Excisional biopsy for CIN

When cervical intraepithelial neoplasia (CIN) requires treatment, loop electrosurgical excision procedure (LEEP) is the most frequently used modality, although cold-knife conization (CKC) of the cervical transformation zone still is preferred in select cases. Since excisional techniques are used with CKC, margin status is known and clinical decisions may be based on this information.

This article reviews current indications for excisional biopsy and presents evidence to direct management and follow-up of patients with positive and negative margins.

Selecting a technique

Several large randomized and prospective studies have demonstrated that LEEP is similar in efficacy to CKC and may even remove less of the normal cervical stroma.^1-3 In general, LEEP is used to excise high-grade and recurrent squamous dysplasia, as it is similar to CKC in its rates of incomplete excision and residual disease.^1,4 However, when adenocarcinoma in situ (AIS) is present, CKC is preferred for diagnosis and treatment, since it results in a lower incidence of involved margins and a lower recurrence rate.^3,5-7

CKC also is preferred when histologic confirmation of the margin status is crucial, such as when invasion with squamous lesions is suspected. This is because thermal artifacts that may result from LEEP will interfere with interpretation, further complicating treatment planning.^1,4,8,9 In cases of microinvasion, the ability to confirm margins makes conservative treatment possible; if the depth of invasion cannot be determined from the specimen, radical surgery may be necessary.

In the hands of an experienced clinician, however, thermal artifact from the LEEP technique generally is not a significant problem. Series reporting high rates of uninterpretable margins have been attributed to operator inexperience.¹⁰ In general, thermal artifact is reduced by limiting the number of sections taken. In ideal cases, only a single-piece specimen is obtained, similar to that achieved using CKC.^8,10,11 Newer loops, such as the cone biopsy excision loop, may decrease the number of sections and further improve margin interpretation.⁸

I use CKC in cases of suspected squamous invasion and in the evaluation of glandular lesions, but feel that in other cases LEEP is efficacious and quicker.

Identifying residual disease

When both the endocervical margin and endocervical curettage (ECC) are positive for squamous dysplasia at the time of excision, there is an increased risk of residual disease (TABLE 1).^12-14 However, it is not clear whether ECC alone is an independent predictor of residual disease. Although 1 study suggests an increased risk of invasive cancer in women over 50 years of age with a positive ECC at the time of conization, other series have failed to demonstrate a difference in treatment failure rates based on ECC.^15-17 Thus, the utility of ECC in directing further therapy at the time of excisional biopsy is unclear. I generally do not perform an ECC with LEEP for squamous dysplasia.

In AIS, a positive ECC is a strong predictor of residual disease, while a negative ECC is of limited significance.¹⁸ I am more likely to perform an ECC with glandular lesions. If it is negative, close follow-up still is indicated. If it is positive, repeat excision may be necessary.

TABLE 1

Residual disease and margin status: squamous dysplasia

Follow-up of squamous lesions

Considerable clinical uncertainty remains over the relative strengths of cytologic, colposcopic, and histologic evaluation for residual or recurrent disease following excisional biopsy. Conservative management includes Papanicolaou smears alone or in combination with ECC and/or colposcopy.

Negative margins. If margins are negative, the success rate of excisional biopsy is high (90%-100%), and careful observation is the preferred follow-up. Repeat cytologic testing will identify the majority of patients with residual high-grade disease. A prospective randomized trial of cytologic surveillance showed that the detection rate was only 1.9% higher for histology.¹⁹ Although 1 report suggests that colposcopy can expedite the diagnosis of recurrent dysplasia, it is unclear from this report whether colposcopy identified significant high-grade dysplasia that cytology missed.²⁰

Positive margins. In most series involving CIN with positive margins, treatment success rates do not differ significantly between patients who undergo repeat surgical procedures and those who have close follow-up. However, endocervical margin involvement appears to carry a higher treatment failure rate than ectocervical margin involvement. Data are conflicting on the proper method of conservative follow-up. Some authors propose only frequent cytologic testing, while others recommend that colposcopy be performed.^19-21

