338 ALX. A\hO N.Z. J O L ' R ~ A L OF OBSTETRICS AND GYNAECOLOGY

fistula is not unique to Ethiopia, but the Hamlins have done a remarkable feat in establishing an efficient and caring hospital, especially dedicated to helping those women with fistulas.

References 1. Iloabachie GC. 260 cases of juxta cervical fistula. East Afr Med

2. Margolis T, Mercer U, Vesicovaginal fistula. Obstet Gynecol J 1992; 6 9 188-190.

Surv 1994; 49: 840-847.

3. Waaldijk K. The immediate surgical management of fresh obstetric fistula with catheter and/or early closure. Int J Gynaecol Obstet 1994; 45: 11-16.

4. Hamlin R, Nicholson C. Zacharin R. Massive vesicovaginal fistula. In: Nichols DH(ed) Gynecologic and Obstetric Surgery, 1993. Mosby.

5. Elkins TE. Surgery for the obstetric vesicovaginal fistula: a review of 100 operations in 82 patients. Am J Obstet Gynecol 1994; 170: 1108-1120.

6.EIkins TE, DeLancey JO, McGuire €3. The use of modified Martius graft as an adjunctive technique in vesicovaginal and rectovaginal fistula repair. Obstet Gynecoi 1990. 75: 727-733.

Aust. NZ J Obsrer Gynaecoi 19%. 3 6 3: 338

OCCASIONAL REVIEW

The Use of Large Loop Excision of the Thinsformation Zone (LLETZ) in an Outpatient Setting

Beverley Powell,' MB, BS Lye11 McEwin Health Service, Adelaide, South Australia

EDITORIAL COMMENT: We accepted rhis paper for publication becuuse it presents a detailed analysis of the results from one centre of treatment of women with cervical intraepithelial neoplasia by large loop excision of the transformation zone. Importantly it provides a very careful review of the reported literuture on the subject: the conclusions warran8 special scrutiny.

Summary: An audit of the results of 129 patients treated in the first 12 months of operation of an outpatient large loop excision of the transformation zone (LLETZ) clinic was performed. It confirmed the efficacy of the procedure in treatment of cervical intraepithelial neoplasia (CIN) with a cure rate of 93.8%. Major deficiencies identified were the lack of compliance with recommended follow-up. a major discrepancy between predicted diagnosis on colposcopically directed punch biopsy and LLETZ specimen histology, and a large proportion of LLETZ specimens which had negative histology and may be regarded as overtreatment. Suggested strategies t o address these include observation of low-grade lesions and treatment with LLETZ at the first clinic appointment.

Large loop excision of the transformation zone (LLETZ) was introduced as an outpatient treatment for cervical intraepithelial neoplasia (CIN) at the Lye11 McEwin Health Service (LMHS) in July, 1993: 129 patients were treated in this clinic in the first 12 months of operation. These patients were subse- quently audited after a follow-up period of 12 months

1 . Registrar. Address for correspondence: Dr Beverley Powell, Department of Obstetrics and Gynaecology, Flinders Medical Centre, Bedford Park, South Australia 5042.

after their treatment to assess the effectiveness o f this relatively new procedure and identify problems with its use.

Up until well into the 1960's total hysterectomy was advocated as a primary method of treatment of CIN. From the 1960's onwards cone biopsy became more the accepted method of diagnosis and more slowly. as adequate treatment if the margins showed complete excision of the dysplastic lesion and follow-up did not suggest residual disease. In 1966 Chanen and Holly- ock at the Royal Women's Hospital in Melbourne set up a unit using electrocoagulation diathermy destruc- tion of the cervix. originally performed under general

BEVERLEY POWELL 339

anaesthetic. Other methods of destruction have been also used. By the mid- 1970's laser ablation became popular, and later the laser cone biopsy was shown to be equally effective ( I ,2).

There is a strong drive to perform more procedures as outpatient or 'office' procedures as cost saving measures become all-important. The ablative techniques can all be used in the outpatient setting under local anaesthesia and except for the laser, are associated with minimal costs. They all have cure rates in the 80-95% range and low morbidity. A major disadvantage to these techniques is the possibility of inadequate sampling of the lesion and resultant inappropriate treatment of a microinvasive or frankly invasive lesion. Treatments which eliminate this risk are desirable. It is well established that destructive techniques may fail. Invasive disease may ensue for a number of reasons. There may be inadequate depth of destruction leaving a focus of CIN which progresses, or microinvasive disease may be missed when the associated CIN lesion is destroyed. A punch biopsy may not be deep enough for complete histological examination or may not sample the most severe area of the lesion.

Excisional techniques decrease the dangers of inadequate diagnosis: however, they have important disadvantages as well. Before the development of LLETZ, excisional therapies consisted of cold knife conization, laser conization and hysterectomy. The efficacy of these procedures has been well established, however they are costly in terms of equipment, hospitalization and anaesthetic requirements and morbidity. Cold knife cone also causes marked cicatrization of the cervix with inability to visualize the squamocolumnar junction (SCJ) and sample appro- priately during follow-up. It is associated with fertility and pregnancy complications such as cervical stenosis, cervical incompetence, increased risks of preterm labour, low birth-weight, and cervical dystocia.

