Impact of histology on prognosis of patients with early-stage cervical cancer treated with radical surgery

Objective

To examine the effect of carcinoma cell type on tumor characteristics, tumor spread, tumor recurrence, and survival of patients with early-stage cervical cancer who had radical hysterectomy and pelvic lymphadenectomy.

Method

Data from 499 patients with stage IA to IIA cervical carcinoma who received primary surgical treatment from 2003 to 2005 at Chiang Mai University were retrospectively reviewed with regard to 3 histologic types; squamous cell carcinoma (SCC), adenocarcinoma (AC), and adenosquamous carcinoma (AS).

Results

Among the 499 patients, 71.1% had SCC, 23.4% had AC, and 5.4% had AS. There was no significant difference in stage, tumor size, tumor characteristics, or rate of loco-regional spread. A higher proportion of women with SCC needed adjuvant radiation (P = 0.001). Five-year recurrence-free survival (RFS) and overall survival (OS) were comparable among the groups. Among patients with pelvic node metastasis, 5-year RFS and OS were significantly lower in those with AC than in those with SCC (RFS, 66.1% versus 86.4%, P = 0.02; OS, 68.2% versus 88.2%, P = 0.05).

Conclusion

There was no difference among SCC, AC, and AS in most tumor characteristics, spread, recurrence, and survival in patients with early-stage cervical cancer. Among patients with pelvic lymph node metastasis, AC was associated with less favorable outcomes than SCC.     

Comparison of treatment outcomes between squamous cell carcinoma and adenocarcinoma in locally advanced cervical cancer

Objective

To compare the treatment outcomes between squamous cell carcinoma (SCC) and adenocarcinoma (ACA) in locally advanced cervical cancer patients.

Methods

All medical records of stages IIB-IVA of cervical cancer patients who had completed treatment between 1995 and 2008 were reviewed. ACA 1 case was matched for SCC 2 cases with clinical stage, tumor size, treatment modalities (radiation therapy (RT) vs concurrent chemoradiation (CCRT)). Treatment outcomes including response to RT/CCRT, time to complete response (CR), patterns of treatment failure and survival outcomes were analyzed.

Results

A total of 423 patients with stages IIB-IVA (141 ACA: 282 SCC) were included. Most of the patients (about 60%) had stage IIB. The overall complete responses (CR) between ACA and SCC were 86.5% and 94.7%, respectively (p = 0.004). Median time to clinical CR from RT/CCRT of ACA were 2 months (0-5 months) compared with 1 month (0-4 months) for SCC (p = 0.001). Pelvic recurrence and distant failure were found in 2.1% and 14.9% in ACA, and corresponding with 3.9% and 15.6% in SCC. The 5-year overall survival rates of ACA compared to SCC were 59.9% and 61.7% (p = 0.191), respectively. When all prognostic factors are adjusted, clinical staging was the only factor that influenced overall survival.

Conclusion

ACA in locally advanced cervical cancer had poorer response rate from treatment and also used longer time to achieve CR than SCC. However, these effects were not determinants of survival outcomes.     

Screening frequency and histologic type influence the efficacy of cervical cancer screening: A nationwide cohort study

Objective

To evaluate the influence of age, screening interval, and histologic type on the effect of Pap smears in cervical cancer screening.

Impact of histological subtype on survival of patients with surgically-treated stage IA2-IIB cervical cancer: Adenocarcinoma versus squamous cell carcinoma

Objectives

To evaluate the significance of adenocarcinoma (AC) compared with squamous cell carcinoma (SCC) with regard to the survival of surgically-treated early stage cervical cancer patients.

Methods

We retrospectively reviewed the medical records of 520 patients with FIGO stage IA2-IIB cervical cancer who were treated with radical hysterectomy with or without adjuvant radiotherapy between January 1998 and December 2008. The patients were classified according to (i) pathological risk factors (low-, intermediate-, or high-risk group) and (ii) adjuvant radiotherapy (concurrent chemoradiotherapy [CCRT group] or radiotherapy alone [RT group]). Survival outcomes were examined by Kaplan-Meier method and compared with Log-rank test. Multivariate analysis for disease-specific survival (DSS) was performed using Cox proportional hazards regression model to investigate the prognostic significance of histological subtype.

