Management of in situ cervical adenocarcinoma

The management of adenocarcinoma in situ of the cervix (ACIS) is difficult because it is often diagnosed in younger women who may wish to preserve their potential of fertility. Conservative treatment has been accepted as an appropriate strategy but interrogations persist as to carcinological safety. We report a complete review of the literature on this subject where conservative attitude appears possible but is associated with recurrence risk (5 to 10%) and invasive disease (2%). Conditions to perform conservative management are: cold knife cone biopsy, negative margins, cone resection of at least 25 mm, realization of endocervical curettage and total patient compliance. In all cases, regular cytological and histological monitoring must be performed. If maintaining reproductive capacity is not desired, hysterectomy is systematically proposed to patient.     

Invasive cervical adenocarcinoma immediately following a cone biopsy for adenocarcinoma in situ with negative margins

BACKGROUND: Cervical adenocarcinoma in situ is often diagnosed in younger women who may wish to preserve the potential for fertility. Given that the rate of recurrent adenocarcinoma in situ is relatively low and the risk of invasive adenocarcinoma is extremely rare, conservative management in this population after a cone biopsy demonstrates negative margins has been accepted as an appropriate management strategy. This case challenges the concept of conservative management of cervical adenocarcinoma in situ. CASE: A 42-year-old G2P2002 with previously normal annual cervical cytology had a Pap smear demonstrating atypical glandular cells of uncertain significance. A 1.5-cm lesion was noted at the endocervix, and a punch biopsy revealed adenocarcinoma in situ. A large cold knife cone biopsy confirmed cervical adenocarcinoma in situ with negative margins. Definitive therapy for in situ disease with an extrafascial hysterectomy was performed 12 days after conization, and demonstrated stage IB1 cervical adenocarcinoma. A radical parametrectomy, radical upper vaginectomy, and pelvic lymphadenectomy were without persistent disease. CONCLUSION: Conservative management of cervical adenocarcinoma in situ after a cone biopsy with negative margins does not exclude the possibility of concurrent invasive cervical adenocarcinoma. This case challenges the current balance between risk and benefit associated with the conservative management of cervical adenocarcinoma in situ.     

Postconization surveillance of cervical adenocarcinoma in situ. A prospective trial

OBJECTIVE: To conduct a surveillance trial after conization to prospectively determine the outcome of conservative management of adenocarcinoma in situ (AIS). STUDY DESIGN: Women diagnosed with AIS were prospectively enrolled from September 2000 to September 2001. Eligibility criteria included patient age younger than 40 years, prior conization with negative margins and the desire to preserve fertility. Each cone biopsy specimen was secondarily reviewed. Postconization surveillance consisted of a liquid-based Pap test and endocervical curettage (ECC) every 4 months. Follow-up ended in September 2002. RESULTS: Ten women with a median age of 32 years (range, 26-37) were enrolled. Six were nulliparous and 2 primiparous. Seven patients were clinically free of disease after a median of 21 months (range, 5-24), 2 were lost to follow-up, and 1 was excluded when AIS could not be confirmed on the original specimen. Twenty-eight Pap smears and 18 ECCs were performed, but no additional surgical procedures were required due to abnormal cytopathology. CONCLUSION: This prospective trial on postconization surveillance demonstrated the safety of conservative management for AIS patients desiring to preserve fertility.     

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.     

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.     

Demonstration of low frequency of human papillomavirus DNA in cervical adenocarcinoma and adenocarcinoma in situ by the polymerase chain reaction and in situ hybridization.

There is evidence that cervical adenocarcinoma is increasing in incidence, particularly in young women. In order to assess the possible role of human papillomaviruses in cervical glandular oncogenesis, 16 cases of invasive adenocarcinoma and eight cases of adenocarcinoma in situ have been examined by in situ DNA hybridization using biotinylated probes to human papillomavirus types 6, 11, 16, 18, and 31, and assessed by polymerase chain reaction analysis for human papillomavirus types 11, 16, and 18 sequences. Of the invasive adenocarcinomas, four of 16 contained human papillomavirus type 16 sequences and one of 16 contained type 18 sequences as assessed by polymerase chain reaction analysis. Five of eight cases of adenocarcinoma in situ contained human papillomavirus type 16 sequences by polymerase chain reaction analysis. Only one invasive adenocarcinoma and one case of adenocarcinoma in situ showed a positive in situ hybridization signal. The low rate of carriage of the human papillomavirus sequences examined suggests that these viral types may not play a major role in cervical glandular neoplasia.     