Prendiville et a1 (3) described the use of a fine wire loop and an electrosurgical unit for the treatment of cervical dysplasia. He termed it large loop excision of the transformation zone or LLETZ. This was a refinement of the technique reported by Cartier for biopsy and removal of the transformation zone (TZ) of the cervix. It is an adaptation of developed principles with an electrosurgical generator used to convert household alternating current into high frequency (500 kHz to 3.3 MHz) alternating current. This is passed through a monopolar electrode to cut or coagulate tissue. The specific waveform used determines whether a cutting or coagulating effect is achieved. The active electrode is either a fine wire loop or a ball electrode. The effect of high-frequency undamped alternating current is to rapidly heat the water within the cells, causing vaporization of the water and cell wall destruction. This is similar to the carbon dioxide laser and provides excellent tissue

cutting. When the high-frequency current is interrupted or damped (spark gap), the tissue heating is slower resulting in coagulation and improved haemostasis. When these 2 waveforms are combined into a blended current, precise cutting and coagulation can be achieved simultaneously. Prendiville lists the principal advantages of LLETZ as being that it is an outpatient procedure performed under local anaesthesia and that tissue is removed rather than destroyed allowing exclusion of possible invasive disease and confirm that the lesion has been entirely removed. It uses cheap simple equipment and is not difficult to learn, and it may be used at the first colposcopic visit to decrease the number of appointments these women need for assessment and treatment of their CIN (3,4).

METHOD At LMHS at the time of the audit, referral for

colposcopy was recommended when screening cyto- logy showed CIN of any degree, or when 2 smears six months apart show 'benign atypia' or evidence of HPV infection.

Colposcopically directed punch biopsies were taken of the most severe areas of a visualized lesion. If histology confirmed CIN, treatment was recommend- ed. At LMHS the mainstay of conservative treatment is now LLETZ, usually performed under local anaesthesia. Conservative treatment is appropriate provided the following criteria are met:

no suspicion of invasion or microinvasion the entire lesion can be visualized no suspicion of glandular disease cytology and histology correspond (within 1 grade). These may be amended if LLETZ cone biopsy is

planned. Follow-up of all CIN was with cytology and

colposcopy at 4-6 months and again 6 months later. If the final diagnosis was >=CIN 2, the colposcopic follow-up is continued for 2 further visits, 6 months apart.

LLETZ was performed in an outpatient setting. Prilocaine 3% with felypressin was injected with a dental syringe into 4 quadrants of the cervix. No prophylactic antibiotics were used, orally or topically. Patients were advised to abstain from sexual intercourse and tampon use for 4 weeks.

Information for the audit was extracted from patient case notes, which were examined 12 months after their treatment in the LLETZ clinic. It is generally accepted that a recurrence within this period is likely to be residual disease and disease after this time represents a new lesion.

RESULTS There were 8 patients who required retreatment,

giving a cure rate of 93.8%. Most of the 129 women

340 AMT. A N D N.Z. JOLIKS.AL OF OBSTETRICS AND GYN.AECOLOGY

Table 1. Biopsy Results of Patients Treated with LLETZ LLETZ RESULTS Colposcopically directed punch biopsy results

Unknown Human Papillomavirus CIN I CIN 2 CIN 3

3 4

46 47 29

CIN= cervical intraepithelial neoplasia

AGE AT TREATMENT

40

<2C 20-24 25-29 33-24 3539 4044 4549 >50

age

Figure 1 . Patients age at time of treatment

at the time of treatment were between the ages of 20 and 34 (figure 1).

The indications for treatment, according to biopsy results are shown in table 1. In those cases where the biopsy showed HPV only, treatment was indicated as in 3 cases the smear showed CIN 2 or 3 i.e. discrepancy of >2 grades, and one case where the Pap smear showed CIN 1 but on colposcopy the upper limit of the lesion could not be seen.

Most of the patients would have been suitable for ablative treatment, however 11 (8.5%) would have required cone biopsy if LLETZ was not available.

The results of the histological examination of the LLETZ specimens are detailed in figure 2.

There were no cases of unexpected microinvasive carcinoma (MIC) or invasive carcinoma, or of adenocarcinoma. Only 1 specimen was reported as unreadable due to thermal artefact (0.8%).

The margins of the specimens were reported as involved in 19 patients (table 2).

Of those 8 patients who required retreatment, the margins were reported as involved in 4 patients only i.e. 4 of 19 with incomplete excision required further treatment. Seven patients had a further LLETZ procedure and 1 older patient opted for total abdomi- nal hysterectomy with the specimen showing CIN 3 at the squamocolumnar junction. Of the 7 treated with LLETZ the repeat specimen showed wart virus changes only in 3, suspected CIN 1 in 2, CIN 2 in one and CIN 3 in one.

Tables 3 and 4 show comparisons of cytology and punch biopsy histology to LLETZ histology. Our results support the literature which has found cytology to be a poor predictor of the final diag- nosis, especially at lower grades of abnormality.

40

n 30- U

e c 10-

HPV CIN 1 CINZ C I N 3 llell histology

Figure 2. LLETZ specimen histology

Table 2. Assessment of the Margins of the LLETZ Specimens Margins

Clear 81 (62.81;) Involved Uncertain No comment

19 (14.7%) 20 (15.5%) 9 (6.96)

Table 3. Indications for Referral (Pap Smear Result) and Corresponding Histology of the LLETZ Specimens

LLETZ Histology ? Normal HPV CIN I CINZ CIN 3 Total

pap Normal 0 0 1 0 1 0 2 Unknown I I 2 0 3 1 8

4 6 32 BA 0 1 1 2 9 0 0 2 HPV 0 0 1 I

CIN 1 0 1 5 17 9 6 38 CIN 2 0 0 3 I I 13 9 36

0 10 I I CIN 3 0 0 BA=benign atypia; HPV=human papillomavirus: CIN=cervical intraepithelial neoplasia: ?=unassessahle LLETZ specimen.