Results

AC histology was associated with significantly decreased DSS compared with SCC histology in the intermediate- and high-risk groups (hazard ratio: 3.06 and 2.88, respectively, both P < 0.05) while there was no survival difference in the low-risk group (P = 0.1). Among patients who received any types of adjuvant radiotherapy, DSS of AC histology patients were significantly poorer than SCC histology. Multivariate analysis demonstrated AC histology to be an independent predictor of decreased DSS in both CCRT and RT groups. Moreover, pelvic nodal metastasis significantly predicted the poor survival of patients with AC histology who received CCRT in multivariate analysis

Conclusions

Adenocarcinoma is an independent prognostic indicator of poor survival in early stage cervical cancer patients with intermediate- and high-risk factors, regardless of the type of adjuvant radiotherapy after radical hysterectomy.     

Comparison of adenocarcinoma (ACA) and squamous cell carcinoma (SCC) of the uterine cervix in a sub-optimally screened cohort: A population-based epidemiologic study of 51,842 women in Brazil

Background

Most cancers of the uterine cervix are SCC, but the relative and absolute incidence of ACA has risen in recent years, and ACA now accounts for approximately 20% of invasive cervical cancers in the screened populations worldwide.

Objective

To compare the epidemiological, clinical characteristics, and treatment outcomes of ACA with those of SCC of the cervix in a sub-optimally screened population.

Methods

Data from cervical cancer patients with SCC and ACA treated from 2000 through 2009 were obtained from the Brazilian Hospital Cancer Register databases. The summary odds ratios and chi-square tests were estimated.

Results

A total of 51,842 patients including 45,540 (87.8%) cases of SCC and 6302 (12.2%) of ACA were analyzed. Compared with the ACA patients, the SCC patients were younger and more frequently black and had a higher degree of illiteracy and alcohol and tobacco consumers. The tumor stage at the time of diagnosis was also significantly different between the two groups. However, initial therapeutic response and death rate after the first course of treatment were similar in both groups.

Conclusions

Differences between ACA and SCC were observed for all demographic and clinical variables analyzed but not for responses to treatment and death at the end of the first course of treatment. Irrespective of the histological subtype, the quality of screening and treatment must be improved in developing countries, since initial therapeutic response of ACA and SCC is similar.     

High cyclooxygenase-2 expression in cervical adenocarcinomas

OBJECTIVE: The purpose of this study was to examine the relationships between cyclooxygenase-2 (COX-2) expression and prognostic factors in cervical carcinomas. METHODS: We studied COX-2 expression in 53 women with cervical cancers, including 35 squamous cell carcinomas (SCCs), 1 adenosquamous cell carcinoma (ASCC), and 17 adenocarcinomas (ACs), using commercially available polyclonal antibodies on Formalin-fixed, paraffin-embedded tissues. Normal cervical tissues were obtained as from other patients with uterine myomas treated with a total hysterectomy (n = 16). The immunoreactivity was quantified using an immunohistochemical scoring system that approximates the use of an image analysis-based system. RESULTS: Twenty-two cervical cancer tissues (41.5%), including 10 SCCs and 12 ACs, expressed COX-2 at a moderate to strong level, which significantly, differed from the negligible expression found in the control group of 16 normal cervical tissues (P = 0.001). Different cell types showed significantly different expression levels of COX-2 (SCC at 28.6% vs AC at 70.6%, P = 0.004). The presence of deep stromal invasion (n = 40) showed a significant inverse relationship to COX-2 expression (32.5% vs 69.2%, P = 0.02). The expression of COX-2 in well-differentiated carcinomas was significantly increased compared to that in moderately and poorly differentiated carcinomas (72.7% vs 33.3%, respectively, P = 0.018). CONCLUSIONS: Overexpression of COX-2 was found in both SCC and AC, but SCCs showed infrequent and low expression. These findings suggest that increased COX-2 expression may play an important role in cervical adenocarcinomas.     

Aggressive characteristics of cervical cancer in young women in Taiwan

Objective

To compare the characteristics and prognosis of cervical cancer in young women (under 30 years) with those of older women (over 30 years).

Methods

A retrospective study of 2443 patients diagnosed with FIGO stage IA-IIA cervical cancer who underwent surgical procedures between January 1983 and December 2007.