Further study of the management of cervical adenocarcinoma in situ

OBJECTIVE: The objective of this study was to study further the management of cervical adenocarcinoma in situ (AIS) with particular regard to the results of conservative management without hysterectomy and the use of large loop excision of the transformation zone (LLETZ). METHODS: Based upon the files of the Pathology Department at the Cleveland Clinic Foundation, recently encountered AIS patients were combined with patients from a previous study that ended in 1994. Charts and clinical materials were retrospectively reviewed and abstracted. RESULTS: Fifty-two patients were identified for a combined study group of 98 patients. The mean age was 37 years. Fifty-two percent were identified due to abnormal squamous elements on a Pap smear and 43% due to abnormal glandular cells. In patients treated with hysterectomy, 67% were found to have residual disease following conization with positive margins including 3 patients with invasive cancer. Among all patients, LLETZ was associated with a positive margin rate of 57.1% vs 27.3% with cold knife conization (CKC) (chi(2), P = 0.008). Among patients treated conservatively with conization, the rates of positive margins were 40.0 and 20.0%, respectively, for LLETZ and CKC (chi(2), P = 0.11); 9.5% of conservatively managed patients with negative initial conization margins eventually had recurrent AIS. CONCLUSION: Cold knife conization is the preferred method of management for cervical AIS patients selecting conservative treatment. Despite initial conization margins being uninvolved, such patients have an approximate risk of 10% for recurrent AIS.     

Persistence and recurrence of in situ cervical adenocarcinoma after primary treatment. About 121 cases

OBJECTIVE: The aim of this study is to assess the results of conservative management of adenocarcinoma in situ (AIS) of the uterine cervix. PATIENTS AND METHODS: Retrospective multicentric study with 121 cases. Patients with cervical invasive lesions were excluded. General characteristics of population, diagnosis circumstances, treatment, histology and evolution were studied. RESULTS: Conservative treatment was performed in 98.3% of cases with 64% of negative margins. In the positive margins group, 80% of conservative treatments were performed by electrosurgical loop. Length of cone resection is significantly higher for conization with negative margins (p<0.001). The rate of residual lesion was 18% in negative margins group and 46% in positive margins group. Two noninvasive and one invasive recurrence were deplored. DISCUSSION AND CONCLUSION: Conservative surgery for patients with AIS could be considered in young patients but several conditions should be respected: careful follow-up after conservative treatment; cold knife conization; length of cone specimen greater than 25 mm and negative margins.     

MMP-2 and TIMP-2 expression correlates with poor prognosis in cervical carcinoma--a clinicopathologic study using immunohistochemistry and mRNA in situ hybridization.

OBJECTIVE: The spread of malignant neoplasms is closely associated with matrix and basement membrane degradation, mediated by various classes of proteolytic enzymes. Matrix metalloproteinases (MMP) appear to have a key role in the sequence of events that lead to local invasion and metastasis. The present study evaluated the role of matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinases-2 (TIMP-2), and membrane-type metalloproteinase (MT1-MMP) in cervical neoplasia. METHODS: We have analyzed 49 uterine cervical squamous cell carcinomas, 10 cases of high-grade cervical intraepithelial neoplasia (CIN II-III), and 10 control cervices for the presence of MMP-2, TIMP-2, and MT1-MMP using in situ hybridization. MMP-2 protein expression was evaluated using immunohistochemistry. Results were analyzed for possible correlation with disease outcome. RESULTS: MMP-2, TIMP-2, and MT1-MMP mRNA were localized to both stromal and tumor cells. However, an intense signal for MMP-2 was detected almost exclusively in tumor cells and was uniformly absent from CIN lesions and control cervices. Conversely, intense signals for TIMP-2 and MT1-MMP were detected in both stromal and tumor cells of invasive carcinomas, more often for the former. As with MMP-2, they were absent from CIN lesions. MMP-2 protein expression was enhanced in tumor cells compared to CIN cases and controls, significantly compared to the latter (P = 0.01). The presence of both MMP-2 and TIMP-2 mRNA in tumor cells correlated with advanced stage (P = 0.003 for MMP-2, P = 0.002 for TIMP-2) and with poor survival (P = 0.003 for MMP-2, P = 0.002 for TIMP-2) in univariate analysis. In addition, their presence in tumor cells intercorrelated (P = 0.002). In multivariate survival analysis, MMP-2 presence retained its association with survival (P = 0.004), in addition to patient age (P = 0.027) and advanced stage (P = 0. 0002). CONCLUSIONS: Both MMP-2 and TIMP-2 have a key role in extracellular matrix invasion in cervical carcinoma, largely through their elaboration by tumor cells. The presence of mRNA for both proteins is interrelated and is associated with poor survival.     

