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تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
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Cervical adenocarcinoma in situ

Cervical adenocarcinoma in situ
Literature review current through: Jan 2024.
This topic last updated: Aug 16, 2022.

INTRODUCTION — Adenocarcinoma in situ (AIS) of the cervix is a premalignant precursor to cervical adenocarcinoma. The usual interval between clinically detectable AIS and early invasion appears to be at least five years, suggesting ample opportunity for screening and intervention [1,2]. Appropriate management can prevent the occurrence of invasive disease in many cases [3].

The diagnosis and management of AIS are reviewed here. Related topics are discussed separately, including:

Glandular cells on cervical cytology (see "Cervical cytology: Evaluation of atypical and malignant glandular cells")

Invasive adenocarcinoma of the cervix (see "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis" and "Invasive cervical adenocarcinoma")

EPIDEMIOLOGY — AIS is much less common than its squamous counterpart, cervical intraepithelial neoplasia (CIN) grade 3 (previously called severe dysplasia or carcinoma in situ). In a multistate surveillance study in the United States from 2008 to 2015, 470 AIS cases were documented compared with 6587 CIN 3 cases [4]. The median age of patients with AIS was older than those with CIN 3: 35 versus 31 years. White patients accounted for 69 percent of AIS cases versus 53 percent of CIN 3 cases. In contrast to previous data reporting an increase in AIS and adenocarcinoma incidence rates in recent decades [5], this study reported AIS decreased significantly in the 21 to 24 year age group, but not in any of the older age groups, and suggested that the decline was due to increasing use of human papillomavirus vaccination.

RISK FACTORS — The risk factors for AIS are the same as for invasive cervical adenocarcinoma, most notably human papillomavirus infection, particularly with subtypes 16 or 18 [6,7]. Risk factors for cervical adenocarcinoma are discussed in detail separately. (See 'Human papillomavirus' below and "Invasive cervical adenocarcinoma", section on 'Epidemiology and risk factors'.)

CLINICAL FINDINGS

Clinical presentation — AIS of the cervix is typically detected as a result of cytologic cervical cancer screening. It is nearly always asymptomatic and generally not visible on physical (speculum) examination.

Rarely, patients with AIS present with vaginal bleeding, which may be postcoital [8,9]. Speculum examination may reveal that the cervix is the source of vaginal bleeding and thus prompt evaluation with cervical cytology.

Cervical cytology — Among patients with atypical glandular cells (AGC) on cervical cytology, 3 to 4 percent are subsequently diagnosed with AIS and 1 to 2 percent with adenocarcinoma [10,11]. Among patients diagnosed with AIS, 55 percent have a coexisting squamous lesion [12-14].

Looked at in another way, in patients who go on to receive a diagnosis of AIS, cervical cytology revealed glandular abnormalities (AGC, AIS, or adenocarcinoma) in 50 to 69 percent of patients, squamous abnormalities in 26 to 31 percent (mostly high-grade squamous intraepithelial lesions), glandular and squamous abnormalities in 15 percent, and no abnormalities in 4 percent [15,16]. (See "Cervical cytology: Evaluation of atypical and malignant glandular cells", section on 'Risk of premalignant or malignant disease'.)

Human papillomavirus — Human papillomavirus (HPV) 16 was detected in 57 percent of patients with AIS and HPV 18 was detected in 38 percent in a population-based surveillance study of patients with AIS or cervical intraepithelial neoplasia (CIN) grade 3 conducted from 2008 to 2015 [4]. By comparison, the rates of HPV 16 and 18 in patients with CIN 3 were 58 and 5 percent, respectively.

Colposcopy — AIS has similar colposcopic findings as high-grade cervical intraepithelial lesions, but the abnormalities are more likely to involve the columnar epithelium, while CIN lesions are almost always at the squamocolumnar junction. (See "Colposcopy", section on 'Findings'.)

DIAGNOSIS — AIS of the uterine cervix is a microscopic histologic diagnosis based on tissue initially obtained from colposcopic-directed cervical biopsy and/or endocervical curettage (ECC) and confirmed by a diagnostic excisional procedure. (See 'Diagnostic excisional procedure' below.)

The diagnostic evaluation leading to cervical biopsy/ECC is guided by the findings on cervical cytology.

