Treatment of CIN after menopause

European Journal of Obstetrics & Gynecology and Reproductive Biology 95 (2001) 175±180

Treatment of CIN after menopause Jean Charles Boulanger*, Jean Gondry, Patrick Verhoest, CeÂcile Capsie, Sandrine Najas Centre de gyneÂcologie obsteÂtrique, CHU AMIENS, 124 rue Camille Desmoulins, 80054 Amiens cedex, France Received 5 February 2000; accepted 30 May 2000

Abstract Objectives: To characterise cervical neoplasia after the menopause. Material and methods: We studied our computerized ®les of CIN from 1993±1999. Of the 738 cases, 78 were after menopause (11%). Results: We made a report of the speci®cities of cytological and colposcopical diagnosis and the treatment given. Cytological results are the same after and before menopause. On the other hand, colposcopical patterns are signi®cantly different because of a particular topography of the lesion. The majority of CIN after menopause are localized in the canal and are 44% versus 12. Incomplete conization is no more frequent after menopause than before. However, stenosis is higher: 73% unseen junction against 15%. Therefore, at this age, a total hysterectomy could possibly be preferable. In this study, we will outline the positive and the negative aspects of this form of treatment. # 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Post menopausal; Cervical intraepithelial neoplasia; Treatment; Conization

1. Introduction Treatment of cervical intraepithelial neoplasia (CIN) has become more simpli®ed with time. Thirty years ago a hysterectomy was usual, then cervix removal and then conization. Today we use an even easier method: LLETZ (large loop excision of the transformation zone) in most cases. This is possible thanks to better knowledge of these diseases and especially important for younger women to reduce obstetric implications. We wondered if it was correct to use the same treatment in post menopausal period? To answer this we reviewed a case series. 2. Material and methods We studied the cases of CIN of our serie between 1993 and 1999. They were patients referred  either by general practitioners for abnormal pap smear,  or by gynecologists for treatment of proven biopsied CIN.

*

Corresponding author. Tel.: ‡33-3-22-53-36-00; fax: ‡33-3-22-53-36-53. E-mail address: [email protected] (J.C. Boulanger).

In every case, colposcopic evaluation was done and a biopsy performed when there was no histological diagnosis or discrepancy between histological and colposcopical diagnosis. Out of 738 cases 78 were post menopausal period: 11%. From these we studied their cytological results, colposcopical patterns and the modalities of treatment. From the cohort we compare our results after and before menopause. Comparisons were made by using Z tests of Student Bates. 3. Results The results of de®nitive histology (on conization or hysterectomy, or only for invasive cancer on a new biopsy) are summarized in Table 1. Our rate of microinvasive cancer is very high when taking into account the number of frayed basal layer cases. 4. Diagnosis 4.1. Cytology In our serie there is no difference before and after menopause (Table 2) except for normal smears which are 34 before menopause and only one after, but numbers are not signi®cant.

0301-2115/01/$ ± see front matter # 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 0 1 - 2 1 1 5 ( 0 0 ) 0 0 4 1 3 - 9

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Table 1 Results of definitive histology in our 738 casesa
>Menopause

N

%

N

%

Nl CIN1 CIN2 CIN3 KMI KI

8 29 64 446 93 20

1 4 10 68 14 3

0 4 4 42 19 9

0 5 5 54 24 12

Total

660

78

NS NS S (P<0.01) S (P<0.01) S (P<0.0001)

a

Nl: Normal, KMI: Micro invasive cancer, KI: Invasive cancer, NS: Not significant, S: Significant.

It does not mean that we have a particularly low rate of false negative smears. Perhaps we missed a lot of cases. 4.2. Colposcopy Using the terminology of the French Society of Colposcopy and Cervicovaginal Pathology, we found 56 cases of

atypical transformation zone grade 2 (ATZG) (83.58%), three cases of ATZG 1 (4.47%), two normal ectocervix with unseen junction (2.98%) and three non-conclusive colposcopies (4.47%). Before menopause the results are signi®cantly different. ATZG2 are still the most numerous (84.4%) but ATZG1 are 12.22% and above all normal ectocervix or non-conclusive colposcopy are only 0.94 and 0.47%. The above results are explained by a particular topography of the lesion. It is more often in the endocervical canal as seen in Table 3. Therefore, unseen junctions are much more frequent after menopause 73.13 versus 14.9%.