The topography and invasive potential of cervical adenocarcinoma in situ, with and without associated squamous dysplasia

Thirty-eight cases of cervical adenocarcinoma in situ (ACIS) were studied to see if the topography of the ACIS and any stromal invasion by adenocarcinoma were associated with the presence (22 cases) or absence (16 cases) of squamous cervical intraepithelial neoplasia (CIN). Neither the topography of the ACIS (proximal linear extent, focality, presence of ACIS beneath the transformation zone, and circumferential extent) or the presence of invasive adenocarcinoma was associated with the presence or absence of CIN. We conclude that the course of ACIS, at least as reflected by cervical topography and invasive potential, seems to be unaffected by the coexistence of squamous neoplasia.     

The anatomic distribution of cervical adenocarcinoma in situ: implications for treatment

The anatomic distribution of cervical adenocarcinoma in situ was ascertained in 23 cases of adenocarcinoma in situ, 10 of which also had "early" invasive adenocarcinoma. The adenocarcinoma in situ involved both surface and gland epithelia in all cases, involved a variable number of quadrants, involved glands beneath the transformation zone in about two thirds of cases, was multifocal only occasionally, extended up the endocervical canal for a variable distance (up to 30 mm), and was associated with squamous dysplasia in about half of cases. From this topographic outline of adenocarcinoma in situ, it is recommended that if cervical conization is chosen as conservative therapy for adenocarcinoma in situ the "cone" be cylindrical in shape, to include the transformation zone and deep glands, and extend at least 25 mm up the endocervical canal.     

Prevalence and clinical relevance of cyclooxygenase-1 and -2 expression in stage IIB cervical adenocarcinoma

Objective

The objective of this study was to determine the relationship between cyclooxygenase (COX)-1 and -2 and prognosis in patients diagnosed with FIGO stage IIB cervical adenocarcinoma who underwent concurrent chemoradiotherapy.

Study design

Twenty-three patients diagnosed with stage IIB cervical adenocarcinoma and treated with concurrent chemoradiotherapy between 1990 and 1995 were included in this study. COX-1 and -2 expression and clinicopathologic features were evaluated. COX-1 and -2 expression was determined by immunohistochemistry.

Results

The prevalence of COX-1 and -2 expression was similar at 73.9%. Significant COX-1 and -2 expression was 47.8 and 60.9%, respectively. COX-2 expression was associated with poor response to treatment and cancer-related death (P = 0.043 and 0.012, respectively). Poor survival was identified in patients who showed high COX-2 expression (P = 0.016). There was no correlation between COX-1 expression and patient prognosis.

Conclusion

Only COX-2 was found to be a potent prognostic factor in patients treated with concurrent chemoradiotherapy for stage IIB cervical adenocarcinoma. However, further studies with more samples are needed to definitely demonstrate the relationship between COX expression and cervical adenocarcinoma.     

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.     

