Cervical Adenocarcinoma In Situ Research Articles

Conservative Treatment for Cervical Adenocarcinoma In Situ: Long-Term Results.

This study aimed to evaluate the effectiveness of conservative treatment for cervical adenocarcinoma in situ (AIS). This is a retrospective study on women with histologically confirmed AIS on cervical loop electrosurgical excision procedure specimen, treated conservatively between 2008 and 2020 in our center, Ospedale Maggiore Policlinico, Milan. The main outcome investigated was the risk of recurrence defined as a subsequent finding of recurrent AIS or invasive adenocarcinoma in a long-term follow-up. The disease-free survival curve was computed using the Kaplan-Meyer method. All patients underwent colposcopy with endocervical curettage and cytology every 6 months for the first 2 years after initial surgery and then annual cytology. Thirty women, aged 26 to 51 years, with histologically proven AIS on excisional specimen with negative margins, negative apex, and negative endocervical curettage were included. The median follow-up was 5.4 years. One woman had a recurrence of AIS after 8 years of follow-up and underwent total hysterectomy. No invasive cervical disease was detected during surveillance. Women with cervical AIS can be managed conservatively by an excisional procedure, provided that the margins are free and a close and long-term follow-up is guaranteed.

Prevalence and frequencies of human papilloma virus types in adenocarcinoma in situ of the uterine cervix

Objective: To examine the prevalence and frequencies of human papillomavirus (HPV) genotypes in cervical adenocarcinoma in situ (AIS). Methods: The cases of cervical AIS with concurrent tests of cytology and HPV typing from January 2007 to February 2020 in the Obstetrics and Gynecology Hospital of Fudan University were collected and analyzed. Results: A total of 478 cases of cervical AIS were obtained. The average age of the patients was 39.4 years (range, 19-81 years). The largest age group was 30-39 years (44.8%), followed by 40-49 years (34.7%). Among the 478 patients, 355 underwent high-risk HPV (hrHPV) testing and had a hrHPV-positive rate of 93.8%. Of the 355 patients, 277 also underwent HPV typing and were mostly positive for either or both HPV16 and HPV18 (93.1%), with 55.6% positive for HPV18 and 48.7% positive for HPV16. Among the 478 cases, 266 cases (55.6%) were diagnosed with both AIS and squamous intraepithelial lesion (SIL), while 212 cases (44.4%) were diagnosed with only AIS. Patients infected with HPV16 in the AIS and SIL group significantly outnumbered those in the AIS alone group (P<0.05). Moreover, the rate of positive cytology was 55.9% (167/299 cases), while that of negative cytology was 44.1% (132/299). Among the 109 patients with negative cytology results and co-tested hrHPV, there were 101 HPV-positive cases (92.7%), of which 88 cases were subject to HPV typing and showed an HPV16/18 positive rate of 94.3% (83/88 cases). Conclusions: The combination of HPV typing and cytological screening can maximize the detection rate of cervical AIS, and should continue to be utilized, ideally on a larger scale, in the future.

Adenocarcinoma in situ or early-stage cervical cancer is a risk factor for preterm delivery after cervical conization: a multicenter observational study

Objective Pregnancy after conization is associated with a high risk of preterm delivery. However, because risk factors for preterm delivery after conization remain unknown, we conducted a multicenter observational study to investigate risk factors associated with preterm delivery. Methods We selected patients who had previously undergone conization and reviewed medical records from 18 hospitals in cooperation with Keio University School of Medicine between January 2013 and December 2019. Women were classified as nulliparous and primiparous, and a multiple logistic regression analysis was performed to evaluate the relative contributions of the various maternal risk factors for preterm delivery (i.e. delivery before 37 gestational weeks). Results Among 409 pregnant women after conization, 68 women delivered preterm (17%). The incidence of nulliparity (p = .014) was higher and a history of preterm delivery (p = .0010) was more common in the preterm delivery group than in the term delivery group. Furthermore, the proportion of women diagnosed with adenocarcinoma in situ (AIS) and cervical cancer in the preterm delivery group was higher than that in the term delivery group (p = .0099 and .0004, respectively). In multiple regression models in nulliparous women, cervical cancer or AIS (Odds ratio [OR]: 4.16, 95% CI: 1.26–13.68, p = .019) and a short cervix in the second trimester (OR: 13.41, 95% CI: 3.88–46.42, p < .0001) increased the risk of preterm delivery. Furthermore, a history of preterm delivery (OR: 7.35, 95% CI: 1.55–34.86, p = .012), cervical cancer or AIS (OR: 5.07, 95% CI: 1.24–20.73, p = .024), and a short cervix in the second trimester (OR: 4.29, 95% CI: 1.11–16.62, p = .035) increased the risk of preterm delivery in the multiple regression models in primiparous women. Conclusion Pregnant women who previously underwent conization are at risk for preterm delivery. The histological type of AIS and cervical cancer was evaluated as a risk factor for preterm delivery. KEY MESSAGES Prior preterm delivery, presence of a short cervix, and cervical cancer or AIS were predictors of preterm delivery after conization. The depth of conization in cervical cancer or AIS group was significantly larger than that in the CIN group.