0 1

Table 4. Indications for LLETZ (Colpowopkally-Directed Punch Biopsy) and Corresponding Histology of the Specimen9

LLETZ Histology Normal HPV CIN I CIN 2 CIN 3 Total

Biopsy Unknown 0 0 1 I I 3 HPV 0 0 2 2 0 CIN I 2 20 19 3 I CIN 2 0 4 14 20 9 CIN 3 I 0 3 4 21 HPV=hunidn papillomaviru\. CIN=ccrvical intraepithcliul neopldsia. '=und\ses\ahlc Lt.kT/ \pecimcn

4 46 47 29

The comparison of biopsy results to definitive diagnosis is also predicted by the literature which. since excisional methods of treatment have been used. reports that diagnostic methods in use today are quite variable in the accuracy with which thcy can predict the degree of abnormality.

The biopsy was correct in 60 cases (46.5%). It undercalled the final diagnosis in 17 patients ( 13.2%). and overcalled i t in 48 patients (37.2%). (Excluding the 1 patient with an unassessable LLETZ specimen and 3 patients with unknown or unassessable biopsy specimens, these figures become 48%. 13.68 and 38.4% respectively.)

BEVERLEY POWELL 34 1

BIOPSY RESULTS WIT11 NEGATIVE HISTOLOGY

Figure 3. Pretreatment biopsy results in those LLETL specimens which did not contain any CIN.

Table 5. Complications of Patients ’Ikated with LLETZ Complications

Nil 68 (52.7%) Incomplete follow-up 48 (37.2%)

Residual disease 8 (6.2%) Cervical stenosis 2 (1.6%)

Secondary haemomhage 12 (9.3%)

Table 6. Pregnancy Outcomes in Patients ‘hated with LLETZ Pregnancy Outcomes

Still meenant at time of writing 4 Nor& iaginal delivery Forcep delivery Lower segment caesarean section Termination of pregnancy Miscarriage

Y

10 1 1 4 4

There was a report of negative histology on the LLETZ specimen in 27 cases (20.9%), including specimens which showed HPV changes only. The predicted diagnoses according to biopsy in these cases are shown in figure 3.

The patient with predicted CIN 3 subsequently had a colposcopy and biopsy showing CIN 1 and was retreated, the LLETZ specimen showing CIN 1. None of the other patients have demonstrated any residual disease on follow-up and have not had any further treatment.

Complications encountered by these patients are shown in table 5.

Incomplete follow-up was when patients did not have 2 reviews within the 12 months. No patients had a primary haemorrhage at the time of treatment or within 24 hours; 12 patients returned complaining of unacceptable blood loss after this time. All were treated with antibiotics, but only 2 required admission for vaginal packing. None required transfusion or cervical sutures. Of the 2 patients said to have cervical stenosis, 1 required dilatation to allow sampling of endocervical cells and the other elected to have a total abdominal hysterectomy. Neither had any menstrual abnormalities.

In the period between treatment and December, 1995, there have been 24 pregnancies in 19 of the women in this series who have been seen at this hospital. The outcomes of those pregnancies are shown in table 6.

None of the women in the audit have been seen at the LMHS complaining of infertility at the time of writing. One patient was approximately 3-4 weeks pregnant at the time of treatment and subsequently had a normal vaginal delivery. One patient has had 3 first trimester miscarriages since treatment.

DISCUSSION Our success rate of 93.8% is comparable to

published reports. In Prendiville’s (3) 1989 report, 11 1 women who were suitable for ablative therapy were treated with LLETZ; 45 of these women had had a pretreatment biopsy and achieved a successful treatment rate of 98%. This compared well with similar follow-up studies of laser treatment, radical diathermy, cold coagulation and cryosurgery. One woman had unsuspected microinvasion on loop specimen. Since then a growing number of studies have reported the efficacy of LLETZ (also known as loop electrosurgical excision procedure, LEEP, or diathermic loop excision, DLE). Success rates have generally ranged from 81-95.5% (5-12).

Complications Complication rates have been low, and LMHS

results (table 5) compare favourably with the published literature. Secondary haemorrhage is the most commonly reported and ranges from 0.6-8%. Other problems include cervical stenosis, which ranges from 0- 1.3% and, like cold knife cone biopsy, is probably related to the depth of the excision (7,9,10).

Long-term problems which may be related to cervical surgery are infertility and pregnancy complications. Bigrigg (13) sent questionnaires to 250 of the 1,OOO women she had originally studied (6) 2 years later and matched them to 250 controls. She concluded that LLETZ is unlikely to have any effects on menstruation, fertility or pregnancy outcome. Keisjer (9) also found no evidence that LLETZ affected fertility or pregnancy. Two patients were pregnant at the time of Prendiville’s study (3) and both proceeded to normal vaginal delivery, similar to our pregnant patient. Kennedy and Hallam (14) felt that there was a small chance of an effect on cervical function and infertility with LLETZ. There have been case-controlled studies to suggest that pregnancy outcomes are not affected (15,16), but one does show a significantly lower birth-weight in patients treated by LLETZ (17). This may be more due to character- istics common to women with CIN and decreased

342 A1 5T. 4 N D N.Z. JOL'RN4L OF OBSTETRICS AND GYNAECOLVCY

fetal weight e.g. smoking. However long-term follow- up studies are lacking.

