Predictors of invasive adenocarcinoma after conization for cervical adenocarcinoma in situ

Objective

Modified radical hysterectomy has been advocated for the definitive treatment of patients with cervical adenocarcinoma in situ (ACIS) with positive conization margins due to the risk of a co-existing invasive cervical adenocarcinoma (ICA). We sought to identify patients who can be safely managed with an extrafascial hysterectomy based on predictors of invasion in the conization specimen.

Methods

Between 1996 and 2010, we identified 33 patients who had definitive surgical management for cervical ACIS following conization with positive margins and/or positive endocervical curettage (ECC). Demographic and pathologic characteristics were collected by chart review. Statistical analysis was performed using Fisher's exact test.

Results

Among 33 patients, 4 (12%) had ICA in the hysterectomy specimen. Predictors of ICA included pathologic suspicion of invasion (PSI) in the conization specimen and positive ECC. In patients with ICA at hysterectomy, PSI and ACIS-positive ECC were found in 75% (p = 0.32) and 100% (p = 0.09) respectively. When PSI was present and the ECC was positive, the positive predictive value (PPV) for ICA was 33% (2 of 6). When PSI was absent, the negative predictive value (NPV) for ICA was 94% (1 of 16). When both PSI and ECC were negative, the NPV for ICA was 100% (0 of 6).

Conclusions

Women with cervical ACIS have the highest risk for ICA in the setting of positive cone margins, positive ECC, and presence of PSI in the conization specimen. Extrafascial hysterectomy remains a viable option for women with positive cone margins when ECC is negative and PSI is absent.     

Management of cervical adenocarcinoma in situ during pregnancy

OBJECTIVE: Adenocarcinoma in situ (AIS) is a precursor of invasive disease that is being more frequently diagnosed during the reproductive years. Few reports have described the treatment of this condition in gravid women. The purpose of this study was to review our collective experience managing cervical AIS during pregnancy. STUDY DESIGN: Retrospective medical record review of all women diagnosed with AIS during pregnancy from 1995 to 2004 at 3 academic institutions. RESULTS: Eleven women with a median age of 32 years were identified. Five who received a diagnosis in the early second trimester underwent uncomplicated cold knife conization (CKC) at 14 to 19 weeks' gestation. Six patients underwent postpartum CKC. All 11 women delivered at term. One patient undergoing postpartum CKC required radical hysterectomy for stage IB1 cervical adenocarcinoma. Four subsequent pregnancies occurred among patients having fertility-sparing surgery. CONCLUSION: Management of cervical AIS during pregnancy by early second trimester CKC is safe for mother and fetus.     

Fertility-sparing treatment in younger women with adenocarcinoma in situ of the cervix

Objective

For women who have completed childbearing, the treatment of choice for adenocarcinoma in situ (ACIS) of the cervix is hysterectomy. In women who desire future fertility, however, conservative therapy is an acceptable alternative. In this study we compare the outcomes for young women who underwent loop conization or were treated with cold knife conization.

Methods

We performed a retrospective analysis in 112 patients with ACIS, age 30 or younger, treated with cold knife conization or loop conization between 1998 and 2010. Decision to perform office loop conization was based on the size of the cervix and the colposcopic lesion. Main outcomes were negative margins after the procedure and recurrence of ACIS.

Results

Fifty-eight patients (52%) were treated with cold knife conization and 54 (48%) underwent loop conization. The odds ratio for cold knife conization to achieve negative cone margins compared with loop conization was 1.4 (95% CI 0.6-3.5). We observed no difference in residual or recurrent ACIS between patients treated with loop conization versus cold knife conization.

Conclusions

In select young patients who desire future fertility, loop conization and cold knife conization have equivalent rates of negative margins and negative follow-up. For optimal results, patients must have a lesion which can be removed in one pass of a loop, confirmed by expert colposcopy. Loop excision should be considered the treatment of choice in this specific group of patients.     

