Depth Of Cervical Stromal Invasion Research Articles

Prospective Phase I/II Trial of Helical Tomotherapy with or without Chemotherapy for Postoperative Cervical Cancer Patients

Prospective Phase I/II Trial of Helical Tomotherapy with or without Chemotherapy for Postoperative Cervical Cancer Patients

Extent of cervical involvement in endometrial cancer as a predictor of outcome

e16566 Background: Endometrial cancer will affect 40,000 women this year. Extent of myometrial invasion and presence of cervical stromal disease are risk-factors for metastasis and recurrence. Uterine cervical involvement is often not known in advance of surgery, and superficial involvement may not be seen at frozen section. The objective of this study was to determine if the extent of cervical invasion is a predictor of outcome. Methods: The institutional cancer registry was searched for cases of stage II uterine cancer from 1996–2006. Inclusion criteria were endometrioid histology and clinical data and pathology available for evaluation. Demographics, extent of surgery, tumor grade, depth of myometrial invasion, presence of lymph-vascular space invasion (LVSI), and last follow up were collected. In addition, a gynecologic pathologist evaluated all slides to determine depth of cervical stromal invasion. Statistical analysis to compare predictors of outcome was performed. Results: There were 800 cases of endometrial cancer diagnosed from 1996–2006, 75 (9%) were stage II. Fifty two cases met all inclusion criteria. Mean age at diagnosis was 63.4 years. Mean BMI was 31.6. Ninety four percent were white, 4% black, and 2% Asian. All patients had a hysterectomy, 6 (11.5%) had a radical hysterectomy and 36 (69%) had lymphadenectomy performed. Eighteen (34.6%) were stage IIA and 32 (61.5%) were IIB. LVSI was seen in 15 (28.8%) cases. On pathologic review, 37.5% had no cervical stromal invasion, 42.5% had invasion of less than half and 20% had invasion of more than half of the cervical stroma. Forty patients (77%) received adjuvant radiation. There were 8 recurrences and 6 disease-related deaths. The mean follow up period was 30 months. Extent of cervical invasion did not correlate with recurrence or survival. Factors associated with increased risk of recurrence were: LVSI (p = 0.017), lack of lymph node sampling (p = 0.035), and age >55 years (p = 0.027). Women with and without recurrence were compared and did not significantly differ. Conclusions: In this study with pathologic review, extent of cervical involvement in stage II endometrial cancer was not associated with increased risk of recurrence or death. Age >55 years, lack of node sampling and presence of LVSI were predictors of recurrent disease. No significant financial relationships to disclose.

Role of Human Papillomavirus Genotype in Prognosis of Early-Stage Cervical Cancer Undergoing Primary Surgery

Our aim was to evaluate the prognostic significance of human papillomavirus (HPV) genotype in early-stage cervical carcinoma primarily treated with surgery in a large tertiary referral medical center. Consecutive patients who underwent primary surgery for invasive cervical carcinoma of International Federation of Gynecology and Obstetrics (FIGO) stage I to IIA between 1993 and 2000 were retrospectively reviewed. Polymerase chain reaction (PCR) using a general primer set followed by reverse-blot detection of 38 types of HPV DNA in a single reaction was performed for genotyping. E6 type-specific PCR was performed to validate multiple types. A total of 1,067 eligible patients were analyzed. HPV DNA sequences were detected in 95.1% of the specimens, among which 9.6% contained multiple types. HPV 16 was detected in 63.8% of the samples, and HPV 18 was detected in 16.5% of the samples. The median follow-up time of surviving patients was 77 months. By multivariate analysis, FIGO stage, lymph node metastasis, depth of cervical stromal invasion, grade of differentiation, and HPV 18 positivity were significantly related to cancer relapse. FIGO stage II, deep stromal invasion, parametrial extension, HPV 18 positivity, and age older than 45 years were significant predictors for death. Using the seven selected variables from either recurrence-free or overall survival analysis, death-predicting (P < .0001) and relapse-predicting (P < .0001) models classifying three risk groups (low, intermediate, and high risk) were constructed and endorsed by internal validation. The independent prognostic value of HPV genotype is confirmed in this study. The prognostic models could be useful in counseling patients and stratifying patients in future clinical trials.