Two studies comparing LLETZ to laser vaporiz- ation under local anaesthesia (1 8,19). report that complications are comparable, with one (18) showing less postoperative haemorrhage, less discomfort, reduced operating time and reduced expenditure for LLETZ. In 2 comparisons between LLETZ and laser conization under local anaesthesia (20,2 1 ) there was little difference in pain, and LLETZ was quicker. and one (20) suggests that thermal artefact was less with LLETZ.

Use for Cone Biopsy Debate is still ensuing over whether LLETZ is an

appropriate substitute for cold knife biopsy. Messing (22) made a pathological evaluation of 46 LLETZ cone specimens and found only 13 were equal to a cold knife cone. with the other specimens having missing mucosa, thermal injury, poor orientation or inadequate transformation zone. Thermal artefact is a function of loop size, time taken, the electrical energy used and the conductivity of the tissue. Small specimens seem to suffer the most injury. Montz (23) found only 52% of LLETZ cones evaluable as regards histological accuracy and assessibility of the endo- and ectocervical margins. Thermal artefact tended to be worse at endocervical margins, and was signi- ficantly worse in fragmented specimens. Naumann (24) performed LLETZ under local anaesthesia in 120 women with indications for cone biopsy. The margins were indeterminate in 25.8% and the specimens were removed in an average of 2.1 slices. 10% had an abnormal cytology showing recurrences.

These reports probably indicate that LLETZ has serious limitations when considered as an alternative for cold knife conization. However these may be lessened by taking care to orient the specimen, taking it in 1 slice and using appropriate power settings.

Some authors (8.25) report insignificant thermal damage, low complication rates and now rarely use cold knife cones. At LMHS cold knife cone was used if cytology, colposcopy or punch biopsy suggested invasive or glandular disease, but LLETZ was used in some patients where there was discrepancy between cytology and colposcopy of a visible lesion, or if the entire transformation zone was not visible.

Follow-Up Ideal follow-up of patients after conservative

cervical treatment is still debated. Some authors recom- mend that follow-up with cytology only will identify those with residual disease ( 1 1,26,27). but others note cases of residual disease at colposcopy which were not identified by cytology (28). It is important to follow patients for at least I year as most residual disease will

become obvious within this time, since the rate of recurrences then drops dramatically ( 13).

Shati (29) tried to identify factors which predicted cytological outcome following LLETZ. He found that the size of the initial lesion and the margin status of the excised tissue were significantly associated with cytological outcome. However, of the 58 women with abnormal smears, only 5 had confirmed CIN on biopsy, and he recommended that all women with abnormal cytology at follow-up should have colposcopic assessment and biopsy rather than retreatment.

In a later case report also by ShaFi (30) of a woman who developed invasive disease after LLETZ whilst showing only borderline abnormalities on smear, he stated that any abnormality, no matter how minor, should be regarded as an indication for colposcopic assessment if there has been prior treatment and that patients should only be discharged if both colposcopy and cytology are negative in the nonpregnant state.

Murdoch (26) identified 721 women with CIN on their LLETZ specimen. Residual CIN was found in 4.6% at first follow-up. This was associated with larger lesions and a report of incomplete excision increased the risk of residual disease, although 21% had a report of complete excision. He recommended that incomplete excision does not equal residual disease and that careful follow-up of these patients is required, not retreatment on the report of positive magins alone. Therefore he would follow with cytology if the margins were clear and colposcopy and cytology if the margins were involved. In Whitely and Olah's ( 8 ) follow-up of 80 patients, 15% had positive margins but 95% of patients had no abnormality at follow-up.

Thus positive margins may indicate residual disease, but certainly not all will demonstrate this. This may be due to the further coagulation of the base of the cervical wound for haemostasis with LLETZ. or an alteration in immune response eliminating residual disease after treatment. Of the 8 LMHS patients who required retreatment, the margins were reported as positive in only 3 cases, and would appear not to be ;I gcnd predictor of treatment failure. During the audit at LMHS it was recommended all patients have colposcopy and cytology at 4 and 10 months posttreatment. If there was a high-grade lesion they were seen for 2 further visits at 6 month intervals.

See and treat A much vaunted advantage of excisional treatment is

the possibility of assessing and treating the patient in a single visit - the 'see and treat' option (6- I I . 18.19.26. 47.51). This policy could potentially also lead t o decreased costs to the health system with fewer clinic appointments and pathology specimens. and also to the patient in terms of time and therefore money. I t may also engender better compliance with treatment and follow-up. A patient survey in Brisbane concluded that

BEVERLEY POWELL 343

Table 7. Rates of Negative Histology on LLETZ Specimen (Overtreatment) in the Literature

Negative Histology Rates See ond treur

Keisjer et a1 (9) 6.8%

Denny et al(51) 14% Luesley et a1 (7) 27% Alvarez et al (19) 32.58

32.8% Others Gunasekera et a1 (18) 0% (CIN 2 and 3 only) Prendiville et al (3) 8% Spitzer et al ( 5 ) 14% McIndoe et al (43) 17% (laser cone) Denny et al(5 I ) 18% Oycsanya et a1 (20) 20.7% (LLETZ)

Bigrigg et a1 (6) 4.7%

Whiteley & Olah (8) 7.5%

Murdoch et al ( I 1 )

tiowe & Vincenti (42) Murdoch et al i I I

16.7% (laser cone) 204 43 Rclc

most women were happy they had their treatment on the same day (52).

