal bleeding.
Practice pointQuestion mark transparent.png

REC11.4: Role of immediate diagnostic excision of 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. versus observation
Immediate diagnostic 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. can be considered for women with atypical glandular/endocervical cells of undetermined significance if they prefer not to take a conservative observational approach. This might apply to:

  • women aged over 45 years
  • women who have completed childbearing
  • women who are particularly anxious about their cancer risk.

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Possible high-grade glandular lesion recommendations

Flowchart 11.2. Management of LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of a possible high grade glandular lesion

Mx LBC predicting a possible HGG lesion.PNG








Consensus-based recommendationQuestion mark transparent.png

REC11.5: ColposcopyThe examination of the cervix and vagina with a magnifying instrument called a colposcope, to check for abnormalities. for possible high-grade glandular lesions
Women who have a positive oncogenic HPV (any type)Women with a positive HPV test result of any oncogenic HPV types detected using routine HPV testing in a pathology laboratory. test result with a LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of possible high-grade glandular lesion should be referred to a gynaecologist with expertise in the colposcopic evaluation of suspected malignancies or a gynaecological oncologist.

Diagnostic excision of the endocervical 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. should be performed in most cases.

Practice pointQuestion mark transparent.png

REC11.6: Women who decline treatment for possible high-grade glandular lesions
Women with a LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of possible high-grade glandular lesion who decline the recommended excision should be offered surveillance with co-testingHPV test and LBC both requested and performed on a cervical sample. (HPV and LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory.) and colposcopy in 6 months.

  • If in 6 months the woman has a positive result, she should be encouraged to have a diagnostic 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..
  • It is important that the woman understands the potential risk of underlying disease (21.5% risk of AISAdenocarcinoma in situ and 5.5% risk of invasive cancer).

See Excision of the endocervical transformation zone.

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Endocervical adenocarcinoma in situ (AISAdenocarcinoma in situ) recommendations

Flowchart 11.3. Management of LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of high grade glandular lesion (AISAdenocarcinoma in situ)

Mx of LBC predicting a HGG lesion (AIS).PNG








Consensus-based recommendation*Question mark transparent.png

REC11.7: ColposcopyThe examination of the cervix and vagina with a magnifying instrument called a colposcope, to check for abnormalities. referral for AISAdenocarcinoma in situ
Women with a LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of AISAdenocarcinoma in situ should be referred to a gynaecologist with expertise in the colposcopic evaluation of suspected malignancies or to a gynaecological oncologist.

Diagnostic excision of the endocervical 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. should be performed.

See Follow-up after excisional treatment for AIS

See Excision of the endocervical transformation zone.

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Adenocarcinoma recommendation

Consensus-based recommendation*Question mark transparent.png

REC11.8: Referral to gynaecological oncologist for LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of invasive disease
Women who have a positive oncogenic HPV (any type)Women with a positive HPV test result of any oncogenic HPV types detected using routine HPV testing in a pathology laboratory. test result with a LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of invasive adenocarcinoma should be referred to a gynaecological oncologist or a gynaecological oncology centre for urgent evaluation, ideally within 2 weeks.

Table 11.1. Roles of investigational modalities in the assessment of LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of a glandular lesion

Cytolog ColposcopyThe examination of the cervix and vagina with a magnifying instrument called a colposcope, to check for abnormalities. Target biopsy Diagnostic excision of the transformation zone Endocervical sampling
Atypical endocervical/ glandular cells of undetermined significance Indicated Indicated if visible lesion at colposcopy Not indicated in investigation of initial

cytology report

Indicated if persistent cytology finding

Can be considered as alternative to observation if woman's preference

Can be considered
Possible high-grade glandular lesion Indicated Indicated if visible lesion at colposcopy Indicated Can be considered
AISAdenocarcinoma in situ Indicated Indicated if visible lesion at colposcopy Indicated Can be considered
Adenocarcinoma Indicated Indicated for clinical invasive carcinoma Indicated if no clinically apparent invasive lesion Not useful

See Excision of the endocervical transformation zone.

