Significance of Serum Human Epididymis Protein 4 and Cancer Antigen 125 in Distinguishing Type I and Type II Epithelial Ovarian Cancers.

OBJECTIVE: The objective of this study was to assess the effectiveness of human epididymis protein 4 (HE4) and cancer antigen 125 (CA125), and risk of ovarian malignancy algorithm (ROMA) in identifying type I and type II epithelial ovarian cancers (EOCs). METHODS: A cross-sectional diagnostic study was conducted of 499 Thai women older than 18 years who had clinically diagnosed pelvic masses and underwent elective surgery at our hospital between July 2012 and July 2014. Preoperative serum HE4 and CA125 levels were measured, and postoperative pathologic slides were reviewed. RESULTS: Of 499 Thai women enrolled in this study, 357 were noncancerous (NC), 79 had type I EOCs (EOCs-I) and 63 had type II (EOCs-II). Risk of ovarian malignancy algorithm revealed significantly better performance than HE4 and CA125 in discriminating between NC and EOCs-I (receiver operating characteristic curve and area under the curve [ROC-AUC]: ROMA, 0.86; HE4, 0.80; and CA125, 0.77), and NC and EOCs-II (ROC-AUC: ROMA, 0.97; HE4, 0.95; and CA125, 0.93). In differentiation between EOCs-I and EOCs-II (setting EOC-II as reference), ROMA yielded a better performance than HE4 and CA125 (ROC-AUC: ROMA, 0.83; HE4, 0.82; and CA125, 0.77); however, CA125 and HE4 showed higher sensitivity (CA125, 77.8%; HE4, 76.2%), whereas ROMA had the highest specificity (79.8%). CONCLUSIONS: In women who present with pelvic masses, ROMA performed very well in distinguishing between noncancer lesions and EOCs but the combined HE4 and CA125 test was more effective in predicting EOC types.

Is the Risk of Ovarian Malignancy Algorithm Better Than Other Tests for Predicting Ovarian Malignancy in Women with Pelvic Masses?

AIM: The study aimed to compare the risk of ovarian malignancy algorithm (ROMA) with risk of malignancy index (RMI), cancer antigen 125 (CA125), human epididymis protein 4 (HE4) and Sassone ultrasonography (US) score in predicting ovarian cancer (OC) in women who present with pelvic or adnexal masses. METHODS: Pelvic US, serum CA125 and HE4 levels were investigated preoperatively in consecutively enrolled Thai women over 18 years with clinically diagnosed pelvic or adnexal masses who were undergoing elective surgery at a super tertiary hospital in Thailand in 2012. ROMA, RMI and Sassone US score were calculated. RESULTS: Of 260 women who were evaluated, 74 had OC. Areas under the receiver operating characteristic curve (AUC) in predicting OC were ROMA, 86.2%; RMI, 87.6%; CA125, 80.6%; HE4, 82.4%; and Sassone score, 77.1%. ROMA and RMI performed similarly well (AUCs 84.4 and 85.6%) in premenopausal women but RMI outperformed ROMA in postmenopausal women (AUCs 87.9 and 84.0%, respectively). At the conventional cutoff value, ROMA and CA125 showed the highest sensitivity (83.8%) but HE4 had the highest specificity (86.0%). CONCLUSIONS: ROMA was comparable to RMI in predicting OC. Either ROMA or RMI can be applied to women with pelvic masses, stratified into low- and high-risk groups for OCs.

Comparison of Survival Outcomes in Early Stage Invasive Adenocarcinoma with Squamous Cell Carcinoma of the Uterine Cervix.

Background: Invasive adenocarcinoma (AC) is the second most common carcinoma of the uterine cervix; however, it is not clear whether this histologic type influences survival outcomes. Objective: To evaluate the survival outcomes of patients with invasive AC compared to those with squamous cell carcinoma (SCC) in early stage cervical cancer following radical hysterectomy. Material and Method: A historical cohort study was conducted of 316 Thai women with cervical cancer clinical stage IA2-IIA (120 AC and 196 SCC) who underwent radical hysterectomy from January 1 to December 31, 2000. Results: With a median follow-up of 65.23 months, the estimated 5-year recurrence-free survival (RFS) and overall survival (OS) for patients with AC did not significantly differ from those with SCC (90.3% vs. 93.1%, p = 0.301 and 90.9% vs. 93.5%, p = 0.342 respectively). Using Cox regression analysis, cervical stroma invasion (CSI) and lymphovascular space invasion (LVSI) were the significant prognostic factors for RFS, whereas CSI was the only significant prognostic factor for OS. Women with AC who had two prognostic factors showed significantly lower 5-year RFS than those with SCC (69.5% vs. 86.3%, p = 0.035). Conclusion: Survival and recurrence were not different for surgically treated cervical cancer in women with early stage AC or SCC.