The critics of this policy consider it may lead to unnecessary treatment of some women (5), but the figures for overtreatment are better in some centres opting for ‘see and treat’ than other more conservative approaches (table 7). The cost savings of ‘see and treat’ may not apply to CIN 1 on Pap smear as many of these may not require treatment, so some recommend colposcopy and biopsy for CIN 1 if patient compliance is expected ( 1 1,19).

Overtreatment One of the constant criticisms of LLETZ is the rate

of negative histology, 20.9% in this audit, which may be regarded as overtreatment. The cause of negative histology may be: - false negatives - false positive cytology, colposcopy or biopsy - complete excision of the abnormality with the punch

biopsy - changed immune response after biopsy leading to

regression - spontaneous resolution in the time elapsed between

biopsy and treatment. The rates of negative histology reported in the

literature have been consistently relatively high (table 7). Overtreatment rates are similar with laser excision and it is likely that it was occurring previously but the destructive treatment techniques used prevented its discovery (20).

The problem is mainly related to those patients who have low-grade abnormalities on their smear and biopsy (figure 3). Observation of low grade abnor- malities for varying periods, by either cytology or colposcopy and biopsy, has been suggested to decrease overtreatment and costs (3 I ) .

In order to decide how to safely manage these lower grade abnormalities it is important to try to understand

the natural history of the disease, unfortunately it becomes obvious on reviewing the literature that currently we are unable to predict the course of lower grade CIN.

Regression rates for mild dysplasia in the order of 25-78% ( I ,32-36) have been described.

Flannelly (32) reported a prospective study with randomization of 902 women with mild or moderate dyskaryosis on cytology to immediate treatment or surveillance for 6,12 or 24 months. They reported that of 158 women with mildly dyskaryotic smears (CIN 1 or atypia) allocated to be followed for 2 years with cytology, only 40 (25%) had normal smears at 2 years. The proportion of patients having to be withdrawn for worsening abnormalities increased with increased duration of follow-up.

According to a study by Fletcher et al (37) a single negative smear was found to be an unreliable indicator of apparent regression and only 24% of CIN 1 or 2 showed a reversion to normal sustained over more than I8 months. Similar to other studies of this type, 40% of women did not complete the follow-up.

Soutter and Fletcher (38) performed a reanalysis of 5 previous studies and report that women with mild cytological abnormalities followed with cytology have a significant risk of developing cervical cancer, an average risk of 208 per 100,OOO women years compared to the national average of 9 per 100,OOO women years for similarly aged women in England and Wales. They concluded that these women followed cytologically have a much higher incidence of cervical cancer than the general population, and that all should be referred for colposcopy after the first report of mild dyskaryosis.

There is also some evidence that smear reports of HPV may behave in a similar way to CIN (39) and a high number may have CIN when further investigated (40).

A significant confounding factor regarding all of these studies is that since excisional treatments such as laser cone biopsy and LLETZ have been used in patients previously considered suitable for local destructive therapy, it has become obvious that the diagnostic accuracy of cytology, colposcopy and directed punch biopsy is less than previously assumed. Evidence for this comes from both our own results and the proliferation of reports with the use of LLETZ or laser cone biopsy providing a definitive diagnosis (table 8).

Buxton (41) reported that in 54% of 243 women managed by colposcopy and biopsy followed by LLETZ, the histology of the biopsy and loop specimen did not agree. In 47% of these the biopsy undercalled the grade of abnormality, missing 3 unsuspected adenocarcinoma- in-situ and one Stage la cancer. In 41% of women whose loop specimen showed CIN 3 or greater, the punch showed a lesser

344

Table 8. Correlation and Dwrepancy Rates Between Biopsy and LLETZ Specimen Histology Reporld in the Literature

Correlation between biopsy and excision specimens

Authors Agree Undercall Overcall Spitzer et a1 ( 5 ) Murdoch et al ( 1 1 ) Messing et a1 ( 2 2 ) Buxton et a1 (41) Howe & Vincenti (42) McIndoe et al (43) Chia et a1 (44) Skehan et a1 (45) Gunasekera et al ( 18) (CIN 2 and 3 only)

63% 47% 354 46% 484 54% 45% 47% 93%

22% 27% 2 8 4 25% 49% 23% 25% 29% 7%

15% 26% 33% 29% 3%

23% 30% 24% -

LLETZ HISTOLOGY OF CIN I ON BIOPSY

Figure 4. Histology of LLETZ specimens of those patients who had CIN 1 on colposcopically directed punch biopsy. HPV=human papillomavirus; N=normal, ?=unassessible LLETZ specimen; CIN-zervical intraepilhelial neoplasia.

lesion. This led him to the conclusion that ‘directed punch biopsy is an inadequate endpoint to judge the severity of a lesion and casts doubt on the results of studies using biopsy as an endpoint’.

Other literature reports rates of agreement between biopsy and excision specimen of between 3540%. with no real tendency towards either under- or overcalling the diagnosis (5.1 I ,22,42-4). Skehan (45) has shown similar discrepancies with the laser cone biopsy.

Our figures using definitive loop diagnosis show that of those patients with benign atypia on smear, 31% had a high-grade lesion, and of those with CIN 1, 39.5% had a high-grade lesion (table 3). This would argue against cytological surveillance of smears showing low-grade abnormalities.

Only 9% of those with predicted CIN 1 on biopsy had a high-grade lesion on loop specimen, 4% of these showed no abnormality and 44% were reported as HPV only. Forty-one percent were CIN I as predicted (figure 4).