2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ

A group of 146 experts representing 29 organizations and professional societies met Sept. 18-19, 2006, in Bethesda, MD, to develop revised evidence-based, consensus guidelines for managing women with abnormal cervical cancer screening tests. The management of low-grade cervical intraepithelial neoplasia (CIN) grade 1 has been modified significantly. Previously, management depended on whether colposcopy was satisfactory and treatment using ablative or excisional was acceptable for all women with CIN 1. In the new guidelines, cytological follow-up is the only recommended management option for women with CIN 1 who have low-grade referral cervical cytology, regardless of whether the colposcopic examination is satisfactory. Treatment is particularly discouraged in adolescents. The basic management of women in the general population with CIN 2,3 underwent only minor modifications, but options for the conservative management of adolescents with CIN 2,3 have been expanded. Moreover, management recommendations for women with biopsy-confirmed adenocarcinoma in situ are now included.     

P16 as a molecular biomarker of cervical adenocarcinoma

OBJECTIVE: Cervical adenocarcinomas are increasing in incidence each year. The aim of this study was to identify a molecular biomarker to improve early detection. STUDY DESIGN: Fifty-five in situ and invasive cervical adenocarcinomas were compared with 5 normal endocervical controls by immunohistochemical analysis of p16, p21, p27, cyclin D1, cyclin E, p53, and Ki-67. Expression was scored from 0 to 8 by using an automated imaging system. Western blotting and polymerase chain reaction-based human papillomavirus (HPV) testing were performed on 16 of the invasive cases having fresh-frozen tissue. RESULTS: P16 exhibited a higher mean expression score for in situ (7.4; P<.0001) and invasive cervical adenocarcinoma (6.6; P<.0001) versus controls (2.0). A cutoff p16 expression score of 5 had a sensitivity of 94.5% and a specificity of 100%. Western blotting confirmed p16 protein expression. Fourteen (88%) of 16 invasive cervical adenocarcinomas were HPV-positive. CONCLUSION: P16 is a putative molecular biomarker of cervical adenocarcinoma. Overexpression appears to primarily reflect HPV-induced cell cycle dysregulation.     

Prior cone biopsy: prediction of preterm birth by cervical ultrasound

OBJECTIVE: This study was undertaken to determine the predictive accuracy for preterm birth of transvaginal ultrasound (TVU) of the cervix in women with a prior cone biopsy. STUDY DESIGN: Pregnant patients with a history of cervical cone biopsy by cold knife, loop electrosurgical excision procedure (LEEP), or laser were monitored prospectively with TVU of the cervix between 16 and 24 weeks. The predictive value of TVU was evaluated by using less than 25 mm cervical length as criteria for the definition of a short cervix. The primary outcome was spontaneous preterm birth less than 35 weeks. RESULTS: Of 109 women with prior cone biopsy identified, 55 had LEEP, 45 cold knife, and 9 laser cone biopsies. Thirty (28%) had a short cervix, with 9 (30%) having spontaneous preterm birth less than 35 weeks. Seventy-nine (72%) did not have a short cervix, with 5 (6%) having spontaneous preterm birth less than 35 weeks. The sensitivity, specificity, and positive and negative predictive values for spontaneous preterm birth were 64%, 78%, 30%, and 94%, respectively (relative risk [RR] 4.7, 95% CI 1.6-15.3). CONCLUSION: TVU of the cervix is predictive of preterm birth in women with prior cone biopsy.     

宫颈环形电切术治疗宫颈上皮内瘤变的价值

目的 探讨宫颈环形电切术(LEEP)治疗宫颈上皮内瘤变(CIN)的价值.方法 回顾性分析2004年1月至2007年5月在重庆医科大学附属第一医院宫颈疾病门诊接受LEEP术的452例患者(CIN 420例,原位癌32例)的相关资料,对患者一般情况、术前阴道镜定位活检、术中情况、术后病检结果和随访资料进行统计分析.结果 (1)所有患者均于月经干净后3～7d手术,手术时间5～20min,术中出血量平均为14.6mL,患者反应轻.(2)术前、术后宫颈环切组织病理结果比较:病变分级一致者270例(59.73%);级别下降者132例(29.20%);其余50例(11.06%)级别上升,其中5例术前为CIN Ⅰ而术后证实为CIN Ⅲ(不包括原位癌).25例术后病检发现切缘有病变累及者(其中CIN 18例,原位癌7例),8例随后行全子宫切除,3例行二次LEEP术.(3)对所有患者定期随访至2007年8月,CIN治愈387例(92.14%),病变残留33例(7.86%).CIN中2例(0.48%)术后12个月复发,6～18个月后复发病变自然消退.(4)切缘无病变累及者术后CIN病变残留复发率为6.22%(25/402),切缘阳性者CIN术后病变残留复发率高达44.44%(8/18),二者比较差异有统计学意义.结论 LEEP术治疗CIN治愈率高,病变残留复发率低.术后切缘累及情况是CIN残留复发的影响因素之一,切缘阳性者病变残留复发率高.     