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Excision of the endocervical transformation zone recommendations

Consensus-based recommendation*Question mark transparent.png

REC11.9: Specimen for histological assessment of glandular abnormalities
When diagnostic 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. is performed in the investigation of glandular abnormalities, the method chosen should ensure that a single, intact specimen with interpretable margins is obtained for histological assessment.

Practice pointQuestion mark transparent.png

REC11.10: Cold-knife cone biopsy is the ‘gold standard’ for glandular abnormalities’
Cold-knife cone biopsy should be considered the ‘gold standard’ for the diagnostic assessment of glandular lesions. However, a diathermy excisional procedure may be appropriate in some circumstances and could provide an appropriate surgical specimen when performed by a gynaecologist with appropriate training, experience and expertise.

Practice pointQuestion mark transparent.png

REC11.11: Size of cone biopsy
The depth and extent of the cone biopsy should be tailored to the woman's age and fertility requirements. A Type 3 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. is usually required.

Practice pointQuestion mark transparent.png

REC11.12: Cone biopsy excision margins and multifocal AISAdenocarcinoma in situ
Multifocal disease has been reported in 13–17% of cases of AISAdenocarcinoma in situ, though the majority of lesions are unifocal. If the margin is close but apparently excised (less than 5 mm), close surveillance by Test of Cure, as recommended in these guidelines, is considered appropriate. In this situation further excision is not considered necessary.

See also Modalities of treatment in Chapter 7. ColposcopyThe examination of the cervix and vagina with a magnifying instrument called a colposcope, to check for abnormalities..

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Benefits and harms

Invasive adenocarcinoma of the cervix has not reduced in incidence since the introduction of the NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears.. These recommendations, in concert with HPV testing in primary screening, should lead to improvements in prevention of invasive adenocarcinoma. Recent Australian data showing a high positive predictive value for AISAdenocarcinoma in situ or invasive cancer, when the referral cytology prediction is atypical endocervical cells of undetermined significance or possible AISAdenocarcinoma in situ,[1] supports a more aggressive approach to investigation in these women.

A potential harm is unnecessary treatment in women who do not have significant disease. However, this would be balanced by the detection of significant disease in a large proportion of these women, who are more likely to be identified by primary HPV screening in the renewed NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears..

See Chapter 5. Benefits, harms and cost-effectiveness of cervical screening in the renewed National Cervical Screening Program (NCSP).

Health system implications of these recommendations

Clinical practice

The recommendations for diagnosis and treatment of screen-detected glandular abnormalities are similar to those in current practice. However surveillance of women treated for AISAdenocarcinoma in situ now involve co-testingHPV test and LBC both requested and performed on a cervical sample. on an annual basis indefinitely until sufficient data has been obtained to limit the time of follow-up.

Resourcing

Because the recommendations are similar to those in the pre-renewal NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears., no substantial resource implications are expected.

Barriers to implementation

Because the recommendations are similar to those in the pre-renewal NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears., no substantial barriers to implementation are expected.

