REVIEW ARTICLE

Adenocarcinoma in Situ of the Uterine CervixVA

Systematic Review
Astrid Baalbergen, MD* and Theo J.M. Helmerhorst, MD, PhD

Objective: This study aimed to review literature if therapeutic strategies in adenocarci-

noma in situ of the cervix could lead to a more conservative approach.
Methods: A review of the literature was conducted using a Medline search for articles
published between 1966 and 2013.
Results: Thirty-five studies showed that after a radical cone, 16.5% residual disease in the
re-cone or uterus was found. After cone with positive margins, residual abnormalities were
found in 49.3%. Thirty-seven studies showed 5% recurrence rate after conservative therapy
(large loop excision transformation zoneYcold knife conization. After conization with
negative margins, the risk of recurrence was 3%.
Conclusions: Adenocarcinoma in situ is a relatively rare premalignant but increasingly
frequent lesion of the cervix. Although there is a risk of relapse (3%) with a chance of
malignancy (G1%), this risk is so small that conservative treatment with negative margins by
large loop excision transformation zone or cold knife conization is justified and justifiable
not only for women to have children.
Key Words: Adenocarcinoma in situ, Conservative therapy, LEEP

Received April 27, 2014, and in revised form May 30, 2014.
Accepted for publication August 7, 2014.
(Int J Gynecol Cancer 2014;24: 1543Y1548)

percentage has risen to 20%.5 The proper management of AIS is

A denocarcinoma
1
in situ of the cervix (AIS), first described
by Hepler in 1952, is the precursory condition for ade-
nocarcinoma (AC). During the past decades, the incidence of
cervical carcinoma in industrialized countries has decreased.
This is due to the success of organized cytology-based cer-
vical screening programs. This decrease is, however, restricted
to cervical squamous cell carcinoma, whereas the incidence of
AC and its precursor AIS has remained stable or increased.2Y4 In
1952, 4.5% of all cervical cancers were ACs.1 Nowadays, this
*Department of Obstetrics and Gynecology, Reinier de Graaf Hos-
pital, Delft, the Netherlands; and Department of Obstetrics and
Gynecology, Erasmus MC University Medical Center, Rotterdam,
the Netherlands.
Address correspondence and reprint requests to Astrid Baalbergen,
MD, Department of Obstetrics and Gynecology, Reinier de Graaf
Hospital, PO Box 5011, 2600 GA Delft, The Netherlands.
E-mail: baalbergen@rdgg.nl.
The authors declare no conflicts of interest.
Copyright * 2014 by IGCS and ESGO
ISSN: 1048-891X
DOI: 10.1097/IGC.0000000000000260
complicated, on the one hand, by the location of the disease as
high endocervical and the potential for multifocal disease, and
on the other hand, by the patient population who wish to un-
dergo fertility-preserving therapy.
The aim of this study was to review literature if therapeutic
strategies in AIS could lead to a more conservative approach.
MATERIALS AND METHODS
A review of the literature was conducted using a
Medline search for articles published between 1966 and 2013.
Search strategies have been carried out with a combination of
the following MeSH headings: adenocarcinoma in situ of the
cervix, adenocarcinoma, AIS, and glandular dyspla-
sia of the cervix. In addition, the references of the selected
studies were checked. Studies were excluded if information
was missing about treatment. We therefore enrolled patients
with AIS, which were treated with a cold knife conization
(CKC), large loop excision transformation zone (LLETZ),
loop electrocautery excision biopsy (LEEP), or hysterectomy.
The study parameters were residual lesions, cutting edges,
and disease recurrence. Studies describing residual disease in

International Journal of Gynecological Cancer & Volume 24, Number 9, November 2014 1543

