Tzu I. Wu

Low Value of [18F]-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography in Primary Staging of Early-Stage Cervical Cancer Before Radical Hysterectomy

PURPOSE The role of positron emission tomography (PET) with [18F]-fluoro-2-deoxy-D-glucose (FDG) in early-stage cervical cancer is unclear. We aimed to investigate the clinical benefit of FDG-PET in primary staging before radical hysterectomy and pelvic lymphadenectomy (RH-PLND). PATIENTS AND METHODS Patients with untreated stage IA2 to IIA adenocarcinoma (AD) or adenosquamous carcinoma (ASC) or nonbulky (< or = 4 cm) squamous cell carcinoma cervical cancer with magnetic resonance imaging (MRI) -defined negative nodal metastasis were enrolled onto a prospective study with a two-stage design. All patients had a preoperative dual-phase FDG-PET, technetium-99m-sulfur colloid lymphoscintigraphy, and intraoperative sentinel lymph node (LN) detection at RH-PLND. The gold standard of LN metastasis is histologic. A sample size of 120 patients was calculated to fit study aims (diagnostic efficacy of PET and sentinel LN sampling). An interim analysis was performed when 60 patients were accrued, which led to the current report. RESULTS There were 36 SCCs, 20 ADs, and four ASCs. Of the 60 patients, 10 (16.7%) had pelvic LN metastases, and one (1.7%) had para-aortic LN (PALN) metastasis histologically. FDG-PET detected the single PALN metastasis (one of one patient) but detected only one (10%) of the 10 pelvic LN metastases. The PET false-negative pelvic LN micrometastases measured a median of 4.0 x 3.0 mm (range, 0.5 x 0.5 to 7 x 6 mm). The second stage of this trial will be continued without PET. CONCLUSION This study shows that dual-phase FDG-PET has little value in primary, nonbulky, stage IA2 to IIA and MRI-defined, LN-negative cervical cancer.

Comparison between the Hybrid Capture II Test and an SPF1/GP6+ PCR-Based Assay for Detection of Human Papillomavirus DNA in Cervical Swab Samples

ABSTRACT We compared the efficacy of human papillomavirus (HPV) DNA detection between a PCR-based genechip (Easychip HPV Blot [hereafter referred to as HPV Blot]; King Car, Taiwan) method and Hybrid Capture II (HCII; Digene, Gaithersburg, MD) in women with previous normal (n = 146) or abnormal (≥atypical squamous cells of undetermined significance [ASCUS] [n = 208]) cytology. A total of 354 cervical swab samples were collected for HPV DNA assay by both HCII and SPF1/GP6+ PCR followed by HPV Blot tests. Colposcopy-directed biopsy was performed if clinically indicated. Of the 354 samples, HPV-positive rates by these two methods (HCII and HPV Blot) were 12.6% and 18.2% in 143 normal samples, 36.2% and 45.7% in 105 ASCUS samples, 57.4% and 57.4% in 94 low-grade squamous intraepithelial lesion samples, and 83.3% and 75.0% in 12 high-grade squamous intraepithelial lesion samples, respectively. The concordance of HPV Blot and HCII was 80.8% (286/354), and the agreement between the methods (κ value, 0.68) was substantial. Discrepancies were further investigated by at least one of the following three methods: direct sequencing, type-specific PCR, and HPV Blot genotyping of cervical biopsy tissue. In the 15 HCII-positive samples, HPV Blot detected only non-HCII HPV genotypes; results of further verification methods were consistent with the latter test in the 15 samples. Of the 20 samples with HCII-negative and HPV Blot-positive results, 18 were found to contain the 13 HCII high-risk genotypes by verification methods. In only 16.7% (3/18) of the HCII-positive but HPV Blot-negative samples, further studies detected the 13 HCII genotypes. We conclude that HPV Blot seemed comparable to HCII for detection of HPV DNA in cervical swab samples.

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

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Clinical presentation and diagnosis of uterine sarcoma, including imaging

Uterine sarcomas are uncommon tumours from mesenchymal elements. They are thought to arise primarily from endometrial stroma and uterine muscle, respectively. When endometrial stroma undergoes malignant transformation, it might be accompanied by a malignant epithelial component. Thus, malignant mesenchymal uterine tumours comprise leiomyosarcoma, endometrial stromal sarcoma, undifferentiated uterine sarcoma and carcinosarcoma. In this chapter, we discusses preoperative presentation, diagnosis and current progress in different imaging modalities, including ultrasonography, computed tomography, magnetic resonance image and positron emission tomography scan. We summarise advances in new technology, which might improve preoperative detection and enhance referral to gynaecologic oncologists for optimal staging surgery and treatment.

