Glandular lesions of the cervix can be difficult to diagnose due to their small size, multifocal nature, and location away from the squamocolumnar junction. High grade glandular intraepithelial neoplasia (CGIN) and adenocarcinoma in situ (AIS) have malignant potential and are associated with HPV 18. Conservative treatment with loop electrosurgical excision procedure (LLETZ) is usually recommended for CGIN/AIS to preserve fertility in young women, with careful examination of margins and long-term cytological follow-up. Hysterectomy may be considered for positive margins, high grade cytology after LLETZ, or if fertility preservation is not a concern.

1. Glandular Disease
Ayman Ewies
Consultant Gynaecologist
October 2014
Sandwell and West Birmingham Hospitals

2. 2
History
o 1953  Friedell and McKay first described
AIS.
o 1980s  Gloor and Hurlimann introduced the
term CGIN and divided the disease into 3
grades to retain conformity with CIN.

3. 3
Glandular lesions of the cervix
√ Occasionally cervical smear reports include a reference to
atypical or dysplastic glandular cells.
√ These may have originated in the endocervical canal, the
endometrium, or very rarely even higher in the genital tract.
√ There is evidence that such smears are associated with a
high incidence of genital tract pathology, particularly in
older women.

4. 4
The challenge
o There is obvious benefit from cervical screening on
incidence & mortality of SCC.
o However, the effect is not clearly seen for cervical
adenocarcinoma.
 Infrequent less defined category!
 Natural history is unknown.

5. 5
Incidence and mortality
o CGIN3 : CIN3 = 1:50
o Data from 9 US registries: 1976-2000
CIN Invasive
SCC
AIS Invasive
adenocarcinoma
Incidence
(per 105
women yrs)
>2 fold
increase
20-58%
reduction
5-6 fold
increase
50% increase
Mortality - 17-38%
reduction
- No change
Sherman et al, 2005; Wang et al , 2004; Herbert et al, 1999

6. 6
Pathology
o Cervical glandular intra-epithelial neoplasia
(CGIN) is graded I, II, III like its squamous
counterpart.
o AIS is still used.
o Quite small areas, often in the base of gland
clefts.
o HPV 18 DNA is identified in up to 90% of cases
of CGIN.

7. 7
Pathology
-High grade CGIN:
o Recognised malignant potential
o CGIN3 is a robust diagnosis
-Low grade CGIN:
o Difficulties defining the most minor changes consistent
with a diagnosis of CGIN
o Poor reproducibility of diagnosis

8. Distribution of CGIN
Uni-centric 85-87%Multi-centric 13-15%
CGIN foci separated with normal epithelium ≥ 2mm

9. 9
Distribution of CGIN
o Mean distance of CGIN from SCJ = 8mm (range 1-25mm).
o Mean depth = 2.3mm (range 0.5 – 6mm).

10. 10
Malignant potential of AIS
o AIS is adjacent to adenocarcinoma in 50% of cases.
o Cellular similarity of lesions.
o Mean age of AIS is 10-20 years less than
adenocarcinoma.
o Identical HPV types in situ and invasive disease
(type 18 is the commonest).

11. 11
?Glandular Neoplasia
o Glandular abnormality x 1  immediate referral
o See urgently within 2 weeks
o Chance of invasive disease: 17-40%
o Chance of pre-invasive disease: 30-60%

12. 12
?Glandular Neoplasia
o (Pre-)Malignancy (77-82%)
CGIN or CIN
Invasive cancer
• Cervical
– Adenocarcinoma or SCC
• Endometrial
• Ovarian / tubal
• Other intra-peritoneal
o Benign ‘Mimics’
– Tuboendometriod
metaplasia
– Microglandular
hyperplasia
– Reactive atypia
– Endometriosis

13. Management
Sandwell and West Birmingham Hospitals

14. 14
1. PMB
2. Obese
3. PCO
4. Menstrual irregularity
5. >35 years of age
YES
NO
Treat as for
high grade
CIN
Deep loop cone +/-
Endocervical curettage +
Endometrial curettage
Abnormal
follow-up
smear
YES
NO
Dysplastic glandular cells or
repeat suspicious glandular cells

15. 15
Diagnosis
o Glandular abnormalities will not be subject to HPV triage
pathway.
o Colposcopy is essential.
o LLETZ (when CGIN is suggested by smear test or punch
biopsy) is a must.
o ? Endocervical curettage.
o Consider endometrial biopsy if:
1. Women >35years of age
2. Irregular vaginal bleeding irrespective of age
3. Cells appear to be of endometrial origin

16. 16
Problems in diagnosis
Cytological
o Cytological screening designed for squamous precursors.
o Cytological diagnosis is possible but not as accurate as
squamous lesions.
o Perhaps 50% detected on routine screening.
o 70% of high grade CGIN is seen in association with CIN.

17. 17
Problems in diagnosis
Histological
o Colposcopic recognition (± punch biopsy) diagnose 30%
of cases.
o Diagnosis of CGIN (or even early invasive
adenocarcinoma) by colposcopy or punch biopsies is
difficult because the lesions:
1. Often small
2. May be multifocal
3. May occur away from the SCJ
4. Overshadowed by CIN
o CGIN may be found unexpectedly (20% of cases) on
histological examination of LLETZ specimen for CIN.