The issue of poor predictive accuracy of cytology and biopsy also has implications for the other end of the spectrum, i.e. high-grade abnormalities. If we examine our results of patients with CIN 2 or 3 on biopsy the correlation rate is slightly improved at 53.9% (41 of 76). if we look at just CIN 3 the rate is 72.4%.

Gunasekera et al (18) studied 98 women who had CIN 2 or 3 on biopsy and in 91 of these patients the biopsy diagnosis agreed with the LLETZ specimen. However, in Murdoch’s ( 1 1 ) report of 299 women treated with LLETZ after punch biopsy, 27.4% of those with CIN 3 on loop specimen had had a negative punch biopsy with persistently abnormal cytology; of the patients with CIN 3 on loop specimen in this audit, 94% had either CIN 2 or 3 on punch biopsy.

It is known that microinvasive disease (MIC) is a difficult diagnosis on colposcopy (46). Murdoch (47) describes a significant increase in reported prevalence of microinvasive disease which was synchronous with the introduction of LLETZ, and stated that ‘this suggests that we previously treated colposcopically occult microinvasive disease with laser ablation’. He reported a significant number of unsuspected carci- nomas - of 1,143 women treated with diathermy loop excision, 18 had MIC (1.6%). 17 with Stage Ib carci- noma (1.5%) and 9 with adenocarcinoma (0.8%). He also reported a significant increase in the annual reportage of Stage l a disease after loop diathermy was introduced to replace destructive methods of treatment.

In McIndoe’s (43) study of 196 women suitable for ablation treated with laser cone, 14% had a negative punch biopsy with CIN in the cone, and 13% had a cone result 2 or more grades worse than the punch biopsy. He noted that the rate of diagnosis o f microinvasive carcinoma fell from 3.5% when cone biopsy was used as the only treatment method to I . 1 % after the introduction of laser vaporization and concluded that a considerable number o f women with MIC were not having the lesions recognized at colposcopy and were being inappropriately treated with vaporization.

However, the risk of metastatic spread in patients with less than 3 mm depth o f invasion is low. and it is likely that such patients were successfully treated with ablating the usual 7 to 1 0 mm depth (42.43.47).

Shumsky (48) found that 1.7 o f $4 patients with cervical carcinoma who had previously h;ld conservative treatment o f CIN, and subsequently had cone biopsies for persistent abnormalities. probably had invasive disease undetected by punch biopsy.

Therefore, the available literature indicates that many patients who have mild or moderate dysplasia will continue to show similar degrees of dysplasia over varying periods of time and many will undergo reversion to normal. However. some arguments against using observational strategies to decrease overtreatment include: - a significant group of patients will develop

- poor compliance with follow-up regimens con- progression

sistently shown in the studies (3.5.7.19)

BEVERLEY POWELL 345

- data now exist with the evolution of excisional modes of treatment that the accuracy of diagnostic methods used in the literature, both by cytology and histology of directed biopsies, is highly questionable.

- the costs of intense observation both economically and in terms of patient anxiety may well be higher than that of immediate assessment and treatment (49)

- a prospective randomized trial which shows patients followed cytologically have a much higher incidence of cervical cancer than the general population (34)

-current methods of treatment give good long-term cure (50)

- many under cytological observation eventually require colposcopic examination (32).

CONCLUSIONS The audit suggests that LLETZ is a successful

method of treatment of CIN, however our current management does lead to a significant degree of overtreatment and many patients did not complete their follow-up. Many had multiple appointments which they had failed to attend. It is particularly worrying in the light of the work which indicates that nonattenders for follow-up are at increased risk of developing carcinoma (37). Also evident is that biopsy results are not a good predictor of the definitive diagnosis on LLETZ specimen.

In order to lead with these issues, 2 options present themselves. Firstly, we may follow the NH and MRC recommendations for an observational strategy for biopsy proven CIN 1. This is an attractive option as the major component of the overtreatment figures had biopsies which showed CIN 1, and the literature would indicate that a policy of surveillance for 6 to 12 months would result in the regression of 25-80% of these lesions. However, the costs involved must be considered, not only in terms of manpower and pathology specimens, but also the anxiety and inconvenience for the patient. Also with a 37% default rate amongst our patients, this management may lead to a failure to prevent cervical carcinoma, due to failure of follow-up with progression, or a failure to diagnose correctly initially. The problem of the inaccuracy of diagnostic methods should stimulate caution in adopting this strategy, although in our patients with biopsy diagnosed CIN 1, only 9% had a high-grade lesion on loop specimen.

The option of ‘see and treat’ as practised in many UK centres is attractive in that the initial punch biopsy correlated poorly with the definitive diagnosis, being correct in 46.5% of cases. It would avoid the costs of pathology of the initiai biopsy. In most centres the rate of overtreatment with ‘see and treat’ is no worse than those doing punch biopsies. A retrospective review found that the rates of negative histology for ‘see and treat’ versus conventional management were not statistically different and concludes that punch biopsy

does not reduce the Occurrence of negative histology on LLETZ (51). This policy might be amended for low-grade abnormalities on smears, performing a colposcopy and biopsy to try to decrease the number of patients treated unnecessarily.

Acknowledgement The author wishes to thank Dr R. Watson and Dr P.

Duggan, LMHS, for their encouragement and critical advice during the preparation of this paper.

References 1. Chanen W. The CIN Saga - The Biological and Clinical

Significance of Cervical Intraepithelial Neoplasia. Aust NZ J Obstet Gynaecol 1990, 30: 18-23.