For patients with positive margins, I perform both cytology and colposcopy in 4 to 6 months. If an endocervical margin was positive, I also perform an ECC. If this evaluation is negative, I repeat cytologic testing every 6 months until 3 consecutive Pap smears are normal and satisfactory. In cases of recurrent high-grade dysplasia with positive margins, hysterectomy may be indicated, depending on the patient’s age and desire for continued fertility.^14,21

Squamous microinvasion

There is a significant risk (50%-80%) of residual disease or true invasion when margins or an ECC are positive and microinvasion is present.^2,5-7 In these cases, a repeat excisional biopsy should be performed to determine the true extent of disease prior to deciding on definitive therapy.²² As previously mentioned, CKC is preferred to limit artifact that could obscure interpretation. If the patient has completed her childbearing, hysterectomy remains the standard treatment for microinvasive squamous cell carcinoma. When the woman wishes to preserve fertility, conservative follow-up appears to be safe if the final pathologic specimen has negative margins. A follow-up protocol including cytologic, colposcopic, and ECC monitoring in the first post-conization visit is recommended.^2,6

Glandular lesions

AIS with involved margins requires further surgery due to the possibility of residual AIS or invasion (TABLES 2 and 3).^2,5-7 In these cases, CKC is preferable to LEEP.^3,5-7 Hysterectomy remains the standard therapy for AIS. Conservative management is an option if fertility is desired and margin status is negative. Patients should be informed that persistent disease or recurrence is possible and that there is a risk of invasive disease.¹⁵

Counseling, thorough documentation, and second surgical and pathologic opinions may be helpful in conservative management. Colposcopy, ECC, and cytology are indicated at the first follow-up visit, with cytology repeated every 6 months until 4 consecutive Paps are normal. More frequent colposcopy and liberal use of ECC also may be considered.

TABLE 2

Residual disease and margin status: adenocarcinoma in situ

TABLE 3

Follow-up recommendations

When further excision is necessary

As noted earlier, repeat excision is necessary in cases of squamous microinvasion or AIS with positive margins. CKC is generally preferred to allow for optimal pathologic interpretation. For squamous intraepithelial lesions, excisional biopsy with close follow-up has a significant cure rate, and hysterectomy usually is not indicated. However, hysterectomy still should be considered part of the treatment continuum for CIN, particularly for patients who have completed childbearing.

Conclusion

Although the risk of recurrence is correlated with a patient’s margin status in cases of squamous dysplasia, conservative follow-up is possible and has a high success rate. Cytology is sufficient surveillance for cases involving negative margins. When margins are positive, colposcopy and ECC also may be useful. Microinvasive lesions with positive margins require further surgical evaluation to determine treatment. For glandular lesions, CKC is preferred for both diagnosis and treatment.

Dr. Dunton reports no affiliation or financial arrangement with any of the companies that manufacture drugs or devices in any of the product classes mentioned in this article.

When cervical intraepithelial neoplasia (CIN) requires treatment, loop electrosurgical excision procedure (LEEP) is the most frequently used modality, although cold-knife conization (CKC) of the cervical transformation zone still is preferred in select cases. Since excisional techniques are used with CKC, margin status is known and clinical decisions may be based on this information.

This article reviews current indications for excisional biopsy and presents evidence to direct management and follow-up of patients with positive and negative margins.

Selecting a technique

Several large randomized and prospective studies have demonstrated that LEEP is similar in efficacy to CKC and may even remove less of the normal cervical stroma.^1-3 In general, LEEP is used to excise high-grade and recurrent squamous dysplasia, as it is similar to CKC in its rates of incomplete excision and residual disease.^1,4 However, when adenocarcinoma in situ (AIS) is present, CKC is preferred for diagnosis and treatment, since it results in a lower incidence of involved margins and a lower recurrence rate.^3,5-7

CKC also is preferred when histologic confirmation of the margin status is crucial, such as when invasion with squamous lesions is suspected. This is because thermal artifacts that may result from LEEP will interfere with interpretation, further complicating treatment planning.^1,4,8,9 In cases of microinvasion, the ability to confirm margins makes conservative treatment possible; if the depth of invasion cannot be determined from the specimen, radical surgery may be necessary.