Evaluation of PTEN expression in cervical adenocarcinoma by tissue microarray

PTEN, a tumor suppressor gene, appears to negatively control the phosphoinositide 3-kinase signaling pathway for regulation of cell proliferation and cell survival. Somatic PTEN mutations are involved in a variety of tumors, including endometrial carcinomas, where PTEN expression is diminished. We examined expression of PTEN in a series of cervical adenocarcinomas and precursors, using tissue microarray (TMA) technology. TMA blocks were constructed using paraffin-embedded, formalin-fixed tissues from 273 samples derived from 16 normal cervical biopsies, 119 cases of invasive adenocarcinoma, and 20 high-grade cervical glandular intraepithelial neoplasia (CGIN). Fresh 3-mum sections were cut and immunostained with PTEN, and expression was correlated with clinicopathologic variables, including histologic subtypes of adenocarcinoma. In 137 patients, PTEN expression was positive in 121 (88%). The intensity and distribution of PTEN staining in the tumor tissue were more heterogeneous than those observed in the normal tissues. There were no significant differences in distribution or intensity of PTEN expression between adenocarcinoma in situ and subtypes of invasive adenocarcinoma. Our findings show that unlike the case in most endometrial carcinomas, PTEN expression is retained during the process of carcinogenesis in the glandular cervix. There is, however, evidence of altered distribution and intensity of PTEN expression in cervical adenocarcinoma cells.     

CXCR4 expression is associated with pelvic lymph node metastasis in cervical adenocarcinoma

The aim of this study is to investigate the expression of CXCR4 receptor in cervical adenocarcinoma and related mechanisms involved in pelvic lymph node metastasis. Immunohistochemistry was used to evaluate the expression of CXCR4 and the association of pelvic lymph node metastasis in archived tissue from clinical stage IB cervical adenocarcinomas (n = 37) and from benign specimens obtained at hysterectomy for other causes (n = 48). The HeLa cell (cervical adenocarcinoma-derived cell) line that expresses CXCR4 was used to study the interaction between the CXCR4 receptor and stromal cell-derived factor 1alpha (SDF-1alpha). Cell migration assays, cell numbers, flow cytometry, cell proliferation assay, and western blot were used to study the function of CXCR4 and its downstream signal transduction. The positive cases were semiquantitatively divided into three score classes according to their staining. Tumors with strong CXCR4 stainings were more likely to have pelvic lymph node metastasis than those with weak or negative stainings (87.5% vs 34.5%; P = 0.014). Only 25% of the benign specimens had weak or negative staining for CXCR4. Functioning CXCR4 receptor was expressed on HeLa cells. SDF-1alpha provoked significant signal transduction events, including chemotaxis and rescue from apoptosis. These actions were apparently mediated by the activation and phosphorylation of the extracellular signal-regulated kinase 1/2 and AKT pathways. We conclude CXCR4 expression is associated with cervical adenocarcinoma cell migration and proliferation, and primary cervical adenocarcinoma cells expressing CXCR4 are significantly more likely to metastasize to pelvic lymph nodes.     

The expression of epithelial specific antigen in cervical intraepithelial neoplasia and adenocarcinoma

There is a spectrum of changes described as cervical glandular intraepithelial neoplasia (CGIN) with adenocarcinoma in situ (AIS) considered to represent the most severe lesion in that spectrum. Although there is evidence to suggest a progression of CGIN to AIS and to invasive adenocarcinoma, the natural history of these potential precursor lesions has not been fully elucidated. The aim of this project was to establish the relationship of endocervical glandular intraepithelial neoplasias to uterine endocervical adenocarcinoma. Our study included 40 cases of glandular lesions of the cervix (15 cases of endocervical glandular intraepithelial neoplasia, eight of adenocarcinoma in situ and 17 cases of invasive adenocarcinoma). An attempt was made to examine the immunohistochemical localization of epithelial specific antigen (ESA) in those lesions and compare the results with ten cases of normal endocervical epithelium. ESA showed positive staining of the basolateral membrane of endocervical cells in the normal endocervix. The expression of ESA was found to increase from the basolateral to the diffuse cytoplasmic membrane in 12 out of 15 cases of CGIN (80%), in seven out of eight cases of AIS (84%) and in all of the 17 invasive adenocarcinomas (100%). This finding indicates that ESA is a useful marker in the diagnosis of glandular intraepithelial neoplasia and suggests that CGIN and AIS may be precursor lesions of cervical adenocarcinoma.     