Risk stratified management of cervical adenocarcinoma in situ based on cone margin state

Objective: To investigate the hierarchical management scheme of cervical adenocarcinoma in situ (AIS) based on cervical conization margin state. Methods: All medical records of 249 patients diagnosed as AIS by loop electrosurgical excision procedure (LEEP) conization from Jan. 2010 to Dec. 2015 in Obstetrics and Gynecology Hospital of Fudan University were retrospectively reviewed, to explore the relationship between the status of the resection margin and the residual lesion after LEEP, and the multivariate logistic regression method was used to analyze the related factors that affect the residual lesion after LEEP in cervical AIS patients. Results: (1) The age of 249 cervical AIS patients was (40±8) years old (range: 23-71 years old). Of the 249 patients, 19 (7.6%, 19/249) had residual lesions; 69 cases were pathologically diagnosed as AIS after LEEP, and the residual lesion rate was 13.0% (9/69), which was significantly higher than that of AIS + high-grade squamous intraepithelial lesion [5.6% (10/180); χ2=3.968,P=0.046]; 33 cases were multifocal lesions, the residual rate of lesions was 21.2% (7/33), which was significantly higher than that of single focal lesions patients [5.6% (12/216); χ2=7.858, P=0.005]; 181 patients underwent endocervical curettage (ECC) before surgery, the residual rate of lesions in ECC-positive patients was 14.0% (14/100) , significantly higher than that of ECC-negative patients [4.9% (4/81); χ2=4.103, P=0.043]. (2) Among 249 cases of AIS patients, the positive rate of resection margins after LEEP was 35.3% (88/249); the residual rate of lesions in patients with positive resection margins (14.8%, 13/88) was significantly higher than those with negative margins [3.8%(6/156); χ2=9.355, P=0.002]. The age of patients underwent total hysterectomy after LEEP was (43±7) years old, which was significantly higher than that of patients who did not undergo total hysterectomy [(37±8) years old; t=6.518, P<0.01].Among the patients underwent total hysterectomy after LEEP, 3 cases (2.0%, 3/152) had fertility requirements, while 38 cases (39.2%, 38/97) did not underwent total hysterectomy, the difference between the two groups was statistically significant (χ2=59.579, P<0.01). Among the 152 patients who underwent total hysterectomy after LEEP, the residual rate of lesions was 11.8% (18/152); the residual rate of lesions in patients with positive resection margins was significantly higher than that of patients with negative resection margins [18.8% (12/64) vs 7.0% (6/86); χ2=4.861, P=0.028]. The median follow-up time of 97 patients who did not undergo total hysterectomy after LEEP was 32 months (range: 4-70 months). During the follow-up period, 3 cases of cervical AIS recurrence (3.1%, 3/97) and were followed by hysterectomy,no invasive adenocarcinoma were seen. (3) Multivariate logistic regression analysis showed that the positive resection margin (OR=4.098, 95%CI: 1.235-13.595, P=0.021), multifocal lesions (OR=5.464, 95%CI: 1.494-19.981, P=0.010) were independent risk factors that affected the residual lesions in patients with cervical AIS after LEEP. Conclusions: The cervical AIS patients after LEEP conization suggested be stratified by cone margin state as the first-line stratified index, age and fertility needs as the second-line stratified management index. The individualized management plan should be developed based on comprehensive assessment of high-risk factors of residual lesions.

Cervical glandular neoplasia referrals and the diagnosis of adenocarcinoma in situ: Correlating cytology, colposcopy findings, and clinical outcomes.

To determine the clinical outcomes of women with possible glandular neoplasia of endocervical type on cervical cytology, and review all diagnoses of cervical adenocarcinoma in situ (AIS) over a 5year period at our institution. A retrospective case-note review was conducted of all women referred to colposcopy with possible glandular neoplasia of endocervical type on cervical cytology or diagnosed with cervical AIS after biopsy or excision, from January 2014 until December 2018 in a London district hospital. Of 55 women referred with possible glandular neoplasia of endocervical type, 47 (85.4%) had a significant pathology on histopathological analysis: AIS (n=22); invasive cancer (n=7); high-grade cervical intraepithelial neoplasia (n=18). Women with a history of borderline abnormality on cervical cytology within the last 5years were significantly more likely to be diagnosed with AIS or invasive cancer (P<.05). For the same period 49 women had histologically proven AIS. Among these 22 (44.8%) were referred as possible cervical glandular intraepithelial neoplasia. Other reasons for referral were the following indications: borderline dyskaryosis (n=13); high-grade dyskaryosis (n=8); low-grade dyskaryosis (n=4); postcoital bleeding (n=2). Due to the raised risk of significant gynaecological pathology in women with possible glandular neoplasia of endocervical type on cervical cytology, excisional biopsy is essential. Colposcopic impression varies significantly and complete excision of the abnormal lesions should be achieved. AIS is a histological diagnosis and should always be considered during colposcopical and cytopathological assessment.