In the hands of an experienced clinician, however, thermal artifact from the LEEP technique generally is not a significant problem. Series reporting high rates of uninterpretable margins have been attributed to operator inexperience.¹⁰ In general, thermal artifact is reduced by limiting the number of sections taken. In ideal cases, only a single-piece specimen is obtained, similar to that achieved using CKC.^8,10,11 Newer loops, such as the cone biopsy excision loop, may decrease the number of sections and further improve margin interpretation.⁸

I use CKC in cases of suspected squamous invasion and in the evaluation of glandular lesions, but feel that in other cases LEEP is efficacious and quicker.

Identifying residual disease

When both the endocervical margin and endocervical curettage (ECC) are positive for squamous dysplasia at the time of excision, there is an increased risk of residual disease (TABLE 1).^12-14 However, it is not clear whether ECC alone is an independent predictor of residual disease. Although 1 study suggests an increased risk of invasive cancer in women over 50 years of age with a positive ECC at the time of conization, other series have failed to demonstrate a difference in treatment failure rates based on ECC.^15-17 Thus, the utility of ECC in directing further therapy at the time of excisional biopsy is unclear. I generally do not perform an ECC with LEEP for squamous dysplasia.

In AIS, a positive ECC is a strong predictor of residual disease, while a negative ECC is of limited significance.¹⁸ I am more likely to perform an ECC with glandular lesions. If it is negative, close follow-up still is indicated. If it is positive, repeat excision may be necessary.

TABLE 1

Residual disease and margin status: squamous dysplasia

Follow-up of squamous lesions

Considerable clinical uncertainty remains over the relative strengths of cytologic, colposcopic, and histologic evaluation for residual or recurrent disease following excisional biopsy. Conservative management includes Papanicolaou smears alone or in combination with ECC and/or colposcopy.

Negative margins. If margins are negative, the success rate of excisional biopsy is high (90%-100%), and careful observation is the preferred follow-up. Repeat cytologic testing will identify the majority of patients with residual high-grade disease. A prospective randomized trial of cytologic surveillance showed that the detection rate was only 1.9% higher for histology.¹⁹ Although 1 report suggests that colposcopy can expedite the diagnosis of recurrent dysplasia, it is unclear from this report whether colposcopy identified significant high-grade dysplasia that cytology missed.²⁰

Positive margins. In most series involving CIN with positive margins, treatment success rates do not differ significantly between patients who undergo repeat surgical procedures and those who have close follow-up. However, endocervical margin involvement appears to carry a higher treatment failure rate than ectocervical margin involvement. Data are conflicting on the proper method of conservative follow-up. Some authors propose only frequent cytologic testing, while others recommend that colposcopy be performed.^19-21

For patients with positive margins, I perform both cytology and colposcopy in 4 to 6 months. If an endocervical margin was positive, I also perform an ECC. If this evaluation is negative, I repeat cytologic testing every 6 months until 3 consecutive Pap smears are normal and satisfactory. In cases of recurrent high-grade dysplasia with positive margins, hysterectomy may be indicated, depending on the patient’s age and desire for continued fertility.^14,21

Squamous microinvasion

There is a significant risk (50%-80%) of residual disease or true invasion when margins or an ECC are positive and microinvasion is present.^2,5-7 In these cases, a repeat excisional biopsy should be performed to determine the true extent of disease prior to deciding on definitive therapy.²² As previously mentioned, CKC is preferred to limit artifact that could obscure interpretation. If the patient has completed her childbearing, hysterectomy remains the standard treatment for microinvasive squamous cell carcinoma. When the woman wishes to preserve fertility, conservative follow-up appears to be safe if the final pathologic specimen has negative margins. A follow-up protocol including cytologic, colposcopic, and ECC monitoring in the first post-conization visit is recommended.^2,6

Glandular lesions

AIS with involved margins requires further surgery due to the possibility of residual AIS or invasion (TABLES 2 and 3).^2,5-7 In these cases, CKC is preferable to LEEP.^3,5-7 Hysterectomy remains the standard therapy for AIS. Conservative management is an option if fertility is desired and margin status is negative. Patients should be informed that persistent disease or recurrence is possible and that there is a risk of invasive disease.¹⁵

Counseling, thorough documentation, and second surgical and pathologic opinions may be helpful in conservative management. Colposcopy, ECC, and cytology are indicated at the first follow-up visit, with cytology repeated every 6 months until 4 consecutive Paps are normal. More frequent colposcopy and liberal use of ECC also may be considered.

