Interobserver reproducibility in determining p16 overexpression in cervical lesions : use of a combined scoring method.

OBJECTIVES: To evaluate interobserver reproducibility of a combined scoring method for immunohistochemical interpretation of p16 overexpression in cervical lesions. MATERIALS AND METHODS: p16 immunostaining was performed in cervical samples from 183 patients, including 69 normal, 42 low grade squamous intraepithelial lesions(LSIL), 36 high grade SIL (HSIL), and 36 squamous cell carcinomas(SCCAs). Each case was evaluated by a combined scoring method based on the percentage of positive cells (score 0-3), the intensity of staining (score 0-3), and the distribution pattern (score 0-2). Immunoexpression for p16 was considered as positive when the combined score was 4-8 and negative with a score of 0-3. Ten pathologists with varied experience in interpretating p16 immunostains evaluated each slide independently. RESULTS: All normal cervical squamous epithelia (69/69) were uniformly negative for p16. All HSILs (36/36), all SCCAs (100/100), and all but one of the LSILs (40/41, 97.6%) showed positive expression. In 172 of 183 cases (93.9%), p16 interpretation was concordant with all pathologists. Eleven cases with discordant results included 10 LSILs and 1 normal mucosa sample. Percentage of agreement of each pathologist pair ranged from 96.7-100% (mean 98.1%) with mean kappa value of 0.96 (range 0.93-1.000). CONCLUSION: The proposed combined scoring method shows good reproducibility among the participating pathologists and good correlation with the histologic diagnosis. This method may be a useful guide in the interpretation of p16 expression in cervical epithelial lesions.

Underlying histopathology of HIV-infected women with squamous cell abnormalities on cervical cytology.

This study was undertaken to evaluate the underlying histopathology of HIV-infected women who had abnormal cervical cytology. HIV-infected women with abnormal cervical cytology undergoing colposcopy at Chiang Mai University Hospital between January 2001 and February 2008 were reviewed. The cohorts were matched and compared with an HIV-negative group. During the study period, 65 HIV-infected women with abnormal cervical cytology were available for review. The abnormal cervical smears were atypical squamous cell (9), low-grade squamous intraepithelial lesion (22), high-grade squamous intraepithelial lesion (27), and squamous cell carcinoma (7). When stratified by severity of abnormal cytology, HIV-infected women had a higher risk of having cervical intraepithelial neoplasia II or higher, whether the cervical smear showed low-grade (P=0.01) or high-grade abnormality (P=0.04) compared with the HIV negative group. After adjustment by age, parity, and menopausal status, HIV-infected women had 2.56 times the risk of having CIN II or higher (69.2% of HIV-infected women compared with 47.7% of HIV negative women; 95% CI=1.21-5.40, P=0.01). In conclusion, HIV-infected women with abnormal Pap smears are a population subset with a higher risk of significant cervical lesions, irrespective of the severity of abnormal cervical smears.

Factors predicting occult invasive carcinoma in women undergoing a 'see and treat' approach.

This study was undertaken to evaluate the incidence and independent predictors of unexpected invasive cancer of cervix in women with high-grade squamous intraepithelial lesions (HSIL) on Pap smear who had undergone a 'see and treat' approach. Women with HSIL on cervical cytology undergoing colposcopy, followed by loop electrosurgical excision procedure (LEEP) at Chiang Mai University Hospital between January 2001 and April 2006 were analyzed. During the study period, 446 women were identified. Mean age was 45.6 years (range, 25-75 years). One hundred and twenty-one (27.1%) women were postmenopausal. Unsatisfactory colposcopy was observed in 357 (80.0%) women. Of the 446 women, 76 (17.04%, 95% CI=13.67 to 20.86) had invasive lesions on LEEP specimens. Multivariate analysis revealed that unsatisfactory colposcopy and premenopausal status were statistically significant independent predictors for invasive lesions in a 'see and treat' LEEP with an adjusted odds ratio of 4.68 (95%CI=1.82 to 12.03, P<0.01) and 2.10 (95%CI=1.12 to 3.94, P=0.02), respectively. In conclusion, occult invasive lesion of the cervix was noted in 17% of women with HSIL Pap smear who underwent a 'see and treat' approach at our institute. Unsatisfactory colposcopy and premenopausal status were significant independent predictors of having such lesion.