Results

Thirty patients (1.2%) were 30 years or younger. The proportion of non-squamous cell carcinoma was higher in patients 30 years or younger compared with in patients over 30 years (14/30, 46.7% vs 10/30, 33.3%; P = 0.001). A higher rate of parametrial involvement was found in the younger group of patients compared with those over 30 years (10/30, 33.3% vs 289/2413, 12.0%; P = 0.001). Patients under 30 years had a higher rate of distant metastases compared with older patients (60% vs 49.7%; P = 0.036).

Conclusions

Non-squamous histology, parametrial involvement, a higher rate of distant metastases, and poorer prognosis are more common in women aged 30 or younger with cervical cancer than in older women with the disease.     

A comparison of pure adenocarcinoma and squamous cell carcinoma of the cervix after radical hysterectomy in stage IB-IIA

Objective

This study was designed to investigate the survival difference between pure adenocarcinoma (AC) and squamous cell carcinoma (SCC) in early cervical cancer (FIGO stage IB-IIA) after radical hysterectomy with or without adjuvant therapy performed at a single institution.

Methods

Patients with AC or SCC between November 1994 and September 2007 at the Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, Korea were evaluated.

Results

Among the 775 patients, 636 patients had SCC, and 139 patients had pure AC. In basal characteristics, preoperative FIGO stage, adjuvant therapy after surgery, as well as chemotherapeutic regimens, were not different between the two groups. However, the median age was about 5 years younger in pure AC patients than in SCC patients (44 years vs. 49 years, P = .001). In the comparison of pathological findings after surgery between the two groups, there were no differences between the two groups, except for LVSI status. The recurrence rate was higher in the pure AC group than in the SCC group (SCC; 36/636; 5.7%, AC; 20/139; 14.4%, P = < 0.001, respectively). The pure AC group had a higher recurrence rate in hematogenous/distant areas than the SCC group (SCC: 8/36; 22.2%, AC; 9/20; 45.0%, P = .076, respectively). In multivariable analysis, positive for pelvic LN and the pure AC cell type were independent factors in both DFS and OS.

Conclusion

We observed that pure AC of the cervix might entail a worse survival outcome than SCC in patients with early cervical cancer (IB-IIA).     

Comparison of clinical outcomes of adenocarcinoma and adenosquamous carcinoma in uterine cervical cancer patients receiving surgical resection followed by radiotherapy: A multicenter retrospective study (KROG 13-10)

Objective

To evaluate the prognostic influence of adenocarcinoma (AC) and adenosquamous carcinoma (ASC) in patients with FIGO stage IB–IIA cervical cancer who received radical hysterectomy followed by adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT).

Methods

We analyzed 1323 patients who satisfied the following criteria: histologically proven squamous cell carcinoma (SCC), AC, or ASC of the uterine cervix; FIGO stage IB–IIA disease; no history of neoadjuvant chemotherapy; and a history of radical hysterectomy with pelvic lymph node (PLN) dissection, followed by postoperative pelvic RT at a dose ≥ 45 Gy. The median age was 50 years. Median RT dose delivered to the whole pelvis was 50.4 Gy, and 219 (16.6%) patients received brachytherapy at a median dose of 24 Gy. Concurrent chemotherapy was delivered to 492 (37.2%) patients.

Results

Pathologic risk factors were not different according to pathologic subtype. The median follow-up duration was 75.7 months. Locoregional recurrence-free survival, relapse-free survival (RFS), and overall survival were significantly affected by histology, tumor size, PLN metastasis, parametrial invasion, lymphovascular invasion, and deep stromal invasion. The 5-year RFS rates were 83.7%, 66.5%, and 79.6% in patients with SCC, AC, and ASC histology, respectively (P < 0.0001). By multivariate analysis, AC histology was the only significant prognostic factor affecting all survival outcomes.

Conclusions

AC histology was associated with poor survival outcomes in patients with FIGO stage IB–IIA cervical cancer who received adjuvant RT or CCRT. Prognosis of ASC histology was closer to that of SCC histology than that of AC histology.     

Value of HPV-DNA test in women with cytological diagnosis of atypical glandular cells (AGC)

Objective

This study analyzed whether HPV (human papillomavirus) testing contributes towards defining histological abnormalities in women with atypical glandular cells (AGC) diagnosed at cervical cytology.