Personalized Medicine and Cervical Screening: Development of Individualized Quantitative Risk Assessments for Cervical Adenocarcinoma and Adenocarcinoma in situ

Introduction: Cervical screening has decreased the incidence of cervical carcinoma around the world primarily by preventing cervical squamous carcinoma, with significantly less measurable protective benefits in prevention of cervical adenocarcinoma. In this study, we apply Bayesian modeling of cervical clinical, screening, and biopsy data from a large integrated health system to explore the feasibility of calculating personalized risk assessments on screened system patients for subsequent histopathologic diagnoses of invasive cervical adenocarcinoma (AdCa) or cervical adenocarcinoma in situ (AIS). Materials and Methods: Diagnoses of cervical AIS or AdCa rendered between 2005 and 2018 were identified in our large health system database with 1,053,713 cytology results, 354,843 high-risk (hr) human papillomavirus (HPV) test results, and 99,012 cervical histopathologic results. Using our continuously updated Bayesian cervical cancer screening model which includes clinical data, cervical screening results, and cervical biopsy results, we projected quantitative estimates of patients’ 5-year cumulative risk for cervical AIS or AdCa. Results: 161 patients were identified with AIS (ages 17–75, mean 37 years), and 99 patients had diagnoses of cervical AdCa (ages 26–91, mean 48 years). Quantitative Bayesian 5-year cumulative risk projections for diagnoses of cervical AdCa or AIS in patients with different cervical screening test and biopsy histories were determined. The highest patient risk projections for subsequent cervical AdCa and/or AIS histopathologic diagnoses were associated with prior cervical screening test results of HPV-positive atypical glandular cells. Prior squamous cytologic abnormalities were associated with lower risk estimates. Prior histopathologic diagnoses of squamous abnormalities also influenced quantitative risk. A prior histopathologic diagnosis of AIS was associated with a very low risk of subsequent AdCa, consistent with effective excisional treatment. AdCa risk was greatest in women aged 30–65 years with prior CIN3 biopsy results, whereas AIS risk was greatest in women <30. Conclusion: Prevention of cervical AdCa in screened patients remains a major challenge for cervical screening. Individualized risk projections for cervical glandular neoplasia reflecting patient age, prior cervical screening test results, and prior cervical biopsy history are feasible using Bayesian modeling of health system data.

Elevated expression of G protein-coupled receptor 30 (GPR30) is associated with poor prognosis in patients with uterine cervical adenocarcinoma.

Uterine cervical adenocarcinoma has a worse prognosis than that of squamous cell carcinoma and useful diagnostic and prognostic markers are needed. Estrogen is one of the key regulators of several cancers, however, the estrogen signaling has not been focused on in cervical adenocarcinoma. Here, we shows expression profile of classical estrogen receptor (ER) and a novel membrane type estrogen receptor, G protein-coupled receptor 30 (GPR30), in surgical specimens (n=53). GPR30 was strongly expressed on the cell membrane and in the cytoplasm in adenocarcinoma in situ (AIS) and adenocarcinoma, and its expression was especially strong at the invasion front in most of the cases of GPR30-positive adenocarcinoma. Nuclear staining of ER was strong in non-neoplastic glands, whereas it was almost absent in most of the AIS and adenocarcinoma cases. There was a weak but statistically significant negative correlation between immunoreactivity of GPR30 and that of ER in cervical AIS and adenocarcinoma lesions (Spearman's correlation, r=-0.324, p=0.017). ROC curve analysis revealed that immunoreactivity of GPR30 successfully distinguished neoplasms from non-neoplastic glands with high specificity (100%) and sensitivity (75.5%). GPR30 positivity was significantly correlated with histological type (p=0.009), tumor diameter (p=0.003), tumor size (p<0.001), lymphovascular infiltration (p=0.005) and UICC stage (p<0.001). ER expression was correlated only with tumor factor (p=0.047). GPR30-high patients had poor prognosis with a significantly shorter overall survival (OS) period (p=0.0309). GPR30 expression is a potential diagnostic and prognostic marker.