Prognostic value of p53 expression in early stage cervical carcinoma treated by surgery.

OBJECTIVE: To evaluate the prognostic significance of p53 protein expression in patients with early stage cervical carcinoma treated by surgery alone in a well-controlled study. METHODS: A matched case-control study was performed in patients with stage Ib-IIa cervical carcinoma who underwent radical hysterectomy with pelvic lymphadenectomy. Patients had neither lymph node metastasis nor involvement of the parametrium and surgical margins, and did not receive any adjuvant treatment. Cases included 30 patients who had tumor recurrence within 5 years after surgery; controls included 60 patients who were disease-free for at least 5 years after surgery. Cases and controls were within 10 years of age, had the same stage and tumor type, and underwent surgery on as close to the same date as possible. The tumor sizes of cases and controls were within 1 cm of each other. Expression of p53 protein was studied by immunohistochemistry. Expression was considered positive when at least 10% of tumor cells showed nuclear staining. RESULTS: No significant difference of p53 expression was observed between the case group and the control group (33% versus 40%). High histologic grade of tumors and lymphovascular space invasion were significantly associated with tumor recurrence in multivariable analysis (p=0.012 and 0.014, respectively). CONCLUSION: In this study, expression of p53 did not correlate with tumor recurrence. Immunohistochemistry for p53 protein appears to provide no prognostic information in the patients with early stage cervical cancer treated by surgery.

How can the overtreatment rate of "see and treat" approach be reduced in women with high-grade squamous intraepithelial lesion on cervical cytology?

Background: The aim of this study was to determine the incidence and predictors of overtreatment in "see and treat" approach using loop electrosurgical excision procedure (LEEP) in women with high-grade squamous intraepithelial lesion (HSIL) on cervical cytology. The overtreatment was considered when LEEP specimens contained no cervical pathology. Between January 2001 and April 2006, 446 women with HSIL on Pap smear underwent colposcopy followed by LEEP at Chiang Mai University Hospital. Mean age of these patients was 45.6 years with a range of 25-78 years. One hundred and twenty-one (27.1%) women were menopausal. Unsatisfactory colposcopy was observed in 357 (80.0%) women. Of 446 women, histologically-confirmed HSIL, invasive cancer, low-grade squamous intraepithelial lesions, and adenocarcinoma in situ were detected in 330 (74.0%), 76 (17.0%), 9 (2.0%), and 5 (1.1%), respectively. The overtreatment rate on LEEP specimens was noted in 26 women or 5.8% (95% confidence interval [CI] = 3.8 to 8.4) of 446 women. By multivariate analysis, postmenopausal status was the only significant independent predictor of overtreatment with an adjusted odds ratio of 2.89 (95% CI = 1.30 to 6.43, P = 0.009). When postmenopausal women were excluded from analysis, the overtreatment rate was reduced to only 4.0%. In conclusion, "see and treat" approach appears to be an appropriate strategy in managing women with HSIL cytology. The overtreatment rate could be reduced when such policy is limited for premenopausal women.

Factors affecting residual lesion in women with cervical adenocarcinoma in situ after cone excisional biopsy.

The objective of this study was undertaken to evaluate the factors affecting residual lesion in women with adenocarcinoma in situ (AIS) on cervical conization specimens. The medical records of women with AIS who had no associated invasive carcinoma after cervical conization and underwent subsequent hysterectomy at Chiang Mai University Hospital were reviewed. During March 1998 and March 2006, 45 women were included for analysis. The mean age was 45.2 years (range, 30-66 years). Thirteen (28.9%) women presented with AIS on Pap smear. Thirty (66.7%) underwent loop electrosurgical excision procedure and the remaining 15 (33.3%) underwent cold-knife conization. Twenty (44.4%) women had mixed lesions of AIS and squamous intraepithelial lesion on cervical specimens. Surgical cone margins were clear in 25 (55.6%) women. Eighteen (40%) and two (4.4%) women had involved and non-evaluable cone margins, respectively. Residual lesion was noted in 14 (31.1%) hysterectomy specimens. There was no residual lesion in women with clear cone margins while 72% and 50% of women with involved and non-evaluable cone margins, had residual lesion, respectively. These differences were statistically significant (P<0.001). No significant association between the ECC results and the residual lesion was noted (P=0.29). In conclusion, approximately one-third of women with AIS on cervical conization have residual lesion on subsequent hysterectomy specimens. Only cone margin status is a significant predictor for residual lesion.