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Baalbergen et al International Journal of Gynecological Cancer
subsequent surgical specimen in relation to margin status in
initial cone were evaluated. Studies describing patients treated
conservatively with cervical conization (CKC or LLETZ)
alone were evaluated for recurrent disease.
Case reports were evaluated for the study but not in-
cluded in the analysis.
Studies were excluded if more recent reports of the
same series of patients were published.
RESULTS
The MEDLINE search using the described search
strategy identified 740 hits. The reference lists were checked,
and the hand searching of congress abstracts did not add any
studies (only abstracts).
Going through all the abstracts of the studies/hits has
produced 104 possible eligible studies, which were retrieved for
more detailed information. We have found no randomized
controlled trials. Of the remaining abstracts obtained, 63 studies
were excluded for the following reasons: invasive carcinoma,
case reports, review article, the study was about cytology, no
abstract, Russian or Chinese language, not about therapy, and
more recent reports of the same series of patients were pub-
lished. Forty-one studies were left for analysis; 3 prospective
studies,7Y10 all other studies were retrospective.
Residual Disease
A total of 35 studies showed that after a radical cone,
75 of 454 or 16.5% residual disease in the re-cone or uterus
was found (Table 1). A radical cone is a conization by cold
knife, LLETZ, or laser in which the margins are without AIS;
it is also called negative margins. After cone with positive
margins (AIS in margins), residual abnormalities were found
in 252 of 511 or 49.3%. Furthermore, 3 invasive carcinomas
were found after a radical cone (0.6%); and after a cone with
positive margins, 31 carcinomas were found (5.9%).
Recurrence
Thirty-seven studies showed 64 of 1277 or 5% recur-
rence rate with 17 carcinomas after conservative therapy
(LLETZYCKC) (Table 2). In most studies, a subdivision of
recurrence after positive and negative margin was indicated.
This shows that after conization with negative margins, the risk
of recurrence was 26 of 870 or 3%; whereas in positive margins,
the recurrence rate rises to 17% (23/135). Mean/median follow-up
varied between 12 and 120 months.
The manner and duration of follow-up was different in the
various studies; as it was already mentioned, the precise his-
tology of the recurrence was also not described in every study.
Conization Versus LLETZ
Several studies compared the conization (with a sur-
gical knife; in the English literature, cold knife cone) with the
LLETZ and found a clinically significantly higher rate (mean,
51%) of incomplete excision at the LLETZ in comparison
with the conization (mean, 30%). However, there are no
prospective studies between the different treatments. Recur-
rence rate after LLETZ was 9% to 29% compared to 6% to
11% after CKC,20,22,29,47 (Table 3).
1544
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& Volume 24, Number 9, November 2014
DISCUSSION
Nowadays, AIS is a well-described entity in pathology.
Arguments supporting the hypothesis that AIS is the precursor
of invasive AC of the uterine cervix,23,47Y50 are the following:
(1) the presence of AIS next to AC, (2) the cytologic and his-
tologic resemblance of AIS to AC, except for the miss-
ing stroma invasion, (3) the mean age of patients with AIS
(37 years) is 6 to 13 years younger than that of the patients with
AC (51 years), and (4) the same type high-risk human papil-
lomavirus. Furthermore, there are case reports that show how
AIS progressed into an AC and the fact of recurrences of AIS as
an AC. 51Y55
Therapy
The treatment of AIS is controversial. In the past, a
hysterectomy, even radical hysterectomy, was recommended as
treatment because AIS was considered a multifocal disease,
because negative margins had a limited predictive value for the
presence of residual lesions, and because of the risk of occult
carcinoma. Since women with AIS usually are in the fertile
phase of life, this is not an acceptable form of treatment.
Contrary to what was adopted, AIS is less than 15% multi-
focal.16,19 In the past few years, there has been a trend to more
conservative treatment. The main reason to abject conservative
treatment is the high incidence of residual disease after various
forms of conization.
Our review of 35 studies showed that after a radical cone,
16.5% residual disease in the re-cone or uterus was found (Table 1).
After cone with positive margins, residual abnormalities were
found in 49%. Furthermore, 3 invasive carcinomas were found
after a radical cone (0.6%); and after a cone with positive
margins, 30 carcinomas were found (5.9%).
Explanations for the percentage of residual lesions after
cone with negative margins:
- Multifocal disease, but research shows that this occurs in
approximately 15%, which is lower than the percentage
of residual lesions after radical cone, namely, 23%.
- Adenocarcinoma in situ is located beyond the proximal end of
the endocervical cutting edge of the cone. This is missed
by the long and tortuous elongated invaginations and turns
of the endocervical mucosa. Goldstein et al21 found no
residual lesions in uterus in a margin of more than 10 mm.
- Inadequate histopathological examination of the cone specimen.
The discrepancies found in the literature can be ex-
plained by different pathological interpretation of AIS. There is
also a difference between a patient with a small focus AIS in a
superficial gland and a patient with multifocal disease ex-
tending into deeper layers; both types are defeated as AIS cone
with negative margins. Young patients often have smaller le-
sions and less frequently positive margins; therefore, they are
candidates for a more conservative treatment with conization
than older women. If strict follow-up is not possible owing to
cervical stenosis, for example, or if there are other complaints
like dysmenorrhoea, this justifies a hysterectomy.
Recurrence
In literature, the risk of recurrence is between 0% and 47%
after conservative treatment. Several authors have attempted to
* 2014 IGCS and ESGO
International Journal of Gynecological Cancer & Volume 24, Number 9, November 2014 Conservative Therapy is Justified