5. Treatment 5.1. Modalities The modalities are summarized in Table 4. Hysterectomy is rare before menopause and signi®cantly more frequent after.

Table 2 Results of cytologya

Nl LG HG Atypical Undone No information Total


%

>Menopause

%

34 124 134 284 28 56 660

5 19 20 43 4 8

1 9 12 38 1 17 78

1 12 15 49 1 22

NS NS NS NS NS

a Nl: normal: false negative cytology, LG: low grade, HG: high grade, Atypical: atypical without detail, Undone: diagnosis on colposcopical abnormality without previous smear.

Table 3 Topography of the lesion

One leep Two leeps Endocervical canal One or two leeps‡endocervical canal No information Total


%

>Menopause

%

60 199 76 304 21 660

9 30 12 46 3

0 2 34 26 16 78

0 3 44 33 21

S S S S

(P<0.01) (P<0.0001) (P<0.0001) (P<0.03)

Table 4 Therapeutic modalitiesa

Ablative treatment Conization or LLEP TH RH No information Total a


%

>Menopause

%

3 597 29 29 2 660

0.45 90 4 4 0.30

1 48 16 12 1 78

1 62 21 15 1

TH: total hysterectomy, RH: radical hysterectomy.

NS S (P<0.0001) S (P<0.0001) S (P<0.0001) NS

J.C. Boulanger et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 95 (2001) 175±180

177

Table 5 Quality of the resection for cases with conization

In sano conization Non-in sano conization Limit Total


%

>Menopause

%

440 48 82 570

77 8 14

33 5 3 41

80 12 7

5.2. Quality of treatment It depends on the margins of the specimen when treated by LLETZ or conization. We differentiate conization into three groups: in sano, non-in sano and limit. The latter is when the security margin is up to 2 mm. Results are given in Table 5. No difference can be seen due to most likely higher cones after menopause. Indeed in sano conizations are 80.48% after menopause and 77.2% before. 5.3. Post treatment stenosis Post treatment stenosis is an important point because it governs the follow up. There are numerous de®nitions of stenosis. We chose to only distinguish the visiblity of the squamocolumnar junction. After conization, unseen junctions are common in the postmenopausal period, 73.13 against 14.9%. 6. Discussion 6.1. Frequency Although CIN is a pathology of young women and now being found in an even younger age group, it is not rare after the menopause. In the French registers, the dif®culty of studying CIN comes from nosological changes. Some pathologists use Table 6 Distribution of 2675 cases of CIN according to age

NS NS NS

Reagan's classi®cation, others use Richart's classi®cation or the Bethesda system (BTS). However, they do continue to classify CIS (carcinoma in situ) as the most severe disease. Therefore, it is dif®cult to know the true incidence of high grade lesions, called severe dysplasia (SD), CIN 3, high grade squamous intraepithelial lesion (HGSIL) or carcinoma in situ. The results shown in Table 6 are based on 815 842 smears taken by a French Federation of Pathologists [1]. In North American literature, the results are similar as seen in Table 7. This pathology remains rare after menopause [2]. 6.2. Diagnosis Colposcopy and cytology are less reliable. 6.2.1. Cytology Roberts [3] notes 8% of false negative smears. He ®nds that four out of 50 patients had undetected CIN due to poor exfoliation at this age. This rate is not so high. Our rate of false negative smears is very low. Other authors write about higher rates at all ages. On the other hand, false positive smears are more frequent. They are impossible to count in our study. LetaõÈeff [4] notes that old women's smears have big nuclei similar to dysplasia. He compares cell and nuclear surfaces of parabasal and intermediate cells before and after menopause: there is a signi®cant decrease in cell surface and consequently an increase in the nucleocytoplasmic ratio.

Table 7 Distribution of cases of CIN according to age (Tabor)