Clinical outcomes and prognostic factors of node-negative cervical cancer patients with deep stromal invasion or lymphovascular space involvement following radical hysterectomy.

OBJECTIVE: To evaluate the clinical outcomes and prognostic factors of node-negative cervical cancer patients who had deep stromal invasion (DSI) and/or lymphovascular space invasion (LVSI) following radical hysterectomy and pelvic lymphadenectomy (RHPL). MATERIAL AND METHOD: The medical records of 150 node-negative stage IA2-IIA cervical cancer patients who had DSI and/or LVSI after RHPL from 1999 to 2004 were reviewed. RESULTS: Eighty-eight (58.4%) patients were treated with RHPL alone. Twenty-eight (18.7%), 23 (15.4%), eight (5.3%), and three (2%) patients received postoperative chemotherapy, chemoradiation, radiotherapy, and brachytherapy, respectively. Overall, 11 (7.3%) patients developed recurrence. The estimated 5-year disease-free survival of the patients was 90.9%. By multivariate analysis, two factors, age of less than 35 years old and a non squamous histology, were significantly independent prognostic. Eight (5.3%) patients experienced treatment-related complications. CONCLUSION: Node-negative cervical cancer patients with DSI and/or LVSI had excellent clinical outcomes. Young age and non-squamous histology are significant independent prognostic factors.

High-grade squamous intraepithelial lesion with endocervical cone margin involvement after cervical loop electrosurgical excision: what should a clinician do?

This study was undertaken to evaluate the incidence and severity of residual lesions in women featuring high-grade squamous intraepithelial lesion (HSIL) histology with endocervical cone margin involvement after the loop electrosurgical excision procedure (LEEP). The medical records of women undergoing LEEP at Chiang Mai University Hospital between October 2004 and February 2006 were retrospectively reviewed and 74 cases were identified. Nineteen women were excluded because of loss to follow-up. The remaining 4 were referred to other hospitals and 2 declined re-excision, leaving a study population of 55 women for analysis. Mean age+/-SD of the patients was 48.5+/-8.9 years. Residual lesions were noted in 26 (47.3%, 95%CI=33.7 to 61.2). Four (7.3%) had unrecognized invasive cervical carcinoma in subsequent specimens. In conclusion, approximately half of women with positive endocervical cone margins after LEEP for HSIL histology have residual disease. Repeat diagnostic excision is recommended for evaluation of lesions and severity.

Histopathological outcomes of women with squamous cell carcinoma on cervical cytology.

The aim of this study was to determine the final histopathological outcome for women with a squamous cell carcinoma (SCCA) diagnosed by cervical cytology. The medical records and computerized colposcopic database of patients with SCCA on cytology who underwent colposcopy at Chiang Mai University Hospital between February 2003 and December 2005 were reviewed and 48 women with SCCA cytology were identified (mean age 50 years, range 31-73). Nineteen (39.6%) women were postmenopausal. Unsatisfactory colposcopy was noted in 42 (87.5%). Thirty one (64.6%) of the patients had a final pathological diagnosis of high-grade squamous intraepithelial lesions (HGSIL), whereas only 16 (33.3%) had invasive cancer. The remaining one patient had a low-grade squamous intraepithelial lesion. Sensitivity and specificity of colposcopic examination for predicting invasive cancer was 50% and 78%, respectively. In conclusion, most women with a SCCA on cervical cytology have high-grade cervical lesions on final pathology, with only one third demonstrating invasive cancer. The loop electrosurgical excision procedure (LEEP) remains an important measure for combined treatment and diagnosis.