2. Baggish MS. Acomparison between laser excisional conization and laser vaporization for the treatment of cervical intraepithe- lial neoplasia. Am J Obstet Gynecol 1986; 155: 39-44.

3. Prendiville W, Cullimore 1, Norman S . Large loop excision of the transformation zone (LLETZ). A new method of manage- ment for women with cervical intraepithelial neoplasia. Br J Obstet Gynaecol 1989; %: 1054-1060.

4. Bloss JB. The use of electrosurgical techniques in the management of prematignant diseases of the vulva, vagina and cervix: An excisional rather than ablative approach. Am J Obstet Gynecol 1993; 169: 1080-1085.

5. Spitzer M, Chernys AE, Seltzer VL. The use of large-loop excision of the transformation zone in an inner-city population. Obstet Gynecol 1993: 82: 731-735.

6. Bigrigg MA, Codling BW, Pearson P, Read MD, Swingler GR. Colposcopic diagnosis and treatment of cervical dysplasia at a single clinic visit. Lancet 1990; 336: 229-231.

7. Leusley DM, Cullimore J, Redman CWE et al. Loop diathermy excision of the cervical transformation zone in patients with abnormal cervical smears. BMJ 1990,300: 1690-1693.

8. Whiteley PF and Olab KS. Treatment of cervical intraepithelial neoplasia: Experience with the low-voltage diathermy loop. Am J Obstet Gynecol 1990, 162: 1272-1277.

9. Keijser KGG, Kenemans P, van der Zanden PH, Schijf CPr, Vooijs GP and Rolland R. Diathermy loop excision in the management of cervical intraepithelial neoplasia: Diagnosis and treatment in one procedure. Am J Obstet Gynecol 1992; 166: 1281- 1287.

10. Wright TC, Gagnon S , Richart RM, Ferenczy A. Treatment of cervical intraepithelial neoplasia using the loop electrusutgical excision procedure. Obstet Gynecol 1992; 7 9 173-178.

11. Murdoch JB, Grimshaw RN, Monaghan JM. Loop diathermy excision of the abnormal cervical transformation zone. Int J Gynecol Cancer 1991; 1: 105-111.

12. Minucci D, Cine1 A, Insacco E. Diathermic loop ireatment for CIN and HPV lesions. Afollow-up of 130 cases. Eur J Gynaw: Oncol 1991; 12: 385-393.

13.Bigrigg A, Haffenden DK, Sheehan AL, Codling BW, Read MD. Efficacy and safety of large-loop excision of the transformation zone. Lancet 1994; 343: 32-34.

14.Kennedy S, Robinson J, Hallam. LLETZ and infertility. Br J Obstet Gynaecol 1993; 100: 965.

15.Cruickshank Me, Flannelly G, Campbell DM, Kitchener HC. Fertility and pregnancy outcome following large loop excision of the cervical transformation zone. Br J Obstet Gynaecol 1995:

16. Haffenden DK, Bigrigg A. Codling BW. Read MD. Pregnancy following large loop excision of the transformation zone. Br J Obstet Gynaecol 1993: 100: 1059-1060.

17.BIomfield PI. Buxton J, Dunn J. Luesley DM. Pregnancy outcome after large loop excision of the cervical transformation zone. Am J Obstet Gynecol 1993: 169 620-625.

18. Gunasekera PC, Phipps JH, Lewis BV. Large loop excision of the transformation zone (LLETZ) compared to carbon dioxide laser in the treatment of CIN: a superior mode of treatment. Br J Obstet Gynaecol 1990,97 995-998.

102: 467-470.

346 ACST. AND N.2. JOURNAL OF OBSTETRICS AXD GYNAECOLOGY

19. Alvarez RD, Helm CW. Edwards RPet al. Prospective random- ized trial of LLETZ versus laser ablation in patients with cervical intraepithelial neoplasia. Gynecol Oncol 1994; 52: 175- 179.

20. Oyesanya OA, Amerasinghe CN, Manning EAD. Outpatient excisional management of cervical intraepithelial neoplasia. A prospective randomized comparison between loop diathermy excision and laser excisional conization. Am J Obstet Gynecol 1993; 168: 485-488.

21. Crompton AC, Johnson N. Which is more painful? A random- ized trial comparing loop with laser excision of the cervical transformation zone. Gynecol Oncol 1994; 52: 392-394.

22.Messing MH, Otken L, King LA, Gallup DG. Large loop excision of the transformation zone (LLETZ): A pathologic evaluation. Gynecol Oncol 1994; 52: 207-21 1.

23. Montz FJ, Holschneider CH, Thompson DR. Large-loop excis- ion of the transformation zone: Effect on the pathologic interpretation of resection margins. Obstet Gynecol 1993; 8 1 : 976-982.

24.Naumann RW, Bell MC. Alvarez RD et al. LLETZ is an acceptable alternative to diagnostic cold-knife conization. Gynecol 0 x 0 1 1994: 55: 224-228.

25.Tumer u1, Rasmussen MI, Flannelly GM, Kelehan P, Leneham PM, Murphy JF. Outpatient loop diathermy conization as an alternative to inpatient knife conization of the cervix. J Reprod Med 1992; 37: 314-316.

26. Murdoch JB, Morgan PR, Lopes A, Monaghan JM. Histological incomplete excision of CIN after large loop excision of the transformation zone (LLETZ) merits careful follow up, not retreatment. Br J Obstet Gynaecol 1992; 99: 990-993.