18F-fluorodeoxyglucose positron emission tomography in uterine carcinosarcoma

PurposeUterine carcinosarcomas clinically confined to the uterus usually harbor occult metastases. We conducted a pilot study to evaluate the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in uterine carcinosarcoma.MethodsPatients with histologically confirmed uterine carcinosarcoma were enrolled. Abdominal and pelvic magnetic resonance imaging (MRI)/whole-body computed tomography (CT) scan, and whole-body 18F-FDG PET or PET/CT were undertaken for primary staging, evaluating response, and restaging/post-therapy surveillance. The clinical impact of 18F-FDG PET was determined on a scan basis.ResultsA total of 19 patients were recruited and 31 18F-FDG PET scans (including 8 scans performed on a PET/CT scanner) were performed. Positive impacts of scans were found in 36.8% (7/19) for primary staging, 66.7% (2/3) for monitoring response, and 11.1% (1/9) for restaging/post-therapy surveillance. PET excluded falsely inoperable disease defined by MRI in two patients. Aggressive treatment applying to three patients with PET-defined resectable stage IVB disease seemed futile. Two patients died of disease shortly after salvage therapy restaged by PET. With PET monitoring, one stage IVB patient treated by targeted therapy only was alive with good performance. Using PET did not lead to improvement of overall survival of this series compared with the historical control (n = 35) (P = 0.779).ConclusionsThe preliminary results suggest that 18F-FDG PET is beneficial in excluding falsely inoperable disease for curative therapy and in making a decision on palliation for better quality of life instead of aggressive treatment under the guidance of PET. PET seems to have limited value in post-therapy surveillance or restaging after failure.

Host and viral factors in relation to clearance of human papillomavirus infection: A cohort study in Taiwan

Human papillomavirus (HPV) persistence is essential for cervical cancer development. We accrued nested‐cohort subjects from a population‐based study to investigate the host and viral factors related to outcome of HPV infection. Women (age ≥ 30 years old) with HPV‐positive but normal cytology and negative colposcopy were invited to participate. After signing informed consent, every participant completed a structured questionnaire and had 6‐monthly follow‐ups of Pap smear, HPV testing and colposcopy. Total and type‐specific HPV clearance rates as well as host and viral factors associated with clearance in 3‐year longitudinal follow‐up were analyzed. Adjusted hazard ratios (HRs) of progression to ≥ cervical intraepithelial neoplasia (CIN) 2 according to baseline HPV of the women with normal cytology were calculated from national registry database. Among the 626 eligible women, 526 (median age 47, 29–75) were enrolled and 412 returned for follow‐up at least once. The median follow‐up of enrolled subjects was 23 months (range 6.8–39). The 3‐year cumulative total HPV clearance rate was 49.0% (95% confidence interval [CI]: 43.3–54.7%). The median 3‐year cumulative type‐specific HPV clearance rate was 50.0% (range 0–100.0%) with a median time to clearance of 12.4 months (6.4–24.5). Older age was associated with significantly decreased total HPV clearance and decreased type‐specific clearance in HPV‐18 and ‐53, while high viral load was associated with decreased total and type‐specific clearance. After adjusting confounding variables, the HR of developing ≥CIN2 in baseline HPV‐positive women was 34.0‐fold (95% CI: 15.5–74.7) as compared to HPV‐negative women.

Prognostic factors predicting recurrence in borderline ovarian tumors

OBJECTIVE We aimed to investigate outcome of borderline ovarian tumors (BOTs) with respect to methods and extent of surgical approach and to evaluate prognostic factors. METHODS A retrospective study included consecutive patients with BOT treated from 1984 to 2008. These cases were confirmed by histological review. The influence of clinico-pathological characteristics upon recurrence and death were analyzed by independent sample t test, Chi-square test, logistic regression model, and Cox proportional hazard model. RESULTS A total of 233 patients were enrolled, 214 in Stage I, 11 Stage II and 8 Stage III. There were 21 relapses, only 5 of which died of disease. 5-year and 10-year overall survival were 97.6% and 96.4%, and recurrence-free survival rates (RFS) were 92.7% and 88.2%, respectively. Median follow-up time for survivors was 81 (range, 0.5-295) months. Median time to recurrence was 31 (range, 5.5-181) months. In multivariate analysis, Stage II/III, cystectomy and higher pretreatment serum CA-125 level (>or=144 U/mL) were selected for a model predicting 5-year RFS, where risk factor=0, 1, and 2-3 had odds ratios of 1, 14.9, and 113.3, respectively (p<0.001). Replacing stage with peritoneal implants, the latter two factors along with invasive peritoneal implants were selected. Of the 5 cases died of disease, all had invasive recurrences. Initial laparoscopic or laparotomy approach had no influence on prognosis. CONCLUSIONS Although BOT has an excellent prognosis, they are not exempted from a risk of recurrence. Stage II/III (or invasive implants), cystectomy and higher pre-operative serum CA-125 were independent variables predicting recurrence.