TABLE 1. Residual AIS lesions in re-cone or uterus in relation to margin of the cone
Year n Age Proportion With Residual Disease
Positive Margin Negative Margin
Qizilbash11 1975 7 38.4 0/7
Luesley12 1987 19 35.0 4/8 1/2
Andersen13 1989 28 33.6 2/4 0/4
Hopkins14 1988 18 37.0 4/5 1/7
Nicklin15 1991 37 36.4 5/11 2/11
Cullimore6 1992 51 35.7 1/8 0/7
Muntz16 1992 40 7/10 (2 ca) 1/12
Im17 1995 18 35.0 4/6 4/9
Poynor18 1995 28 37.0 4/8 (1 ca) 4/10
Denehy19 1997 42 37.0 8/10 4/7
Houghton20 1997 19 31.0 0/3 0/2
Goldstein21 1998 61 43.0 8/18 13/43
Maini22 1998 50 37.1 8/16 (1 ca) 2
Azodi23 1999 40 37.0 9/16 (2 ca) 5/16
Tay24 1999 21 44.2 3/6 0/5
Kuohung25 2000 48 35.8 6/18 (3 ca) 0/3
Ostor26 2000 100 35.0 9/12 2/8
Shin8 2000 132 29.0 13/21 1/16
McHale27 2001 42 36.7 10/14 1/6
Soutter28 2001 84 37.3 11/27 (2 ca) 0/4
Kennedy29 2002 98 37.0 14/21 (3 ca) 0/6
Bryson30 2004 22 0/6 0/2
Hwang31 2004 95 35.8 10/24 1/11
Bull32 2007 101 29.0 3/24
Young33 2007 74 34.3 11/18 (3 ca) 1/13
Dalrymple34 2008 82 34.0 4/11 (1 ca) 2/13
Dedecker35 2008 115 37.5 12/26 2/11
Kim36 2009 78 42.0 14/29 (5 ca) 5/30 (1 ca)
Kim 201137 2011 99 40.0 3/10 2/45
Desimone38 2011 43 34.0 13/19 5/11
Kietpeerakool39 2012 60 45.1 17/26 0/26
Hanegem40 2012 112 25.0 6/25 0/15
Costales41 2013 180 33.8 3/13 (1 ca) 7/52 (1 ca)
Hiramatsu42 2013 10 44.0 3/4 (2 ca) 0/5
Tierney43 2013 78 40.0 23/34 (4 ca) 10/44(1 ca)
TOTAL 2125 252/511 = 49.3% 75/454 = 16.5%
30 ca = 5.9% 3ca = 0.6%
ca, carcinoma.

determine (prognostic) factors, which predict residual lesions or
recurrence after conservative treatment, as the depth and length of
the cone,56 volume deviation, number of quadrants in which AIS
existed,57 age, and endocervix curettage. None of these factors,
however, has a significant meaning.
Thirty-six studies showed 64 of 1277 or 5% recur-
rence rate with 17 carcinomas after conservative therapy
(LLETZYCKC). After conization with negative margins, the
risk of recurrence was 26 of 870 of 3%; whereas in positive
margins, the recurrence rate rises to 17% (23/135). The mar-
gin of the cone seems to be a predictor for the risk of recur-
rence. The manner and duration of follow-up were different
in the various studies; as already mentioned, the precise his-
tology of the recurrence was also not described in every study.

* 2014 IGCS and ESGO 1545

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Baalbergen et al International Journal of Gynecological Cancer & Volume 24, Number 9, November 2014

