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Predicting residual disease after excision of cervical dysplasia

Nicholas Johnsona,*, Mansoureh Khalilib, Lynn Hirschowitza,Fran Rallia, Richard Porterc

Dysplastic epithelium at the resection margin after a cervical cone is known to predict persisting disease.We followed 702 women for 30 months after cervical excision to see which resection margin waspredictive. The risk of persisting cytological abnormalities was doubled when CIN extended to theendocervical resection margin and was doubled when there was evidence of HPV. In contrast, disease atthe ectocervical resection margin and the grade of CIN were not associated with a higher risk of residualdisease.

Introduction

Many previous papers have demonstrated that incom-

plete excision of CIN is a risk factor for treatment failure.

This is biologically plausible, as disease extending to a

resection margin is more likely to indicate residual CIN in

the cervix. The risk of recurrent CIN in relation to a

specific resection margin (ectocervical or endocervical or

both) has not yet been established. It is also reasonable to

believe that high grade CIN might be associated with a

greater risk of treatment failure but the evidence to support

this is conflicting and needs further investigation.

It is important to be able to predict the risk of recurrent

disease. More resources should be directed to women with

a high risk of severe, persisting abnormalities, while others

might be more suitable for community-based surveillance.

Many units follow up all women with a colposcopic

examination and smear followed by annual cytology for

at least five years. Other units limit follow up to two smears

if the pathology suggests complete excision of low risk

disease. We prospectively determined the risk of treatment

failure after excision of dysplastic cervical epithelium to

help us develop a logical protocol that uses resources

effectively. We chose a large sample size and collected

data from all women to increase statistical power and

minimise bias.

Methods

A medically qualified colposcopist reviewed the medical

records, histopathological reports and follow up cytology

reports from 702 consecutive women, all of whom had been

treated with excisional surgery (cone biopsy or LLETZ)

between 1992 and 1994 at the United Colposcopy Service.

The service treats women from West Wiltshire, East

Somerset and Bath and North–East Somerset (BANES)

and is co-ordinated by the Royal United Hospital in Bath. It

includes hospitals in Frome, Malmesbury, Trowbridge and

Westbury. Women who had had benign disease, previous

cervical surgery, cancer or a colposcopic suggestion of a

microinvasive carcinoma were excluded from this study.

Some histological reports were difficult to interpret and the

original slides were re-examined by a Consultant Pathol-

ogist with special expertise in gynaecological pathology

and cervical cytology. Follow up cytology data were

extracted from the cytology laboratory computer system.

Women who had fewer than two follow up smears were

traced and the General Practitioner was asked to provide

further follow up details or organise appropriate follow up.

The National Screening Programme provided data on

women who had moved from the region and had inadequate

local follow up.

Treatment success was defined as negative post-treat-

ment cytology. Treatment failure was classified according

to follow up cytology. Minor persistent cytological abnor-

malities were defined by a single mildly dyskaryotic smear

or two smears with borderline nuclear abnormalities. Major

treatment failure was defined by more severe abnormalities

(either a severely dyskaryotic smear, a moderately dyskary-

otic smear, two mildly dyskaryotic smears, a mildly dys-

karyotic smear and a second smear of borderline nuclear

abnormalities or three smears containing borderline nuclear

changes).

The primary focus of the research was to determine

whether treatment failures were more common when

BJOG: an International Journal of Obstetrics and GynaecologyOctober 2003, Vol. 110, pp. 952–955

D RCOG 2003 BJOG: an International Journal of Obstetrics and Gynaecology

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aRoyal United Colposcopy Services for West Wiltshire,

BANES and East Somerset, Royal United Hospital, Bath,

UKbNo. 39 Adalat Street, Beheshty Avenue, Urmia, IrancWest Wiltshire Health Care NHS Trust, Royal United

Hospital, Bath, UK

* Correspondence: Dr N. Johnson, Department of Gynaecology, Royal

United Hospital, Bath, BA1 3NG, UK.

pathologists reported disease at the endocervical or ecto-

cervical resection margins for women who had been fol-

lowed up for 30 months with at least two smears. Complete

follow up with two smears was not available for all women

and therefore two separate analyses were performed to help

assess the effect of selection bias. We calculated the

recurrent disease rate for all women with at least one smear

and repeated the analysis for the group with at least two

follow up smears. The effects of time and operator bias

were excluded by examining treatment failure rate with

time and with differing technique, respectively. Women

who had a hysterectomy before they could have another

smear were considered to have had one follow up exam-

ination defined by the histological examination of the

hysterectomy specimen. Data were expressed as percent-

ages with the relative risk (RR) and 95% confidence

intervals (CIs). The effect of CIN grade on treatment failure

was analysed with a m2 test.