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According to Kaminski [5] there is a close link between squamous atypia and estrogen de®ciency. With the treatment for estrogen de®ciency, the squamous atypia reverts to normal in a statistically signi®cant percentage of patients. 83% had a normal smear, 16% still had cytologic atypia. Cytology is not satisfactory to decide the best treatment: a colposcopy is mandatory. 6.2.2. Colposcopy Colposcopical patterns of dysplasia are different after menopause because of topographical changes rather than morphological changes. Our results point out this particularly. The lesions are more often localized in the endocervix, because SCJ is seldom seen, specially without a hormonal replacement therapy (HTR). Colposcopical examination is not so conclusive: high grade lesions are localized at the SCJ which is not visible during the colposcopy. In the same way, cervical punch biopsy is dif®cult. We could use microcolposcopy as some authors do [6,7] or endocervical curettage (ECC) [8]. We rarely perform ECC because we don't ®nd a signi®cant difference between the colposcopic biopsy and the ®nal histological diagnosis. In spite of these dif®culties we are most often satis®ed with colposcopical assessment. 6.3. Therapy Today the treatment of LGSIL may use ablative treatment when the SCJ is seen, or excisional treatment when this junction is unseen or in HGSIL [9]. Ablative treatments are not common because lesions with a visible junction are not the most frequent. Excisional treatments pose other problems:  incomplete eradication  stenosis On the other hand, conization often reveals a microinvasive lesion needing a hysterectomy. 6.4. Risk of incomplete eradication In spite of the frequent unseen junction at this age, the quality of the excision is not statistically different. In fact, we use cold knife more often than loop to obtain a larger cone and therefore stenosis are frequent. 6.5. Risk of stenosis In 3 to 17% of the cases, conization causes stenosis [10]. As a result, colposcopy and cytology become dif®cult or even impossible. Stenosis is more often correlated with the size of the cone than with the age of the patient [11]. Unfortunately, we do not have enough patients to compare the size of the cone with age. All the same, we notice 73.13%

Table 8 Rate of invasion according to age (Wetrich) Age

No. of cases

Microinvasion

Invasion

% Microinvasion or invasion

15±18 19±20 21±25 26±30 31±40 41±50 >50 Total

190 348 717 350 241 100 87 2194

1 0 5 5 3 3 6 23

0 0 2 2 4 3 10 19

0.53 0 0.98 1.4 2.9 6 18 1.9

of unseen junction after the menopause and only 14.9% before. 6.6. Frequency of microinvasion The patient's age is correlated with the severity of the disease. Wetrich [12] tells that more than 39% of the lesion are CIS or microinvasive carcinoma after 50 years of age compared to 3% at 20 and 13% at 30. For this author, invasive cervical cancer incidence increase with age as seen in Table 8. In our study, we have a high rate of invasive and microinvasive cancer in patients referred for HGSIL. But many are only a frayed basal layer. In most cases when we ®nd a microinvasive cancer in the ®nal histology of a conization in the post menopausal period, we perform a total hysterectomy. Given the above, we ask ourselves whether it would not be better to perform a hysterectomy from the beginning. 6.7. Is total hysterectomy the right solution? 6.7.1. Advantages A new intraepithelial disorder or an invasive cancer after conization are not so rare as we can see in our data [13]: 5% and 0.2%, respectively. Follow up after conization has to be done by cytology and colposcopy: Falcone and Ferenczy [14] found 20% of false negative cytology and only 3% when associated with colposcopy. SCJ has to be seen to make a conclusive colposcopy. However, conization often causes stenosis [9] which disturbs junction visualization and cytologic accuracy.  A hysterectomy ensures a better ulterior follow-up because it is easier to check the vaginal cuff by colposcopy, cytology or when HRT is used.  Incomplete eradication disappears. If conization is not in sano, this infers that abnormal tissue remains in the endocervix. Eradication is always complete in the case of a hysterectomy. When the CIN reaches the vagina, a total hysterectomy may be adapted to the lesion. It is even easier by the vaginal route.

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179

 If there is a discrepancy between colposcopy and the results of the biopsy, the diagnosis has to be reevaluated.  If a total simple hysterectomy is performed for occult invasive cancer there are two solutions: ± a second surgical excision for parametrectomy, lymphadenectomy, and colpectomy [18]. The survival rate is from 82 to 85% [19,20], results similar to classic treatment of invasive cancer. ± Brachy therapy: Hopkins speaks about five years of survival of 88% [21].

 A hysterectomy is sufficient for most cases of microinvasive cancer [15]. Additional treatment in the case of microinvasion depends on invasion depth.  early stromal invasion (<1 mm) needs only conization,  for invasion between 1 and 3 mm, a hysterectomy is preferable according to most authors,  invasion from 3 to 5 mm must be considered to be true cancer and consequently treated by radical hysterectomy and lymphadenectomy. Conization has to be performed ®rst because the punch biopsy is unable to adequately assess the true depth of invasion.