TABLE 2

Residual disease and margin status: adenocarcinoma in situ

TABLE 3

Follow-up recommendations

When further excision is necessary

As noted earlier, repeat excision is necessary in cases of squamous microinvasion or AIS with positive margins. CKC is generally preferred to allow for optimal pathologic interpretation. For squamous intraepithelial lesions, excisional biopsy with close follow-up has a significant cure rate, and hysterectomy usually is not indicated. However, hysterectomy still should be considered part of the treatment continuum for CIN, particularly for patients who have completed childbearing.

Conclusion

Although the risk of recurrence is correlated with a patient’s margin status in cases of squamous dysplasia, conservative follow-up is possible and has a high success rate. Cytology is sufficient surveillance for cases involving negative margins. When margins are positive, colposcopy and ECC also may be useful. Microinvasive lesions with positive margins require further surgical evaluation to determine treatment. For glandular lesions, CKC is preferred for both diagnosis and treatment.

Dr. Dunton reports no affiliation or financial arrangement with any of the companies that manufacture drugs or devices in any of the product classes mentioned in this article.

When cervical intraepithelial neoplasia (CIN) requires treatment, loop electrosurgical excision procedure (LEEP) is the most frequently used modality, although cold-knife conization (CKC) of the cervical transformation zone still is preferred in select cases. Since excisional techniques are used with CKC, margin status is known and clinical decisions may be based on this information.

This article reviews current indications for excisional biopsy and presents evidence to direct management and follow-up of patients with positive and negative margins.

Selecting a technique

Several large randomized and prospective studies have demonstrated that LEEP is similar in efficacy to CKC and may even remove less of the normal cervical stroma.^1-3 In general, LEEP is used to excise high-grade and recurrent squamous dysplasia, as it is similar to CKC in its rates of incomplete excision and residual disease.^1,4 However, when adenocarcinoma in situ (AIS) is present, CKC is preferred for diagnosis and treatment, since it results in a lower incidence of involved margins and a lower recurrence rate.^3,5-7

CKC also is preferred when histologic confirmation of the margin status is crucial, such as when invasion with squamous lesions is suspected. This is because thermal artifacts that may result from LEEP will interfere with interpretation, further complicating treatment planning.^1,4,8,9 In cases of microinvasion, the ability to confirm margins makes conservative treatment possible; if the depth of invasion cannot be determined from the specimen, radical surgery may be necessary.

In the hands of an experienced clinician, however, thermal artifact from the LEEP technique generally is not a significant problem. Series reporting high rates of uninterpretable margins have been attributed to operator inexperience.¹⁰ In general, thermal artifact is reduced by limiting the number of sections taken. In ideal cases, only a single-piece specimen is obtained, similar to that achieved using CKC.^8,10,11 Newer loops, such as the cone biopsy excision loop, may decrease the number of sections and further improve margin interpretation.⁸

I use CKC in cases of suspected squamous invasion and in the evaluation of glandular lesions, but feel that in other cases LEEP is efficacious and quicker.

Identifying residual disease

When both the endocervical margin and endocervical curettage (ECC) are positive for squamous dysplasia at the time of excision, there is an increased risk of residual disease (TABLE 1).^12-14 However, it is not clear whether ECC alone is an independent predictor of residual disease. Although 1 study suggests an increased risk of invasive cancer in women over 50 years of age with a positive ECC at the time of conization, other series have failed to demonstrate a difference in treatment failure rates based on ECC.^15-17 Thus, the utility of ECC in directing further therapy at the time of excisional biopsy is unclear. I generally do not perform an ECC with LEEP for squamous dysplasia.

In AIS, a positive ECC is a strong predictor of residual disease, while a negative ECC is of limited significance.¹⁸ I am more likely to perform an ECC with glandular lesions. If it is negative, close follow-up still is indicated. If it is positive, repeat excision may be necessary.