Cervical Screening Results Leading to Detection of Adenocarcinoma in Situ of the Uterine Cervix

Background:Adenocarcinoma in situ (AIS) of the uterine cervix is a preinvasive lesion of the invasive adenocarcinoma. We analyzed the cervical screening results leading to detecting the AIS lesions including the co-existence of AIS lesions with high-grade squamous intra-epithelial lesions (HSIL) and invasive carcinoma. Methods:Women who were diagnosed and received treatment for AIS at Chiang Mai University Hospital between January 1, 2007 and August 31, 2016 were retrospectively reviewed. The inclusion criteria were the women who had pathological diagnosis of AIS obtained from cervical punch biopsy or excisional cone biopsy with either loop electrosurgical excision procedure (LEEP) or cold-knife conization (CKC). The patient characteristics, diagnostic work-up and treatment details were reviewed, including the cervical screening results prior to the diagnosis of cervical AIS, pathologic results of excisional cone biopsy and hysterectomy specimens.Results:During the study period, 75 women with AIS pathology undergoing excisional cone biopsy with either LEEP (n=62) or CKC (n=13) were identified. The abnormal cytologic screening leading to detection of AIS was the squamous cell abnormality accounting for 57.3%. Abnormal glandular cytology accounted for 37.3%. The most common abnormal cervical screening results was HSIL cytology (n = 25) followed by AIS cytology (n = 13). Normal cytology was noted in 4 women in whom 3 were positive for HPV 18 and 1 had AIS on the endocervical polyp. AIS coexisted with HSIL and invasive carcinoma were detected in cone biopsy specimens in 21 (28%) and 29 (38.7%) patients, respectively. Conclusion:The majority of cervical screening results leading to detection of cervical AIS was the squamous cell abnormality accounting for 57.3% in which, HSIL cytology was the most common. Abnormal glandular cytology accounted for only 37.3%. Diagnostic cone excision is recommended if AIS lesion is noted in cervical biopsy specimen since nearly 40% have coexisting invasive lesions.

Analysis of the expression and localization of tight junction transmembrane proteins, claudin-1, -4, -7, occludin and JAM-A, in human cervical adenocarcinoma.

Tight junction proteins have recently been reported to be useful for distinguishing between neoplastic and non-neoplastic tissues. In this study, we evaluated the expression and localization of tight junction transmembrane proteins in human cervical adenocarcinoma and adenocarcinoma in situ (AIS), and we determined whether their expression patterns could distinguish cervical adenocarcinoma from non-neoplastic cervical glands. Fifty-five patients with cervical adenocarcinoma or AIS were included in this study. Surgical specimens were immunohistochemically stained for claudin (CLDN) -1, -4, -7, occludin, and JAM-A. Significantly higher expression levels of CLDNs and JAM-A were found in cervical AIS and adenocarcinoma than in non-neoplastic glands. In cervical AIS and adenocarcinoma, localization of CLDN1 and JAM-A was extended throughout the whole cell membranes, whereas they were predominantly expressed at the most apical cell-cell junction in non-neoplastic glands. ROC curve analysis revealed that immunoreactivities of CLDN-1 or JAM-A successfully distinguished neoplasms from non-neoplastic cervical glands with high specificity (CLDN-1, 79.1%; JAM-A, 79.1%) and high sensitivity (CLDN-1, 84.1%; JAM-A, 95.5%). As expected, there were immunohistochemical differences between cervical adenocarcinoma and non-neoplastic cervical glands by using antibodies against tight junction transmembrane proteins. These results suggest that CLDN-1 and JAM-A are potential biomarkers for cervical adenocarcinoma.

The effect of coexisting squamous cell lesions on prognosis in patients with cervical adenocarcinoma in situ

ObjectiveThe aim of this study was to assess the relative incidences of cervical adenocarcinoma in situ (AIS) and squamous cell carcinoma in situ (sCIS) and to determine the effect of coexisting squamous cell lesions on prognosis in patients with cervical AIS. Study designWe performed a retrospective review of patients diagnosed with AIS or sCIS who underwent cervical conization at a University hospital between 2000 and 2011. ResultsA total of 1184 patients with cervical carcinoma in situ were included. The ratio of sCIS to AIS was 16:1. Among 71 patients with AIS, AIS with coexisting squamous cell lesions and AIS alone were detected in 41 patients (58%) and 30 patients (42%), respectively. During the median follow-up of 57.1 months, 5 episodes of AIS recurrences and one episode of invasive recurrence occurred. The recurrence rate was significantly higher in patients with AIS alone than in patients with AIS and coexisting squamous cell lesions (17% versus 2%; P=0.043). ConclusionThese results suggest that patients with cervical AIS and coexisting squamous cell lesions have a more favorable prognosis than patients with AIS alone.

Cervical Adenocarcinoma In situ Presentation of the Case and Review of Incidence, Recurrence Rate and Therapeutic Options

Cervical adenocarcinoma in situ (AIS) is a Adenocarcinoma in situ of the cervix (AIS) is a premalignant lesion that was first described by Helper in 1952 in his review of adenocarcinoma of the cervix.The following year Friedal reported two women who had undergone therapy for squamous cervical lesions and had concomitant cervical AIS.These authors postulated that this glandular lesion was a precursor to invasive adenocarcinoma similar to preinvasive squamous cell carcinoma in situ. An increase in the incidence of cervical AIS has been reported in recent years. In this fact may contributed an increased prevalence of HPV18, the pathologist’s awareness of the lesion and an increase in use of oral contraceptives.