(See "Cervical cytology: Evaluation of atypical and malignant glandular cells".)

(See "Cervical cancer screening: Risk assessment, evaluation, and management after screening".)

Histopathology — The normal glandular architecture of the endocervical glands may be preserved in AIS, but the glands are lined by atypical columnar epithelial cells (picture 1) similar to those of invasive cervical adenocarcinoma but without stromal invasion. The most common histologic subtype is endocervical [17,18].

AIS lesions usually originate at the transformation zone with contiguous extension proximally within the endocervical canal. Lesions may also be located high in the endocervical canal and involve the deeper portions of the endocervical clefts. However, the pattern of AIS lesions varies, making diagnosis of the full extent of disease difficult in some cases. Ten to 15 percent of patients have multifocal disease ("skip" lesions) with foci of AIS that are separated by at least 2 mm of normal mucosa [19].

CONFIRMATION OF DIAGNOSIS AND ASSESSMENT OF EXTENT OF DISEASE — Nonpregnant patients with cervical AIS diagnosed with colposcopic-directed biopsy or endocervical curettage (ECC) require a diagnostic excisional procedure to confirm the diagnosis (ie, exclude invasive disease) and assess the extent of disease.

AIS is rarely diagnosed during pregnancy [20]. A diagnostic excisional procedure and ECC are generally discouraged in pregnant patients but may be performed if invasive disease is suspected. Evaluation and management of preinvasive and invasive cervical cancer in pregnant patients are discussed separately. (See "Cervical cancer in pregnancy".)

Diagnostic excisional procedure — A diagnostic excisional procedure is performed in order to obtain an intact specimen with interpretable margins. One of several techniques can be used, including cold knife conization (CKC), loop electrosurgical excision procedure (LEEP), or laser conization (see "Cervical intraepithelial neoplasia: Diagnostic excisional procedures"). Ideally, a single surgical specimen should be obtained measuring at least 10 mm in length [21]. In patients in whom future pregnancy is not planned and the concerns about potential adverse pregnancy complications are low, this can be increased to 18 to 20 mm. These measurements are preferred, regardless of whether hysterectomy is planned.

There is no evidence that the type of diagnostic excisional procedure impacts outcomes as long as a negative margin is achieved. In our practice, we prefer CKC because:

CKC specimens typically have a greater depth and width compared with LEEP specimens [22-24].

LEEP and laser conization specimens may have significant thermal artifact at the edges, especially when not expertly performed, which may obscure assessment of the margins.

CKC specimens are designed to be excised in one piece and are easily marked at the 12 o'clock position, allowing the pathologist to report the anatomic location of a positive margin. LEEP specimens may be removed in two or more pieces, typically unoriented, so that margins are more likely to be uninterpretable by the pathologist.

In expert hands, CKC, LEEP, and laser conization are all reasonable approaches, yet CKC may have a higher likelihood of negative margins for the reasons stated above. LEEP may be selected because of clinician preference for an office procedure rather than a procedure under anesthesia in the operating room or, more commonly, because there was no preoperative suspicion of glandular disease during treatment of a high-grade squamous intraepithelial lesion [15,25]. If LEEP is performed, an additional pass with a smaller diameter loop ("top hat") should not be performed as one uninterrupted surgical specimen is preferred [21]. Patients who undergo LEEP are managed the same way as those who undergo CKC [25]. Laser conization results in a specimen of comparable size to CKC but is limited by the need for specialized training and equipment.

Post-diagnostic excisional procedure endocervical curettage — Endocervical sampling above the excisional bed is preferred after completing the diagnostic excisional procedure since it does not add to operative risk and potentially provides additional reassurance (if negative) or indicates the need for another excision (if positive) [21,26]. We consider the ECC results to be part of the margin status (ie, a positive ECC is a positive margin). Data conflict regarding whether performing ECC provides additional information regarding the likelihood of residual disease beyond that provided by positive or negative margin status of the cone biopsy [26-28].

APPROACH TO MANAGEMENT — Hysterectomy is the standard treatment for AIS; the alternative is an excisional procedure followed by surveillance. The choice of approach depends on future childbearing plans and whether excisional margins and endocervical curettage (ECC) specimens are free of disease. Some patients with AIS on colposcopic-directed biopsy will not have AIS in the cone biopsy or ECC specimen: We manage them the same way as patients with AIS in the excisional specimen and negative ECC and excisional margins since a histologic diagnosis of AIS has been previously documented.