Results

Seven hundred and two women had excisional surgery

between January 1992 and December 1994 (median age 32;

range 17–63 years). It was impossible to determine the

completeness of disease resection in four cases at both the

endo- and ectocervical margins because multiple specimens

(loop biopsies) were submitted in each case for histological

examination. In a further two cases, it was not possible to

confirm complete excision at the ectocervical margin, and

in another case, the endocervical margin could not be

confidently judged to be free of disease. The follow up

data were supplemented with information provided by

general practitioners in 52 cases and the National Screening

Programme traced 15 more women. One woman had

emigrated and provided cytology follow up data from

Africa but two other emigrants could not be traced. One

woman declined any post-treatment examinations. Two had

a hysterectomy before they had had any cytological follow

up. Histological examination of the hysterectomy specimen

excluded residual CIN in both cases. This provided two

groups for analysis, 699 women with at least one adequate

follow up visit and 648 women who had been followed up

for at least 30 months with at least two adequate smears.

Tables 1 and 2 show outcome data.

Residual disease rates were independent of age and

operation technique. The average age at treatment for

women whose follow up revealed (a) no residual disease,

(b) a minor abnormality and (c) a major abnormality was

(a) 33, (b) 33 and (c) 35 years, respectively (ANOVA F ¼0.80; P ¼ 0.4). The risk of any subsequent cytological

abnormality was 18% and 14% for cone biopsy and loop

excision, respectively. The risk of a major recurrent cyto-

logical abnormality was 6% and 4%, respectively (m2 ¼ 2;

P ¼ 0.2).

The relative risk of a major treatment failure doubled if

disease was seen at the endocervical resection margin (RR

2.2; 95% CI 1.1–4.3). The relative risk was similar if the

database was expanded to include all subjects. There is also

a statistically significant increase in treatment failure even

if minor subsequent cytological abnormalities are included

in the definition of treatment failure. Incomplete resection

at the endocervical resection margin is associated with a

relative risk of any (minor and major) abnormality of 1.8

(95% CI 1.2–2.6).

Disease at the ectocervical resection margin is not

associated with a risk of persistent disease. The relative

risk of any abnormality after a pathologist reports disease at

the ectocervical resection margin is 0.8 (95% CI 0.5–1.3:

no significant effect). The relative risk is the same even if

data are included from women who have only had one

follow up smear.

Table 1. Outcome after 30 months of follow up: women with at least two smears after treatment, n ¼ 648. Values are given as n (%).

Subsequent abnormal

cytology requiring

treatment

Abnormal

cytology requiring

surveillance

Normal cytology

after treatment

Ectocervical margin (six cases uninterpretable) Disease at margin (n ¼ 134) 5 (4) 15 (11) 114 (85)

No disease at margin (n ¼ 508) 31 (6) 63 (12) 414 (81)

Relative risk of any abnormality ¼ 0.8 (0.5–1.3)

Endocervical margin (five cases uninterpretable) Disease at margin (n ¼ 108) 11 (10) 19 (18) 78 (72)

No disease at margin (n ¼ 535) 25 (5) 58 (11) 452 (84)

Relative risk of abnormality needing

treatment ¼ 2.2 (1.1– 4.3)

Relative risk of any abnormality ¼ 1.8 (1.3–2.6)

HPV HPV in resection

specimen (n ¼ 300)

25 (8) 48 (16) 227 (76)

Resection specimen free

of HPV (n ¼ 348)

11 (3) 30 (9) 307 (88)

Relative risk of abnormality needing

treatment ¼ 2.6 (1.3– 5.3)

Relative risk of any abnormality ¼ 2.1 (1.5–2.9)

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The initial grade of CIN had no effect on the risk of

recurrent disease. Three percent of women who initially

had CIN 1 in their excision biopsies required further

treatment. The treatment failure rate for women with CIN

2 was 6%. Treatment failure rates for CIN 3 were 5%.