Long-Term Follow-Up Results From Women With Cervical Adenocarcinoma In Situ Treated by Conization

Cervical adenocarcinoma in situ (AIS) is the precursor to adenocarcinoma, and early management will often prevent the occurrence of invasive adenocarcinoma. Conservative treatment with conization has been proposed for the initial treatment for cervical AIS. To evaluate the risk of residual/recurrent disease after conization, we investigated the long-term follow-up results for patients with cervical AIS treated by conization. One hundred thirty-six patients with a biopsy diagnosis of cervical AIS followed by conization were followed up with cytologic, histologic, and human papillomavirus testing. The rate of residual AIS in the following hysterectomy was significantly increased in patients with positive margins on the conization (48.6%, 17/35) compared to patients with negative margins (0/30). No significant disease was identified in patients treated by hysterectomy as primary treatment. More importantly, only 2 patients with conization as primary management had adenocarcinoma or focal AIS, respectively, during a long-term follow-up period (mean, 45 mo). However, one of them had positive margin on the conization and did not proceed to further treatment. The other one had negative margin on the conization but only had focal AIS on the hysterectomy. Human papillomavirus-positive rate showed no significant difference between patients treated by conization and patients treated by hysterectomy during the long-term follow-up. Therefore, if a negative resection margin is achieved, conservative management with conization and careful surveillance is suitable for patients with cervical AIS and desire for future childbearing.

Premalignant lesions of the lower female genital tract: cervix, vagina and vulva

Premalignant lesions of the lower female genital tract encompassing the cervix, vagina and vulva are variably common and many, but by no means all, are related to infection by human papillomavirus (HPV). In this review, pathological aspects of the various premalignant lesions are discussed, mainly concentrating on new developments. The value of ancillary studies, mainly immunohistochemical, is discussed at the appropriate points. In the cervix, the terminology and morphological features of premalignant glandular lesions is covered, as is the distinction between adenocarcinoma in situ (AIS) and early invasive adenocarcinoma, which may be very problematic. A spectrum of benign, premalignant and malignant cervical glandular lesions exhibiting gastric differentiation is emerging with lobular endocervical glandular hyperplasia (LEGH), including so-called atypical LEGH, representing a possible precursor of non HPV-related cervical adenocarcinomas exhibiting gastric differentiation; these include the cytologically bland adenoma malignum and the morphologically malignant gastric type adenocarcinoma. Stratified mucin producing intraepithelial lesion (SMILE) is a premalignant cervical lesion with morphological overlap between cervical intraepithelial neoplasia (CIN) and AIS and which is variably regarded as a form of reserve cell dysplasia or stratified AIS. It is now firmly established that there are two distinct types of vulval intraepithelial neoplasia (VIN) with a different pathogenesis, molecular events, morphological features and risk of progression to squamous carcinoma. These comprise a more common HPV-related usual type VIN (also referred to as classic, undifferentiated, basaloid, warty, Bowenoid type) and a more uncommon differentiated (simplex) type which is non-HPV related and which is sometimes associated with lichen sclerosus. The former has a relatively low risk of progression to HPV-related vulval squamous carcinoma and the latter a high risk of progression to non-HPV related vulval squamous carcinoma. Various aspects of vulval Paget's disease are also discussed.

Risk of residual disease and invasive carcinoma in women treated for adenocarcinoma in situ of the cervix

ObjectiveCervical adenocarcinoma in situ (AIS) is increasing in incidence among reproductive-age women. Cervical conization is an alternative to hysterectomy that allows future fertility, however reports regarding the risk of residual AIS and underlying adenocarcinoma are conflicting. The purpose of this study was to determine the outcomes of a large cohort of women treated for AIS. MethodsThe medical records of 180 women with cervical AIS evaluated at the University of Texas MD Anderson Cancer Center and its outlying clinics between 1983 and 2011 were reviewed for demographic information, treatment history, pathologic findings and outcomes. ResultsThe mean age at diagnosis was 33.8years (range 17.6–76.1years). 172 of the 180 women had at least one cone biopsy performed, with 110 (64.0%) undergoing a cold knife cone (CKC), and 62 (36.0%) undergoing a loop electrosurgical excision procedure (LEEP) as their initial method of treatment. Positive margins were noted in 35.0% of patients undergoing CKC compared with 55.6% undergoing LEEP (p=0.017). 71 patients ultimately underwent hysterectomy with residual disease noted in 10 patients (14.1%), 8 patients (11.3%) with residual AIS and 2 patients (2.8%) with invasive carcinoma. Of the 101 patients who did not undergo hysterectomy, 2 patients (2.0%) developed recurrent AIS at a median of 27.5months (range 18–37months) from the last cone, and none developed invasive carcinoma. ConclusionPatients undergoing conservative management for AIS with cervical conization alone should be monitored closely and counseled regarding the potential risks of residual and recurrent disease, even when negative cone margins are obtained.