Northern Thai women with high grade squamous intraepithelial lesion on cervical cytology have high prevalence of underlying invasive carcinoma.

The aim of this study was to determine the underlying pathology of women with high grade squamous intraepithelial lesion (HSIL) on cervical cytology. A total of 681 women with HSIL cytology undergoing colposcopic examination at Chiang Mai University Hospital (CMUH) between January 2000 and December 2005 were evaluated for the underlying cervical pathology. The final pathology was diagnosed from the most severe lesions obtained by punch biopsy, loop electrosurgical procedure, cold knife conization or hysterectomy. Underlying high grade cervical lesions including cervical intraepithelial neoplasia grade 2, 3 and adenocarcinoma in situ were noted in 502 (73.7%) women. Invasive cervical carcinoma was identified in 141 (20.7%). The remaining 38 (5.6%) had either low grade or no intraepithelial lesions. No significant difference in the prevalence of underlying high grade and invasive lesions was noted between women with cytologic diagnosis of HSIL from CMUH and other hospitals. In conclusion, northern Thai women with HSIL cytology are at significant risk of having underlying severe cervical lesions, and especially invasive carcinoma which is detected in approximately one-fifth of the cases.

Extent of lymphovascular space invasion and risk of pelvic lymph node metastases in stage IB1 cervical cancer.

OBJECTIVE: To evaluate whether the extent of lymphovascular space invasion (LVSI) is a risk factor for pelvic lymph node metastases in stage IBI cervical cancer. MATERIAL AND METHOD: The clinicopathological data of 397 patients with stage IB1 cervical cancer undergoing radical hysterectomy and pelvic lymphadenectomy (RHPL) at Chiang Mai University Hospital between January 1998 and December 2002 were analyzed. The histology, tumor grade, depth of stromal invasion, uterine corpus involvement, parametrial invasion and LVSI were analyzed for their association with pelvic node metastases. The extent of LVSI was classified as negative, minimal (< 10 LVSI/cervical specimen), and extensive (> or = 10 LVSI/cervical specimen). RESULTS: Of the 397 patients, 146 (36.8%) had tumors containing LVSI, 82 (20.7%) and 64 (16.1%) had minimal and extensive LVSI, respectively. Fifty nine (14.9%) patients had pelvic node metastases. Using multivariable analysis, LVSI (p < 0.001), depth of stromal invasion (p < 0.001), tumor grade (p < 0.001), and parametrial invasion (p < 0.001) were significant predictors of pelvic node metastases. The extent of LVSI either minimal or extensive degree significantly influenced pelvic node metastases. CONCLUSION: The presence of LVSI especially extensive involvement was significantly associated with the risk of pelvic node metastases in stage IB1 cervical cancer.

A "See and Treat" approach for high grade squamous intraepithelial lesion on cervical cytology.

OBJECTIVE: To examine the final histologic findings as well as to correlate colposcopic and histologic findings in patients who had a high-grade squamous intraepithelial lesion (HGSIL) on the Pap smear and underwent colposcopy followed by LEEP on the "See and Treat" basis without intervening colposcopically directed biopsy. MATERIAL AND METHOD: The medical records of patients with HGSIL on cytology who underwent LEEP without prior cervical biopsy at Chiang Mai University Hospital over a 5-month period were reviewed. The authors summarized the final LEEP histologic results and correlated colposcopic and histologic findings in these patients. RESULTS: Of 55 patients who had a see-and-treat LEEP, 53 patients (96%) had a high-grade intraepithelial lesion or higher. There were 11 patients (20%) who had invasive squamous cell carcinoma. Of 4 patients with a low-grade lesion on colposcopic examination, all had a high-grade lesion or higher on final histology. Forty-four patients (96%) with high-grade impression on colposcopy had high-grade or more severe lesion on the final histologic diagnosis. CONCLUSION: For patients with a high-grade lesion on the Pap smear, LEEP according to the "See and Treat" approach appeared to be a reasonable alternative to conventional colposcopically directed biopsy, especially in low resource settings.