Adenocarcinoma in situ coexisting with carcinoma in situ of the cervix during pregnancy

Case report We report a pregnant patient with adenocarcinoma in situ (AIS) coexisting with carcinoma in situ (CIS) of the cervix diagnosed by conization at 16 weeks' gestation. Apoptotic activity was higher in the CIS lesion than in the AIS lesion in the cone biopsy specimen. Postpartum evaluation confirmed the disappearance of CIS lesion with positive cone margins, however, multifocal AIS with negative cone margins was found. Conclusion Clinical course and biological features of AIS associated with pregnancy may be different from those of CIS.     

The role of loop electrosurgical excisional procedure in the management of adenocarcinoma in situ of the uterine cervix

Objectives

To evaluate the occurrence of residual or recurrent disease after loop electrosurgical excisional procedure (LEEP) for adenocarcinoma in situ (AIS) of the uterine cervix.

Study design

Records of 78 patients with a histological diagnosis of AIS of uterine cervix on LEEP who were treated and followed at our center between 1992 and 2008 were, retrospectively, reviewed.

Results

Of 78 patients who underwent LEEP, 47 had negative and 31 had positive resection margins. Of the 47 patients with negative margins, 30 underwent subsequent hysterectomy and residual AIS, including 1 invasive adenocarcinoma, was present in 17% (5/30) of patients. The remaining 17 had no additional procedures. Of the 31 patients with positive margins, 29 patients underwent subsequent hysterectomy and residual AIS, including 4 invasive adenocarcinomas, was present in 48% (14/29) of patients. The remaining two had no additional procedures. After a mean follow-up time of 28 months (range, 1–74 months), no recurrences were observed among the 19 patients who did not undergo hysterectomy.

Conclusions

The incidence of residual disease in patients with negative margins after LEEP for AIS of the uterine cervix is low but not negligible. Therefore, conservative management in these patients seems to be feasible but careful surveillance is required. However, positive resection margin carries a higher risk for residual AIS or occult invasive adenocarcinoma, warranting additional LEEP or hysterectomy in these patients.     

Human papillomavirus DNA detection and histological findings in women referred for atypical glandular cells or adenocarcinoma in situ in their Pap smears

OBJECTIVE: To evaluate the association between high-risk human papillomavirus (HPV) DNA detection and histological diagnosis in women referred for atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) at Pap smear. METHODS: In this cross-sectional study, 146 women referred for AGC (124), AGC with high-grade squamous intraepithelial lesion (HSIL) (15), or AIS (7) were tested for HPV DNA using Hybrid Capture II (HC II). All women underwent colposcopic examination, and cervical biopsy was performed for 95 patients. Fifty-one women referred due to AGC with normal colposcopy and normal second Pap smear were scheduled for control visits every 4 months. RESULTS: The overall prevalence of HPV DNA was 38%. HPV DNA was detected in 93% of the women with HSIL associated with AGC and in 71% of women with AIS Pap smear, being significantly higher when compared with the prevalence (29%) in women with AGC alone. Forty-five women (30.8%) had clinically significant histological lesions (CIN 2 or worse). High-risk HPV DNA was detected in only 16% of the women without significant abnormalities in biopsy, in contrast to 96% of those who had CIN 2 or CIN 3 and 75% of women with AIS. Eighty-five percent of women with invasive cervical carcinoma (squamous or adenocarcinoma) tested positive for HPV DNA. HPV DNA detection was significantly associated with histological diagnosis of CIN 2 or worse, with an odds ratio (OR) = 51.8 (95% CI 14.3-199.9). CONCLUSION: HPV DNA detection was strongly associated with the severity of cervical lesion (CIN 2 or worse) in women referred for AGC or AIS in their Pap smear. These data implicate the use of HPV testing in triage of women with AGC Pap smears.     