Outcomes of pregnant patients with Pap smears classified as atypical glandular cells

The incidence of cervical cancers increases with age. Due to the trend of increasing age of first pregnancy, abnormal Pap smears including those classified as atypical glandular cells (AGC) are being found more often in early pregnancy. Once invasive cancer is excluded, conservative management of squamous intraepithelial lesions (SIL) in pregnancy is considered safe; however, optimal management of AGC is not well established. The aim of our study was to evaluate the outcome of patients with AGC diagnosed from smears during pregnancy. The study included 17 patients referred to us in early pregnancy with Pap smears reported as AGC: 11 not otherwise specified (AGC-NOS), five favour neoplasia (AGC-FN) and one adenocarcinoma in situ (AIS). Thirty-one with high-grade SIL (HSIL) Pap smears confirmed on punch biopsy in early pregnancy comprised a control group. Human papillomavirus (HPV) positivity was found in seven patients with persistent AGC-NOS (including all four who had CIN3 postpartum). All the women were initially examined by expert colposcopy and those with AGC-FN or AIS smears also by transrectal ultrasound to exclude invasive endocervical cancer. Follow-up controls were carried out every 8-12 weeks and, if there were no signs of progression, revaluation was scheduled 6-8 weeks after delivery. The mean age of the women was 31.4 years. Conization in one patient in the study group was performed in the 16th week of pregnancy due to colposcopic signs of microinvasive squamous cell cancer confirmed on histology. Progression to invasive cancer was not found in any of the other 16 patients in the study group or in the control group. Cervical intraepithelial neoplasia or AIS was confirmed postpartum by conization or punch biopsy in 47.1% (8/17) of patients in the study group and, in 77.4% (24/31) of patients in the control group. Conservative management of women with AGC in pregnancy is safe where invasive cancer is excluded. As histological verification of glandular pre-cancerous lesions by punch biopsy is not reliable and the postpartum regression rate cannot be determined precisely, conization should be performed in all cases with AGC-FN or AIS. Triage of persistent AGC-NOS with HPV testing is useful in distinguishing significant underlying lesions.

Cervical adenocarcinoma in situ with negative conization margin: negligible or not?

Frequently, clinicians confront situations that a pile of cumulated data about a disease does not help them to make clear decision. Cervical adenocarcinoma in situ (AIS) is one of them. It has been commonly believed that the disease has multifocal location and this raised the concern for the safety of conservative management in treatment of cervical AIS. Thus, even with negative conization margins, many recommend further surgery in fear of a risk of residual or recurrent disease. However, due to its relatively lower incidence than its counterpart, many studies regarding of outcome of AIS are small-sized and retrospective, which limited their usefulness as an evidence for decision-making evidence. In this issue of Journal of Gynecologic Oncology, Kim et al. [1] reported the retrospective observational data of 99 women with AIS in single institution. Despite its retrospective nature, the study provides helpful insight of the disease and is one of the large-scale observational sets currently available. The most intriguing data in the study were the incidence of residual margin and recurrence data of AIS with negative margin. The authors found the residual disease only in 4.4% of patients who underwent further surgery. On the other hand, they also found the 3.6% of recurrence rate in the AIS patients who received conservative management, which was corresponds well to the pathologic outcome of surgically managed cases. The good correspondence between incidence rate of residual lesion and the recurrence rate is very interesting, especially in light of recent systemic review by Salani et al. [2]. In the report, the authors estimated the recurrence rate as 2.6% in the conservatively-managed patients, which is well corresponds to the study by Kim et al. However, the estimated incidence of residual disease in the hysterectomy specimen was as much as 20.3%, which is evidently higher than that of data presented by Kim et al. This discrepancy is not surprising. First, in the systemic review, the authors included many case reports. Many case reports reported the disastrous outcome of conservative expectation after conization when the margin was negative. Therefore, it can be serious source of bias exaggerating the incidence of failure in margin-negative patients. Indeed, simple application of random-effect model in the previous systemic review, we can easily found that the incidence decreased to 15%. On the other hand, in the Kim's data, selection bias might have influenced and decreased the incidence of conization failure in margin-negative patients because clinicians would advise hysterectomy more frequently in the patient with higher risk. Despite the discrepancy of rate of residual disease, the good correspondence of recurrence rate of margin-negative patients between two studies (2.6% and 3.6%, respectively) gave us important insight for selecting treatment strategy because the known recurrence rate of cervical carcinoma in situ is about 2% [3,4]. For the patients with margin-negative AIS, what treatment strategy can be drawn from these data? First, it is evident that margin-negative young patients who want to preserve their fertility can be treated with conservative expectation. Second, the collective evidences suggests that margin-negative patients should be given with the choice to select between decisive hysterectomy and conservative expectation with careful follow-up, even they do not wish to retain fertility. Adequate information including warning for the chance of residual disease and low incidence of recurrence rate should be provided through patient counseling. However, considering subsequent rate of residual disease and limited accuracy in surveillance technique, definite hysterectomy still should be regarded as the gold standard in margin-negative patients.