27. topes A, Mor-Yosef S. Pearson S, Ireland D, Monaghan JM. Is routine colposcopic assessment necessary following laser ablation of cervical intraepithelial neoplasia? Br J Obstet Gynaecol 1990; 97: 175-177.

28.Mahadevan N, Horwell DH. The value of cytology and colposcopy in the follow up of cervical intraepithelial neoplasia after treatment by laser excision. Br J Obstet Gynaecol 1993: 100: 563-566.

29. Shafi MI, Dunn JA, Buxton W. Finn CB, Jordan JA, Luesley DM. Abnormal cervical cytology following large loop excision of the transformation zone: a case controlled study. Br J Obstet Gynaecol 1993; 100: 145-148.

30. Shafi MI, Chenoy R, Buxton W, Luesley DM. Invasive cervical disease following large loop excision of the transformation zone. Br J Obstet Gynaecol 1992; 99: 614.

31.Report by the National Health and Medical Research Council for the Organised Approach to Preventing Cancer of the Cervix. Guidelines for the management of women with screen detected abnormalities. Australian Government Publishing Service Canberra. 1994.

32. Montz FJ, Monk BJ, Fowler Jm. Nguyen L. Natural history of the minimally abnormal Papanicolaou smear. Obstet Gynecol 1992: 80: 385-388.

33. Robertson JH. Woodend BE, Crozier EH, Hutchinson J. Risk of cervical cancer associated with mild dyskaryosis. BMJ 1988: 297: 18-23.

34. Garuai P, Segala V, Folegatti MR, Frigo MG. Buoso R, Mollica G. Evolution of cervical intraepithelial neoplasia grades 1 and 2:

A two-year follow up of untreated and treated cases. Cervix 1991; 9 21-25.

35. Carmichael JA. Maskens PD. Cervical dysplasia and human papillomavirus. Am J Obstet Gynecol 1989; 160: 916-918.

36. Flannelly G. Anderson D. Kitchener HC et al. Management of women with mild and moderate cervical dyskaryosis. BMJ

37. Fletcher A, Metaxas N, Grubh C, Chamberlain J. Four and a half year follow up of women with dyskaryotic cervical smears. BMJ 1990,301: 641-644.

38. Soutter WP, Fletcher A. Invasive cancer of the cervix in women with mild dyskaryosis followed up cytologically. BMJ 1994; 308: 1421-1423.

39. Sujanen K, Mantyjarvi R, Saarikoski S et al. Factors associated with progression of cervical human papillomavirus (HPV) infections into carcinoma in situ during a long term prospective follow up. Br J Obstet Gynecol 1988; 95: 1096-1 102.

40. Planner RS. Hobbs JB. Human papilloma virus infection and associated intraepithelial neoplasia of the cervix. vagina and vulva. Aust NZ J Obstet Gynaecol 1987; 27: 132-135.

41. Buxton EJ, Luesley DM, Shafi MI, Rollason M. Colposcopi- cally directed punch biopsy: a potentially misleading investi- gation. Br J Obstet Gynaecol 1991 : 98: 1273- 1276.

42. Howe DT, Vincenti AC. Is large loop excision of the transform- ation zone (LLETZ) more accurate than colpscopically directed punch biopsy in the diagnosis of cervical intraepithelial neoplasia? Br J Obstet Gynaecol 1991; 98: 588-591.

43. McIndoe GAJ, Robson MS. Tidy JA, Mason WP, Anderson MC. Laser excision rather than vaporization: The treatment of choice for cervical intraepithelial neoplasia. Obstet Gynecol 1989; 74: 165-168.

44.Chia KV, Fayle JS, Sobowale OA. Efficacy of large loop excision of the transformation zone for cervical intraepithelial neoplasia. Aust NZ J Obstet Gynaecol 1992; 33: 287-289.

45.Skehan M, Soutter WP, Lim K, Krausz T, Pryse-Davies J. Reliability of colposcopy and directed punch biopsy. Br J Obstet Gynaecol 1990,97: 811-816.

46.Choo YC. Chan OLY. Hsu C. Ma HK. Colposcopy in microinvasive carcinoma of the cervix - an enigma of diagnosis. Br J Obstet Gynaecol 1984; 9 I : I 1 56- I 160.

47. Murdoch JB. Grimshaw RN, Morgan PR. Monaphan JM. The impact of loop diathermy on management of early invasive cervical cancer. int J Gynecol Cancer 1992: 2: I 29- 133.

48. Shumsky AG. Stuan GCE. Nation 1. Carcinoma of the cervix following ronservativc managemcnt of cervical intracpithclial neoplasia. Gynecol Oncol 1994; 53: 50-54.

49. Johnson N. Sutton 1. Thornton JG. Lilford RJ. Johnson VA. Pecl KR. Decision analysis for best managenicnt of mildly dyskaryotic smear. Lancet 1993: 342: 91-96,

5O.Tay S. Yonp T. High long-term cure rate justifies routinc treatment of cervical intracpithclial ncoplasia Grade I . Aust N% J Obstet Gynaecol 1995; 35: 192-195.

51. Denny LA. Soeten R. Dehaeck K. Blwh R. I ) C w colpo.icopi- cally directed punch biopsy reduce thc incidcncc of ncgativc LLEIZ? Br J Ohstet Gynaecol 1995: 102: 545-548.

52. Wcbster J. Moore K. Barry A. An cvaluation of patients’ responses to LLETI. in an outpatient setting (Icttcr). Aust N% J Obstet Gynaecol 1993; 33: 450-451.

1994; 308: 1399-1403.