Value of preoperative serum CA125 in early-stage adenocarcinoma of the uterine cervix without pelvic lymph node metastasis

Objective. This investigation attempted to clarify the value of preoperative serum CA125 in predicting histopathological prognostic factors for early-stage cervical adenocarcinoma without lymph node metastasis. Methods. This study initially surveyed 163 patients with clinical stage Ib or IIa cervical adenocarcinoma treated with radical hysterectomy and pelvic lymphadenectomy. Of the 163 patients, 116 had preoperative serum CA125 levels, and 14 had pelvic lymph node metastasis. The investigation group comprised 102 lymph node-negative patients. Results. A cutoff value of 26 U/ml was obtained after the discriminant function analysis for identifying patients with positive lymph vascular space invasion (LVSI) or depth of stromal invasion ≧2/3 thickness. Multivariate analysis revealed that among the preoperative clinicopathological variables, including age, tumor size, parametrial invasion, and CA125 level, raised CA125 most significantly influenced the assessment of the LVSI ( P = 0.040) and depth of cervical stromal invasion ( P = 0.002). Conclusions. In early-stage cervical adenocarcinoma with negative pelvic lymph node metastasis, preoperative serum CA125 levels at the cutoff value of 26 U/ml impacted the determination of the poor histopathological prognostic factors.

The role of the preoperative serum carcinoembryonic antigen level in early-stage adenocarcinoma of the uterine cervix

Objective. The purpose of the study was to identify the relationship between preoperative serum levels of carcinoembryonic antigen (CEA) and clinicopathological variables in early-stage adenocarcinoma of the uterine cervix. Methods. From February 1990 to August 2002, 117 patients with surgically treated early-stage cervical adenocarcinoma that had had preoperative serum CEA evaluations were retrospectively reviewed. The cut-off value for CEA, based on the manufacturer's recommendations, was 5 ng/ml. For an evaluation of the relationship between the clinicopathological factors and increased levels of serum tumor markers, the Chi-Square/Fisher's exact test and logistic regression were used for univariate and multivariate analysis, respectively. Results. The mean age of the patients was 46 years (range, 21–78). Of the 117 patients, 28 had preoperative serum CEA levels greater than 5 ng/ml. In a univariate analysis, the increased marker was associated with a larger tumor size, presence of lymphovascular invasion, and deeper cervical wall invasion. However, in a multivariate analysis, the preoperative CEA level had a significant impact on the determination of the depth of stromal invasion (OR 4.12, 95% CI 1.97–8.68, P < 0.001). Conclusion. In early-stage cervical adenocarcinoma, preoperative serum CEA levels seem to be useful in estimating the depth of cervical stromal invasion. Assessment of tumor antigen CEA levels should be integrated with the routine examination in the work-up of patients with adenocarcinoma of the uterine cervix.

Depth of cervical stromal invasion as a prognostic factor after radical surgery for early stage cervical cancer

Introduction. In the United Kingdom, the Royal College of Pathologists have issued guidelines detailing how the depth of stromal invasion (DOI) in cervical cancer should be measured as a percentage of the overall cervical radius in millimeters. Several studies have found the assessment of the depth of stromal invasion by cancer of the cervix to be of prognostic value. These studies did not take into account patients whose diagnostic procedures required removal of much tumor (large loop excision of the transformation zone [LLETZ] and knife cone biopsies). Furthermore, the Royal College of Pathologists guidelines do not address this issue. Materials and methods. Over the period of 6 years, 228 women had radical hysterectomy (RH) for stage Ib/IIa cervical cancer. The percentage of the depth of stromal invasion was measured according to the Royal College of Pathologist's guidelines in the UK. Patients who had large loop excision of the transformation zone and knife cone biopsies were excluded (91 patients). Results. A Cox regression analysis showed that when nodal involvement, depth of stromal invasion, endothelial lined space invasion (ELSI), and tumor type were fitted simultaneously, only nodal involvement remained as a marker of adverse outcome. Conclusions. We recommend that when the DOI is measured, account should be taken of the LLETZ/knife cone biopsy size. A randomized controlled trial, which concludes that DOI is an independent prognostic factor, is needed. Until this is properly evaluated, we feel that including DOI as an essential part of the standard pathological report is not warranted.

Multivariate analysis of histopathologic prognostic factors for invasive cervical cancer treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy.