Intestinal-Type Cervical Adenocarcinoma In Situ and Adenocarcinoma Exhibit a Partial Enteric Immunophenotype With Consistent Expression of CDX2

Most cases of cervical adenocarcinoma in situ (AIS) and adenocarcinoma are of the usual or endocervical type. However, intestinal types of AIS and adenocarcinoma exist. With an intestinal-type adenocarcinoma in the cervix, the question may arise as to whether one is dealing with a primary cervical neoplasm or direct or secondary spread from an intestinal adenocarcinoma. In organs such as the ovary, urinary bladder, esophagus, and gallbladder, intestinal-type glandular epithelium often expresses enteric markers, but this has hardly been studied in the cervix. The purpose of this study was to investigate whether intestinal-type AIS and adenocarcinoma in the cervix express enteric markers and to ascertain whether these antibodies are of value in the distinction from a metastatic intestinal adenocarcinoma. We compared the immunophenotype of these lesions with that of usual-type AIS and adenocarcinomain the cervix. Cases included were AIS of usual type (n = 6), primary cervical adenocarcinoma of usual type (n = 6), AIS of intestinal type (n = 21), primary cervical adenocarcinoma of intestinal type (n = 3), primary cervical adenocarcinoma with signet ring cells (n = 2), and colorectal adenocarcinoma involving the cervix (n = 5). All cases were stained with cytokeratin (CK) 7, CK20, monoclonal carcinoembryonic antigen (CEA), p16, and CDX2. Staining was categorized as negative, focally positive (<50% cells), or diffusely positive (50% or more cells). Usual-type AIS was always diffusely CK7 positive, typically diffusely CEA and p16 positive, and always CK20 negative. CDX2 was positive in 1 case. All usual cervical adenocarcinomas were diffusely CK7 and p16 positive, and all were immunoreactive with CEA. Five and 2 cases were CK20 and CDX2 positive, respectively. Intestinal-type AIS was diffusely CK7 positive (all cases) and typically CK20 negative and diffusely CEA and p16 positive. All but 1 case exhibited diffuse nuclear positivity with CDX2. In addition, usual-type AIS adjacent to intestinal type was CDX2 positive in 13 of 21 cases. The 3 cases of primary cervical intestinal-type adenocarcinoma were diffusely CK7 positive, focally or diffusely positive with CK20 and CDX2, and focally positive with CEA. One case was diffusely p16 positive, 1 focal and 1 negative. The foci of signet ring cells in the 2 primary cervical adenocarcinomas were diffusely CK7 and p16 positive and negative with CK20 and CDX2. Colorectal adenocarcinomas involving the cervix were typically diffusely positive with CK20, CEA, and CDX2; negative with CK7; and negative or focally positive with p16. Intestinal types of cervical AIS and adenocarcinoma exhibit a partial enteric immunophenotype, usually with diffuse expression of CDX2 and, in some cases, staining with CK20. They maintain their CK7 immunoreactivity and are usually p16 positive. Although there is immunophenotypic overlap, focal staining with CK20 together with diffuse CK7 and sometimes p16 positivity helps to distinguish intestinal types of cervical adenocarcinoma from involvement by a colorectal adenocarcinoma; CEA and CDX2 are of no value in this regard. CDX2 positivity in usual-type AIS adjacent to intestinal type and in occasional cases of pure usual-type AIS may be a reflection of early intestinal differentiation before this is morphologically apparent. Using a set of cases of AIS diagnosed in a single institution over a 7-year period (77 usual type; 13 intestinal type), intestinal type was more likely to be associated with early invasive adenocarcinoma than usual type (31% vs 17%), suggesting that intestinal differentiation may be a risk factor for invasion in premalignant cervical glandular lesions.