The following recommendations are consistent with guidelines from the American Society for Colposcopy and Cervical Pathology, the United States National Comprehensive Cancer Network, and the American College of Obstetricians and Gynecologists [21,29,30]. Based upon the complexity of managing AIS, referral to a gynecologic oncologist is generally preferred [30].

Patients with AIS who do not desire fertility preservation — We recommend hysterectomy for patients with AIS who do not desire fertility preservation. Hysterectomy eliminates residual disease, which is likely to progress to invasive disease, although this may take five or more years [1,2]. Hysterectomy also reduces the risks of developing recurrent AIS and missing a concomitant or subsequent adenocarcinoma. Although there are rare reports of a diagnosis of cervical adenocarcinoma years after hysterectomy for treatment of AIS [31,32], these reports most likely represent adenocarcinoma that was not recognized at the time of hysterectomy, even though in both of the reported cases the hysterectomy specimen showed AIS without evidence of invasive disease with negative margins.

For patients with excisional margins or ECC positive for AIS, an excisional procedure alone is associated with a high risk for residual/recurrent AIS or adenocarcinoma. In a meta-analysis of observational studies evaluating the predictive value of excisional margin status in patients with AIS, when the initial excisional margin was positive, the rate of residual or recurrent AIS was 19.4 and 52.8 percent, respectively, and the rate of concomitant or subsequent invasive adenocarcinoma was 5.2 percent, based on data from patients who underwent hysterectomy or repeat conization [14].

For patients with excisional margins and ECC negative for AIS, we still recommend hysterectomy because the alternative, surveillance, has not been proven effective in preventing progression to invasive disease. Because of the pattern of disease distribution of AIS (multifocal, high in the endocervical canal, inside endocervical clefts), negative margins on a cone biopsy specimen or a negative ECC does not necessarily ensure that the lesion has been completely excised. This also greatly limits the ability of surveillance with cervical cytology, colposcopy, biopsy, and endocervical sampling to detect residual or recurrent disease or adenocarcinoma, so adenocarcinoma may be diagnosed at a more advanced stage, reducing survival compared with hysterectomy soon after conization. In the meta-analysis described above, when the initial excisional margin was negative, the rate of residual or recurrent AIS was 2.6 and 20.3 percent, respectively, and the rate of concomitant or subsequent invasive adenocarcinoma was 0.07 percent [14]. By comparison, the risk of morbidity from extrafascial hysterectomy is 4 to 6 percent (table 1). (See "Hysterectomy: Abdominal (open) route", section on 'Complications'.)

Patients with AIS who desire fertility preservation — For patients who desire fertility preservation and who have excisional margins or ECC positive for AIS, we perform a repeat diagnostic excisional procedure approximately six weeks after the first excisional procedure to allow for sufficient healing and resolution of inflammation of the cervix. If the repeat excisional margin or ECC is also positive, we recommend hysterectomy to reduce the risks of residual or recurrent disease and concomitant or subsequent invasive adenocarcinoma, as described above. Although a third excisional procedure is sometimes technically feasible, the risk of operative complications and preterm delivery in subsequent pregnancy increases with repeat procedures (see "Cervical intraepithelial neoplasia: Diagnostic excisional procedures", section on 'Complications' and "Reproductive effects of cervical excisional and ablative procedures"). If hysterectomy becomes necessary, patients of reproductive age who have not undergone concomitant oophorectomy may be candidates for in vitro fertilization using a gestational carrier. (See "Gestational carrier pregnancy".)

If the initial or repeat excisional margin and the ECC are negative, surveillance is an acceptable option for patients who are willing to accept a higher risk of subsequent diagnosis of cervical adenocarcinoma since negative margins do not eliminate the risk of residual or recurrent AIS or concomitant or subsequent invasive adenocarcinoma, as described above [14]. (See 'Patients with AIS who do not desire fertility preservation' above.)