TABLE 2. AIS/AC recurrence after conservative therapy only in relation to margin status
Year Conservative Positive Margin Negative Margin
Recurrence, n (%)
Luesley12 1987 1/6 nm nm
Andersen13 1989 0/23 0/1 0/22
Hopkins14 1988 0/3 nm 0/3
Nicklin15 1991 0/12 0/1 0/11
Cullimore6 1992 0/35 na 0/35
Muntz16 1992 0/18 na 0/18
Im17 1995 0/3 0/1 0/2
Poynor18 1995 7/15 (2 ca) 4/8 (1 ca) 3/7 (1 ca)
Denehy19 1997 1/19 (1 ca) 1/3 (1 ca) 0/14
Houghton20 1997 0/15 0/6 0/9
Maini22 1998 3/32 (1ca) 3/18 (1 ca) 0/14
Azodi23 1999 2/13 (1 ca) Na 2/13 (1 ca)
Tay24 1999 0/10 0/1 0/7
Kuohung25 2000 1/12 na 1/12
Ostor26 2000 0/53 0/6 0/47
Shin8 2000 0/95 0/3 0/92
McHale27 2001 3/20 (1 ca) 3/5 (1 ca) 0/15
Soutter28 2001 4/59 2/26 2/33
Kennedy29 2002 9/61 (1 ca) 5/17 (1 ca) 4/42
Andersen7 2002 4/60 1/15 3/43
Schorge9 2003 0/7 0/7
Omnes44 2003 0/9 0/9
Bryson30 2004 0/17 0/2 0/15
Hwang31 2004 3/67 3/9 0/35
Akiba45 2005 0/15 0/15
Bull32 2007 0/101
Young33 2007 6/40(1 ca) 1/4 5/27 (1 ca)
Dedecker35 2008 3/61 (1 ca) 0 3/61 (1 ca)
Kim36 2009 0/19 0/2 0/17
Costa46 2012 15/119 (8 ca)
Desimone38 2011 0/11 0/1 0/10
Kim37 2011 0/28 0/5 1/23
Hanegem40 2012 0/109 0/103
Kietpeerakool39 2012 0/6 0/1 0/5
Hiramatsu42 2013 0/3 0 0/3
Costales41 2013 2/101 0 2/101
TOTAL 64/1277 = 5% 23/135 = 17% 26/870 = 3%
17 ca (1.3%) 5 ca (3.7%) 4 ca (G1%)
ca, carcinoma.

The discrepancy between the high residual disease
(17%Y49%) and the low change of recurrence (3%Y17%) is
explained by the fact that residual AIS in conservatively treated
patients after conization is often eradicated, possibly from
postsurgical inflammation and granulation tissue reaction,
tissue devascularization, necrosis, and reepithelialization by
benign columnar mucosa. This might be similar to processes in
breast that showed that 50% of breast reexcision specimens
are devoid of invasive carcinoma despite positive margins on
initial excision.58

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International Journal of Gynecological Cancer & Volume 24, Number 9, November 2014 Conservative Therapy is Justified

TABLE 3. Margins in cold knife conization versus LLETZ versus laser conization
Conus Pos Margin LLETZ Pos Margin Laser Pos Margin
49
Wolf 43 18 7 5
Denehy19 24 8 13 9
Kuohung25 39 11 9 6
Azodi23 25 6 8 6 7 4
Soutter28 10 4 43 25 24 14
Houghton20 19 8
Maini22 50 34
Kennedy29 37 10 49 28 4 0
Widrich57 18 6 14 7
Bryson30 22 8
Hwang31 20 9 23 9 41 11
Akiba45 15 0
Bull32 69 13 32 11
Young33 52 15 9 4
Dalrymple34 38 8 44 6
Dedecker35 38 6 64 31 11 2
Costa46 74 31 60 33 21 11
Desimone38 26 12 17 8
Hanegem40 58 11 54 14
Kietpeerakool39 23 6 37 21
Costales41 110 35 54 30
Hiramatsu42 10 4
Total 704 209 (30%) 594 301 (51%) 167 48 (28%)
ca, carcinoma

Conization Versus LLETZ REFERENCES

Recurrence rate after LLETZ is 9% to 29% compared to
6% to 11% after CKC.20,22,29,57 The safety of conservative
treatment with LLETZ is comparable to CKC when negative
margins are achieved.30 Large loop excision transformation
zone as treatment will lead to better obstetric outcome.30 Every
additional excised millimeter will increase the risk of preterm
partus by 6%.60
CONCLUSION
Adenocarcinoma in situ is a relatively rare premalignant
but increasingly frequent lesion of the cervix. It is considered
a preinvasive disease of invasive AC. Although there is a risk
of relapse (3%) with a chance of malignancy (G1%), this risk
is so small that this review encourages to consider conser-
vative treatment if AIS is completely resected by LLETZ or
CKC and the patient is well informed about the follow-up.
Nowadays, patients should choose whether they want a strict
follow-up with the small change of recurrence of definite
therapy with hysterectomy.
Follow-up after conservative treatment should preferably
be done by endocervical cytology, and human papillomavirus
and deviations should be subjected to further histological
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