Factors predicting the outcome of conservatively treated adenocarcinoma in situ of the uterine cervix: an analysis of 166 cases

Objective

The present study assessed the clinical outcome of patients conservatively treated for cervical adenocarcinoma in situ (AIS) and their predictive factors using univariate and multivariate population averaged (PA) generalized estimating equation (GEE) model in a longitudinal setting.

Methods

A series of 166 consecutive women (mean age 39.8 yrs; range 23-63 yrs) underwent conservative treatment of AIS as the primary treatment and were followed-up (mean 40.9 mo) using colposcopy, PAP-smear, biopsy and HPV-testing with Hybrid Capture 2.

Results

Hysterectomy was performed as part of the primary management in 47 patients, who were excluded from the follow-up (FU) analysis. Out of 119 women closely followed-up, additional therapeutic procedures were performed in 69. At study conclusion, 7 patients (5.9%) showed persistent disease, while 8 (6.7%) had progressed to invasive adenocarcinoma (AC). Positive HR-HPV test was the only independent predictor of disease recurrence (adjusted OR = 2.72; 95%CI 1.08-6.87), and together with free cone margins (OR = 0.20; 95%CI 0.04-0.92), HR-HPV positivity was also the single most powerful predictor of disease progression to AC, with OR = 3.74; 95%CI 1.84-7.61 (p = 0.0001) in multivariate PA-GEE.

Conclusions

These results suggest that testing HR-HPV positive at any time point during FU is the most significant independent predictor of progressive disease, while showing free margins in cone has a significant protective effect against progression to AC. Furthermore, because 4.3% women with persistent, recurrent or progressive disease experienced a late (5th and 6th FU) diagnosis of HG-CGIN or microinvasive AC, a close surveillance should be scheduled for at least three years in conservatively treated AIS patients.     

电热圈环切术诊断治疗宫颈原位癌的临床评价

目的:评价电热圈环切术(1oop electrical excision procedure,Leep)在诊断和治疗宫颈原位癌的价值。方法:回顾分析2003年1月至2004年12月,因宫颈病变行Leep且Leep病理诊断为宫颈原位癌45例的临床病理资料。结果:宫颈原位癌45例Leep术切缘阳性16例,占35.6%。切缘阳性16例中10例不要求保留生育功能,8例行筋膜外全子宫切除术,2例行广泛子宫切除+盆腔淋巴结清扫术,术后病理证实3例残存宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)病灶,分别为CINⅠ2例、CINⅡ1例;要求保留生育功能6例中3例再次Leep,术后病理证实1例残存CINⅠ,3例拒绝进一步治疗。切缘阴性29例中15例直接随访,14例术后接受筋膜外全子宫切除术,术后无1例有残存病灶。Leep切缘阳性者与阴性者病变残留率相比差异有统计学意义(χ2=0·041,P(0.05)。随访41例12~36个月,平均23个月,均未发现病变复发;保留子宫的21例中近期有生育要求的5例,3例分别在术后6~21个月妊娠,1例足月分娩,其余2例在妊娠中,均未见宫颈机能不全的表现。结论:Leep是宫颈原位癌患者可供选择的治疗方法之一,年轻未育、Leep切缘阴性或切缘阳性但切缘病灶仅为CINⅠ~Ⅱ的宫颈原位癌患者保留子宫是可以接受的。     

FISH技术检测宫颈组织TERC基因扩增

目的应用荧光原位杂交技术（FISH）检测子宫颈病变组织中人端粒酶RNA（TERC）基因异常扩增的临床意义。方法应用双色荧光原位杂交技术（FISH）检测195例宫颈组织TERC基因的异常扩增。结果①195例各类宫颈病变中,慢性宫颈炎33例,ClN134例,CIN2/3（包括原位癌）37例,宫颈鳞状细胞癌30例,宫颈腺癌61例,用FISH检测TERC基因的阳性表达率分别是3.03%（1/33）、29.41%（10/34）、72.97%（27/37）、100%（30/30）、91.80%（56/61）,子宫颈鳞癌与腺癌TERC基因的表达较宫颈上皮内瘤变各组差异有统计学意义（P〈0.05）。TERC基因的扩增阳性率随着宫颈病变程度增加呈逐渐上升趋势,且TERC扩增在子宫颈鳞癌与腺癌患者中无明显差异性;②TERC基因异常扩增与高危型HPV感染呈正相关。结论应用FISH技术检测TERC基因的异常扩增可以作为组织学诊断困难的病变确诊、病变预测及治疗后风险评估的手段。     