Patients who desire fertility preservation should be informed that excisional cervical procedures are associated with a range of adverse reproductive outcomes in subsequent pregnancies. Fertility and obstetric outcomes for patients managed conservatively for AIS are believed to be similar to those for patients who have undergone an excisional procedure for cervical intraepithelial neoplasia (see "Reproductive effects of cervical excisional and ablative procedures"). Reproductive outcomes have not been well studied specifically in patients with AIS, but in one of the largest series (n = 101 patients with AIS), 35 patients achieved a total of 49 pregnancies during a mean follow-up of 52 months [22]. There were 35 term deliveries (76 percent), 2 preterm births secondary to preterm prelabor rupture of membranes, 8 spontaneous first-trimester miscarriages, 3 elective pregnancy terminations, and 1 ectopic pregnancy.

Patients with adenocarcinoma on cone biopsy — Patients with adenocarcinoma on conization are upstaged and evaluated and treated as appropriate. (See "Invasive cervical adenocarcinoma".)

Patients with concurrent squamous intraepithelial neoplasia or carcinoma — Coexistent squamous lesions are managed as appropriate for the squamous finding. (See "Cervical intraepithelial neoplasia: Management" and "Invasive cervical cancer: Staging and evaluation of lymph nodes".)

PREPARATION AND CHOICE OF PROCEDURE FOR HYSTERECTOMY IN PATIENTS WHO CHOOSE DEFINITIVE THERAPY — For patients with negative excisional margins, total extrafascial hysterectomy, performed either vaginally or by minimally invasive technique, is adequate treatment for AIS. If a laparoscopic approach is used, morcellation should be avoided because an intact specimen is important for evaluation of disease margins, particularly given the likelihood of skip lesions in AIS or an occult invasive adenocarcinoma that might have been missed with a diagnostic excisional procedure. (See "Hysterectomy: Vaginal" and "Hysterectomy: Laparoscopic".)

The choice of procedure for patients with positive excisional margins is less clear.

One of our contributors (JS) proceeds directly to definitive treatment with an extrafascial hysterectomy given the chance of a patient having more than a microscopic invasion (stage IA1: measured stromal invasion ≤3 mm in depth) is small (5.2 percent based on the data above [14]) and stage IA1 disease would also be treated with an extrafascial hysterectomy. A minimally invasive modified radical hysterectomy with sentinel lymph node mapping is an acceptable alternative to extrafascial hysterectomy in these patients [21].

On the other hand, another of our contributors (BG) repeats the excisional procedure in order to exclude invasive disease beyond the margin. This avoids the possibility of performing only an extrafascial hysterectomy in the setting of an occult invasive cancer that should be staged and treated with a more radical surgical procedure.

If the second excisional margin is negative for invasive disease, she then performs an extrafascial hysterectomy six weeks later (to allow the conization bed to heal).

If the second excisional margin continues to be positive for AIS, she performs a modified radical hysterectomy with concomitant lymph node dissection or sentinel lymph node mapping. The decision to perform an open procedure versus a minimally invasive approach is discussed elsewhere. (See "Radical hysterectomy".)

The American Society for Colposcopy and Cervical Pathology guideline considers a repeat excisional procedure to achieve negative margins the preferred approach, followed by definitive treatment with either a simple or modified radical hysterectomy [21].

The ovaries may be conserved. (See "Elective oophorectomy or ovarian conservation at the time of hysterectomy".)

MONITORING AFTER SURGICAL THERAPY

Monitoring post-hysterectomy — Patients in whom adenocarcinoma is discovered in the hysterectomy specimen should be evaluated and managed as appropriate. (See "Invasive cervical adenocarcinoma".)

The optimal surveillance strategy for patients without adenocarcinoma has not been established, and clinical practice is variable. We follow the protocol advised by the American Society for Colposcopy and Cervical Pathology (ASCCP (algorithm 1)) and perform vaginal fornix testing for high-risk (ie, carcinogenic or cancer associated) human papillomavirus (HPV) types annually for three years after hysterectomy [21,33].

After three consecutive negative tests, HPV-based testing is performed at 3-year intervals for at least 25 years. If the patient remains in good health, testing can continue beyond the age of 65.

If HPV is positive, cytology should be performed. If cytology is abnormal, we evaluate with vaginal colposcopy. If colposcopy and biopsy are positive for high-grade vaginal dysplasia (glandular or squamous), the patient is treated either with an ablative procedure (eg, carbon dioxide laser or ultrasonic surgical aspiration) or excision.