We conclude from our study that a total hysterectomy is an excessive procedure for CIN and whose bene®ts are slightly better than conservative treatment.

6.7.2. Disadvantages and pitfalls  A hysterectomy is an excessive procedure for dysplasia in comparison to electrosurgical excision or conization which can be performed under local anesthesia.  Mortality is very low but increases with age [16] (Table 9). However, complications can occur and the psychological effects are significant. Moreover, the cost is far higher.  Some authors feel that a hysterectomy is excessive even in microinvasive cancer and prefer to perform a conization up to 3 mm and an enlarged cervicectomy for deeper lesions.  A hysterectomy does not avoid a vaginal recurrence in 0.5±1% of the cases or sometimes more. Bremond [17] finds 3% of recurrence after in sano conization and 2.7% after a total hysterectomy.  A simple total hysterectomy is an inadequate procedure in cases of unrecognized invasive cancer. In our study of 462 cases referred for HGSIL, 14 had an unrecognized invasive occult cervical cancer. The diagnosis was put right after new biopsies under colposcopy in 13 cases, and in one case with the conization specimen. The diagnosis using punch biopsy is accurate when there is a colpo-cyto-histological concordance and no clinical signs.  CIS or microinvasive cancer have no clinical signs: metrorraghia are observed in invasive cancer.

7. What must be the right therapy after menopause 1. Cytology cannot be the only factor to choose the necessary treatment. 2. Prior to treatment, careful assessment is needed because of the high frequency of false positive smears and invasive cancer.  Cytology is positive and colposcopy does not find any lesion whereas the SCJ is seen: it is probably a false positive smear. Cytology will be redone after HRT.  Cytology is positive and colposcopy does not find any lesion but SCJ is unseen: a new colposcopy must be done under HRT using Koogan forceps or for some authors hygroscopic dilatator [22]. If there is no lesion, conization must be done if abnormal smears remain at the second visit.  LGSIL with SCJ seen: it is very unfrequent, ablative treatment can be made.  LGSIL with SCJ unseen and HGSIL : two procedures are possible: conization and electrosurgical excision. They both allow a histological control of the whole lesion. For lesions less than 10 mm in length in the canal, we choose electrosurgical excision with loop. Above 10 mm or when the SCJ is unseen we choose cold knife conization or electrosurgical conization with straight wire.

Table 9 Mortality in hysterectomy according to agea Age

Vaginal hysterectomy No. of death

<25 25±34 35±44 45±54 55±64 65±74 75 a

0 2 4 4 3 13 20

Rate/10000 (Wingo).

Abdominal hysterectomy Rate

0 0.90 0.5 2.7 1.9 18.3 56.8

Cancer

Other

No. of death

Rate

No. of death

Rate

0 1 6 18 63 91 100

0 7.1 26.8 41.4 80.4 138.4 349.5

3 16 32 33 28 32 24

2.5 2.3 2.8 4.6 19 46.4 121.2

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 Indications for hysterectomy: As we have shown, a hysterectomy is an exagerated procedure except for some cases  associated lesions: prolapse, endometrial abnormalities, ovarian pathology. Most of our hysterectomies were performed because there was an associated prolapse,  cervical lesions extended to the vagina. Rather than conization and CO2 laser vaporization of the vaginal lesion, we prefer a hysterectomy with upper colpectomy,  Proved or likely microinvasive cancer: a radical hysterectomy must be done,  Non-in sano conization: When conization margins are not free, the failure rate is not 100% but 10±55% [23]. In our serie, we observe 21.8% of failure and 12.5% of recurrence in non-in sano conization and respectively, 2.7 and 1.4% when margins are free. When necessary, a new conization is possible but the risk of stenosis is very high and we prefer a vaginal hysterectomy,  Stenosis after treatment: Some authors perform a hysterectomy [24], we are used to performing a stomatoplasty.

[10]

8. Conclusion

[15]

Cervical dysplasia are not very different before or after menopause. Yet, the diagnosis characteristics are changed at this period.

[16]

 more false positive smears: a see and treat procedure would be often an overtreatment,  more microinvasive and occult invasive cancer: therefore ablative treatment almost have no place. The histological evaluation of the specimen is mandatory. Because of that LLETZ, or conization are the best treatment. Total hysterectomy has unfrequent indication.

[6] [7] [8] [9]

[11]

[12] [13]

[14]

[17] [18] [19] [20]

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