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References

  1. 1.01.11.21.31.41.51.61.71.81.9 Australian Institute of Health and Welfare. Cervical screening in Australia 2012–2013. Cancer series no. 93. Cat. no. CAN 91. Canberra: AIHWAustralian Institute of Health and Welfare; 2015 Available from: http://www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id=60129550872.
  2. 2.02.12.22.32.42.52.62.72.8 Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, et al ;American Society for ColposcopyThe examination of the cervix and vagina with a magnifying instrument called a colposcope, to check for abnormalities. and Cervical Pathology Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013 Apr;17(5 Suppl 1):S1-S27 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23519301.
  3. 3.03.13.2 Wilbur DC, Chhieng DC, Guidos B, Mody DR. Epithelial abnormalities: glandular. In: Nayar R, Wilbur DC (Eds).The Bethesda system for reporting cervical cytology. Definitions, criteria and exploratory notes. 3rd ed.Springer; 2015.
  4. 4.04.14.24.34.44.5 National Health and Medical Research Council. Screening to prevent cervical cancer: guidelines for the management of asymptomatic women with screen detected abnormalities. Canberra: NHMRCNational Health and Medical Research Council; 2005.
  5. Costa S, Venturoli S, Negri G, Sideri M, Preti M, Pesaresi M, et al. Factors predicting the outcome of conservatively treated adenocarcinoma in situ of the uterine cervix: an analysis of 166 cases. Gynecol Oncol 2012 Mar;124(3):490-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22188786.
  6. Chummun K, Fitzpatrick M, Lenehan P, Boylan P, Mooney E, Flannelly G. Diagnostic and therapeutic dilemma associated with atypical glandular cells on liquid-based cervical cytology. Cytopathology 2012 Dec;23(6):378-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22583085.
  7. Jadoon BA, Kehoe S, Romain K, Clelland C, Sundar SS. Analysis of outcome in women with borderline glandular change on cervical cytology. Eur J Obstet Gynecol Reprod Biol 2009 Nov;147(1):83-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19740591.
  8. Ullal A, Roberts M, Bulmer JN, Mathers ME, Wadehra V. The role of cervical cytology and colposcopy in detecting cervical glandular neoplasia. Cytopathology 2009 Dec;20(6):359-66 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18557985.
  9. 9.09.1 Bentley J, Society of Canadian ColposcopistsHealth professionals, usually gynaecologists, trained to perform colposcopy.. Colposcopic management of abnormal cervical cytology and histology. J Obstet Gynaecol Can 2012 Dec;34(12):1188-206 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23231803.
  10. Jordan J, Arbyn M, Martin-Hirsch P, Schenck U, Baldauf JJ, Da Silva D, et al. European guidelines for quality assurance in cervical cancer screening: recommendations for clinical management of abnormal cervical cytology, part 1. Cytopathology 2008 Dec;19(6):342-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19040546.
  11. 11.011.1 Munro A, Leung Y, Spilsbury K, Stewart CJ, Semmens J, Codde J, et al. Comparison of cold knife cone biopsy and loop electrosurgical excision procedure in the management of cervical adenocarcinoma in situ: What is the gold standard? Gynecol Oncol 2015 May;137(2):258-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25769659.
  12. Baalbergen A, Molijn AC, Quint WG, Smedts F, Helmerhorst TJ. Conservative Treatment Seems the Best Choice in Adenocarcinoma In Situ of the Cervix Uteri. J Low Genit Tract Dis 2015 Jul;19(3):239-43 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25943864.
  13. Latif NA, Neubauer NL, Helenowski IB, Lurain JR. Management of adenocarcinoma in situ of the uterine cervix: a comparison of loop electrosurgical excision procedure and cold knife conization. J Low Genit Tract Dis 2015 Apr;19(2):97-102 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25089550.
  14. Taylor JS, Panico V, Caputo T, Gerber D, Gupta D, Pirog E, et al. Clinical outcomes of patients with adenocarcinoma in situ of the cervix treated by conization. Eur J Gynaecol Oncol 2014;35(6):641-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25556268.
  15. 15.015.115.2 Baalbergen A, Helmerhorst TJ. Adenocarcinoma in situ of the uterine cervix--a systematic review. Int J Gynecol Cancer 2014 Nov;24(9):1543-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25238167.
  16. Dalrymple C, Valmadre S, Cook A, Atkinson K, Carter J, Houghton CR, et al. Cold knife versus laser cone biopsy for adenocarcinoma in situ of the cervix--a comparison of management and outcome. Int J Gynecol Cancer 2008 Jan;18(1):116-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17506846.
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Appendices

Jutta's magnifying glass icon.pngPICO questions 5a & 5b View Systematic review report q 5aView Systematic review report q 5a View Systematic review report q 5bView Systematic review report q 5b View General evidence summary table q 5aView General evidence summary table q 5a
View General evidence summary table q 5bView General evidence summary table q 5b
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