Human Papillomavirus (HPV) Test and PAP Smear as Predictors of Outcome in Conservatively Treated Adenocarcinoma In Situ (AIS) of the Uterine Cervix

An increasing proportion of cervical carcinomas are adenocarcinomas, and many studies have shown that both adenocarcinoma and adenocarcinoma in situ (AIS) are frequently missed by conventional cytologic study. This study examined clinical outcomes in 42 consecutive women who had conservative treatment of AIS by cervical conization and were prospectively followed up for 40 months on average by colposcopy, Pap smear, biopsy, and human papillomavirus (HPV) testing (with hybrid capture II). Six follow-up assessments were planned at 6-month intervals. All but one of the women had been referred for colposcopy because of an abnormal Pap smear. Only 43% of the 42 women had atypical glandular cells in their referral Pap smears. Colposcopy was negative in 17% of cases and unsatisfactory in another 55%. Twenty-four patients, 57% of those studied, had pure AIS, while 18 had AIS combined with a squamous-cell lesion. Four of the latter patients had invasive squamous-cell carcinoma. Persistent or recurrent disease was documented in 17 women, 40% of those enrolled in the study. The incidence was 19% in patients with free margins and 65% when involved margins were seen on initial conization. Four patients were diagnosed during follow-up as having stage IA1 adenocarcinoma. All 42 women were free of disease at the end of follow-up. Results of HPV testing were a significant predictor of the clearance or persistence of disease (odds ratio, 12.6; 95% confidence interval, 1.18-133.89). In contrast, at no time did the Pap smear have significant predictive power. The combination of a Pap smear and HPV testing was 90% sensitive and 50% specific, with positive and negative predictive values of 53% and 89%, respectively, at initial follow-up. At the second follow-up visit, the combination was 100% sensitive and 53% specific, and had positive and negative predictive values of 40% and 100%, respectively. All AIS lesions had disappeared by the time of the fourth follow-up assessment. A combination of cytology and HPV testing is clearly superior to cytology alone when monitoring women who have been conservatively treated for cervical AIS.

Fertility-sparing surgery in 101 women with adenocarcinoma in situ of the cervix

Objectives Cervical adenocarcinoma in situ (AIS) is a precursor of invasive disease that is increasing in incidence primarily among reproductive-age women of low parity. Conization is an alternative to hysterectomy that allows future pregnancy, but has an inherent risk of residual AIS. The purpose of this study was to determine the outcomes of patients treated by this fertility-sparing strategy over an extended period of surveillance. Methods Women diagnosed with cervical AIS who underwent primary fertility-sparing surgery with either loop excision or cold knife conization between 1993 and 2001 were identified at three institutions. A retrospective medical record review was performed. Patients 40 years of age and older and those undergoing hysterectomy within 12 months of diagnosis were excluded. Results A total of 101 women underwent cone biopsy and expectant management. The median age was 29 years. Fifty-seven percent were nulliparous and 23% primiparous. Cold knife conization was most commonly performed (69 vs. 32 procedures) and had a higher efficacy of achieving negative margins (72% vs. 47%; P = 0.036). Thirty-five women had a total of 49 pregnancies during a mean follow-up of 51 months. Thirty-five gestations were delivered at term. There were two preterm births, eight spontaneous miscarriages, three elective terminations, and one ectopic pregnancy. Thirty-six patients had a repeat cone biopsy. Five ultimately underwent hysterectomy. No invasive cervical adenocarcinomas were observed during the study interval. Conclusion Fertility-sparing surgery enables women with cervical AIS to achieve pregnancy with minimal risk of developing invasive disease during surveillance.

Human papillomavirus (HPV) test and PAP smear as predictors of outcome in conservatively treated adenocarcinoma in situ (AIS) of the uterine cervix

Objective The present study assessed (i) the clinical outcome of patients with conservatively treated cervical adenocarcinoma in situ (AIS), (ii) the accuracy of diagnosing AIS by cytology, colposcopy and histology, as well as (iii) the performance of cervical cytology and HPV testing in detection of residual or recurrent disease after conservatively treated AIS. Methods A series of 42 consecutive women (mean age 40.5 years; range 27–63 years) underwent conservative (cone) treatment of AIS and were prospectively followed up for a mean of 40 months (median 42 months), using colposcopy, PAP smear, biopsy and HPV testing (with hybrid capture II) repeated at 6-month intervals. Results In their referral PAP test, only 42.9% of patients had atypical glandular cells (AGC) smear. Colposcopy was unsatisfactory in 54.8% cases and negative in 16.7%. Twenty four patients (57.1%) had AIS as a pure lesions and 18 combined with squamous cell lesion (four had invasive SCC). Persistent or recurrent disease was observed in 17 (40.4%) cases, 19% in patients with free margins, and 65% among those with involved margins on the first conization. In four patients, an adenocarcinoma (AdCa) stage IA1 was diagnosed during the follow-up. HPV testing significantly predicted disease persistence/clearance with OR 12.6 (95% CI 1.18–133.89), while the predictive power of PAP smear did not reach statistical significance at any of the follow-up visits. The combination of PAP smear and HPV testing gives SE of 90.0%, SP 50.0%, PPV 52.9% and NPV 88.9% at first follow-up, and 100% SE and 100% NPV at the second follow-up visit. Conclusions These results suggest that HR-HPV test in conjunction with cytology offers clear advantages over single cytology in monitoring the women conservatively treated for cervical AIS.