Study design

One hundred and eight women with conventional cervical cancer screening smears suggestive of AGC not otherwise specified (AGC-NOS) and favor neoplastic (AGC-FN) were consecutively enrolled. All women underwent colposcopic examinations and biopsy was performed according to the cytopathologic and/or colposcopic abnormalities present. All specimens were tested for high risk HPV genotypes by Roche's polymerase chain reaction reverse line blot assay. The chi-square test was used to evaluate the association between HPV findings and a diagnosis of high-grade pre-invasive or invasive disease (CIN 2 or worse) taking negative tests or CIN 1 as a reference. Odds ratios (OR) with their respective 95% confidence intervals (95%CI) were used to evaluate the magnitude of the association between HPV testing and CIN 2 or worse. Sensitivity, specificity and their respective 95% confidence intervals (95%CI), positive predictive values (PPV) and negative predictive values (NPV) were also calculated.

Results

Final diagnosis revealed a negative outcome in 80 cases (74%), cervical epithelial neoplasia 1 (CIN 1) in 13 cases (12%), CIN 2 or worse in 12 cases (11%) and glandular neoplasia in 3 (3%) cases. The overall detection rate of HPV was 21% (23/108). Neoplasia was significantly associated with positive HPV-DNA in women with AGC-NOS (OR = 15.21; 95%CI: 2.64-87.50); however, there was no significant association between a histological diagnosis of neoplasia and HPV positivity in women with AGC-FN (OR = 3.00; 95%CI: 0.36-24.92). The sensitivity, specificity, positive predictive value and negative predictive value of HPV-DNA testing for the detection of CIN 2 or worse in women with AGC-NOS were 71%, 86%, 29% and 97%, respectively. In women with AGC-FN, these values were 50%, 75%, 66% and 60%, respectively.

Conclusions

HPV testing at the time of colposcopy for patients with AGC in whom no colposcopic abnormality is found may be a powerful ancillary tool for identifying women at a high risk of underlying significant cervical lesions.     

Comparison of gene expression in squamous cell carcinoma and adenocarcinoma of the uterine cervix

OBJECTIVES: Microarray expression analysis of cervical tumors has revealed differential expression of genes that may be useful as markers or targets for treatment. We question the application of array findings across the major categories of cervical cancer. We sought to identify differences between normal squamous epithelium (NSQ) and glandular epithelium (NGL) of the uterine cervix and their malignant variants: squamous cell cancer (SCC) and adenocarcinoma (ACA). METHODS: Eight genes were selected: 12-lipoxygenase (12-LOX), keratin 4, trypsinogen 2 (TRY2), Rh glycoprotein C (RhGC), collagen type V alpha 2, integrin alpha 5, integrin alpha 6, and c-myc. Ten cases each of SCC and ACA of the cervix were selected from our tumor bank. NSQ and NGL epithelia were obtained from consecutive patients undergoing surgery for benign disease. RNA extraction, cDNA synthesis, and DNA amplification of all samples were performed according to an established protocol. Electrophoresis of the multiplexed polymerase chain reaction (PCR) products was performed under standard conditions, followed by digital image capture. A ratio of target to control gene (beta-actin) was obtained for each sample. Analysis of variance was applied to the mean ratios for each tissue to establish significant differences. Individual pairwise comparisons were made by Student t tests and verified with the Tukey-Kramer test. RESULTS: Clinically valid comparisons are NSQ to NGL, NSQ to SCC, NGL to ACA, and SCC to ACA. Various expression patterns were observed between the epithelia and their malignant phenotypes. Significant differences in gene expression were observed between benign squamous and glandular epithelium in four of the eight genes and between malignant squamous and glandular epithelium in three of the eight genes. Significant differences in gene expression between benign and malignant tissues were demonstrated in four of the eight genes. CONCLUSIONS: We have defined significant differential expression changes between the two principal cervical tumor types. Differences in genes are demonstrated and must be considered if array technology is applied to the study of the biologic behavior of these tumors as well as their screening and management. The observed differential expression should be a compelling argument to perform type-specific expression analysis for other tumors with histological variants.     