Overexpression of gelsolin in human cervical carcinoma and its clinicopathological significance

OBJECTIVES Cervical carcinoma is the second most common cause of death from gynecological cancers worldwide. Knowledge of the molecular mechanisms underlying the tumorigenesis of cervical cancer cell, except human papilloma virus infection, is limited. METHODS A microarray was used to study the differential expression of genes in cancerous tissues to identify new molecular markers for diagnosis and prognosis. Their differential expression was confirmed with Western blotting and immunohistochemical analyses. The clinical correlations and prognostic significance of the aberrantly expressed proteins were evaluated to identify novel biomarkers of cervical cancer. RESULTS The expression of gelsolin was significantly upregulated in 78% of patients with cervical cancer, and gelsolin was selected for further study. Gelsolin expression was stronger in cervical tumor tissues than in the surrounding noncancerous tissues (P<0.001). Gelsolin expression in the plasma of cervical cancer patients was increased 2.2-fold compared with that of healthy control subjects (P<0.001). The levels of plasma gelsolin in the early and late stages were significantly different (P=0.006). According to immunohistochemical analysis, increased gelsolin expression was associated with histological type and FIGO stage II. The 5-year overall survival and recurrence-free survival rates for the low-expression group (cut-off=115) were significantly higher than those of the high-expression group. Cancer cells with reduced gelsolin expression exhibited reduced migration and proliferation. CONCLUSIONS These results provide strong evidence that gelsolin plays an important role in cellular proliferation and migration in cervical cancer and suggest that gelsolin is a promising marker for cervical cancer screening and prognosis.

Glucose-regulated protein 58 modulates cell invasiveness and serves as a prognostic marker for cervical cancer

Human papilloma virus infection is critical but not sufficient to cause cervical cancer. Molecular markers of cervical carcinogenesis are essential. The aim of this study was to identify aberrantly expressed proteins in cervical cancer and determine their clinical significance. A two‐dimensional polyacrylamide gel electrophoresis (2‐DE) proteomic strategy was used for screening candidate proteins. Immunoblotting and immunohistochemical (IHC) analyses were performed to confirm the results of 2‐DE, and the clinical significance was estimated. Glucose‐regulated protein 58 (Grp58) was overexpressed in 73% of cancers. The IHC staining showed that the Grp58 histoscore was significantly higher in patients with adenocarcinoma (AD) compared with squamous cell carcinoma (P < 0.05). Grp58 staining was intense in AD with a penetration depth greater than half of the cervical stroma (P = 0.033). High Grp58 expression was associated with low overall survival and recurrence‐free survival (RFS) rates (P = 0.007 and P = 0.013, respectively). In multivariate analysis, high Grp58 expression (P = 0.042) and lymph node metastasis (P = 0.026) were determined as independent prognostic factors for RFS. Patients exhibiting both high Grp58 expression and lymph node metastasis displayed poorer outcomes than the other patient groups. In functional studies, knockdown of Grp58 in HeLa cells led to decreased cell invasiveness and inhibition of lung metastasis in a xenograft mouse model. In conclusion, Grp58 serves as a potent prognostic factor of cervical AD. Estimation of the Grp58 index in conjunction with the lymph node metastasis status might aid in predicting the prognosis of cervical AD. (Cancer Sci 2011; 102: 2255–2263)

Potential of an age-stratified CA125 cut-off value to improve the prognostic classification of patients with endometrial cancer

OBJECTIVE It is not clear whether the prognostic value of pretreatment serum CA125 levels is independent or through association with other clinicopathological features in endometrial cancer. METHODS All patients with endometrial cancer treated between 2000 and 2010 were retrospectively reviewed. The correlation of clinicopathological characteristics, CA125 and treatment outcomes was analyzed. Receiver operating characteristics (ROC) curves were used to determine the CA125 cut-off values. Cox proportional hazard regression was used for multivariate analysis. RESULTS Of the 923 eligible patients, 757 had serum CA125 levels measured before treatment. We identified 264 (34.9%) patients with pretreatment serum CA125>35 U/mL. By multivariate analysis, advanced stage (P=0.001), serous or clear cell carcinoma (P=0.008), positive peritoneal cytology (P=0.042), and lymph node metastases (P=0.004) were significant risk factors for cancer-specific survival (CSS), while serum CA125>35 U/mL (P=0.067) was of borderline statistical significance. Using ROC curve stratified by age, we found that a serum CA125>35 U/mL was significant for CSS (HR=2.34, 95% CI=1.04-5.29) among patients >49 years old. After adjustment for confounding factors, serum CA125>105 U/mL was significant (HR=6.03, 95% CI=1.19-30.63) in patients ≤49 years old. CONCLUSIONS These results suggest that an age-stratified cut-off level for CA125 (35 U/mL in patients >49 years old and 105 U/mL in patients ≤49 years old) can improve the prognostic stratification of patients with endometrial cancer.