If vaginal cytology results are normal, but high-risk HPV testing is positive, both tests are repeated at the next surveillance visit. If the vaginal cytology remains normal and the HPV test remains positive, colposcopy is performed with biopsy and further treatment based on the findings. (See "Colposcopy", section on 'Vaginal colposcopy'.)

Monitoring post-excisional procedure — There are no data to establish the optimal surveillance schedule for patients treated for AIS with a diagnostic excisional procedure alone. We follow the protocol advised by the ASCCP, the United States National Comprehensive Cancer Network, and the American College of Obstetricians and Gynecologists (algorithm 1) [21,29,30,33,34].

Co-testing with cervical cytology and high-risk HPV testing with endocervical curettage (ECC) every six months for three years. Colposcopy may also be performed, but it is often difficult to see the entire transformation zone and thus is unsatisfactory.

When both cervical cytology and high-risk HPV testing have been consistently negative for three years, the surveillance interval may be extended to annually for two years. If testing remains negative, HPV-based testing is performed at 3-year intervals until a hysterectomy has been performed or for at least 25 years. If the patient remains in good health, testing can continue beyond the age of 65.

If either cytology or HPV testing are abnormal during follow-up, the patient should be evaluated with colposcopy and ECC. Patients with adequate and negative colposcopy and a negative ECC may resume the surveillance protocol described above. Patients with recurrent AIS or high-grade squamous dysplasia on colposcopic-guided biopsy and/or ECC should undergo a repeat cervical excisional procedure or hysterectomy.

Options after completion of childbearing — After completion of childbearing, we suggest that patients with AIS who were treated with a diagnostic excisional procedure alone undergo hysterectomy. Hysterectomy reduces the risk of adenocarcinoma almost entirely compared with a 1 percent risk following an excisional procedure alone, as discussed above [14]. (See 'Patients with AIS who do not desire fertility preservation' above.)

No trials have compared continued surveillance versus deferred hysterectomy in this patient population, no studies have evaluated treatment decisions based on the results of interim cytology/HPV testing, and most studies of conservative management have followed patients for less than five years. Given the absence of data showing worse outcomes, continued surveillance is also a reasonable choice for patients who have had consistently normal testing, particularly for five or more years, following an excisional procedure. Patients can be informed that the largest series of patients who chose treatment of AIS with conization to preserve fertility included only 101 patients and had a follow-up period of an average of four years (range: 4 months to 12 years) [22]. There were no cases of adenocarcinoma, two of five patients who ultimately underwent hysterectomy had residual AIS in the hysterectomy specimen and had also had a positive excisional margin, but whether surveillance findings were the indication for hysterectomy was not reported.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cervical cancer screening, prevention, and management" and "Society guideline links: Treatment of cervical cancer".)

SUMMARY AND RECOMMENDATIONS

Epidemiology – Adenocarcinoma in situ (AIS) of the cervix is a premalignant precursor to cervical adenocarcinoma. It is less common than its squamous counterpart, cervical intraepithelial neoplasia grade 3 (CIN 3). The median age of patients with AIS is approximately 35 years, and White patients account for most cases. (See 'Introduction' above and 'Epidemiology' above.)

Risk factors – Risk factors are the same as for invasive cervical adenocarcinoma, most notably human papillomavirus (HPV) infection, particularly with subtype 16 or 18. (See 'Risk factors' above.)

Clinical presentation – AIS is nearly always asymptomatic and is not visible upon gross visual examination. It is typically detected as a result of cytologic cervical cancer screening. Either glandular or squamous cytologic abnormalities may precede the histologic diagnosis of AIS. (See 'Clinical presentation' above and 'Cervical cytology' above.)

Diagnosis

AIS is histologic diagnosis based on tissue initially obtained from colposcopic-directed cervical biopsy and/or endocervical curettage (ECC) and confirmed by a diagnostic excisional procedure. (See 'Diagnosis' above.)

The pattern of AIS lesions varies, making diagnosis of the full extent of disease difficult in some cases. Lesions usually originate at the cervical transformation zone and extend proximally within the endocervical canal. Lesions may also be located high in the endocervical canal and involve the deeper portions of the endocervical clefts. Most lesions are contiguous, but 10 to 15 percent of patients have multifocal disease ("skip" lesions). (See 'Histopathology' above.)