Human papillomavirus DNA in adenocarcinoma in situ, microinvasive adenocarcinoma of the uterine cervix, and coexisting cervical squamous intraepithelial neoplasia

Previously, human papillomavirus (HPV) DNA, mainly HPV-18 DNA, was detected in more than 40% (17/40 cases) of invasive adenocarcinoma of the uterine cervix in our laboratory. In order to identify HPV DNA in the precursor lesions of adenocarcinoma of the cervix, 11 cases of adenocarcinoma in situ containing microinvasive adenocarcinoma and 10 cases of adenocarcinoma in situ were studied for the presence of HPV DNA by in situ hybridization using highly sensitive 3H-labeled HPV-16 and HPV-18 DNA probes. HPV types present in cervical squamous intraepithelial neoplasia (CIN) coexisting with adenocarcinoma in situ and microinvasive adenocarcinoma were also studied. Apart from the coexisting CIN II-III with glandular neoplasms, 48 cases of CIN III (severe dysplasia and squamous carcinoma in situ) removed by conization or hysterectomy and known to be free of adenocarcinoma were used for comparison. HPV DNA was detected in 64% of microinvasive adenocarcinoma, 70% of adenocarcinoma in situ, and 63% of the control CIN III. HPV-18 DNA was the preponderant type of HPV DNA found in adenocarcinoma in situ and microinvasive adenocarcinoma. All cases of HPV DNA-positive microinvasive adenocarcinoma contained the same type of HPV DNA as the lesions of coexisting adenocarcinoma in situ. CIN coexisting with microinvasive adenocarcinoma or adenocarcinoma in situ contained the same type of HPV as identified in the glandular lesions, whereas all of the HPV DNA-positive control CIN III cases contained HPV-16 DNA. These results suggest that adenocarcinoma in situ is a precursor lesion of adenocarcinoma of the cervix that contains HPV DNA, and that CIN coexisting with adenocarcinoma may be a result of a metaplastic process of adenocarcinoma or of bidirectional differentiation of the affected reserve cells.     

Bilateral and synchronous cervical carcinoma in situ in a didelphic uterus.

A case is reported of a bilateral and synchronous cervical squamous cell carcinoma in situ in a patient with uterus didelphys. Bilateral simultaneous conizations of both cervices were curative. Theories of tumor origin in such a case are discussed.     

The clinicopathologic significance of laminin-5 γ2 chain expression in cervical squamous carcinoma and adenocarcinoma

Carcinoma of the uterine cervix is one of the most prevalent malignancies among women in developing countries and the third most common type worldwide. Squamous cell carcinoma predominates in the cervix uteri, while adenocarcinoma and adenosquamous carcinomas represent about 10-15% of all cervical cancers. Many studies have confirmed that the human papillomavirus (HPV) is the most important etiologic factor in the development of cervical cancer. The aim of our study was to investigate the expression of the laminin-5 gamma2 chain in primary malignancies of the cervix uteri and to focus on the clinicopathologic significance of the expression of the laminin-5 gamma2 chain in cervical squamous carcinoma and adenocarcinoma with respect to age and survival of the patients. The study consisted of a total of 89 cases of invasive cervical cancer (54 squamous carcinomas and 35 adenocarcinomas). The laminin-5 gamma2 chain was found in 80% of all the squamous carcinoma and in 66% of cervical adenocarcinoma. There was no correlation of the high expression of laminin-5 with survival. The univariate analysis in squamous cell carcinoma showed that factors such as the stage of the disease and positive lymph nodes had an impact on the survival of the patients, whereas in the multivariate analysis, only age at diagnosis was an independent prognostic factor. However, in cases with cervical adenocarcinoma, only the stage of the disease was an independent prognostic factor. There was no difference between HPV-positive and HPV-negative tumors concerning the high expression of laminin-5 gamma2 chain. Our results indicate that the majority of the primary cervical tumors, especially squamous cell carcinoma, showed expression of laminin-5 gamma2 chain immunoreactivity. Independent prognostic values for the survival of the patients were age and stage of the disease.