Differential Diagnosis between Primary Endocervical and Endometrial Adenocarcinoma using Immunohistochemical Staining of Estrogen Receptor, Vimentin, Carcinoembryonic Antigen and p16.

BACKGROUND: When clinical and histopathological evaluation is not effective in discriminating primary endocervical adenocarcinoma (ECAs) and endometrial adenocarcinoma (EMAs), an immunohistochemistry (IHC) method is regularly used in practice, which involves staining of estrogen receptor (ER), vimentin (Vim), monoclonal carcinoembryonic antigen (mCEA) and p16. OBJECTIVE: To evaluate the performance of IHC markers, ER, Vim, mCEA and p16, in differentiating between primary ECAs and EMAs and to compare the performances of two-, three- and four-marker panels. MATERIAL AND METHOD: Women with cervical or uterine cancers who were diagnosed with mucinous or endometrioid adenocarcinoma or adenocarcinoma of non-otherwise specified, after cervical biopsy, endometrial biopsy or curettage, and who underwent elective surgery at Rajavithi Hospital between January 1, 2011 and June 30, 2012 were retrospectively reviewed. Paraffin-embedded tissue sections from pre-operative specimens were reviewed and stained with ER, Vim, mCEA and p16. Postoperative pathologic slides was reviewed and installed as the reference standard. RESULTS: Of 110 cases, 44 were primary ECAs and 66 were primary EMAs. ER and Vim were significantly expressed in EMAs (p < 0.001), while mCEA and p16 were significantly expressed in ECAs (p < 0.001). From multivariable analysis, Vim and p16 were the significant markers for differentiating ECAs and EMAs. A comparison of different combinations showed that panels of Vim/p16, ER/Vim/p16, Vim/mCEA/p16 and ER/Vim/mCEA/p16 achieved the highest overall accuracy of97.9%. CONCLUSION: Vim and p16 are the significant IHC markers and a two-marker panel of Vim/p16 is recommended for using in differentiating primary ECAs and EMAs; which a pattern of negative Vim and positive p16 expression favors diagnosis of ECAs while the converse pattern of positive Vim and negative p16 staining points to diagnosis of EMAs.

Rajavithi-ovarian cancer predictive score (R-OPS): A new scoring system for predicting ovarian malignancy in women presenting with a pelvic mass.

OBJECTIVE: To develop a new scoring system based on menopausal status, ultrasound (US) findings, serum cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) to predict ovarian cancer (OC) in women presenting with a pelvic or adnexal mass. METHODS: Consecutive female patients aged over 18years with pelvic or adnexal masses investigated preoperatively by pelvic US, serum CA125 and HE4 who underwent elective surgery were enrolled. The "Rajavithi-Ovarian Cancer Predictive Score (R-OPS)" was developed using data from 2012 and validated using data from 2013 to 2014. The diagnosis of OC was based on pathological findings. Data were analyzed by logistic regression and area under the receiver operating characteristic curve (ROC-AUC). RESULTS: Based on a development set of 260 women including 74 with OC, menopausal status (M), serum CA125 and HE4, and US findings of solid lesions (U) were identified as significant predictors of OC. R-OPS=M×U×(CA125×HE4)(1/2) revealed good calibration (goodness-of-fit test, p=0.972) and discrimination (ROC-AUC=92.8%). Performance validation in 266 women, 82 with OC, showed good discrimination with ROC-AUC of 94.9%. Performance in the validation sample with a cutoff value of R-OPS>330 revealed sensitivity, specificity, and positive and negative predictive values of 93.9%, 79.9%, 67.5%, and 96.7%, respectively. CONCLUSIONS: The new R-OPS scoring system showed good discrimination between non-cancerous lesions and OC. However, a prospective study in a different setting is required to confirm these preliminary data.

