Investigation of cytological glandular abnormalities

GUIDELINE UPDATES - This guideline was last updated 01/07/2022

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 NCSP, 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 AIS 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, AIS 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 NCSP 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.

Possible high-grade glandular lesion

Guidelines for the pre-renewal NCSP 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 NCSP, 44.7% of cases of possible high-grade endocervical glandular lesions predicted by cytology in 2012 (HPV status unknown) were histologically confirmed as AIS 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, AIS was confirmed in 21.5% and adenocarcinoma in 5.5%.[1]

AIS

AIS 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 NCSP, 63.3% of cases of AIS predicted by cytology in 2012 (HPV status unknown) were histologically confirmed as AIS and 26.7% were confirmed as adenocarcinoma.[1] Among all cases of AIS predicted by cytology in 2012, including cases where no histology was performed within 6 months, AIS was confirmed in 57.1% and adenocarcinoma in 24.1%.[1]

Guidelines for the pre-renewal NCSP recommended that women in whom AIS 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 AIS is controversial. AIS lesions can present with only minimal changes on colposcopy and can extend into the endocervical canal. As a result the full extent of AIS lesions may not be evident on colposcopic examination which complicates the determination of excisional approaches.[2] As AIS lesions can be multifocal, the finding of negative margins for AIS 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 NCSP 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 (LLETZ).[4] Current American Society for Colposcopy and Cervical Pathology (ASCCP) consensus guidelines recommend that any modality can be used for diagnostic excision of the transformation zone (TZ) in the treatment of AIS, 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. Colposcopy).[2]

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

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

Back to top

Adenocarcinoma

Guidelines for the pre-renewal NCSP 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]

Evidence

Immediate excision versus surveillance following a normal (negative) colposcopy for women with a positive oncogenic HPV test result and referral cytology predicting a glandular lesion less than AIS

Systematic review evidence

Systematic reviews were conducted to answer the following questions:

For women who have a positive oncogenic HPV (any type) 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) 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-positive women with cytology suggestive of a glandular lesion less than AIS. 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-positive 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 AIS and a normal (negative) colposcopy:

AIS or CIN 2+ 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 2+ 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 LLETZ, 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 TZ /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 2+ 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 2+ 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 LBC (co-testing). A negative co-test is defined as a test in which both oncogenic HPV is not detected and LBC is reported negative.

For women with high-grade glandular abnormalities, the evidence strongly supports the use of diagnostic excision of the TZ for these women. In the pre-renewal NCSP, a cytology report predicting a possible high-grade glandular abnormality was associated with a substantial risk of underlying AIS (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]

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 (AIS), or histologically confirmed AIS. The systematic review compared cold-knife cone biopsy with diathermy excision procedures (loop electrosurgical excision procedure [LEEP], LLETZ), Fischer cone, laser cone, straight wire excision of the TZ (SWETZ) or needle excision of the TZ (NETZ).

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 (AIS) glandular lesion, or histologically-confirmed AIS (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 LLETZ.[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 LLETZ (51%) than with cold-knife cone biopsy (30%) or laser cone (28%). This review reported rates of recurrence of AIS ranging from 9% to 29% after LLETZ and from 6% to 11% after cold-knife cone biopsy and concluded that the safety of LLETZ 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 Register of WA) Munro 2015[11] reported that after adjusting for margin status, no significant differences in cancer outcomes between women with AIS who underwent LEEP or cold-knife cone biopsy after a median follow-up of 3.6 years. In this study LEEP 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 AIS 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.

Recommendations

Atypical glandular/endocervical cells of undetermined significance recommendations

Flowchart 11.1. Management of LBC predicting atypical glandular/endocervical cells of undetermined significance

Consensus-based recommendation*

REC11.1: Colposcopy referral for atypical glandular/endocervical cells
Women who have a positive oncogenic HPV (any type) test result with a LBC 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*

REC11.2: Follow-up after normal colposcopy and LBC prediction of atypical glandular/endocervical cells
Women who have a positive oncogenic HPV test result (any type) with a LBC prediction of atypical glandular/endocervical cells of undetermined significance and normal colposcopy can be offered repeat co-testing (HPV and LBC) at 6–12 months:

If the follow-up co-test is negative, co-testing 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) test result or an abnormal LBC (any report other than negative), the woman should be referred for colposcopic assessment, and diagnostic excision of the TZ should be considered.