These differences are probably due to chance ( P ¼ 0.6).

Koilocytes (which probably reflect underlying HPV

infection) associated with CIN in the initial resection

specimen significantly increased the subsequent risk of

high grade cervical dysplasia (RR ¼ 2.6; 95% CI 1.3–

5.3). Koilocytes in the initial excision specimen also

increased the risk of any abnormality (minor and major)

(RR ¼ 2.1; 95% CI 1.5–2.9). This increased risk of

persisting disease is not limited to treatment resistant warts.

It refers to a fourfold increase in high grade residual

disease. Three hundred and twenty-nine women had an

initial resection specimen with evidence of HPV in addition

to CIN. Twenty-one of these (6%) had moderate or severe

cervical dyskaryosis after treatment. Nine of the abnormal-

ities were severe dyskaryosis. This compared with six cases

of severe dyskaryosis and three cases of moderate dyskar-

yosis (2%) that followed treatment in 370 women who did

not have HPV in their resection specimens (RR ¼ 3.9; 95%

CI 1.6–9.4).

Discussion

These data demonstrate a statistically and clinically

significant increase in treatment failures if a pathologist

reports CIN (of any grade) at the endocervical resection

margin in a loop/cone biopsy of the cervix. However, there

is no increase in risk if disease reaches the ectocervical

resection margin. The data also associate HPV with a

clinically and statistically significant increase in treatment

failure. However, the grade of the initial CIN did not

influence treatment failure rates. One explanation may be

that disease at the ectocervical resection margin may not

reflect the true extent of treatment. Colposcopists often

begin the resection close to the visible area of abnormality

and may deliberately cut through disease in the ectocervix

before returning to vaporising peripheral residual disease.

This does not apply to endocervical lesions because they

cannot be seen easily.

Baldauf et al.1 have reviewed the studies showing that

disease at an unspecified resection margin is linked with

higher risk of treatment failure and this is supported by

later work2. This clinical and epidemiological observation

is also supported by the analysis of hysterectomy speci-

mens following cone biopsies3. Studies from Gateshead

(UK)4,5 attempted to assess whether there was a difference

in prognosis depending on which resection margin (prox-

imal or distal) was involved and whether the grade of CIN

was related to risk of recurrence three to four months after

excisional surgery. Two out of 56 women in Gateshead

with CIN extending to the ectocervical resection margin

had residual CIN detected at follow up (3.6%). This

compared with 9 out of 75 women who had disease at

the endocervical resection margin (12%) (Fisher’s exact

test, P ¼ 0.11, not statistically significant; OR ¼ 0.27). A

similar survey from Melbourne (Australia)6 quoted a cure

rate for incomplete excision at the ectocervical margin of

86% compared with 68% if incomplete excision was at the

endocervix. Our data support these suggestions that disease

Table 2. Outcome after 30 months of follow up: all women treated by excision over three years for CIN (n ¼ 702). Data on 699 (99.6%) cases

(two emigrated, one declined surveillance). Values are given as n (%).

Subsequent abnormal

cytology requiring

treatment

Abnormal

cytology requiring

surveillance

Normal cytology

after treatment

Ectocervical margin (six cases uninterpretable) Disease at margin (n ¼ 148) 5 (3) 15 (10) 128 (86)

No disease at margin (n ¼ 545) 31 (6) 63 (12) 451 (83)

Relative risk of any abnormality ¼ 0.8 (0.5– 1.2)

Endocervical margin (five cases interpretable) Disease at margin (n ¼ 122) 11 (9) 19 (16) 92 (75)

No disease at margin (n ¼ 535) 25 (4.4) 58 (10) 452 (84)

Relative risk of abnormality needing

treatment ¼ 1.9 (1.0– 3.8)

Relative risk of any abnormality ¼ 1.6 (1.1– 2.3)

HPV associated changes HPV changes resection

specimen (n ¼ 329)

25 (8) 48 (15) 256 (78)