Nonpregnant patients with cervical AIS diagnosed with colposcopic-directed biopsy or ECC require a diagnostic excisional procedure to confirm the diagnosis (ie, exclude invasive disease) and assess the extent of disease. In our practice, we prefer cold knife conization (CKC) to a loop electrosurgical excision procedure since CKC better preserves the specimen's margins for interpretation. We perform ECC after completing the cone biopsy and consider the ECC results to be part of the margin status (ie, a positive ECC is a positive margin). (See 'Confirmation of diagnosis and assessment of extent of disease' above.)

Outcomes – Outcomes of conservative management of AIS vary by excisional margin status. In patients with negative margins from the initial excisional procedure, the rates of residual AIS, recurrent AIS, and concomitant or subsequent invasive adenocarcinoma are approximately 2.6, 20, and <1 percent, respectively; with positive margins, these rates are approximately 19, 53, and 5 percent, respectively. (See 'Patients with AIS who do not desire fertility preservation' above.)

Management for patients done with childbearing

With negative margins – For patients with AIS who do not wish to preserve fertility and have negative margins on conization, we suggest total extrafascial hysterectomy, preferably performed vaginally or as a laparoscopic-assisted vaginal hysterectomy rather than surveillance (Grade 2C). Hysterectomy eliminates residual AIS (if present), which is likely to progress to invasive disease, and reduces the risks of developing recurrent AIS and missing a concomitant or subsequent adenocarcinoma. Surveillance is an option for those who value avoiding the potential morbidity of hysterectomy more than avoidance of an approximately 1 percent risk of cervical adenocarcinoma. (See 'Patients with AIS who do not desire fertility preservation' above.)

With positive margins – For patients with AIS who do not wish to preserve fertility and have positive margins on the initial diagnostic excisional procedure, the choice of procedure is less clear. Our contributors differ in their practice, with one proceeding directly to hysterectomy and another performing a repeat excisional procedure to exclude the presence of invasive disease beyond the initial margin. After the repeat excisional procedure, if margins are still positive, this contributor suggests a modified radical hysterectomy with concomitant pelvic lymph node dissection or sentinel lymph node mapping, rather than extrafascial hysterectomy, since invasive disease has not been adequately excluded (Grade 2C). (See 'Preparation and choice of procedure for hysterectomy in patients who choose definitive therapy' above.)

Management for patients desiring fertility preservation

With negative margins or ECC – For patients with AIS who desire fertility preservation and have a negative initial or repeat excisional margin and negative ECC, surveillance is an acceptable option if they are willing to accept a higher risk of subsequent diagnosis of cervical adenocarcinoma, as negative margins do not eliminate the risk of residual or recurrent AIS or concomitant or subsequent invasive adenocarcinoma. (See 'Patients with AIS who desire fertility preservation' above and 'Monitoring post-excisional procedure' above.)

With positive margins or ECC – For patients with AIS who desire fertility preservation and have excisional margins or ECC positive for AIS, we perform a repeat excisional procedure approximately six weeks after the first excisional procedure to allow for sufficient healing and resolution of inflammation of the cervix. If the repeat excisional margin or ECC is also positive, we suggest a modified radical hysterectomy with concomitant pelvic lymph node dissection or sentinel lymph node mapping rather than another excisional procedure (Grade 2C). The risk of operative complications and preterm delivery in subsequent pregnancy increases with repeat excisional procedures. (See 'Patients with AIS who desire fertility preservation' above.)

After completion of childbearing – For patients who opt for fertility preservation, we suggest hysterectomy after completion of childbearing (Grade 2C). Continued surveillance is a reasonable option for patients who have had consistently normal testing, particularly for five or more years, following an excisional procedure. (See 'Monitoring post-excisional procedure' above and 'Options after completion of childbearing' above.)

Postprocedure monitoring – The optimal surveillance strategy for patients with AIS treated with hysterectomy or a diagnostic excisional procedure has not been established, and clinical practice is variable. We follow the protocol advised by the American Society for Colposcopy and Cervical Pathology (ASCCP (algorithm 1)). (See 'Monitoring after surgical therapy' above.)

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References

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