18. 18
Can CGIN be predicted before cervical
conization?
± 33% of CGIN is missed by pre operative assessment.
± 50% of CGIN co exists with CIN.
Birmingham study,
1992
Kietpeerakol et al,
2006
Number 51 51
Pre cone smear with
atypical glandular
27 (53%) 22 (43%)
CGIN on directed
biopsy/ECC
10 (20%) 9 (18%)
Pre-operative evidence of
CGIN
37 (73%) 31 (60.8%)
Co-existent CIN 26 (51%) 24 (47%)

19. Normal Endocervical Cells
Normal Endocervical Cells

20. Normal Endocervical Cells
Benign Tubular Metaplasia

21. Atypical Glandular Cells

22. Atypical Glandular Cells
Borderline nuclear glandular changes

23. 23
Role of colposcopy
o Recommended for suspected glandular
lesions, but
1. Low sensitivity
2. May see fused villi
3. White lesions proximal to SCJ
o Useful in
1. Excluding invasion
2. Identifying CIN
3. Planning treatment

24. 24
Treatment
o Treatment: Conservative i.e. LLETZ
 Many women presenting with this disease are young
and nulliparous
 The incidence of skip lesions is low
 Recurrences / residual disease can be detected by
cytology/colposcopy
 No role for ablative/destructive surgery

25. 25
The ideal specimen for accurate diagnosis &
treatment of glandular abnormality
o Aim: to remove TZ and lower canal  to exclude invasion
confidently.
o Shape: Cylindrical

26. CIGN
CYLINDRICAL CONE
CIGN
STANDARD CONE

27. 27
The ideal specimen for accurate diagnosis &
treatment of glandular abnormality
o Size: depends on Age and distance from SCJ:
 Extent of disease appears to be related to age.
 When age is ≤35 years  usually less extensive, within
1cm of SCJ  more conservative excisions may
suffice.
 Go for ≥1 cm depth: if SCJ is visible + age ≤ 35 (if
wishing to retain fertility)  remove the lesion in 95%
of cases.
 Go for 2-2.5 cm: if SCJ is not visible or age >35 years.

28. 28
Potential problems with LLETZ for CIGN
1. Endocervical distribution:
conventional LLETZ unlikely to include 10mm
endocervix
2. Multiplicity of specimens:
more margins to assess/ orientation problems /
diathermy artefact
3. High incidence of +ve margins:
high rates of 2ry procedures

29. 29
Outcome of Conservative Management
o 14 studies , 1987-2000, n =234, median FU 3 years
After negative margins n=212
o CGIN/CIN (9) = 4.2%
o Invasion (3) =1.4%
After positive margins n=22
o CGIN(4) = 18.2%
o Invasion (1) = 4.5%

30. 30
Recommendation for management after LLETZ
Positive margins  Hysterectomy or repeat cone.
Negative margins  Cytological follow up for 10 years (as
for CIN II-III):
o Endocervical sampling is a must (cells must be present
on assessment)
o LBC ± ?Cytobrush
o ?Colposcopy

31. 31
Counselling regarding conservative
management
1. 15% possibility of residual disease.
2. 21.5% risk of some abnormality at follow up.
3. Heightened surveillance endo/exo cytology / ?colposcopy.
4. Hysterectomy after childbearing.

32. 32
Consider hysterectomy if…
1. If fertility is not an issue.
2. Positive margin after adequate local excision.
3. High grade cytological abnormality after local excision.
4. Patient is unwilling to undergo conservative management.
5. Failure to achieve adequate cytological follow-up e.g.
cervical stenosis.
6. Other clinical indications exist.

33. 33
Knife Cone v LLETZ
o Knife cone is the method of choice for treatment
in some centres:
 Less likely to have positive margins.
 Easier assessment of margins (no thermal artefact).
 Less recurrence rate.
 However, volume of tissue is much higher.

34. 34
Why do we need further studies?
o How diagnosis could be improved?
Lack of good data , no national evaluation performed
o A particularly problematic category is BNC – glandular:
√ Limited data
√ Impossible to audit
√ Divergence of opinion on initial management i.e. early
repeat versus refer all
√ Potential for misclassification

35. 35
Summary
o Glandular lesions are under recognized.
o Pathology is a difficult area and must be assessed carefully.
o In managing CGIN:
o Assessment of excision margins is most important
o Depth and shape of excision important
o Conservative management is an option provided follow up is optimal.
o Cytological follow-up is possible provided good smears are taken.

36. 36
Adenocarcinoma
 Adenocarcinoma represents 20-30% of all primary cervical
cancers.
60% purely glandular 40% mixed adeno-squamous pattern
 Adenocarcinoma is more likely to be diagnosed in younger
women.
Poorer outcome than squamous lesions; reflective of delayed
diagnosis because of endocervical distribution.
Screening has not affected incidence.

37. Site of Origin of Adenocarcinoma

38. Adenocarcinoma
Healthy endocervical cells Malignant endocervical cells

39. Adenocarcinoma