Resection specimen free

of HPV (n ¼ 370)

11 (3) 30 (8) 329 (89)

Relative risk of abnormality needing

treatment ¼ 2.6 (1.3– 5.1)

Relative risk of any abnormality ¼ 2.0 (1.4– 2.8)

Grade of initial pathology CIN I (n ¼ 96) 3 (3% of CIN I) 15 (16) 78 (81)

CIN II (n ¼ 249) 14 (6% of CIN II) 25 (10) 210 (85)

CIN III (n ¼ 354) 19 (5% of CIN III) 38 (11) 297 (84)

m2 ¼ 3.0; P ¼ 0.5

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at the endocervical margin is more significant for predict-

ing residual disease than disease at the ectocervical margin.

The significantly increased risk of treatment failure

associated with wart virus change is relevant to current

follow up protocols. The risk of significant cytological

abnormalities within 30 months of treatment is approxi-

mately 3% if there are no features of HPV infection in the

initial specimen. It increases to 8% if HPV changes are

present. This is also compatible with our understanding of

HPV associated dysplastic lesions. It is impossible to

eradicate virus from the cervix despite excising dysplastic

lesions. It is also relevant that the presence of HPV in the

initial biopsy predicts high grade residual disease. It is

important to emphasise that our primary outcome variable

was focussed on resection margins. A causal relationship

cannot be assumed from an analysis that did not set out to

study this specific question but this certainly warrants

further investigation.

The implications of these data are important for deter-

mining follow up protocols and helping clinical practi-

tioners to know what to tell their patients. Therefore, it is

important to establish that these data are robust. Firstly, the

conclusions are biologically plausible and compatible with

other reports on the same subject. Secondly, the amount of

missing data has been reduced to 0.4% by trawling General

Practitioners’ records, the cytology laboratory database and

the National Screening Service to ensure that our follow up

is as complete as it could be. The data have been analysed

separately according to women who have been completely

followed up and those that have not and similar follow up

results confirm that the conclusions will not be affected by

selection bias. The data were collected according to pro-

spectively defined criteria and were analysed with a single

primary hypothesis and two other secondary questions. The

statistical power (h) of the study is adequate for conven-

tional statistical analysis and the probability of an a

(Type 1) error on any of the conclusions is less than 5%.

Therefore, it is reasonable to conclude that:

� clinicians do not need to be especially concerned about

residual disease if excision of CIN is incomplete at the

ectocervical margin.� disease at the endocervical resection margin doubles the

relative risk of disease requiring treatment in the next

30 months.� the grade of CIN in the initial pathological specimen

does not significantly affect the risk of residual disease.� the presence of the HPV is associated with a 2.6

increased relative risk of requiring further treatment.

This suggests that the risk of residual disease is not

increased if there is high grade CIN or disease at the

ectocervical resection margin and we should concentrate

post-treatment surveillance on HPV infection and disease

that extends to the endocervical resection margin.

References

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ogy and colposcopy after loop electro-surgcial excision: implications

for follow-up. Obstet Gynecol 1998;92:124–130.

2. Flannelly G, Bolger B, Fawzi H, De Lopes AB, Monaghan JM. Follow

up after LLETZ: could schedules be modified according to risk of

recurrence? Br J Obstet Gynaecol 2001;108(10):1025–1030.

3. Buxton EJ, Luesley DM, Wade-Evans T, Jordan JA. Residual disease

after cone biopsy: completeness of excision and follow-up cytology as

predicted factors. Obstet Gynecol 1987;70:529 –532.

4. Lopes A, Morgan P, Murdoch J, Piura B, Monaghan JM. The case for

conservative management of incomplete excision of CIN after laser

conisation. Gynecol Oncol 1993;49:247– 249.

5. Murdoch JB, Morgan PR, Lopes A, Monaghan JM. Histological in-

complete excision of CIN after large loop excision of the transforma-

tion zone (LLETZ) merits careful follow-up, not retreatment. Br J

Obstet Gynaecol 1992;99:990– 993.

6. Mohamed-Noor K, Quinn MA, Tan J. Outcomes after cervical cold

knife conization with complete and incomplete excision of abnormal

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Accepted 1 May 2003

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