Prognostic significance of residual lymph node status after definitive chemoradiotherapy in patients with node-positive cervical cancer

Objective

Lymph node involvement is an important prognostic factor in patients with cervical cancer. However, the prognostic significance of lymph node response to chemoradiotherapy remains unclear. We retrospectively analyzed the relationship between residual lymph node status after definitive chemoradiotherapy and survival.

Atypical glandular cells and adenocarcinoma in situ according to the Bethesda 2001 classification: cytohistological correlation and clinical implications

BACKGROUND: The objective of this study was to evaluate the correlation between the 2001 Bethesda classification of endocervical glandular abnormalities and histological diagnosis. STUDY DESIGN: A series of 155 women with endocervical glandular abnormalities on cervical smears were included: 91 with atypical glandular cells (AGC) not otherwise specified (NOS), 15 with AGC-favor neoplastic (FN); 35 with AGC associated with high-grade squamous intraepithelial lesion (HSIL) as combined diagnosis and 14 with adenocarcinoma in situ (AIS). RESULTS: Histological outcome of squamous neoplasias (CIN 2 or worse) and adenocarcinoma were significantly associated with AGC-FN and AIS, taking as reference AGC-NOS, and more associated with AIS than AGC-FN. Similar associations were observed for histological outcome of adenocarcinoma, but no association was observed for only squamous neoplasia. Histological outcome of CIN2 or worse was strongly associated with AGC when HSIL was also present, but no association was observed with only for adenocarcinoma histological outcome. CONCLUSIONS: AGC-NOS, AGC-FN and AIS cytological diagnosis represent a progressively increasing association with neoplastic diagnosis, due to progressively increasing association with adenocarcinoma. Histological outcome of squamous neoplasia is frequent but does not differ with these cytological interpretations. The presence of HSIL associated with AGC represents greater probability of squamous neoplasia but not adenocarcinoma.     

High-grade histologic lesions in women with low-grade squamous intraepithelial lesion cytology from a region of Thailand with a high incidence of cervical cancer

Objective

To evaluate the prevalence of and predictors for underlying significant lesions in women with low-grade squamous intraepithelial lesion (LSIL) smears.

Methods

Records were retrospectively reviewed for 208 women with LSIL who underwent colposcopy and histological evaluation from October 2004 through April 2009.

Results

Mean age of the patients was 38.5 years. Forty-four (21.2%) women were nulliparous; 20 (9.6%) women were postmenopausal; 29 (13.9%) women tested positive for HIV. Thirty-three (15.9%) women were current users of combined oral contraceptive pills. The pathological results of initial colposcopic evaluations were: 63 (30.3%) with cervical intraepithelial neoplasia (CIN) 2-3; 62 (29.8%) with CIN 1; 4 (1.9%) with cervical cancer; and 79 (38.0%) with no epithelial lesion. Current use of combined oral contraceptive pills, a positive HIV test, and multiparity were significant independent predictors for high-grade disease.

Conclusion

Approximately one-third of women with LSIL in our population have underlying significant lesions. Current use of combined oral contraceptive pills, a positive HIV test, and multiparity are significant predictors for high-grade lesions.     

Tubal ligation frequency in Oklahoma women with cervical cancer

Objective

Infrequent Pap screening is an important risk factor for cervical cancer. We studied the association between contraceptive methods, screening frequency, and cancer.

Methods

Women (n = 2004) enrolled in the cross-sectional Study to Understand Cervical Cancer Endpoints and Determinants (SUCCEED) underwent colposcopy to evaluate an abnormal Pap test. Questionnaire data were compared between those with cervical intraepithelial neoplasia (CIN) 3/adenocarcinoma in situ (AIS) and those with invasive cancer to identify factors associated with cancer. Logistic regression was used to calculate age-stratified measures of association between contraceptive method and Pap frequency as well as tubal ligation (TL) and cancer risk.