The aim of this study was to identify the independent histopathologic prognostic factors for patients with cervical carcinoma treated with radical hysterectomy including paraaortic lymphadenectomy. A total of 187 patients with stage IB to IIB cervical carcinomas treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy were retrospectively analyzed. The median follow-up period was 83 months. Cox regression analysis was used to select independent prognostic factors. Using multivariate Cox regression analysis, lymph node (LN) status (negative vs. metastasis to pelvic nodes except for common iliac nodes vs. common iliac/paraaortic node metastasis), histopathologic parametrial invasion, lymph-vascular space invasion (LVSI), and histology of pure adenocarcinoma were found to be independently related to patients' poor survival. For patients who had a tumor histologically confined to the uterus and have neither parametrial invasion nor lymph node metastasis, LVSI was the most important prognostic factor, and histologic type, depth of cervical stromal invasion, and tumor size were not related to survival. The survival of patients with a tumor extending to parametrium or pelvic lymph node(s) was adversely affected by histology of pure adenocarcinoma. When the tumor extended to common iliac or paraaortic nodes, patients' survival became quite poor irrespective of LVSI or histologic type of pure adenocarcinoma. Patients' prognosis could be stratified into low risk (patients with a tumor confined to the uterus not associated with LVSI: n = 80), intermediate risk (patients with a tumor confined to the uterus associated with positive LVSI, and patients with squamous/adenosquamous carcinoma associated with pelvic lymph node metastasis or parametrial invasion: n = 86), and high risk (patients with pure adenocarcinoma associated with pelvic lymph node metastasis or parametrial invasion, and patients with common iliac/paraaortic node metastasis: n = 21) with an estimated 5-year survival rate of 100 +/- 0 (mean +/- SE)%, 85.5 +/- 3.9%, and 25.1 +/- 9.7%, respectively. LN status, parametrial invasion, LVSI, and histology of pure adenocarcinoma are important histopathologic prognostic factors of cervical carcinoma treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy. Prognosis for patients with cervical carcinoma may be stratified by combined analysis of these histopathologic prognostic factors. Postoperative therapy needs to be individualized according to these prognostic factors and validated for its efficacy using randomized clinical trials.

Altered CD44 Variant 6 Expression in FIGO Stage IB Cervical Carcinoma

Objective. CD44 is an adhesion molecule which plays an important role in metastatic cascade by mediating tumor cell interaction with the endothelium and the subendothelial matrix. In this study CD44v6 expression was immunohistochemically investigated on 88 uterine cervical cancers. Correlation between expression and prognostic variables and the survival was examined.Methods. Eighty-eight patients with stage IB disease, treated primarily with surgery, were examined histopathologically and immunohistochemically. CD44v6 expressions of tumoral tissue and the nonneoplastic tissue nearby were examined using antiCD44v6 monoclonal antibody. CD44v6 expression was compared to the known clinicopathologic prognostic variables and survival of patients.Results. Nonneoplastic epithelium of the sections showed CD44v6 expression predominantly in basal and parabasal layers at least in traces. CD44v6 overexpression in neoplastic islands was evaluated as “general,” “basal” (only in the basal portion of neoplastic islands), and “nonbasal” (also in the central portion of the neoplastic islands) separately. When expression and prognostic variables were compared, CD44v6 non-basal expression was found to be significant in nonsquamous cancers, when the tumor diameter was greater than 3 cm and in the tumors that showed recurrences. Univariate survival analysis with the Kaplan–Meier method showed that only the age of the patient is significantly correlated with disease-free survival. Interestingly when the same analysis was done for 5-year overall survival, diameter of the primary tumor, depth of cervical stromal invasion, existence and number of lymph node involvement, positivity for general CD44v6 expression, and positivity for nonbasal expression were found to be statistically significant. Furthermore multivariate analysis with Cox regression showed that nonbasal CD44v6 expression and lymph node involvement are independent variables for 5-year overall survival.Conclusion. These results indicate that CD44v6 expression is associated with some of the important clinicopathologic prognostic variables and appears to be a predictor of advanced pathological–surgical stage of early clinical stage cervical carcinoma. CD44v6 nonbasal expression is significantly correlated with overall survival.

Influence of Quantity of Lymph–Vascular Space Invasion on the Risk of Nodal Metastases in Women with Early-Stage Squamous Cancer of the Cervix

Objective.To determine if the quantity of lymph–vascular space invasion influences the risk of pelvic nodal metastases in women with early-stage cervical squamous carcinoma.Methods.Between 1991 and 1997, 105 women with stages IA2, Ib, and IIa squamous carcinoma of the cervix underwent radical hysterectomy and pelvic lymphadenectomy. The histopathology slides were prospectively reviewed. If lymph–vascular space invasion (LVSI) was present, the amount was quantified in four ways: percentage of cervical histopathologic sections containing LVSI, percentage of sections with tumor containing LVSI, total number of foci of LVSI, and maximal number of foci of LVSI in 10 high-powered fields. These measures of LVSI were correlated with the risk of nodal metastases.Results.Seventy-three (70%) women had tumors with LVSI. Of these, 23 had pelvic nodal metastases. All women with nodal metastases had tumors with LVSI. Using logistic regession, independent predictors of nodal metastases were depth of cervical stromal invasion (P= 0.01) and tumor size (P= 0.04). LVSI was also a significant predictor of nodal metastases based on the Mantel–Haenszel test (P= 0.01). In women whose tumors contained LVSI, logistic regression identified tumor size (P= 0.004) and LVSI in >45% of all cervical histopathologic sections (P= 0.002) as significant predictors of nodal metastases.Conclusion.The quantity of LVSI, as defined by the percentage of all cervical histopathologic sections containing LVSI, correlates significantly with the risk of nodal metastases in women with early-stage squamous carcinoma of the cervix.