Diagnostic Accuracy and Optimal Cutoff Value of Serum HE4 to Predict Ovarian Cancer in Thai Women with Pelvic Masses.

Background: Serum human epididymis protein 4 (HE4) is highly expressed in women with ovarian cancers (OCs), but data about its clinical application of HE4 for Thai women is limited. Objective: To evaluate the diagnostic accuracy and optimal cutoff for HE4 in distinguishing benign lesions, borderline ovarian tumor (BOTs), and OCs compared with CA125 in Thai women at Rajavithi Hospital. Material and Method: The cross-sectional study was conducted in Thai women aged older than 18 years old with pelvic masses whom underwent elective surgery at Rajavithi Hospital between 2012 and 2013. Preoperative serum HE4 and CA125 levels were measured and pathologic specimens were reviewed. Results: Of the 518 participants evaluated, 316 had benign lesions, 43 had BOTs, and 159 had OCs. Between non-cancers and OCs, area under receiver operating characteristic curve (ROC-AUC) for HE4 hardly differed from CA125 (0.85 vs. 0.83, p = 0.402) but was significantly lower in postmenopausal women (0.79 vs. 0.86, p = 0.049). The optimal cutoff value of HE4 was 72 pM/L for all menopausal status. Lower HE4 was seen in 30.8% of mucinous carcinoma and 31.7% of clear cell carcinoma. The HE4 ROC-AUC was significantly higher than CA125 ROC-AUC in distinguishing benign diseases and BOTs (0.71 vs. 0.53, p<0.001), HE4 in 70% of BOTs was 51 to 95 pM/L. Conclusion: Although the 72 pM/L cutoff for HE4 was appropriate in distinguishing between non-cancers and OCs for both pre- and postmenopausal women, the limitation for postmenopausal women, mucinous carcinomas, and clear cell carcinomas require to be complemented with CA125.

Risk factors of pelvic lymph node metastasis in cervical adenocarcinoma following radical hysterectomy and pelvic lymphadenectomy.

BACKGROUND: Lymph node metastasis is the most important prognostic factor in cervical cancerpatients. However, most of the available knowledge about risk factors of pelvic nodal metastasis in cervical cancer has come from studies in which the majority of patients had the squamous cell carcinoma (SCC) subtype. OBJECTIVE: To determine the risk factors of pelvic lymph node metastasis in early-stage cervical adenocarcinoma (AC) patients following radical hysterectomy and bilateral pelvic lymphadenectomy. MATERIAL AND METHOD: Retrospective reviews were carried out of the medical charts and pathologic slides of 251 patients with cervical AC stage IB1-IIA who underwent radical hysterectomy and bilateral pelvic lymphadenectomy at Rajavithi Hospital from January 1, 2000 to December 31, 2011. The risk factors of pelvic lymph node metastasis were analyzed by multiple logistic regression. RESULTS: Of the 251 patients, pelvic node metastasis in stage IB1-IIA cervical AC was detected in 29 patients (11.6%). Multivariable analysis revealed that clinical stage IB2-IIA (adjusted OR 3.4, 95%CI 1.2-9.7), tumor size more than 2 cm (adjusted OR 3.5, 95%CI 1.1-11.8), and positive lymphovascular invasion (LVSI) (adjusted OR 55.5, 95%CI 7.2-427.6) were significantly associated with pelvic nodal metastasis. Early-stage cervical AC patients with no risk factor, one risk factor other than LVSI, LVSI factor alone, two risk factors, and three risk factors were identified as having pelvic nodal metastasis in 0%, 2.3%, 9.1%, 29.1% and 58.8% of cases respectively. CONCLUSION: Clinical stage IB2-IIA, tumor size of more than 2 cm, and positive LVSI were significant risk factors for pelvic nodal metastasis in early-stage cervical AC patients. Those with no risk factors were not found to have pelvic nodal metastasis and might be candidates for less radical surgery, whereas patients with the presence of LVSI and/or 2 other risk factors were found to be at high risk of pelvic node metastasis and might benefit from extensive lymphadenectomy and adjuvant therapy.