In situ adenocarcinoma and squamous carcinoma of uterine cervix. Pathological and immunohistochemical analysis with cytokeratin 13

OBJECTIVES: The aim of the study was the pathological and immunohistochemical analysis of cytokeratin 13 (CK13) in intraepithelial cervical tumors. STUDY DESIGN: We studied 415 in situ squamous carcinomas and 13 in situ mucinous cervical type adenocarcinomas of the uterine cervix. All patients underwent laser cervical conization and had a follow-up ranging 12-135 months. RESULTS: 3% of the squamous carcinoma patients recurred during the follow-up period, while the percentage of recurrence of in situ adenocarcinoma patients was 7.6%. We observed positive surgical edges in 46.1% of glandular tumors, and in 5% of squamous tumors. The percentage of recurrence was high among the cases with positive borders independently from their histopathologic type (14.3% in the squamous carcinomas versus 50% in the adenocarcinomas), compared to cases with negative edges (2.3% in the squamous carcinomas versus 0% in the adenocarcinomas). We observed CK13 positive staining in cervical squamous tumors and in mucinous cervical type adenocarcinomas, while there was no positive staining in non-neoplastic cervical glandular elements. CONCLUSION: CK13 positive immunostaining among in situ squamous and in situ mucinous cervical type adenocarcinoma cases adds additional evidence to data supporting a common origin of the two lesions.     

Targeting topoisomerase IIa in endometrial adenocarcinoma: a combined chromogenic in situ hybridization and immunohistochemistry study based on tissue microarrays

Topoisomerase IIa is a nucleic enzyme that affects the topological structure of DNA and also is a target for chemotherapy (ie, anthracyclines). In this study, we coevaluated its protein expression with chromosome 17 and gene status. Using tissue microarrays, 40 cases of sporadic, primary endometrial adenocarcinomas, 5 cases of atypical hyperplasia, and 5 cases of benign hyperplasia were obtained and reembedded into two paraffin blocks with a core diameter of 1 mm. Immunohistochemistry combined with chromogenic in situ hybridization was performed in 2 and 5 microm sections, respectively. Finally using a semiautomated Image Analysis System, we evaluated the levels of Nuclear labeling index of topoisomerase IIa expression. Statistical analysis was performed by SPSS version 11.0 software. The results indicate that chromosome 17 instability (aneuploidy in 7/40 cases) and Topo IIa gene deregulation (amplification in 3/40 and deletion in 1/40 cases) are significant genetic events correlated with biologic behavior in endometrial adenocarcinoma. Because protein overexpression was observed in a significant proportion of the tumors (18/40), detection of the specific gene deregulation mechanism is a crucial process for application of targeted chemotherapies, which are characterized by different levels of cardiotoxicity and other serious effects.     

Primed in situ labeling for rapid prenatal diagnosis

OBJECTIVE: Our purpose was to assess the feasibility of primed in situ labeling for analysis of prenatal diagnostic specimens. STUDY DESIGN: Prenatal diagnostic specimens were chosen at random for analysis without knowledge of clinical indication. Primed in situ labeling with primers for chromosomes 18, 21, X, and Y was performed separate from conventional cytogenetic analyses. All clinical management considerations were based solely on conventional cytogenetic analyses. RESULTS: Forty-one samples were analyzed by primed in situ labeling: 35 direct preparations of chorionic villi and 6 uncultured amniotic fluid samples. In all cases analysis confirmed the particular chromosome number determined by conventional cytogenetic analysis. CONCLUSIONS: Although conventional metaphase studies remain the standard for prenatal cytogenetic analyses, the preliminary feasibility study finds primed in situ labeling to be a rapid and reliable adjunctive diagnostic technique applicable for prenatal diagnosis in certain clinical situations. Further study is needed to assess the efficacy of primed in situ labeling in comparison to fluorescent in situ hybridization and conventional cytogenetic analyses for prenatal diagnoses. (Am J Obstet Gynecol 1998;178:1313-20.)