The uses and limitations of DNA flow cytometry in stage IB or II cervical carcinoma

The role of flow cytometry in predicting prognosis for cervical carcinoma remains unclear. Flow cytometric analysis was performed on tissues, fixed in formaldehyde solution and embedded in paraffin, from 411 patients with Stage IB or II cervical carcinoma who had been treated with radical abdominal hysterectomy and bilateral pelvic lymphadenectomy. DNA aneuploid-multiploid tumors were found in 37.5%, tetraploid in 4.6%, and diploid-peridiploid in 57.9%. Five-year recurrence-free survival rates of the three groups were 74.3%, 77.8%, and 76.4%, respectively (P > 0.05). DNA aneuploidy and DNA index (DI) of greater than 1.3 were highly correlated to parametria extension. In univariate analysis, pelvic lymph node metastases, stage, parametrial extension, depth of cervical stromal invasion, tumor size, and DI (1.3, 1.4, 1.5 as breakpoint) were significant prognostic factors. DNA ploidy, S-phase fraction, and S-G2M fraction were not significant. In multivariate analysis, DI of greater than 1.3, pelvic node metastases, clinical Stage II, and depth of stromal invasion greater than two-thirds of full cervical thickness were independent and significant variables. The prognostic index (PI), defined by the model, was able to categorize the patients into three distinct risk groups. The 5-year recurrence free survival rates of the low-, intermediate-, and high-risk groups were 89.5%, 73.0%, and 58.9%, respectively (P < 0.0001). The prognostic value of the DI as a single variable is promising and warrants additional investigation to establish its appropriate use.

Multivariate analysis of the histopathologic prognostic factors of cervical cancer in patients undergoing radical hysterectomy

Three hundred forty-five patients with invasive carcinoma of the uterine cervix, Stages Ib (211 patients) and II (134 patients), underwent radical hysterectomy and pelvic lymphadenectomy. The influence of histologic factors including histologic subtype, maximum depth of cervical stromal invasion, degree of stromal invasion, longitudinal tumor diameter, lymph-vascular space invasion, corpus invasion, parametrial invasion, vaginal invasion, and pelvic lymph node (PLN) metastases on survival were examined by multivariate analysis. Univariate analysis revealed that all the variables except corpus invasion and vaginal invasion were significant in survival (P less than 0.05). Among these variables, however, PLN metastases, histologic subtype, and longitudinal tumor diameter were identified as independent and significant prognostic factors by multivariate analysis using Cox regression models. The prognostic index (PI), defined by the model (an indicator of the patient's place in the prognostic spectrum), was able to divide the patients into three prognostic groups. The key factors in the definition of these groups were (1) squamous cell carcinoma, small tumor diameter, and no PLN metastases for the good prognostic group and (2) PLN metastasis in two or more node groups, adenocarcinoma with one positive PLN group, or squamous cell carcinoma with one PLN group and large diameter for the poor prognostic group. These prognostic findings could predict the prognosis more precisely than that of clinical staging.

Selective postoperative radiotherapy in stage ib cervical carcinoma following radical hysterectomy and pelvic lymphaoenectomy

Eighty-two patients with Stage IB squamous cell carcinoma of the cervix treated by radical hysterectomy and bilateral pelvic lymphadenectomy were analyzed for histopathologic prognostic factors including depth of cervical stromal invasion, degree of differentiation of the tumor and lymph node involvement. The influence of these factors on the outcome was studied. A correlation was found in that advanced depth (outer one-third) of cervical stromal invasion appeared to increase the risk of nodal involvement (44% vs 7%:P<O.O5) and subsequent recurrence in patients with negative nodes (36% vs 4%:P<O.O5). Grade-3 disease was more often present in patients with outer one-third cervical stromal invasion. A subgroup of patients is described, who are at high risk for recurrent disease following surgery and who may benefit from adjuvant postoperative radiotherapy.

Selective radiation therapy in stage IB uterine cervical carcinoma following radical pelvic surgery

Thirty-five patients with squamous cell cancer of the cervix, Stage IB, treated by radical hysterectomy and bilateral pelvic lymph node dissection are analyzed for histopathologic factors including (1) depth of cervical stromal invasion, (2) degree of differentiation of the tumor, (3) vascular tumor invasion, and (4) lymph node involvement. The influence of these factors on the outcome is studied. A correlation is found in that the advanced depth of cervical stromal invasion appears to increase the risk of nodal involvement and also the subsequent recurrence in patients with negative nodes. The Grade 2 and Grade 3 disease is more often present in patients with outer one-third cervical stromal invasion, while the vascular tumorous invasion was only found in patients with middle and mostly with outer one-third cervical stromal invasion. A subgroup of patients is described, who are at high risk for recurrent disease following surgery and who may benefit from adjuvant radiation therapy.