Practice point

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 TZ 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 point

REC11.4: Role of immediate diagnostic excision of TZ versus observation
Immediate diagnostic excision of the TZ 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.

See Excision of the endocervical transformation zone.

Possible high-grade glandular lesion recommendations

Flowchart 11.2. Management of LBC prediction of a possible high grade glandular lesion

Consensus-based recommendation

REC11.5: Colposcopy for possible high-grade glandular lesions
Women who have a positive oncogenic HPV (any type) test result with a LBC 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 TZ should be performed in most cases.

Practice point

REC11.6: Women who decline treatment for possible high-grade glandular lesions
Women with a LBC prediction of possible high-grade glandular lesion who decline the recommended excision should be offered surveillance with co-testing (HPV and LBC) 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 TZ.
It is important that the woman understands the potential risk of underlying disease (21.5% risk of AIS and 5.5% risk of invasive cancer).

See Excision of the endocervical transformation zone.

Endocervical adenocarcinoma in situ (AIS) recommendations

Flowchart 11.3. Management of LBC prediction of high grade glandular lesion (AIS)

Consensus-based recommendation*

REC11.7: Colposcopy referral for AIS
Women with a LBC prediction of AIS 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 TZ should be performed.

See Follow-up after excisional treatment for AIS

See Excision of the endocervical transformation zone.

Adenocarcinoma recommendation

Consensus-based recommendation*

REC11.8: Referral to gynaecological oncologist for LBC prediction of invasive disease
Women who have a positive oncogenic HPV (any type) test result with a LBC 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 LBC prediction of a glandular lesion

Cytology	Colposcopy	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
AIS	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.

Excision of the endocervical transformation zone recommendations

Consensus-based recommendation*

REC11.9: Specimen for histological assessment of glandular abnormalities
When diagnostic excision of the TZ 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 point

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 point

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 TZ is usually required.

Practice point

REC11.12: Cone biopsy excision margins and multifocal AIS
Multifocal disease has been reported in 13–17% of cases of AIS, 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. Colposcopy.

Benefits and harms

Invasive adenocarcinoma of the cervix has not reduced in incidence since the introduction of the NCSP. 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 AIS or invasive cancer, when the referral cytology prediction is atypical endocervical cells of undetermined significance or possible AIS,[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 NCSP.

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 AIS now involve co-testing 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 NCSP, no substantial resource implications are expected.

Barriers to implementation

Because the recommendations are similar to those in the pre-renewal NCSP, no substantial barriers to implementation are expected.

Author(s):

A/Professor Lyndal Anderson — Co-author
Dr Alison Budd — Co-author
Professor Ian Hammond — Co-author
A/Professor Selvan Pather — Co-author
Mr. C. David H. Wrede — Co-author
Professor Gordon Wright — Co-author
Cancer Council Australia Cervical Cancer Screening Guidelines Working Party — Co-author

References

Australian Institute of Health and Welfare. Cervical screening in Australia 2012–2013. Cancer series no. 93. Cat. no. CAN 91. Canberra: AIHW; 2015 Available from: http://www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id=60129550872.
Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, et al ;American Society for Colposcopy 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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23519301.
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.
National Health and Medical Research Council. Screening to prevent cervical cancer: guidelines for the management of asymptomatic women with screen detected abnormalities. Canberra: NHMRC; 2005.
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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22188786.
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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22583085.
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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19740591.
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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18557985.
Bentley J, Society of Canadian Colposcopists. Colposcopic management of abnormal cervical cytology and histology. J Obstet Gynaecol Can 2012 Dec;34(12):1188-206 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23231803.
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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19040546.
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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25769659.
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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25943864.
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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25089550.
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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25556268.
Baalbergen A, Helmerhorst TJ. Adenocarcinoma in situ of the uterine cervix--a systematic review. Int J Gynecol Cancer 2014 Nov;24(9):1543-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25238167.
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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17506846.

WEBSITE UPDATES - This website was last updated 01/07/2022