Results

In all age groups, women with TL were more likely to have had no Pap screening in the previous 5 years compared to women using other contraception: 26-35 years (OR 4.6, 95% CI 2.4-8.6; p < 0.001), 36-45 years (OR 3.8, 95% CI 2.1-7.0; p < 0.001), and 46-55 years (OR 2.2, 95% CI 1.0-4.9; p = 0.050). Subjects with cancer (n = 163) were more likely to have had a TL (41% vs. 21%, p < 0.001) than those with CIN 3/AIS (n = 370). Age-stratified analyses showed increased odds of tubal ligation in women with cancer versus those with CIN 3/AIS between 25 and 45 years, with a significant increase in women 26 to 35 years old (OR 3.3, 95% CI 1.4-8.1; p = 0.009). Adjusting for Pap frequency changed the effect only slightly, suggesting that increased risk was not fully mediated by lack of screening.

Conclusion

Contraceptive type is associated with Pap screening. Women with TLs obtain less frequent Pap testing and may be at an increased risk for cervical cancer.     

Synchronous invasive squamous cell carcinoma and clear cell adenocarcinoma of the uterine cervix: a different human papillomavirus status

BACKGROUND: A multiple primary invasive carcinoma of the cervix is a rare condition and is seldom composed of squamous cell carcinoma and clear cell adenocarcinoma. CASE: A 47-year-old woman presented with contact bleeding. The anterior lip of the cervix revealed a 2.0-cm protruded mass. Preoperative pathological and imaging studies demonstrated the squamous cell carcinoma of the exocervix alone. Radical hysterectomy was performed on the diagnosis of stage 1B cervical cancer. Histological examination of the specimen manifested a coexisting invasive clear cell adenocarcinoma in the endocervix. Human papillomavirus (HPV) 18 was detected in the squamous cell carcinoma; however, no HPV was detected in the clear cell adenocarcinoma. CONCLUSION: This finding suggests that there was an obvious difference in association of HPV with the two neoplasms.     

Pretreatment levels of serum squamous cell carcinoma antigen and urine polyamines in women with squamous cell carcinoma of the cervix.

OBJECTIVES: To investigate whether pretreatment levels of serum squamous cell carcinoma antigen (SCCA) and urine polyamines can predict lymph node metastases in patients with early stage cervical carcinoma. METHODS: Pretreatment measurement of serum SCCA and urine polyamine levels was carried out for 419 women. Of those women, 104 with stage IB and IIA cancer received radical surgery and had tumor size reassessed postoperatively. RESULTS: The women had increased levels of serum SCCA (>2.0 ng/mL) and elevated urine polyamines (>45 micromol/g of creatinine) with advanced cancer stage (P<0.01). The median SCCA level was significantly higher in women with metastatic disease than that in those without lymph node involvement (3.9 vs. 1.1; P<0.01). Women with nodal involvement also had significantly higher median levels of urine polyamines than those without nodal disease. CONCLUSIONS: Pretreatment measurement of SCCA and urine polyamine levels may help in predicting lymph node metastases in women with early stage cervical carcinoma.     

Prognostic significance of low volume sentinel lymph node disease in early-stage cervical cancer

Objective

Evaluate prognostic significance of low volume disease detected in sentinel nodes (SN) of patients with early stages cervical cancer. Although pathologic ultrastaging of SN allows for identification of low volume disease, including micro-metastasis and isolated tumor cells (ITC), in up to 15% of cases, prognostic significance of these findings is unknown.

Methods

A total of 645 records from 8 centers were retrospectively reviewed. Enrolled in our study were patients with early-stage cervical cancer who had undergone surgical treatment including SN biopsy followed by pelvic lymphadenectomy and pathologic ultrastaging of SN.

Results

Macrometastasis, micrometastasis, and ITC were detected by SN ultrastaging in 14.7%, 10.1%, and 4.5% patients respectively. False negativity of SN ultrastaging reached 2.8%. The presence of ITC was not associated with significant risk, both for recurrence free survival and overall survival. Overall survival was significantly reduced in patients with macrometastasis and micrometastasis; hazard ratio for overall survival reached 6.85 (95% CI, 2.59-18.05) and 6.86 (95% CI, 2.09-22.61) respectively. Presence of micrometastasis was an independent prognostic factor for overall survival in a multivariable model.

Conclusion

Presence of micrometastasis in SN in patients with early stage cervical cancer was associated with significant reduction of overall survival, which was equivalent to patients with macrometastasis. No prognostic significance was found for ITC. These data highlight the importance of SN biopsy and pathologic ultrastaging for the management of cervical cancer.