Objective: Using highly sensitive polymerase chain reaction (PCR) techniques, we reanalysed all cervical carcinomas (CCs) found to be human papillomavirus (HPV)‐negative by Hybrid Capture 2 (HC2) to determine the prevalence of true HPV‐negativity. We also evaluated the characteristics of the patients with tumours with confirmed HPV‐negativity.Design: Observational study.Setting: Barcelona, Spain.Population: A cohort of 136 women with CC (32 adenocarcinomas, 104 squamous cell carcinomas) who had pre‐treatment HC2 testing.Methods: All negative cases were reanalysed and genotyped for HPV using three PCR assays (SPF10, GP5+/6+ and E7‐specific assay).Main outcome measures: Percentage of confirmed HPV‐negative and HPV‐positive tumours. Clinicopathological features and disease‐free survival (DFS) and overall survival (OS) of both groups.Results: Fourteen of 136 women (10.2%) were negative for HPV by HC2. After reanalysis by PCR‐based techniques only 8/136 (5.8%) tumours were confirmed as HPV‐negative, whereas in six cases different HPVs were identified [HPV–11, −16 (two tumours), −18, −45, and −68]. Confirmed HPV‐negativity was more frequent in adenocarcinomas than in squamous cell carcinomas (5/32, 15.6% versus 3/104, 2.9%, respectively; P = 0.017). Patients with CCs with confirmed HPV‐negativity had significantly worse DFS than women with HPV‐positive tumours [51.9 months (95% CI 12.2–91.7 months) versus 109.9 months (95% CI 98.2–121.5 months); P = 0.010]. In the multivariate analysis HPV‐negativity and International Federation of Gynecology and Obstetrics (FIGO) staging were associated with increased risk of progression and mortality.Conclusions: An HC2‐negative result is an uncommon finding in women with CC, but in almost half of these cases HPVs are identified by more sensitive techniques. CCs with confirmed HPV‐negativity are more frequently adenocarcinomas, and seem to be associated with worse DFS.

BACKGROUND: Human epididymis protein 4 (HE4), a precursor of human epididymis protein, has been proposed as a tumor marker for ovarian cancer. We evaluated HE4 in comparison with cancer antigen 125 (CA 125) in healthy individuals and in patients with benign and malignant diseases. METHODS: CA 125 and HE4 serum concentrations were determined in 101 healthy individuals, 535 patients with benign pathologies (292 with benign gynecologic diseases) and 423 patients with malignant diseases (127 with ovarian cancers). CA 125 and HE4 cutoffs were 35 kU/L and 140 pmol/L, respectively. RESULTS: HE4 and CA 125 results were abnormal in 1.1% and 9.9% of healthy individuals and in 12.3% and 37% of patients with benign diseases, respectively. Renal failure was the most common cause of increased HE4 in patients with benign disease, who had significantly higher HE4 concentrations (P = 0.001) than patients with other benign diseases. HE4 showed a higher specificity than CA 125 in patients with benign gynecologic diseases, with abnormal concentrations in 1.3% and 33.2% of the patients, respectively. HE-4 concentrations were abnormal primarily in gynecologic cancer and lung cancer. By contrast, CA 125 was increased in many different nonovarian malignancies, including nonepithelial tumors. A significantly higher area under the ROC curve was obtained with HE4 than with CA 125 for differentiating benign from malignant diseases (0.755 vs 0.643) and in the differential diagnosis of gynecologic diseases (0.874 vs 0.722). CONCLUSIONS: HE4 has significantly higher diagnostic specificity than CA 125, and the combination of CA 125 and HE4 improved the detection of ovarian cancer in all stages and histological types.

The aim of this study is to evaluate a new tumour marker, HE4, in comparison with CA 125 and the Risk of Ovarian Malignancy Algorithm (ROMA) in healthy women and in patients with benign and malignant gynaecological diseases. CA 125 and HE4 serum levels were determined in 66 healthy women, 285 patients with benign gynaecological diseases (68 endometriosis, 56 myomas, 137 ovarian cysts and 24 with other diseases), 33 patients with non-active gynaecological cancer and 143 with active gynaecological cancer (111 ovarian cancers). CA 125 and HE4 cut-offs were 35 U/mL and 150 pmol/L, respectively. ROMA algorithm cut-off was 13.1 and 27.7 for premenopausal or postmenopausal women, respectively. HE4, CA 125 and ROMA results were abnormal in 1.5%, 13.6% and 25.8% of healthy women and in 1.1%, 30.2% and 12.3% of patients with benign diseases, respectively. Among patients with cancer, HE4 (in contrast to CA 125) had significantly higher concentrations in ovarian cancer than in other malignancies (p < 0.001). Tumour marker sensitivity in ovarian cancer was 79.3% for HE4, 82.9% for CA 125 and 90.1% for ROMA. Both tumour markers, HE4 and CA 125 were related to tumour stage and histological type, with the lowest concentrations in mucinous tumours. A significantly higher area under the ROC curve was obtained with ROMA and HE4 than with CA 125 in the differential diagnosis of benign gynaecological diseases versus malignant ovarian cancer (0.952, 0.936 and 0.853, respectively). Data from our population indicate that ROMA algorithm might be further improved if it is used only in patients with normal HE4 and abnormal CA 125 serum levels (cancer risk for this profile is 44.4%). ROMA algorithm in HE4 positive had a similar sensitivity and only increases the specificity by 3.2% compared to HE4 alone.

Mesonephric (wolffian) neoplasms of the female genital tract are infrequent and found in sites where embryonic remnants of wolffian origin are usually detected, such as the uterine cervix, broad ligament, mesosalpinx, and ovary. Their diagnosis is difficult because of the absence of specific immunohistochemical markers for mesonephric derivatives. We present the first report of adenocarcinoma of mesonephric type arising as a purely myometrial mass without endometrial or cervical involvement in the uterine corpus of a 33-year-old woman. The tumor showed a combination of patterns, with retiform areas, ductal foci, and small tubules with eosinophilic secretion, which merged with solid sheets of cells with a sarcomatoid appearance. Immunohistochemically, neoplastic cells were diffusely positive for cytokeratin 7, epithelial membrane antigen, and CD15 and focally positive for BerEP4 and vimentin. A hitherto unreported feature was the positivity for CD10 in neoplastic cells, which was also present in a large number of control tissues obtained from male mesonephric derivatives and female mesonephric remnants and tumors. Furthermore, CD10 was negative in controls from müllerian epithelia of the female genital tract and in their corresponding tumors. Therefore, the expression of CD10 by mesonephric remnants may be useful in establishing the diagnosis of tumors with mesonephric differentiation.