TABLE 1

Residual disease and margin status: squamous dysplasia

Follow-up of squamous lesions

Considerable clinical uncertainty remains over the relative strengths of cytologic, colposcopic, and histologic evaluation for residual or recurrent disease following excisional biopsy. Conservative management includes Papanicolaou smears alone or in combination with ECC and/or colposcopy.

Negative margins. If margins are negative, the success rate of excisional biopsy is high (90%-100%), and careful observation is the preferred follow-up. Repeat cytologic testing will identify the majority of patients with residual high-grade disease. A prospective randomized trial of cytologic surveillance showed that the detection rate was only 1.9% higher for histology.¹⁹ Although 1 report suggests that colposcopy can expedite the diagnosis of recurrent dysplasia, it is unclear from this report whether colposcopy identified significant high-grade dysplasia that cytology missed.²⁰

Positive margins. In most series involving CIN with positive margins, treatment success rates do not differ significantly between patients who undergo repeat surgical procedures and those who have close follow-up. However, endocervical margin involvement appears to carry a higher treatment failure rate than ectocervical margin involvement. Data are conflicting on the proper method of conservative follow-up. Some authors propose only frequent cytologic testing, while others recommend that colposcopy be performed.^19-21

For patients with positive margins, I perform both cytology and colposcopy in 4 to 6 months. If an endocervical margin was positive, I also perform an ECC. If this evaluation is negative, I repeat cytologic testing every 6 months until 3 consecutive Pap smears are normal and satisfactory. In cases of recurrent high-grade dysplasia with positive margins, hysterectomy may be indicated, depending on the patient’s age and desire for continued fertility.^14,21

Squamous microinvasion

There is a significant risk (50%-80%) of residual disease or true invasion when margins or an ECC are positive and microinvasion is present.^2,5-7 In these cases, a repeat excisional biopsy should be performed to determine the true extent of disease prior to deciding on definitive therapy.²² As previously mentioned, CKC is preferred to limit artifact that could obscure interpretation. If the patient has completed her childbearing, hysterectomy remains the standard treatment for microinvasive squamous cell carcinoma. When the woman wishes to preserve fertility, conservative follow-up appears to be safe if the final pathologic specimen has negative margins. A follow-up protocol including cytologic, colposcopic, and ECC monitoring in the first post-conization visit is recommended.^2,6

Glandular lesions

AIS with involved margins requires further surgery due to the possibility of residual AIS or invasion (TABLES 2 and 3).^2,5-7 In these cases, CKC is preferable to LEEP.^3,5-7 Hysterectomy remains the standard therapy for AIS. Conservative management is an option if fertility is desired and margin status is negative. Patients should be informed that persistent disease or recurrence is possible and that there is a risk of invasive disease.¹⁵

Counseling, thorough documentation, and second surgical and pathologic opinions may be helpful in conservative management. Colposcopy, ECC, and cytology are indicated at the first follow-up visit, with cytology repeated every 6 months until 4 consecutive Paps are normal. More frequent colposcopy and liberal use of ECC also may be considered.

TABLE 2

Residual disease and margin status: adenocarcinoma in situ

TABLE 3

Follow-up recommendations

When further excision is necessary

As noted earlier, repeat excision is necessary in cases of squamous microinvasion or AIS with positive margins. CKC is generally preferred to allow for optimal pathologic interpretation. For squamous intraepithelial lesions, excisional biopsy with close follow-up has a significant cure rate, and hysterectomy usually is not indicated. However, hysterectomy still should be considered part of the treatment continuum for CIN, particularly for patients who have completed childbearing.

Conclusion

Although the risk of recurrence is correlated with a patient’s margin status in cases of squamous dysplasia, conservative follow-up is possible and has a high success rate. Cytology is sufficient surveillance for cases involving negative margins. When margins are positive, colposcopy and ECC also may be useful. Microinvasive lesions with positive margins require further surgical evaluation to determine treatment. For glandular lesions, CKC is preferred for both diagnosis and treatment.

Dr. Dunton reports no affiliation or financial arrangement with any of the companies that manufacture drugs or devices in any of the product classes mentioned in this article.